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Library of Congress Cataloging-in-Publication Data

Barkovich, A. James, 1952- author.
Pediatric neuroimaging / A. James Barkovich, Charles Raybaud, charles.raybaud@sickkids. — Fifth
Edition.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-60547-714-5 (alk. paper)
1. Nervous system—Magnetic resonance imaging. 2. Nervous system—Ultrasonic imaging.
3. Pediatric diagnostic imaging. 4. Pediatric neurology—Diagnosis. I. Raybaud, C. (Charles), author.
II. Title.
[DNLM: 1. Central Nervous System Diseases—diagnosis. 2. Child. 3. Infant. 4. Magnetic
Resonance Imaging. 5. Tomography, X-Ray Computed. WS 340]
RJ488.5.M33B37 2012
618.92’8047548—dc22
2010049611

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 To our families, without whose inspiration none of
this would have been possible.

Barkovich_FM.indd iii 5/25/2011 11:31:48 AM

Barkovich_FM.indd iv 5/25/2011 11:31:48 AM
 P R E FAC E TO T H E F I R S T E D I T I O N
ew techniques for pediatric brain and spine diagnoses
N have rapidly developed over the past ten years. Computed
tomography, ultrasound, and magnetic resonance imaging
have opened a new window to the pediatric central nervous system.
Through the use of these imaging modalities, an increased under-
standing of the pathological processes that occur in the pediatric
brain has emerged. However, in spite of the wealth of new concepts
that have evolved from these new resources, there has been a nota-
ble lack of textbooks on the subject, particularly in dealing with CT
and MR. In this book, I attempt, at lease in part, to fill the gap of
knowledge that exists in pediatric neuroimaging.
This book strongly emphasizes CT and MR in pediatric neurodi-
agnosis. The reasons for this are twofold. First, there are a number
of good textbooks available that focus on plain film and sonographic
evaluation of the pediatric central nervous system. Second, and more
important, I feel that CT and MR, particularly MR, are the best
Barkovich_FM.indd v
modalities by far for imaging the pediatric brain. In those areas where
ultrasound and plain film radiology are important adjuncts or are of
primary importance in diagnosis, they have been included. Specifi-
cally, this includes the diagnosis of intracranial pathology in prema-
ture infants.
Readers will note that this is not an encyclopedic work on diseases
of the pediatric central nervous system. Those disease processes that
are well covered in other texts, or are extremely uncommon, are de-
emphasized here. Instead, I have attempted to cover subjects that are
encountered in everyday practice. Furthermore, I have emphasized
concepts that are crucial to proper imaging techniques and image inter-
pretation. Embryology, normal development, and pathophysiology are
explained. Once these basic concepts are understood, interpretation of
images is greatly facilitated. Finally, an attempt was made to present the
information in a concise and straightforward manner that will make
reading this book an enjoyable learning experience.
5/25/2011 11:31:48 AM
Barkovich_FM.indd vi 5/25/2011 11:31:48 AM
 P R E FAC E
he rapid evolution of Pediatric Neuroimaging continues to
T accelerate. New imaging techniques continue to emerge and
improve to the point where they become useful in the imag-
ing evaluation of children. New diseases continue to be described,
along with new categories of diseases and new ways to classify them. In
addition, the diseases are better understood, as a result of advances in
genetics, molecular biology, biochemistry, and imaging. It has become
difficult to keep up with all of it; thus, for the first time, it no lon-
ger seemed feasible for a single author to update the entire book. As
a result, the fifth edition of Pediatric Neuroimaging is a collaborative
effort. Charles Raybaud and James Barkovich have written much of it
and edited the work of seven other authors (Christopher Hess, Pratik
Mukherjee, Zoltan Patay, Erin Schwartz, Gilbert Vezina, Gary Hedlund,
and Phil Meyers), who have graced this edition with information from
their areas of expertise. The result is a more complete book, which
shares the experience and opinions of dedicated pediatric neuroradi-
ologists with many decades of experience in many different locations.
Contributions by many authors increase the risk of an uneven text,
with much overlap, differences in style, and the potential for contra-
dictions. The authors, indeed, have different styles, but the book was
edited to minimize those differences and, at the same time, keep the
book readable so that it can be used as a tool for learning, as well as
a reference text. In all chapters, the readers will find extensive use of
tables to help to organize the disorders and images to illustrate them.
Chapter 1 on imaging techniques and Chapter 2 on normal devel-
opmental features seen by imaging have been updated with attention to
new information on limiting exposure to ionizing radiation while dis-
cussing both more traditional and new imaging techniques (diffusion
tractography, arterial spin labeling, and volumetrics) and protocols for
MRI. Chapter 2 also has a new section on resting state functional MRI,
potentially a very interesting and useful technique.
Readers will note that, after Chapter 2, all new techniques have been
integrated into the discussion of specific disease entities, which is still
organized by category of disease. Thus, fetal images, perfusion studies,
diffusion imaging, PET images, or proton spectroscopy are illustrated
when they are useful for diagnosis. For malformations, hydrocepha-
lus, and brain injury, in particular, fetal imaging is extremely useful
for early detection of disease. These fetal images show all of the same
features of these disorders that are identified in infants and children
and can be identified using the same search patterns; there is no reason
to put them in a separate section.
Chapter 3 on metabolic diseases has been expanded to include many
newly described disorders and groups of disorders. It also includes a new
section on genetic disorders with extensive cerebellar involvement (par-
ticularly cerebellar hypoplasia and cerebellar atrophy) as the major imag-
ing finding. In addition, new information on diffusivity, spectroscopy,
and clinical/genetic manifestations has been added. We have retained the
two section approach, with the initial section having a brief, diagnosis-
oriented discussion and the longer second section giving a more detailed
explanation of the disorders and their imaging manifestations.
Chapter 4 on destructive lesions of the brain and spine includes
new information on imaging of pediatric stroke, imaging of brain
Barkovich_FM.indd vii
injury in preterm and encephalopathic term neonates (including birth
asphyxia), as well as traumatic brain injury (accidental and inflicted,
both of which continue to be topics of hot debate). We have tried to
give a fair and balanced view of controversial issues.
Chapter 5 on malformations has been extensively updated with
newly described disorders, as well as new information, theories, genet-
ics, and classifications. The organization of the chapter has changed; it
is now organized according to the part of the brain primarily involved
by the disease process: (dorsal forebrain [cerebral cortex and com-
missures], ventral forebrain [base of the brain], midbrain/hindbrain,
craniocervical junction, brain coverings) in order to help the reader
locate the disorder within the text; we believe that this will be useful to
readers. Chapters 6 (Phakomatoses) and 7 (Brain Tumors) have been
updated with new genetic information, new classifications, many new
images, and several new disorders being described.
Chapter 8 on hydrocephalus has been significantly modified and
upgraded to include new theories of hydrocephalus that better explain
the effects upon the ventricular system and the underlying brain.
Chapters 9 (Spine Anomalies), 10 (Spine Tumors), and 12 (Disorders
of Cerebral Blood Vessels) have all been carefully updated with new
data, new theories, and new images that facilitate the diagnosis and
understanding of these disorders. Chapter 11 (Infection) has been
greatly expanded and improved by adding many new disorders and
images, in order to expand our understanding of viruses, disorders
that are prevalent outside of North America and Europe, and newly
described diseases.
Despite the many changes in this edition, we hope the reader will
notice that the philosophy of the book remains the same. A large num-
ber of disorders are discussed and illustrated, as it is much easier to
recognize a disorder by seeing imaging than by reading about imag-
ing features. The cause of the disorder, the main clinical features, and
the underlying cause/pathophysiology are discussed whenever possible
because it is easier to remember disorders when the genetic or embryo-
logic or destructive cause is understood, rather than trying to match
imaging characteristics to a disease name.
For the convenience of the reader, some topics are discussed
more than once in the text. The purpose of this is to avoid forcing
the reader to page back through the book, trying to find the previ-
ous mention of a disorder. For example, Chiari II malformations are
discussed in Chapter 5, under disorders of the craniocervical junction,
as a brain malformation and also in Chapter 9 under myelomenin-
goceles because they are almost always associated. Within Chapter 5,
disorders secondary to abnormal pial basement membrane formation
are discussed in both the dorsal forebrain section and the midbrain/
hindbrain section because both regions are variably involved in the
pathologic process, such that they might present as a forebrain or a
hindbrain malformation.
We hope that this new edition of Pediatric Neuroimaging will serve
as a textbook for residents, fellows, and practicing physicians who are
interested in diseases of the pediatric brain and spine while, at the same
time, serving as a reference book for clinicians seeing patients with
these diseases in their daily work.
vii
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Barkovich_FM.indd viii 5/25/2011 11:31:49 AM
 CONTENTS

Preface to the First Edition v

Preface vii
List of Disorders xi
Contributors xvii

1. Techniques and Methods in Pediatric Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

CHRISTOPHER P. HESS AND A. JAMES BARKOVICH

2. Normal Development of the Neonatal and Infant Brain, Skull, and Spine . . . . . . . . . . . . . . . . . 20
A. JAMES BARKOVICH AND PRATIK MUKHERJEE

3. Metabolic, Toxic, and Inflammatory Brain Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

A. JAMES BARKOVICH AND ZOLTAN PATAY

4. Brain and Spine Injuries in Infancy and Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

ERIN SIMON SCHWARTZ AND A. JAMES BARKOVICH

5. Congenital Malformations of the Brain and Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

A. JAMES BARKOVICH AND CHARLES A. RAYBAUD

6. The Phakomatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

GILBERT VEZINA AND A. JAMES BARKOVICH

7. Intracranial, Orbital, and Neck Masses of Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

CHARLES RAYBAUD AND A. JAMES BARKOVICH

8. Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
A. RAYBAUD AND A. JAMES BARKOVICH

9. Congenital Anomalies of the Spine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857

ERIN SIMON SCHWARTZ AND A. JAMES BARKOVICH

10. Neoplasms of the Spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923

A. JAMES BARKOVICH

11. Infections of the Developing and Mature Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954

GARY HEDLUND, JAMES F. BALE, JR, AND A. JAMES BARKOVICH

12. Anomalies of Cerebral Vasculature: Diagnostic and Endovascular Considerations . . . . . . . . 1051

PHILIP M. MEYERS, VAN V. HALBACH, AND A. JAMES BARKOVICH

Index 1109

ix

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Barkovich_FM.indd x 5/25/2011 11:31:49 AM
 LIST OF DISORDERS
CHAPTER 3: METABOLIC, TOXIC, AND INFLAMMATORY
BRAIN DISORDERS
IV.B. Metabolic Disorders Primarily Affecting White
Matter
1. White matter diseases initially affecting periventricular cere-
bral white matter
a. Metachromatic leukodystrophy
b. Globoid cell leukodystrophy (Krabbe disease)
c. Classic X-linked adrenal leukodystrophy/adrenomy-
eloneuropathy/acyl-CoA-oxidase deficiency
d. Leukoencephalopathy with vanishing white matter
e. Giant axonal neuropathy
f. Phenylketonuria
g. Maple syrup urine disease
h. Hyperhomocysteinemia (formerly known as homocysti-
nuria)
i. Cystathionine beta synthase deficiency
j. 5, 10 methylenetetrahydrofolate reductase deficiency
(MTHFRD)
k. Errors affecting cobalamin (vitamin B12) metabolism
l. Biotinidase deficiency
m. Methionine adenosyltransferase deficiency
n. Oculocerebrorenal syndrome (Lowe syndrome)
o. Merosin-deficient congenital muscular dystrophy
(MDC1A)
p. Mucolipidosis type IV
q. Autosomal recessive spastic paraplegia with thin corpus
callosum
r. Sjögren-Larsson syndrome
s. Brain injury from radiation and chemotherapy
2. White matter disorders with dysmyelination initially affect-
ing subcortical cerebral white matter
a. Megalencephalic leukoencephalopathy with subcortical
cysts (MLC)
b. Cystic leukoencephalopathy without megalencephaly
c. Aicardi-Goutières syndrome
d. Cockayne syndrome
e. Galactosemia
3. White matter disorders due to hypomyelination
(hypomyelinating leukodystrophies)
a. Pelizaeus-Merzbacher disease
b. Pelizaeus-Merzbacher-like disease
c. Leukodystrophies with trichothiodystrophy
d. 18q-Syndrome and other chromosome 18 mutations
e. Sialuria
f. Hypomyelination with congenital cataracts
g. Fucosidosis
h. Hypomyelination with atrophy of the basal ganglia and
cerebellum (HABC)
Barkovich_FM.indd xi
4. White matter diseases with nonspecific patterns
a. Nonketotic hyperglycinemia (glycine encephalopathy)
b. Dihydropyrimidine dehydrogenase deficiency
c. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency
d. Congenital white matter hypoplasia/familial spastic
paraplegia
5 Idiopathic inflammatory, autoimmune, infectious, and toxic
disorders affecting white matter
a. Multiple sclerosis
b. Neuromyelitis optica (Devic disease)
c. Acute disseminated encephalomyelitis (ADEM)
d. Acute hemorrhagic encephalomyelitis
e. Collagen vascular diseases/systemic lupus erythematosus
f. Osmotic myelinolysis in childhood
g. Toxins
h. Lead encephalopathy
i. Solvent abuse
j. Progressive multifocal leukoencephalitis
IV.C. Metabolic Disorders Primarily Involving
Gray Matter
1. Gray matter disorders primarily involving the deep gray
cerebral nuclei
a. Pantothenate kinase-associated neuropathy (neurode-
generation with brain iron accumulation 1, formerly
Hallervorden-Spatz disease)
b. Juvenile Huntington disease
c. Isovaleric acidemia
d. Succinic semialdehyde dehydrogenase deficiency
e. Creatine deficiency syndromes
f. Wernicke encephalopathy
g. Extrapontine myelinolysis
h. Hemolytic-uremic syndrome
i. Sydenham chorea
j. Chronic liver disease
2. Gray matter disorders primarily involving cortex
a. Neuronal ceroid lipofuscinosis
b. Aspartylglucosaminuria
c. Anti-N-methyl-D-aspartate receptor (NMDAR) encepha-
litis in children and adolescents
d. Infantile neuroaxonal dystrophy
e. Niemann-Pick disease
f. Rett syndrome
g. Toxins
h. Progressive cerebral poliodystrophy (Alpers disease)
IV.D. Metabolic Disorders that Affect both Gray and White
Matter
1. Canavan disease (aspartoacylase deficiency, spongiform
leukodystrophy)
2. Fibrinoid leukodystrophy (Alexander disease)
xi
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 xii List of Disorders

3. Mucopolysaccharidoses 17. Cerebrotendinous xanthomatosis

a. Multiple sulfatase deficiency 18. Wolfram syndrome
4. Peroxisomal disorders 19. Marinesco-Sjögren syndrome
a. Peroxisomal biogenesis disorders 20. X-linked nonprogressive congenital cerebellar hypoplasia
b. Acyl-CoA-oxidase deficiency 21. Höyeraal-Hreidarsson syndrome
c. Rhizomelic chondrodysplasia punctata 22. Revesz syndrome
d. Nonrhizomelic chondrodysplasia punctata
5. Wilson disease CHAPTER 4: BRAIN AND SPINE INJURIES IN INFANCY AND
6. Mitochondrial disorders (respiratory chain disorders) CHILDHOOD
a. Mitochondrial encephalomyopathy with lactic acidosis II. Basic Patterns of Brain Destruction
and strokelike episodes (MELAS) 1. Porencephaly
b. Kearns-Sayre syndrome/progressive external ophthal- 2. Hydranencephaly
moplegia 3. Encephalomalacia
c. Mitochondrial neurogastrointestinal encephalomyopathy
d. Disorders causing Leigh syndrome III. Hypoxic-ischemic Brain Injury
e. Alpers disease 1. Localized infarctions
f. Trichopoliodystrophy (Menkes disease) a. Manifestations and causes of infarctions in children
g. Glutaric aciduria type I (glutaryl-CoA-dehydrogenase b. Choice of radiologic study in pediatric stroke
deficiency) c. Arterial infarctions
h. Glutaric aciduria type II (multiple acyl-CoA-dehydrogenase Presumed perinatal ischemic stroke
deficiency) Transient cerebral arteriopathy
i. Neonatal lactic acidosis, complex I/IV deficiency, and fetal d. Infarction secondary to venous occlusion
cerebral disruption 2. Diffuse ischemic or inflammatory brain injury
j. Friedreich ataxia a. Patterns of diffuse hypoxic-ischemic brain injury
k. Ethylmalonic encephalopathy b. Injury in the premature infant
l. Nonspecific mitochondrial disorders Periventricular and intraventricular hemorrhage
7. Pyruvate dehydrogenase deficiency Cerebellar hemorrhage
8. Disorders of the urea cycle and ammonia Venous infarctions
9. Methylmalonic and propionic acidemias White matter injury
10. GM1 and GM2 (Tay-Sachs and Sandhoff diseases) gangliosi- Cerebellar injury
doses Imaging findings in premature neonates
11. Fucosidosis Profound hypotension in premature neonates
12. l-2-Hydroxyglutaric aciduria c. Injury in the term infant
13. Acute necrotizing encephalitis Parasagittal/watershed injury
14. Hypomyelination with atrophy of the basal ganglia and Profound hypotension
cerebellum Parenchymal and intraventricular hemorrhage in the
15. 3-Methylglutaconic aciduria and Barth syndrome term neonate
16. Molybdenum cofactor deficiency d. Injury in older infants and children
17. Isolated sulfite oxidase deficiency e. Ischemia secondary to venous occlusion
18. Toxin ingestions IV. CNS Injury in Multiple Pregnancies
IV.E. Metabolic Disorders Primarily Involving the Cerebellum V. Neonatal Hypoglycemia
1. Friedreich ataxia
VI. Bilirubin Encephalopathy (Kernicterus)
2. Ataxia-Telangiectasia
3. Late onset GM2 gangliosidosis VII. Brain Injury Associated with Congenital Heart Disease
4. Ataxia with oculomotor apraxia, types 1 and 2 VIII. Hypernatremic Dehydration
5. Autosomal recessive spastic ataxia (of Charlevoix-
IX. CNS Trauma in Infancy and Childhood
Saguenay)
1. Birth trauma
6. Mitochondrial disorders causing cerebellar atrophy
a. Spinal cord injury
a. Coenzyme Q10 deficiency
b. Nerve root and brachial plexus injuries
b. SANDO syndrome
c. Head trauma
c. Infantile onset spinocerebellar ataxia
2. Postnatal trauma
7. Infantile olivopontocerebellar atrophy
a. Spinal trauma
8. Pontocerebellar hypoplasia
Injuries to young children
9. Congenital disorders of glycosylation
Adolescent injuries
10. Mevalonic kinase deficiency (Mevalonic aciduria)
Torticollis/rotational deformities of C-1 and C-2
11. Progressive encephalopathy with edema, hypsarrhythmia,
Back pain in children
and optic atrophy (PEHO)
b. Head trauma
12. Dentatorubral and pallidoluysian atrophy
Extraparenchymal hematomas
13. Neuronal ceroid lipofuscinoses
Subarachnoid hemorrhage
14. Langerhans cell histiocytosis
Injury to the brain parenchyma
15. Hypomyelination with atrophy of the basal ganglia and
Sequelae of trauma
cerebellum (HABC)
16. Spinocerebellar ataxias X. Nonaccidental Trauma (Child Abuse)

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 List of Disorders xiii

CHAPTER 5: CONGENITAL MALFORMATIONS OF THE BRAIN f. Cerebellar duplication

AND SKULL g. Pontine tegmental cap dysplasia
II. Anomalies of Dorsal Prosencephalon Development 4. Combined hypoplasia and atrophy in putative prenatal onset
1. Anomalies of the cerebral commissures—corpus callosum, degenerative disorders
anterior commissure, hippocampal commissure, septum a. Pontocerebellar hypoplasias
pellucidum b. Congenital disorders of glycosylation and other metabolic
2. Malformations of cortical development disorders
a. Malformations secondary to abnormal cell proliferation c. Cerebellar hemisphere hypoplasia
and apoptosis V. Anomalies of the Craniocervical Junction
Microcephaly 1. Chiari I
Focal cortical dysplasia type II 2. Chiari II
Hemimegalencephaly 3. Chiari III
b. Malformations secondary to abnormal cell migration VI. Anomalies of the Mesenchyme (Meninges and Skull)
Lissencephalies 1. Cephaloceles and other calvarial and skull base defects
Malformations due to defects in the pial basement 2. Intracranial lipomas
membrane (Walker-Warburg, muscle-eye-brain, Fukuy- 3. Arachnoid cysts
ama congenital muscular dystrophy, bilateral frontopa- 4. Craniosynostosis syndromes
rietal polymicrogyria phenotypes) a. Nonsyndromic synostosis
Heterotopia b. Synostosis syndromes
c. Malformations secondary to abnormal late migration and Apert syndrome
cortical organization Saethre-Chotzen syndrome
Polymicrogyria Pfeiffer syndrome
Schizencephaly Crouzon syndrome
Focal cortical dysplasia types I, III
VII. Specific Chromosomal Anomalies
III. Anomalies of Ventral Prosencephalon Development 1. Down syndrome
1. Holoprosencephalies 2. Trisomy 18
a. Alobar holoprosencephaly 3. Trisomy 13
b. Semilobar holoprosencephaly 4. Fragile X syndrome
c. Lobar holoprosencephaly
2. Arrhinia/arrhinencephaly CHAPTER 6: THE PHAKOMATOSES
3. Septooptic dysplasia
4. Isolated absence of septum pellucidum I. Neurofibromatosis Type I
5. Anomalies of the hypothalamic-pituitary axis II. Neurofibromatosis Type II
a. Pituitary absence, hypoplasia, and duplication
III. Other Forms of Neurofibromatosis
b. Pituitary dwarfism
c. Kallmann syndrome (hypogonadotropic hypogonadism) IV. Tuberous Sclerosis
d. Hypothalamic dysgenesis V. Sturge-Weber Disease
6. Anomalies of the eyes
VI. Von Hippel-Lindau Disease
a. Ocular malformations
b. Anophthalmia VII. Ataxia-Telangiectasia
c. Microphthalmic malformations VIII. Neurocutaneous Melanosis
d. Macrophthalmia
e. Other congenital ocular anomalies IX. Incontinentia Pigmenti

IV. Anomalies of Midbrain-Hindbrain Development X. Hypomelanosis of Ito

1. Defects of AP and DV patterning
2. Malformations associated with later generalized develop-
mental disorders that significantly affect the brainstem and
cerebellum
a. Cerebellar aplasia/hypoplasia
b. Rhombencephalosynapsis
c. Dandy-Walker continuum
d. Cerebral malformations (including microcephaly) with
cerebellar anomalies
e. Joubert syndrome and related disorders (molar tooth
malformations)
3. Localized brain malformations that significantly affect the BS
and CBL: isolated cerebellar and brain stem malformations
a. Horizontal gaze palsy with progressive scoliosis
b. Congenital fibrosis of extraocular muscles
c. Midbrain clefts
d. Cerebellar nodular heterotopia with overlying dysgenesis
e. Cerebellar foliation disorders
XI. Basal Cell Nevus Syndrome
XII. Cutaneous Hemangioma-Vascular Complex Syndrome
XIII. Chediak-Higashi Syndrome
XIV. Progressive Facial Hemiatrophy (Parry-Romberg
Syndrome)
XV. Epidermal Nevus Syndrome
XVI. Encephalocraniocutaneous Lipomatosis
XVII. Other Overgrowth Syndromes
CHAPTER 7: INTRACRANIAL, ORBITAL, AND NECK MASSES
OF CHILDHOOD
I. Introduction
1. Introduction and severity of brain tumors in children
2. Changing concepts of the biology of brain tumors
3. Clinical features of brain tumors

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 xiv List of Disorders

II. Techniques of Imaging Pediatric Brain Tumors c. Infantile myofibromatosis

III. Imaging Characteristics Used to Identify Brain d. Leukemia and lymphoma
Tumors e. Langerhans cell histiocytosis
f. Extramedullary hematopoiesis
IV. Posterior Fossa Tumors g. Calvarial tumors
1. Intraparenchymal tumors
a. Medulloblastoma VI. Brain Tumors in the First Year of Life
b. Atypical teratoid-rhabdoid tumor VII. Radiation Induced Tumors of the Central Nervous
c. Cerebellar astrocytomas System
d. Ependymomas VIII. Tumors of the Head and Neck
e. Brain stem tumors 1. Ocular tumors
f. Hemangioblastoma a. Retinoblastoma
2. Extraparenchymal tumors b. Medulloepithelioma
a. Schwannomas 2. Extraocular orbital masses
b. Dysembryoplastic tumors (epidermoids, dermoids, and a. Vascular masses (hemangiomas, venolymphatic
enteric cysts) malformations, varices)
c. Teratomas b. Orbital cysts
d. Miscellaneous tumors of posterior fossa/skull base c. Leukemia
(meningiomas, langerhans cell histiocytosis, chordoma, d. Metastatic neuroblastoma
chondrosarcoma, neuroblastoma, aneurysmal bone cyst, e. Langerhans cell histiocytosis
Ewing sarcoma) f. Plexiform neurofibroma
V. Supratentorial Tumors g. Dermoids and epidermoids
1. Tumors of the cerebral hemispheres 3. Masses of the face and neck
a. Hemispheric astrocytomas a. Thyroglossal duct cyst
b. Neuronal and mixed neuronal-glial tumors b. Branchial cleft cyst
(gangliogliomas, desmoplastic infantile ganglioglioma/ c. Thymic cyst
desmoplastic astrocytoma of infancy, dysembryoplastic d. Venolymphatic malformations
neuroepithelial tumor (DNET) e. Hemangiomas
c. Supratentorial ependymoma f. Neurofibromas/schwannomas
d. Tumors with neuroblastic or glioblastic elements g. Teratoma
(primitive neuroectodermal tumor (PNET), h. Cervical lymphadenitis
medulloepithelioma) i. Fibromatosis colli
e. Atypical teratoid/rhabdoid tumor j. Rhabdomyosarcoma
f. Astroblastoma k. Nasopharyngeal carcinoma
g. Oligodendroglioma l. Juvenile angiofibroma
h. Neuroglial hamartomas m. Melanotic neuroectodermal tumors of infancy
i. Plasma cell granulomas (inflammatory n. Fibrous dysplasia of the skull base
pseudotumors)
j. Lymphoproliferative disorders CHAPTER 8: HYDROCEPHALUS
k. Germ cell tumors I. Embryology and Physiology of CSF Kinetics and
l. Meningioangiomatosis Dynamics
2. Sellar and suprasellar tumors 1. Choroid plexuses and CSF formation
a. Chiasmatic/hypothalamic astrocytomas 2. CSF circulation
b. Craniopharyngioma 3. CSF absorption
c. Hypothalamic hamartomas
d. Langerhans cell histiocytosis II. Mechanisms of Hydrocephalus
e. Pediatric pituitary tumors III. Classification of Hydrocephalus
f. Rathke cleft cysts 1. Obstructive hydrocephalus
g. Lymphocytic hypophysitis 2. Communicating hydrocephalus
h. Suprasellar germ cell tumors
IV. Clinical Aspects if Hydrocephalus
3. Pineal region masses
a. Germ cell tumors V. Radiologic Diagnosis of Hydrocephalus
b. Pineal parenchymal tumors (pineocytoma, 1. The tools
pineoblastoma) 2. Fetal diagnosis of hydrocephalus
c. Pineal region gliomas 3. Postnatal diagnosis of hydrocephalus and distortions of the
d. Pineal cysts brain from hydrocephalus
4. Extraparenchymal tumors VI. Specific Categories of Hydrocephalus
a. Choroid plexus tumors 1. Hydrocephalus resulting from excessive formation of CSF
b. Tumors of the meninges (meningiomas, plasma cell (choroid plexus papillomas)
granulomas, meningeal fibromas and myofibromas, and 2. Hydrocephalus secondary to intraventricular obstruction of
meningeal sarcomas) CSF flow

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 List of Disorders xv

3. Hydrocephalus secondary to extraventricular obstruction CHAPTER 11: INFECTIONS OF THE DEVELOPING AND
of CSF MATURE NERVOUS SYSTEM
4. Communicating hydrocephalus I. Congenital Infections
VII. Benign Enlargement of Subarachnoid Spaces in 1. Cytomegalovirus
Infants 2. Toxoplasmosis
VIII. Treatment of Hydrocephalus and the Resulting 3. Congenital/neonatal herpes simplex encephalitis
Complications 4. Rubella
1. Radiologic assessment of third ventriculostomies 5. Congenital syphilis
2. Shunt malfunctions 6. Lymphocytic choriomeningitis virus
3. Shunt infections 7. Neonatal parechovirus
4. Subdural hematoma formation 8. Congenital varicella
5. Slit ventricle syndrome 9. Human immunodeficiency virus (perinatal transmission)
6. Imaging of intracranial hypotension 10. Disorders mimicking congenital infections
II. Meningitis and Complications
CHAPTER 9: CONGENITAL ANOMALIES OF THE SPINE 1. Neonatal meningitis
I. Normal and Abnormal Embryogenesis of the Spine: an 2. Meningitis in infants, children, and adolescents
Overview 3. Pathophysiology of meningitis
4. Imaging manifestations
II. Clinical Manifestations of Spinal Anomalies
III. Empyema Secondary to Sinusitis and Otomastoiditis
III. Terminology
IV. Bacterial, Spirochetal, and Rickettsial Infections
IV. Imaging Techniques 1. Bacterial cerebritis
V. Abnormalities of Neurulation 2. Brain abscess
1. Disorders resulting from nondisjunction: myelocele, 3. Cat-scratch disease
myelomeningocele, dorsal dermal sinuses, cervical 4. Lyme disease
myelocystocele 5. Rocky Mountain spotted fever
2. Disorders resulting from premature disjunction—spinal V. Viral Infections
lipomas 1. General concepts
VI. Anomalies of the Caudal Cell Mass 2. Herpesvirus family—herpes simplex, varicella zoster,
1. Normal conus medullaris and filum terminale Epstein-Barr, human herpesvirus-6
2. The terminal ventricle 3. Nonpolio enteroviruses
3. Fibrolipomas of the filum terminale/tight filum terminale 4. Arthropod-borne viruses—eastern equine encephalitis,
4. Syndrome of caudal regression western equine encephalitis, Venezuelan equine encepha-
5. Terminal myelocystocele litis, Japanese encephalitis, St. Louis encephalitis, West
6. Anterior sacral meningocele Nile, dengue virus, LaCrosse encephalitis virus, California
7. Sacrococcygeal teratoma encephalitis viruses, Colorado tick fever virus
5. Influenza-associated encephalitis/encephalopathy
VII. Anomalies of Development of the Notochord
6. Acute cerebellitis
1. The split notochord syndrome
7. Rabies
2. Split cord malformation (diastematomyelia and
8. Chronic viral infections—AIDS encephalopathy, progressive
diplomyelia)
multifocal leukoencephalopathy, Rasmussen encephalitis,
VIII. Malformations of Unknown Origin postrubella panencephalitis, subacute sclerosing encephalitis,
1. Segmental spinal dysgenesis variant Creutzfeldt-Jakob disease
2. Dorsal meningocele
VI. Fungal Infections
3. Lateral meningocele
1. Neonatal candidiasis
IX. Congenital Tumors of the Spine 2. Aspergillosis
X. Syringohydromyelia 3. Coccidioidosis
4. Cryptococcus
CHAPTER 10: NEOPLASMS OF THE SPINE VII. Parasitic Infections
II. General Imaging Characteristics of Spinal Tumors 1. Neurocysticercosis
2. Visceral larva migrans
III. Intramedullary Tumors: Clinical Presentation, Pathology,
3. Cerebral malaria
Imaging Characteristics
VIII. Sarcoidosis
IV. Extramedullary Tumors
1. CSF dissemination of intracranial neoplasms IX. Infections of the Spine
2. Tumors of the spinal column 1. Discitis/osteomyelitis
3. Meningeal tumors 2. Spinal empyemas
4. Tumors of nerve roots and nerve root sheaths X. Emerging Infections of the CNS
5. Extraspinal tumors invading the epidural space 1. Nipah virus
V. Congenital Spinal Tumors 2. Dengue virus
3. Chikungunya virus

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 xvi List of Disorders

CHAPTER 12: ANOMALIES OF CEREBRAL VASCULATURE: VI. Arteriovenous Fistulas

DIAGNOSTIC AND ENDOVASCULAR CONSIDERATIONS 1. Dural arteriovenous fistulas
II. Technical Considerations in Pediatric Neuroangiography 2. Direct carotid cavernous fistulas
and Intervention 3. Vertebral fistulas

III. Intracerebral Hemorrhage in Children VII. Intracranial Aneurysms

IV. Intracerebral Vascular Malformations
1. Arteriovenous malformations
2. Vein of galen malformations
3. Cavernous malformations
4. Venous malformations
5. Capillary telangiectasias
V. Extradural Vascular Malformations and Neoplasms
Requiring Endovascular Treatment
1. Hemangioma
2. Venous malformation
3. Facial AVM
4. Epistaxis and juvenile angiofibroma
1. Saccular aneurysms
2. Mycotic aneurysms
3. Traumatic aneurysms
VIII. Spinal Cord Arteriovenous Malformations
1. Intramedullary arteriovenous malformations
2. Perimedullary arteriovenous fistulas
3. Epidural fistulas
IX. Cerebral Vasculopathy in Childhood
1. Moyamoya syndrome
2. Sickle cell disease
3. Hereditary hemorrhagic telangiectasia
X. Arterial Dissection in Childhood

Barkovich_FM.indd xvi 5/25/2011 11:31:49 AM

 C O N T R I B U TO R S

A. James Barkovich, MD Pratik Mukherjee, MD, PhD

Professor Associate Professor in Residence
Radiology, Neurology, Pediatrics, and Neurosurgery Department of Radiology & Biomedical Imaging
University of California at San Francisco Chief of Functional Neuroimaging
Chief University of California at San Francisco
Pediatric Neuroradiology San Francisco, California
UCSF Medical Center/Benioff Children’s Hospital
San Francisco, California Zoltán Patay MD, PhD
Professor of Radiology
Van V. Halbach, MD Department of Radiology
Clinical Professor of Radiology and Neurological Surgery University of Tennessee Health Science Center
University of California at San Francisco College of Medicine
San Francisco, California Chief
Section of Neuroimaging
Gary L. Hedlund, DO Department of Radiological Sciences
Adjunct Professor St. Jude Children’s Research Hospital
Department of Radiology Memphis, Tennessee
University of Utah
Director Charles A. Raybaud MD, FRCPC
Pediatric Neuroradiology Professor of Radiology
Department of Medical Imaging University of Toronto
Primary Children’s Medical Centre Division Head of Neuroradiology
Salt Lake City, Utah Hospital for Sick Children
Toronto, Canada
Christopher P. Hess, MD, PhD
Assistant Professor in Residence Erin Simon Schwartz, MD
Department of Radiology & Biomedical Imaging Associate Professor
University of California, San Francisco Department of Radiology
Chief University of Pennsylvania School of Medicine
Neuroradiology Clinical Director
Department of Radiology Magnetoencephalography
San Francisco Veterans Administration Medical Center Department of Radiology
San Francisco, California The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
Philip M. Meyers, MD
Associate Professor L. Gilbert Vezina, MD
Radiology and Neurological Surgery Professor of Radiology and Pediatrics
Columbia University, College of Physicians & Surgeons George Washington University
Director Director of Neuroradiology
Neuroendovascular Services Children’s National Medical Center
Radiology and Neurological Surgery Washington, D.C.
New York Presbyterian Hospitals—Columbia
New York, New York

xvii

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Barkovich_FM.indd xviii 5/25/2011 11:31:49 AM
 CHAPTER
Techniques and Methods
1 in Pediatric Neuroimaging
CHRISTOPHER P. HESS AND A. JAMES BARKOVICH
Sedation
MR scanning without sedation
Sedation techniques
Monitoring
Special problems in the imaging of premature infants
Contrast agents
Iodinated contrast agents
Paramagnetic contrast agents
Ultrasound indications and techniques
CT scanning indications and techniques
Routine MR imaging sequences
Brain
Spine
Fetal MRI
odern imaging modalities have greatly advanced both the
M understanding and the diagnosis of pathology of the pediatric
central nervous system. In order to maximize the information
gained from these studies, high-quality images must be obtained. The
use of high-frequency transducers and acquisition of images via the
anterior and posterolateral fontanelles allows outstanding sonographic
visualization of the brain and intracranial blood vessels in neonates and
young infants (1,2). Helical (spiral) computed x-ray tomography (CT)
scanners obtain images in fractions of a second, permitting high-quality
vascular imaging and facilitating rapid, high-quality three-dimensional
(3D) and two-dimensional (2D) reformations. The effects of physio-
logic and bulk motion during scanning are minimized and high-quality
images can be rapidly obtained (but one must always remember that
higher image quality comes with a price of increasing radiation dose).
Although the use of fractional k-space acquisitions, echo-planar imag-
ing (EPI) and other fast-scan techniques, and PROPELLER help reduce
sensitivity to patient motion in magnetic resonance imaging (MRI),
artifacts remain an issue for certain applications, especially when seda-
tion is inadequate. Moreover, optimal imaging parameters for the
pediatric patient (especially the neonate and young infant) differ from
those of the adult because standard adult imaging sequences do not
consider the changing chemical composition of the developing brain.
Finally, the increasing use of 3 tesla (3 T) scanners requires alterations
of imaging techniques and parameters to compensate for differences in
T1 relaxation times and magnetic susceptibility that result from higher
field strength. The purpose of this chapter is to outline techniques for
safely and effectively obtaining high-quality imaging studies in pediat-
ric patients. In addition, the techniques that we currently use in the CT
and MR evaluation of infants and children at the University of Califor-
nia, San Francisco, are summarized. These techniques are referred to
throughout the remainder of this book.
Barkovich_Chap01.indd 1
Special MR techniques
MR and CT angiography
CSF flow imaging
Magnetic resonance neurography
Magnetization transfer
Perfusion imaging
Diffusion tensor imaging
Proton MR spectroscopy
Automated morphometric analysis and tissue
segmentation
Imaging of brain function
Summary
SEDATION
The most important factor for obtaining high-quality MR images in
children is making sure that they remain still while the images are
acquired. When children do not remain still, motion artifacts will
obscure important diagnostic information. In general, sedation is not
necessary for CT when modern scanners are being used; indeed, seda-
tion was required in only 1.4% of 219 children on a multisection helical
CT scanner (3). Younger children can usually be adequately restrained,
and older children will hold still long enough for a good CT examina-
tion to be obtained. The technologist should watch the patient during
the CT exam and initiate scanning while the patient is not moving;
rapid reconstruction times allow acquisition of new images at targeted
levels that are motion degraded on the initial scans. In those difficult
cases where sedation is required, the protocols outlined in this section
are applicable. In general, however, the use of helical acquisition has
made sedation rare for CT in most institutions (3,4).
MR Scanning Without Sedation
Although sedation is necessary for most MR studies of children younger
than 8 years, fast MR techniques such as EPI, half-Fourier acquisition
single-shot turbo spin echo (HASTE, also called single-shot fast spin
echo or ssFSE by manufacturers) and rapid acquisition with relaxation
enhancement (RARE, also called fast spin echo, FSE, or turbo spin
echo, TSE) (5,6) allow high-quality images of the entire brain to be
obtained within a sufficiently short examination time (<1 minute) to
avoid significant motion artifacts. Alternatively, the periodically rotated
overlapping parallel lines with enhanced reconstruction (PROPELLER
or PROP) acquisition and reconstruction scheme is relatively tolerant
of patient motion (7,8). EPI and HASTE/ssFSE are often adequate for
5/5/2011 11:43:32 PM
 2 Pediatric Neuroimaging
diagnosis of ventriculomegaly/shunt failure or acute infarcts but are
not, at this time, of adequate quality to allow diagnosis of subtle mal-
formations, leukodystrophies, or tumor progression. PROPELLER will
allow identification of malformations and tumors but does not have
the contrast resolution to detect subtle white matter abnormalities.
If sedation can be avoided, it should be, as complication rates are
generally in the range of 0.4% to 1% even in the best of hands (9). The
incidence of complications seems to be significantly higher if the child
has a history of respiratory illness or if more than one agent is used
for sedation (9). Therefore, it is important to remember that sedation
is not universally necessary for obtaining standard MR sequences of
pediatric patients. Neonates can often be scanned without sedation if
they are fed immediately prior to the study, kept warm, and earmuffs/
earplugs are used to reduce the noise; we have found the use of 24%
oral sucrose (Sweet Ease) and nonnutritive sucking (i.e., a sucrose paci-
fier) immediately prior to the scan to be useful by promoting a calm
state and reducing stress. Mathur et al. report considerable success in
scanning unsedated neonates (10). We have had success with this, as
well, as described in the section below on Special Issues in Scanning of
Premature Neonates. Scanning neonates requires an armamentarium
of MR compatible life-support and monitoring equipment, trained
transport personnel, at least 1 hour of preparation time before the baby
is transported to the scanner, and a similar amount of time after the
scan (10).
With adequate personnel and equipment, it can be achieved with
a high success rate. The success rate diminishes with the maturity of
the baby, however. As they mature, infants become increasingly aware
of their surroundings and sedation becomes increasingly necessary in
order to obtain diagnostic scans; by the age of 2 to 3 months, sedation
is nearly always necessary. Fewer older children need sedation if some
sort of MR-compatible audiovisual system is available. We find that
most children aged 8 years and older as well as some 6- and 7-year-olds
can hold still for an MR study if they are adequately enraptured by a
movie. Harned and Strain (11) found a 25% reduction in the number
of sedations for children aged 3 to 10 years and a 50% reduction in
sedations of children more than 10 years old when they began to use an
audiovisual system in their MR scanner. They also found a 17% reduc-
tion in the MR room time for patients who were examined without
sedation. Hallowell et al. (12) prepared children (aged 3.7–17 years)
in a practice MRI unit (without real magnets); of the 78% who per-
formed adequately during preparation and underwent an MR scan,
they were able to obtain diagnostic noncontrast images in 96%. How-
ever, contrast-enhanced images were not obtained and motion artifact
was seen in more than 60% of studies.
Sedation Techniques
When sedation is necessary, the practitioner should be familiar with the
guidelines published by the American Academy of Pediatrics (13,14), the
American Society of Anesthesiologists (15), and the American College of
Radiology (16). These guidelines require the following provisions:
1. Preprocedural medical history, physical examination, and physical
status evaluation
2. Informed consent according to local, state, and institutional
requirements
3. Fasting guidelines appropriate for age to prevent pulmonary
aspiration
4. Uniform training and credentialing for sedation providers
5. Baseline, intraprocedural, and postprocedural monitoring with
devices appropriately sized for children and compatible with the
magnetic field in the case of MRI
Barkovich_Chap01.indd 2
6. Method of continuous patient observation (window, camera)
7. Resuscitation equipment, including oxygen delivery and suction,
that is checked and maintained on a scheduled basis
8. Uniform system of record-keeping and charting (with continuous
assessment and recording of vital signs)
9. Location and protocol for recovery and discharge
10. Program for continuous quality improvement that tracks compli-
cations and morbidity
In addition, the 2008 update of the AAP guidelines requires the fol-
lowing (14); please read all of these guidelines before embarking on
pediatric MRI sedation.
1. No administration of sedating medication without the safety net
of medical supervision
2. Careful presedation evaluation for underlying medical or surgical
conditions that would place the child at increased risk from sedat-
ing medications
3. Appropriate fasting for elective procedures and a balance between
depth of sedation and risk for those who are unable to fast because
of the urgent nature of the procedure
4. A focused airway examination for large tonsils or anatomic airway
abnormalities that might increase the potential for airway obstruc-
tion
5. A clear understanding of the pharmacokinetic and pharmacody-
namic effects of the medications used for sedation as well as an
appreciation for drug interactions
6. Appropriate training and skills in airway management to allow res-
cue of the patient
7. Age- and size-appropriate equipment for airway management and
venous access
8. Appropriate medications and reversal agents
9. Sufficient numbers of people to carry out the procedure and moni-
tor the patient
10. Appropriate physiologic monitoring during and after the proce-
dure
11. A properly equipped and staffed recovery area
12. Recovery to presedation level of consciousness before discharge
from medical supervision
13. Appropriate discharge instructions
Although the most common complications from sedation are related
to respiratory compromise, special attention must be given to monitor-
ing body temperature in the neonatal and the young pediatric popula-
tion. Temperature monitoring equipment that is approved for use in
the MR suite is becoming more readily available. A growing number of
commercial MR-approved neonatal isolation transport units and other
warming devices have also become more readily available for use dur-
ing MR scans.
A number of different drugs can be and have been used safely for
pediatric sedation (17–27). Specific anesthetic regimens vary region-
ally and institutionally, and a comprehensive discussion of appropriate
medications for sedation during imaging is beyond the scope of this
text. Some regimens that have been used safely by physicians creden-
tialed in pediatric sedation in our practice are listed below for reference.
The reader should consult with local anesthesiologists and/or pediatri-
cians before employing any anesthesia protocol, whether listed here or not.
Moreover, close contact should be maintained with an anesthesiologist or
experienced pediatrician for consultation in difficult cases.
Sedation can be administered by many routes: oral (PO), rectal
(PR), intramuscular (IM), or intravenous (IV). PO, PR, and IM routes
have the important advantage that they do not require special skills
for administration. However, the absorption of many drugs from the
5/5/2011 11:43:32 PM
 Chapter 1 • Techniques and Methods in Pediatric Neuroimaging
muscle and gastrointestinal tract can be erratic. Thus, sedatives and
anesthetics administered in large doses by these routes can be difficult
to reverse in the event a complication arises during sedation. The rec-
ommendation of the American Academy of Pediatrics is that infants
should be given nothing by mouth for at least 4 hours prior to deep
sedation; older children for at least 6 hours (28). This accelerates bioab-
sorption in the case of PO and PR medications but, more importantly,
decreases the risk of pulmonary aspiration during the examination.
Sodium pentobarbital (Nembutal) is a useful short-acting bar-
biturate for enteral or parenteral sedation in pediatric patients (20),
although it should be used with care in patients who have hepatic or
metabolic disease, as the drug may alter the metabolism of other medi-
cations. The usual dose of sodium pentobarbital is 6 mg/kg for the first
15 kg of body weight, followed by 5 mg for each additional kg up to
a total dose of no more than 100 mg (as a single IM injection). The
drug should be administered 35 to 45 minutes before the anticipated
imaging time.
Historically and in a previous edition of this book, the safest drug
for sedating children was considered to be chloral hydrate. Others have
also reported on the safety and efficacy of chloral hydrate, especially in
infants under the age of 18 months (22) and even up to age 4 years (29).
However, because questions have been raised concerning the potential
carcinogenicity of this drug (30), its use has been restricted in some
countries. In the United States, the American Academy of Pediatrics
has judged the evidence insufficient (31), and many physicians con-
tinue to use chloral hydrate without incident. Usually administered
orally, known side effects include prolonged somnolence (>4 hours),
unsteadiness, and hyperactivity in some children after waking (32).
Such symptoms may require the child to be kept at the imaging center
and observed for a prolonged time period. In addition, one study sug-
gested that the complication rate, particularly for episodes of oxygen
desaturation, is lower with oral pentobarbital than with chloral hydrate
and recommended that oral pentobarbital be used as an equally effec-
tive and safer drug than chloral hydrate in infants (33). If used, chloral
hydrate is administered orally in a dose of 50 to 75 mg/kg for the first
10 kg of body weight, then 50 mg/kg for each kg of body weight above
10 kg. If the child is still awake after 20 minutes, supplementary doses
can be given up to a total dose of 2000 mg. Chloral hydrate is not cur-
rently used for infant sedation at UCSF.
After enteric or intramuscular sedatives have been administered,
the patient and parent should be transferred to a dark, quiet room. The
noise and activity of a busy waiting room will otherwise keep the child
awake. Sleep deprivation is also helpful. If the imaging study is per-
formed in the morning, keep the child awake several hours past nor-
mal bedtime the night preceding the exam and awaken the child earlier
than usual on the morning of the exam. If the imaging is performed in
the afternoon, deprive the child of his or her normal naps. Do not allow
the child to fall asleep during travel to the imaging facility. Finally, per-
mit a parent to enter the scanner with the patient, if desired, in order
to reassure the child that security is nearby. The second body will not
create artifact, as long as the parent has been screened adequately for
prosthetics or other metallic objects.
IV sedation offers a number of advantages over other routes of
administration. Once IV access is obtained, sedation can be rapidly
achieved. Dosage can be titrated more easily, and supplemental doses
are easily administered without disturbing the patient. Finally, and per-
haps most importantly, the effects of many drugs (e.g., opiates and ben-
zodiazepines) can be rapidly reversed. Reversal agents should be readily
available for all cases in which sedation is administered. Flumazenil
(Romazicon), a benzodiazepine receptor agonist, is administered in IV
doses of 0.01 mg/kg (up to 0.2 mg) over 15 seconds and repeated up to
a maximum of four additional times. Naloxone (Narcan), in contrast,
Barkovich_Chap01.indd 3
3
is used for reversal of respiratory depression from opioids and given
intravenously in increments of 0.005 to 0.01 mg at 2 to 3 minute inter-
vals. It is important to keep in mind that the half-life of both reversal
agents is less than most of the drugs that they are used to reverse, and
that patients should thus be monitored following the procedure in the
event that additional doses of these agents are necessary.
The most popular drug used for IV sedation is pentobarbital
(21,22), which is administered intravenously in the following manner.
Approximately 2.5 mg/kg is given over 30 to 40 seconds while closely
observing the patient. If the patient does not fall asleep within 60 sec-
onds, a second dose of 1.0 mg/kg is administered. If the patient remains
awake, a third and fourth administration of 1.0 mg/kg can be given
up to a total dose of 6 mg/kg. Repeated doses of 1 to 1.25 mg/kg are
then administered, as needed, to maintain sedation during the exam.
Small motions of the arms and legs are usually an indication that the
level of sedation is diminishing. At UCSF, our pediatric anesthesiolo-
gists have recommended that pentobarbital be used in conjunction
with morphine sulfate, as the two drugs have complimentary actions.
This regimen consists of an initial dose of 1 to 2 mg/kg pentobarbital,
followed by 0.05 mg/kg morphine, followed by another dose of pen-
tobarbital, another of morphine, etc., until the patient is adequately
sedated. Additional doses are given, as needed, if the level of sedation
appears to be diminishing.
IV sedation using propofol (Diprivan), an ultrashort-acting sed-
ative-hypnotic, has been successfully used instead of pentobarbital
in some studies (26). Propofol acts rapidly and, more importantly, is
rapidly metabolized so that the sedated children rapidly recover after
imaging. The disadvantage of this drug is the significantly higher rate
of respiratory events compared to, for example, pentobarbital, requir-
ing significantly more airway manipulations to relieve obstruction
(34). Therefore, in the United States, it has been recommended that
only anesthesiologists administer propofol (15). As a result, those wish-
ing to take advantage of the rapid induction and recovery of pediatric
patients sedated with propofol need to arrange to have pediatric seda-
tion performed by anesthesiologists or nurse anesthetists. This is cur-
rently the situation at UCSF. The reader should be aware that the use
of propofol with 100% oxygen can cause artifacts in fluid attenuation
inversion recovery (FLAIR) images, with the cerebrospinal fluid (CSF)
appearing abnormally hyperintense in the sulci and cisterns (35,36).
If CSF hyperintensity is seen in the cisterns on FLAIR sequences in a
sedated child, the agent used for sedation and the percent of supplemen-
tal oxygen must be researched before the scan is interpreted as abnormal.
Using lower concentrations of supplemental oxygen (50%–60% works
well) eliminates this artifact (37,38).
MONITORING
The American Academy of Pediatrics and the American Society of
Anesthesiologists recommend that the following parameters be moni-
tored in all sedated infants and children: heart and respiratory rates,
blood pressure, and arterial oxygen saturation (13–15). Monitoring a
patient in the CT suite is relatively simple. A patient who is undergo-
ing MRI is more difficult to monitor because of the safety issues and
because biomonitoring devices (a) may not work properly in the mag-
netic environment and (b) may cause distortion of the magnetic field,
especially within the narrow confines of the bore of the magnet. Moni-
toring must be performed using equipment composed of diamagnetic
metals (e.g., aluminum) and/or plastics; several MRI-compatible mon-
itoring devices are commercially available and are the best option for
patient safety and optimal imaging. However, in the absence of MRI-
compatible monitoring equipment, other techniques may be used.
A plastic stethoscope with very long tubing may be taped to the
5/5/2011 11:43:32 PM
 4 Pediatric Neuroimaging
patient’s chest so that heart rate can be monitored from outside the
bore of the magnet. Electrocardiogram leads, if necessary, may be run
underneath the patient and as far away as possible from the body part
being imaged. A CO2-sensitive apnea monitor connected by long, small
caliber tubing to the patient in the scanner provides visual display of
respiration and audio and visual alarms during apnea episodes with-
out affecting image quality. Disposable, pediatric size nasal cannulae
are available. Fortunately, pediatric-sized MR-compatible monitoring
equipment is now available from many manufacturers. If the practi-
tioner is performing MR examinations on a large number of sedated
children, this equipment is well worth the investment.
Although some lower field strength magnets and some shielding
configurations will allow life support equipment to be in close proxim-
ity to the patient, most high field MR suites require significant modifi-
cations to achieve intense, close-in electronic monitoring. As a general
rule, CT should be used for the identification of life-threatening con-
ditions in highly unstable patients. More and more commonly, how-
ever, unstable patients are also being imaged with MR. MR-compatible
pediatric ventilators are commercially available; in their absence,
respirator-dependent patients must be manually ventilated. When
MRI is necessary in patients with significant respiratory or hemody-
namic instability, the physician or nurse may sometimes have to crawl
into the bore of the magnet and observe the child from this extremely
uncomfortable position throughout the examination.
SPECIAL PROBLEMS IN THE IMAGING OF
PREMATURE INFANTS
Premature infants present the special problems of small size and
inability to maintain constant body temperature. In general, prema-
ture infants should be imaged initially with ultrasound in the neona-
tal intensive care unit. Cranial ultrasound is the initial examination of
choice in these patients because it is inexpensive and portable (exams
can be performed without moving infant from the neonatal intensive
care unit). Moreover, transfontanelle ultrasonography with high fre-
quency transducers is excellent for the detection of edema, blood or
infarction in deep white matter of the brain, the location of most cen-
tral nervous system pathology in the premature infant (see Chapter 4),
and for development or progression of hydrocephalus. However, MR
has an increasing role in the evaluation of the premature infant, as it
can detect abnormalities that are not visible by sonography (39,40) and
these abnormalities are of prognostic significance (41–44).
When an MR examination is necessary, special precautions must be
observed to ensure the safety of the neonate. It is best to enlist neona-
tologists or neonatal nurses to assist in the transport of the patient and
monitoring during the imaging study, as they are most experienced in
maintaining homeostasis in the neonate. This is especially the case for
preterm infants, who have traditionally been managed with mechanical
ventilation but more recently are being extubated at an earlier time point
and ventilated using nasal continuous positive airway pressure (45). At
UCSF, where MR imaging of prematurely born neonates is commonly
performed, we use a prototype MR-compatible incubator with forced air
heating and an infrared video system (46). Small windows in the walls
of the incubator allow monitoring equipment to be utilized while the
patient is in the incubator. The child is not disturbed during the entire
trip to and from the scanner (including the scan) except on the very rare
occasions when problems occur. A similar system is now commercially
available and reportedly works well, providing excellent images while
allowing safety and close monitoring for the infant (47,48). We have
found that when the baby is minimally disturbed in the incubator, we can
perform the MR scan without sedation in as many as 70% of premature
neonates; this should be attempted before sedation is administered.
Barkovich_Chap01.indd 4
If MR imaging of premature infants is uncommonly performed at an
institution and an MR-compatible incubator is not cost-effective, the
infant may be wrapped in an air bag that is warmed to body tempera-
ture or in prewarmed towels. Alternatively, chemical “blankets” contain-
ing mixtures of chemicals that maintain a temperature of 37°C when
mixed can be used to maintain body heat. A stockinet hat may be used
to prevent heat loss from the head. Earmuffs reduce noise exposure and
further reduce heat loss. Monitoring of the vital signs in these infants is
critical. The child should be disturbed as little as possible.
CONTRAST AGENTS
Iodinated Contrast Agents
CT scans in children should initially be performed without IV contrast.
If a noncontrast scan reveals an abnormality and an MR cannot be
obtained in a timely fashion, IV contrast should be given. If the noncon-
trast CT scan is normal, very little information is gained by administering
contrast unless a vascular lesion is suspected (49). Nonionic, iso-osmolar
(Visipaque) or low-osmolar (Omnipaque) contrast media should be
used because they are safer and less uncomfortable for the patient. The
exact type of iodinated contrast is not important, as long as the concen-
tration of iodine is approximately 300 mg/mL. The recommended dose
is 3 mL/kg of body weight up to a total dose of 120 mL. The child should
be scanned as soon as possible after the contrast has been administered.
Adverse reactions to iodinated contrasts are rare in the pediatric popula-
tion. They are most rare in the youngest patients (50). Acute reactions are
most common in children weighing 24 to 40 kg. Asthma and previous
reactions to contrast medium are risk factors for acute reactions (50).
Paramagnetic Contrast Agents
MRI can be performed in most cases without paramagnetic MR con-
trast agents, although the administration of gadolinium chelates may
improve the identification and evaluation of primary and metastatic
brain tumors (especially extraparenchymal tumors), infections (abscess,
empyema, cerebritis, and meningitis), neoplasms of the spinal cord and
spinal canal, and some neurocutaneous disorders (neurocutaneous
melanosis, neurofibromatosis type II, Sturge-Weber syndrome) (51,52)
and permits the assessment of cerebral perfusion using dynamic sus-
ceptibility contrast MRI (DSC-MRI) methods (53,54). Administration
of contrast to infants or children with developmental delay is unlikely
to be of any diagnostic benefit unless a space-occupying lesion is iden-
tified on a noncontrast study or a cutaneous lesion suggesting one of
the neurocutaneous disorders mentioned above is present. Similarly,
no advantage is gained by administering paramagnetic contrast agents
to children with malformations of the brain or spine, with the excep-
tion of dermal sinus tracts (see Chapter 9).
Once widely administered in the setting of impaired renal func-
tion, gadolinium chelates are now known to be associated with neph-
rogenic systemic fibrosis (NSF) in patients with renal insufficiency
(55,56). This rare but serious systemic disorder causes fibrosis of the
skin and other tissues, thereby leading to considerable morbidity or
even death. To the date this chapter was revised; there have been nine
reported cases of NSF in children after gadolinium injection (57,58).
All of these occurred in patients with low glomerular filtration rate
(GFR < 30), although there are a few case reports of NSF in adults
with slightly higher GFR between 40 and 60. A proinflammatory state
(e.g., systemic infection, limb or major tissue injury, recent surgery or
thrombosis) may increase the risk of developing this complication.
With the recognition of the relationship between gadolinium and NSF,
there is no longer a justification for administering contrast to every
sedated patient “just in case,” that is, in order to avoid resedating the
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 Chapter 1 • Techniques and Methods in Pediatric Neuroimaging
child for a repeated contrast-enhanced scan. When gadolinium is
necessary, screening for NSF risk factors is essential, and the relative
risks and benefits in patients with renal failure should be carefully con-
sidered in consultation with referring physicians.
At high and repeated doses, IV gadolinium is teratogenic in animal
studies (59). Although no similar effects have been observed in human
studies of teratogenicity, gadolinium is known to cross the placenta
and may be excreted in the amniotic fluid, where the dwell time of
the agent may exceed several days. There are no indications for which
maternal paramagnetic contrast agent administration is necessary for
fetal MRI.
From a diagnostic efficacy standpoint, no significant difference has
been demonstrated among the different paramagnetic contrasts that
are commercially available. All are given intravenously; the standard
dose is 0.1 mmol/kg (corresponding to a volume of 0.2 mL/kg for
nearly all commercial preparations). After infusion of contrast, only
T1-weighted spin-echo, three-dimensional Fourier transform (3DFT)
gradient echo, (i.e., spoiled gradient recalled [SPGR], or magnetiza-
tion prepared rapid acquisition gradient echo [MPRAGE]), FLAIR, or
dynamic contrast-enhanced MRI perfusion sequences should be
obtained; fat suppression may be useful if meningeal disease is sus-
pected (60) or if suspected pathology lies in the orbits or neck, where fat
may obscure the enhancing lesion. T2-weighted images have no value
in this situation. It is likely that higher doses of contrast (0.3 mmol/
kg) or the use of magnetization transfer pulses to suppress white mat-
ter signal allows a higher sensitivity for detection of enhancing lesions,
particularly CSF-borne metastases from brain tumors (4); however,
higher doses likely increase the incidence of NSF and, therefore, should
be used only when the benefits of added contrast, such as identification
of a condition that might alter therapy, outweigh the potential risks.
ULTRASOUND INDICATIONS AND
TECHNIQUES
Ultrasound is nearly always the first study of choice in neonates, as
it is noninvasive, inexpensive, and portable (can be performed at the
bedside) and produces no ionizing radiation. Sedation is not neces-
sary. Ultrasound technique has markedly improved in recent years
with the manufacture of high-frequency transducers, the introduction
of high-bandwidth tissue harmonic imaging techniques, and the use of
multiple acoustic windows, to the point where much information can
be gathered about most regions of the brain from a good ultrasound
study. Indeed, measurements of brain structures with ultrasound and
MRI are nearly identical (61), with the small differences (mainly cor-
tical thickness and interhemispheric fissure size) most likely due to
inability to differentiate the cortex from the overlying leptomeninges
on ultrasound. The peripheral aspects of the brain may also be difficult
to visualize with ultrasound, particularly if the fontanelles are small,
reducing the size of the acoustic window.
Meticulous technique on the part of well-trained sonographers
must be used to optimize the study. Imaging should always be per-
formed using multiple transducers functioning at variable frequencies.
Vector, curved, and linear array transducers should all be used. Resolu-
tion and depth penetration can be optimized by adjusting the frequen-
cies (between 8 and 17 MHz) and the focal zone of the ultrasound
beam. When the brain is thus analyzed via the anterior and posterior
fontanelles and the temporal, mastoid, and occipital synchondroses, all
regions of the brain (central and peripheral) can be seen well. Abnor-
malities will be shown best if images are acquired in sagittal, paras-
agittal, coronal, and axial planes. The radiologist should review both
static and real-time images; the latter allows a better appreciation of
Barkovich_Chap01.indd 5
5
subtle changes in echogenicity. Finally, major arteries and veins should
be assessed by Doppler techniques, looking for peak systolic velocities,
end diastolic velocities, and resistive indices.
CT SCANNING INDICATIONS AND
TECHNIQUES
Radiation dose is always a consideration in pediatric radiology, as
younger patients have a greater chance of developing radiation-
associated diseases (62–64) and, possibly, developmental impairment
(65). The increasing utilization of CT over the past decade among the
entire US population, including pediatric patients, and the variability
in scan parameters for CT (66) have resulted in an increased focus
on the need to consider alternative modalities first (67). When CT is
necessary, one must also consider whether dose reduction techniques
(68,69) should be used, recognizing that the diagnostic quality of the
imaging study may suffer when image contrast-to-noise is reduced by
dose reduction (70,71). Institutional approaches based on systematic
consideration of clinical indications and prior history of exposure
to ionizing radiation may help increase the consistency with which
specific parameters are used for pediatric CT scanning and to reduce
overall radiation exposure (72).
The indications for the study and scan parameters should be
weighed together. For example, when a child has sustained acute head
trauma, the concern is mainly for fractures, pneumocephalus, or a
space-occupying hematoma that may alter emergent management.
The goal in this scenario is rapid diagnosis and not necessarily high-
resolution evaluation of the brain parenchyma; therefore, low-dose CT
is adequate for most cases. If indicated, an MR can be acquired when
the patient is more stable to better evaluate the extent of any brain
injury. In contradistinction, in the acutely encephalopathic child with
new neurological signs or symptoms, our approach is to get an MR
on a timely basis. If MR is contraindicated or unavailable, we obtain
a standard-dose CT scan of good quality in order to avoid repeating
the scan or necessitating another type of scan. When arterial or venous
thrombosis is suspected, we will usually obtain a magnetic resonance
angiography (MRA) or magnetic resonance venograhy (MRV). If
questions arise due to saturation effects resulting from complex flow,
contrast-enhanced MRA or MRV will almost always answer them. Very
rarely, CT angiography (CTA) may be necessary, as it is less affected by
artifacts and can be performed rapidly and without sedation. However,
the scan should be limited to specific regions of concern, and exposure
of the eyes, thyroid, and breasts should be minimized.
When patients have conditions that will require a number of imag-
ing studies over many years, the imaging technique of choice requires
considerable thought. For example, patients with hydrocephalus will
often have multiple, possibly dozens, of scans during childhood and
the accumulated radiation dose can become significant (73). If the pur-
pose of the scan is only to check ventricular size after placement or
revision of a ventricular catheter in a child with known hydrocephalus,
a high-dose technique is not necessary; instead, one should consider a
CT technique using lower kilovoltage or lower amperage. By reducing
CT dose from 220 to 80 mA, one study showed a reduction in radia-
tion dose of 63% while maintaining diagnostically acceptable images
(74); as noted above, however, the reduction of signal-to-noise that
accompanies the dose reduction severely limits assessment of brain
parenchyma. Alternatively, a fast MR sequence, such as HASTE/ssFSE,
or a PROPELLER sequence, may be used, thereby eliminating ioniz-
ing radiation altogether. In the age of magnetically adjustable pressure
valves, however, the use of MR requires a second visit to the neurosur-
geon after the scan to readjust the valve; thus, the decision is complex.
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 6 Pediatric Neuroimaging
If, after careful consideration, CT is chosen as the imaging
technique of choice, the study should be performed with the lowest
possible dose that allows a diagnostic quality scan. Some recent reviews
of methods for calculating and reducing dose for patients of all ages
elegantly describe how to accomplish this (68,69). These methods
should be familiar to all physicians involved in imaging. The techniques
for scanning older children with CT are identical to those for scanning
adults. Axial images are obtained using ≤5 mm slice thickness; an eye
shield may be used and the plane of section should be chosen to mini-
mize exposure to the eyes. As CT scanning has become more rapid,
little time penalty is paid for relatively thin slice profiles and significant
additional information may be acquired, especially in the small heads
of infants and young children. However, a price is paid in that the sig-
nal-to-noise diminishes with decreasing slice thickness, and this must
be compensated with increased kilovoltage or milliamperes per second,
which increases dose. To mitigate that issue, the thinner sections can
be reformatted as thicker (4–5 mm) sections, giving good signal-to-
noise and the ability to look at the thinner sections (e.g., when look-
ing for fractures) if desired (68). We typically acquire sequential scans
rather than using spiral acquisition for head studies, as signal-to-noise
is improved, artifacts are avoided, and there is little time penalty (75).
If coronal images are needed, strong consideration should be given to
reformatting axial images; this saves the added radiation of an extra
sequence. In such cases, spiral acquisition may be desirable. A low pitch
(<1) should be used if higher resolution is needed; reducing milliam-
pere settings can ameliorate any increase in radiation dose. If spiral
CT is not available, the higher resolution may be obtained via the use
of direct coronal images; the unsedated patient may be examined in
the prone or supine positions, but coronal scans of sedated patients
are best performed in the supine position to avoid compromising the
airway. Ideally, the plane of scanning should be perpendicular to the
planum sphenoidale.
Another special situation in pediatric CT imaging in which tech-
niques can be modified is in the scanning of patients with craniofacial
anomalies or craniosynostosis. These patients should be scanned using
≤2.5 mm slice thickness. Thicker slices allow too much averaging and
obscure detail. Reconstruction algorithms that give high-detail bone
resolution should be used to evaluate the cranium; they give better
images with a lower radiation dose. If no MR scan will be obtained,
discuss with the referring surgeon the use of a soft tissue algorithm to
assess the underlying brain for abnormality; the unnecessary data can
then be discarded during the process of reconstructing 3D reforma-
tions. Software that allows 3D surface- and volume-rendered recon-
structions of the bones of the face and skull is available from most
manufacturers; this has significant value in assessing suture patency
and in planning reconstructive surgery (see Chapter 5).
Because the newborn brain has a very high water content, proper
windowing of the CT scan is essential for optimal analysis of brain
abnormalities. In general, CT images of the newborn brain should be
reviewed and filmed with a window of 60 and level of 20. Use of normal
adult brain windows will result in pathology being missed.
ROUTINE MR IMAGING SEQUENCES
Brain
A sagittal, T1-weighted sequence should be performed on all patients.
This sequence allows critical assessment of the midline structures that
are frequently abnormal in congenital brain malformations. Sagittal
images are optimal for evaluating the corpus callosum, pituitary gland,
hypothalamus, and cerebellar vermis, common locations of pediatric
brain tumors. They are also excellent for assessing the lateral convexities
Barkovich_Chap01.indd 6
of the cerebral hemispheres, especially around the sylvian fissures.
When acquired as the first sequences in the examination, this sequence
can also be used as a localizer for additional axial or coronal sequences.
Using a standard quadrature head coil at 1.5 T, suitable parameters
for T1-weighted imaging are a repetition time (TR) of 500 to 600
milliseconds, echo time (TE) as short as possible (20 milliseconds or
less), 3 to 4 mm slice thickness (1 mm gap), acquisition matrix 192 × 256,
and one signal average. Using these parameters, it is possible to cover
most of the brain in the sagittal plane. If the option of 192 acquisitions
in the phase encoding direction is not available, 128 phase encodings
(at the expense of decreased spatial resolution) or 256 phase encodings
(at the expense of increased imaging time and diminished signal-to-
noise ratio) can be used. Using a short TR (<500 milliseconds) will save
imaging time while still allowing assessment of the midline structures,
but a price is paid in that signal-to-noise decreases and multislicing may
not allow the lateral portions of the brain to be covered unless fractional
k-space acquisitions or a rectangular field of view is also employed. If a
phased-array head coil and parallel imaging are available, particularly
at 3 T, a 3D radiofrequency or gradient-spoiled gradient-echo volu-
metric sequence (SPGR, MPRAGE, 3D-FLASH, CE-FFE-T1, T1-FAST)
should be obtained in the sagittal plane (employing the largest, cran-
iocaudal dimension as the readout axis for quickest acquisition) and
high-quality reformations in the coronal and axial (and, if necessary,
true sagittal) planes can be easily obtained. This has become our most
useful sequence for the diagnosis of structural abnormalities. For this
sequence, we use TR/TE = 35 milliseconds/minimum, flip angle 35°,
22 × 22 cm FOV, 1 mm partition size, and 256 × 192 acquisition matrix
with no signal averaging. If imaging at 3 T is not available or thin volu-
metric images are not desired, FLAIR T1 acquisition using TR/TE =
600/20 milliseconds and inversion time (TI) of 750 milliseconds also
gives excellent T1-weighted images.
After the sagittal T1 images have been obtained, axial T2-weighted
images should be acquired in all patients. For patients older than
24 months, only these T2-weighted images are necessary for the most
basic imaging protocol. If a volumetric sequence has not been acquired
and reformatted axially in infants with developmental delay or sei-
zures, we also obtain an axial T1-weighted sequence (inversion recov-
ery, spin echo). For patients less than 18 months of age, both T1- and
T2-weighted images are necessary for accurate interpretation. Brain
maturation is evaluated best by T1-weighted images from birth to
6 months of age. However, from 6 to 8 months of age until approxi-
mately 24 months of age (at which time the brain is essentially mature
by MR standards), T2-weighted images are more useful for assessing
myelination and brain maturity. During the process of white matter
maturation, the cerebral cortex and subcortical white matter of the
brain become isointense for a variable period of time on MR images;
this isointensity obscures structural detail (see Chapter 2). Therefore,
during the first 8 months of life (while the white matter is matur-
ing on T1-weighted images), T2-weighted images are necessary to
see the details of the gyral and sulcal patterns. Similarly, as the white
matter matures on T2-weighted images between 8 and 24 months
of age, T1-weighted images are essential for evaluation of structural
abnormalities.
The optimal imaging parameters may vary from one scanner to
another and at different field strengths. 3DFT spoiled gradient-echo
techniques that use radiofrequency or gradient pulses to “spoil” residual
transverse magnetization have the ability to acquire very thin (1 mm or
less) contiguous images through the brain in a relatively short imaging
time. These techniques are particularly useful in looking for small, subtle
cortical malformations (see Chapter 5) and for subtle areas of T1 short-
ening (injured brain) in neonates and young infants (see Chapter 4).
As discussed earlier, they also have the important advantage that they
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 Chapter 1 • Techniques and Methods in Pediatric Neuroimaging
can be reformatted in any plane (sagittal, axial, coronal, or any obliq-
uity), allowing acquisition of only one T1-weighted sequence. We
routinely obtain volumetric gradient-echo sequences in all neonates,
all patients with developmental delay, and patients being imaged for
epilepsy. For brain tumors, neuronavigation techniques are used at
our institution, and these require volumetric techniques as well, for
T1-weighted images. As visualization of enhancement is important
in these patients, we use slightly different parameters for postgado-
linium imaging, with TR/TE = 34 milliseconds/minimum, flip angle
70°, and partition size of 3 mm. If volumetric images cannot or are
not acquired, T1 FLAIR or spin-echo sequences can be used. Although
T1 FLAIR gives better T1 information than conventional spin-echo
sequences, an SE 600/minimum sequence (similar to that outlined for
the sagittal images) can be routinely used for T1-weighted images on
1.5 T scanners. Spin echo is the sequence of choice when paramagnetic
contrast is to be administered. Use of this imaging sequence produces
excellent images; moreover, the imaging time is shorter than with most
inversion recovery sequences, resulting in less motion artifact. Spin-
echo T1 images do not work as well at 3 T due to the prolongation
of T1 relaxation times, however. Therefore, T1 FLAIR (usually using
short TEs in the range of 20 milliseconds and TIs of 750 milliseconds)
sequences are used; these give excellent T1 weighting but do not show
contrast enhancement as well as spin-echo images or spoiled gradient-
echo images.
For T2-weighted sequences, dual spin-echo sequences with a 4 to
5 mm slice thickness (2–2.5 mm gap), TR of 2500 to 3000 milliseconds,
TE of 30 to 60 milliseconds (first echo) and 70 to 120 milliseconds (sec-
ond echo), 192 × 256 acquisition matrix, and 0.75 to 1 excitation are
recommended. In infants less than 12 months old, heavily T2-weighted
sequences are highly recommended, as the water content of the brain
in young children is considerably higher than in older children and
adults (76,77). We routinely use TR = 3000 milliseconds and TE = 60,
120 milliseconds (first and second echoes) for this patient group.
Others use a dual-echo short tau inversion recovery (STIR) sequence
with TR = 5400 milliseconds, TI = 130 milliseconds, and TE = 30,
128 milliseconds (52). Although RARE (also called fast spin echo [FSE]
or turbo spin echo [TSE]) images are used by some groups for infants
and children and seem to show myelination with fair accuracy (78), we
and others (52) are not completely satisfied with the contrast between
gray and white matter of commercially available RARE sequences, espe-
cially with long echo train lengths. Contrast between gray and white
matter, and between normal and pathologic tissues, is less in infants
than in older children and adults; therefore, imaging parameters and
sequences must be adjusted to maximize contrast. Moreover, although
missing a single small white matter lesion in an adult is relatively
unimportant, the same type of abnormality may be the only clue to the
correct diagnosis in a child (79). Therefore, we continue to use conven-
tional spin-echo technique in infants with nonspecific developmental
delay. However, we do use RARE sequences to supplement our standard
images; they are ideal for obtaining T2-weighted images in a second
plane for infants with focal neurologic signs or symptoms and for eval-
uation of congenital anomalies or tumors (80). In addition, children
who are imaged without sedation can benefit from the shorter acquisi-
tion time of RARE sequences. Typical parameters include TR = 2500
to 3000 milliseconds (up to 4000 milliseconds in infants <12 months
old), effective TE = 17 to 100 milliseconds, and echo train length = 8.
We also use 3D RARE sequences to assess for subtle cortical anomalies
in infants at times when subcortical white matter is isointense to cortex
on our volumetric T1-weighted images (usually between ages 3 and 8
months). For this technique, we use TR = 4000 milliseconds, TE = 85
milliseconds, echo train length = 16, partition size = 1.5 mm, and a 192
× 256 acquisition matrix.
Barkovich_Chap01.indd 7
7
Low-field scanners (≤1.0 T) do not produce adequately T1-weighted
images with conventional spin-echo technique. The reasons for the
poorer images are twofold. First, T1 relaxation times increase with
increasing static magnetic field strength; therefore, images obtained
with identical parameters will be more T1-weighted at higher field
strengths than at lower field strengths. Second, lower field strength
scanners, in general, are unable to achieve TEs as short as high-field
scanners. The combination results in unsatisfactory T1-weighted spin-
echo images in infants scanned on most midfield and low-field scan-
ners. Inversion recovery or 3DFT GE images should be used instead.
The parameters for these sequences are similar to those used at 1.5 T,
although the flip angle and TR in particular may require fine-tuning in
order to maximize gray-white contrast.
Some authors have advocated the use of T2 FLAIR sequences to
look for regions of abnormal T2 prolongation. In our experience and
that of others (81), FLAIR images are not sensitive to cerebral pathol-
ogy in neonates or infants but are useful in older children in whom
myelination is complete or nearly complete. We do not use FLAIR as a
primary sequence in infants, but we do sometimes use it as a second-
ary sequence for lesion characterization. In children beyond the age of
2 years, when myelination is nearly complete, FLAIR becomes a part of
our routine protocol because of its high sensitivity for subtle supraten-
torial lesions, particularly in the cerebral cortex and periventricular
white matter. Sargent and Poskitt found that FLAIR is complementary
to T2-weighted infants and children (82). They found fast spin-echo
FLAIR to have better CSF nulling and better gray matter–white matter
differentiation than echo-planar FLAIR. Our standard parameters for
2D FLAIR imaging are TR/TE = 10,000/140 milliseconds, TI = 2200
milliseconds, with 3 mm contiguous slices and 192 phase encoding
steps. More recently, we have started to use single slab 3D FSE FLAIR
sequences (CUBE, SPACE, VISTA, depending on the manufacturer),
which combine parallel imaging and variable flip angle excitation to
convert slowly decaying longitudinal magnetization back to transverse
magnetization. These have the benefit of very high spatial resolution
of 1 to 2 mm and relatively short imaging times of 7 to 8 minutes,
and like volumetric gradient-echo T1 images can be reformatted in
any plane. However, longer imaging times render these images more
susceptible to artifacts from patient motion, and in our experience the
tissue contrast of these sequences does not always compare favorably
to 2D FLAIR sequences.
A significant drawback of T2-weighted and FLAIR sequences is
longer imaging times when compared to T1-weighted imaging. Some
extremely fast MR techniques can be used in selected cases without seda-
tion. These include the previously discussed single-shot RARE (called
ssFSE or HASTE by manufacturers) (5,6) and periodically rotated
overlapping parallel lines with enhanced reconstruction (called PRO-
PELLER or PROP) (7,8). These techniques are currently useful only for
gross assessments such as ventricular size in patients with hydrocepha-
lus or follow-up of extraparenchymal fluid collections. PROPELLER
has the advantage of better contrast to noise, more flexible contrast,
and the ability to compensate for motion by retrospectively correcting
the acquisitions (called “blades”), but has the disadvantage of slightly
longer acquisition times (7); in our experience, tissue contrast is not as
good in PROPELLER sequences as in conventional spin-echo or STIR
sequences. For half-Fourier single-shot RARE images, we use TR/TE =
20,000/90 milliseconds, 0.5 excitations, 24 cm field of view, 256 × 256
acquisition matrix, and 4 mm slice thickness. For the PROPELLER
FSE sequence, we use TR/TE = 4000/83 milliseconds, 2 excitations,
24 cm field of view, 224 × 224 acquisition matrix, and 4 to 5 mm slice
thickness.
After sagittal and axial images have been obtained, coronal images
through the brain may be helpful in certain patients for further
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 8 Pediatric Neuroimaging
elucidation of pathology. Coronal images are particularly helpful for
imaging of the cerebellum, the temporal lobes, and the skull base. They
are also very valuable in the imaging of tumors, where the relationship
of the mass to the surrounding brain and dura is of great importance
to the neurosurgeon. Our primary coronal sequence is the reformat-
ted T1-weighted 3DFT volumetric spoiled gradient-echo sequence
described above. For seizure and tumor protocols, and between the
ages of 3 and 8 months when gray-white differentiation is especially
difficult on T1-weighted images, 3D RARE sequences are added to
obtain supplementary T2-weighted coronal images.
T2*-weighted gradient-echo images and susceptibility weighted
images (SWIs) are sometimes useful in pediatric imaging, particularly
when looking for areas of old hemorrhage, as in suspected trauma or
vascular malformations (83–85). Beyond infancy, these images may
sometimes also provide the only clue on MRI that calcification is pres-
ent, for example, within a brain tumor or as the result of congenital
infection. Whereas short TR, short TE (<15 milliseconds) GE acqui-
sition results in primarily T1 weighting, short-TR, long TE (25–100
milliseconds) GE acquisition results in T2* weighting. The T2*-
weighted GE images are particularly useful in the evaluation for hem-
orrhage because they are quite sensitive to the magnetic susceptibility
changes and local heterogeneity of magnetic fields caused by the blood
breakdown products hemosiderin and ferritin. Images show marked
signal loss in the regions of the blood products (see Chapters 4 and
12). SWI, which uses the magnitude and phase images from volumet-
ric long-TE GE acquisition, shows even more dramatic loss of signal
intensity in regions with calcium or blood products than do conven-
tional magnitude-only T2*-weighted GE images (86); however, paren-
chymal contrast is reduced, and acquisition time is much longer, up to
8 minutes. Recommended technique is TR/TE = 57/40 milliseconds,
flip angle 20°, Nz = 32 slices, slice thickness = 2 mm, and matrix size
of 256 × 512. New versions that use echo-planar acquisition are being
developed that should shorten the acquisition time (83).
We routinely obtain diffusion-weighted images in nearly every
patient that we scan. The technique is a single shot using TR/TE =
8000 milliseconds/minimum, BW = 166.7 kHz, FOV = 36 cm × 27 cm,
slice thickness = 3 to 5 mm. We use b = 600 s/mm2 in prematurely
born babies scanned before term, b = 700 s/mm2 in neonates born at
term, and b = 1000 s/mm2 in infants and children older than 3 months
adjusted age. Because these images are acquired rapidly, there is very
little time penalty incurred by measuring diffusion in six or more direc-
tions to improve the numerical accuracy of the average diffusivity (Dav
or apparent diffusion coefficient [ADC]) and to allow calculation of
diffusion tensors, which consequently permit analysis of white matter
pathways (diffusion tensor imaging, see below) (87,88).
Spine
MR is the study of choice for imaging the pediatric spine in the setting
of neurological dysfunction. CT is a useful exam in the setting of acute
trauma without neurological deficits and can be useful for evaluating
vertebral body or craniocervical junction anomalies. CT myelography
may be necessary when the spine has been instrumented for scoliosis,
as the resulting metallic artifact sometimes renders MR useless (the
use of titanium instrumentation will markedly reduce the susceptibil-
ity effects, but it is not yet widely used). Optimally, multidetector spiral
scanning should be performed to increase speed while still allowing
adequate coverage and multiplanar reformations (75). Best results are
obtained by acquiring the study with relatively low (<1) pitch values,
narrow (0.75 mm) collimation, and reconstructing 3-mm thick slices
(75). However, when neurological deficits are present, CT is only use-
ful after the injection of intrathecal contrast and is, therefore, more
Barkovich_Chap01.indd 8
invasive and more difficult. A normal ultrasound is sufficient to exclude
most developmental spine pathology in neonates and young infants,
but becomes less useful in older infants and children as the posterior
elements of the spinal column ossify (see Chapter 9). Moreover, it is
still not clear that sonography can consistently detect a fatty filum if
the conus medullaris is at a normal level (89). Moreover, even if sonog-
raphy detects a developmental spine anomaly, additional pathology is
picked up by MR in 20% of cases (89).
In MR imaging of the spine, different techniques are used depend-
ing upon the clinical situation. When scanning a child with suspected
or confirmed spinal dysraphism, sagittal T1-weighted images (TR/TE =
600 ms/min) should be obtained initially using 3 mm slice thickness.
Axial images should then be obtained through any areas of abnormal-
ity or suspected abnormality. We acquire both T1-weighted and RARE
T2-weighted axial images (note, however, that use of RARE sequences
at 3 T in infants may result in high specific absorption rates, which
slow acquisition). The T1-weighted images show the spinal cord with-
out the associated artifacts from circulating CSF that are so common
on T2-weighted images of the spine and will nicely show lipomas; the
T2-weighted RARE images nicely show the cauda equina, the filum ter-
minale, adhesions (such as meningocele manqué, see Chapter 9), and
any bony or fibrous spurs. Another approach to the problem of spine
imaging is to perform 3D spoiled GE or RARE volumetric imaging
(90). Weinberger et al. suggested using a TR of 500 milliseconds, TEeff
of 21 milliseconds, ETL= 8, echo spacing = 21 milliseconds, 256 × 256
in plane matrix, 20 to 32 cm FOV, 1.0 mm sagittal partition thickness,
receive bandwidth of 16 kHz, and one signal average. They typically
obtained 32 partitions in each slab (minus 4 peripheral slices). One
potential problem with 3D acquisition in the spine, however, is the
addition of a second phase-encoding direction that can result in signal
being mismapped onto the spine from moving protons in the chest or
abdomen.
Patients with scoliosis present a challenge for any imaging modal-
ity. Initially, a coronal T1-or T2-weighted image should be obtained
to assess vertebral anomalies and look for a split cord malformation
(Chapter 9). Oblique sagittal (parallel to a straight segment of spine)
and oblique axial (perpendicular to a straight segment of spine, see
Chapter 9) planes can then be defined to give optimal information. If
a split spinal cord is seen, thin-section axial T2- or T2*-weighted GE
images should be obtained through the entirety of the split to look for
a fibrocartilagenous or calcified spur. Alternatively, a 3D spoiled GE or
RARE sequence, as in the prior paragraph, can be obtained; each seg-
ment of the spine can be displayed quite well after postprocessing.
Patients who present with myelopathy but no suspicion of dysra-
phism should have sagittal 3-mm RARE T2-weighted images (TR =
3500 milliseconds, TEeff = 102 milliseconds) through the entire spinal
cord, in addition to the T1-weighted sagittal and axial images. Axial GE
or RARE (TSE, FSE) images can then localize any abnormal region of
T2 prolongation within the cord. We prefer GE (TR = 600 milliseconds,
TE = 25 milliseconds) images in the cervical and upper- to midthoracic
spine, where rapid CSF flow causes considerable artifact on axial FSE
images. Axial RARE images are usually better in the low thoracic and
lumbar spine. In either case, the use of flow-compensating readout gra-
dients can help reduce these artifacts. T1-weighted images after infusion
of IV paramagnetic contrast are often very helpful for evaluating intrin-
sic spinal cord pathology, particularly when neoplasm is suspected.
Standard 2D spin-echo images are most often used for the postcontrast
scans; however, when patient motion is not a problem, 3DFT gradient-
echo postcontrast images with multiplanar reformations may be slightly
more sensitive to small foci of CSF tumor spread (6).
To look at bone injury (pars interarticularis stress reaction or
edema from a fracture) or tumor involving the vertebrae, sagittal
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 Chapter 1 • Techniques and Methods in Pediatric Neuroimaging
3 mm STIR sequences are very useful. In our experience, they are more
sensitive than fat-suppressed RARE or contrast-enhanced T1 images
and well worth the slightly increased imaging time. We use TR = 5000
milliseconds, TI = 150 milliseconds, and TE = 58 milliseconds with
ETL = 8 and 2 excitations.
The portions of the spine that should be imaged depend not only
on the clinical indication for the study but also on coil geometry and
total imaging time. At many institutions, a dedicated spine coil can
be useful for cases in which the entire spinal axis requires imaging
(e.g., drop metastases or scoliosis) and eliminates the need to switch
coils in the middle of the examination. In premature or young infants,
an adult head coil may provide sufficient coverage of the entire spine.
To reduce the total time necessary for the examination and the associ-
ated motion artifacts that come with long imaging times, automated
techniques for breath-hold, high-resolution gradient-echo survey of
the entire pediatric spine have been proposed (91).
Fetal MRI
MRI is rapidly becoming the study of choice when fetal sonography
shows abnormalities, both in order to verify the presence of a suspected
abnormality and to specify the severity and extent of the abnormality
(92–96). With adequate attention to detail, excellent images of the fetal
brain and spine can be obtained. The study begins before the gravid
mother arrives at the MR scanner, as it is important that she does not
take any oral nourishment for 4 hours prior to the MR examination.
The lack of food reduces the amount of intestinal peristalsis, which
reduces the amount of misregistration artifact that is registered over
the fetus. It also seems to reduce the amount of fetal motion. Upon
arriving at the MR site, the mother is asked to lie supine in the scan-
ner and an 8-channel phased-array torso coil is applied for optimal
imaging. If the mother cannot tolerate the supine position (because of
back pain or compression of the inferior vena cava, not usually a prob-
lem until after 30 weeks), the exam can be performed with her in the
left lateral decubitus position (lying on her left side). In our practice,
excellent studies are typically produced without using maternal or fetal
(via the umbilical cord) sedation (93).
Once the mother is positioned comfortably, a series of ultrafast
T2-weighted ssFSE (HASTE) images are acquired, complemented
by echo-planar gradient-echo images and, whenever possible, by
T1-weighted images. The ultrafast T2-weighted images are the most
important diagnostically, as each image can be acquired in less than
1 second, reducing the likelihood of fetal motion during image acqui-
sition. An initial localizer is obtained in three orthogonal planes
with respect to the mother, using 6- to 8-mm thick ssFSE (HASTE)
T2-weighted slices with 1 to 2 mm gap and a large (40 cm) field of view.
The localizer is useful for visualizing the position of the fetus, deter-
mining the location of the placenta within the uterus, and determining
which side of the brain is located on the side of the heart (left) and
which is on the side of the liver (right). It is usually then easy to figure
out which side of the brain is located posteriorly (closer to the maternal
spine) and which side is located anteriorly. Importantly, the localizer
is also used to ensure that maximal signal is obtained from the area
of interest. In certain cases, such as imaging of twins and fetuses with
myelomeningoceles, the coil may need to be repositioned in the middle
of the examination (e.g. when switching from one twin to the other, or
from the fetal brain to the spine). The initial diagnostic ssFSE (HASTE)
T2-weighted images of the fetal brain are prescribed from this local-
izer. Each subsequent image set is prescribed from the preceding set by
determining a plane orthogonal to that set. In this manner, axial, sagit-
tal, and coronal image sets of the fetal brain are obtained. We routinely
obtain at least two image sets of good quality in each plane.
Barkovich_Chap01.indd 9
9
When evaluating the fetal brain, the optimal slice thickness is
3 mm with no interslice gap; this slice thickness allows adequate signal-
to-noise without excessive volume averaging in the small fetal brain.
For the fetal spine, we have found a slice thickness of 2 mm to be ideal
for identifying small structures such as the spinal cord, bony spurs, and
myelomeningoceles. Images are acquired during free maternal breath-
ing, although we have found respiratory triggering useful in decreasing
motion. Field of view is typically small, although should be adjusted for
increased fetal and/or maternal size, and when aliasing artifacts obscure
important structures. Our routine imaging parameters are TEeff = 90
milliseconds, TR = 4000 milliseconds, bandwidth = 25 kHz, matrix =
192 × 160, field of view = 24 cm, and number of excitations = 0.5.
Images are acquired in an interleaved manner in order to reduce the
possibility of signal loss resulting from crosstalk between slices. On
some scanners, a pause of 1 second between acquisitions of images may
be needed to allow sequential scanning in an interleaved manner.
Some manufacturers have developed interactive scanning pro-
grams that can be applied to fetal MRI. These programs allow adjust-
ment of scanning parameters, such as slice angle and orientation, in
“real time” (95,97). Such programs allow the technologist to adjust the
angle of a prescribed image without having to exit and reprogram a
new sequence; they are invaluable when the fetus is active (moving)
during the scan. This ability is particularly critical when trying to
acquire high-quality images of midline structures. Moreover, in cases
of aliasing artifact, the field of view can be increased and/or the phase
encoding and frequency encoding directions can be changed during
image acquisition. Overall, image quality is improved, and scan time is
reduced when this program is utilized.
Whenever possible, T1-weighed images are acquired to supplement
the ssFSE (HASTE) T2-weighted images, but these are generally of lim-
ited value, especially in fetuses less than 27 gestational weeks, as the
signal-to-noise is invariably poor. Fast, multiplanar, spoiled gradient-
echo techniques are primarily used, mainly to detect hemorrhage or
calcification; both are seen as hyperintense compared to the fetal brain.
T1-weighted images cannot be programmed as single-shot images in a
rapid manner and require longer acquisition times (18 seconds). Scan-
ning parameters include TR = 120 milliseconds, TE = minimum, flip
angle = 70°, field of view = 24 cm, matrix = 256 × 160, number of exci-
tations = 1, slice thickness = 5 mm, interslice gap = 1 mm, and bandwidth
= 31.25 kHz, which yields eight slices in the axial plane. If possible,
the images are acquired while the mother holds her breath. However,
there is usually some maternal motion during the breath-holding,
and, as a result, this sequence is more susceptible to both maternal
(from the breath-hold) and fetal (from the duration of the sequence)
motions. Other techniques for obtaining T1-weighted images have
been explored, but all are subject to the limitations resulting from the
long T1 relaxation time of the fetal brain (poor tissue contrast and
either long acquisition time or low signal-to-noise). Gradient-echo
echo-planar T2*-weighted images are routinely acquired and can be
useful in detecting hemorrhage.
Advanced MR techniques such as diffusion-weighted imaging,
spectroscopy, and parallel imaging are being successfully applied
to fetal MRI, although their development is still in the early stages
(98,99). Diffusion-weighted imaging provides quantitative informa-
tion about water motion and tissue microstructure. Single-shot echo-
planar diffusion-weighted images are acquired in 18 seconds during
a single maternal breath hold (98,99). Scanning parameters include
TR = 4500 milliseconds, TE = minimum, field of view = 32 cm, matrix =
128 × 128, slice thickness = 5 mm, interslice gap = 2 mm, and band-
width = 167 kHz. Gradients are applied in three orthogonal direc-
tions using a b-value of 0 and 600 s/mm2. Because of the relatively
long scan time, images are susceptible to both fetal and maternal
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 10 Pediatric Neuroimaging
motion. With increasing gestational age and engagement of fetal head
in the pelvis, the amount of motion is decreased and the quality of the
studies improves. Diffusion-tensor imaging (DTI) is currently only
applicable when the fetal head is already engaged in the pelvis (100),
because otherwise too much fetal motion occurs during the acquisi-
tion time. Similar troubles, in addition to the large size of the voxel
relative to the fetal brain size, plague fetal MR spectroscopy. There-
fore, proton MRS is limited to application during the latter half of
the third trimester, when the fetal head is relatively large and engaged
in the pelvis. Hopefully, the advent of faster sequences and improved
coil design will allow these techniques to be more widely used in the
near future.
SPECIAL MR TECHNIQUES
MR and CT Angiography
For studies of the intracranial vasculature, 3D Fourier transform time
of flight (3D TOF) studies using multiple overlapping time of flight
acquisitions (MOTSA) are the most useful (101,102). For 3D TOF
studies, a GE 45/min (TR/TE) sequence is performed with flip angle
20°, partition thickness of 0.9 mm, 128 partitions, and 1 acquisition. A
superior saturation band is applied to eliminate, as much as possible,
contamination of the images by flowing blood from venous struc-
tures. Flow compensation gradients are applied in the read and phase-
encoding directions. After data acquisition is completed and each of
the partitions is reconstructed, separate MR angiograms of each major
intracranial arterial circulation (right internal carotid, left internal
carotid, basilar) are created by means of drawing a region of inter-
est around each and creating maximum-intensity projections (MIPs)
using the technique described by Laub and Kaiser (103). Creating a
separate MIP for each circulation is critical in order to avoid overlap
of vessels and to reduce artifacts. The reader should remember that the
process of creating the MIP generates a number of artifacts (104,105) and
that, therefore, the individual partition images should always be scruti-
nized in every MRA or MRV. Sometimes, multiplanar reformations of
the partition images are more useful than the MIP images for assessing
vascular pathology.
For studies of the cervical carotid and vertebral arteries, 2D Fou-
rier transform time of flight (2D TOF) images are fast and efficient
(101,106,107) and are usually quite adequate in children because the
vessels are typically straight and stenoses (which make flow more com-
plex and give rise to artifacts with 2D TOF) are uncommon. Contrast-
enhanced MRA or 3D TOF MOTSA sequences can be used in the neck
for higher resolution in specific areas. 2D TOF is also useful in place of
3D TOF for studies of intracranial vessels when complicated by exces-
sive patient motion, although it is primarily used for imaging of vessels
in the neck and for venography. We perform 2D TOF studies using a GE
4.5/min sequence. Fifty-five consecutive axial MR images are obtained
with a section thickness of 1.5 mm, flip angle 60°, and bipolar gradients
for flow compensation. Walking superior saturation pulses are applied
cephalad to the axial images to eliminate signal intensity from venous
blood returning via the jugular veins. MIP images of the right carotid/
right vertebral circulation and separate MIP images of the left carotid
vertebral circulation are reconstructed in multiple planes.
In adults, 3D TOF MRA with bolus injection of contrast allows
production of high-resolution MRA images with minimization of
saturation and dephasing artifacts (108). Although there have now
been a number of studies describing high-quality depiction of the
great vessels in the chest and abdomen using this technique in chil-
dren, we are not aware of any work on its utility for imaging the pedi-
atric cervical vessels. It is expected that the results would be similar to
Barkovich_Chap01.indd 10
those in adults, however, and gadolinium-enhanced MRA may have
added value in children with underlying vasculopathy or in whom the
normal neck circulation is distorted by tumors or infections. Difficult
peripheral venous access and differences in hemodynamic parameters
require that bolus injection protocols be modified for safe application
to pediatric studies, however. Newer techniques for balancing spatial
and temporal resolution, such as time-resolved imaging of contrast
kinetics (TRICKS), may prove useful for arterial-venous separation
(109).
Phase-contrast (PC) techniques are useful for imaging slow flow
within vessels, analyzing flow direction, quantifying flow parameters,
and reducing saturation effects from slow flow (101,110). In pediat-
ric neuroimaging, multislice 2D PC is most often used to determine
flow direction, as it is significantly quicker than 3D PC imaging. 2D PC
studies are performed using a GE 27/4.5 sequence, a 192 × 256 acquisi-
tion matrix, slice thickness 5 mm, flip angle 20°, and 15 acquisitions.
The image is obtained using a presaturation band technique. Encod-
ing velocity (Venc), the velocity at which there is a phase shift of 180°
between acquisitions, is typically set at 80 cm/s for arterial studies and
at 30 cm/s for venous studies.
Studies of the dural venous sinuses are best achieved using the
TRICKS technique described above. 2D TOF venograms (111) can still
be used but are less reliable, as complex or in-plane flow can give equiv-
ocal results. 2D TOF studies are acquired in the coronal plane to avoid
saturation effects in the transverse sinuses secondary to in-plane flow.
Contiguous 1.5-mm GE 45/4.9 images are obtained using a flip angle
of 60°, 256 × 160 matrix, and 1 excitation. Note that shorter TEs result
in less in-plane saturation of protons and, therefore, in fewer appar-
ent “flow gaps” within the sinuses (112). Walking saturation pulses are
applied posteriorly for coronal acquisition, and an inferior saturation
slab is applied to saturate arterial inflow. As with arteriograms, regions
of complex flow and dephasing can sometimes be better assessed with
postcontrast studies, although it is important to recognize that many
smaller veins will be visualized after contrast administration and that
these smaller veins may obscure some details. Recently, we have begun
to use contrast-enhanced 3D venography using a 3D gradient-echo
technique (TR = 1.74 milliseconds, TE = 0.64 milliseconds, flip angle
15°, 128 × 128 matrix, 25 cm FOV, 64 sagittal 2-mm sections with zero
filling of k-space in the partition direction) (113,114) as our routine.
The first dataset is discarded, and magnitude subtraction of the sub-
sequent volumes from the second dataset is performed to remove
background signal intensity. This technique requires a rapid injection
of paramagnetic contrast and timing of the image acquisition to the
entrance of the contrast into the superior sagittal sinus. The advantages
of the contrast-enhanced, dynamic 3D data set are that no artifactual
flow gaps are present and that specific portions of the venous sinuses
can be carefully analyzed by reconstructing 1 to 2 cm slabs of data. For
example, midline vessels can be carefully evaluated by reconstructing
a sagittal slab of the central 2 cm and the transverse sinuses by recon-
structing axial slabs.
CTA has become a useful tool with the advent of helical, multidetec-
tor CT scanners (75). However, it should be reserved for cases in which
Doppler sonography and MRA are not diagnostic, as the radiation dose
is high. A high-quality CTA requires contrast administration in a tight
bolus of iodinated contrast through a large gauge IV catheter (usu-
ally with a power injector) and properly timed acquisition of images
through the area of interest. In order to acquire images while contrast
is in the arteries but not yet in the veins, a test bolus is administered and
images are obtained through a single level until the bolus arrives. The
time required for this bolus to arrive determines when image acqui-
sition begins after the bolus injection is begun. Alternatively, when
obtained as a part of the examination, perfusion CT can be used to
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 Chapter 1 • Techniques and Methods in Pediatric Neuroimaging
estimate the optimal timing of the bolus. Helical acquisition CTA on
our scanners consists of 16 sections at 0.75 mm collimation, 0.5 sec-
ond rotation time, and pitch of 1.5 using a small (typically 10–15 cm,
depending upon patient size) field of view (75). 2D and 3D reforma-
tions can then be constructed to optimally show the blood vessels of
interest. Both CTA and MRA are accurate and easy; both show the ves-
sels of the neck, the dural venous sinuses, and circle of Willis quite well.
However, considering the considerable dose of ionizing radiation from
CTA, MRA is probably a better initial study in children, even when
sedation is necessary. At UCSF, we only perform CTA if the necessary
diagnostic information cannot be obtained by other methods.
CSF Flow Imaging
CSF flow can be visualized and quantitatively analyzed using PC stud-
ies (115,116). MR studies of CSF flow are most useful when looking
for interruptions of normal flow patterns. In particular, we use these
studies in patients with Chiari I and II malformations (see Chapter 5)
when they are being considered for foramen magnum decompression
surgery. We use PC sagittal studies because the CSF flow can be quanti-
fied (116,117). For studies of patients with Chiari malformations, the
images are centered at the foramen magnum. Our typical parameters
include Venc of 5 cm/s, TR = 27 milliseconds, TE = 11.7 milliseconds,
flip angle 30°, 22 cm field of view, a 128 × 256 acquisition matrix, and
2 excitations. Peripheral cardiac gating is used.
If only qualitative information is desired about CSF flow, other
flow-sensitive sequences can be used. Steady-state free procession
sequences (CISS or FISP or SSFP) using 3D Fourier transformation
can be very useful to show rapid CSF flow that disturbs the steady
state and, therefore, appears as low signal intensity. We use a TR of
30 milliseconds, TE of 14 milliseconds, flip angle 40°, and 200 phase
encoding steps. Using this technique, 128 partitions and an 18 cm
field of view yield a partition size of 1.4 mm. Because of the 3D acqui-
sition, the images can be formatted in any plane. RARE and FLAIR
sequences are also motion sensitive and can be used to qualitatively
evaluate CSF flow.
Magnetic Resonance Neurography
RARE and STIR sequences can be used to highlight nerve fascicles as
they course through the brachial plexus, arms, legs, or neck and are
particularly useful for evaluating these structures in cases of trauma,
inflammatory or radiation injuries. Either sequence should use long
TR (4000–5000 milliseconds) and long TEeff (100–110 milliseconds)
and flow saturation bands on all sides of the imaging volume (to sup-
press high signal from incoming flow). If RARE sequences are used,
fat suppression must be applied as well. In general, STIR sequences
work better for the neck and brachial plexus, as fat suppression pulses
are often affected by bulk susceptibility in this region, resulting in het-
erogeneous fat saturation and water saturation; STIR alleviates these
problems. If fat-suppression pulses are used, for the neck or brachial
plexus, water bags, oil bags, or commercially available neck pads should
be used to help reduce such artifacts. Alternatively, chemically selec-
tive radiofrequency excitation pulses or modified Dixon techniques
(IDEAL, iterative decomposition of water and fat with echo asymmetry
and least squares estimation) may help achieve more homogeneous fat
suppression (118). For all sequences, we acquire sections of 3- to 4-mm
slice thickness with no interslice gap. The acquisition matrix should be
no less than 256 × 256; if possible, a matrix size of 512 × 512 should
be used. The resultant images highlight nerve bundles as longitudinal
bands of high signal intensity. These sequences are excellent for search-
ing for intrinsic pathology in peripheral nerves (119,120).
Barkovich_Chap01.indd 11
11
Magnetization Transfer
The technique of magnetization transfer contrast (MTC) is useful
in assessing myelination and demyelination (121,122). MTC imag-
ing relies on detecting differences in relaxation properties of free and
bound water (122–124). The technique is based on the fact that water
protons bound to macromolecules (such as those composing myelin)
have very short T1 and T2 relaxation times; thus, bound protons do
not normally contribute to the signal obtained by MR imaging. How-
ever, a constant exchange of water molecules is occurring between the
free water molecules and the bound water molecules. Those protons
in water molecules that are bound to macromolecules at the time of
the initial radiofrequency pulse and separate from the macromolecule
before the readout gradient is applied will have considerably shorter
T1 and T2 relaxation times than the rest of the free water proton mol-
ecules. The measured relaxation times of the entire population of water
protons will be shortened by this process, which is known as magne-
tization transfer. The amount of magnetization transfer will depend
upon the quantity of macromolecular components available to bind
within the free water molecules and the rate of exchange between the
two pools of water molecules.
If an RF pulse is applied slightly (5–10 kHz) off the peak resonance
frequency of free water, it will saturate the bound water protons, which
have a much broader absorption peak, with minimal effect upon the
free water protons. Application of the off-resonance RF pulse, there-
fore, will negate any contribution of bound water protons to the overall
T1 and T2 relaxation times and to the MR image is negated. Subtrac-
tion of the image obtained with the off-resonance RF saturation pulse
will show the contribution from the bound protons, that is, the amount
of magnetization transfer. The amount of magnetization transfer can
be assessed qualitatively or quantitatively (125).
Magnetization transfer images can be obtained by acquiring
two sets of gradient-echo scans with gradient spoilers. Data are best
acquired using a TR of 300 milliseconds, TE of 7 milliseconds, flip
angle 20°, 3 mm partition thickness, 12 cm field of view, and 3DFT
reconstruction techniques. A RF saturation band applied to the sec-
ond set at 5 kHz off the resonance frequency of free water will satu-
rate the pool of bound protons. Subtraction of the second data set
from the first results in a magnetization transfer image. The amount
of magnetization transfer in the different regions of the brain, which
should reflect the state of myelination, can be calculated from region
of interest measurements from those regions of brain (MTR =
[Mo − Ms]/Mo, where MTR is the magnetization transfer ratio, Mo is
the magnitude of signal without saturation by an off frequency radiof-
requency pulse, and Ms is the magnitude of tissue signal with the satu-
ration pulse on).
Perfusion Imaging
Perfusion imaging in infants and young children is difficult. Limita-
tions include difficulty in gaining proximal IV access, the use of small
IV catheters that limit injection rates and prolong injection times,
the necessity of using low doses of contrast, and a high incidence of
motion artifacts. If these limitations can be overcome, the potential
exists for gaining useful information, especially in older children, using
this method.
With the widespread availability of helical CT scanners, CT per-
fusion imaging has become feasible and is now commonly used in
adults (126,127). However, because of the limitations mentioned in
the previous paragraph and the associated radiation, CT perfusion has
not gained widespread acceptance for use among young children. The
few studies employing this technique in children have focused on the
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 12 Pediatric Neuroimaging
variation in perfusion parameters with age (128) or on the use of the
CT perfusion in the emergency setting (129).
Several approaches exist for performing dynamic MR imaging
after administration of a contrast agent (130–133). One method is
the use of fast gradient-echo sequences with inversion prepulses. This
sequence allows strongly T1-weighted sequences to be acquired in as
little as 1 second. Enhancement with paramagnetic contrast is mani-
fested as an increase in brain signal intensity of the images. Alterna-
tively, T2*-weighted pulse sequences can be used. If EPI is available, it
should be used, as it allows acquisition of images at multiple levels with
a single bolus administration of contrast. Gradient-echo images are
used instead of spin echo because they are more sensitive to medium
to large vessels, and, therefore, greater signal drop is seen during the
first pass of a contrast agent. Although more prone to susceptibility
artifact, gradient-echo techniques are more sensitive to small changes
in blood volume. Therefore, the majority of the literature for tumor
imaging favors using a gradient-echo sequence to estimate cerebral
blood volume (susceptibility weighted perfusion imaging). If echo-
planar techniques are not available, standard gradient-echo techniques
using sufficiently long TEs will work, as well. During first pass of the
paramagnetic contrast agent through the brain, the shortened T2*
results in a loss of signal intensity (134). Region of interest intensity
measurements are acquired from the images sequentially to generate
a curve (called the DR2* curve) in which relaxivity (DR2*) is plotted
versus time (see Chapter 7). From the DR2* curve, mean transit time,
relative blood volume, and relative blood flow can be deduced. Our
experience and that of others (133) indicates that superior contrast
to noise is obtained using the T2*-weighted sequence, so we use that
method to evaluate for brain ischemia and to assess tumors (see sec-
tion at the beginning of Chapter 7). The DR2* curve can be used to dif-
ferentiate low-grade from high-grade gliomas, recurrent tumor from
treatment-related injury, intraparenchymal from extraparenchymal
tumors, and abscesses and demyelinating plaques from intraparenchy-
mal tumors (53,135,136).
The patients are imaged during infusion of paramagnetic con-
trast, given intravenously as a bolus injection. For EPI, we use a single-
shot GE technique with TR/TE = 1250/54 milliseconds, bandwidth =
178 MHz, FOV = 26 × 26 cm, 4 mm slice thickness, acquisition matrix
of 256 × 128, and 1 excitation. This sequence allows acquisition of
70 sets of images from 7 slice locations in 2 minutes. The imaging
sequence for standard gradient-echo sequences utilizes TR/TE = 35/25
milliseconds, flip angle 10°, 1 excitation, 10 mm slice thickness, and
256 × 64 acquisition matrix. This sequence allows acquisition of images
every 2 seconds, acquired over 30 seconds. As the cerebral circulation
time (including arterial, capillary, and venous phases) varies from 7 to
9 seconds, 30 seconds provides adequate “buffer” capacity for the tim-
ing. Data analysis can provide local blood volume, approximate local
blood flow, and perfusion delay measurements (131,133). Although
most of our experience with pediatric perfusion imaging has been in
older children, the method can be also be safely used when specifically
tailored for infants (54,137).
Perfusion imaging can also be performed using blood water as an
endogenous tracer. This technique is referred to as the spin tagging,
arterial spin labeling (ASL), or black blood method (130,138,139); it is
entirely noninvasive and is theoretically quantitative. In spin tagging,
the spins of incoming protons are inverted at the level of the carotid
arteries. A series of images through a section in the brain downstream
from the site of inversion are subsequently obtained. A change in net
magnetization of the tissue in the plane being imaged will occur due to
thin inflow of protons with inverted spins; this change in magnetiza-
tion is a function of perfusion of the tissue in that plane. Although this
technique works with spin-echo techniques (140), the change in signal
Barkovich_Chap01.indd 12
intensity as a function of tissue perfusion is small; measurements are,
therefore, easily impaired by head motion or instability of instrumen-
tation. Spin tagging is therefore better performed using echo-planar
techniques, which reduce instrumental drift and head motion artifacts
(141), making the results more reproducible. Probably the best of the
current ASL techniques is called quantitative signal targeting by alter-
nating radiofrequency pulses labeling of arterial regions (QUASAR)
(142). This sequence is capable of acquiring images at multiple TIs after
labeling of the arterial water protons with a high temporal resolution;
it features a bolus saturation scheme for clear definition of the arterial
blood bolus (142). The readout is performed by using conventional
multisection single-shot gradient-echo EPI with a small flip angle.
Typical parameters for QUASAR are four sections of 7 mm thickness;
ascending section order; 2 mm section gap; 64 × 64 imaging matrix;
24 cm field of view; 30° flip angle; TR of 4000 milliseconds; TE of
23 milliseconds; first TI of 50 milliseconds, DTI of 200 milliseconds;
bolus length (start time for bolus saturation) of 1050 milliseconds;
stop time for bolus saturation of 2250 milliseconds; 18 acquisition
time points (i.e., TIs); single-shot EPI; sensitivity encoding factor of
3.0; inversion slab width of 15 cm; and inversion gap of 3 cm (143).
Another approach to ASL is the technique of continuous ASL,
in which arterial spins are continuously labeled and a steady-state
condition is measured in the cerebral parenchyma. This method has
suffered from unwanted effects of magnetization transfer and micro-
vascular “noise” (138). A method has been introduced that assesses
changes in magnetization of multiple sections during continuous
ASL. This technique appears to overcome the magnetization transfer
effects and allows a quantitative brain perfusion study to be acquired
noninvasively in 10 to 15 minutes (144). Although this duration may
still be a little long for the study of a child, it seems to be a big step
forward in the development of a noncontrast, quantitative MR perfu-
sion technique.
Diffusion Tensor Imaging
The availability of very strong, rapidly acting gradients on MR scanners
has permitted the measurement of the net motion of water molecules
within the brain. These motions arise predominantly from diffusion,
but also from the flow of blood in capillaries and probably active trans-
port of water with macromolecules within cells. The combination of
these motions causes a loss of signal when strong gradients are applied;
this loss of signal can be measured and is called the ADC or average
diffusivity (Dav) (145). The Dav can be measured in any direction by
acquiring images in the presence of very large field gradients in that
direction; acquisition of a series of images with different strengths
of applied gradients allows quantification of the Dav (145). Although
diffusion imaging is theoretically possible using standard spin-echo
and gradient-echo techniques, the high level of susceptibility to even
slight motion makes these techniques practically impossible. Therefore,
diffusion imaging is nearly always performed using EPI techniques.
At UCSF, we use a single-shot technique with TR of 10,000 millisec-
onds, minimum TE, with a 256 × 128 acquisition matrix, bandwidth
of 166.7 MHz, 36 × 27 cm FOV, 3 to 5 mm slice thickness, and 1 exci-
tation. Use of strong gradients (with appropriate “b” value [145]) is
critical to achieving good diffusion images. We utilize different b values
depending on the age of the patient. For premature neonates, we use
b = 600 s/mm2; for term neonates, we use b = 700 s/mm2; and for older
infants and children, we use b = 1000 s/mm2. Diffusion gradients must
be applied in a minimum of three orthogonal planes in order to obtain
high sensitivity to changes in proton diffusion (in a minimum of six
planes for DTI, see below). It is important to be consistent in the use of
diffusion gradients, especially if quantifying the ADC. Work has shown
5/5/2011 11:43:33 PM
 Chapter 1 • Techniques and Methods in Pediatric Neuroimaging
that the magnitude of the Dav varies with the b value utilized when the
number of acquired directions is small (200). In addition, absolute Dav
measurements should be interpreted with the knowledge that numeri-
cal values may vary between 4% and 9% depending on scanner vendor,
field strength, and sequence parameters (147).
The work of Basser et al. (148,149) in the mid-1990s allowed
widespread use of a more sophisticated method of diffusion imaging,
known as diffusion tensor imaging (DTI). DTI is really a mathematical
description (the tensor) of water motion in a voxel. To determine the
diffusion tensor, it is necessary to acquire diffusion-weighted images in
a minimum of six different planes, along with an image acquired with-
out diffusion weighting (i.e., b = 0). Once the diffusion tensor is calcu-
lated for each voxel, it is possible to calculate the Dav and the degree of
anisotropy (asymmetrical water diffusion) of the motion of the water
molecules in that voxel (150). As it is difficult to display tensor data with
images, the concept of diffusion ellipsoids is often used. An ellipsoid is
a 3D representation of the distance and direction traveled in space by
the average water molecule in a voxel during a give time Td. The axes of
the ellipsoid are directed along the three orthogonal eigenvectors (n1,
n2, and n3, the principal diffusion orientations) and the lengths of the
vectors are scaled by the corresponding eigenvalues (l1, the primary
eigenvalue [sometimes also called the parallel eigenvalue, a measure
of longitudinal diffusivity], l2, the intermediate or median eigenvalue,
and l3, the minor eigenvalue [note that (l2 + l3)/2 is sometimes called
the perpendicular eigenvalue, a measure of transverse diffusivity]). By
using the concept of the ellipsoid and its eigenvalues, it is possible to
discuss diffusion anisotropy relatively simply. Diffusion anisotropy is
generally expressed as relative anisotropy (RA), fractional anisotropy
(FA) or the coefficient of variation of the eigenvalues (As). The relative
strengths and weaknesses of these parameters are still being worked out.
However, FA appears to be more sensitive to small differences among
white matter tracts when anisotropy is low (as in neonates and infants)
(151) and has higher signal-to-noise ratio than RA (152); therefore, we
use FA in studies of neonates and infants. Although most radiologists
and MR scientists currently use RA, FA, or As to describe anisotropy,
it is important to realize that combining the individual eigenvalues to
calculate these values leads to an overall loss of information and that, if
possible, it is optimal to calculate and analyze the individual eigenvalues
after acquiring DTI data (151). The details of DTI are beyond the scope
of this book. Interested readers are referred to the excellent review by
Le Bihan et al. (150), the reviews of Mukherjee et al. (153,154), or the
series of excellent reviews in the November to December, 2002, issue of
NMR in Biomedicine (155–159).
Three features of DTI are of interest in pediatric neuroimaging.
First, diffusion characteristics can be used to assess brain maturation
(151) because both the rate of water diffusion (Dav) and the direction
of water diffusion (diffusion anisotropy) vary with maturation in both
immature white matter and in immature cerebral cortex (160,161).
In premature neonates, water molecules in the cerebral cortex move
more radially (perpendicular to the surface of the cortex) than hori-
zontally (parallel to the surface of the cortex) (161); this anisotropy
disappears with maturation (see Chapter 2, Section “Diffusion Tensor
Imaging and Tractography” and Figure 2-35). In white matter, the rate
of diffusion parallel to axon fascicles is faster than the diffusion per-
pendicular to them (162,163). This anisotropy increases as the axons
myelinate, although, interestingly, anisotropy is present even before
myelination (162,163). Measurement of both the Dav and the anisot-
ropy may be useful in assessing brain maturation (151,164,165) and
brain injury (81). In addition, tensor information in conjunction with
connectivity algorithms allows axonal tracts to be mapped in the brain
(155); although currently a research tool, this diffusion “tractography”
has tremendous potential to identify the causes of neurologic defects
Barkovich_Chap01.indd 13
13
in children (87,166) and to help us better understand white matter
anomalies associated with developmental brain disorders (see Chapter
2, Section “Diffusion Tensor Imaging and Tractography”) (167–170).
Finally, diffusion characteristics can be used to differentiate different
layers of the developing cerebral mantle in fetuses and prematurely
born neonates (171). For example, the developing cerebral cortex had
different diffusion characteristics than the subplate (a transient layer
beneath the cortex that is important in the establishment of permanent
axonal connections within the developing brain), and both have differ-
ent characteristics than the intermediate zone (the layer of developing
axons and glia between the subplate and the germinal matrices) (171).
The ability to distinguish these layers on imaging studies may be cru-
cial to unraveling the cause of developmental difficulties in premature
neonates.
A second potentially important aspect of diffusion imaging in
pediatric neuroradiology is that water appears to diffuse more and
more randomly (i.e., there is greater diffusivity and less anisotropy)
in patients with developmental delay of unknown cause than in devel-
opmentally normal patients (172). The full significance of this finding
has not been elucidated but the implication is that, not surprisingly,
abnormally formed or abnormally organized white matter does not
function as well as normal white matter in transmitting action poten-
tials through the brain.
The third aspect of diffusion imaging that is of value in pediatric
neuroimaging is the ability to detect reduced diffusion in the acute
phase after a traumatic, metabolic, or toxic injury to the brain. For
reasons that are not entirely clear, the injury results in an acute
reduction in water motion (and hence the Dav) in affected regions
of the brain. For this function, the “trace,” which is the average of
the Dav in three perpendicular directions, is the most useful mea-
surement (note that trace is least sensitive to anisotropic differences
in Dav). An abrupt reduction in Dav is indicative of acute cerebral
injury. This aspect of diffusion imaging is discussed extensively in
Chapters 3 and 4.
Proton MR Spectroscopy
Proton MR spectroscopy is useful in the assessment of encephalopathic
neonates (173,174), in detection and diagnosis of some inborn errors
of metabolism (175,176), in developmental delay (177), and in pre-
therapeutic and posttherapeutic assessment of intracranial tumors
(178,179). Single voxel spectra are obtained from volumes of approxi-
mately 6 cm3, but 2D and 3D spectroscopy packages allow acquisition
of spectra from voxels sized 1 cm3 (or smaller on 3 T scanners). The
voxel is prescribed from MR images obtained in an imaging sequence
during the same examination. A stimulated echo sequence (180)
is combined with chemical shift selective pulses for localization and
water suppression, yielding only a signal from the region of interest
at the spatial intersection of three section selective pulses. Most mod-
ern MR scanners now have “push button” spectroscopy sequences that
automatically perform shimming and water suppression. One hun-
dred twenty-eight averages are obtained to achieve adequate signal-
to-noise. Short TE spectra (TR/TE = 2.0 seconds/20–30 milliseconds,
TM = 10.7 milliseconds) require use of the stimulated echo acquisition
mode (STEAM) technique; they allow assessment of the peaks of many
metabolites and are most useful for assessing patients with inborn errors
of metabolism (175). Long TE spectra (TR/TE = 2.0 seconds/272–288
milliseconds) are typically acquired using a point resolved spectro-
scopic (PRESS) technique (which gives better signal-to-noise ratio than
STEAM) and are more useful in injury states, in which optimal evalu-
ation and quantification of lactate and N-acetylaspartate (NAA) are
needed (173,182), and in tumors, in which quantification of choline,
5/5/2011 11:43:33 PM
 14 Pediatric Neuroimaging
creatine, and NAA is needed (183). Spectra are routinely acquired with
a standard imaging quadrature head coil, although signal-to-noise and
resolution can be improved by the use of specially designed pediatric
coils (46) or surface coils.
When using 2D and 3D spectroscopic imaging techniques, mul-
tiple spectra from a variety of locations can be acquired during a single
acquisition. The location of the smaller voxels within a larger acquisi-
tion area can be modified retrospectively, allowing a great deal of flex-
ibility in the regions sampled. The 2D spectroscopy is nearly as fast as
single voxel acquisition, but the 3D currently increases the acquisition
time considerably (184,185). The use of higher field strength MR scan-
ners with echo-planar and spiral acquisition techniques promises to
allow faster acquisition in the near future, which will likely make 3D
spectroscopy, using both long and short TEs, clinically viable sequences
in the near future (186,187). Proton spectroscopy can currently be used
to evaluate brain maturation (Chapter 2), to assess disorders of metabo-
lism (Chapter 3), to determine the severity of brain injury (Chapter 4),
and to evaluate intracranial masses (Chapters 3 and 7).
Automated Morphometric Analysis
and Tissue Segmentation
The more widespread use of volumetric T1-weighted GE sequences
and the increasing availability of off-line, computationally intense
advanced processing tools have recently enabled the systematic study
of brain morphology using automated techniques. Although not yet
implemented clinically, techniques for analyzing cortical folding pat-
terns have shown promise for studying brain development and in the
evaluation of disorders such as autism (188) and schizophrenia (189).
In the neonatal brain, twins and newborns with intrauterine growth
restriction show alterations in brain gyration and sulcation compared
to normal singletons that appear to correlate well with outcomes
(190,191). Beyond assessment of folding, automated tissue segmenta-
tion allows the targeted study of cortical gray matter development in
the maturing neonatal (192) and even the fetal brain (193). More work
will be necessary before these tools can be applied to study the individ-
ual patient, but in the future, automated evaluation of morphometry
may serve as a useful adjunct to subjective interpretation.
Imaging of Brain Function
A number of different techniques can be used to map the spatiotem-
poral distribution of neuronal activity during specific cognitive states.
These include magnetoencephalography (which, when mapped onto
an MR scan is referred to as magnetic source imaging), electroencepha-
lographic mapping, positron emission tomography, and blood oxygen
level–dependent functional MR imaging (fMRI). Among these, fMRI
has several advantages. fMRI combines relatively high temporal and
spatial resolution without ionizing radiation or externally adminis-
tered contrast agents. It also allows rapid and flexible experimental
protocols. Finally, fMRI allows functional and structural images to
be acquired during the same examination; these images can easily be
coregistered to produce maps that show the precise relationship of
function to anatomy. Functional MR data can be based upon local
cerebral blood volume, local cerebral blood flow (perfusion, see above),
or blood oxygenation. As the blood oxygenation–based methods are
the most widely used, they are briefly discussed.
The capillary and venous blood in the vascular network around
the normal resting cerebral cortex has a relatively high concentra-
tion of deoxyhemoglobin. When the cortex is activated, the increased
metabolic demand results in a nearly instantaneous increase in local
blood flow that raises the local concentration of oxyhemoglobin and
Barkovich_Chap01.indd 14
reduces the local concentration of deoxyhemoglobin. The reduction
of local deoxyhemoglobin results in an increase in local signal inten-
sity. Subtracting the image acquired during the resting state from that
obtained during the activated state results in an image that (indirectly)
shows local brain activity. This technique, known as blood oxygen
level–dependent (BOLD) imaging (194), is the primary technique used
for functional MR. Because the sensitivity to changes in the oxyhemo-
globin/deoxyhemoglobin ratio is increased at higher magnetic field
strength, BOLD imaging is likely to become more widely used as more
3 and 4 T MR scanners become available.
fMRI in older children is performed in a manner identical to that in
adults (194–196). At 1.5 T, we use a single-shot spin-echo echo-planar
sequence with TR/TE = 2000/60 milliseconds, acquisition matrix of
256 × 128, 10 mm slice thickness, and one acquisition. We choose spin-
echo echo-planar because it has greater sensitivity to signal arising from
capillaries and venules, whereas gradient-echo echo-planar images are
more sensitive to larger veins and have the potential for greater spatial
mismapping. In addition, spin-echo sequences have fewer susceptibility-
related artifacts (however, susceptibility is advantageous for BOLD
imaging techniques). Use of echo-planar sequences is essential in stud-
ies of children, as motion artifacts are typically more of a problem in
children than in adults (197). Patient cooperation becomes a problem
in younger children, particularly those below the age of 8 years and
those with developmental delay or mental retardation (198). In this
group, conditioning of the patients to the experimental situation by
going through the necessary tasks in a mock MR scanner can save con-
siderable time when the actual experiment is performed (199). Pedi-
atric fMRI shows particular promise in the evaluation of disorders of
language acquisition (200). In infants and young children, resting state
fMRI shows particular promise as a means of assessing normal and
abnormal brain function. An introduction to this topic is presented in
Chapter 2, Section “Functional MR Imaging”.
SUMMARY
To summarize, the many differences between the pediatric and adult
nervous systems require that different strategies be used for diagnos-
tic neuroimaging. Sedation is often crucial in acquiring diagnostic
images in children. MR-compatible life support equipment must be
suitable for pediatric patients if unstable patients are to be imaged
in the hospital setting. The choice between neurosonography, CT,
and MRI depends upon the age and clinical status of the patient, the
indications for the study, and a consideration of radiation dose in the
short and long term. The need for iodinated or paramagnetic contrast
media should be determined, and quantities of contrast agents must
be adjusted. Imaging protocols must be modified to compensate for
the different water content, changes in amount of myelin, changes in
metabolite levels, and the different size of the pediatric brain. If these
factors are considered and proper modifications are made to imaging
protocols, then functional and anatomic neuroimaging techniques can
add valuable diagnostic information and greatly improve the medical
care of children with neurological disorders.
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 CHAPTER
Normal Development of the
2 Neonatal and Infant Brain,
Skull, and Spine
A. JAMES BARKOVICH AND PRATIK MUKHERJEE
Introduction
Normal prenatal brain development
Embryology
Imaging of the preterm brain (premature infant and
fetus)
Grading of brain maturation in premature infants
Normal postnatal brain development
Embryology
Spin-echo MRI of postnatal brain development
Terminal zones
Milestones
Postulated causes of T1 and T2 shortening associated with
myelination
Other approaches to brain maturation by MR
Normal postnatal MR development of the corpus callosum
Normal MR development of the pituitary gland
INTRODUCTION
The brain matures in an organized, predetermined pattern that
correlates with the functions the newborn or infant performs at various
stages of development. Prior to the development of modern neuroim-
aging techniques, it was not possible to analyze normal brain matura-
tion in vivo. Neuroimaging allows analysis of many aspects of brain
maturation, including development of sulci, myelination, maturation
of brain chemistry, changes in free water diffusion, changes in blood
velocity, and changes in location of specific brain activities. Although
transfontanelle ultrasonography, x-ray computed tomography (CT)
and magnetic resonance imaging (MRI) all show gross morphologic
changes in the maturing brain, MRI supplies the most information.
MRI permits highly sensitive assessment of the maturation of gray and
white matter, in addition to assessment of microstructural changes
including those secondary to myelination. Myelination is an important
component of brain maturation because it facilitates the transmission
of neural impulses through the central nervous system (CNS); myeli-
nation can be studied by the changes in the T1 and T2 relaxation times
of the brain tissue, by assessing changes in magnetization transfer or,
indirectly, by assessing changes in the degree and direction of micro-
scopic motion (diffusion) of water in the brain. Magnetic resonance
spectroscopy allows us to assess some of the chemical changes that
occur as the brain develops. Finally, changes in regions of brain activity
(sometimes called functional MRI or fMRI) may be determined
by looking at changes in local cerebral blood oxygenation resulting
20
Barkovich_Chap02.indd 20
Normal development of the skull and paranasal sinuses
The skull
The cranial fontanelles and sutures
Maturation of the paranasal sinuses
Normal development of brain iron
Normal development of the spine
Embryology
CT of spine development
MRI of spine development
Evaluation of brain development using physiologic
MR techniques
MR spectroscopy
Diffusion tensor imaging and tractography
Magnetization transfer imaging
Perfusion imaging
Functional MRI
from the activity through the use of blood oxidation–level dependent
(BOLD) imaging. Imaging correlations of these changes that occur
during normal brain maturation are described in this chapter.
NORMAL PRENATAL BRAIN
DEVELOPMENT
Embryology
The bilateral cerebral vesicles that will form the cerebral hemispheres
first appear at about 35 days of gestation as outpouchings of the tel-
encephalon from the regions of the foramen of Monro. At the time of
these outpouchings, the walls of the vesicles are uniformly thin and
are connected in the midline by the lamina terminalis, a midline area
derived from the roof plate that has shrunken due to apoptosis. The
lamina terminalis does not grow as development proceeds; however, the
cerebral vesicles exhibit marked expansion laterally, rostrally, ventrally,
and caudally. As the vesicles expand, cellular layers develop within their
walls, forming the germinal matrices from which the cells that form the
cerebrum will eventually develop. The germinal matrices are initially
composed only of a single region of proliferating cells (the ventricular
zone), but as development proceeds, a more peripheral subventricu-
lar germinal zone develops, separated from the ventricular zone by a
periventricular fiber-rich zone. These germinal zones are divided based
upon their location, the type of neurons generated, and the ultimate
destination of the neurons: (a) medial ganglionic eminence (located
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 21

near the developing third ventricle, GABAergic neurons generated,

including cortical interneurons, hippocampal interneurons, and glo-
bus pallidus interneurons), (b) lateral ganglionic eminence (located
near the developing third ventricle, GABAergic neurons generated,
mainly striatal projection neurons and olfactory interneurons, also
some thalamic interneurons), (c) preoptic area (located near the bot-
tom of the developing third ventricle, GABAergic neurons generated,
including cells to the preoptic area, amygdala, posterior globus palli-
dus, and cortex), and (d) dorsal neocortical germinal zone (located in
walls of developing lateral ventricles, glutamatergic neurons destined
for the neocortex) (1–7). Neurons migrate from these germinal zones
through the developing hemispheres to form the cerebral cortex, ini-
tially in an incomplete form that is often called the preplate. As the
neurons migrate, they develop axonal connections with other cortical
and subcortical neurons. These connections form a prospective zone
of white matter that is called the intermediate zone because it is in the
region intermediate between the ventricular zone and the develop-
ing cortex. In addition to afferent and efferent axons, the intermedi-
ate zone contains migrating neurons and oligodendrocyte progenitor
cells (8). Between the preplate and the intermediate zone is a transient
area of loosely packed and loosely organized neurons that form tem-
porary neuronal circuits, particularly with the thalamus (9); this zone
is known as the subplate. The subplate is largest at the 22nd gestational FIG. 2-1. Schematic demonstrating normal development of the fetal
week (10). At that time, it is about four times thicker than the cortex brain. During the early weeks of gestation, the cerebral hemispheres are
and is easily seen on fetal MRI as an area of T1 hypointensity and T2 smooth. The earliest fetal sulcus is the sylvian fissure, which first appears
hyperintensity between the intermediate zone and cortex (10–12). It during the fifth gestational month. By about 27 weeks, the Rolandic, inter-
parietal, and superior temporal sulci have appeared. Secondary and tertiary
gradually disappears after the 30th gestational week, as definitive corti-
sulci develop during the last 2 months of gestation. Because of the differ-
cal connections are established (10). Details of the development of the ent appearance of the brain in premature infants as compared with term
hemispheres are described in more detail in Chapter 5. For the pur- infants, it is important to know the gestational age of a child at the time of
poses of the discussion to follow, it is sufficient to understand that the delivery before assessing the structure of the brain.
occipital pole begins to develop at about the 43rd gestational day and
the temporal pole at approximately the 50th gestational day. During
the early weeks of gestation, the surfaces of the cerebral hemispheres proceeds most rapidly in the area of the sensorimotor and visual
are smooth. The fetal sulci appear in an orderly sequence; the phyloge- pathways. These are also the areas in which myelination occurs earliest
netically older sulci appear first, and the more recently acquired sulci (22 and following section), in which glucose uptake increases earliest
appear later. The principal sulci and gyri form the characteristic pat- (23), in which relative cerebral perfusion increases earliest (24), in
tern of the human cortex that can be identified in the full-term infant which cortical microstructure matures most rapidly (25), and in which
(Table 2-1). The primitive Sylvian fissure, the earliest fetal sulcus, is brain chemistry matures most rapidly (26). Gyral development takes
usually present when the fetus is imaged in the fourth gestational place most slowly in the frontobasal, frontopolar, and anterior tempo-
month. The next sulci to appear are the calcarine, parietooccipital, and ral regions, which are the slowest regions to myelinate and to mature
cingulate sulci during the fifth month (by 20–22 weeks); the Rolandic metabolically (23,24,26).
(central), interparietal, and superior temporal sulci that appear toward
the end of the sixth month (by 25 weeks); and the precentral, postcen- Imaging of the Preterm Brain (Premature Infant
tral, superior frontal, and middle temporal sulci that appear during the
and Fetus)
seventh gestational month (24–28 weeks) (13) (Fig. 2-1 and Table 2-1).
Because sulcal formation occurs so late in gestation, imaging studies of As mentioned earlier, the imaging modality being used determines
premature infants show sulci that are shallow and few in numbers. It which features of brain development can be evaluated. If the anterior
is, therefore, important to know the postconceptional age of a child before fontanelle is large enough, ultrasound shows development of the gyri
assessing the sulcal pattern. Otherwise, a false diagnosis of lissencephaly and sulci nearly as well as CT and MRI but does not give information
may be made. In addition, as will be discussed in more detail later in about brain myelination. CT allows fairly good information about sul-
the chapter, sulcation, myelination, and corpus callosum development cal development but gives a poor assessment of myelin development.
tend to be delayed in prematurely born neonates compared to fetuses of MRI allows excellent assessment of myelination, sulcation, and chemi-
the same postconceptual age. cal maturation. As CT requires the use of ionizing radiation and does
Van der Knaap et al. (19) have devised a method by which gyral not provide any information that cannot be obtained by ultrasound and
development can be divided into five stages: (a) before 32 weeks, (b) 33 MR, it is not recommended for brain imaging in the fetus or the prema-
to 34 weeks, (c) 35 to 37 weeks, (d) 38 to 41 weeks, and (e) beyond ture neonate. Because we no longer use CT for premature neonates and
41 weeks. The gyral maturity is determined by measurements of the because the changes visible on CT (restricted to progressively increas-
width of the gyri and depth of the sulci. The stage of gyral develop- ing sulcation) are seen better on MR, this edition does not show CT
ment is then assigned based upon the degree of gyral maturity in seven images of preterm infants, instead concentrating on the more extensive
different regions of the brain. Battin et al. (20) and Ruoss et al. (21) changes detected with maturation by MR.
have also developed systems of assessing sulcal development based on Fetal MRI has been successfully utilized in a large number of
ratios of the width and depth of the sulci and gyri. Gyral development centers for the past decade (11,12,27–33). Improvements in coil

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 22 Pediatric Neuroimaging

and ventricular volume parallel that of supratentorial volume, while

TABLE 2-1 Chronology of Sulcation supratentorial white matter volume grows more rapidly than overall
supratentorial volume (Dr. Piotr Habas, personal communication).
of the Brain Prior to 24 weeks of gestation, the brain is essentially agyric with
the exception of the wide, vertically oriented Sylvian fissures. The size
Location Age of Sulcation of the brain is very small, and the cerebral cortex is extremely thin,
Medial Surface so thin imaging sections (≤3 mm) must be used for optimal evalua-
tion. MR images show the cortex to be very hyperintense with respect
Callosal sulcus 14–23 wk to the underlying white matter on T1-weighted images and very
Parietooccipital sulcus 16–23 wk hypointense compared to white matter on T2-weighted images (Figs.
2-2 and 2-3). The germinal matrix has not yet involuted and is seen
Calcarine sulcus 16–25 wk
as a stripe in the walls of the lateral ventricles that is isointense to the
Cingulate sulcus 18–24 wk gray matter of the cortex on T1- and T2-weighted images (Fig. 2-2);
Marginal sulcus 22–27 wk it is thicker in younger fetuses (18–20 weeks) and becomes thinner
and discontinuous with further maturation (Fig. 2-3). The germinal
Secondary cingulate sulci 32–33 wk
matrix is thickest at the region of the caudate heads and should not
Secondary occipital sulci 34 wk be mistaken for a germinal matrix hemorrhage at this location. The
Ventral Surface more central ventricular zone and adjacent subventricular zone can-
not be distinguished by in vivo imaging. Between the germinal zones
Hippocampal sulcus 16–23 wk and the cortex, MRI also shows a layer of intermediate signal inten-
Collateral sulcus 23–26 wk sity, separated from the more peripheral cerebral cortex and more
Occipitotemporal sulcus 30–33 wk central germinal matrix (Fig. 2-2C–E). Although previously believed
to represent migrating glial cells, this layer has recently been identi-
Lateral Surface fied as the intermediate zone, or the developing fetal white matter
Superior frontal sulcus 25–29 wk (10). Projection and commissural axons are present and glial cells are
actively migrating through this region (34). Immediately peripheral
Inferior frontal sulcus 28–29 wk
to the intermediate zone and deep to the cerebral cortex is a region of
Superior temporal sulcus 23–27 wk T1 hypointensity/T2 hyperintensity (Fig. 2-2E), which is likely to be
(posterior part) the subplate, the region where thalamocortical afferent axons accu-
Superior temporal sulcus 28–32 wk mulate and wait before entering the cortical plate to establish defini-
(anterior part) tive synapses (10,35,36). These zones are most prominent in younger
fetuses (18–20 weeks); they can still be seen but are less conspicuous at
Inferior temporal sulcus 30–33 wk
23 to 24 weeks (12,37). The lateral ventricles and the cisterns around
Interparietal sulcus 26–28 wk the brainstem and cerebellum are visible and more prominent at this
Insular sulci 34 wk age than in the mature infant; they are smaller by 23 to 24 weeks
(Fig. 2-3) than at 18 to 20 weeks (Fig. 2-2). The third and fourth ven-
Central sulcus 20–26 wk tricles are difficult to visualize at this age unless very thin sections are
Precentral sulcus 24–27 wk obtained because the size of the brain is so small (38,39). The globi
Postcentral sulcus 25–28 wk pallidi typically appear hyperintense on T1-weighted images start-
ing at about 20 weeks. This likely represents premyelination changes,
Cerebellum such as the appearance of proteolipid protein in oligodendrocyte
Primary fissure 25–28 wk processes (40).
Between 24 and 30 weeks, the cerebral cortex shows development
In general, the earlier numbers are from pathology studies and the later ones of shallow Rolandic (central), calcarine, pericallosal/callosomarginal,
from radiology studies. Imaging numbers (later numbers) indicate when the
interparietal, and superior temporal sulci (Figs. 2-4 and 2-5); in some
sulcus is seen in more than 75% of studies.
patients, the precentral, postcentral, superior frontal, and middle tem-
From (14–18).
poral sulci may be visualized. The subplate is still seen in the subcortical
white matter as a layer of T1 hypointensity/T2 hyperintensity; it begins
to disappear on imaging in the posterior frontal and parietal lobe at
about 28 weeks, but remains visible in less mature areas such as the
technology (particularly the use of multiarray phased array coils and anterior frontal and temporal lobes for some time thereafter (12,37).
improved pulse sequences) have allowed progressive improvement in Myelination is seen in some brainstem structures during this period,
the quality of the images. Studies (18,27–29,33) indicate that brain including the median longitudinal fasciculus (MLF, bright at 25 weeks
development follows a similar progression of sulcation in fetuses as in on T1-weighted images, dark at 29 weeks on T2-weighted images),
prematurely born infants; sulci are increasingly identified with increas- the lateral lemnisci (bright at 26 weeks on T1-weighted images, dark
ing postconceptional age. However, it appears that sulcal development at 28 weeks on T2-weighted images), the medial lemnisci (bright at
occurs earlier in utero than ex utero. In other words, sulci are seen earlier 27 weeks on T1-weighted images, dark at 30 weeks on T2-weighted
in fetuses still in the uterus than in neonates of similar postconceptional images), and the superior and inferior cerebellar peduncles (bright at
ages that have been born prematurely. The reasons for this are not yet 28 weeks on T1-weighted images, dark at 29 weeks on T2-weighted
clear, nor are the precise differences in timing. Studies also show that images) (41). The basal ganglia and thalami are better seen at this age
the cerebrum and its components grow largely proportionally. For on MRI and have intensity similar to the cerebral cortex on both T1-
example, the volume of cortical gray matter, basal ganglia volumes, and T2-weighted images, although not as hyperintense on T1-weighted

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 23

FIG. 2-2. Fetal MR at 20 postconceptional weeks. A–D. Axial images show that the germinal zones (low intensity rims around the ventricles, small
black arrows) and lateral ventricles (v) are rather large at this age. The intermediate zones (large white arrows) are best seen at higher levels (C and D).
E. Coronal image nicely shows the germinal zone (very low intensity, small white arrows), intermediate zone (intermediate intensity, large white arrow),
subplate (higher intensity, large black arrow), and cerebral cortex (similar low intensity to germinal zone, small black arrows).

images or as hypointense on T2-weighted images (Fig. 2-4E–L). The
ventrolateral nucleus of the thalamus becomes hypointense compared
with the remainder of the thalamus on T2-weighted images by about
25 weeks and hyperintense on T1-weighted images by 27 to 28 weeks,
probably due to hypercellularity and possibly to early myelination,
as well. The lateral ventricles, particularly the trigones and occipital
horns, are less prominent at this age than at 22 to 23 weeks, probably
secondary to both growth of the cerebral white matter and develop-
ment of the calcarine sulci.
By 31 to 32 weeks, an increased number of gyri and shallow sulci
become visible in the cerebral cortex of prematurely born neonates
(Fig. 2-5). The Sylvian fissures retain their immature appearance,
although some development of the opercula can be detected. The cis-
terns around the brainstem and cerebellum remain large at this age and
the CSF spaces in the occipital region and in the interhemispheric fissure
remain prominent, although the interhemispheric fissure is more vari-
able in size. The cavum septi pellucidi and cavum Vergae are prominent
and will remain so throughout the first 40 postconceptual weeks
(38,39). The dorsal brainstem (relatively hyperintense on T1-weighted
images and hypointense on T2-weighted images) is contrasted by the
unmyelinated ventral pons (Fig. 2-5A and E). The thalami and globi
pallidi are contrasted by the unmyelinated (relatively hypointense on
T1-weighted images and hyperintense on T2-weighted images) inter-
nal capsule (Fig. 2-5B and F). The signal intensity of the entire cerebral
cortex is uniform at this age on both T1- and T2-weighted images. The
subplate is poorly seen on T1-weighted images and is best identified
in the anterior temporal lobes on T2-weighted images. The germinal
matrix has involuted to a large degree and only a few scattered rem-
nants may be seen. These remnants are most consistently seen just
anterior to the tips of the frontal horns of the lateral ventricles at this
age (Fig. 2-5C and G) (42). The dorsal brainstem and superior and
inferior cerebellar peduncles remain bright on T1-weighted images,
but the middle cerebellar peduncles remain unmyelinated, isointense
to the cerebral white matter. T2-weighted MR shows hypointensity
in the dorsal brainstem (predominantly due to the MLF, medial and
lateral lemnisci), superior and inferior cerebellar peduncles, nuclei of

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 24 Pediatric Neuroimaging

FIG. 2-3. Fetal MR at 23 postconceptional weeks. A–D. Axial T1-weighted images show formation of calcarine and parietooccipital fissures.
The high intensity surrounding the lateral ventricles (open arrows) is the germinal matrix. Note the layer of migrating cells (solid arrows) in the
cerebral white matter, seen best on images (C and D); this is believed to represent migrating glia. Note also the small size of the cerebellum at
this age. (These images courtesy Dr. Nadine Girard).

the inferior colliculi, far lateral putamen, and ventrolateral thalamic
nucleus (43) (Fig. 2-5). The cerebral white matter still appears com-
pletely unmyelinated.
At 34 to 36 weeks, the cerebral cortex has further thickened and
more sulci have developed. Little change occurs in the signal intensity
of the white matter between 32 and 36 postconceptional weeks (43).
On T1-weighted MR, the posterior limb of the internal capsule remains
hypointense as compared to the lentiform nucleus (Fig. 2-6C and D);
some patients will show a small dot of hyperintensity in the posterior
aspect of the posterior limb at 39 weeks (41). On T2-weighted images,
the posterior limb of the internal capsule remains entirely hyperintense
compared with surrounding structures (Fig. 2-6J). The Sylvian fissures
and, to a lesser extent, the CSF spaces near the occipital pole, remain
prominent (Fig. 2-6D, E, J and K). Considerable variation in brain
maturity can be seen at this age, some infants having a gyral pattern
that resembles a term infant and others still appearing quite immature
(Fig. 2-6) (38,39).
By 38 to 40 weeks, the brain has a nearly normal adult sulcal pat-
tern (Fig. 2-7); the sulci are formed but are not as deep as they will
become in the next several weeks. On T1-weighted MR studies, the
dorsal brainstem, posterior portion of the posterior limb of the inter-
nal capsule, and the central portion of the corona radiata (the corti-
cospinal tracts) are hyperintense compared to the rest of the brain. On
T2-weighted images, the dorsal brainstem is hypointense and, at 39 to
40 weeks, a characteristic spot of hypointensity is present in the pos-
terior limb of the internal capsule, lateral to the hypointense lateral
thalamic nuclei. There are few differences between the CT images of
a newborn term infant and those of older infants. The frontal white

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 25

FIG. 2-3. (Continued) E–H. Axial single-shot half-Fourier RARE images through the same levels show the same features.
Note the complete absence of myelination in the white matter at this age and the smaller germinal zones compared with
the 20-week fetus illustrated in Figure 2-2. Note also that the subplate and intermediate zones, although still visible, are less
conspicuous at this age than at 20 weeks.

matter and parietooccipital white matter remain relatively low in
attenuation compared to the gray matter (Fig. 2-7A–E). This probably
results from the known high water content of the newborn brain and
the lack of myelination. The MR appearance of the newborn brain, on
the other hand, is considerably different from that in older children,
as discussed in the following section. The Sylvian fissures may remain
prominent in the immediate newborn period; the occipital CSF spaces
may also remain somewhat large for several months. A cavum Vergae
and cavum septi pellucidi are usually present at birth; they disappear
rapidly in the first few months after birth as the septal leaves fuse.
The cisterna magna and basilar cisterns are relatively large through-
out infancy. This enlargement is quite apparent on MR scans, but less
so on CT where only the axial plane is available and beam hardening
artifact frequently obscures details in the basilar cistern area.

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 26 Pediatric Neuroimaging

FIG. 2-4. MR of 28-week fetus and of 28-week

prematurely born neonate. (A–D) are single-shot
half-Fourier RARE images, (E–H) are SE 550/15 MR
images, and (I–L) are SE 3000/120 MR images. Note
that sulcation in more advanced in the fetus than in
the prematurely born neonate of a similar gestational
age. By this age, gyri and sulci other than the sylvian
fissure become detectable. The development of shal-
low Rolandic (central), calcarine, pericallosal/callo-
somarginal, interparietal, and superior temporal sulci
can be visualized. In addition, the germinal matrix is
less prominent. The basal ganglia and thalami are
better seen at this age and have intensity similar to the
cerebral cortex on both T1- and T2-weighted images,
although not as hyperintense on T1-weighted images
or as hypointense on T2-weighted images. The lat-
eral ventricles, particularly the trigones and occipi-
tal horns, are less prominent at this age than at 22
to 23 weeks, probably secondary to both growth of
the cerebral white matter and development of the
calcarine sulci.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
Grading of Brain Maturation
in Premature Infants
Childs et al. (44) have proposed a scoring system for assessment of brain
maturation in premature infants. The scoring system takes into account
the degree of myelination, extent of sulcation, amount of involution of
the germinal matrix of the lateral ventricles, and the character of the
band of migrating cells (if present) in the white matter of the brain.
This method shows considerable potential for determining whether
the brains of neonates are developing properly. However, norms and
standard deviations will need to be established for each weekly post-
conceptional age, and it must be determined whether these scores are
sensitive and specific for predicting developmental abnormality.
Another way to assess brain maturation is size. Several authors have
performed the service of measuring many structures of the developing
Barkovich_Chap02.indd 27
27
FIG. 2-4. (Continued)
fetal brain. A summary of these measurements is listed in Table 2-2. For
more extensive lists of measurement, the book by Garel (11) and the
paper by Parazzini (31) are recommended.
NORMAL POSTNATAL BRAIN
DEVELOPMENT
Embryology
From the imaging perspective, postnatal brain development consists
primarily of changes in signal intensity secondary to the process of
myelination. Myelination of the brain begins during the fifth fetal month
with the myelination of the cranial nerves and continues throughout
life. In general, the myelination progresses from caudal to cephalad, and
from dorsal to ventral. The brainstem, therefore, myelinates prior to
5/7/2011 2:41:54 AM
 28 Pediatric Neuroimaging

FIG. 2-5. MR of normal 31-week premature infant. Images (A–D) are SE 600/11 images and (E–H) are SE 3000/120 images. More sulci have developed by
this age, although they are still rather shallow. The myelinated dorsal brainstem is contrasted by the unmyelinated ventral pons (A and E) and the thalami
and globi pallidi are contrasted by the completely unmyelinated internal capsule (B, C, F, and G). The germinal matrix has involuted considerably, but some
gray matter signal remains present along the lateral walls of the lateral ventricles, most prominently seen at the tips of the frontal horns (arrows in C and G);
this can persist until the end of the 44th gestational week. The cisterns in the occipital region remain prominent (C, G, and H). The signal intensity of the
entire cerebral cortex is uniform at this age on both T1- and T2-weighted images. Foci of gray matter intensity are seen just anterior to the tips of the frontal
horns of the lateral ventricles (arrows in C), representing foci of residual germinal matrix. Hyperintensity on T1-weighted images and hypointensity on
T2-weighted images is present in the dorsal brainstem, superior and inferior cerebellar peduncles, far lateral putamen, and ventrolateral thalamic nucleus.
The cerebral white matter still appears completely unmyelinated.

the cerebellum and basal ganglia, and the cerebellum and basal ganglia
myelinate prior to the cerebral hemispheres. Another generalization is
that, within any particular portion of the brain, the posterior region
tends to myelinate first. Therefore, the dorsal brainstem, containing the
medial lemniscus and medial longitudinal fasciculus, myelinates prior
to the ventral brainstem, which contains the corticospinal tracts. Like-
wise, the occipital lobes of the cerebral hemispheres myelinate early,
whereas the prefrontal regions myelinate late.
Another general trend in the maturation of the brain is that
myelination progresses more rapidly in functional systems that are
utilized in early life than in those that are not utilized until the child
is older. Therefore, in the brainstem the medial longitudinal fascicu-
lus, lateral and medial lemnisci, and inferior and superior cerebellar
peduncles, which transmit vestibular, acoustic, tactile, and proprio-
ceptive sense, are myelinated at birth, whereas the middle cerebellar
peduncles, which transmit motor impulses into the cerebellum, acquire

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 29

FIG. 2-5. (Continued)

FIG. 2-6. Normal 34/35-week premature

infant. Images (A–F) are SE 550/15 MR
images, and (G–L) are SE 3000/120 MR
images. More sulci are forming, as can be
seen along the interhemispheric fissure
and over the convexities. Sulcal develop-
ment varies considerably at this age. The
sylvian fissures have markedly diminished
in prominence due to opercular develop-
ment. Notice that the dorsal brainstem
and globi pallidi have increased in signal
intensity on the axial T1-weighted MRI
(A–F). The posterior limb of the inter-
nal capsule remains completely unmyeli-
nated at this age. On T2-weighted images,
the brainstem nuclei, the periphery of
the cerebellar dentate nuclei, and the cer-
ebellar vermis are relatively hypointense
structures in the posterior fossa (G and
H). The subthalamic nuclei (arrows in I)
have become hypointense.

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 30 Pediatric Neuroimaging

FIG. 2-6. (Continued)

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 31

FIG. 2-7. CT/MR of normal 38 to 40 week infant. A–E. With the exception of increased lucency of the frontal and temporo-parietooccipital white
matter, the CT scan of this infant resembles any normal infant during the first year of life. The sulcal pattern is nearly mature. A cavum septi pel-
lucidi is frequently prominent at this age. F–J. SE 550/15 images show high signal intensity in the dorsal brainstem, the decussation of the superior
cerebellar peduncles, the optic tracts, the posterior limbs of the internal capsules, the lateral thalamus, the optic radiations, and the central corona
radiata. There is also increased signal intensity in the Rolandic and perirolandic gyri, corresponding to known myelination of the white matter
within these gyri shortly after birth.

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 32 Pediatric Neuroimaging

FIG. 2-7. (Continued) K–O. SE 3000/120 images show low signal intensity in the cerebellar
vermis, dorsal brainstem, posterior aspect of the posterior limb of the internal capsule, the
ventrolateral thalamus and the perirolandic gyri of the cortex. The T2-weighted images cor-
respond more closely to the temporal sequence of brain myelination as demonstrated with
histochemical staining techniques.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 33

TABLE 2-2 Normal Fetal Brain Measurements

Measurement 20 wk 21 wk 22 wk 23 wk 24 wk
Antero-posterior vermis Minimum 5 mm 5 mm 6 mm 7 mm 7 mm
Median 6 mm 7 mm 7 mm 8 mm 8 mm
Maximum 7 mm 9 mm 9 mm 10 mm 11 mm
Supero-inferior vermis Minimum 8 mm 8 mm 8 mm 9 mm 10 mm
Median 9 mm 10 mm 11 mm 11 mm 12 mm
Maximum 10 mm 12 mm 12 mm 13 mm 14 mm
Transverse cerebellum Minimum 18 mm 19 mm 20 mm 21 mm 23 mm
Median 19 mm 21 mm 22 mm 24 mm 25 mm
Maximum 21 mm 23 mm 24 mm 27 mm 28 mm
Length corpus callosum Minimum 16 mm 16 mm 17 mm 17 mm 23 mm
Median 18 mm 18 mm 21 mm 22 mm 24 mm
Maximum 18 mm 23 mm 24 mm 27 mm 28 mm
Fronto-occipital diameter Minimum 49 mm 50 mm 54 mm 57 mm 65 mm
Median 52 mm 56 mm 58 mm 63 mm 67 mm
Maximum 55 mm 60 mm 62 mm 67 mm 74 mm
Cerebral biparietal diameter Minimum 37 mm 36 mm 40 mm 41 mm 47 mm
Median 39 mm 40 mm 43 mm 46 mm 49 mm
Maximum 40 mm 45 mm 45 mm 49 mm 52 mm

Adapted from Parazzini C, Righini A, Rustico M, Consonni D, Triulzi F. Prenatal magnetic resonance imaging: brain normal linear biometric values
below 24 gestational weeks. Neuroradiology 2008;50:877–883. With permission.

myelin later and more slowly. Similarly, in the cerebrum, the geniculate
and calcarine (optic), postcentral (somesthetic), and precentral (pro-
prio-kinesthetic) regions acquire myelin early, whereas the posterior
parietal, temporal, and frontal areas, which are association areas that
integrate the sensory experience, acquire myelin later (22,45–47).
Yakovlev and Lecours (47), staining the brain with the Weigert stain
for myelin, showed that myelination proceeds rapidly within the brain
up to about of 2 years of age. The process slows markedly after 2 years,
although fibers to and from the association areas of the brain continue
to myelinate well into the third and fourth decades of life.
Spin-Echo MRI of Post-Natal Brain Development
In general, changes in white matter maturation are seen best on
T1-weighted images during the first 6 to 8 months of life and on the long
echo time T2-weighted images between the ages of 6 and 18 months.
Maturation of both the brainstem and cerebellum seem to be more
sensitively assessed on T2-weighted images (48–50). We obtain both
T1- and T2-weighted axial sequences for imaging patients in these age
groups, using parameters described in Chapter 1 (three-dimensional
[3D] spoiled gradient-echo sequence for T1-weighted images and
conventional spin-echo T2-weighted images with long repetition and
echo times). Other imaging sequences that give heavily T1-weighted
and T2-weighted images will work, as well. For example, fast spin-echo
T2-weighted sequences will show changes of myelination, although
the brain appears slightly more myelinated on fast spin-echo than on
conventional spin-echo images (51). Although visually apparent signal
changes of the white matter seem to be complete by about the age of
2 years, measurements of relaxation rates have shown that T1 shorten-
ing of white matter and gray matter continues into adolescence, prob-
ably secondary to continued myelination and consequent diminution
of brain water (52). The inability to qualitatively detect this continuing
change by conventional MR imaging probably reflects the fact that the
relaxation rates of gray and white matter change proportionately; thus,
no relative change is appreciated.
T1-Weighted Images
The changes of white matter maturation are visually detected at dif-
ferent rates and at different times on T1-weighted images than on
T2-weighted images. On T1-weighted images, the appearance of the
newborn brain is grossly similar to that of T2-weighted images in
adults in that white matter has lower signal intensity than gray matter.
As white matter matures, its signal intensity increases relative to gray
matter.
Neonatal posterior fossa structures that exhibit high signal inten-
sity at birth include the medial lemniscus, lateral lemniscus, MLF,
brachium of the inferior colliculus, and the inferior and superior cer-
ebellar peduncles (Fig. 2-7) (50). An increase in signal intensity of the
deep cerebellar white matter appears near the end of the first month of
life and steadily increases, with high signal intensity developing in the
subcortical white matter of the cerebellar folia by the third month. At
3 months of age, the cerebellum has an appearance similar to that seen
in the adult on both axial and sagittal images. Signal intensity in the
basis pontis (ventral pons) increases less rapidly, occurring during the
third through the sixth months.
In the supratentorial region, the decussation of the superior cer-
ebellar peduncles, the ventral lateral region of the thalamus, the globus
pallidus, the posterior portion of the posterior limb of the internal
capsule, and the central portion of the corona radiata (the corticospi-
nal tracts) exhibit high signal intensity at birth (Fig. 2-7) (50). In addi-
tion, small foci of gray matter intensity are seen just anterior to the
tips of the frontal horns of the lateral ventricles in term neonates and
premature infants. These foci, which are believed to represent persis-
tent germinal matrix, disappear by about 44 postconceptional weeks

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 34 Pediatric Neuroimaging
(42,53). The development of high signal intensity proceeds rostrally
from the pons along the corticospinal tracts into the cerebral pedun-
cles, posterior limb of the internal capsule and the central portion of
the centrum semiovale. The white matter of the precentral and post-
central gyri is of high signal intensity compared with surrounding
cortex by about 1 month of age (Fig. 2-7). The change to high sig-
nal intensity in the subcortical motor tracts is essentially complete by
age 3 months. In infants less than 1-month-old, high signal intensity
is present in the optic chiasm and optic tracts; by age 3 months, the
occipital white matter surrounding the calcarine fissure is of high sig-
nal intensity. The posterior aspect of the posterior limb of the internal
capsule is of high signal intensity at birth; high signal intensity does
not develop in the anterior limb until 2 to 3 months of age. The sple-
nium of the corpus callosum shows high signal intensity in all infants
by age 4 months (Fig. 2-8). The increase in signal intensity proceeds
anteriorly; the genu is always of high signal intensity by age 6 months
(Fig. 2-9). Typically, at 4 to 5 months of age, the splenium is high in
signal intensity, while the genu is low in signal intensity. Maturation of
the subcortical white matter, other than the visual and motor regions,
begins at 3 months. The deep white matter matures in a posterior-
to-anterior direction, with the deep occipital white matter maturing
first and the anterior frontal and temporal white matter last. Peripheral
extension and increasing hyperintensity of the subcortical white mat-
ter continue until approximately age 7 months in the occipital white
matter and 8 to 11 months in the frontal and temporal white mat-
ter (Fig. 2-10). Only minimal changes are seen on the T1-weighted
images after 11 months, consisting of increasing signal intensity in the
most peripheral regions of the anterior frontal, anterior temporal, and
parietal white matter (22).
T2-Weighted Images
The overall appearance of the newborn brain on T2-weighted images
is grossly similar to that of adult T1-weighted images in that the white
matter has higher signal intensity than the gray matter. On T2-weighted
sequences, white matter maturation is seen as a reduction in signal
intensity. As stated earlier, T2-weighted images are probably superior
to T1-weighted images for assessment of maturation of the cerebellum
(54) and brainstem (48).
At birth, low signal intensity is present in the inferior and superior
cerebellar peduncles and the cranial nerve nuclei (particularly cranial
nerves VI, VII, and VIII) (50). Small foci of gray matter intensity are
seen just anterior to the tips of the frontal horns in premature and term
neonates. As discussed in the prior section on T1-weighted images,
these represent foci of persistent germinal matrix that disappear by
about 44 postconceptional weeks (42,53). The cerebellar vermis (Fig.
2-7K) and the flocculi cerebellum are also of low signal intensity. The
ventral brainstem becomes of similar low intensity to the dorsal brain-
stem at about the fifth postnatal month. The middle cerebellar pedun-
cles begin to decrease in signal intensity during the second month of
life and are of uniform low intensity by age 3 months (55). The cerebral
peduncles become low in intensity by 4 months and the red nuclei by
5 months (55). Low signal intensity is seen in the subcortical white
matter of the cerebellar folia during the fifth to eighth month and the
cerebellum reaches an adult appearance at approximately 18 months.
Supratentorial structures that show low signal intensity at birth
include the decussation of the superior cerebellar peduncles, the medial
and lateral geniculate bodies, the subthalamic nuclei, the ventral lateral
regions of the thalami, a small patch of the posterior portion of the
posterior limbs of the internal capsules, and, a small linear region in
the lateral putamina (50). By less than 1 month of age, the cortex in the
precentral and postcentral gyri has lower intensity than the surround-
ing cortex (Fig. 2-7). By age 2 months, patches of low signal intensity
Barkovich_Chap02.indd 34
are seen in the central centrum semiovale; this makes it difficult to
distinguish white matter from the surrounding cortex because both
have low signal intensity. By age 4 months, the intensity of the precen-
tral and postcentral gyri is indistinguishable from that of adjacent gyri,
which have also diminished in signal intensity (Fig. 2-8). Low signal
intensity is seen in the optic tracts at birth in some patients and at
age 1 month in most; the decrease in signal intensity extends poste-
riorly along the optic radiations during the subsequent 2 months; by
4 months of age, the calcarine fissure shows some low signal intensity.
By age 4 months, the globi pallidi are slightly hyperintense compared
to the putamina; they will remain hyperintense until 8 to 10 months,
when the globi pallidi and putamina become isointense again.
Most deep white matter tracts of the cerebrum decrease in signal
intensity between 6 and 12 months of age (Figs. 2-9 to 2-12). The inter-
nal capsule matures in a posterior-to-anterior fashion. The more ante-
rior portion of the posterior limb contains a thin strip of hypointensity
by approximately 7 months; progressive thickening of the hypointense
area continues up to 10 months of age. The anterior limb of the inter-
nal capsule is completely hypointense by 11 months in normal patients;
hypointensity can be detected as early as 7 months in some patients but
is always preceded by the presence of low signal intensity in the poste-
rior limb. The corpus callosum matures from posterior to anterior; the
splenium shows low signal intensity by age 6 months and the genu by
age 8 months (Figs. 2-9 and 2-10). The basal ganglia begin to dimin-
ish in signal intensity relative to the subcortical white matter at 5 to
7 months of age. This appearance gradually fades as the surrounding
brain decreases in signal intensity as a result of myelination. The basal
ganglia appear essentially isointense with the subcortical white matter
by the age of approximately 10 months (Fig. 2-11). The globus pallidus
will become hypointense with respect to white matter again around the
end of the first decade of life; this decrease in intensity results from iron
deposition and will be described later in this chapter.
The subcortical white matter (other than the calcarine and Rolan-
dic areas) matures last, proceeding from the occipital region anteri-
orly to the anterior frontal and temporal lobes. In the past, subcortical
white matter maturation was described as being complete by about
24 months (22). With improved signal-to-noise and thinner imag-
ing sections on modern MR scanners, some unmyelinated subcortical
white matter can still be detected a bit later, but it is still essentially
complete by 30 months. Myelination of deep white matter begins at 9
to 12 months of age in the occipital lobe and at 11 to 14 months fron-
tally (Figs. 2-12 and 2-13); deep white matter in the anterior temporal
lobe matures last. Extension of the low signal intensity into the subcor-
tical white matter begins at about 1 year in the perirolandic region and
is essentially complete, even on modern images, by 24 to 28 months
(Fig. 2-14). Thus, with the exception of the so-called terminal zones
(see following section), white matter maturation, as assessed by MR, is
complete in the early part of the third year of life. During the progress
of the peripheral extension of the low signal intensity within the white
matter, the mantle of gray matter gives the appearance of progressive
thinning, and the subcortical white matter often has a heterogeneous
appearance.
Terminal Zones
As maturation in the centrum semiovale progresses, nearly all sub-
jects have persistent areas of high signal intensity in the white matter
lateral to the bodies of the lateral ventricles and, more prominently,
dorsal and superior to the ventricular trigones on T2-weighted images
(Fig. 2-15). These areas are most often homogeneous, although in
some patients they may be patchy. They are more difficult to identify on
the first echo of the long TR sequence than on the second and usually
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 35

FIG. 2-8. MRI of the brain of a normal 4-month-old. A–E. SE 550/15 images show rostral progres-
sion of the maturation of the internal capsule; the anterior limbs of the anterior capsule are now well
myelinated. The splenium of the corpus callosum should always have high signal intensity by this age.
Notice the isointensity of the cortical gray matter and subcortical white matter, resulting in difficulty
in the identification of structural abnormalities at this age on T1-weighted images. F–G. Note the
relative lack of change on the T2-weighted image from the neonate (Fig. 2-7).

Barkovich_Chap02.indd 35 5/7/2011 2:42:06 AM

 36 Pediatric Neuroimaging

FIG. 2-9. MRI of the brain of a normal 6-month-

old. A–E. SE 550/15 images show further progres-
sion of brain maturation. Both the splenium and
the genu of the corpus callosum are of high signal
intensity at this age. There has been progression
of the maturation of the centrum semiovale with
increasing hyperintensity of subcortical white
matter, most notably in the occipital and para-
central regions. F–J. SE 3000/120 images reveal a
diminution of signal intensity within the centrum
semiovale. Additionally, there is a relative decrease
in the signal intensity of the basal ganglia with
respect to the surrounding brain. The splenium
of the corpus callosum is of low signal intensity at
this age and there are patches of low signal inten-
sity within the callosal genu.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 37

FIG. 2-9. (Continued)

FIG. 2-10. MRI of the brain of a normal

8-month-old. A–E. SE 550/15 images at
this age show essentially an adult appear-
ance at first inspection. Hyperintensity of
the subcortical white matter tracts is seen
in the paracentral and occipital regions
but is not yet present in the frontal or
parietal regions.

Barkovich_Chap02.indd 37 5/7/2011 2:42:11 AM

 38 Pediatric Neuroimaging
appear isointense to surrounding white matter on a proton density
image. The primary cause of this high signal intensity is probably the
known delayed myelination of the fiber tracts involving the associa-
tion areas of the posterior and inferior parietal and posterior temporal
cortex. Large perivascular spaces probably contribute to the high signal
intensity, particularly in the peritrigonal area (see subsequent para-
graph in this section). Yakovlev and Lecours have called these regions
the “terminal zones” because some of the axons in these regions do not
stain for myelin until the fourth decade (47). These areas of persistent
high signal intensity are seen throughout the first decade and, in some
patients, into the second decade of life.
It is important to differentiate the terminal zones from white mat-
ter injury resulting from prematurity (“periventricular leukomalacia”
[see Chapter 4]) and hydrocephalus (see Chapter 8), and from meta-
bolic disorders (see Chapter 3); all can also be associated with areas
of prolonged T2-relaxation in the peritrigonal region. In general, the
white matter injury of prematurity is more sharply defined and is situ-
ated more inferiorly, lateral to the trigones and near the optic radia-
tions. Injured white matter is of very high intensity and is typically
bright on the first echo of the T2-weighted sequence. Moreover, white
matter injury is associated with loss of brain tissue, typically resulting
Barkovich_Chap02.indd 38
FIG. 2-10. (Continued) F–J. On SE 3000/120
images, the anterior limbs of the internal capsule are
starting to show diminished signal intensity. Both
the splenium and the genu of the corpus callosum
are of low signal intensity at this age. The white
matter in the occipital and paracentral regions is
now isointense with the overlying cortex.
in irregularity of the ventricular wall, abnormally deep cortical sulci,
with the cortex sometimes extending down to the ventricular surface,
and thinning of the body of the corpus callosum (see examples of white
matter injury of prematurity in Chapter 4). Baker et al. (56) suggested
that the differentiation between these normal peritrigonal areas of high
signal intensity and white matter injury of prematurity is very difficult.
They noted, however, that a layer of myelinated white matter is present
between the trigone of the ventricle and the terminal zones in normal
patients (Fig. 2-15). When the peritrigonal high signal is due to periven-
tricular leukomalacia, this layer of normally myelinated white matter is
absent. Differentiation from hydrocephalus is usually easier as a shunt
or third ventriculostomy (see Chapter 8) can be detected on the MR
study. White matter disease due to metabolic disorders is typically much
more extensive than peritrigonal; details are described in Chapter 4.
Large Perivascular Spaces
Another condition that can mimic both the terminal zones and periven-
tricular leukomalacia on MR is enlargement of perivascular spaces
(Fig. 2-15D–F). Indeed, as stated above, the high signal of the perivas-
cular spaces may contribute to the T2 hyperintensity of the terminal
zones. Studies have shown that perivascular spaces are commonly seen
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
with modern, high quality MR studies. With thin section volumetric
T1-weighted images, Groeschel et al. (57) were able to identify them
in 125 out of 125 normal volunteers below the age of 30 years; with
routine 5 to 6 mm sections, they were identified in 80% of a group
of pediatric clinical scans. Focally expanded or “dilated” perivascular
spaces, as defined by Groeschel et al., are seen in 1.5% to 3% of nor-
mal subjects (57,58). Although most patients with dilated perivascular
spaces, and even those with “giant” perivascular spaces (57), are neu-
rologically normal, evidence has been presented that affected patients
have a higher incidence of neuropsychiatric disorders than the general
pediatric population (58).
Milestones
Barkovich et al. (22) charted the ages at which the changes of myeli-
nation appeared on T1- and T2-weighted images, as well as nor-
mal MRI milestones for myelination of brain (Table 2-3). During
Barkovich_Chap02.indd 39
39
FIG. 2-11. SE 3000/120 MRI of the normal
10-month-old infant. T2-weighted images
demonstrate decreasing signal intensity of
the white matter diffusely throughout the
brain. This causes a recession of the appear-
ance of hypointensity of the basal ganglia
(C,D) with respect to the white matter noted
in the 6- and 8-month-old patients. The cor-
tex and underlying white matter are essen-
tially isointense throughout most of the brain
at this age. For this reason, structural abnor-
malities of the brain at this age are identified
best on T1-weighted images. The anterior
limbs of the internal capsule are hypointense
with respect to surrounding structures in
essentially all patients at this age (C,D).
the first 6 months of life, T1-weighted images are most useful for
assessing normal brain maturation. On T1-weighted images, high
signal intensity should appear in the anterior limbs of the internal
capsules and should extend distally from deep cerebellar white mat-
ter into the cerebellar folia, by 3 months of age. The splenium of the
corpus callosum should be of moderately high signal intensity by
the fourth month, and the genu of the corpus callosum should be
of high signal intensity by age 6 months. An essentially adult pat-
tern is seen by approximately 8 months of age with the exception
that some of the most subcortical white matter fibers (particularly in
the anterior frontal and anterior temporal lobes) have not acquired
high signal intensity. After age 6 months, T2-weighted images are
more useful in the assessment of normal brain maturation. On
T2-weighted images, the splenium of the corpus callosum should
be of low signal intensity by 6 months of age, the genu of the corpus
callosum by 8 months of age, and the anterior limb of the internal
capsule by 11 months of age. The deep frontal white matter should
5/7/2011 2:42:14 AM
 40 Pediatric Neuroimaging
be of low signal intensity by age 14 months. With the exception of
the subcortical white matter, the entire brain should have an adult
appearance by 18 months, and the subcortical white matter should
be mature by about 30 months.
Postulated Causes of T1 and T2 Shortening
Associated with Myelination
It is interesting to note that brain maturation occurs at different rates
and times on T1-weighted SE images, T2-weighted SE images, and
inversion recovery images with short inversion time (STIR) (22,59).
The exact reasons for these differences have not been entirely worked
out. It is known that there are two distinct components of water con-
tributing to MR images in white matter; these lead to a biexponential
curve of T2 relaxation during white matter development (60). The
first, composed of intramyelinic water, has relatively short T1 and
Barkovich_Chap02.indd 40
FIG. 2-12. SE 2500/80 MRI of the brain of
a normal 12-month-old. There is increasing
low signal intensity of the white matter in the
paracentral and occipital regions. The images
are otherwise very similar to the 10-month-
old infant.
T2 relaxation times. The second component, composed of axonal
and extracellular water, has longer T1 and T2 relaxation times (61).
The new technique of myelin water imaging allows specific analysis
of myelination by this technique (62), but such techniques are not yet
available for clinical use.
In the time scale of typical T1 values, myelin water can diffuse
across axonal and myelin membranes and interact with water mol-
ecules in the other compartments. It is known that the T1 shortening
in developing white matter correlates temporally with the increase in
cholesterol and glycolipids that accompany the formation of myelin
from oligodendrocyte processes (22,63). In addition, galactocerebro-
sides, which are among the most prevalent glycolipids in myelin, cause
marked T1 shortening and magnetization transfer in saline solutions
in vitro (64). Galactocerebrosides are prevalent on the oligodendrocytic
processes as they begin to envelop the axon in response to increasing
electrical activity (65). Thus, the aqueous interaction of cholesterol (66)
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 41

FIG. 2-13. SE 2500/80 MRI of the

brain of a normal 15-month-old. The
maturation of the deep white matter
has progressed significantly since the
12-month-old stage. Although somewhat
patchy, the subcortical white matter is
now hypointense in a great deal of the
cerebrum. The maturation of the white
matter is slowest in the frontal and tem-
poral lobes.

FIG. 2-14. SE 2500/80 MRI

of the brain of a normal
22-month-old. The appearance
of the brain is essentially identi-
cal to that of an adult. Notice,
however, that there is still some
patchy high signal intensity in
the anterior frontal white mat-
ter and in the white matter
parallel to the lateral ventricles.
This is most prominent dorsal
to the bodies and trigones of the
lateral ventricles.

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 42 Pediatric Neuroimaging

FIG. 2-14. (Continued)

FIG. 2-15. Terminal zones and large perivascular spaces. A–C. Axial SE 2500/80 (A) and coronal SE 2500/80 (B) and FLAIR (C) images show persistent
increased signal intensity lateral, superior, and posterior to the lateral ventricles (arrows), particularly in the region of the trigones. These regions probably
represent areas of known slow myelination within the brain (sometimes called “terminal zones”) and should not be mistaken for areas of ischemia or brain
damage. They are seen from about age 16 months until age 10 years. D–F. T1 (C) and first and second echo T2-(D and E) weighted images show curvilinear
periventricular areas that are isointense to CSF on all imaging sequences. This is the classic appearance for perivascular spaces.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 43

TABLE 2-3 Ages when Changes of Myelination Appear

Anatomic Region T1-Weighted Images T2-Weighted Images
Superior cerebellar peduncle 28 gest wk 27 gest wk
Median longitudinal fasciculus 25 gest wk 29 gest wk
Medial lemnisci 27 gest wk 30 gest wk
Lateral lemnisci 26 gest wk 27 gest wk
Middle cerebellar peduncle Birth Birth to 2 mo
Cerebral white matter Birth to 4 mo 3–5 mo
Posterior limb internal capsule
Anterior portion First month 4–7 mo
Posterior portion 36 gest wk 40 gest wk
Anterior limb internal capsule 2–3 mo 7–11 mo
Genu corpus callosum 4–6 mo 5–8 mo
Splenium corpus callosum 3–4 mo 4–6 mo
Occipital white matter
Deep 3–5 mo 9–14 mo
Subcortical 4–7 mo 11–15 mo
Mid-frontal white matter
Deep 3–6 mo 11–16 mo
Subcortical 7–11 mo 14–18 mo
Anterior frontal white matter
Deep 5–8 mo 12–18 mo
Subcortical 10–15 mo 24–30 mo
Centrum semiovale 2–4 mo 7–11 mo
gest wk, gestational weeks; mo, month.

and galactocerebrosides on the surface of the myelin bilaminar
membrane are most likely responsible for the early T1 shortening we
see in developing white matter.
At the relatively long echo times used in acquiring T2-weighted
images in neonates, only the signal from axonal and extracellular water
is likely to contribute to the MR signal (67). Furthermore, the increas-
ing hypointensity seen on T2-weighted images of the maturing brain
correlates temporally with chemical maturation of the myelin sheath,
specifically with tightening of the myelin spiral around the axon (asso-
ciated with conformational changes of myelin proteins) and satura-
tion of polyunsaturated fatty acids within the myelin membranes
(22,68–71). If, indeed, this T2 signal is entirely from extracellular and
axonal water, it may reflect decreasing proton density. This decrease in
proton density is possibly related to the further (hydrophobic) chemi-
cal maturation of myelin, to decreasing axonal water secondary to
microtubule and microfilament production, or to decreasing extracel-
lular free water secondary to myelin production and the elaboration of
glia and glial processes in the white matter.
Other factors are likely to be of importance, as well, and some of
these are important for our understanding of white matter diseases.
Proper packing of lipids in the bilaminar membrane is critical to the
stability of myelin and results in short T2 relaxation times in vitro (72).
Altered packing of these lipids results in increases in T2 relaxation
times (72), a point that is important in the imaging of inborn errors
of metabolism, discussed in Chapter 3. Cholesterol, glycolipids, and
portions of the myelin proteins are hydrophilic; that is, they hydrogen
bond strongly with water molecules (73–75). Therefore, it is likely that
the initial T1 shortening seen by MR results from an increase in the
amount of bound water in the brain (and consequent decrease in the
amount of free water) secondary to hydrogen bonding of free water to
surface galactocerebrosides and, possibly, cholesterol and proteins.
Other Approaches to Brain Maturation by MR
Many different approaches have been used to grade brain matura-
tion according to the changes in T1 and T2 relaxation. Some authors
(59,76–78) have been largely descriptive. Others (22,39) have tried to
quantify myelination and create milestones of normal myelination
by which delayed myelination can be identified. Dietrich et al. (79)
approached the subject of normal brain maturation by dividing the
appearance of the brain on T2-weighted spin-echo images into three
patterns: (a) infantile (birth to 6 months), (b) isointense (8–12 months),
and (c) early adult (10 months onward). In the infantile pattern, the
cerebral white matter is hyperintense relative to gray matter, whereas

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 44 Pediatric Neuroimaging
the adult pattern shows hypointense white matter. The appearance of
the isointense and early adult patterns is delayed in patients with devel-
opmental delay. A similar, but more complex staging system, dividing
brain maturation into five stages, has been proposed by Staudt et al.
(80,81). Bird et al. (82) determined that the gray and white matter
should be isointense by age 4 months on T1-weighted images and by
9 to 10 months on T2-weighted images. They considered the age at
which gray and white matter are isointense as a critical factor in evalu-
ating patients for developmental delay. Some authors have analyzed the
images in terms of patterns and attempted to assess degree of, and delay
in, maturation on the basis of the pattern (48,49,83–85). We choose to
assess maturation through the use of the normal milestones described
above, as it is a rapid and reliable method that does not require any post
processing of the imaging data. Indeed, any of the methods described
above are easy to use and reliable.
A number of studies (86,87) have postulated the existence of a win-
dow of time during which delayed myelination can be detected by MR.
This window seems to be between the ages of 4 months and 2 years.
Delayed myelination can be detected in children older than 24 months
only when it is very severe.
The advent of diffusion tensor imaging (DTI) (88) allows brain
maturation to be quantified by the calculation of regional water diffu-
sion and diffusion anisotropy in the developing brain (25,89–92). This
is extremely useful in research but is not essential in the routine assess-
ment of pediatric brain MR in the reading room. DTI and its use in
assessing brain maturation are discussed in more detail in section on
“Diffusion Tensor Imaging and Tractography” of this chapter.
NORMAL POSTNATAL MR DEVELOPMENT
OF THE CORPUS CALLOSUM
The embryological development of the corpus callosum is discussed in
Chapter 5. Briefly, the axons of the corpus callosum navigate from the
cerebral cortex to the midline in response to cues from the developing
hemisphere (93–96). These axons initially cross the midline near the
foramina of Monro, at a point that will eventually be the junction of
the callosal genu and body, and in the hippocampal commissure, the
axons of which act as guides that are followed by axons forming the
callosal splenium. Specialized groups of midline glial cells form a bed
for ingrowth and midline crossing of the callosal fibers; axons will not
cross if the proper substrates are not present in the interhemispheric
fissure (97–100). The earliest pioneer axons cross at approximately
12 weeks; the last axons cross the midline at 18 to 20 weeks of gestation.
Although all the components of the corpus callosum are present by
20 weeks, growth of the structure is far from complete. From 20 weeks
to term, the length increases 25%; the thickness of the body increases
by 30% and the genu by 270% (101). The length of the corpus can
be measured postnatally by cranial ultrasound and has been found to
grow an average of 0.11 mm/d (range 0.05–0.29), with the rate being
similar for infants born at all gestational ages (102). As all of the cal-
losal axons are presumed to be present at the time of birth, the post-
natal callosal growth presumably directly reflects the myelination of
the axons. Because the corpus callosum is easily evaluated by MRI and
transfontanelle sonography, an understanding of the normal appear-
ance of the developing corpus has become important.
The appearance of corpus callosum is quite different in the fetus
and preterm infant than the term neonate and different in the term
neonate and infant than in the adult. An adult appearance evolves
slowly over the first 8 to 10 months of life. In the fetus and preterm neo-
nate, the corpus callosum is hypointense compared with cortical gray
matter on T1-weighted images and isointense with surrounding brain
on T2-weighted images; it is extremely thin and of uniform size and
Barkovich_Chap02.indd 44
may be difficult to see on routine sagittal images, particularly in fetuses
of gestational age less than 24 weeks (Fig. 2-16A–C). In the near-term
and term infant, the corpus is usually visible and the signal intensity
approaches that of cortical gray matter on T1-weighted images. The
callosal shape at this age is thin and flat; the bulbous enlargements seen
at the adult genu and splenium are not present (103) (Fig. 2-16D and E).
The first postnatal change is a substantial, albeit variable in time, thick-
ening of the genu, which frequently occurs as early as the second and
third months of life. DeLacoste et al. (104) have demonstrated that the
axons crossing through the genu come from the inferior frontal and
anterior, inferior parietal regions. The enlargement of the genu, there-
fore, presumably relates to the myelination of the interhemispheric
connections of the inferior portions of the precentral and postcentral
gyri; these areas, which are involved with basic motor and sensory
function, develop early in life.
At birth, the splenium is intermediate in size between the body
and the genu of the corpus callosum. It enlarges slowly until the fourth
or fifth postnatal month and then rapidly increases in size (Fig. 2-16F
and G). By the end of the seventh month, the splenium is equal in size
to the genu; it then gradually enlarges in proportion with the genu
and the rest of the brain through the remainder of the first year (103)
(Fig. 2-16G and H). By about 9 to 10 months, the appearance of the
corpus callosum becomes similar to that in the adult (Fig. 2-16I). The
axons in the splenium arise from the visual and visual association areas
of the cortex (104,105). Not surprisingly, the rapid development of the
splenium corresponds temporally with increasing visual awareness at
4 to 6 months of age. It is during this period that the infant devel-
ops binocular vision and visual accommodation and begins to iden-
tify objects (106). Both binocular vision and object identification are
dependent on interhemispheric connection. Thus, the enlargement of
the splenium presumably relates to the myelination of connections
between the visual cortex and the association areas of the brain in the
increasingly visually aware child.
The body of the corpus callosum steadily enlarges throughout
childhood without any detectable growth spurts. The size of the body
is relatively uniform, except that a focal thinning is frequently seen at
the junction of the body and splenium (Fig. 2-16H); Raybaud refers
to this section of the corpus as the callosal “isthmus” (107). This focal
thinning is seen in adults as well. McLeod et al. (108) found an isthmus
in 22% of 450 randomly selected patients. The normal variant should
not be mistaken for a segment of hypoplasia.
The lesser enlargement of the callosal body compared with the
genu and splenium probably represents the anatomic origin of these
fibers and the phylogenetic development of the brain. Sensory and
visual function is important early in life for all animals. It is, there-
fore, not surprising that the areas of the brain serving these functions
myelinate first and that the association tracts related to these func-
tions, which run through the corpus callosum, develop early as well.
The more gradual growth of the body of the corpus callosum probably
reflects the lesser importance of association areas in the temporal and
parietal lobes (from which these fibers originate [104,105]) in early life
and in lower orders of animal life. The fact that the axons from the
association areas myelinate later as well (as seen by the late myelina-
tion of the temporal lobes and the persistent areas of prolonged T2
relaxation superior and dorsal to the trigones) further supports this
hypothesis.
The length of the corpus callosum changes slowly and erratically
during the first year of life. Callosal length seems to vary more with
respect to head size and shape than with age (103), probably because
normal infants vary more in head size and shape than in head enlarge-
ment during the first year of life. This hypothesis is supported by
the fact that the ratio of callosal length to AP brain diameter is quite
5/7/2011 2:42:19 AM
 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 45

FIG. 2-16. Normal corpus callosum development. A. Midline sagittal single-shot half-Fourier RARE image of a 23 gestational week fetus shows that the
corpus callosum (arrows) is uniformly thin and isointense to surrounding brain. It is, therefore, somewhat difficult to differentiate from surrounding brain.
B. In a 28 gestational week fetus, the corpus is more easily seen, but remains uniformly thin and isointense to surrounding brain. C. Corpus callosum in
a premature neonate of 29 postconceptional weeks. On this SE 500/11 image, the corpus is very hypointense compared to gray matter and very thin. The
presence of the corpus is verified by the normal cingulate gyrus and sulcus above the expected callosal position. D. Corpus callosum in a premature infant of
34 postconceptional weeks. On this SE 500/11 image, the corpus is slightly hypointense compared with gray matter. It is still very thin, but is barely visible.
Note that the cerebellum is still very small at this age.

constant in infants throughout the first year of life (103). Some authors
have investigated the relationship of the area of the corpus callosum to
maturity (109). Although analysis of callosal area on midline sagittal
images is an accurate method of quantification of white matter matu-
ration, it is time consuming and, in the clinical setting, has not proven
useful in most practices. The length of the corpus callosum has been
studied in fetuses and premature neonates; findings indicate that the
corpus grows more slowly in prematurely born infants than in fetuses
of the same gestational age (102). As described earlier, similar delays of
maturation have been found in sulcation and myelination of prema-
turely born neonates. Overall, however, owing to the insensitivity of
callosal length and the difficulty of calculating callosal area as markers
of normal growth, the changes in callosal shape and signal intensity
(see earlier section on “Normal Myelination”) are the preferred means
of judging normal maturation of the corpus callosum and, thereby,
normal brain development.
NORMAL MR DEVELOPMENT
OF THE PITUITARY GLAND
In the fetus and neonate, the pituitary gland has a convex superior
surface and a shorter T1 relaxation time (higher signal intensity on
T1-weighted images) than the remainder of the brain (Fig. 2-17A)
(110–112). The signal intensity and size diminish slowly and linearly
until approximately 2 months after birth (Fig. 2-17B), the time at which
the anterior lobe of the pituitary gradually assumes the appearance of a
child, with a flat or slightly concave superior margin and a signal inten-
sity of normal gray matter on T1-weighted spin-echo images (113,114).

Barkovich_Chap02.indd 45 5/7/2011 2:42:20 AM

 46 Pediatric Neuroimaging

FIG. 2-16. (Continued) E. Normal 1-month-old. On this SE 600/20

image, the corpus callosum is isointense with the rest of the brain. The
corpus callosum is uniformly thin at this age without the normal bulbous
enlargement of the genu and splenium; the genu, body and splenium are
all of the same thickness. F. Normal 4-month-old. By 3 to 4 months of
age, the splenium of the corpus callosum increases in size and begins to
show an increased signal intensity as compared to the rest of the brain
on SE 600/20 images. These changes probably result from the process
of myelination in the visual association fibers. G. Normal 7-month-old.
By 6 to 7 months of age, the corpus callosum is of uniform high signal
intensity as compared with surrounding brain. The genu and splenium
of the corpus are now large as compared to the body. The corpus is still
relatively thin. H. Normal 10-month-old. By 8 to 9 months, the corpus
callosum begins to thicken in the genu and splenium, taking on more of
an adult appearance. The thinning of the corpus at the junction of the
posterior body and splenium (arrow) is a normal variant and does not
connote pathology. I. Normal mature corpus callosum in a 19-year-old.

Barkovich_Chap02.indd 46 5/7/2011 2:42:21 AM

 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
FIG. 2-17. Development of normal pituitary gland. A. Normal newborn pituitary. The gland is upwardly convex and is uniformly bright on T1-weighted
images. B. Normal infant pituitary gland. By age 2 to 3 months, the adenohypophysis (anterior pituitary) loses its high signal on T1-weighted images,
allowing the bright neurohypophysis (posterior pituitary) to be identified as a separate structure.
Of note, the evolution of signal is similar in infants born at term and in
those born prematurely, indicating that the changes result from adjust-
ments to extrauterine life and are not related to the infant’s devel-
opmental stage (115). The low signal of the anterior pituitary gland
contrasts with the intrinsic high signal of the posterior pituitary gland
on T1-weighted images. This high signal is postulated to result from
the effects of the proteins (neurophysins) that transport the posterior
pituitary hormones from the hypothalamus to the neurohypophysis
(116). During childhood, the pituitary gland slowly grows in all dimen-
sions, maintaining a flat or mildly concave upper surface, with a height
of 2 to 6 mm in the sagittal plane. Note that during childhood, until
puberty begins, the anterior lobe of the pituitary is typically small.
Although the normal size of the developing pituitary stalk (infundibu-
lum) has never been determined, the size of the mature infundibulum
is established and this number can be used in children. The infundibu-
lum should be no more than 2.6 mm in its thickest portion on coro-
nal and sagittal MR images; greater thickness is highly suspicious for
pathologic infiltration (see the section on “Suprasellar Tumors” in
Chapter 7) (117,118). The size of the stalk relative to the size of the
brain never changes, and, as a general rule, it should never be as large
as the basilar artery on axial images (119).
With the arrival of puberty, the pituitary gland increases dramati-
cally in size and (in girls, but not boys) demonstrates a marked upward
convexity (Fig. 2-18). Of note, the gland is homogeneous on all imag-
ing sequences, both prior to and after contrast administration; this aids
in differentiation from an adenoma and a Rathke cleft cyst. The height
of the gland may reach 10 mm in girls and 7 to 8 mm in boys (120,121).
The appearance then slowly evolves into that of the adult gland over
the subsequent 5 to 8 years.
NORMAL DEVELOPMENT OF THE SKULL
AND PARANASAL SINUSES
The Skull
At birth, the T1 signal intensity of the bone marrow in the clivus and
in the diploic space of the calvarium is of low signal intensity with
respect to brain and to the sphenooccipital synchondrosis (Fig. 2-19A).
Barkovich_Chap02.indd 47
47
The low signal intensity is believed to result from the presence of red
(actively hematopoietic) marrow. By the end of the second year of life,
the marrow in the crista galli and the nasal processes of the frontal
bone develop high signal intensity on T1-weighted images (Fig. 2-19B).
During the third year of life, patchy areas of increased signal intensity
begin to appear in the body of the sphenoid bone and in the clivus on
T1-weighted images (Fig. 2-19C). These foci of T1-shortening may ini-
tially appear in the basiocciput or the basisphenoid. As time progresses,
most of these regions of fatty marrow will undergo pneumatization
to become parts of the paranasal sinuses, although the mechanisms
by which this occurs are unknown (122). Slowly, over the next 3 to
4 years, these foci of short T1 relaxation time enlarge and coalesce
(Fig. 2-19C–E). By 10 years of age, the marrow in almost all children
is almost entirely of high signal intensity on the T1-weighted images
(Fig. 2-19F). A few small foci of low signal intensity may remain well
into the second decade.
After intravenous administration of paramagnetic contrast, the
immature skull and skull base show variable enhancement in infants
and young children (123). Most likely, the enhancement is the result
of the vascularity of the hematopoietic marrow in the calvarial diploë
and, particularly, the skull base of infants. The amount of enhance-
ment is age-related, as the immature homogeneous marrow of younger
children enhances more and to a greater degree than the heterogeneous
marrow of older children (123). The amount of enhancement seen in
older children after fat suppression pulses have been applied is not
known. The normal enhancement of bone marrow in infants can be
problematic in patients with diseases such as leukemia and neuroblas-
toma; differentiation of normal hematopoietic marrow from meta-
static neuroblastoma may not be possible by MR alone unless the bone
is expanded or periosteum is lifted from the surface of the bone. Cor-
relation with CT and radionuclide studies is essential.
Prior to pneumatization of the sphenoid sinus, an area of mark-
edly increased signal intensity appears in the presphenoid portion of
the sphenoid bone (Fig. 2-19C). This high signal, believed to represent
fatty change, appears between 7 months and 2 years of age, and then
regresses as pneumatization of the sphenoid sinus occurs after the age
of 2 years (Fig. 2-19D–G). Some of the high signal may persist into the
second decade (124).
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 48 Pediatric Neuroimaging
FIG. 2-18. Menarchal pituitary gland. As seen on these contrast-enhanced T1-weighted sagittal (A) and coronal (B) images, children entering puberty have
enlarged pituitaries, typically larger in girls than in boys.
The maturation of the diploic space of the calvarium occurs at
almost the identical time as the clivus. Foci of high signal intensity
on T1-weighted images begin to appear within the diploic space at
approximately age 3 years. More and more areas of high signal intensity
develop over the next 4 years until, at about 7 years of age, the diploic
space is of nearly uniform high signal intensity (125). Enhancement of
the diploic space parallels that of the clivus.
On MR, the sphenooccipital synchondrosis remains prominent
throughout childhood and can be seen well into the third decade of
life. This persistence of the synchondrosis on MR is in marked contrast
to the appearance on CT. On CT, the sphenooccipital synchondrosis
appears widely patent until the age of 8 years, when ossification centers
appear. In boys, the ossification center is single and appears in the mid-
line, whereas in girls, bilateral paramedian ossification centers appear.
In the study of Okamoto et al. (126), fusion of the basisphenoid and
basiocciput appeared complete by CT at age 13 years; no sphenooccipi-
tal synchondrosis was seen beyond that age. Madeline and Elster found
complete fusion of the sphenooccipital synchondrosis in 95% of girls
by age 16 years and in 95% of boys by age 18 years (127).
The importance of understanding the normal temporal sequence
of skull maturation lies in the evaluation of the patient with systemic
disease. For example, several disease entities will cause reactivation of
erythropoiesis within the bone marrow. In particular, states of chronic
anemia, such as sickle cell disease and thalassemia, will cause a rever-
sion of bone marrow to the immature low signal intensity. Other
disease processes, such as leukemia, can infiltrate the bone marrow;
such infiltration will also cause a lengthening of the T1 relaxation time
resulting from replacement of fat by a proliferative marrow. If low sig-
nal intensity is seen diffusely throughout the clivus beyond the age of
4 years, some underlying condition such as an anemia or a systemic,
infiltrative disease should be sought.
The Cranial Fontanelles and Sutures
In the newborn, the calvarium is composed of many small bones that
are separated by linear strips of connective tissue (sutures) and carti-
lage (synchondroses). At several areas, broader, more irregular patches
of connective tissue, known as fontanelles, separate the bones. These
Barkovich_Chap02.indd 48
areas of elastic, pliable connective tissue allow the calvarium to mold
during the process of birth and also allow the head to grow rapidly dur-
ing the first 2 years after birth. These sutures and fontanelles are well
described in most standard pediatric texts and will not be discussed
at length here. Suffice it to say that the neonate has six major sutures
in the cranial vault that may be involved in pathologic conditions:
one midline metopic suture between the paired frontal bones, derived
from metopon (Greek for forehead); two coronal sutures between the
frontal and parietal bones bilaterally, from corona (Latin for crown
or garland); two lambdoid sutures between the parietal and occipital
bones (named because of the resemblance to the Greek letter lambda);
and one midline sagittal suture that separates the two parietal bones,
derived from sagitta (Latin for arrow) (128). In addition, one major
fontanelle is present in the neonate: the anterior (at the junction of the
sagittal, metopic, and two coronal sutures). Five smaller fontanelles, the
paired anterolateral fontanelles at the junction of the squamosal and
coronal sutures, the (single) posterior fontanelle (at the junction of the
lambdoid sutures and the sagittal suture), and the paired posterolateral
fontanelles at the junction of the mendosal and lambdoid sutures, are
important mainly as potential acoustic windows for sonography.
The normal times of closure of the sutures and fontanelles is of
some importance, as premature closure often requires surgical cor-
rection or may be a sign of and underlying syndrome or metabolic
disorder (see section “Craniosynostosis”, Chapter 5). The fontanelles
close first, with the posterior closing by 8 weeks, the anterolateral by
3 months, the anterior by 15 to 18 months, and the posterolateral by
24 months. The first major suture to close is the metopic, which starts
to close as early as 3 months and is completely closed by 9 months,
as assessed by 3D CT reformations (129). The precise time of closure
of the other sutures has not been established; these sutures don’t fully
close until adulthood (128). However, as a general rule, no part of the
sagittal, coronal, or lambdoid sutures should appear closed within the
first year of life.
Maturation of the Paranasal Sinuses
The maxillary sinus is the first of the paranasal sinuses to develop. The
sinuses are rudimentary at birth, lying entirely medial to the orbit.
5/7/2011 2:42:23 AM
 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 49

FIG. 2-19. Development of normal bone marrow in the clivus as

seen on T1-weighted images. A. Normal clivus of a 3-month-old.
The marrow within the basiocciput and basisphenoid (white arrows)
is of uniform low signal intensity as compared to the sphenooccipi-
tal synchondrosis. The presphenoid region of the sphenoid bone
is isointense to the basisphenoid. B. Normal 12-month-old infant.
During the second year of life, the crista galli (closed arrow) and
the nasal process of the frontal bone (open arrow) develop high sig-
nal intensity within their marrow. C. Normal 18-month-old infant.
Between the age of 6 months and 2 years, fatty change occurs within
the presphenoid portion of the sphenoid bone. The basisphenoid
and basiocciput remain of uniform low intensity. D. Normal 4-year-
old child. The fatty change in the presphenoid region has begun to
recede as pneumatization occurs. There are patches of high signal
intensity within the basisphenoid and basiocciput as normal yellow
marrow begins to appear. E. Normal 5-year-old child. The regions
of high signal intensity within the basisphenoid and basiocciput are
becoming more apparent and beginning to coalesce.

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 50 Pediatric Neuroimaging
FIG. 2-19. (Continued) F. Normal 10-year-old. The sphenoid sinus is nearly completely pneumatized at this age. Only a small amount of fatty
change remains in the most inferior portion of the presphenoid (arrow). The basisphenoid and basiocciput are now composed of mainly yellow
marrow; the clivus therefore shows mainly a high signal intensity compared to the synchondrosis with a few patchy areas of low signal intensity
persisting. G. Mature clivus in a normal 16-year-old. The basiocciput and basisphenoid are now of uniform high signal intensity.
They are commonly partially or completely opacified. The sinuses
grow rapidly through childhood, with a growth rate of 2 mm/y in
the vertical dimension and 3 mm/y in the anteroposterior dimension
(130). Growth continues until the end of puberty, when facial growth
ceases. The following milestones are useful: (a) Lateral margin of the
sinus projects under the medial orbital wall by the end of the first year.
(b) Sinus extends laterally past the infraorbital canal by age 4 years.
(c) Sinus reaches maxillary bone and plane of hard palate by age
9 years (131).
At birth, the ethmoid sinuses are developed more anteriorly than
posteriorly. Lack of aeration of the posterior ethmoid sinuses is consid-
ered normal until the age of approximately 6 years (130). Pneumatiza-
tion progresses posteriorly, with resultant enlargement of the posterior
air cells. By the late phases of pneumatization, the posterior cells are
larger and fewer than the anterior cells. The last phase of ethmoid
pneumatization involves development of the extramural air cells, the
agger nasi, Haller cells, and concha bullosa, which lie in the anterior
ethmoidal region (131).
The fetal sphenoid sinuses consist of small cavities (conchal
sinuses) within the developing sphenoid bones. Soon after birth, the
conchal sinuses fuse to the sphenoid bone and begin to pneumatize
(130). High resolution CT may show pneumatization of the sphenoid
sinuses as early as age 2 years; pneumatization is preceded by conver-
sion of red marrow to fatty marrow, as described earlier in this sec-
tion in the discussion of maturation of the skull (124). Pneumatization
proceeds inferiorly, posteriorly, and laterally, with the presphenoid
portion developing first (usually between the ages of 5 and 10 years
[122]), followed by the basisphenoid (typically after age 10 years [122])
and, in some patients, greater sphenoid wings and pterygoid processes.
As noted in the previous section, care must be taken not to mistake
the normal fatty changes that occur prior to pneumatization (124) for
hemorrhage, proteinaceous fluid, or inclusion tumor.
The frontal sinuses are the last of the paranasal sinuses to develop.
They originate as extensions of the anterior ethmoidal air cells (130).
At birth, they are normal bone containing red marrow. They follow
Barkovich_Chap02.indd 50
the same prepneumatization transition as the sphenoid sinuses in that
yellow, fatty marrow develops prior to pneumatization (131). Earliest
pneumatization is seen around the age of 2 years in the orbital pro-
cesses of the frontal bone. By age 4 years, pneumatization reaches the
nasion, advancing to the level of the orbital roof by age 8 years and into
the vertical portion of the frontal bone by age 10 years. Growth contin-
ues until the end of puberty. The extent of frontal sinus development is
extremely variable (131).
NORMAL DEVELOPMENT OF BRAIN IRON
In the adult, certain regions of the brain show a marked diminution in
signal intensity on T2-weighted spin-echo and gradient-echo images,
particularly at high field strength; the diminution in signal intensity is
less apparent on fast-spin echo images. This diminished T2 relaxation
time has been suggested to result from the presence of relatively high
quantities of iron in those locations (132), although the cause and effect
relationship is disputed (133). The most prominent areas in which this
phenomenon occurs are the basal ganglia, particularly the globus pal-
lidus, the substantia nigra (mostly in the medial pars reticularis), the
red nuclei, and the dentate nuclei of the cerebellum. Please note that
this work was done at 1.5 T, and that the iron deposition will become
apparent sooner if MR is performed at 3 T.
At birth, this accentuated T2 shortening is not seen anywhere in
the brain (134) (Fig. 2-20). The basal ganglia begin to manifest low
intensity with respect to the cerebral cortex on T2-weighted images at
approximately age 6 months. However, the globus pallidus and puta-
men at this age are isointense to one another and hypointense with
respect to the internal capsule. This initial decrease in signal intensity
on T2-weighted images is, therefore, believed to be secondary to myeli-
nation of the axons within the lentiform nuclei. Indeed, as the cerebral
white matter begins to myelinate, the basal ganglia become hyperin-
tense with respect to the surrounding white matter on T2-weighted
images. A second phase of T2 shortening in the globus pallidus, sub-
stantia nigra, and red nuclei becomes noticeable at 9 or 10 years of age
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 51

FIG. 2-20. Immature pattern of brain iron. A–C. In this normal 4-year-old, we see that the globus pallidus, red nucleus, pars reticularis of the substantia
nigra, and dentate nuclei of the cerebellum are all hyperintense as compared to normal white matter of the brain (arrows). This appearance usually changes
to isointensity with white matter before the age of 10 in the globus pallidus, substantia nigra, and red nucleus. The changes in the dentate nucleus occur
later and less consistently.

(134) (Fig. 2-21). At this age, the signal intensity of these areas becomes
equal to, and then less than, that of the surrounding white matter. The
NORMAL DEVELOPMENT OF THE SPINE
globus pallidus will be of lower signal intensity than surrounding brain Embryology
in 90% of patients by age 15 years (134) (Fig. 2-22). The signal intensity
At the end of the second gestational week, the normal human embryo
continues to diminish on T2-weighted images throughout the second
is a bilaminar structure comprised of a flat sheet of cells adjacent to the
decade and may continue at a slower rate throughout life.
amnion, termed the epiblast, and a second layer adjacent to the yolk sac,
The dentate nuclei of the cerebellum begin to show lower signal
known as the hypoblast. The hypoblast will eventually be replaced by
intensity at a slightly later age, with noticeable changes beginning to
the endoderm, which is believed to be a derivative of the epiblast. Soon
occur at about age 15 years (Fig. 2-21). This low signal intensity also
after, cells in the caudal midline of the embryo proliferate to form a
progresses slowly throughout life; however, there is less accumula-
primitive knot (also known as Hensen node, which defines the cephalic
tion of iron in the dentate nuclei than in the other iron-containing
end) and the primitive streak caudal to it. By about embryonic day 16,
regions of the brain. The dentate nuclei will be of lower signal inten-
the primitive streak begins to regress and cells at the rostral lip of the
sity than surrounding cerebellum in only 30% of patients at age
primitive knot migrate between the epiblast and hypoblast, forming the
25 years (134).

FIG. 2-21. Intermediate stage of maturation of brain iron. A–C. In this normal 13-year-old, the iron-concentrating regions of the brain are now isoin-
tense with white matter. Iron accumulates more rapidly in the globus pallidus than the other areas of the brain and the globus pallidus will be of lower
signal intensity than surrounding brain in 90% of patients by age 15. The substantia nigra and red nuclei are hypointense with respect to white matter in
50% of normal patients by age 20.

Barkovich_Chap02.indd 51 5/7/2011 2:42:25 AM

 52 Pediatric Neuroimaging
notochordal process. The notochordal process elongates as cells from
the primitive knot are added to it at its caudal end; after canalization, the
more caudal portion will be known as the notochord. The notochord
induces surrounding mesoderm (the paraxial mesoderm, derived from
the primitive streak) to condense into paired blocks of somites. The
somites eventually develop into myotomes, which will form the para-
spinous muscles and overlying skin, and sclerotomes, which will form
the cartilage, bones, and ligaments of the vertebral column (135,136.)
During the fourth or fifth gestational week, resegmentation of the
sclerotomes occurs, with eventual development of the vertebral bodies.
In this resegmentation, the cells within the caudal half of each sclero-
tome separate from the cranial half (of the same sclerotome) at the
sclerotomal cleft and then fuse with the cranial half of the inferior scle-
rotome (Fig. 2-23) to form a new, primitive vertebral body (135,136).
As a result, the intersegmental arteries become trapped in the centers of
the new vertebral bodies. At the same time, the segments of notochord
within the newly formed vertebrae disintegrate and the notochordal
segments in the intervertebral regions proliferate and convert into
nucleus pulposis. The mesenchymal vertebrae then undergo chondrifi-
cation, starting at specific chondrification centers within the vertebrae,
Barkovich_Chap02.indd 52
FIG. 2-22. Brain iron in normal young adult.
A–C. By the age of 25, the globus pallidus, sub-
stantia nigra, and red nuclei will be hypointense
with respect to white matter in 80% of normal
patients. However, only 30% of normal 25-year-
old people will show hypointensity of the dentate
nuclei, which accumulate iron more slowly and
less consistently than the other areas.
between days 40 and 60. Finally, ossification begins in four ossification
centers (two in the vertebral body and one in each side of the vertebral
arch), a process that continues into postnatal life (135,136).
The newborn vertebral body has a membranous central compo-
nent, with ossification centers and endplates of hyaline cartilage that
lie superior and inferior to the central component. The endplates are
each about one half the size of the central vertebral component (137).
The vertebral body and cartilaginous endplates of the newborn have a
more substantial vascular supply than those of the adult. The vertebral
bodies contain hematopoietic marrow, with large vascular pools and
sinusoidal channels that lack blood–brain barrier and contain large
extracellular spaces. The cartilaginous endplates are perfused by vessels
from the margins of the vertebral bodies and by vessels branching from
the lumbar arteries (138,139).
CT of Spine Development
In the spine, the major developmental process that is demonstrated by
CT is the ossification of the synchondroses between ossification cen-
ters. The persistence of these synchondroses in infants and children
5/7/2011 2:42:27 AM
 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 53

FIG. 2-23. Diagram of formation of vertebral bodies. A. Each sclerotome consists of a cranial mass of loosely packed cells (anterior sclero-
tome, A, dotted areas) and a caudal mass of densely packed cells (posterior sclerotome, P, vertical lines). The sclerotomes are closely related
to the notochord (N) and the myotomes (M, cross-hatched areas). B. The caudal, dense cell mass of one sclerotome unites with the cranial
loose cell mass of the adjacent caudal sclerotome to form a structure (the centrum of the vertebral body) that contains equal parts of adjacent
sclerotomes. The notochord has regressed; its remnants (N) will become nuclei pulposi. Myotomes are evolving into paraspinous muscles
(M). Note relationship of intersegmental arteries (A) to the vertebrae and sclerotomal segments.

can create problems in the interpretation of CT scans. Therefore, it is on axial images as oblique low intensity lines. The lines are seen from
important to recognize their normal sequence of closure (Table 2-4). infancy and presumably represent dense cortical bone plus cartilage.
Except for C-2, all of the vertebrae develop from three primary ossifica- The synchondroses disappear from MR at a different time than they do
tion sites: the body (anteromedial) and the two neural arches (postero- on CT and plain films, suggesting that MR and CT visualize different
lateral). The neural arches are separated from the body by neurocentral aspects of the process. On MR, the lines begin to disappear laterally,
synchondroses (140). At C-1, the anteromedial ossification center is the at a point about midway between the superior and inferior endplates
anterior arch. C-2 differs from the other vertebrae in that it has four (143,144). In the lumbar spine, the synchondroses appear approxi-
ossification centers: the body, the two neural arches, and the dens. The mately 75% closed at age 4 years. Complete disappearance of the lines
dens forms in utero from two separate paramedian ossification centers begins in the mid- and lower cervical region at about age 6 years. In the
that fuse in the midline, usually by the seventh fetal month; the syn- lumbar region, the lines disappear between the ages of 10 and 14 years,
chondrosis between the two ossifications centers may persist in infancy while in the thoracic region they disappear between the ages of 10 years
and should not be mistaken for a fracture (141). (upper thoracic) and 15 to 16 years (midthoracic) (140,143,144).
At birth, nonossified synchondroses are present within the ante-
rior arch of C-1, within the posterior arch of C-1, and between the two
arches. The anterior arch synchondrosis typically ossifies between the TABLE 2-4 Closure of Synchondroses of
ages of 8 and 12 months, the posterior arch synchondrosis between the
ages of 1 and 7 years, and the synchondrosis between the two arches the Cervical Spine (Assessed
between the ages of 7 and 9 years (142). At the C-2 level, the synchon- by CT)
drosis between the two posterior ossification centers ossifies between
the ages of 4 and 7 years. The center between the C-2 vertebral body and Synchondrosis Age at Ossification
the base of the odontoid ossifies between 3 and 7 years. The superior
odontoid ossification center appears on CT between the ages of 2 and 6 Anterior arch of C-1 8–12 mo
years and fuses with the odontoid between the ages of 11 and 12 years. Posterior arch of C-1 1–7 y (usually by 4 y)
Below the level of C-2, the vertebral bodies consist of one anterior ossi-
Lateral masses of C-1 7–9 y
fication center and two posterolateral ossification centers (Fig. 2-24). At
C-3 and below, the ossification of the synchondroses is fairly constant. C-2 body-odontoid 3–7 y
The posterior synchondrosis ossifies between the ages of 4 and 7 years, Superior odontoid center
and the synchondrosis between the vertebral body and the posterior
Appears 2–6 y
ossification center ossifies between the ages of 3 and 7 years (142).
Fuses 11–12 y
MRI of Spine Development Posterior C-2 synchondrosis 4–7 y
The neural synchondroses (between the neural arches and the verte- Below C-2 level
bral body) can be assessed by MR as well as by CT. These synchon- Posterior synchondrosis 4–7 y
droses can be seen on both T1- and T2-weighted images as linear
bands of low signal intensity. They can be assessed on sagittal and axial Vertebral body-posterior 3–7 y
images (Fig. 2-25) appearing on the sagittal images as low-intensity ossification center
lines running from the superior endplate to the inferior endplate and

Barkovich_Chap02.indd 53 5/7/2011 2:42:28 AM

 54 Pediatric Neuroimaging
FIG. 2-24. CT of immature vertebral body shows the anterior ossification
center (A) and the two posterolateral ossification centers (L). Small arrows
show the anterior synchondroses and the large arrow marks the posterior
synchondrosis.
The MR appearance of the vertebral bodies and intervertebral discs
of the infant spinal column has been described as evolving through
three stages (145). Stage I, occurring from birth through the first month
of life, is characterized by biconvex-appearing vertebral bodies that are
markedly hypointense centrally on T1-weighted images; this likely rep-
resents the vertebral body ossification center (Fig. 2-26A). The carti-
laginous endplates of the vertebral bodies, which are about one half the
size of the osseous body at this age, are mildly hyperintense compared
with muscle, but significantly hyperintense compared with the central
Barkovich_Chap02.indd 54
osseous portion. T2-weighted images show the vertebral body ossifica-
tion centers to be hypointense centrally and slightly more hyperintense
peripherally (Fig.2-26B). Administration of paramagnetic contrast at
this age will result in mild to marked enhancement of both the verte-
bral body and the cartilaginous endplates. The intervertebral disc does
not change significantly during childhood, appearing hypointense on
T1-weighted images, hyperintense on T2-weighted images, and show-
ing minimal to no enhancement (145,146).
Stage II (Fig. 2-27A–E), taking place from approximately 1 to
6 months, is characterized by T1 shortening in the vertebral bodies that
starts at the superior and inferior borders of the body and moves cen-
trally, eventually affecting the entire vertebral body. Thus, the upper
and lower portions of the vertebral body are more hyperintense than
the central portion (Fig. 2-27A). A band of hypointensity (the exact
correlate of which is not known) separates outer portions of the ver-
tebral body from the cartilagenous endplate. The intervertebral disc
is hypointense. Note that the cartilagenous synchondrosis between
the body of C-2 and the dens, the cartilagenous apical dens, and the
sphenooccipital synchondrosis (in the clivus) are all hyperintense on
T1-weighted images during this stage (Fig. 2-27E). T2-weighted images
also show increasing intensity in the superior and inferior portions of
the vertebrae; the vertebral body slowly becomes isointense with the
endplates by about age 3 months. The vertebral endplates are mildly
hypointense compared to the vertebral body, while the intervertebral
disc is very hyperintense. Note that different techniques of T2 and T2*
weighting will result in a slightly different appearance of the immature
spine (Fig. 2-27B–D). The enhancement pattern of the vertebral body
and endplate at Stage II is not significantly different than that at Stage I;
the vertebral body uniformly enhances (Fig. 2-27C) (145,146).
Stage III (Fig. 2-27F–H) takes place from about age 7 months
onward. At this stage, the vertebral bodies are becoming hyperintense
with respect to the cartilaginous endplates and surrounding muscle on
T1-weighted images. The cartilaginous endplates gradually become
ossified and are incorporated into the vertebral body, which becomes
rectangular in shape by about age 2 years. T2-weighted images
(Fig. 2-27G) show the vertebral bodies to be homogeneous, isointense
with the cartilaginous endplates, and mildly hyperintense compared
with surrounding muscle. Uniform contrast enhancement of variable
intensity (Fig. 2-27H) is seen in the endplates and vertebral bodies in
FIG 2-25. Appearance of immature vertebrae
on MR. Parasagittal T2-weighted image (A)
and axial SE T1-weighted image (B) show the
synchondroses (arrows) between the anterior
(A) and posterolateral (L) ossification centers
as linear bands of low signal intensity.
5/7/2011 2:42:29 AM
 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 55

FIG. 2-26. Neonatal spine, Stage I. A. T1-weighted image shows

horizontal bands of high intensity (small white arrows) located within
the centers of the vertebral bodies, probably representing the basiver-
tebral venous plexuses. The cartilagenous endplates of the vertebral
bodies (larger white arrows), which are about one half the size of the
osseous body at this age, are mildly hyperintense compared with mus-
cle, but markedly hyperintense compared with the hemiovoid-shaped
central osseous portion. B. T2-weighted image shows the ossification
centers to be markedly hypointense and the endplates (black arrows)
mildly hyperintense compared with muscle. The intervertebral discs are
markedly hyperintense.

FIG. 2-27. Spine at age 3 months (Stage II) and

9 months (Stage III). A. Fat suppressed sagittal
T1-weighted image shows horizontal bands of low
intensity (small white arrow) located within the cen-
ters of the vertebral bodies, probably representing
the residual vertebral body ossification center. The
periphery of the vertebral body shows alternating
hyperintensity (large black arrows) bordered by a
curvilinear band of hypointensity. Just peripheral to
the thin curvilinear hypointensity is a slightly thicker
curvilinear hyperintense band (white arrowheads) that
represents the cartilagenous endplate of the vertebral
bodies (large white arrowheads); these are markedly
hyperintense compared with the central osseous por-
tion of the vertebrae. The intervertebral disc (small
black arrow) is hypointense. B. Sagittal T2-weighted
image shows vertebral body ossification center to be
hypointense (small black arrow). This is surrounded
by a thin rim of hyperintensity relatively hyperin-
tense (large black arrow) and the markedly hypoin-
tense cartilagenous endplate (small white arrows). The
intervertebral disc (large white arrow) is markedly
hyperintense. C. Sagittal STIR image shows findings
similar to the T2-weighted image except that the ver-
tebral body ossification center is less well differenti-
ated from the surrounding cartilagenous endplate and
the intermediate layer is poorly seen. D. Sagittal T2*-
weighted gradient-echo image nicely differentiates the
hypointense vertebral body ossification center (large
black arrow) from the more hyperintense surround-
ing peripheral vertebral body (black arrowheads).
However, the hyperintense cartilagenous endplate
and intervertebral disc are both hyperintense (white
arrows) and cannot be differentiated.

Barkovich_Chap02.indd 55 5/7/2011 2:42:30 AM

 56 Pediatric Neuroimaging
most children up to the age of 9 or 10 years, during which time the
hematopoietic marrow is being slowly replaced (145,146).
EVALUATION OF BRAIN DEVELOPMENT
USING PHYSIOLOGIC MR TECHNIQUES
MR Spectroscopy
The Normal MR Spectrum
The evaluation of the developing brain with MR spectroscopy is still at
an early stage of development. Before dealing with specifics of changes
in spectra during development, two important concepts need to be dis-
cussed. The first is that the observed spectra vary with the echo time
(TE) used in acquiring them. As discussed in Chapter 1, many more
peaks are seen on short (20–30 milliseconds) TE than on intermedi-
ate (135–144 milliseconds) or long (270–288 milliseconds) TE spectra.
The reason for this is that excited protons lose coherence at variable
Barkovich_Chap02.indd 56
FIG. 2-27. (Continued) E. Sagittal T1-weighted image of the
craniocervical junction shows that the synchondrosis between
the body of C-2 and the dens (white arrowhead), the cartilag-
enous apical dens (large white arrow), and the sphenooccipital
synchondrosis (small white arrows) are all hyperintense com-
pared to bone at this stage. F. Sagittal noncontrast image at age
9 months. The vertebral bodies now appear nearly homogeneous
and the cartilagenous endplates are no longer hyperintense. The
intervertebral disc is hyperintense compared with the vertebral
bodies. G. T2-weighted image shows a homogenous vertebral
body; the superior and inferior cartilagenous endplates remain
hypointense, while the intervertebral disc remains hyperin-
tense. H. Postcontrast sagittal T1-weighted image shows nearly
uniform enhancement of the vertebral bodies.
rates, depending of their chemical surroundings (T2 relaxation). As
they lose coherence, their respective MRS peaks broaden and their
amplitude is decreased. In general, short TE spectra are used to assess
patients with suspected metabolic disorders where one needs to analyze
as many peaks as possible and look for the appearance of new, unex-
pected ones. Long TE spectra generally detect peaks from only four
compounds (N-acetylaspartate [NAA], choline, creatine, and lactate).
However, they are easier to quantify and are used in our institution
to assess patients with brain injury (147–150) and brain tumors (151).
Another important concept is that each area of brain has slightly
different concentrations of metabolites. For example, the cerebellum
has a different spectrum than the brainstem, the basal ganglia have dif-
ferent spectra than the cerebral white matter, and the thalamus has a dif-
ferent spectrum than the putamen. Beyond that, each thalamic nucleus
has a slightly different spectrum. Furthermore, the spectra change with
maturation. Infants have high choline and myo-inositol and relatively
low creatine and NAA peaks; as they grow the choline and myo-inositol
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
peaks shrink, while the NAA and creatine peaks grow. Therefore, it will
be necessary to establish norms based upon small voxel spectra in every
part of the brain in very large numbers of completely normal infants
in order to quantitatively establish whether spectra are normal in every
different part of the brain. This has been accomplished in small studies
(152), but a study of sufficient size to establish definitive norms will
require many years. In the mean time, it suffices to look at patterns of
peak heights and peak ratios in different parts of the brain to deter-
mine whether gross abnormalities are present. Before discussing these
patterns, let us first discuss the different peaks seen on proton (1H) MR
spectra (Fig. 2-28), the origin of their signals, and their significance.
After understanding the origin of the signals, the major changes that
occur during development will be discussed.
Metabolites Seen in MR Spectra of the Brain
Peaks Seen on Long Echo Time (Long TE) Spectra
NAA is the most obvious peak on 1H MRS and is the peak (at 2.01 parts
per million [ppm]) that is used as a reference for chemical shift deter-
mination (153,154). The peak actually includes contributions from
NAA, N-acetylaspartylglutamate (NAAG), glycoproteins, and amino-
acid residues in peptides (153,154); therefore, the peak is, perhaps,
more appropriately termed “N-acetyl groups.” NAA is synthesized in
the mitochondria of neurons and present in very high concentrations
in the CNS. NAA is a marker of the functional integrity of neuronal
mitochondrial metabolism and may be critical for myelinogenesis,
whereas NAAG modulates glutamatergic transmission and may have
a role in neuroprotection and synaptic plasticity (155). NAA has been
postulated to have at least two functions in the adult brain: (a) it is a
precursor of brain lipids and (b) it is involved in coenzyme A inter-
actions (155,156). Others have suggested that NAA is an osmolyte
(a metabolically inert compound that functions only to protect neural
tissues during metabolic disturbances of extracellular osmotic pressure
[157]), that it is a neurotransmitter/neuromodulator precursor, and
that it functions as a free storage form for aspartate (158,159). In adult
brains, NAA concentrations are higher in the cortex than in the white
matter (160), as most NAA is located in neurons and their branches.
Acetyl-CoA-L-aspartate-N-acetyltransferase, the synthetic enzyme
for making NAA, is localized in mitochondria, where NAA is synthe-
sized from aspartate and acetylcoenzyme A (161). Acetoaspartase, the
enzyme that degrades NAA, is located primarily in astrocytes (162);
thus, NAA breakdown occurs primarily in glial cells, explaining the low
concentration of NAA in mature glia. Because NAA is located almost
Barkovich_Chap02.indd 57
57
exclusively in neurons and axons, and because glia are not affected in
many neurodegenerative processes, NAA is reduced in most neurode-
generative processes (163). Animal experiments have confirmed that
reduced NAA correlates with neuronal necrosis (164). Thus, an abso-
lute or relative (to Cr) decrease of this peak is generally considered to
be an indicator of neuronal and/or axonal damage (165–167). How-
ever, because NAA is synthesized in the mitochondria, energy deple-
tion, without permanent neuronal damage, can also result in transient
reduction of NAA. Indeed, recovery of NAA has been seen in mito-
chondrial disorders (168), epilepsy (169), and treatment of AIDS with
antiviral agents (170). NAA is broken down to acetate and aspartate in
oligodendrocytes, where the acetate is subsequently used in the syn-
thesis of myelin lipids (155). It is converted to NAAG in presynaptic
terminals; NAAG is then released into the synapse, where it may block
presynaptic calcium channels, thus inhibiting glutamate (Glu) release
(155). In the infant, concentrations of NAA in the gray and white mat-
ter are similar. As NAA breakdown products may be used for myelino-
genesis, the relatively high NAA concentrations of immature white
matter have been attributed to very active membrane synthesis (156);
work in the immature brain has shown that oligodendroglia precursors
contain twice as much NAA as immature neurons (171). As a conse-
quence, NAA levels have potential as an indicator of normal oligoden-
droglial development.
The choline (sometimes called trimethylamine) peak at 3.21 ppm
is composed of contributions of the trimethylammonium (−N(CH3)3+)
protons in choline, betaine, and carnitine plus the H5 proton of myo-
inositol and taurine (153,154). The “choline” contribution is a sum
signal from several choline-containing compounds (i.e., phosphoryl-
choline, phosphorylethanolamine, glycerophosphorylcholine, glycero-
phosphorylethanolamine, and free choline), possibly in conjunction
with the choline that is present as a polar head group in membrane
lipids. In the neonate, phosphorylethanolamine dominates the spec-
trum; it decreases with age along with phosphorylcholine (172); both
of these compounds are precursors for membrane synthesis (173).
Glycerophosphorylethanolamine and glycerophosphorylcholine are
products of membrane breakdown; they increase in concentration
with postnatal age (172). Membrane-bound choline compounds may
not be visible by MRI (174); however, when the cell membranes are
broken down in disease processes, the bound choline is released and
becomes visible (174). The choline reflects the structural components
of cell membranes, especially myelin sheaths (153,154). Thus, the cho-
line peak tends to be enlarged in highly cellular processes such as high
FIG. 2-28. 1H spectral peak identification (short TE). 1. CH3 of lac-
tate. 2. CH3 of NAA and NAAG, C-2 CH2 of Glu and Gln, C-3 CH2 of
GABA. 3. C-4 CH2 of Glu and C-2 CH2 of GABA. 4. C-4 CH2 of Gln
and C-3 CH2 of NAA. 5,6. C-3 CH2’s of NAA. 7. CH3 of creatine and
C-4 CH2 of GABA. 8. CH3 of cholines. 9. C-1 CH2 of taurine. 10. C-1
and C-3 CH of inositol and C-2 CH2 of glycine. 11. C-2 CH of Glu and
Gln, C-4 and C-6 CH of inositol. 12. C-2 CH2 of creatine. 13. CH2’s of
cholines. 14. C-2 CH of lactate.
5/7/2011 2:42:32 AM
 58 Pediatric Neuroimaging
grade tumors and in neurodegenerative disorders. Focal inflamma-
tion, which results in marked local cellularity and, often, in significant
breakdown of cell membranes, can also result in large choline peaks.
In the mature brain, choline concentration is higher in cerebral white
matter than in cerebral cortex and higher in the thalami and cerebel-
lum than in the cerebral cortex or cerebral white matter.
The creatine peak at 3.03 ppm is from methyl (CH3) protons of
creatine and phosphocreatine plus minor contributions from gamma-
aminobutyrate, lysine, and glutathione (153,154). A second, smaller
creatine peak is seen at 3.94 ppm (175,176). Phosphocreatine appears
to be a crucial molecule in maintenance of energy-dependent systems
in all brain cells (177). Its concentration is highest in the cerebellum,
followed by the thalami, basal ganglia, cortical gray matter, and white
matter (178). The overall level of Cr is usually considered to remain
stable in most situations; therefore, Cr is used as a standard for com-
parison with other metabolites. In rats, Cr concentrations are higher
in astrocytes than in neurons; therefore, Cr may be elevated in injured
tissue (179).
Lactate, detected by a characteristic doublet centered at 1.3 ppm
(the peaks are at 1.27 and 1.36 ppm) on 1H MRS, can be seen in trace
Barkovich_Chap02.indd 58
amounts in AGA (appropriate for gestational age) term neonates (see
Chapter 3). More than a trace amount, particularly after the first few
hours of life, is generally considered to be indicative of some degree of
brain injury (26). However, lactate, is a normal finding on 1H MRS in
the cerebrospinal fluid of premature and term neonates, with a con-
centration up to 2.7 mm/L (26,180–182). This lactate disappears by the
time the baby is a few months old. The normal presence of the lactate
in the CSF is important, because one may falsely diagnose the presence
of anaerobic glycolysis, and hence ischemia, in the parenchyma if the
spectroscopy voxel includes a large third ventricle or a large portion
of the lateral ventricle. Exclusion of CSF is, therefore, very important in
analyzing neonatal proton MR spectra in the presence of encephalopathy.
It is important to realize that propane-1,2-diol, an injection sol-
vent for the administration of anticonvulsants given to neonates, has
a spectroscopic appearance nearly identical to lactate (183). Propane-
1,2-diol appears as a doublet centered at approximately 1.1 ppm
(Fig. 2-29) (183). Therefore, if a doublet is seen in the aliphatic region
(about 1–1.4 ppm) in an encephalopathic neonate, the precise chemical
shift of the doublet should be determined before assuming the presence
of lactate.
FIG. 2-29. Presence of propane-1,2-diol in neona-
tal spectrum. (A) is a proton spectrum (TE = 270
milliseconds) from the basal ganglia. (B) is a proton
spectrum from the frontal watershed white matter.
Note that two doublets are present, the one cen-
tered at 1.1 ppm (p) representing propan-1,2-diol
and the one centered at 1.3 ppm (la) representing
lactate.
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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
Peaks Seen on Short Echo Time (Short TE) Spectra
When proton spectra are acquired using a short TE, many additional
peaks may be identified (these peaks disappear at long echo times
because of their relatively short T2-relaxation times). Several small
peaks that correspond to protons from glutamine (Gln) and Glu are
seen in the 2.1 to 2.4 ppm region (153,177). A second peak, at 3.75
ppm, can be seen and is from resonance of the alpha CH moiety. Glu is
an excitatory neurotransmitter that is released from excited axons into
the synapse, where it binds to postsynaptic Glu receptors. Some of the
released Glu is then transported into adjacent glial processes, while the
rest is taken up into presynaptic and postsynaptic neuronal processes.
The Glu absorbed into glial cells is converted into Gln by the enzyme
Gln synthetase or metabolized to oxoglutarate (by Glu dehydrogenase)
and aspartate (by aspartate aminotransferase) (184). Glu is an impor-
tant molecule in brain injury, from hypoxia-ischemia, seizures, and
possibly trauma (185). Unfortunately, at clinically used magnetic-field
strengths, the peaks at 2.1 to 2.4 ppm overlap each other and cannot be
separated well from the NAA peak, gamma-aminobutyric acid (GABA)
peaks, and each other, while the peak at 3.75 ppm is difficult to separate
from the creatine peak at 3.9 ppm. It is possible to better separate and
evaluate these peaks at higher static magnetic-field strengths, such as
3 T. As higher field strength scanners become used more frequently in
clinical practices, it is possible that analysis of these peaks will become
important in assessing excitotoxic brain injury, which is often mediated
by Glu (186). Higher field strength may also allow better assessment of
astroglial reaction to brain injury, as Gln is mainly seen in astrocytes,
while Glu is synthesized in neurons.
Myo-inositol, which has two peaks, at 3.56 and at 4.06 ppm, is
thought to be the storage pool for membrane phosphoinositides, which
are second messengers that are involved in many hormonal systems and
in enzyme regulation in the CNS (158,187). It is an essential growth
factor (188) and is the precursor of phosphatidylinositol, a constituent
of phospholipid membranes (153). It is located primarily in glial cells,
with particularly high concentrations in astrocytes (173) and, there-
fore, may be a specific marker for astrogliosis. Other possible roles
include osmoregulation, cell nutrition, and detoxification (158,187).
Minor contributions to the peak at 3.56 ppm come from glycine and
inositol-1-phosphate (174). Scyllo-inositol is a nonmetabolized isomer
of myo-inositol that may inhibit the transport and incorporation of
myo-inositol into phospholipids (189,190). Most experts believe that
the singlet peak at 3.35 ppm is from the six equivalent methine protons
of the cyclic alcohol of scyllo-inositol, not from taurine as previously
believed, based upon the exact chemical shift, the singlet nature of the
resonance, agreement with biochemical concentration levels, a link to
myo-inositol levels, and exclusion of other metabolites in 1H MR spec-
tra of mammalian brain in vivo and in vitro (178,190). Cerebral glucose
may be detected on short TE proton MR spectra by a singlet at 3.43
ppm. The area under the singlet may be used as a gross measurement
of glucose concentration in the brain (191).
Taurine is an amino acid that is reported to act as an osmoregulator
and as a modulator of the action of neurotransmitters (192). It is found
at high concentration in infants but the concentration drops with mat-
uration, to approximately 1.5 mmol in adults. The spectrum contains
two triplets centered at 3.25 and 3.42 ppm (192). Unfortunately, on
most clinical scanners, these peaks overlap with the resonances from
myo-inositol, scyllo-inositol, and choline, so they are difficult to see
unless markedly elevated, as sometimes seen in brain tumors (193).
Two broad peaks are typically seen in short echo spectra of infants,
one between 0.5 and 1.0 ppm approximately and another between 1.0
and 1.6 ppm approximately. They are commonly referred to as “macro-
molecular peaks.” They are composed primarily of methylene (centered
at about 1.3 ppm) and methyl (centered at about 0.9 ppm) protons
Barkovich_Chap02.indd 59
59
from all sorts of aliphatic hydrocarbons (lipids) and amino acids.
These peaks gradually diminish in size over the first 12 to 18 months
after birth and are usually of no clinical importance unless the peak
heights approach about half that of NAA; when large, the peaks may
indicate cellular breakdown rather than production and, thus, a degen-
erative process. These peaks are seen more commonly in inborn errors
of metabolism and in child abuse than in the “normal” infant popula-
tion (Dr. William Ball, personal communication).
Most commercially available MR spectroscopy programs do not
allow phosphorus MRS to be performed. However, some knowledge
of 31P MRS is useful. Presently, the progressive decrease of phosph-
omonoester and the complementary increase of phosphodiester,
caused by lipid metabolism, seem to be the best indicators of brain
development on 31P MRS (194). Spectra from preterm infants show
increased resonances from phosphomonoesters and comparatively
lower signals from phosphodiesters compared with full-term infants.
Phosphodiesters arising from phospholipid degradation products
and phospholipids are found to increase further in infants and adults
but there is relatively little diminution in the signal intensity from
the phosphomonoesters (which are mainly phospholipid precur-
sors). However, changes in the chemical shift and spectral width of
the phosphomonoester signals are observed between the neonates and
the adults, indicating that a change occurs in the composition of the
phosphomonoesters. This is likely the result of changing proportions
of the contributions of phosphorylethanolamine, phosphorylcholine
(195), glycerophosphorylethanolamine, and glycerophosphorylcho-
line (172). Additionally, the correlation of 31P MRS and neurologic
exam (examination of reflexes, motor-and sensory functions) in new-
born dogs demonstrated that exponential increases in phosphocre-
atine, inorganic phosphate, and phosphodiesters, with maintenance
of the phosphocreatine/inorganic phosphate ratio, preceded matura-
tional changes in the neurological examination (196). The spectro-
scopic evolution is postulated to result from increasing ATP turnover
in the maturing mitochondria.
Variations of Spectra in Brain Regions
Proton spectra vary with the location of the prescribed voxel in which
the spectrum is acquired. This should not be surprising, as the cyto-
architecture of the cerebral cortex differs considerably from one region
of the cortex to the other (197). The importance of this concept can-
not be overstated. Spectra obtained from the mature frontal cortex
differ from those in the mature parietal cortex; both differ from the
spectra of the mature hippocampus (198). Spectra obtained from the
thalamus differ from those obtained from the striatum (199). It is not
possible to show spectra from every location in the brain at every age.
However, a few patterns can be described. The height of the NAA peak
varies in different regions of the brain. NAA/Cr values are lower in
the brainstem and cerebellum than in the cerebral hemispheres and
are lower in the basal nuclei (thalami, caudates, putamina) than in
the cerebral white matter (Fig. 2-30). Within the cerebral white mat-
ter, NAA/Cr is higher in the frontal than the parietal white matter. In
addition, the ratios of choline and creatine vary, with choline usually
being larger than creatine in white matter and thalami, while creatine
is usually larger than choline in mature striatum and in cerebral cortex
(198–203).
Changes in Spectra with Brain Maturation
Changes in in vivo MR spectra with brain maturation vary with tech-
nique. As discussed earlier, spectra acquired with short echo times
(Fig. 2-31) have a different appearance than those acquired with long
echo times (Fig. 2-32) because T2 relaxation and J-coupling cause
broadening and decreased amplitude of peaks (187). As many more
5/7/2011 2:42:33 AM
 60 Pediatric Neuroimaging

FIG. 2-30. Variation in proton spectra with location in the brain (TE = 288 milliseconds) in a mature (3-year-old) child. A. Spectrum of the cerebellar
cortex shows large choline (Ch) and creatine (Cr) peaks compared with NAA. B–F. Spectrum of the frontal white matter (B), frontal cortex (C), occipital
cortex (D), putamen (E), and thalamus (F) all show slightly different ratios of choline, creatine, and NAA.

peaks are identified, the maximum information is obtained by using
short echo times. However, a stable baseline is more easily obtained
and peaks are more easily quantified using long echo times.
Changes in MRS that reflect brain maturation include a rela-
tive decrease in the size of the phosphomonoester peak and relative
increases in the size of the phosphocreatine and phosphodiester peaks
on 31P spectra and increase in the size of the large NAA peak (at chemi-
cal shift 2.01 ppm) relative to the choline (at 3.21 ppm) and the cre-
atine-phosphocreatine peaks (at 3.03 ppm) on 1H spectra (Figs. 2-31
and 2-32) (187,202). This pattern of evolution is seen in fetuses (204)
and premature infants (199,205), as well as term infants (199,205) and
young children (177,202). In addition, the large myo-inositol peak pres-
ent at 3.56 ppm in the spectra of newborns diminishes substantially
during the first year of life (Fig. 2-31) (158,205). The scyllo-inositol
(190) peak is highest in newborns (158,206).
Absolute concentrations of metabolites are very difficult to
determine by in vivo MR spectroscopy (205,207,208). Therefore, the
time course of most metabolites has been expressed most exactly by
comparing the spectral peaks with each other and calculating ratios
(158,159,167). Compared to Cr, for example, a decrease of choline (the
Ch/Cr ratio) and myo-inositol (myo-Ins/Cr ratio) develops as matura-
tion progresses (167); the choline/myo-inositol ratio is stable (158,159).
In addition, the temporal evolution of the peaks differs in gray matter
as compared to white matter. Whereas the Cr/Ch ratio stays nearly con-
stant in white matter, the ratio increases in gray matter during the first
2 years of life (167).

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 61

FIG. 2-31. Changes in short echo time (26 milliseconds) 1H spectra with maturation. Basal ganglia spectra from a 5-day-old neonate (A),
a 3-month-old (B), a 14-month-old (C), and a 22-month-old (D). Myo-inositol and choline are large peaks in neonates. Choline and creatine remain large
in older infants. NAA is the dominant peaks in older infants, children, and adults. In older children and adults, choline is usually larger in white matter,
creatine in cortex. Broad peaks at 0.9 and 1.3 ppm (macromolecular peaks, arrows in A) are normal in infants on short TE spectra.

Quantification of proton MRS signals from specific compounds
is difficult because the signal intensity of each peak depends upon its
concentration, spin saturation effects, and T2 relaxation times (209).
All of these must be taken into account before any accurate data can be
constructed. Nonetheless, methods for absolute quantification of peak
areas have been developed and, because they are more reproducible
and reliable than ratios of compounds, these methods are becoming
the standard way of analyzing spectra (177,187,193,205,210). However,
different groups obtain slightly different values, even using these “abso-
lute” measurements (177,211–213). One reason for these differences is
that the spectra of different parts of the brain mature at different times
and different rates (see Fig. 2-32A–D) (199,205). Thus, just as certain
regions of the brain myelinate earlier than others (see earlier parts of
this chapter), the same regions undergo earlier biochemical maturation.
The thalami, basal ganglia, sensorimotor system, and visual system
mature earlier than the prefrontal and temporal association areas, for
example, and spectra of the more mature areas will give lower values of
myo-inositol and higher values of NAA than less mature areas on pro-
ton spectra (199,212,213). On phosphorus spectra, the more mature
areas will give lower values of phosphomonoester and higher values
of phosphodiester, phosphocreatine, and ATP (195). Using absolute
measurements, myo-inositol has been found to be the dominant peak
in neonates, with a concentration of 10 to 12 mmol/kg (177,211). Cho-
line, with a concentration of 2.5 to 3.5 mmol/kg, is the dominant peak
in older infants (177,211). Creatine and N-acetyl groups, which have
concentrations of 5 to 6 mmol/kg and 4 to 5 mmol/kg, respectively,
in the neonate, increase in concentration to 7 to 10 mmol/kg and 9 to
10 mmol/kg, respectively in the adult; thus, they become the dominant

Barkovich_Chap02.indd 61 5/7/2011 2:42:36 AM

 62 Pediatric Neuroimaging

FIG. 2-32. Changes in long echo time (288 milliseconds) 1H spectra with maturation. A. Normal 35-week neonate. Spectrum through the basal nuclei
shows a dominant choline peak, with relatively small NAA and creatine/phosphocreatine peaks. B. Normal 35-week neonate. Spectrum in frontal white
matter is less mature than that through the basal nuclei. The creatine/phosphocreatine and NAA peaks are relatively lower than the choline and myo-
inositol peaks compared to (A). Some lactate (arrows in A and B) is normal in the white matter at this stage. C. Normal term neonate. By this stage, the
NAA is relatively more abundant compared to choline. Lactate has essentially disappeared. D. Normal term neonate. Spectrum in frontal white matter
is still less mature than that through the basal nuclei, but more mature than at 35 weeks (B). The creatine/phosphocreatine and NAA peaks are relatively
lower than the choline and myo-inositol peaks compared to the basal ganglia (C) but the NAA is relatively larger compared with 35 weeks. E. Normal
12-month-old infant. A relative increase is seen in the size of the creatine/phosphocreatine and NAA peaks compared to the choline peak. Myo-inositol
remains fairly prominent at this age. F. Normal 24-month-old child. The spectrum begins to resemble that of an adult, with dominant NAA peak and
relatively small creatine/phosphocreatine and myo-inositol peaks.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
peaks in the adult proton spectrum. Myo-inositol, conversely, decreases
to a concentration of 6 mmol/kg in the adult, resulting in its decreasing
prominence in the spectrum of the older child and adult (177,211).
Diffusion Tensor Imaging and Tractography
As discussed in Chapter 1, special techniques that were initially devel-
oped in the 1960s (214,215) allow MRI to be used in measuring the
rate and direction of diffusion of water in the brain (216,217). The
rate of diffusion of free water in the brain seems to be primarily related
to the maturity of the white matter; as the brain matures, the amount
of motion of the water molecules (as measured by the diffusivity, also
called average diffusivity [Dav] or apparent diffusion coefficient [ADC],
see Chapter 1) decreases, probably as a result of increased complexity
of white matter pathways and increasing myelination. The develop-
ment of anisotropy of water motion along white matter pathways, as
measured by fractional anisotropy (FA), seems to correlate best with
the development of immature oligodendrocytes (218). High levels of
anisotropy can be present in the absence of myelin (219–221), sug-
gesting that factors other than myelin—neurofilament development,
aligned axons, single membrane barriers, cohesive and compact fiber
tracts, and changes in the extracellular and intracellular matrices—are
all important factors in the development of anisotropic water motion
in white matter (218,219).
Diffusion Imaging of Brain Maturation
Depending upon the manufacturer of the MR scanner, diffusion infor-
mation may be displayed in several different forms. The most common
of these forms are the diffusion-weighted image (DWI), which con-
tains both T2 and diffusion information, and the diffusivity map (ADC
map), in which image contrast is determined only by the magnitude of
water motion in each voxel. As information on water diffusion may be
useful in assessing injury to (148,222,223), or metabolic derangement
of (224) the neonatal and infant brain, an understanding of the appear-
ance of diffusion-based images in normal children of various ages is
critical. However, when the brain is diffusely injured, DWI and diffusivity
maps may appear normal despite widespread reduced diffusion. In such
cases, calculation of diffusivity values and correlation of those values with
established norms for the patient’s age and the region being measured
(25,90,225,226) are absolutely essential.
DWIs contain information from both T2 relaxation and diffu-
sion. In premature neonates, the diffusion effects dominate, resulting
in nearly all white matter being hypointense relative to cortical gray
matter (Fig. 2-33A–D). The posterior limbs of the internal capsules are
exceptions to this, being iso- to slightly hyperintense to cortical gray
matter (Fig. 2-33A and B). In term infants (Fig. 2-33E–H), the white
matter in the perirolandic region is slightly more hyperintense than
in premature infants, becoming nearly isointense to overlying cortex,
and the posterior limbs of the internal capsules are isointense to sur-
rounding structures (Fig. 2-33D). By age 3 months (Fig. 2-33I–L), the
central white matter becomes isointense to relatively hypointense to
overlying cortex, presumably due to an increasing predominance of
T2 effects over diffusion effects. The frontal white matter, which is the
last area to mature, remains hyperintense compared with overlying
gray matter (Fig. 2-33K and L). Between the ages of 3 and 9 months
(Fig. 2-33M–P), the anterior and posterior cerebral white matter also
becomes more hypointense compared to overlying cortex. During the
first few post-term months, the internal capsule becomes progres-
sively hypointense, with the posterior limb attaining mature contrast
(hypointensity) by age 3 to 4 months (Fig. 2-33K) and the anterior limb
by age 20 months. Beyond the age of about 9 months (Fig. 2-33Q–X),
the cerebral white matter becomes uniformly hypointense compared
Barkovich_Chap02.indd 63
63
to overlying cortex and remains that way until late adulthood when
degenerative changes develop.
On ADC maps, the signal intensity is proportional to the amount
of water diffusion only, without T2 information. As discussed in Chap-
ter 1, areas of reduced diffusion appear brighter than normal tissue on
DWIs, whereas reduced diffusion appears darker on diffusivity (ADC)
images. As premature and term neonates have a great amount of water
in their unmyelinated brain and, as a result, very long T1 and T2 relax-
ation times of the white matter, diffusivity maps are typically more
sensitive to subtle injury than DWIs. Therefore, a series of normal
diffusivity images during development are shown in Figure 2-34. On
diffusivity images of preterm and term neonates, marked contrast is
present between hypointense gray matter and hyperintense white mat-
ter (Fig. 2-34A–H). This contrast is more marked in premature neo-
nates (Fig. 2-34A–D) than in term neonates (Fig. 2-34E–H). If residual
germinal matrix is present, it has diffusion characteristics similar to
cortex (Fig. 2-34B and C). The posterior limb of the internal capsule,
which myelinates early and has compact axons, has reduced diffusion
(hypointense, Fig. 2-34B and D) compared to the hemispheric white
matter. As the child matures during the first year, the contrast between
gray and white matter diminishes (Fig. 2-34I–P) until they become
isointense in much of the cerebrum by age 9 months. The early devel-
oping pathways, such as the sensorimotor pathways, become hypoin-
tense compared to cortex by about 9 months, while the late developing
pathways in the anterior frontal and parietal lobes remain hyperin-
tense compared to cortex (Fig. 2-34M–P). Beyond age 12 months, the
cerebral cortex and cerebral white matter remain largely isointense
(Fig. 2-34Q–X) except for persistent white matter hyperintensity in the
peritrigonal and frontal subcortical regions, which persists until the
end of the second year.
Diffusion Tensor Imaging of Brain Maturation
As discussed in Chapter 1, diffusion measurements can also be used to
calculate measurements of diffusion anisotropy (88). Several measure-
ments can be used to calculate anisotropy. Of these, FA provides the
most detailed and extensive depiction of anisotropy and achieves high-
est signal-to-noise, volume ratio provides the strongest contrast between
low and high anisotropy areas (but has decreased signal-to-noise and
therefore decreased resolution of mildly anisotropic areas), and rela-
tive anisotropy is intermediate between the other two (227). The dif-
fusion information can be displayed numerically, or as images. Several
groups have published the evolution of calculated diffusivity and diffu-
sion anisotropy of the brain during development (89,90,225,226,228).
Sometimes, however, display of the data as an image is more useful
from the perspective of the radiologist, particularly when management
decisions need to be made quickly on a sick neonate or child.
If DTI is performed with adequately high signal-to-noise, aniso-
tropic water motion is seen throughout the white matter of the brain,
even in the unmyelinated brains of premature neonates (226,229,230).
Although the amount of anisotropy in any region varies depending
upon the voxel size and the signal-to-noise ratio, the greatest degree
of anisotropy is found in the corpus callosum, internal capsules, brain-
stem, and cerebellar peduncles (89,224), and all of the major white
matter tracts show some degree of anisotropy. The maximum eigen-
value, corresponding to the magnitude in the direction of greatest dif-
fusion, is larger in white matter than in gray matter throughout brain
development. In contradistinction, the intermediate and minimum
eigenvalues are larger in white matter than in gray matter during the
newborn period, but become smaller in white matter than in gray mat-
ter with progressive myelination. As the brain matures, anisotropic
water motion becomes visible in all white matter regions, including
the subcortical association axons. The amount of anisotropy increases
5/7/2011 2:42:40 AM
 64 Pediatric Neuroimaging

FIG. 2-33. DWIs at two levels of the devel-

oping brain. Signal intensity in these images
reflects both T2 weighting and diffusion
weighting. A–D. Premature neonate with
adjusted gestational age of 32 weeks. In pre-
mature neonates, the diffusion effects domi-
nate, resulting in nearly all white matter being
hypointense relative to cortical gray matter.
The posterior limbs of the internal capsules
are exceptions to this, being iso- to slightly
hyperintense to cortical gray matter (A and
B). E–H. Two-week-old neonate, born at
term. In term infants, the white matter in the
perirolandic region is slightly more hyperin-
tense than in premature infants, becoming
nearly isointense to overlying cortex, and the
posterior limbs of the internal capsules are
isointense to surrounding structures (D).

Barkovich_Chap02.indd 64 5/7/2011 2:42:40 AM

 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 65

FIG. 2-33. (Continued) I–L. Three-month-old

infant. By age 3 to 4 months, the central white
matter becomes isointense to relatively hypoin-
tense to overlying cortex, presumably due to an
increasing predominance of T2 effects over dif-
fusion effects. The frontal white matter, which
is the last area to mature, remains hyperintense
compared with overlying gray matter (K and L).
During the first few post-term months, the inter-
nal capsule becomes progressively hypointense,
with the posterior limb attaining mature con-
trast (hypointensity) by age 3 to 4 months (K)
and the anterior limb by age 20 months. M–P.
Nine-month-old infant. Between the ages of 3 and
9 months, the anterior and posterior cerebral white
matter also becomes more hypointense compared
to overlying cortex. Note, however, that the less
mature regions, such as the anterior frontal and
anterior temporal lobes, remain isointense.

Barkovich_Chap02.indd 65 5/7/2011 2:42:41 AM

 66 Pediatric Neuroimaging

FIG. 2-33. (Continued) Q–T. Fifteen-month-

old infant. Beyond the age of about 9 months, the
cerebral white matter progressively becomes uni-
formly hypointense compared to overlying cortex.
U–X. Four-year-old child. By the end of the sec-
ond postnatal year, the white matter is uniformly
hypointense and remains that way until late
adulthood when degenerative changes develop.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 67

FIG. 2-34. ADC images of the developing brain.

On these images, low signal intensity reflects
a small amount of free water motion, and high
signal intensity results from a high degree of free
water motion. A–D. Diffusion images of a pre-
term (28 week) neonate. The white matter is very
hyperintense compared with the cortex and deep
gray matter. Note the normal hypointensity of
the residual germinal matrix in the walls of the
lateral ventricles. The internal capsule is slightly
more hypointense than the white matter of the
centrum semiovale. E–H. Term neonate. The
appearance is similar to that in the preterm infant
with the exception that some hypointensity, rep-
resenting reduced water motion, is now pres-
ent in the corticospinal tracts within the corona
radiata (H).

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 68 Pediatric Neuroimaging

FIG. 2-34. (Continued) I–L. 3-month-old

infant. At age 3 months, the white matter is
becoming isointense to the gray matter in the
sensorimotor pathways. The deep gray nuclei
are slightly hyperintense. M–P. 9-month-old
infant. At this age, most hemispheric white mat-
ter is isointense to cortex. In the regions that
mature late (anterior frontal and parietal, P),
the white matter remains slightly hyperintense.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
over the first decade of life, with the compact white matter pathways
(corticospinal tracts and corpus callosum) showing early matura-
tion of anisotropy while the anisotropy of the noncompact white
matter of the centrum semiovale matures later (231). In the slowest
maturing regions, the subcortical white matter and the frontal white
Barkovich_Chap02.indd 69
69
FIG. 2-34. (Continued) Q–T. Fifteen-month-old
infant. At this age, most white matter is isointense to
cortex, and the sensorimotor white matter is slightly
hypointense compared to cortex. U–X. Four-
year-old child. In the mature brain, white matter
has become slightly hypointense compared to cor-
tex except for some patchy hyperintensity (in W)
posterior and superior to the ventricular trigones.
matter, anisotropy continues to increase beyond the first decade of life
(231,232).
It seems rather clear that much of the diffusion anisotropy in the
maturing brain results from the presence of myelin sheaths around the
axons (216,233,234). However, the initial development of anisotropy
5/7/2011 2:42:47 AM
 70 Pediatric Neuroimaging

precedes the formation of myelination (220,221) and seems to corre-
late with the developmental expansion of immature oligodendrocytes
during the premyelination period (218). Additionally, diffusion anisot-
ropy occurs in unmyelinated nerve bundles (235,236) and this anisot-
ropy can be eliminated by administration of tetrodotoxin, suggesting
that it results from a physiologic process, possibly the rapid flux of ions
into the developing axon immediately prior to myelination (220,221).
Thus, DTI, by allowing us to assess characteristics of water motion in
the brain, has the potential to help us assess cerebral maturation, and,
perhaps to better understand cerebral physiology and maturation.
However, it is important to remember that anisotropy is not exclusively
caused by myelination; many of the causes of anisotropy are yet to be
determined.
Although the brains of near-term and term neonates, infants, and
children show no anisotropy of gray matter, DTI of very preterm neo-
nates and infants shows an interesting phenomenon of anisotropic
water diffusion in the cerebral cortex (Fig. 2-35). This anisotropy is
believed to result from the radial organization of the immature cere-
bral cortex (237). In the immature cortex, the predominant features
are radial glial cells and large pyramidal neurons with prominent,
radially oriented apical dendrites; these structures cause horizontal
water motion to be relatively impaired, resulting in radially oriented
anisotropy. As the cortex matures, neurons extend horizontally ori-
ented basal dendrites and horizontally oriented thalamocortical axons
invade the cortex (237). In addition, intracortical association axons
navigate horizontally through the developing cortex. The developing
horizontal, or laminar, organization causes impairment of radially
directed water motion, resulting in increasing isotropic water motion
in the cortex. The cortical anisotropy disappears first in the periro-
landic region of the cortex, where it is no longer seen after about 30
postconceptional weeks (238). Anisotropy persists the longest in the
anterior temporal and prefrontal cortex, where is seen as late as 37
postconceptional weeks (Fig. 2-35B) (238). This loss of cortical anisot-
ropy is the result of a decrease in the maximum eigenvalue (oriented
perpendicular to the cortical surface) while the two minor eigenvalues
remain unchanged. This analysis of cortical maturation via DTI may
prove useful in predicting long-term developmental outcome in pre-
mature neonates.
DTI can also be used to identify transient regions of differing
anisotropy in the developing brain. For example, the subplate (also
called cortical layer 7) is a transient region that lies deep to the cerebral
cortex but superficial to the intermediate zone (developing white mat-
ter). Many axons that will eventually synapse with neurons in the cor-
tex temporarily synapse with neurons in the subplate until the cortex is
sufficiently mature. The moderate diffusivity and low anisotropy of the
subplate differentiate it from the low diffusivity and high anisotropy
of the overlying cortex and from the low diffusivity and medium-to-
high anisotropy of the intermediate zone (239). Altered development
of the subplate may be a clue to future developmental abnormalities
in the child and to what aspects of prematurity and its therapy put the
neonate at risk.
Diffusion Tensor Tractography of Brain Maturation
Since white matter pathways in the brain exist in three dimensions, two
dimensional (2D) representations of DTI such as ADC and FA maps
are intrinsically limited. This shortcoming has led to the development
of 3D DTI fiber tractography techniques. There are many different
techniques for performing fiber tractography, but most of the currently
used methods are variations on the same underlying principle of track-
ing along the orientation of the primary eigenvector of the diffusion
tensor from voxel to voxel (240–242). Note that, because the process of
water diffusion exhibits antipodal symmetry, DTI tractography cannot
distinguish forward from backward (i.e., antegrade versus retrograde)
along a fiber trajectory. Tractography can be used to separate func-
tionally distinct white matter pathways using the multiple region-of-
interest (ROI) method in which a priori anatomic knowledge of the
course of a white matter tract is used to delineate its entire 3D trajec-
tory (242). The fiber tracking is initiated at an ROI placed in one part

FIG. 2-35. Diffusion anisotropy of the premature cerebral cortex. A. FA images of a 28-week preterm neonate. Note the hyperintensity in much of the
cerebral cortex (other than the central regions), indicating high anisotropy of most of the cortex. The most mature cortical area, the sensorimotor region
(white arrows) is hypointense, indicating low anisotropy due to more cortical maturation. B. FA images of a 37-week preterm neonate. Most of the cortex
is now hypointense, indicating low anisotropy. The prefrontal cortex (white arrows) is still slightly hyperintense, indicating persistent anisotropy in this
late-maturing region. Central hyperintensity (white asterisks) shows anisotropy in the developing white matter pathways.

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 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine
of the pathway, and only those fiber tracks that pass through an ROI
placed in another portion of the pathway are retained. This power-
ful method, which has been experimentally verified (243), can be used
to “dissect” out adjacent but functionally distinct white matter con-
nections of the developing human brain, such as the pyramidal tract
and the somatosensory radiation. 3D tractography can also be used to
measure tract-based diffusivity, FA, or other DTI parameters, by inte-
grating the parameters in all the voxels intersected by the fiber tracks.
The advantages of this tract-based quantitation over traditional ROI
measurements from DTI are that it is more specific to the functionally
distinct axonal pathway of interest, that it reflects the entire 3D course
of the pathway rather than just one location within the pathway, and
that it is more reproducible than manually placed ROIs, as has been
shown in the adult brain by a cross-sectional study (244) and by a lon-
gitudinal study (245).
Applying 3D DTI fiber tracking to the developing brain of pre-
mature newborns, Partridge et al. (246) found that tract-based mea-
surements of ADC, FA, and the three diffusion tensor eigenvalues in
the pyramidal tract are all more reproducible than manual 2D ROI
measurements, with less interoperator and intraoperator variability.
DTI tractography has also been used by Berman et al. (247,248) to
gauge maturational changes separately in the pyramidal tract, soma-
tosensory radiations, and visual pathways of premature newborns.
At any given age, tract-based diffusivity in the motor pathway was
less than that of the somatosensory radiations, whereas tract-based
FA was greater in the motor pathway, while visual maturation was
strongly associated with FA of the optic radiations. More recently,
large-scale DTI investigations have characterized the time course of
age-related white matter microstructural changes across the entire
lifespan, all of which have a “U” or inverted “U” shape reflecting the
effects of maturation early in life and of senescence late in life. A fiber
tractography study of the corpus callosum in 315 normal volunteers
of ages 5 to 59 years showed that peak FA values were reached in
the third decade of life, whereas the minimum diffusivity values were
reached somewhat later, often during the fourth decade of life (249).
An atlas-based DTI study of 16 different white matter tracts in 430
healthy subjects ranging in age from 8 to 85 years showed similar
results, with peak FA values in the third decade of life and minimum
diffusivity values in the fourth to fifth decade of life (250). Notably,
the corticospinal tract showed evidence of particularly early and
rapid maturation whereas the dorsal and ventral cingulum bundles
showed more protracted development compared to the other tracts
examined. Clearly, fiber tracking will be used extensively in the future
to study white matter tracts, both in development and in aging.
Magnetization Transfer Imaging
Another technique that may be useful in the analysis of brain develop-
ment is magnetization transfer. It has been shown that the amount
of magnetization transfer in the brain increases during myelination
(251). In addition, the increase in magnetization transfer parallels
that of myelination as determined by histology (251). As discussed
in Chapter 1, almost all magnetization transfer in the brain seems to
result from interactions of free water with components of myelin, in
particular the hydroxyl and amine moieties of cholesterol and glyco-
cerebrosides on the myelin surface (252,253). Destruction of myelin
results in decreased magnetization transfer (254). Moreover, the onset
of T1 shortening seen during the early phases of myelination on
T1-weighted images corresponds temporally and topographically to
the onset of magnetization transfer (Fig. 2-36) (255). Thus, it appears
Barkovich_Chap02.indd 71
71
that the T1 shortening on spin-echo images results from a magnetiza-
tion transfer interaction of glycocerebrosides and cholesterol on the
surface of the myelin molecule with free water in the brain. Because
magnetization transfer ratios can be calculated by use of magnetiza-
tion transfer in imaging sequences, it may ultimately be possible to
use increases in magnetization transfer to quantify brain maturation.
This can be done by looking at changes in magnetization transfer
in regions of the brain or in global magnetization transfer changes
(256). It remains to be seen which is more sensitive to subtle changes
in myelination.
Perfusion Imaging
Perfusion imaging is uncommonly performed in children. It is occa-
sionally necessary in children with vasculopathies such as moyamoya,
where revascularization is contemplated. Susceptibility-weighted per-
fusion imaging, as described in Chapter 1, is usually performed, as it
allows the evaluation of relative cerebral blood flow, blood volume,
and the time it takes a bolus to reach the region of interest (257,258).
However, age-related changes require the use of a quantitative method
such as arterial spin labeling (ASL) (259); at the time of writing of this
chapter, ASL is still not widely available and is rather difficult to apply
in infants. Some preliminary work suggests that ASL can be used in
children and that cerebral blood flow increases with age in both gray
matter and white matter (260). The cerebral blood flow appears to sud-
denly decrease in adolescence (260). It is likely that ASL will be applied
more frequently in the future and that this section will grow in future
editions of this book.
Functional MRI
Blood oxygenation level–dependent (BOLD) fMRI has been a pow-
erful research tool for mapping human brain activity for the past
two decades (261,262). The T2*-weighted echo-planar acquisition
required for BOLD fMRI is sensitive to differences in the oxygenation
content of blood. The ratio of oxyhemoglobin to deoxyhemoglobin
rises when cortical regions become more metabolically active due to
a concomitant increase in blood flow; this results in an increase of
the BOLD signal and thereby enables identification of activated areas
in response to a specific sensorimotor, cognitive, or behavioral task.
However, compared to the adult brain, there has been relatively little
application of BOLD fMRI techniques to the study of brain devel-
opment in newborns, infants, and children or for the investigation
of developmental disorders. This is largely because these pediatric
populations are often unable to cooperate with the task paradigms,
such as tests of speech, language, and motor function, required to
localize activation using fMRI. This has recently changed with the
advent of “resting-state” fMRI techniques, which do not require a
task paradigm, but rather rely on BOLD “functional connectivity” to
map functionally-specific cortical regions. Functional connectivity
refers to the phenomenon of temporal synchronization of function-
ally related brain areas. For BOLD fMRI, this was first demonstrated
in the motor cortex where it was observed that the spontaneous
fluctuations of the BOLD signal were highly correlated between left
and right motor cortex even in the absence of a motor task or any
other goal-directed behavior (263). Currently, two different meth-
ods are widely used to map functionally connected brain regions,
one hypothesis-driven and the other data-driven. The hypothesis-
driven method is called seed-voxel correlation and requires placing
a ROI on the area to be studied and calculating the temporal cor-
5/7/2011 2:42:49 AM
 72 Pediatric Neuroimaging

FIG. 2-36. Magnetization transfer images in a neonate. A and B. SE 550/15 images show T1 shortening in the
dorsal brainstem and the posterior limb of the internal capsule/lateral thalamus. C and D. Magnetization transfer
images show considerable magnetization transfer in the areas of T1 shortening on the T1-weighted images, but
nowhere else.

relations of the BOLD signal with those of other regions of inter-
est in the brain (263). The data-driven method, called independent
component analysis (ICA), is fully automated and can be applied
to the whole brain to derive multiple functionally connected brain
networks (264).
Examples of resting-state networks, also known as intrinsically
connected networks, computed from ICA of BOLD fMRI at 3 Tesla
(3 T) are shown in Figure 2-37. More than a dozen such cortical net-
works have been identified in the human brain to date (265,266). The
motor network represents the temporal synchrony between left and
right motor cortical regions; a visual network similarly includes left
and right visual cortex. The default mode network (DMN) is the name
given to cortical areas that have the greatest metabolic activity when
the subject is at rest; they deactivate (have less activity) during goal-
directed behavior. The DMN is more complex than the motor or visual
networks, consisting of bilateral posterior cingulate gyrus, precuneus,
inferior parietal lobules, ventromedial prefrontal cortex, and variable
other regions including temporal cortex (267,268).
Resting-state fMRI has begun to be used in the research setting
to investigate the process of human brain development. The hypoth-
esis is that, as white matter tracts in the brain mature and myelinate,
the functional connectivity between intrinsically connected cortical
regions will strengthen. More importantly, it is hoped that abnormali-
ties of functional connectivity might help to determine the effect of
brain injury on brain function and be a means of directing therapy
in neonates and children with brain injury. Resting state networks,
including motor, auditory, visual, and DMN, can be detected in prema-
ture infants scanned at term-equivalent age (269), indicating that cor-
tical regions are functionally connected well before the onset of white
matter myelination in many pathways connecting these networks. In a
study of preterm infants as young as 26 weeks postmenstrual age, the
most mature functional connections were found between homologous

Barkovich_Chap02.indd 72 5/7/2011 2:42:49 AM

 Chapter 2 • Normal Development of the Neonatal and Infant Brain, Skull, and Spine 73

FIG. 2-37. Resting-state functional connectivity MRI (fcMRI) of infants. The colored areas of cortex in
these images show those cortical areas that have the greatest metabolic activity when the subject is at rest;
they deactivate (have less activity) during goal-directed behavior. A. ICA of resting-state fMRI reveals cor-
related BOLD activity of bilateral regions of the posterior cingulate and adjacent precuneus, inferior pari-
etal lobules, ventromedial prefrontal cortex, and lateral temporal cortex. These comprise the DMN, those
areas that are maximally activated in the resting state. B. ICA of visual network fMRI reveals correlated
BOLD activity of bilateral regions of the occipital lobes corresponding to visual cortex.

cortical regions of the two cerebral hemispheres (270). The DMN could
not be detected in premature newborns, but was identified in term-born
infants (270). In a study of 71 healthy infants and children ages 2 weeks
to 2 years, only a few elements of the DMN were present in newborns,
but the number of connected cortical regions of the DMN increased
up to 1 year of age (271). By 2 years of age, the DMN resembled that
of the adult brain. A comparison of resting state networks between
23 children ages 7 to 9 years and 22 young adults ages 19 to 22 years
revealed that subcortical to cortical connectivity was relatively greater
in children, whereas adults showed more predominant corticocortical
connectivity (272). This may be explained by the relatively delayed and
prolonged maturation of corticocortical association and commissural
white matter tracts compared to subcortical-cortical projection tracts.
A larger resting-state fMRI study of 210 subjects ranging in age from
7 to 31 years of age reported that children showed more short-range
functional connectivity and less long-range functional connectivity
than adults (273). This may relate to the protracted development of
long white matter fibers compared to shorter connections and reflect
an overall change in cortical information processing during develop-
ment from more local to more distributed. However, research into the
development of brain networks using functional connectivity informa-
tion from fMRI and structural connectivity information from DTI is
itself in its infancy, and much more remains to be discovered that may
paint a more complex picture than these initial investigations.

Barkovich_Chap02.indd 73 5/7/2011 2:42:50 AM

 74 Pediatric Neuroimaging

FIG. 2-37. (Continued) C. ICA of auditory network fMRI reveals correlated BOLD activity of bilateral
regions of the superior temporal gyri corresponding to auditory cortex. D. ICA of dorsal attention mode
fMRI reveals correlated BOLD activity of bilateral parietal lobe cortex.

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 CHAPTER
Metabolic, Toxic, and
3 Inflammatory Brain Disorders
A. JAMES BARKOVICH AND ZOLTAN PATAY
Introduction
Imaging techniques in metabolic disorders
A simple pattern approach to metabolic diseases
White matter versus gray matter
Gray matter disorders
White matter disorders
Disorders affecting gray and white matter
Deeper analysis of toxic/metabolic/inflammatory diseases
A Few comments about classifi cations
Clinical aspects of metabolic diseases
Deeper analysis of gray and white matter diseases
Diseases primarily affecting white matter
Metabolic disorders primarily affecting gray matter
Metabolic disorders affecting both gray and white matter
INTRODUCTION
This chapter includes a very diverse group of brain disorders that have
a number of similarities, particularly in their imaging characteristics.
Inborn errors of metabolism are usually caused by a gene mutation
that results in formation of an abnormal protein, disrupting the func-
tion of one or more metabolic pathways. Some metabolic disorders
have no neurological manifestations. Others present with signs and
symptoms of central nervous system involvement exclusively; these are
true neurometabolic disorders. Some others may have both systemic
and central nervous system manifestations, and in a broader sense, if
the neurological implications of the disease are significant, these may
also be referred to as neurometabolic disorders.
In neurometabolic diseases, brain injury and clinical symptoms
result from lack of production of a necessary biochemical or from
formation of an abnormal biochemical that is, directly or indirectly,
toxic to the brain. Sometimes the disruption of metabolism (usu-
ally fetal, occasionally maternal) affects in utero brain development,
resulting in a malformation (Table 3-1). Much more typically, how-
ever, toxic chemicals are removed and necessary chemicals supplied
via the placenta; thus, brain injury does not begin until sometime
after birth. Children with more profound enzymatic changes tend
to have earlier clinical onset (neonatal, infantile), whereas those
with milder biochemical phenotypes typically develop symptoms
later (juvenile, adult). Both endogenous (caused by inborn meta-
bolic errors) and exogenous (ingested, injected, or inhaled) toxins
may interfere with normal brain metabolism in similar ways and,
therefore, cause similar patterns of brain damage; therefore, both are
included in this chapter. Still other processes, such as autoimmune
Barkovich_Chap03.indd 81
Metabolic and neurodegenerative disorders primarily
involving the cerebellum
Differentiation of cerebellar atrophy from hypoplasia
Cerebellar ataxias
Cerebellar atrophy
Cerebellar atrophy with adolescent/young adult onset
Cerebellar hypoplasia
diseases, and injury from radiation or chemotherapy, can be associ-
ated with similar histologic and imaging changes. These inflamma-
tory conditions are included in this chapter, as well. Infections are
discussed separately, in Chapter 11.
The diagnosis of the disorders discussed in this chapter is challeng-
ing for all concerned with the care of the affected child. The presenting
signs and symptoms are usually nonspecific ones that may be acute,
subacute, or slowly progressive; these may include hypotonia, seizures,
spasticity, ataxia, movement disorder, delay in achieving develop-
mental milestones, or focal neurologic deficits. The imaging study is
most often suggestive of a certain type of disorder—metabolic/toxic
or demyelinating—but rarely is diagnostic. Biochemical tests may be
normal or nonspecific, while genetic analyses are often unrewarding
unless a specific genetic defect is suspected and sought. As a result, at
least 60% of children with inborn metabolic errors never receive a spe-
cific diagnosis despite extensive investigations (1,2). Even if a diagnosis
is made, the expectations for outcome may be uncertain, as the precise
distinctions among, for example, the various mitochondrial disorders
and autoimmune inflammatory disorders are far from clear, especially
in children (3–9).
In order to establish a diagnosis, some method of organizing the
diseases from an imaging perspective is helpful, as narrowing the dif-
ferential diagnosis facilitates the clinical workup, saving time and
expense. In the future, all of these disorders may be diagnosed, classi-
fied, and treated according to the underlying genetic mutation and its
effect on metabolic pathways. However, our understanding of genet-
ics, epigenetic factors, and metabolic pathways is not yet good enough
to accomplish these goals. Therefore, we are a long way from a useful
genetic classification of these diseases.
81
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 82 Pediatric Neuroimaging
TABLE 3-1 Malformations of the CNS Described in the Context
of Inborn Errors of Metabolism
Abnormalitya
Cerebellar dysgenesis and
other posterior fossa
abnormalities
Cerebral dysgenesis
Cerebral lobar hypoplasias
Corpus callosum abnormalityc
Cortical dysplasia
Dentate nuclei abnormalities
Gray matter heterotopia/
cortical heterotopia
Barkovich_Chap03.indd 82
Metabolic Disorder
3-hydroxyisobutyric aciduria (hypoplasia)
Bifunctional enzyme deficiency (dysplasia)
Congenital disorders of glycosylation type 1a (cerebellar hypoplasia)
Folate and 5,10 methylene-tetrahydrofolate reductase deficiencies (in
maternal disease, Chiari type 2 malformation)
Fumarase deficiency (cerebellar dysplasia)
Glutaric aciduria type 2 (dysgenesis of cerebellar vermis)
Infantile Refsum disease (dysplasia)
Menkes disease (cerebellar dysplasia, vermian hypoplasia/agenesis)
Nonketotic hyperglycinemia (cerebellar hypoplasia)
Pseudoneonatal adrenoleukodystrophy (cerebellar dysplasia)
Pyruvate dehydrogenase deficiency (absence of pyramids,
heterotopia of the inferior olivary nuclei)
Respiratory chain deficiencies involving complex IV (hypoplasia
of cerebellar hemispheres with relative sparing of the vermis,
pontocerebellar hypoplasia)
Smith-Lemli-Opitz syndromeb (cerebellar hypoplasia, abnormal
foliation, small inferior cerebellar vermis)
Zellweger syndrome (cortical dysplasia)
Glutaric acidemia type 2 (warty protrusion of the surface of the
cerebral cortex)
Neonatal carnitine palmitoyl-transferase 2 deficiency
Glutaric aciduria type 1 (frontotemporal)
Smith-Lemli-Opitz syndromeb (frontal lobe hypoplasia)
3-hydroxyisobutyric aciduria (agenesis)
Congenital disorders of glycosylation (dysgenesis, hypoplasia)
Dihydropyrimidine dehydrogenase deficiency (partial agenesis)
Fumarase deficiency (agenesis)
Glutaric aciduria type 2 (hypoplasia)
Infantile Refsum (dysgenesis)
Menkes disease (dysgenesis)
Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral
disruption
Phenylketonuria (maternal, dysgenesis)
Pyruvate dehydrogenase deficiency (dysgenesis)
Smith-Lemli-Opitz syndromeb (absence, dysgenesis)
Zellweger syndrome (agenesis, partial dysgenesis)
Peroxisomal disorders
Smith-Lemli-Opitz syndromeb
Pyruvate dehydrogenase deficiency (dysplasia)
Zellweger syndrome (dysplasia)
Peroxisomal disorders
Carnitine palmitoyl transferase 2 deficiency
Fumarase deficiency (cerebral and cerebellar)
Glutaric acidemia type 2
Menkes disease
Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral
disruption
Pyruvate dehydrogenase deficiency (subcortical heterotopia)
Smith-Lemli-Opitz syndromeb
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 83

TABLE 3-1 Malformations of the CNS Described in the Context

of Inborn Errors of Metabolism (Continued)
Abnormalitya Metabolic Disorder
Holoprosencephaly Smith-Lemli-Opitz syndrome
Inferior olivary nucleus Bifunctional enzyme deficiency (dysplasia)
abnormalities Pontocerebellar hypoplasia type 2 (histologically)
Pontocerebellar hypoplasia type 4 and 5 (C-shaped inferior olivary
hypoplasia)
Pseudoneonatal adrenoleukodystrophy (dysplasia)
Pyruvate dehydrogenase deficiency (ectopic inferior olives)
Zellweger syndrome (dysplasia)
Lissencephaly 3-hydroxyisobutyric aciduria
Open opercula Fumarase deficiency
Glutaric aciduria type1
Pachygyria 3-Hydroxyisobutyric aciduria (pachygyria/lissencephaly)
Bifunctional enzyme deficiency (pachygyria/lissencephaly)
Glutaric aciduria type 2
Pyruvate dehydrogenase deficiency
Rhizomelic chondrodysplasia punctata
Smith–Lemli–Opitz syndromeb
Polymicrogyria Peroxisomal disorders
Fumarase deficiency
Smith-Lemli-Opitz syndrome
a
The number of reported cases of CNS malformations associated with metabolic disorders is small and are often
published as single case reports. Some of them, therefore, may be coincidental. As a general rule, metabolic disorders are
more likely to interfere with normal brain development if they start prenatally (e.g., peroxisomal biogenesis disorders,
nonketotic hyperglycinemia) or if they present as a maternal metabolic abnormality (e.g., hypovitaminosis).
b
Smith-Lemli-Opitz syndrome (OMIM 270400) is a recently described inborn error of cholesterol metabolism (biosyn-
thesis); indeed the first truly polymalformative metabolic disorders. The imaging diagnosis of this disease heavily relies
on the recognition of the peculiar constellation of multiple CNS malformations (see above).
c
Callosal hypoplasia nearly always accompanies prenatal, perinatal, or infantile white matter injury. Such cases are not
included.

In this chapter, the disorders are classified by the most typical MR
pattern of brain involvement, which frequently coincides with the ini-
tial clinical presentation. Discussion will center mainly on the pattern
of brain involvement (“pattern recognition”), as detected by morpho-
logic MRI, diffusion imaging, and proton MR spectroscopy (Table 3-2).
By proper neuroimaging analysis of the early pattern of brain involve-
ment, many disorders may be identified and differentiated from others
with similar clinical presentations (2,10). It is important to recognize
that the patterns of injury are dynamic (they change over time). Ini-
tial imaging findings may be very subtle or may not be detected until
the disease progresses. Moreover, many toxic/metabolic/inflamma-
tory brain disorders ultimately have a nonspecific imaging appearance
(diffuse white matter injury or diffuse atrophy) in the late stages of the
disease. Therefore, if an imaging study is to have a role in the diagnosis
of inborn metabolic errors, the study should be performed early in the
course of the disease. Follow-up studies should be performed if the
disorder progresses.
The first part of this chapter is a listing of many toxic/metabolic/
inflammatory disorders based solely upon their imaging character-
istics; this section should be useful for those who merely want a list
of differential diagnoses for a particular pattern of brain involvement.
Please refer to Tables 3-3 to 3-5 when reading this initial section. The
second part of the chapter discusses the same disorders in greater depth,
including some genetic, biochemical, and clinical information, as well
as references for those interested in pursuing additional information
about the diseases. This second part follows the order of the outline at
the beginning of the book (the List of Diagnoses), not the order of Tables
3-3 to 3-5. Keep this in mind in order to avoid becoming confused. Also
please remember that the discussions are intended to provide an over-
view of only the pertinent points of the disorders; a complete discussion
of inborn errors of metabolism is well beyond the scope of this book.
Interested readers are referred to textbooks on the subject, such as those
by van der Knaap and Valk (11) or Scriver et al. (12,13).
IMAGING TECHNIQUES IN METABOLIC
DISORDERS
MRI is the modality that will be primarily discussed in this chapter,
because the ability to detect subtle abnormalities of brain tissue is far
superior with MRI than with CT or ultrasound. Ultrasound often

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 84 Pediatric Neuroimaging

TABLE 3-2 Separation of Types of White Matter Histopathology by MR

Hypomyelination Demyelination Myelin Vacuolization Cystic Degeneration Controls
MTR - - - -- NL
T2 + + ++ +++ NL
Dav NL + ++ +++ NL
FA - -- --- -- NL
MRS +Cr NL Cr --Cr --Cr NL Cr
NL NAA --NAA --NAA --NAA NL NAA
NL Ch +Ch -Ch --Ch NL Ch
++mI +++mI -mI --mI NL mI
+Lac ++Lac +Lac ++Lac No Lac
NL Glu -Glu --Glu ---Glu NL Glu
NL Gln ++Gln -Gln NL Gln NL Gln

MTR, magnetization transfer ratio; T2, T2 relaxivity; Dav, average diffusivity; FA, fractional anisotropy; MRS, MR spectroscopy; +, mildly increased; ++, moderately
increased; +++, markedly increased; -, mildly decreased; --, moderately decreased; ---, markedly decreased; Cr, Creatine; NAA, N-acetylaspartate; Ch, Choline;
mI, myo-inositol; Lac, lactate; Glu, glutamate; Gln, glutamine.
Source: After van der Voorn JP, Pouwels PJW, Hart AAM, et al. Childhood white matter disorders: quantitative MR imaging and spectroscopy. Radiology
2006;241(2):510–517.

shows abnormalities in metabolic disorders that have onset prenatally,
in the neonatal period, or early in infancy. However, the findings are
nearly always nonspecific such as ventricular dilation, germinolytic
cysts, echogenic branching vessels in the basal ganglia (“lenticulostriate
vasculopathy”), or echogenic white matter (14), findings that are just
as likely to be seen in infection or injury. These findings are discussed
when helpful. CT is sometimes useful to detect calcification and will be
mentioned when appropriate.
When performing morphologic MR scans of patients with
metabolic disorders, heavily T1-weighted images (inversion recov-
ery, spoiled gradient-echo images) are very useful to assess myelin
injury and delayed or hypomyelination during the first year of life.
T2-weighted images are usually much more useful than T1-weighted
images in the assessment of myelination and white matter injury after
the first birthday; however, T1-weighted images are still useful to look
for discrepancies between the T1 and T2 appearances, which might
give a clue to diagnosis in hypomyelinating disorders (such as in 18q
deletion syndrome). T2 FLAIR images are superb for the detection of
supratentorial white matter changes in children beyond the age of 1
to 2 years (after myelination is largely completed). Conventional spin-
echo T2-weighted images are very useful on the initial study for detec-
tion of subtle cortical malformations that might help in the diagnosis
of a congenital infection (such as cytomegalovirus, see Chapter 11),
cobblestone malformation (see Chapter 5), or generalized peroxisomal
disorder; cortical malformations are more difficult to discern with T2
FLAIR because of reduced contrast between gray matter and white
matter. T2 FLAIR is also less sensitive in the detection of lesions within
the posterior fossa (15). Rapid acquisition relaxation-enhanced (also
known as RARE, fast spin echo, and turbo spin echo) T2-weighted
images show cortex and white matter well but are less sensitive to the
presence of iron deposition or calcification; a long echo time gradient-
echo sequence or susceptibility-weighted sequence should always be
added if fast spin echo or FLAIR is used as the primary T2-weighted
sequence. PROPELLER T2 (see Chapter 1), sometimes used to minimize
motion artifact, has poor white matter contrast and should be avoided in
studies for developmental delay or suspected metabolic disorder; faster is
not always better! Most of the MR discussions in this chapter concern
findings on T2-weighted images; they apply to T2 FLAIR and RARE as
well as conventional spin-echo sequences.
Some authors have advocated the production of calculated T2
maps of the brain and calculation of quantities such as relative water
content and myelin water fraction as an approach to the study of white
matter disease (16,17). Although these methods may help determine
the extent of myelin abnormality (16), they have not yet been shown
to help in distinguishing among metabolic disorders; they are not
discussed in this book.
In general, for morphological imaging. 3D volume acquisitions
are useful but are somewhat hampered by inherent quality limitations.
Best results are obtained by high in-plane resolution (512 matrix),
thin section (3 mm) 2D sequences, especially when taking advantage
of high field strength (3T) imaging. Susceptibility-weighted imaging
has the potential to differentiate between posthemorrhagic stigmata
and calcifications in general, but capability needs to be yet validated
in the case of neurometabolic diseases. In order to enhance the accu-
racy of lesion pattern analysis, high spatial resolution imaging is
needed.
Diffusion imaging (and magnetization transfer) may be useful in
separating regions of acute inflammation or cellular injury (reduced
diffusivity) from those disorders with hypomyelination, myelin vac-
uolization, or cystic degeneration (increased diffusivity) and those
involved more chronically (normal or increased diffusivity, Table
3-2) (10). MR spectroscopy (MRS) may provide important diagnos-
tic information in those disorders in which an abnormal metabolite
is present or a normal metabolite is present in abnormal quantity. We
perform MRS routinely in patients with suspected metabolic disease,
as the combination of anatomic MRI, diffusion imaging, and MRS
provides the best chance for making a diagnosis (10,18). See Chapter 1
for MRS techniques and Chapter 2 for the evolution of normal metab-
olite levels during development. Single photon emission tomography
(SPECT) and positron emission tomography (PET) are occasionally

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
useful, especially in gray matter diseases; when useful, these modalities
will be discussed.
For evaluation of the white matter, it may be useful to determine
whether the white matter abnormality represents hypomyelination,
demyelination, myelin vacuolization, or cystic degeneration of the
white matter (10). As the metabolic and microstructural characteris-
tics of toxic/metabolic/inflammatory disorders become better known,
this type of differentiation will become more important because dif-
ferent types of metabolic disorders cause different microstructural and
biochemical disturbances to the axons, oligodendrocytes, and myelin
itself. Thus, by using magnetization transfer ratios, diffusion tensor
imaging, and proton MR spectroscopy, in addition to anatomic images,
one may be able to better specify the type of white matter abnormality
(Table 3-2). As with all MR analyses of these disorders, imaging is most
valuable when obtained early in the course of the disease and, if pos-
sible, during an exacerbation of disease: findings may be very different
in active phases of the disease (typically showing reduced diffusivity
or high levels of abnormal metabolites) than in more chronic phases
(where diffusivity is more typically increased and metabolite levels
return to normal or lower). These characteristics are mentioned, when
known, in the following discussions.
A SIMPLE PATTERN APPROACH TO
METABOLIC DISEASE
The imaging characteristics of toxic/metabolic/inflammatory brain
diseases can be very confusing. The white matter, which nearly always
TABLE 3-3 Disorders with Exclusive or Dominant Gray Matter Involvement
A. Cortical Gray Matter
1. Neuronal ceroid lipofuscinoses
2. Mucolipidoses type I
3. Rett syndrome
4. Alpers syndrome
5. Autoimmune anti-NMDA receptor encephalitis (19)
B. Deep Gray Matter
1. Prolonged (hyperintense) T2 in striatum
a. Leigh syndrome (usually white matter involvement)
b. Alpha-ketoglutaric aciduria
c. Type I and IV 3-methylglutaconic aciduria
d. Juvenile Huntington disease
e. MELAS
f. Wilson disease (often involves white matter, periaqueductal)
g. Propionic acidemia (usually white matter involvement)
h. Ethylmalonic acidemia (usually white matter involvement)
i. Neuropathy/Striatal necrosis from SLC25A19 mutation (20)
j. Hypoxic-ischemic injury (older infants, adolescents, and adults)
k. Hypoglycemic injury (older infants, adolescents, and adults)
2. Short (hypointense) T2 in globus pallidus
a. Pantothenate kinase associated neurodegeneration (formerly
Hallervorden-Spatz disease – T2 hyperintensity in center of T2
hypointensity)
b. Oculodigital dental dysplasia
c. Infantile neuroaxonal dystrophy (atypical, PLA2G6 mutation)
3. Prolonged (hyperintense) T2 in globus pallidus
a. Methylmalonic acidemia
b. Toxins (carbon monoxide, manganese, cyanide involves
cerebellum too)
c. Kernicterus (chronic; subthalamic nuclei involved)
Barkovich_Chap03.indd 85
85
appears abnormal, may be involved primarily or secondarily. The ven-
tricles and sulci are often big. The basal nuclei (the thalami and basal
ganglia), brainstem, or cerebellum may be affected. We use a system-
atic approach to the analysis of these disorders based upon the pattern
of cerebral involvement (Tables 3-3 to 3-5), based upon the work of
van der Knaap and Valk (2,11). (Note that disorders predominantly
affecting the cerebellum are discussed at the end of this chapter). This
approach is a simplification because many of the metabolic disorders
have a different appearance on imaging studies when imaged at differ-
ent stages of the disease. In addition, some disorders may have nearly
identical neuroimaging features but have different ophthalmologic or
dermatologic features. This imaging approach is, therefore, most use-
ful when correlated with other clinical features and when the images
are acquired and evaluated in the early stages of the disease. As men-
tioned earlier, many diseases have very similar appearances when in
the chronic phase, with diffuse loss of brain tissue and increased water
in the remaining tissue. Another potential source of error is that dif-
ferent disorders (i.e., disorders with different genotypes, resulting in
different enzyme deficiencies) can result in the accumulation of the
same biochemical(s) in the serum or cerebrospinal fluid (CSF) (simi-
lar biochemical phenotypes); as a result, distinctly different diseases
are sometimes classified together as a single entity. It is not surpris-
ing, therefore, that some of them appear to have “atypical” patterns
on imaging studies! Clinical manifestations of genetically, or even
biochemically, similar disorders may differ as to age of onset, clini-
cal course, or outcome. These differing clinical phenotypes are likely
modulated by modifier genes or environmental factors, which further
confound this complex subject. Finally, classification of many diseases
d. Succinate semialdehyde dehydrogenase deficiency
e. Guanidinoacetate methyltransferase deficiency
f. Isovaleric acidemia
g. Pyruvate dehydrogenase (E2) deficiency
h. Beta-ketothiolase deficiency
4. Prolonged (hyperintense) T2 in claustrum
a. Wilson disease
5. Prolonged (hyperintense) T2 in subthalamic nucleus
a. Leigh syndrome
b. Kernicterus (chronic, with globus pallidus involvement)
C. Cerebellar and Brainstem
1. Prolonged (hyperintense) T2 in periaqueductal gray matter
a. Leigh syndrome
b. Wernicke encephalopathy
c. Wilson disease
2. Prolonged (hyperintense) T2 in cerebellar nuclei
a. Propionic acidemia
b. Ethylmalonic aciduria
c. Leigh disease
c. 3-methylglutaconic aciduria (type 1 and 4)
d. Beta-ketothiolase deficiency
e. Biotin-responsive basal ganglia disease
f. Ethylmalonic aciduria
g. Glutaric aciduria type 1
3. Short (hypointense) T2 in cerebellar nuclei
a. Cerebrotendinous xanthomatosis
4. Prolonged (hyperintense) T2 in inferior olivary nucleus
a. Dihydropyrimidine dehydrogenase deficiency
b. Leigh syndrome
5/6/2011 12:07:52 AM
 86 Pediatric Neuroimaging
is likely to change as we gain knowledge and experience. Nonetheless,
this systematic approach will allow the user to get close to the diagnosis
much of the time.
White Matter Versus Gray Matter
The first important decision is whether the disease involves predomi-
nantly gray matter (poliodystrophies), white matter (leukodystro-
phies), or both (pandystrophies). In general, disorders that primarily
affect cortical gray matter will cause thinning of the cortex and, thus,
have prominent cortical sulci. In the acute phase (during metabolic
decompensation), most disorders primarily affecting deep gray mat-
ter will show swelling, reduced diffusivity, and either low attenuation
(CT) or T1 hypointensity and T2/FLAIR hyperintensity (MRI) in the
involved structures; chronically, the structures are shrunken and have
increased diffusion. The cerebral white matter will often have an abnor-
mal appearance in disorders of gray matter, as Wallerian degeneration
of axons causes diminished white matter volume and decreased white
matter attenuation (CT) or mildly to moderately prolonged white mat-
ter T2 relaxation time (MRI). This white matter appearance can often
be differentiated from that of primary white matter disorders if the
imaging study is performed early in the course of the disease. Disorders
predominantly affecting white matter (other than hypomyelinating
disorders) cause marked hypoattenuation (CT) or T2 hyperintensity
(MRI) before any volume loss is apparent. Indeed, in some white mat-
ter diseases (such as Canavan disease), the white matter frankly enlarges
in early stages because the myelin expands (spongiform myelinopathy)
before it degenerates. Other white matter disorders, such as X-linked
adrenoleukodystrophy, have an inflammatory component in the early
stages. The inflammation causes edema, with accompanying mass
effect upon adjacent sulci, and blood–brain barrier breakdown with
resultant enhancement. Moreover, many white matter disorders, such
as infantile Alexander disease, start locally (frontal lobe in the case of
Alexander disease) and progress into adjacent areas (both white mat-
ter and gray matter). Many white matter disorders result in devasta-
tion of the involved areas, with necrosis and cavitation of the affected
brain and marked ex vacuo dilatation of the ventricles, whereas the
abnormal white matter secondary to gray matter disorders appears less
severely damaged. Finally, the clinical presentation of patients with
cortical gray matter disorders (seizures, visual loss, dementia in early
stages) often differs from that of deep gray matter disorders (chorea,
athetosis, dystonia) and both differ from the presentation of white
matter disorders (pyramidal signs such as spasticity, hyperreflexia or
cerebellar signs such as ataxia). Clinical information is often critical in
the proper evaluation of these patients, and, therefore, consultation of
the imaging physician with the referring physician (geneticist or neu-
rologist, in most cases, who may have detected important findings on
dermatologic or ophthalmologic exam) is essential for proper care of
the child.
Gray Matter Disorders
Once identified as being primarily of gray matter, the next step is to
determine if the disorder involves cortical or deep gray matter. Exam-
ine the deep gray nuclei for abnormal attenuation (CT) or abnormal
T2/FLAIR signal intensity (MRI). Sometimes MR spectroscopy or dif-
fusion imaging is useful, although it is uncommon for diffusion to be
abnormal in the setting of a normal FLAIR image. For confirmation
of cortical involvement, a specific search for sulcal effacement, cortical
swelling and reduced diffusion (acute phase) or cortical thinning with
sulcal enlargement (chronic phase), and abnormal signal intensity of
the cortex may be helpful.
Barkovich_Chap03.indd 86
If the pattern of the imaging study indicates that it is primarily one
of cortical involvement (cortical thinning with enlarged cortical sulci),
consideration should be given to such disorders as the neuronal ceroid
lipofuscinoses, Rett syndrome (in girls), Alpers disease, or glycogen
storage diseases (Table 3-3).
If only deep gray matter is involved, the signal intensity and loca-
tion of the affected structures are pivotal (Table 3-3). Involvement
of the striatum (caudate and putamen) is seen in mitochondrial
disorders (primarily Leigh syndrome, MELAS, and the glutaric aci-
durias), many organic acidemias (propionic and ethylmalonic aci-
demias), juvenile Huntington disease, hypoxic-ischemic injury (in
older infants, children, and adults, see Chapter 4), and hypoglycemia
(in older children and adults, see Chapter 4). Many of these disorders
may also cause white matter injury. If involvement is restricted to the
globus pallidus and consists of T2 hypointensity or T2 hypointensity
with central T2 hyperintensity, the diagnosis of pantothenate kinase
associated neurodegeneration (formerly called Hallervorden-Spatz
disease) or oculodental digital dysplasia can be suggested; these
are easily differentiated on clinical exam. If isolated globus pallidus
involvement shows T2 hyperintensity, methylmalonic acidemia, suc-
cinate semialdehyde dehydrogenase deficiency, guanidinoacetate
methyltransferase deficiency, poisoning (as from carbon monoxide
or cyanide), or kernicterus (see Chapter 4) should be considered.
High signal in the globi pallidi on T1-weighted images in a neonate
or young infant suggests urea cycle disorders if the insular cortex
is similarly involved. In infants and children, T1 hyperintensity of
the globi pallidi should suggest hepatic failure. Injury to subthalamic
nuclei in conjunction with the globi pallidi should suggest kernict-
erus, while subthalamic nuclei/putaminal injury suggests Leigh
syndrome.
White Matter Disorders
If the abnormal signal intensity involves predominantly white matter,
determine whether the white matter is being broken down (demyeli-
nation, cystic degeneration, or myelin vacuolation, see Table 3-2) or
whether the myelin is merely deficient or delayed (hypomyelination).
If white matter is being broken down, the location of the abnormality
(periventricular, deep, or subcortical white matter) and its progression
pattern should be determined (Table 3-4). Initially, the white matter
should be assessed to determine whether involvement is localized, mul-
tifocal, or diffuse. Localized white matter involvement may represent
early multiple sclerosis (MS), acute disseminated encephalomyelitis
(ADEM), autoimmune angiitis, or radiation injury (a history of radia-
tion therapy should be sought). Asymmetric multifocal white matter
involvement typically suggests autoimmune/inflammatory disorders
such as MS, ADEM, autoimmune angiitis, or systemic lupus erythema-
tosus (SLE), or unusual genetic disorders such as polyglucosan body
disease, or hereditary diffuse leukoencephalopathy with neuroaxonal
spheroids.
If white matter involvement is symmetric, it should be analyzed
to determine whether the subcortical, deep, or periventricular white
matter is initially involved and whether it starts in the frontal, pari-
etal, or occipital lobes or in the cerebellum or brainstem. An attempt
should be made to find out whether the patient has macrocephaly. If
early involvement is restricted to primarily deep and periventricular
white matter, the thalami should be specifically analyzed. High attenu-
ation (CT) or T2 hypointensity (MRI) bilaterally in the thalami sug-
gests Krabbe disease (demyelination with early involvement of internal
capsules and cerebellar nuclei) or GM1 or GM2 gangliosidosis (demy-
elination with hyperintensity of deep cerebral nuclei). If the internal
capsules, cerebral peduncles, dorsal pons, and cerebellar white matter
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 87

TABLE 3-4 Disorders Involving White Matter Only

A. Subcortical White Matter (U Fibers) Early
1. Large head
a. Megalencephalic leukoencephalopathy with cysts (formerly called van der Knaap disease)—subcortical cysts
b. Infantile Alexander disease—frontal involvement, extends into caudates and putamina-large myo-inositol and small NAA peak on MRS
2. Normal head size
a. Galactosemia
b. Cystic leukoencephalopathy without megalencephaly—cysts in anterior temporal lobe
3. 4-hydroxybutyric aciduria—also has cerebellar atrophy (21)
4. Aicardi-Goutières syndrome—progressive microcephaly and extensive punctate calcifications
B. Deep White Matter Early initially spares subcortical U fibers
1. Symmetric confluent white matter involvement
a. Calcium or short T1 and T2 in thalami
i. Krabbe disease (involves corticospinal tracts and cerebellar nuclei)
ii. GM1 or GM2 gangliosidoses
b. Normal thalami
i. Pons/Medulla corticospinal tract involvement
a. X-linked adrenoleukodystrophy,
b. Giant axonal neuropathy
c. Acyl CoA oxidase deficiency
ii. No specific brain stem tracts involved
a. Metachromatic leukodystrophy
b. Phenylketonuria
c. Lowe disease (cysts in deep white matter)
d. Sjögren-Larsson syndrome
e. Hyperhomocysteinemia (5, 10 methylenetetrahydrofolate reductase deficiency or errors involving cobalamin metabolism)
f. Radiation/Chemotherapy
g. Childhood ataxia with diffuse central nervous system hypomyelination and cavitation of affected white matter
(leukoencephalopathy with vanishing white matter)
h. Merosin-deficient congenital muscular dystrophy associated with small pons, sometimes small vermis
iii. Brain stem involved.
a. Maple syrup urine disease—myelinated white matter, including dorsal brain stem and corticospinal tracts
b. Dentatorubral and pallidoluysian atrophy—atrophy of dorsal brain stem and cerebellum
c. Juvenile Alexander disease
2. Multifocal white matter involvement
a. Multiple sclerosis
b. Acute disseminated encephalomyelitis
c. Polyglucosan body disease (22,23)
d. Autoimmune angiitis of the CNS (24,25)
e. Systemic lupus erythematosus
f. Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (26)
C. Hypomyelination
1. Pelizaeus-Merzbacher disease (27)
2. Pelizaeus-Merzbacher-like disease (28,29)
3. Trichothiodystrophy
4. 18q- syndrome (30,31)
5. Sialuria (32,33)
6. Cockayne syndrome type II
7. Hypomyelination with atrophy of the basal ganglia and cerebellum (34)
8. Hypomyelination with congenital cataracts (35,36)
9. 3-phosphoglycerate dehydrogenase deficiency
D. Nonspecific White Matter Pattern
1. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (37)
2. Congenital and acquired infections (see Chapter 11), particularly viral encephalitides, can involve gray and white matter symmetrically or
asymmetrically and should be included in the differential diagnosis in the proper clinical setting.
(References Given for Some Disorders Not Otherwise Discussed in the Chapter)

Barkovich_Chap03.indd 87 5/6/2011 12:07:52 AM

 88 Pediatric Neuroimaging
are affected in a newborn, maple syrup urine disease (myelin vacuola-
tion) should be considered.
If sequential MR studies are available, the pattern of progression
of white matter involvement may be useful. Some disorders, such as
L-2-hydroxyglutaric aciduria and Canavan disease, have a centripetal
progression pattern; the subcortical white matter is involved early and
involvement progresses centrally. In contrast, other disorders such as
Krabbe disease and X-linked adrenoleukodystrophy, exhibit a centrifu-
gal progression pattern; the periventricular white matter is involved
early with progression to the deep and subcortical white matter. Pro-
gression may also advance from anterior to posterior as in infantile
Alexander disease or from posterior to anterior as in X-linked adreno-
leukodystrophy or Krabbe disease.
The pattern of hypomyelination, as opposed to damaged or
destroyed myelination, is seen in the so-called hypomyelinating dis-
orders. It can be recognized by the appearance of delayed myelination
on T2-weighted images, often accompanied by a much more normal
appearance on T1-weighed images.
Congenital and acquired infections (see Chapter 11), particularly
viral encephalitides, can involve gray and white matter symmetrically
or asymmetrically and should be included in the differential diagnosis
in the proper clinical setting.
Disorders Affecting Gray and White Matter
Exclusive damage of either gray matter or white matter structures
is rather rare in neurometabolic disorders. Most commonly both
are involved, but in variable proportions. Disorders with significant
damage to both gray and white matter (Table 3-5) can be divided
into those involving only the cerebral cortex and those involving
deep gray nuclei (with or without cortical involvement). Those dis-
orders involving only cortical gray matter can be subdivided depend-
ing on whether the patient has normal long bones and spinal column
(Table 3-5).
If deep gray matter is involved, differential diagnosis is depen-
dent upon which nuclei are primarily involved. As seen in Table 3-5,
various combinations of deep gray nuclei can be involved at the same
time as various parts of the white matter are affected. Close analysis
of the patterns of both gray matter and white matter involvement,
as well as the presence of calcification, may aid in establishing the
diagnosis (38).
DEEPER ANALYSIS OF TOXIC/METABOLIC/
INFLAMMATORY DISEASES
The following sections describe a large number of toxic, metabolic
and autoimmune inflammatory disorders, their major clinical mani-
festations, underlying genetic and/or biochemical causes, numerical
listing in Online Mendelian Inheritance in Man (OMIM (44) ), and
imaging characteristics. The classification of each disorder in this sec-
tion is based mainly on standard anatomic imaging characteristics.
When diffusion MRI, proton MR spectroscopic, and positron emis-
sion tomographic characteristics of disorders have been described,
these characteristics are discussed. In some disorders that have rather
nonspecific imaging characteristics (such as the creatine synthesis
disorders), metabolic characteristics on MR spectroscopy may be
diagnostic and are discussed at greater length; more commonly, these
“functional” studies are nonspecific but may narrow the differential
diagnosis.
Barkovich_Chap03.indd 88
A Few Comments About Classifications
White matter diseases of children were traditionally divided into the
categories of dysmyelinating and myelinoclastic diseases. This is not
a useful distinction unless analysis is histologic, because many abnor-
malities of white matter are the result of inflammatory infiltrates or
accumulation of toxins from inborn errors of metabolism, which do
not fit well into either group. Dysmyelinating diseases result from an
inherited enzymatic deficiency that causes abnormal formation or
increased breakdown of the components of myelin. Areas of abnor-
mal myelination in dysmyelinating diseases are relatively symmetri-
cal, central (sparing subcortical U fibers in early stages), affect both
cerebral and cerebellar white matter, and are poorly marginated (45).
Myelinoclastic disorders involve destruction of intrinsically normal
myelin; causes include extrinsic and intrinsic toxins, infection, chemo-
therapy, radiation, and inflammatory autoimmune disorders such as
MS. Myelinoclastic injury is characteristically sharply defined, asym-
metric, and involves the subcortical U fibers early in the course of the
disease (45). As discussed above, the use of these morphologic charac-
teristics allows a diagnosis to be established in less than half of affected
patients.
In many sources, disorders of white matter are classified by the
intracellular organelle in which the malfunctioning enzyme is located
(45–47). For example, metachromatic leukodystrophy, in which the
defective enzyme is situated in lysosomes, is classified as a lysosomal
disorder, and X-linked adrenoleukodystrophy, in which the defective
enzyme is in the peroxisomes, is a peroxisomal disorder. However,
the phenotypic appearance of the brain (e.g., white matter involve-
ment versus gray matter involvement) usually depends more upon
the specific metabolic pathway involved than the organelle in which
the enzyme is located; indeed, some enzymes are synthesized in one
organelle but have their function in another. Therefore, classifica-
tion by organelle is impractical from the imaging perspective. Some
understanding of the organelle approach to classification is necessary,
however, if one is to read and understand the literature. Therefore, one
should know that lysosomes are intracellular organelles that contain
lysosymes, hydrolytic enzymes that aid in the phagocytosis of unde-
sirable molecules and particles. Dysfunction of specific lysosomal
enzymes results in a variety of disorders that affect the brain. Those
that affect oligodendrocytes result in white matter diseases (46). It is
also important to know that mitochondria are the organelles that pro-
duce ATP, the energy source for intracellular processes. As a result, dis-
orders of mitochondrial function typically result in impaired function
in organs that require high energy such as the heart, skeletal muscle,
and the brain (and within the brain, the gray matter structures) (4).
One should also know that peroxisomes are small organelles measur-
ing 0.2 to 1.0 mm. They are limited by a single membrane and contain
a minimum of one oxidase, to form hydrogen peroxide, and one cata-
lase to decompose it (45,48–50). Although peroxisomes can contain
many enzymes, their most important functions from the perspective
of this chapter are synthesis of plasmalogens (ether-phospholipids), a
type of phospholipid that constitutes the vast majority of membrane
phospholipids in myelin; beta oxidation of very long chain (>26 car-
bons) fatty acids, dihydroxycholestanoic and trihydroxycholestanoic
acid, pristanic acid, and long chain dicarboxylic acids; and cholesterol
biosynthesis. The process of beta oxidation results in the synthesis of
hydrogen peroxide. Plasmalogens, long chain fatty acids, and choles-
terol are important components of myelin. If these structures are not
properly formed, they result in formation of unstable myelin that is
more easily broken down by normal metabolic processes of the body
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 89

TABLE 3-5 Disorders Involving Gray Matter and White Matter

A. Cortical Gray Matter and White Matter Only (No Deep Gray Matter Involvement)
1. Normal bones
a. Cortical dysgenesis
i. Congenital infection (most commonly cytomegalovirus)
ii. Cobblestone malformations of the cerebral cortex (see Chapter 5)
b. No cortical dysgenesis
i. Alpers disease
ii. Menkes disease
2. Abnormal bones
a. Mucopolysaccharidoses
b. Lipid storage disorders
c. Peroxisomal disorders
B. Deep Gray Matter and White Matter Involvement
1. Primarily thalamic involvement
a. Krabbe disease—early corticospinal tract, cerebellar nuclear involvement
b. GM1 Gangliosidoses
c. GM2 Gangliosidoses
d. Wilson disease—also periaqueductal gray matter
e. Profound neonatal hypotensive encephalopathy
f. Many viral encephalitides
2. Primarily globus pallidus involvement
a. Canavan disease—thalami involved, large NAA peak on MRS
b. Kearns-Sayre syndrome—with subcortical white matter, often caudate
c. Methylmalonic acidemia—occasionally with deep white matter
d. Toxins (carbon monoxide and cyanide)
e. Maple syrup urine disease—with dorsal brain stem, corticospinal tracts
f. L-2-hydroxyglutaric aciduria—with subcortical white matter (centripetal progression), mild striatal involvement, and cerebellar nuclei
g. Fucosidosis (T2/FLAIR hypointensity)
h. Dentatorubral and pallidoluysian atrophy—extensive cerebellar/midbrain atrophy
i. Urea cycle disorders—with insular involvement
j. Cree leukoencephalopathy—with dorsal brain stem
3. Primarily striatal involvement
a. Leigh syndrome
b. MELAS—usually cortical involvement
c. Wilson disease
d. Alexander disease (with frontal white matter)
e. Ethylmalonic acidemia (39)
f. Propionic acidemia (40)
g. Glutaric aciduria Type I (Glutaryl-CoA dehydrogenase deficiency)—with anterior temporal lobe hypoplasia
g. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (37)
h. Molybdenum co-factor deficiency
i. Mitochondrial ATP synthetase deficiency (41)
j. 3-methylglutaconic aciduria
k. Beta ketothiolase deficiency. (41)
l. Malonic acidemia (41)
m. Alpha ketoglutaric aciduria (42)
n. Biotinidase deficiencies (41)
o. Biotin responsive basal ganglia disease (43)
p. Toxins
q. Hypoxic-ischemic injury in older child or adult
r. Hypoglycemic injury in older child or adult
s. Cockayne disease (38)
t. Hypomyelination with atrophy of basal ganglia and cerebellum—with atrophic caudate, putamen, cerebellum

(References Given for Some Disorders Not Otherwise Discussed in the Chapter)

Barkovich_Chap03.indd 89 5/6/2011 12:07:52 AM

 90 Pediatric Neuroimaging
(50,51). In addition, if long chain fatty acids are not properly formed,
the result is disrupted lipid packing in myelin with resultant abnormal
T2 relaxation time of white matter (52). Unfortunately, classification
by organelle is not useful for an imaging approach, as most organ-
elles contain many proteins that can be involved in many metabolic
pathways.
The use of physiologic techniques such as diffusion, magnetization
transfer, and proton spectroscopy characteristics (Table 3-2) has great
potential in the classification of toxic and metabolic disorders. Unfor-
tunately, these characteristics are incompletely known for many toxic/
metabolic/inflammatory disorders. Therefore, at this time, a combina-
tion of morphologic and physiologic data (when known) seems the
best method. In the following sections, disorders of white matter are
organized by the pattern of initial white matter involvement on ana-
tomic MRI. Characteristics of diffusion imaging, magnetization trans-
fer, proton spectroscopy, and PET are discussed when they are useful in
further refining the diagnosis.
Clinical Aspects of Metabolic Diseases
Pattern recognition alone is often insufficient to characterize a particu-
lar disorder. The integration of clinical data (gender, age of onset, and
type of clinical manifestations; disease course; physical or ophthalmo-
logical stigmata) and imaging abnormalities (lesion types and patterns,
as well as advanced MR data) allows recognition of the more specific
clinical-radiological pattern. Therefore, knowledge of some clinical
data is often important for the neuroradiologist involved in the diag-
nostic workup and follow-up of patients with suspected or confirmed
neurometabolic disorders. The most important categories of clinically
relevant data are discussed here.
Age of Onset
The age of onset of metabolic diseases is a very useful clinical pattern
element. Depending on age of onset, the following categories may be
used: neonatal (from birth to 1 month), early and late infantile (1–6
months and 6 months to 3 years), early and late childhood-juvenile
(3–6 and 6–16 years), and adult (16 and over). It is important to recog-
nize that the onset of the clinical signs and symptoms does not neces-
sarily correspond to the onset of the metabolic derangement.
As a clear manifestation of their considerable phenotypic varia-
tions, almost all neurometabolic diseases have several clinical forms
depending on the age of onset. Within the same disease category, ear-
lier onsets usually suggest a more profound metabolic derangement,
whereas later onset often reflects clinically milder but not necessarily
benign variants. Most metabolic disorders of neonatal onset fall into
the category of the so-called devastating metabolic diseases of the
newborn. The underlying metabolic derangements in these diseases
typically result in global brain toxicity (encephalopathy), leading to
diffuse brain edema and neurological manifestations reflecting varying
proportions of white or gray matter involvement. The term “devastat-
ing metabolic diseases of the newborn” actually refers to a fairly well-
defined clinical syndrome. The neonate is typically normal at birth. The
prodrome begins a few days later and is characterized by refusal to feed
and vomiting (occasionally misinterpreted as pyloric stenosis). This
is followed by lethargy and coma, which may clinically mimic central
nervous system infection. At this point, seizures and changes in muscle
tone (hypotonia or hypertonia) are common. If the disease is not diag-
nosed and treated promptly, the progressive toxicity leads to irrevers-
ible neurological deficit or death. Most devastating metabolic diseases
of the newborn are organic or amino acidopathies (Table 3-6).
If a “devastating metabolic disease” is suspected in a newborn or
young infant, in addition to anatomical MRI, advanced MR techniques
Barkovich_Chap03.indd 90
TABLE 3-6 Most Common Devastating
Metabolic Diseases of the
Newborn
Isolated sulfite oxidase deficiency
Propionic acidemia
Methylmalonic acidemia
Isovaleric acidemia
HMG-CoA lyase deficiency
3-methylglutaconic aciduria (some forms)
Primary lactic acidosis
Glutaric aciduria type 2
Pyroglutamic aciduria
Urea cycle defects (citrullinemia, ornithine transcarbamylase
deficiency)
Maple syrup urine disease
Non-ketotic hyperglycinemia
Menkes disease
Nesidioblastosis
Peroxisomal biogenesis disorders
are useful. Diffusion-weighted imaging may be pathognomonic in
maple syrup urine disease; MR spectroscopy may be diagnostic in
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) lyase deficiency
(unpublished observation) or suggestive in energy metabolism disor-
ders (lactate) and urea cycle defects (glutamate), as well as in nonke-
totic hyperglycinemia (glycine).
Systemic Manifestations of Metabolic Disorders
Systemic manifestations of neurometabolic disorders may include
dysmorphia (e.g., coarse facial features), organomegaly, skeletal abnor-
malities, or, more generically, failure to thrive. Systemic complications
in metabolic disorders are common but often misleading clinically.
Patients with metabolic diseases are prone to intercurrent infections
with or without CNS involvement, but intercurrent infectious diseases
can trigger episodes of metabolic crisis in patients with neurometabolic
disorder. Acute pancreatitis is increasingly recognized as a possible
complication of organic- and aminoacidopathies and usually occurs
during an acute ketoacidotic crisis. Hematological abnormalities,
notably anemia, neutropenia, and thrombocytopenia are often seen in
organic acidopathies.
Neurological Abnormalities
Neurometabolic diseases may present as an acute or chronic
encephalopathy. Mixed forms can be characterized by progressive
encephalopathy and occasional metabolic deterioration. Acute enceph-
alopathy develops during acute decompensation (lactic acidosis, ketosis
or ketoacidosis, hyperammonemia, hypoglycemia, hyperglycinemia).
Neurological manifestations include hypotonia, seizures, metabolic
stroke with rapid onset of extrapyramidal movement disorders, and
coma. Other metabolic disorders may be associated with a more insidi-
ous course and result in a chronic progressive encephalopathy with
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
neurological manifestations that may include seizures, pyramidal and
extrapyramidal movement disorders, and neurocognitive and behav-
ioral problems.
Seizures
Seizures are frequent but nonspecific complications of metabolic dis-
orders. Inborn errors of metabolism are a common cause (16%) of
first-time seizures in infants under the age of 6 months. Seizures reflect
cerebral cortex involvement in the pathological process. In some met-
abolic diseases (e.g., fatty acid oxidation disorders, nesidioblastosis),
especially in those with early infantile onset, seizures may be secondary
to hypoglycemia.
Stroke or Strokelike Clinical Presentation
While the development of neurological deficit (pyramidal signs,
extrapyramidal signs) in neurometabolic diseases is often slowly pro-
gressive or insidious, inherited metabolic disorders may also present
with focal neurological signs of acute onset. These clinical events may
be related to true strokes (ischemic or hemorrhagic) or stroke-like
episodes. Some organic acidopathies (e.g., propionic, isovaleric and
methylmalonic acidemias) are known to predispose to intracranial
hemorrhage due to coagulation abnormalities related to thrombocy-
topenia. Acute ischemic complications (i.e. true infarctions) occur in
some aminoacidopathies, likely due to direct vessel-wall damage, and
in lysosomal storage disorders such as Fabry disease and cystinosis.
In Fabry disease, both ischemic and hemorrhagic complications may
occur since endothelial damage (glycosphingolipid deposits within
the endothelium) leads initially to occlusive arterial disease, followed
by bleeding from overloaded collaterals, somewhat similar to child-
hood moyamoya syndrome. Rare other neurometabolic causes of
ischemic stroke are Menkes disease, sulfite oxidase deficiency (molyb-
denum cofactor deficiency), and carbohydrate-deficient glycoprotein
syndrome.
Stroke-like events probably represent episodes of regional met-
abolic decompensation with subsequent functional disturbances
within brain parenchyma, which may or may not lead to permanent
structural damage. Stroke-like episodes with hemiparesis or hemiano-
psia are characteristic in “mitochondrial disorders” such as MELAS.
Occasionally, extrapyramidal movement disorders (dystonia, chore-
oathetosis or tremor) may develop suddenly and mimic stroke, typi-
cally in organic acidurias (e.g., glutaric aciduria type 1, methylmalonic
acidemia) and are usually associated with severe basal ganglia dis-
ease, typically without thalamic involvement. This can be contrasted
with perinatal hypoxic-ischemic brain damage, in which thalami
and posterior parts of putamina are usually affected (see Chapter 4).
Clinically, both may present later in childhood with extrapyramidal
“cerebral palsy.”
Muscle Tone Changes
Muscle tone changes are common in neurometabolic disorders.
Hypotonia is common in many metabolic disorders, especially in
those associated (directly or indirectly) with impairment of energy
metabolism (mitochondrial disorders) and peroxisomal disorders. In
nonketotic hyperglycinemia and propionic acidemia, hypotonia may
be caused by increased blood glycine levels, since glycine is known
to have an inhibitory effect on spinal ventral motor neurons. In fatty
acid oxidation disorders, and perhaps in many of the mitochondrial
cytopathies too, affected children are hypotonic because of associated
myopathy. Hypertonia is typical of Krabbe disease and with methylma-
lonic and isovaleric acidemia, while contractures are seen in rhizomelic
chondrodystrophia punctata. Alternating muscle tonus (hypotonia and
Barkovich_Chap03.indd 91
91
hypertonia, presenting with opisthotonus) is typical of maple syrup
urine disease.
Additional Useful Clinical Features
Other useful features in the diagnosis of metabolic disorders include
a characteristic odor caused by the production of abnormal metabo-
lites, facial dysmorphia (present in peroxisomal disorders and muco-
polysaccharidoses), ophthalmologic and dermatologic disorders.
A discussion of these features is beyond the scope of this book; for
details, readers are referred to standard texts of metabolic disor-
ders such as those by van der Knaap and Valk (11) or Scriver et al.
(12,13).
DEEPER ANALYSIS OF GRAY AND WHITE
MATTER DISEASES
Diseases Primarily Affecting White Matter
White Matter Diseases Initially Affecting Periventricular
Cerebral White Matter
Metachromatic Leukodystrophy
Metachromatic leukodystrophy (OMIM 250100) causes diffusely
abnormal myelination of the cerebral hemispheres; it can be mani-
fested in a variety of forms. All forms are caused by decreased activity
of arylsulfatase-A or, very rarely, a cofactor of arylsulfatase-A (saposin
B, or sphingolipid activator protein B), which degrade sulfogalactosyl-
ceramide into galactocerebroside and sulfate. The responsible genes are
ARSA, located at chromosome 22q13.31-qter (53), and PSAP, located
at chromosome 10q22.1 (54). The decreased activity of arylsulfatase-A
or saposin B results in failure of myelin breakdown and reutilization
in the central and peripheral nervous systems. Furthermore, ceramide
sulfatide accumulates and impairs function of neurons, macrophages,
and Schwann cells (55).
The most common clinical form of metachromatic leukodystro-
phy is the late infantile variant, which typically presents with a gait
disorder and strabismus early in the second year of life. Impairment
of speech, spasticity, and intellectual deterioration appear gradually.
Progression is steady, with death occurring usually within 4 years of
the onset of symptoms (56). The juvenile form is slightly rarer. Neu-
rologic symptoms become evident between 5 and 7 years of age and
progress slowly; affected patients often present with declining school
performance (56,57). In the uncommon adult form, patients develop
an organic mental syndrome and progressive corticospinal, corticobul-
bar, cerebellar, or extrapyramidal signs (58).
The imaging findings in metachromatic leukodystrophy are non-
specific. CT scans show progressive atrophy and diffusely low attenua-
tion in the central cerebral white matter. No enhancement occurs after
contrast administration (58,59). MR scans show progressive symmetric
areas of prolonged T1 and T2 relaxation times in the deep and periven-
tricular cerebral white matter (Fig. 3-1); the subcortical white matter
is spared until late in the course of the disease (Fig. 3-1A) (46,59).
High-resolution images show stripes of affected and unaffected myelin
(called a “tigroid” pattern) that extend peripherally from the surface
of the lateral ventricles (Fig. 3-1A); these represent relatively spared
myelin and lipid-containing glial cells (60). In my experience, these
are rather characteristic, although van der Voorn et al. describe similar
(but less obvious) stripes in Krabbe disease and GM1 gangliosidoses
(both described later in this chapter). Eichler et al. found a charac-
teristic evolution of white matter involvement that is similar among
the late infantile, juvenile, and adult-onset groups (61). A homogenous
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 92 Pediatric Neuroimaging
region of T2 hyperintensity is initially found in the frontal and parietal
periventricular and deep white matter; it is faintly hyperintense in mild
disease and more hyperintense in more severe disease; callosal involve-
ment is mild. As the disease progresses, the signal abnormality extends
toward the subcortical white matter and the tigroid pattern becomes
evident (61). Involvement of the corticospinal tracts, cerebellar white
matter, and basal ganglia is only seen late in the course of the disease
(61,62), along with progressive loss of hemispheric brain tissue. An MR
scoring system has been devised to assess severity of brain involvement
(61). If paramagnetic contrast is administered, the cranial nerves and
cauda equina may enhance (Fig. 3-1C and D) (63); the reason for this is
not known, but it is likely due to the inflammatory response to myelin
breakdown.
Diffusion-weighted imaging shows decreased water diffusivity in
affected regions (64,65) early in the course of the disease (Fig. 3-1B),
and increased diffusivity in later phases of the disease (66). If high-
resolution diffusion-weighted images can be obtained, one can see the
same horizontal stripes of affected and unaffected white matter, with
Barkovich_Chap03.indd 92
FIG. 3-1. Metachromatic Leukodystrophy. A. Axial T2-weighted
image shows abnormal hyperintensity in the deep and periventricu-
lar white matter; the subcortical white matter (white arrowheads) is
spared. Note the horizontal stripes of relatively spared (darker) white
matter. B. Axial diffusion weighted image shows abnormal hyper-
intensity of the white matter, indicating reduced diffusivity.C. Axial
postcontrast T1-weighted image in a different patient shows enhance-
ment (white arrowheads) of the cisternal portion of the oculomotor
nerves. D. Sagittal postcontrast T1-weighted image of the lumbar
spine shows enhancement of the cauda equina (white arrowheads).
the unaffected regions showing normal diffusion characteristics and
the affected regions exhibiting increased water motion. Proton MRS
shows decreased N-acetylaspartate (NAA) and elevated myo-Inositol
(myo-I)(67).
Globoid Cell Leukodystrophy (Krabbe Disease)
Clinical manifestations of Krabbe disease (OMIM 245200), also
known as globoid cell leukodystrophy, typically begin acutely between
age 3 and 6 months with restlessness, irritability, intermittent fever,
feeding problems, poor head control, hyperactive reflexes, and delayed
development (68). Optic atrophy and hyperacusis often develop, fol-
lowed by episodes of apnea and need for nasogastric or gastrostomy
feedings. Terminally, the infants are flaccid and develop bulbar signs;
they die within the first few years of life (56,57). The basic defect in
this condition is a deficiency of galactosylceramide beta-galactosidase,
a lysosomal enzyme that is a key component in metabolic pathways of
myelin turnover and breakdown. Deficiency of this compound results
in the accumulation of galactosylsphingosine (psychosine), which is
5/6/2011 12:07:53 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
toxic to neurons, oligodendrocytes, and Schwann cells (56,69). The
gene for galactosylceramidase (GALC) has been mapped to chromo-
some 14q31; a number of mutations in this region have been shown
to cause clinical Krabbe disease (70). For those who evaluate adult
patients as well as children, it is important to note that the disease
may present at different ages and with different clinical and radiologic
manifestations, depending upon the exact site and type of mutation
(71–73).
Pathologic examination shows replacement of cerebral white mat-
ter with rubbery, hard, translucent material; pseudocysts may develop
adjacent to the frontal horns and in the corpus callosum (74). Micro-
scopically, severe neuronal loss is observed in the thalami, cerebellar
cortex, cerebellar dentate nuclei, and inferior olivary nuclei (74). Severe
destruction of myelin and axons with reduced numbers of oligoden-
drocytes is observed in white matter throughout the CNS, but is most
pronounced in the corona radiata, corpus callosum, and cerebellar
peduncles (74).
Although diagnosis in these patients is based upon the assay of
beta-galactosidase from white blood cells or skin fibroblasts, the CT
features can occasionally be very helpful. Early in the disease, high den-
sity is seen bilaterally in the thalami (Fig. 3-2A), caudate nuclei, corona
radiata, and cerebellar dentate nuclei. The high density may be seen
before or in conjunction with the decrease in attenuation of the white
matter (75). As the disease progresses, diffuse white matter atrophy
ensues; at this stage, the CT appearance of Krabbe disease resembles
that of the end stage of all other dysmyelinating diseases (75,76). On
T1-weighted MR images in young infants, the thalami are often abnor-
mally bright and the normal hyperintensity of the internal capsules is
delayed in appearance (Fig. 3-2B); these findings are useful if present
(77). On T2-weighted images, the hila of the cerebellar nuclei remain
hyperintense, and the corticospinal tracts are abnormally hyperin-
tense in the internal capsules, medial medullary pyramids, and cere-
bral white matter (Fig. 3-2C–E) (72); in our experience these findings
strongly suggest the diagnosis. Later in the first year and in the second
year, the deep cerebral white matter shows T2 hyperintensity, particu-
larly in the posterior frontal/anterior parietal lobes (Fig. 3-3) (78,79)
with extension into the callosal splenium or posterior limb of the inter-
nal capsule; the cerebellar white matter is more severely involved, and
significant volume loss is often present (Fig. 3-3D–G) (80,81). By the
second year, the MR appearance of Krabbe disease is that of nonspe-
cific T1 hypointensity and T2 hyperintensity in the cerebellar nuclei
and the deep cerebral and cerebellar white matter (72). Van der Voorn
et al. describe the presence of stripes of relatively spared white mat-
ter representing perivenular clusters of globoid cells (Fig. 3-3G) (60),
but these stripes are not found as consistently in Krabbe disease as in
metachromatic leukodystrophy. The subcortical white matter is spared
early in the course of the disease (82). The thalami may be normal or
show T1 hyperintensity or T2 hypointensity (Fig. 3-3) (59). Enhance-
ment and enlargement of the cranial nerves (83,84) and nerve roots
of the cauda equina (85) have been reported after administration of
paramagnetic contrast, presumably secondary to myelin breakdown
and associated inflammatory response; such enhancement may be a
common finding.
Diffusion tensor imaging may be useful in the early diagnosis of
Krabbe disease, because affected neonates have significantly lower
fractional anisotropy than age-matched controls (86). Diffusion-
weighted images show reduced diffusion early in the course of the
disease, particularly in the subcortical white matter, caudate head,
and anterior limb of the internal capsule. As the disease progresses,
the white matter begins to show uniformly increased diffusion
(65,66).
Barkovich_Chap03.indd 93
93
Few reports of proton MRS of patients with Krabbe disease have
been published. In infantile Krabbe disease, reports show marked ele-
vation of choline and myo-I, moderate elevation of creatine, moder-
ate to marked NAA reduction, and inconsistent lactate elevation in the
white matter (Fig. 3-2F); these changes were less marked in gray matter
(87–89). These findings are attributed to changes in glial membrane
composition and microglia activation for synthesis of phospholipid
membranes. We have also noted increase in the size of the “macromo-
lecular peaks,” broad peaks centered at 0.9 and 1.3 ppm (Fig. 3-2F).
Changes in juvenile Krabbe disease were much less marked and con-
sisted mainly of elevated myo-I in white mater and normal spectra of
gray matter (88). In adults, MRS of white matter shows mild decrease
in the concentration of NAA and mild elevations of creatine, choline,
and myo-I (73,88).
Classic X-Linked Adrenal Leukodystrophy/
Adrenomyeloneuropathy/Acyl CoA
Oxidase Deficiency
Classic, X-linked adrenal leukodystrophy (OMIM 300100) is the
result of a mutation of the ABCD1 gene, which has been mapped to
chromosome Xq28 and codes for a peroxisomal membrane protein
of the ATPase binding cassette type (90,91). Abnormality of the pro-
tein impairs the transport of very long chain fatty acids into the per-
oxisome, where they are normally metabolized into shorter chain fatty
acids that can be used for the biosynthesis of complex lipids and acy-
lated proteins in the cytoplasm (92). Thus, plasma analysis for very
long chain fatty acids is the best initial biomarker for the disease, allow-
ing unambiguous diagnosis in males (although false negative results
are found in about 20% of obligate heterozygote carriers (93,94). So
far, more than 500 different mutations of the ABCD1 gene have been
described (94); there is no clear correlation between location of the
mutation and phenotype (95,96). This disorder is characterized by two
major pathophysiologic components, a severe inflammatory demyeli-
nation that predominates in the cerebral white matter and an axonal
degeneration that predominates in the posterior fossa and spinal cord
(97). The axonopathy and inflammation are both thought to result
from accumulation of very long chain fatty acids in the nervous tis-
sue; normal cells are protected by plasmalogens (structural phospho-
lipids in nervous tissue), but plasmalogens are also affected in many
patients with ABCD1 mutations (98). Three different zones of white
matter involvement are identified within the cerebrum; these affect the
radiologic appearance. A central burned-out zone of scarring (Zone A)
contains only astrogliosis. Just peripheral to the central zone is an
inflammatory zone (Zone B), with perivascular inflammatory cells and
demyelination; axons are preserved. Peripheral to the inflammation is
a zone of ongoing demyelination (Zone C), where myelin is breaking
down in the absence of inflammation. Some authors also suggest the
presence of a zone of impending or incipient demyelination (Zone D),
peripheral to Zone C; a decrease in NAA (with or without increased
choline) can be found in this zone when proton MR spectroscopy is
performed (99).
Although many different clinical forms of adrenoleukodystrophy
have been described (Table 3-7) (92,100), the most common (and the
one of interest to those caring for children) is the childhood cerebral
form, which is characterized mainly by the inflammatory demyelina-
tion of the cerebrum. Affected patients are almost exclusively boys,
who usually present between age 5 and 12 years (mean 7.2 years) (92);
all ethnic groups are affected with no apparent difference in frequency
(94). Many children present with learning difficulties at school and
are initially given a diagnosis of attention deficit hyperactivity disor-
der. Other early features of the disorder include impaired visuospatial
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 94 Pediatric Neuroimaging

FIG. 3-2. Krabbe disease in a 4-month old infant. A. Axial noncontrast CT shows hyperdensity of the thalami (white arrows). B. Axial T1-weighted image
shows abnormal hyperintensity of the thalami and absence of the normal hyperintensity in the internal capsules. C–E. Axial T2-weighted images show
abnormal hyperintensity (white arrows) in the hila of the cerebellar nuclei (C), the posterior limbs of the internal capsules (D), and the perirolandic region
of the centrum semiovale (E). F. Single voxel short echo proton MR spectrum from frontal white matter shows abnormally elevated “macromolecular” peaks
(large arrows), a small NAA peak (small arrow), and large choline (Ch) and myo-inositol (mI) peaks for age.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 95

FIG. 3-3. Evolution of Krabbe disease in an infant. A. Axial T2-weighted image at age 14 months shows
abnormal hyperintensity (white arrow) in the left pontine corticospinal tract. B and C. Axial T2-weighted
images show abnormal hyperintensity (white arrows) fairly well localized to the corticospinal tracts. No
volume loss is present. Some horizontal stripes of hypointensity can be seen within the affected white
matter in (C). D. Axial T2-weighted image at age 21 months shows abnormal hypointensity of the medial
aspect of the middle cerebellar peduncles (white arrowheads) and the brainstem corticospinal tracts (black
arrows). E–G. Axial T2-weighted images show more pronounced involvement of the corticospinal tracts
(white arrows, compare with A–C), increased extent of white matter involvement in the periventricular
and deep cerebral white matter (F and G), and loss of volume (enlarging sulci and diminished white
matter volume compared to B and C). Note the horizontal stripes of hypointensity in (G). These are less
marked than in metachromatic leukodystrophy.

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 96 Pediatric Neuroimaging

TABLE 3-7 Phenotypes of X-ALD Carriers

Phenotype Description Estimated Relative Frequency
Male X-ALD Carriers
Asymptomatic (MRI normal) Patients up to 10 y old Increasing as diagnostic tests
improve
Asymptomatic (MRI Patients between 2 and 10 y old. Usually initially diagnosed as Increasing as diagnostic tests
abnormal) another leukodystrophy. improve
Cerebral (mild) without Patients usually between 3 and 10 y, but up to 21 y. Present with 45%
adrenomyeloneuropathy behavior changes, school failure, dementia. Typically initially
(AMN) diagnosed as ADHD, autism, or Asperger syndrome.
Cerebral (severe) without Onset between 5 y old and adulthood. Progressive behavioral, 2%–3%
AMN cognitive, and neurologic (epilepsy, visual loss, speech loss,
bulbar palsy) deficit. Often leads to total disability within
3 y. May be misdiagnosed as other neurodegenerative
diseases, tumor, or psychosis
Pure adrenomyeloneuropathy Onset 28 ± 9 y. Paraparesis, sphincter disturbances, sensory changes, 35%
(AMN) incoordination, pain, impotence. Progressive over decades.
Involves primarily spinal cord with minimal or no inflammatory
response. Often misdiagnosed as multiple sclerosis, progressive
spastic paraparesis, cervical spondylosis, amyotrophic lateral
sclerosis. ∼20% will develop brain involvement.
AMN with cerebral Onset 28 ± 9 y. Like pure AMN plus dementia, behavioral distur- 15%
involvement bances, psychosis, epilepsy, aphasia, visual loss bulbar palsy.
Cerebellar Cerebellar/brain stem involved in adolescence or adulthood. Patients 2%–3%
present with ataxia, cranial neuropathies or long tract signs
Addison only Onset usually before 10 y. Adrenal insufficiency without neurologic 20%
signs or symptoms. Rarely brain MRI abnormal.
Asymptomatic Biochemical and gene abnormality without demonstrable adrenal or Common <4 y
neurologic deficit. ∼50% will become symptomatic within 10 y. Rare >40 y
Female X-ALD Carriers
Asymptomatic No evidence of adrenal or neurologic disease ∼50%. Diminishes with age. Most
women <30 y old have this form
Mild myelopathy Increased deep tendon reflexes and distal sensory changes in lower Increases with age. ∼30% of
extremities women >40 y
Moderate to severe Resembles AMN, but later onset and milder Increases with age. ∼15% of
myeloneuropathy women >40 y
Cerebral involvement Rare in childhood. Slightly more common in middle age or later ∼2%
Clinically evident adrenal Rare at any age ∼1%
insufficiency

Source: Adapted from Moser HW, Raymond G, Dubey P. Adrenoleukodystrophy: new appraoches to a neurodegenerative disease. J Am Med Assn 2005;294:3131–3134.

acuity, a gradual disturbance in gait, and slight intellectual impairment.
Abnormal skin pigmentation or other signs and symptoms of adrenal
insufficiency sometimes precede neurologic abnormalities; in other
cases, adrenal symptoms never develop. About 10% of patients pres-
ent acutely with seizures, acute adrenal crisis, acute encephalopa-
thy, or coma (101). Progression of the disease is usually fairly rapid.
Hypotonia, seizures, visual complaints, and difficulty in swallowing
appear with time. Spinal cord and peripheral nerve involvement may
occur without central symptoms and, rarely, adrenal insufficiency may
occur without neurological involvement (102–104).
The other major form of this disorder is characterized mainly by
axonal degeneration in the brainstem and spinal cord; this form is
called adrenomyeloneuropathy (105). Adrenomyeloneuropathy typi-
cally presents in young adults (mean age 28 years) with incontinence,

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
progressive paraparesis, or progressive cerebellar dysfunction (100);
peripheral neuropathy may be detected (94). Affected patients can
develop inflammatory demyelination in the cerebrum at any age; this
form is referred to as “cerebral AMN” and also most commonly occurs
during the third and fourth decades (94,97). In addition, although
this is an X-linked disorder and presents predominantly in males,
about 20% of heterozygous females develop neurological disability
that resembles adrenomyeloneuropathy but is of later onset (mean
age 43 years, range 8–75 years) and somewhat milder than in affected
males (100,106). The reasons for the differing clinical presentations of
patients with identical mutations have not been clarified, but a likely
cause in women is variable X chromosome inactivation.
The diagnosis of X-linked adrenoleukodystrophy is confirmed by
chromosomal studies and by assay of plasma, red cells, or cultured skin
fibroblasts for the presence of increased amounts of very long chain
fatty acids (104,107). False negative results occur in about 15% to 20%
of women heterozygotes. Therefore, women suspected of this disorder
should undergo mutation analysis (92).
Barkovich_Chap03.indd 97
97
Imaging studies show several characteristic patterns. About 80% of
affected patients with cerebral ALD have predominant posterior white
matter involvement (108); the first area affected in this group is the mid-
dle of the callosal splenium. CT reveals low attenuation, starting in the
splenium of the corpus callosum and extending into the central parietal
and occipital white matter (corresponding to what later becomes Zone
A described earlier, Fig. 3-4A); very early in the course of the disease,
involvement may be restricted to the central splenium. The anterior
edge of this low attenuation region often shows contrast enhancement,
secondary to an immune-mediated inflammation (Zone B). MR scans
demonstrate marked T1 hypointensity and T2/FLAIR hyperintensity
(Fig. 3-3B), increased diffusivity, and reduced diffusion anisotropy in
Zone A (109), characteristically with enhancement of the inflamma-
tory leading edge of demyelination (Zone B, Fig. 3-4C) if paramagnetic
contrast is administered. The enhancing areas typically show reduced
diffusion (Fig. 3-4D) because of the increased cellularity. The presence
of contrast enhancement seems to be associated with clinical worsening
of the disease (110). In early phases of the disease, the subcortical white
FIG. 3-4. Adrenoleukodystrophy; classic
imaging appearance. A. Axial noncontrast
CT shows low attenuation in the callosal
splenium (s), peritrigonal white mat-
ter (p), and posterior thalami (t). B. Axial
FLAIR image shows abnormal hyperinten-
sity involving the callosal splenium, poste-
rior periventricular and deep white matter
(sparing subcortical white matter), posterior
thalami, and posterior aspect of the poste-
rior limb of the internal capsule. C. Axial
postcontrast T1-weighted image shows a
rim of enhancement (white arrowheads) in
the inflammatory zone that surrounds the
area of damaged white matter. D. Diffusion
weighted image shows that the inflamma-
tory zone is slightly hyperintense (white
arrowheads), indicating reduced diffusivity.
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 98 Pediatric Neuroimaging
FIG. 3-4. (Continued) E and F. Map from a two-dimensional spectroscopic imaging acquisition (E) and the spectra themselves with echo time of 144 ms
(F). The spectra show high choline, low creatine, and low NAA in the peritrigonal regions (voxels 37, 41, 44, 48) and generally low metabolite levels in the
splenium (voxels 38–40 and 45–47).
matter is spared on standard imaging sequences (Fig. 3-4) (46,47), but
diffusion tensor imaging may show mildly increased water diffusivity
and reduced anisotropy (109). The corticopontine and corticospinal
tracts in the pons and medulla often show T2 hyperintensity (Fig. 3-5)
(111) and enhancement. The splenium of the corpus callosum appears
with low signal intensity on the midline sagittal, T1-weighted image
(112); in chronic disease, it is small and atrophic. Less common pat-
terns have been described (47,113,114), including calcification in the
parietooccipital white matter.
The second most common pattern is predominantly frontal
involvement (Fig. 3-6) (115), seen in about 15% of affected patients
(108). In this pattern, the genu of the corpus callosum, frontal white
matter, anterior limbs and genus of the internal capsules, and, occasion-
ally, the cerebellar white matter are predominantly involved. Contrast
enhancement is seen on the peripheral margins (Zone B), as in the pos-
terior form. Other patterns include predominantly unilateral involve-
ment restricted to an entire hemisphere, both frontal and occipital
(Fig. 3-5) (107), and a pattern with supratentorial involvement
restricted to the genus of the internal capsules (111).
Affected heterozygous women usually have normal MR scans but
may have findings similar to those in affected boys, with involvement
of parietooccipital white matter and involvement of the corticospinal
tracts (106).
Proton MRS shows decreased NAA; increased choline, glutamine,
and glutamate; decreased myo-I; and increased lactate resonances in
areas of active disease (116,117). In more chronic disease, or with
longer echo times, findings may be limited to low NAA and elevated
choline (Figs. 3-4 and 3-6). MRS shows abnormalities before the
MRI study becomes abnormal in some children (116) and in normal
appearing white matter peripheral to the regions of T2 prolongation
and enhancement; this area of abnormal MRS may represent Zone
C. Indeed, it is suggested that reduction in the NAA/choline ratio
to below 5.0 is predictive of disease progression within the next 2
to 3 years (118). Therefore, proton MRS should be performed in all
Barkovich_Chap03.indd 98
individuals with ALD, particularly in those with stable MRI exams
and in siblings (of patients with ALD) who are known to have the
ALD mutation but are not symptomatic. Heterozygous women have
reduced NAA/Cr and NAA/Cho in the corticospinal tracts (both in
the cerebral hemispheres and in the internal capsules) and reduced
NAA/Cho in the parietooccipital white matter when compared to age-
matched controls (106).
The imaging findings in adrenomyeloneuropathy (Fig. 3-7) differ
from those in classic childhood form of adrenoleukodystrophy in that
the cerebrum is less commonly involved, whereas the cerebellar white
matter and corticospinal tracts (in the internal capsules and brainstem)
are more commonly involved (Fig. 3-7) (105,119). Lesion progression
appears to be slower than in ALD (119). No inflammatory component
is present and, therefore, no enhancement is seen.
No extensive radiologic differential diagnosis exists for the classic
pattern of ALD. Another peroxisomal disorder, acyl CoA oxidase defi-
ciency, has very similar imaging findings, with early involvement of
the pontomedullary corticospinal tracts, and cerebellar white matter,
followed by involvement of the splenium, and deep parietooccipital
white matter (120). However, the clinical presentation is quite differ-
ent, as both boys and girls are affected, often with delayed cognitive and
motor development, followed by developmental regression during the
third year of life (120).
Leukoencephalopathy with Vanishing White Matter
Leukoencephalopathy with vanishing white matter (VWM, OMIM
603896, formerly called childhood ataxia with diffuse central nervous
system hypomyelination, CACH) is a disorder in which patients typi-
cally have normal development in early childhood, then develop pro-
gressive ataxia and spastic diplegia with relapsing-remitting phases,
development of bulbar symptoms, optic atrophy, and epilepsy, leading
to death in the second decade of life. Involvement of the peripheral
nervous system is uncommon (121). Onset occurs from childhood
to early adulthood (122) or even middle age (123); rarely patients
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 99

FIG. 3-5. Severe ALD with atypical pattern. A. Axial T2-weighted image shows involvement of the corticospinal and corticopontine tracts in the ventral
pons (black arrows) as well as the middle cerebellar peduncles (white arrows). B. Axial T2-weighted image shows involvement of the genus of the internal
capsules (white arrows) with sparing of the more posterior aspects of the capsules. C. Axial postcontrast T1-weighted image shows enhancement of both the
genu and splenium of the corpus callosum (white arrows). D. Coronal T2-weighted image shows extension of abnormal hyperintensity from the internal
capsules (white arrowheads) inferiorly into the pontine corticospinal tracts (black arrows).

may present as neonates (124) or in infancy (or even as fetuses) and
have rapidly fatal courses (125,126). Patients tend to have episodes
of deterioration after trauma or infection (127–129) or sometimes
fright (130). Rarely, extreme macrocephaly may develop (131,132).
Analysis of CSF, serum, or urine may show elevation of glycine (133).
Cree leukoencephalopathy (134), described in previous editions of
this book as a distinct disorder in Native American populations (par-
ticularly the Cree and the Chippewa), is an early-onset form of VWM,
with onset between 3 and 9 months (126). Affected children typically
present with abnormalities of tone (hypotonia or spasticity), then
progress to seizures, posturing, and death within a few months (134).
Imaging findings are identical to those in early-onset VWM (135).
Adult variants are also described, usually presenting in the teenage
years or 20s with occasional seizures or psychiatric symptoms or
dementia (136); some affected adult women have associated ovarian
failure (137).
The disease is familial and appears to be autosomal recessive. It can
be caused by mutations in any of the five genes encoding subunits of
the eukaryotic translation initiation factor EIF2B: EIF2B1 at 2p23.3,
EIF2B2 at 14q24, EIF2B3 on chromosome 12, EIF2B4 at 1p34.1, or
EIF2B5 at 3q27 (34,138). The mechanism of cell injury is incom-
pletely understood, but is believed to be related to stress conditions
(heat stress, head injury) that result in a reduction in protein synthe-
sis within affected cells (121,136); glial cells appear to be selectively

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 100 Pediatric Neuroimaging

FIG. 3-6. Atypical adrenoleukodystrophy with predominant frontal involve-

ment. A. Axial T2-weighted image shows abnormal T2 hyperintensity of the
callosal genu and the surrounding frontal white matter (white arrows). B and
C. Map from a two dimensional spectroscopic imaging acquisition (B) and
the spectra themselves (C), acquired with echo time of 144 ms. The spectra are
abnormal in the callosal genu and frontal white matter (voxels 1–8), showing low
NAA and increased choline. Spectra from the region of the callosal splenium and
peritrigonal white matter (voxels 9–21) are normal.

FIG. 3-7. Adrenomyeloneuropathy. A. Axial

T2-weighted image through the mid-pons
shows abnormal hyperintensity in the lateral
pons (arrowheads) and cerebellar white mat-
ter (small arrows). B. Axial FLAIR image at
the level of the bodies of the lateral ventricles
is normal.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 101

TABLE 3-8 MRI Criteria for the Diagnosis of VWM

Obligatory Criteria
1. Cerebral white matter shows either diffuse or extensive signal abnormalities; the immediately subcortical white matter may be spared.
2. Part or all of the abnormal white matter has a signal intensity close to or the same as cerebrospinal fluid on proton density or FLAIR
images, suggestive of white matter rarefaction or cystic destruction.
3. If proton density and FLAIR images suggest that all cerebral white matter has disappeared, there is a fluid-filled distance between
ependymal lining and the cortex, but not a total collapse of the white matter.
4. The disappearance of the cerebral white matter occurs in a diffuse “melting away” pattern.
5. The temporal lobes are relatively spared, in the extent of the abnormal signal, degree of cystic destruction, or both.
6. Cerebellar white matter may be abnormal, but does not contain cysts.
7. There is no contrast enhancement.
Suggestive
1. Within abnormal white matter there is a pattern of radiating stripes on sagittal and coronal T1-weighted or FLAIR images; on axial images
dots and stripes are seen within the abnormal white matter as cross-sections of the stripes.
2. Lesions within the central tegmental tracts in the pontine tegmentum.
3. Involvement of the inner rim of the corpus callosum; the outer rim is spared.

Adapted from van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol 2006;5:413–423, with permission.

vulnerable. The effect of the mutation on the function of the protein
probably determines the severity of the disease (136,139); most patients
have residual eIF2B activity of 30% to 80%, while carriers have normal
activity (140).
Diagnostic criteria, as suggested by van der Knaap et al. (122,129),
include the following: (a) Normal or mild delay of initial motor and
mental development. (b) Neurologic deterioration has a chronic pro-
gressive course, with episodes of deterioration precipitated by minor
infection, minor head trauma or fright, and may lead to lethargy or
coma. (c) Neurologic signs consist mainly of cerebellar ataxia and spas-
ticity. Optic atrophy may develop but is not obligatory. Epilepsy may
occur, but is not the predominant sign of the disease. Mental abilities
may also be affected, but not to the same degree as the motor functions.
(d) MRI criteria as in Table 3-8.
Histopathologic analysis of affected brains shows axonal loss,
hypomyelination, demyelination, gliosis, and “foamy” oligodendro-
cytes, primarily in the deep white matter (127,141,142). The cortical
gray matter, subcortical U fibers, corpus callosum, and internal cap-
sules are relatively spared (141,142). Within the ventral pons, sharply
demarcated symmetric areas of demyelination are seen primarily in the
transverse pontine fibers, with intact pontine nuclei. The dorsal pons
shows a symmetric area of demyelination involving the central teg-
mental tract and the superior central nucleus on both sides. Whereas
some studies suggest that this is a primary axonopathy, with myelin
being secondarily affected (122), others suggest a primary disease of
oligodendrocytes, resulting in excessive oligodendroglial apoptosis
with secondary axonal degeneration (121,141,142), or impaired astro-
cyte function (143).
MRI shows diffuse white matter signal abnormality (T1 hypoin-
tensity and T2 hyperintensity) in which the white matter ultimately
cavitates to become CSF intensity on T1- and T2-weighted images
(Figs. 3-8 and 3-9). Diffusivity is variably reduced compared to CSF
on diffusion-weighted images; tissue in the process of cavitating has
reduced diffusivity (144), whereas cavitated white matter has increased
diffusivity, with signal identical to CSF (Fig. 3-9). Cavitated (cystic)
white matter is hypointense on FLAIR and proton density images and
thus can be differentiated from the hyperintense rarefied (but noncavi-
tary) white matter (Fig. 3-9). Subcortical fibers may be spared at the
time of presentation (Fig. 3-8B). Degeneration to CSF intensity starts
in the central white matter (Fig. 3-8) but eventually involves the entirety
of the white matter in the cerebrum; only the ventricular lining is
spared at this point (Fig. 3-9E and F). Signal changes of myelination are
seen only in the striatal region and cerebellum. Contrast enhancement
has never been reported. Cerebellar white matter may have normal or
abnormal signal (Fig. 3-9), but cavitation is not seen in the cerebellum
or brainstem (136). Cerebellar atrophy varies from mild to severe and
primarily involves the vermis (129). In the brainstem, abnormal hyper-
intensity is seen initially in the pontine central tegmental tracts, but
ultimately involves the ventral pons as well (122,145). Later stages of
involvement are characterized by nearly complete loss of white matter,
with ex vacuo ventricular enlargement.
When presentation is in neonates, the initial MRI may be normal
(144) or the cerebral gyri may appear slightly broader than normal,
indicating either delayed sulcation or slight white matter swelling
(124,136); this appearance may be initially interpreted as immaturity.
More commonly, the initial MRI is characterized by white matter that
is abnormally hypointense on T1-weighted images and abnormally
hyperintense on T2-weighted images (Fig. 3-9). On proton density
and FLAIR images, white matter signal intensity is lower than normal
in some regions of cerebral white matter, suggesting white matter rar-
efaction, and possible impending cystic degeneration. No evidence of
myelination is seen at term.
Proton MR spectroscopy is normal early in the disease. As rar-
efaction and cavitation ensue, white matter spectra show a progres-
sive decrease and, ultimately, complete disappearance of all “normal”
signals; some lactate and glucose remains and may become more evi-
dent as the amplitude of the other signals decreases (127–129). NAA
progressively decreases, whereas Cr is decreased but stable (67). Cortex
maintains a more normal spectrum, apart from a decrease in NAA and
a variable elevation of lactate and glucose (122,128,146).
Giant Axonal Neuropathy
Giant axonal neuropathy (OMIM 256850) is a generalized disorder of
cytoplasmic intermediate filaments that results in the accumulation
of ovoid aggregates in many different cell types (147). The responsible
gene (GAN) has been mapped to chromosome 16q24.1 and encodes

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 102 Pediatric Neuroimaging
a ubiquitously expressed protein that has been named gigaxonin
(148,149). Affected patients initially present in childhood with fea-
tures of a peripheral sensory and motor neuropathy and extremely
kinky hair (150). However, central nervous system involvement is an
important component of the disease (151,152). Typically, muscular
hypotonia is noticed early in life, along with delayed motor develop-
ment. Walking may be eventually achieved, but is broad-based and
ataxic and then regresses until the child becomes wheel-chair bound.
Ultimately, the neurological exam shows hypotonia, muscle weakness
and wasting, absent reflexes, and contractures. Optic discs are pale and
visual acuity is diminished.
Imaging is nonspecific, showing T1 and T2 prolongation of the
white matter, with sparing of the subcortical U fibers in both the cere-
brum and cerebellum. The posterior limbs of the internal capsules are
commonly involved early (Fig. 3-10A), as is the cerebellar white matter
(Fig. 3-10B). On noncontrast T1-weighted images, the ependymal lining
Barkovich_Chap03.indd 102
FIG. 3-8. Vanishing white matter disease in a 12 month old
with developmental regression after viral illness. A. Axial
T1-weighted image shows diffuse low signal intensity in the
white matter with several areas of lower intensity (black arrows).
B. Axial T2-weighted image shows extensive hyperintensity of
the white matter; the cavitating areas are more difficult to appre-
ciate than on the T1-weighted image (A). C. Axial diffusion-
weighted image shows the cavitating areas (black arrows) as very
low signal intensity. Note the relative preservation of subcortical
white matter.
of the lateral ventricles is often hyperintense compared to surrounding
white matter (11). Later in the course of the disease, the corticospinal
tracts in the brainstem show T2 hyperintensity and will enhance after
paramagnetic contrast administration (11). Thus, this disease has an MR
appearance somewhat similar to X-linked adrenoleukodystrophy. Thal-
ami may show T2 hyperintensity (153). MRS shows reduced NAA, but
increased choline and myo-I (154). Creatine values are roughly normal.
Phenylketonuria
Phenylketonuria (OMIM 261600) is an autosomal recessive disorder
most often caused by a mutation to the PAH gene, which has been
mapped to chromosome 12q24.1 (155). This mutation causes phe-
nylalanine hydroxylase (PAH) deficiency, although other biochemical
defects can cause hyperphenylalaninemia and manifest similar signs
and symptoms (156,157). More than 400 mutations (318 missense
mutations) of the PAH gene have been identified (158,159), partially
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 103

FIG. 3-9. Vanishing white matter disease in a 9-month old infant. A. Axial FLAIR image shows two levels of abnormality in the cerebral white matter. The
outer layer (o) shows abnormally high water content, while the inner layer (i) shows signal intensity identical to CSF, indicating frank cavitation. Note the
relative sparing of subcortical white matter. B. Axial T2-weighted image appears to show homogeneous signal intensity. T2-weighted images do not reliably
show cavitation. C. Coronal T2-weighted image shows nearly homogeneous hyperintensity of the posterior frontal white matter, as well as involvement
of the periventricular temporal (small white arrows) and cerebellar white matter (large white arrows). D. Coronal diffusion weighted image shows marked
hyperintensity (arrows), indicating reduced diffusion in the pre-cavitary white matter of the centrum semiovale, internal capsules, periventricular tempo-
ral white matter, and ventral cingula. E and F. Vanishing white matter with nearly complete white matter cavitation. First echo (E) and second echo (B)
T2-weighted images show nearly homogeneous isointensity of white matter with the enlarged lateral ventricles. Only the remaining ependymal (arrows) can
be seen to separate the ventricles from the liquefied surrounding white matter. (Figure 3-9E and F courtesy Dr. Jaap Valk, Amsterdam.)

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 104 Pediatric Neuroimaging

FIG. 3-10. Giant axonal neuropathy in a 14-year-old adolescent. Axial T2-weighted image (A) and coronal FLAIR image (B) show extensive cerebral and
cerebellar white matter hyperintensity with relative sparing of subcortical white matter (small white arrowheads) and corpus callosum (white arrows). Note
involvement of the internal capsules (large white arrowheads). (These images courtesy Dr. Susan Blaser, Toronto.)

accounting for the marked clinical, biochemical, and neuroimaging
variability. Most PAH missense mutations cause misfolding of the PAH
protein, resulting in increased protein turnover and loss of enzymatic
function (159), with consequent production of compounds (phe-
nylpyruvic and phenylacetic acids and phenylacetylglutamine) that are
toxic to the developing brain (59,156). Untreated patients are charac-
terized by growth retardation; global developmental delay; eczematous
dermatitis; hypopigmentation; and a peculiar musty odor of the urine,
skin, and hair (155,156). Treatment is by dietary control and, occasion-
ally, dietary supplements (156,158,160); benefit from control of diet is
variable, probably due to the heterogeneity of the disease.
Imaging studies show primarily abnormal signal in the white mat-
ter that corresponds to delayed and defective myelination. In older
patients, ventriculomegaly is found as a result of white matter degen-
eration (161). MRI shows T2/FLAIR hyperintensity that is initially
seen in the periventricular white matter of the cerebral hemispheres
(Fig. 3-11) (59,162). Subcortical white matter is initially spared. Some
reports suggest that the amount of white matter disease is related to
the adequacy of biochemical control of the disease (163). In the acute
phase, diffusion is reduced in the affected white matter, possibly due to
spongiotic changes of myelin (164); some studies suggest a relationship
between the serum phenylalanine level and degree of reduced diffusion

FIG. 3-11. Phenylketonuria. A. Axial FLAIR image shows abnormal hyperintensity in the frontal and parietal white matter. Note sparing of the subcortical
white matter (white arrows). B. Axial diffusivity (Dav) map shows hypointensity (white arrows), indicating reduced diffusivity, in the affected white matter.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 105

(165). Contrast enhancement has not been reported. The volume of
the cerebral hemispheres is reduced (166).
In the minority of cases caused by dihydropteridine reductase
deficiency or defect in the synthesis of tetrahydrobiopterin, the fron-
tal cortex, occipital cortex, subcortical white matter, and putamina are
affected. Putaminal and frontal/occipital subcortical calcification is
often seen in these cases on CT (155). MRI shows cortical and subcor-
tical atrophy, particularly in the intervascular boundary zones (“water-
shed zones”) (11). T1 shortening (T1 hyperintensity) may be present in
damaged regions of cortex.
Proton MR spectroscopy shows the presence of a peak from ele-
vated phenylalanine at 7.37 ppm (163,167). The size of this peak may
be useful for monitoring treatment, although it is currently not trivial
to assess this peak on most clinical MR scanners. Other peaks seem
to be normal. Diffusion imaging reveals reduced water motion in the
affected regions of the brain (164) in younger children while it shows
increase in the median and minor eigenvalues and decreased fractional
anisotropy in the deep parietal and occipital white matter in children
older than 3 years (168).
Maple Syrup Urine Disease
Maple syrup urine disease (OMIM 248600) is a genetically heteroge-
neous disorder; the causative genes encode the catalytic proteins of
the branched-chain alpha-ketoacid dehydrogenase complex (BCKD)
that catalyzes the oxidative decarboxylation of the branched-chain
amino acids leucine, isoleucine, and valine (169). Treatment requires
lifelong dietary restriction and monitoring of branched-chain amino
acids to avoid brain injury. Despite careful management, children
commonly suffer from metabolic decompensation in the context of
catabolic stress associated with nonspecific illness (170). The mecha-
nisms underlying this decompensation and brain injury are poorly
understood. Five clinical phenotypes are described; these seem to
correlate with the degree of residual enzymatic activity (171). In the
classic type, onset of clinical signs and symptoms occurs during the
first week of life when poor feeding, vomiting, dystonia, opisthotonic
posturing, and seizures become manifest (156). If the disease is not
recognized and treated, infants develop signs of increased intracranial
pressure, become comatose, and may die in a few weeks (156,172).
The severity of neurologic sequelae is strongly correlated with the
duration of the acute toxic phase in the neonatal period (173). The
less severe forms of the disease, with higher residual enzymatic activ-
ity, can present later in childhood with metabolic crises resulting in
lethargy, irritability, nausea, and vomiting that may progress to stupor
or coma (171).
Imaging is normal in the first few days of life. Because classic
maple syrup urine disease presents in the neonatal period, it is one of
the few metabolic diseases in which transfontanelle sonography may
play a role in diagnosis. Starting with the onset of symptoms, cranial
sonography shows symmetric increase in echogenicity of periventricu-
lar white matter, basal ganglia, and thalami in the acute stage (174).
The CT and MR findings are quite characteristic, revealing profound
localized edema (low density on CT, long T1, T2 on MR) in the deep
cerebellar white matter, dorsal brainstem, cerebral peduncles, poste-
rior limb of the internal capsule, sensorimotor tracts in the centrum
semiovale, and, sometimes, globi pallidi (Fig. 3-12A–D) (59,172).
The regions involved correspond to those that are myelinated or
myelinating at the time of birth. Generalized vasogenic edema of the
cerebral hemispheres may be superimposed on the localized abnor-
malities (172,175), particularly in the first weeks of life. Diffusion
imaging may be very useful at this stage of the disease, as the areas
with (intramyelinic (176) ) MSUD edema (cerebellar white matter,
dorsal brainstem, cerebral peduncles, corticospinal tracts, and globi
pallidi) show reduced diffusivity during the acute phase of the disease
(Fig. 3-12E–G), with ADC values falling to 20% to 30% of their normal
values (177). When relapses occur after the brain has fully or nearly
fully myelinated, reduced diffusion will be seen in most of the white

FIG. 3-12. Maple syrup urine disease. A. Axial noncontrast CT scan shows hypodensity in the frontal white matter ( f ) as well as in the globi pallidi (white
arrows). B–D. Axial T2-weighted images show abnormal hyperintensity in the brainstem (b), cerebellar white matter (c), frontal white matter ( f ), globi
pallidi (g), posterior limbs of the internal capsules (black arrowheads), optic radiations (black arrows), and the entirety of the subcortical and deep cerebral
white matter. E–G. Axial diffusivity (Dav) maps shows reduced diffusivity in the brainstem (b), cerebellar white matter (c), globi pallidi (g), posterior limbs
of the internal capsules and lateral thalami (white arrowheads), optic radiations (white arrows), and perirolandic white matter (w). H and I. Short echo
(26 ms) and long echo (288 ms) proton MRS from the basal ganglia show the characteristic broad peak at 0.9 ppm that represent branched chain amino
acids and branched chain ketoacids (bca). This peak is differentiated from the normal macromolecular peak at 0.9 ppm by its presence on long echo spectra.
Reduced NAA and lactate are also common findings.

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 106 Pediatric Neuroimaging

FIG. 3-12. (Continued)

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
matter of the cerebral and cerebellar hemispheres (175), supporting the
concept that myelinated or myelinating white matter is preferentially
affected and that the reduced diffusion is the result of intramyelinic
edema. After the acute phase of the disease has resolved, the patients
are left with a variable degree of brain damage, dependent upon how
quickly treatment was initiated (156,172).
In the milder (intermittent, intermediate) forms of the disease that
present with decompensation later in infancy or in early childhood, the
main finding is a profound lack of myelination that may be superim-
posed upon damage to the dorsal brainstem, cerebellar white matter,
internal capsules, and globi pallidi. These are the same regions affected
in the classic form of the disease during the early postnatal crisis. From
the imaging perspective, the intermittent form of maple syrup urine
disease may resemble early Canavan disease (including diffusion find-
ings, since both present with reduced water diffusion in affected white
matter structures), but the clinical context and the laboratory findings
allow easy differentiation.
In the acute phase of illness, proton MRS of patients with maple
syrup urine disease shows slight reduction of NAA and slight eleva-
tion of lactate; these abnormalities disappear after treatment. More
importantly, a somewhat broad peak at 0.9 ppm (Fig. 3-7H and I) is
also present; it is believed to represent resonances of methyl protons
from branched-chain amino acids and branched-chain alpha ketoac-
ids that accumulate as a result of defective oxidative decarboxylation
of leucine, isoleucine, and valine (178,179). It can be differentiated
from the “macromolecule” peak typically seen at about 0.9 ppm on
short TE spectra (see Chapter 1) because it is present on long echo
(TE = 270–288 ms, Fig. 3-12I), as well as short echo spectra (Fig.
3-12H) (178). This peak may not totally disappear, even in patients
who respond to therapy, because branched-chain amino acids are
essential nutrients and, therefore, total dietary withdrawal is not
possible.
Hyperhomocysteinemia (Formerly Known as Homocystinuria)
Homocysteine is the end product of the so-called transmethylation
pathway, a multistep metabolic process by which methyl groups from
methionine are transferred to essential acceptor molecules (DNA,
neurotransmitters, proteins, phospholipids, polysaccharides). Homo-
cysteine may either be recycled into methionine (remethylation
pathway) or catabolized into cystathionine, cysteine, and sulfate (trans-
sulfuration pathway). The three key enzymes involved in the pathogen-
esis of hyperhomocysteinemia are cystathionine beta-synthetase (on
the transsulfuration pathway), methionine synthetase (also known as 5-
methylhydrofolate:homocysteine methyltransferase), and 5,10-methyl-
ene-tetrahydrofolate reductase (on the remethylation pathway); folate,
B12 (cobalamin), and B6 (pyridoxine) vitamins play a role as cofactors.
Hyperhomocysteinemias may, therefore, develop in several different
conditions, which include cystathionine beta-synthetase enzyme defi-
ciency (“classic” homocystinuria), methionine synthetase deficiency,
folate deficiency, defect of folate metabolism (5,10-methylene-tetrahyd
rofolate reductase deficiency), cobalamin (vitamin B12) deficiency, and
defects of cobalamin metabolism (methionine synthetase deficiency in
isolated methylcobalamin and combined methylcobalamin and adeno-
sylcobalamin deficiencies) (180).
The major clinical manifestations of hyperhomocysteinemia are
ophthalmological (lens dislocation), vascular (steno-occlusive arte-
rial and venous disease), and neurological (demyelination in brain and
spinal cord).
Cystathionine Beta Synthase Deficiency Cystathionine beta syn-
thase deficiency (OMIM 236200) is caused by mutations in the cystathi-
onine beta synthase (CBS) gene at 21q22.3. The resulting biochemical
Barkovich_Chap03.indd 107
107
disorders cause intimal irregularities with subsequent arteriosclerosis,
arterial dissection, arterial thromboembolism, and venous thrombosis
in children and young adults. The main factor appears to be excessive
homocysteine, which generates superoxide and hydrogen peroxide,
changes coagulation factor levels (encouraging clot formation), pre-
vents small arteries from dilating (increasing likelihood of obstruc-
tion), and causes proliferation of smooth muscle cells in arterial walls
(181). Patients have characteristic clinical abnormalities, including dis-
location of the lens, osteoporosis, and thinning and lengthening of the
long bones. Half of untreated patients will suffer from strokes before
the age of 30 years. Affected patients can also manifest mental retarda-
tion, seizures, and dystonia. Outcome is markedly improved in vitamin
B6 responsive patients and nonresponsive patients who are compliant
with treatments (182). In most cases, neuroimaging studies reveal mul-
tiple small infarcts of different ages throughout the brain. Demyelina-
tion, white matter vacuolization, and spongy degeneration have been
observed only rarely (155,183).
5, 10 Methylenetetrahydrofolate Reductase Deficiency (MTH-
FRD) 5, 10 methylenetetrahydrofolate reductase deficiency (OMIM
236250) causes homocystinuria and hypomethioninemia due to
mutations of the 5,10 alpha methylenetetrahydrofolate reductase gene
(MTHFR at 1p36.3); at least 24 mutations have been reported to cause
disease (184). There is a direct correlation between methylenetetra-
hydrofolate reductase activity in fibroblasts and clinical severity of
the disease (185). This disorder has less pronounced vascular pathol-
ogy than cystathionine beta synthase deficiency and cerebral infarcts
are rare; however, children with abnormal MTHFR activity may be
predisposed to cerebral infarction (186), particularly due to venous
thrombosis (187). Patients with this disorder most commonly pres-
ent in childhood with gait abnormalities, seizures, and psychomotor
retardation of variable severity. Affected patients may also present in
infancy with hypotonia, progressive lethargy, recurrent apnea, and
seizures; progression to respiratory failure, coma, and death may
ensue (188). Certain mutations (in particular, the 677 C-T mutation
in the 5,10 methylenetetrahydrofolate reductase gene) are risk factors
for neural tube defects, as they impede the metabolism of folic acid
(see Chapter 9 for comments regarding the importance of folic acid
in preventing neural tube defects). MTHFR mutations are also a risk
factor for stroke in childhood (see Chapter 4 for discussion of child-
hood stroke) and for cervical arterial dissections (189). Treatment
with betaine, folic acid, and cobalamin is recommended to prevent or
mitigate symptoms (190).
Demyelination of the white matter of the brain and spinal cord is the
most commonly observed pathology in 5,10-methylenetetrahydrofolate
reductase deficiency. The demyelination starts as perivascular foci of
spongiform change, that is, separation of myelin layers. Less com-
monly, demyelination of the dorsal and lateral columns of the spinal
cord may be present.
MRI shows infarctions, when they occur, in addition to nonspe-
cific white matter abnormalities ranging from small foci of high signal
intensity (predominantly medial and bifrontal) to more diffuse, gener-
alized white matter T1 hypointensity and T2 hyperintensity (Fig. 3-13)
(155,183,188). Proton MR spectroscopy is reported to show reduced
NAA in the white matter (191).
Errors Affecting Cobalamin (Vitamin B12) Metabolism Errors
affecting cobalamin (vitamin B12) metabolism have been shown to
cause homocystinuria and methylmalonic aciduria (MMA/HC), a
genetically heterogeneous disorder caused by impaired conversion
of dietary vitamin B12 (cobalamin) to its two metabolically active
forms, methylcobalamin and adenosylcobalamin. The consequence
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 108 Pediatric Neuroimaging
of reduction of these compounds is a buildup of methylmalonic acid
and homocystine and their increased excretion in the urine (192). The
different forms of the disorder are classified according to complemen-
tation groups of cells in vitro: cblC (OMIM 277400, the most com-
mon, resulting from mutations of the MMACHC gene at 1p34.1), cblD
(OMIM 277410), and cblF (OMIM 277380) (193). These disorders
differ from the isolated forms of methylmalonic acidemia and homo-
cysteinemia, which have different biochemistry, different genetics, and
different clinical-neuroradiological attributes. Cerebral infarcts and
vascular thrombosis have not been reported, although intimal thicken-
ing and fibrosis are generally present. Not surprisingly, affected patients
have a variable clinical picture (193–196). Some present in infancy with
feeding difficulties, hypotonia, failure to thrive, seizures, microcephaly,
megaloblastic anemia, or developmental retardation; some develop
hemolytic-uremic syndrome. Others may present later in childhood
or in adolescence or adulthood with dementia, progressive gait dis-
turbance, acute neurologic dysfunction, or myelopathy (155,192,197).
Diagnosis is made by typical metabolic profile with increased urinary
excretion of methylmalonic acid, methylcitric acid, and homocystine,
increased plasma methylmalonic acid and free disulfide homocys-
tine, and hypomethioninemia (193). Confirmation of an intracellu-
lar defect of cobalamin metabolism is made by analysis of cultured
fibroblasts (193) or by identification of mutation of a causative gene
(198). Treatment includes hydroxycobalamin, betaine, and carnitine,
but response and outcome vary (193,194). Pathologic analysis of the
brains of affected patients typically shows spongiform demyelination
of the white matter.
Neuroimaging is variable, reflecting the heterogeneity of the dis-
order. It may be normal early in the course of the disease, particularly
when presentation is in adulthood (199). MRI shows the effects of the
myelin destruction, with variably reduced volume of cerebral white
matter and abnormal T2 hyperintensity of the deep white matter with
sparing of the internal capsule, peripheral white matter, and subcorti-
cal U fibers (155,183,192,193). Other reports describe hydrocephalus
with diffuse white matter swelling, patchy cavitation of the basal gan-
glia, and loss of T2 hypointensity of white matter (200). In the sin-
gle case of cobalamin C deficiency at our institution, the MRI shows
features of enlarged cortical sulci, mildly enlarged lateral ventricles,
Barkovich_Chap03.indd 108
FIG. 3-13. Hyperhomocysteinemia (5, 10
methylenetetrahydrofolate reductase deficiency)
in a 10-month old infant. Axial T1 (A) and T2
(B)-weighted images show marked hypomyeli-
nation throughout the brain.
and smudgy T2 prolongation in the peritrigonal white matter. Proton
MRS is reported to show loss of NAA and presence of lactate in the
basal ganglia (200).
Biotinidase Deficiency
Biotin is an imidazole derivative that acts as a cofactor for many
enzymes, including pyruvate carboxylase, propionyl CoA carboxylase,
and beta-methylcrotonyl-CoA carboxylase, which play a role in fatty
acid synthesis, amino acid catabolism, and gluconeogenesis (201). It
has a twofold enzymatic function: catalyzing the detachment of bio-
tin from proteins through which alimentary biotin enters the body;
and recycling biotin after it is released from the various carboxylase
enzymes. Biotinidase deficiency (also called multiple carboxylase
deficiency, OMIM 253260) is caused by mutation of the biotinidase
gene (BTD) at chromosome 3p25; the loss of biotin function inhibits
the cleavage of biotin from a compound named biocytin, resulting
in reduced function of these biotin-dependent carboxylases. Children
with this autosomal recessive disorder can become symptomatic at
any age, but typically present in early to middle infancy with acute
or insidious lethargy, hypotonia, anorexia or vomiting, developmental
delays, ataxia, seizures, or coma (180,201). Dermatologic complica-
tions are common, including alopecia, rashes, and mucocutaneous
candidiasis. Hearing loss and optic atrophy can be long-term compli-
cations. When presenting later in childhood or adolescence, children
may complain of motor weakness or diminishing visual acuity (201).
With early diagnosis, response to pharmacologic doses of biotin is
rapid.
There are few reports of imaging studies in biotinidase deficiency.
MRI shows early loss of brain volume, with increased ventricular size
and increased subarachnoid spaces; subdural hygromas or hematomas
may develop (202,203). T1- and T2-weighted images show reduced
myelination, with reduced diffusion and increased fractional anisot-
ropy in the deep, white matter of the cerebral hemispheres (Fig. 3-14)
(204). One report suggests that, uncommonly, cortical injury may
occur (203). Proton MRS at long and intermediate (135 ms) echoes
shows marked elevation of lactate with decreased NAA and choline
(203). All of these abnormalities reverse rapidly if therapy is started
early (204).
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 109

FIG. 3-14. Biotinidase deficiency; 8-week-old infant with seizures. A. Axial T1-weighted image shows delayed myelination with absence of any hyperin-
tensity in the anterior aspect of the posterior limb of the internal capsule. B. Axial diffusivity (Dav) map shows abnormally reduced diffusivity (low signal
intensity, arrows) in the deep cerebral white matter; fractional anisotropy (FA) was abnormally increased in the same areas. The Dav and FA normalized
after treatment with biotin. (These images courtesy of Dr. J Soares-Fernandes, Braga, Portugal.)

Methionine Adenosyltransferase Deficiency
Methionine adenosyltransferase (MAT) I/III (OMIM 250850),expressed
solely in liver, catalyzes the biosynthesis of S-adenosylmethionine
from methionine. MAT I/III deficiency, caused by mutations in the
MAT1A gene at 10q22, is characterized by persistent isolated hyper-
methioninemia (205–207). Clinical manifestations are variable and
poorly understood. Patients with moderate impairments in MAT I/III
activity have no clinical manifestations, but those with severe impair-
ments of MAT I/III activity have neurological signs and symptoms
and MR findings of abnormal cerebral white matter (205–207). Those
with the highest plasma methionine levels also have mild to moderate
abnormal elevations of plasma total homocysteine, which may lead to
a misdiagnosis of homocystinuria due to cystathionine beta synthase
deficiency (see IV.B.1.h) (207).
On imaging studies, patients with MAT I/III deficiency show abnor-
mal T1 and T2 prolongation in the cerebral white matter, with sparing
of the subcortical U fibers (Fig. 3-15A). Diffusion images show reduced
diffusivity (Fig. 3-15B). Proton MRS findings have not been reported.

FIG. 3-15. Methionine adenosyltransferase I/III deficiency in a 3-year-old boy. A. Axial T2-weighted image shows abnormal hyperintensity in the cere-
bral white matter. The subcortical white matter (white arrows) is spared. B. Axial diffusion weighted image shows high signal intensity, indicating reduced
diffusivity, in the affected white matter. (This case courtesy Dr. Jun-ichi Takanashi, Chiba, Japan.)

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 110 Pediatric Neuroimaging

Oculocerebrorenal Syndrome (Lowe Syndrome)
Lowe syndrome (oculocerebrorenal syndrome, OMIM 309000) is an
X-linked recessive disorder that predominantly affects males. In addi-
tion to the central nervous system, the lens and kidneys are involved.
The responsible gene, located at Xq26.1 is called OCRL1; it encodes a
phosphatidylinositol-4,5-biphosphate-5 phosphatase that is located in
the Golgi complex (208–210) and is postulated to play a role in mediat-
ing trafficking of proteins from endosomes to the trans-Golgi network
(2,11). Primary clinical manifestations include congenital cataracts,
glaucoma, mental retardation, renal tubular dysfunction (Fanconi syn-
drome—proteinuria, generalized amino aciduria, carnitine wasting,
and phosphaturia), and metabolic bone disease leading to arthropathy
(212,213). Mild cases have been reported with cataracts and glomerular
disease, but lacking renal tubular defects and mental retardation (214).
Imaging studies are characteristic. CT shows nonspecific hypoden-
sity in the cerebral white matter; calcification of the lens (cataract) may
be apparent if the scan is performed prior to surgery (Fig. 3-16A).
MRI shows three distinct lesions: (a) dilated perivascular spaces in
the periventricular and deep white matter (Fig. 3-16B), (b) confluent
regions of T2/FLAIR hyperintensity that spare the subcortical white
matter in the early course of the disease (Fig. 3-16D), and (c) later in the
disease course the appearance of multiple small spherical cysts in deep
and periventricular white matter (Fig. 3-16C and D) (212,215,216).
The cysts may be the result of progressive enlargement of the perivas-
cular spaces. Proton MRS in some patients shows a slight to moderate
elevation of the peak at 3.56 ppm that is typically assigned to myo-I
(217,218). This may represent accumulation of phosphatidyl inositol
4,5-biphosphate, which is not degraded, or may represent astrogliosis
in response to tissue injury from the disease. However, not all patients
with Lowe syndrome have elevation of this peak. It has been postulated
that the size of the peak at 3.56 ppm is related to the severity of the
enzymatic defect (217).

FIG. 3-16. Lowe syndrome; early and later phase images. A. Axial CT scan in early infancy shows bilateral calcifications (white arrows) in the ocular lenses,
diagnostic of congenital cataracts. B. Axial T2-weighted image at age 15 months shows myelination delay and the presence of multiple dilated perivascular
spaces. Some more rounded foci of hyperintensity (white arrows) likely represent early cyst formation. C. Axial T1-weighted image in childhood shows ven-
triculomegaly and multiple small cysts (black arrows) in periventricular and deep white matter of the cerebral hemispheres. D. Coronal FLAIR image shows
hyperintensity in the periventricular and deep white matter. Not the multiple small, hypointense cysts within the abnormal white matter.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 111

Merosin-Deficient Congenital Muscular Dystrophy (MDC1A)
The congenital muscular dystrophies (CMDs) are a heterogeneous
group of disorders characterized by hypotonia, weakness, and fre-
quently congenital contractures in conjunction with dystrophic changes
of muscle as demonstrated by muscle biopsy (219). At present, CMDs
are separated into three groups: (a) patients with normal brain MR
and no central neurologic signs or symptoms; (b) those with central
neurologic signs or symptoms whose imaging studies show abnormal
myelination but normal cerebral and cerebellar cortex (almost all of
these patients have absence of merosin, a molecular component of the
basement membrane of muscle fiber, on muscle biopsy (220) ); and (c)
those with central neurologic signs and symptoms and imaging studies
showing associated cerebral cortical malformations. The first group is
not considered in this book. The second is included here and the third
is discussed in Chapter 5, in the section on malformations of cortical
development secondary to abnormal neuronal migration.
Merosin-deficient congenital muscular dystrophy (OMIM 607855,
also called MDC1A) seems to be recessively inherited and the genetic
defect appears to be a result of mutation of the lamina-alpha-2 gene
(LAMA2) located at chromosome 6q22-23 (221). Most affected
patients are hypotonic and weak from birth. They may be born with
arthrogryposis, resulting from diminished movements in utero. As
a result of their hypotonia, deep tendon reflexes are diminished and
motor milestones are delayed. Intelligence is usually normal but may
be slightly impaired. Seizures may develop, but seem to be uncom-
mon (219,222). Serum creatine kinase is moderately elevated, usually
to levels near or above 1,000 U/L (223). Some patients, however, have
a milder course with later onset, slowly progressive muscle weakness
(designated “limb-girdle muscular dystrophy”), and lower values of
creatine kinase; in this group, mental retardation is found in only 6%
and seizures in 8% (224).
MRI is the neuroimaging study of choice. Affected patients typi-
cally have delayed myelination or hypomyelination of the central cere-
bral white matter (Fig. 3-17). Mild pontine and cerebellar vermian
hypoplasia is present in 10% to 20% and, when present, may be help-
ful in suggesting the diagnosis (145,220); occipital agyria is present in
about 10% (Fig. 3-17). Short echo proton MRS shows mildly reduced
concentrations of most metabolites in white matter (but essentially
normal myo-I and normal metabolite ratios) (225), while diffusion-
weighted imaging shows increased water diffusion in the affected white
matter (226). Definitive diagnosis is made by a combination of muscle
biopsy, brain MR, and clinical examination.

FIG. 3-17. Merosin deficient congenital muscular dystrophy. A. Sagittal T1-weighted image shows
atrophy of the cerebellar vermis, particularly in the central portions (white arrows). B. Paras-
agittal T1-weighted image shows localized occipital agyria (black arrows). C. Axial T2-weighted
image shows abnormal hyperintensity of the periventricular and deep white matter of the cerebral
hemispheres. Note relative sparing of the subcortical white matter (white arrows).

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 112 Pediatric Neuroimaging
FIG. 3-18. Mucolipidosis type IV. A. Midline sagittal T1-weighted image shows a small, thin corpus callosum (white arrows); the splenium is particularly
thin. The ventral pons is small. B. Coronal T2-weighted image shows abnormal hyperintensity of the periventricular and deep white matter, with sparing
of the subcortical fibers. The cerebellar hemispheres appear atrophic with enlarged fissures.
Mucolipidosis Type IV
Mucolipidosis type IV (OMIM 252650) is an autosomal recessive dis-
order of lysosomal storage that occurs most commonly in the Ashke-
nazi Jewish population. It is caused by mutation of the MCOLN1 gene
at chromosome 19p13.2-13.3; this gene encodes the MLN1 protein,
which may play a major role in calcium transport, regulating lysosomal
exocytosis and potentially other phenomena related to the trafficking
of late endosomes and lysosomes (227,228). Typically, the first sign
of disease is progressive visual impairment. Psychomotor retardation
becomes apparent in early childhood; this includes delayed motor and
speech development and may be static or progressive (69). Patients may
rarely develop spastic paraplegia or lack corneal or retinal abnormali-
ties (229). Seizures are rare. Examination reveals corneal opacification,
progressive retinopathy, and hypotonia, which progresses to spasticity.
No organomegaly has been reported.
Imaging studies show striking hypogenesis and hypoplasia of the
corpus callosum (Fig. 3-18A). The entire corpus is dramatically thin,
and the rostrum and splenium may be absent. A markedly diminished
volume of white matter is present in the cerebral hemispheres; the little
white matter that is present shows central T2 prolongation (Fig. 3-18B)
with sparing of the subcortical U fibers. In older patients, cerebellar or,
less commonly, cerebral atrophy may appear (Fig. 3-18B) (230). Proton
MR spectroscopy shows reduced NAA throughout most of the brain
with no difference between younger and older patients, implying a
static developmental encephalopathy associated with diffuse neuronal
or axonal abnormalities (231).
Autosomal Recessive Spastic Paraplegia
with Thin Corpus Callosum
Hereditary spastic paraplegias are neurodegenerative conditions
in which the main clinical features are progressive spasticity and
weakness of the lower limbs associated with posterior column or
bladder involvement (232,233). This is a heterogeneous group of dis-
orders, with autosomal dominant, autosomal recessive, and X-linked
inheritance. Autosomal dominant forms typically present in young
Barkovich_Chap03.indd 112
adults. X-linked forms are often associated with mutation of the PLP1
gene; this form is discussed in the section on Pelizaeus-Merzbacher
disease later in this chapter. Autosomal recessive forms often present
in childhood and are also very heterogeneous (234). Of note, about
30% of these patients have a strikingly thin corpus callosum when
imaged by MRI, associated with variable (but often severe) cognitive
deficit (235). Nearly all of these patients appear to have mutations
of the spatacsin gene (SPG11) at chromosome 15q13-15 (236), with
resultant impaired axonal transport in long projection neurons (237).
A patient with spatizin (SPG15) mutation has also been reported and
appears to have a very similar phenotype (238). Children with spatac-
sin mutations present with slowly progressive paraparesis (clumsiness,
difficulty walking, or frequent falls), lower extremity hyperreflexia,
mental retardation of variable severity and, sometimes, upper extrem-
ity signs (236,239). MRI shows slowly progressive cerebral white
matter and cortical atrophy with progressive T2 prolongation of the
periventricular white matter and progressive thinning of the corpus
callosum (splenium and rostrum are proportional to body, Fig. 3-19)
(238,240,241).
Sjögren-Larsson Syndrome
Sjögren-Larsson syndrome (OMIM 270200) is an autosomal recessive
disorder characterized by congenital ichthyosis, mental retardation,
and progressive spastic tetraplegia (242). The severity of the disorder
varies markedly even within families (243). The cause of the disorder is
impaired fatty aldehyde dehydrogenase (FALDH) activity (this enzyme
catalyzes the oxidation of fatty aldehydes to their corresponding fatty
acids), which results in the accumulation of long chain fatty alco-
hols (244). The gene (ALDH3A2) has been mapped to chromosome
17p11.2 (244), but mutations of many different aldehyde dehydroge-
nase genes can cause the syndrome (44). Diagnosis is established either
by finding the mutation or by finding deficient fatty alcohol-NAD+
oxidoreductase activity in leukocytes and cultured fibroblasts. Prenatal
diagnosis is possible by assessing enzymes in cultured amniocytes and
fetal skin (155).
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 113

FIG. 3-19. Hereditary spastic paraplegia in an 8 year old. A. Midline sagittal T1-weighted image shows thin corpus callosum, particularly the anterior body
(white arrows), while the rostrum and splenium are relatively spared; contrast with Figure 3-18A. B. Axial FLAIR image shows markedly reduced volume of
white matter with abnormal hyperintensity of periventricular and deep white matter.

Pathologic examination of affected brains shows ballooning of
myelin sheaths, with lipid-laden macrophages and histiocytes in the
areas of myelin degradation. Myelin loss is seen primarily in the deep
white matter of the cerebrum and in the corticospinal tracts in the
brainstem and spinal cord (245).
Imaging shows delayed myelination during the first years of life,
with T2/FLAIR hyperintensity (Fig. 3-20A) (246). Later MR studies
show T2 prolongation in the periventricular white matter, particularly
in the regions around the trigones and frontal horns, without a great
deal of volume loss (247). Of note, small areas of subcortical white
matter remain incompletely myelinated for many years, even into
adulthood (246). Mild cerebral atrophy is found in most patients older
than 10 years (246). DTI shows normal diffusivity values but reduced
FA in the white matter (248), likely representing impaired formation or
impaired maintenance of myelin.
Proton MRS of the occipital white matter shows a fairly charac-
teristic, narrow peaks at 0.9 and 1.3 ppm (the peak at 1.3 ppm is the
larger and more characteristic of the two) that are seen even at longer
echo times (of 288 ms, Fig. 3-20B) (247) and, therefore, can be differ-
entiated from the broader “macromolecular” peaks (probably methyl

FIG. 3-20. Infant with Sjögren-Larsson syndrome. A. Axial FLAIR image shows diffuse white matter hyperintensity. No volume loss is seen at this stage.
B. Proton MRS with TE = 288 ms from frontal white matter shows normal ratios of choline (Ch), creatine (Cr), and NAA. An abnormal peak is seen at 1.3
ppm that is characteristic of the disease and is therefore labeled SL for Sjögren-Larsson. The presence of the peak with TE = 288 ms and the narrowness of
the peak differentiate it from the macromolecular peak often seen at 1.3 ppm. Lactate would be a doublet with this technique. The chemical source of the
peak is not known.

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 114 Pediatric Neuroimaging
and methylene proton resonances, respectively) with those chemical
shifts that are often seen in infants (246,247,249). These peaks are
smaller in other regions of the brain and are not seen in gray mat-
ter (246). It has been postulated that these peaks are the result of
accumulation of long chain fatty alcohols (247); the area under these
curves, particularly the one at 1.3 ppm, diminishes as the patients
mature into adulthood, suggesting unknown pathogenic mechanisms
to compensate for the responsible biochemical defect in this disease
(243). Choline, creatine, and myo-I peaks are slightly elevated in the
white matter (246).
Brain Injury from Radiation and Chemotherapy
The pathophysiology of brain injury from radiation and chemother-
apy is not fully understood. Recent information suggests that damage
to vascular endothelial cells is an important component of radiation
effects and that the damage is largely ischemic (250,251); however, an
inflammatory component has been suggested (252). Variables relevant
to damage potential include total radiation dose, size of radiation field,
size of radiation fractions, and the number and frequency of radia-
tion doses. Other factors include duration of survival, age of patient at
treatment, the specific chemotherapeutic agent, and whether therapy is
single (radiation or chemotherapy) or combined (radiation and che-
motherapy) (252,253).
New data is emerging regarding unusual sensitivities to radia-
tion or chemotherapies in certain individuals. It has been known for
some time that syndromes caused by impaired DNA damage repair
(e.g., Fanconi anemia, ataxia-telangiectasia, etc.) predispose to child-
hood brain tumors, but recent reports suggest that affected patients
are at increased risk for treatment-related toxicities, as well (254). For
example, patients with dual mutation in breast cancer susceptibility
gene (BRCA2) may develop symptomatic neurotoxicity (leukoenceph-
alopathy), myelosuppression, and poor immune response after “regu-
lar” therapeutic doses of chemotherapeutic agents (255). Patients with
other genetically determined cancer syndromes (ataxia-telangiectasia
or Gorlin syndrome) show excessive sensitivity to ionizing radiation
(254). If such patients develop brain tumors and require radiation
therapy, conventional radiation doses may not be tolerated and could
FIG. 3-21. Localized radiation necrosis in a child treated for a frontal lobe glioma. A. Axial FLAIR image shows marked edema in the frontal lobe extending
into the internal and external capsules and basal ganglia and causing right to left subfalcine herniation. B. Axial postcontrast T1-weighted image shows rim
enhancement (black arrows) in the right frontal lobe, suggesting recurrent tumor. C. MR susceptibility weighted blood volume map shows low blood volume
(blue color, black arrows) in the location of the rim enhancement, strongly suggesting radiation necrosis, not tumor recurrence.
Barkovich_Chap03.indd 114
actually be fatal. These data need to be taken into account prior to
planning therapeutic strategies in such “high-risk” patients
White Matter Injury With a few exceptions, the clinical and imag-
ing manifestations of white matter injury secondary to radiation or
chemotherapy in children are not significantly different from those in
adults. Radiation injury to the brain is most commonly divided into
three major groups: (a) acute reactions (1–6 weeks after treatment),
(b) early delayed reactions (3 weeks to several months after treatment),
and (c) late delayed reaction (several months to years following treat-
ment) (256–258).
Acute and early delayed reactions are mild, often asymptomatic,
and self-limiting, consisting of mild localized interstitial edema (sec-
ondary to transient vasodilatation with variable changes in capillary
permeability (259) ) or perhaps transient myelin injury due to radia-
tion effects on oligodendrocytes (7). They are seen on imaging studies
as subtle low density (CT) or T1 and T2 prolongation (MR) without
significant mass effect or change in contrast enhancement (256,260).
DTI studies show that Dav (average diffusivity) is increased and FA
(fractional anisotropy) decreased in T2 hyperintense white matter but
FA was higher in adjacent normal appearing white matter (261). On
proton MRS, a decrease in the size of the NAA and Cho peaks is noted,
even in normal-appearing white matter, for at least 6 months after
radiation treatment (262).
Late delayed injury is believed to result primarily from permanent
damage to blood vessels, perhaps associated with inflammation (7). It
may be seen as early as 3 to 4 months or as late as several years after
conclusion of therapy. Breakdown of the capillary endothelium leads
to blood–brain barrier breakdown and exudation of fibrin from the
blood vessel lumen. Eventually, endothelium becomes hyalinized and
proliferates, compromising the lumen of the vessel and decreasing local
blood flow, with subsequent white matter infarction (258,259). All of
these effects seem to be exacerbated when the patient also receives
chemotherapy, particularly methotrexate (7). Pathologically, the white
matter exhibits areas of necrosis, with rarefaction and fragmentation of
myelin, and cellular disruption. Patients may develop localized neuro-
logic deficits or obtundation.
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 115

FIG. 3-22. Diffuse white matter injury from radiation and chemotherapy. A. Axial FLAIR image shows hyperintense white matter in the parietal and, to a
lesser extent, frontal white matter. B. Follow-up axial FLAIR image several months later show increased white matter injury and enlargement of ventricles
and subarachnoid spaces, suggesting progression of leukoencephalopathy and volume loss. C. Axial diffusivity (Dav) image at the time of the second scan
shows reduced Dav (white arrows) in both parietal and frontal white matter, confirming tissue injury. Fractional anisotropy may also be reduced due to
radiation/chemotherapy injury.

Imaging studies show variable patterns of injury, ranging from
single, focal lesions (Fig. 3-21) to diffuse white matter abnormality
(Fig. 3-22). Signal abnormalities reflect the edema and loss of myelin,
as CT shows low attenuation and MRI shows T1 hypointensity and
T2/FLAIR hyperintensity (Figs. 3-21 and 3-22) (256,260). If tissue is
injured, diffusivity may be reduced (Fig. 3-22). Contrast enhancement
is variable and may be transitory. Significant mass effect can be pres-
ent. Central necrosis within the lesions is uncommon in children (256).
Petechial hemorrhage may be present, appearing as multifocal areas of
short T1 and T2 superimposed upon the edema. Hemorrhage is much
more common following radiation therapy and is uncommon if treat-
ment is limited to chemotherapy (263). Knowledge of radiation ports
or the location of interstitial implants (if used) can be extremely useful
in making the proper diagnosis, as the injury is almost always limited
to the irradiated field.
Preliminary work suggests that diffusion tensor imaging may allow
detection and quantification of treatment-induced white matter injury
(264). Compared with age-matched controls, reduction of the frac-
tional anisotropy by 15% to 20% (see Chapter 1) can be detected in
children treated with chemotherapy and radiation therapy even in the
setting of normal-appearing white matter. These changes were found
to be most severe in children treated at younger age (<5 years old),
children with longer interval since treatment (>5 years), and children
with deteriorating school performance (264). Susceptibility-weighted
perfusion imaging shows reduced blood volume compared to unaf-
fected white matter (265); this is particularly useful in differentiation
between radiation injury and recurrent tumor in children treated for
CNS malignancies.
Hemorrhagic Vasculopathy Secondary to Radiation Hemor-
rhagic lesions may be seen in white matter of children who have been
irradiated (263,266,267). The pathophysiology of these lesions has not
been ascertained; capillary damage is a likely candidate. The imaging
and surgical appearance are that of occult vascular malformations or
cavernomas: sharply marginated lesions with little or no vasogenic
edema and variable signal intensity depending upon the nature of the
hemoglobin breakdown products within the lesions (see Chapter 12)
(266). Affected children may present up to 19 years after therapy (mean
8.1 years, earliest 2–3 years) (267,268). Presenting symptoms may be
headaches, seizures, or focal neurologic signs and symptoms; others are
asymptomatic and found incidentally (263,266,267). The lesions may
develop after a wide range of radiation doses; in the series of Young-
Poussaint et al., the range was 1,800 to 6,000 cG (267). Although there
was no clear correlation between dose and development of these
lesions in the series of Koike et al. (268), Chan et al. found a corre-
lation between the number of hemorrhages and the radiation dose
(263). Pathologic examination shows locally abnormal blood vessels.
Currently, the lesions are only resected if they are symptomatic or have
caused symptomatic hemorrhage (269,270).
Occlusive Vasculopathy Secondary to Radiation Young children
are more susceptible than adults to radiation injury of the large ves-
sels of the circle of Willis. Children at greatest risk are those younger
than 4 years old who receive large doses of radiation to the sellar/supra-
sellar/parasellar region for supratentorial midline tumors (271–274)
(patients with neurofibromatosis type 1 seem particularly susceptible
(275,276) ), but vasculopathy can develop after whole brain irradiation
for posterior fossa tumors such as medulloblastoma or ependymoma
(277) or for CNS involvement by leukemia (274). Rarely, the vasculop-
athy can develop as early as 15 months after radiation (277), although
it is more commonly seen after many years (273).
Patients develop intimal hyperplasia and fibrous thickening
of the adventitia, leading to progressive narrowing of the supracli-
noid carotid artery (Fig. 3-23) and the proximal anterior and middle
cerebral arteries; this may evolve into a moyamoya vascular pattern
(see Chapter 12). Clinically, this condition is manifested as growth
retardation, cognitive impairment, transient ischemic attacks, frank
infarction, or developmental delay secondary to chronic cerebral
ischemia (278). Imaging shows multiple small infarctions (Fig. 3-23),
which may appear, as areas of T2 prolongation or areas of frank cystic
necrosis.
Neoplasia Secondary to Irradiation Occasionally, neoplasia can
develop as a long-term consequence of irradiation; this is felt to be

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 116 Pediatric Neuroimaging

FIG. 3-23. Radiation-induced vasculopathy in an 18-year-old girl with history of

radiation for her suprasellar tumor. A. Axial FLAIR image shows abnormal hyperin-
tensity in the basal ganglia, and external/extreme capsules. Note also pial hyperinten-
sity (white arrows) that is often associated with supraclinoid vasculopathy. B and C.
Axial FLAIR images show multiple small foci of periventricular T2 prolongation (black
arrows) as well as small cysts (white arrows). D and E. Postcontrast T1-weighted images
show curvilinear enhancement (small black arrows in E) representing dilated lenticu-
lostriate arteries in the basal ganglia. Solid white arrows in (D) point to small cysts.
Solid white arrows in (E) point to residual craniopharyngioma. Small black arrow in
(D) points to radiation-induced meningioma. F. Arterial phase image from left internal
carotid arteriogram shows occlusion of supraclinoid left internal carotid artery with
moya-moya-like collaterals (black arrows).

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
a rare occurrence and it is difficult to prove causation (260). Of radi-
ation-induced tumors in adults reported in the literature, 70% are
meningiomas (Fig. 3-23D), 20% are gliomas, and 10% are sarcomas
(279). However, malignant gliomas seem to be much more common
than meningiomas in children, and a significant incidence of sarcomas
and low-grade gliomas have been noted (280). Features associated with
radiation-induced tumors include high histologic grade of gliomas
in young people, multiplicity of gliomas, earlier age at presentation,
and higher doses of radiation (280). The neuroimaging appearance of
radiation-induced tumors does not differ from that of those not asso-
ciated with radiation. The neuroimaging appearance of brain tumors
is discussed in Chapter 7.
Small (“Lacunar”) Cysts Small asymptomatic cysts develop in the
white matter of approximately 15% of children who have been irradi-
ated prior to the age of 6 years with doses in the range from approxi-
mately 36 to 54 Gy; all patients received chemotherapy, as well (281,282).
The cysts appear after a typical latency period of 2 to 3 years and may
grow on subsequent scans. These cysts (Fig. 3-23B and D) resemble
large perivascular spaces, as they are isointense to CSF on all imag-
ing sequences and do not enhance after administration of intravenous
contrast. They may result from localized brain atrophy or disturbance
in the CSF dynamics of interstitial fluid draining into the perivascu-
lar spaces. It has not been established whether these may develop into
tumefactive cysts (see next section).
Tumefactive Cysts Sometimes, slowly growing cysts develop within
the area of the radiation ports. The time at which these cysts develop
is unknown, but affected patients typically become symptomatic 2 to
8 years after therapy. Headache is probably the most common symp-
tom, with other symptoms being dependent upon the location of the
cyst and the structures that are affected. Tumefactive cysts seem to be
most commonly found after radiosurgery for arteriovenous malfor-
mations (283), but we have seen similar cyst formation secondary to
high-dose conventional radiation therapy, as well (fortunately, radia-
tion doses for children are much lower than in the past and these are
very uncommon today). The incidence seems to increase with increas-
ing time after therapy and may be as high as 25% to 30%. The patho-
genesis is unknown.
On imaging, the cysts are typically complex and multilocular;
often, one cyst is dominant and surrounded by multiple smaller
cysts. The cysts may have signal intensity of CSF but often are slightly
hyperintense compared to CSF on T1-weighted images, suggesting
the presence of proteinaceous fluid. This may be useful in differen-
tiating the cyst from a tumor cyst. The wall of the cyst is thin and
similar in signal intensity to white matter; it enhances moderately
after intravenous administration of contrast material (283). Adjacent
tissue is typically heterogeneous, showing areas of T2 prolongation
that are probably the result of both surgery and radiation; heteroge-
neous nodular enhancement is often seen in these areas after contrast
administration (283). The main differential diagnosis is radiation-
induced glioma.
Effects of Irradiation on the Pituitary Gland It is known that
hypothalamic-pituitary function may be affected by irradiation of
the sella and parasellar regions (284). This is manifest on MRI as
reduced pituitary gland size (285). No precise correlations between
degree of size reduction and degree of dysfunction have been dem-
onstrated.
Post Irradiation Changes of the Bone Marrow The bone mar-
row of young children is still actively hematopoietic. On neuroimaging
Barkovich_Chap03.indd 117
117
studies, this is most easily appreciated in the skull base and spine (see
Chapter 2). Actively dividing cells are more susceptible to damage by
radiation than are nondividing cells. Therefore, bone marrow of chil-
dren is transiently damaged by irradiation, and hematopoietic cells
are replaced by fat cells. This phenomenon is seen on MR as homoge-
neous T1 shortening in the skull base and vertebral bodies (from fatty
replacement of marrow) that develops as early as 6 weeks after irradia-
tion (286). Normal marrow signal will return in slightly more than half
of patients irradiated with 16 to 36 Gy (286), and in one series, return
of singal was reported in 90% (287). No recovery is seen in patients
treated with 50 Gy or more (288). Marrow regeneration occurs in a
“band” pattern, with the more vascularized endplates recovering first.
MRI shows the development of bands of peripheral low signal inten-
sity on T1-weighted images of the vertebral bodies, slowly converging
toward the center of the body. This signal change has been confirmed
histologically as repopulation by hematopoietic cells (289).
White Matter Injury Secondary to Chemotherapeutic
Agents Abnormalities of the cerebral white matter can also result
from treatment with chemotherapeutic agents (290). The drugs
that most commonly cause leukoencephalopathy are temozolomide,
methotrexate, cisplatin, 5-fluorouracil, BCNU, melphalan, fludara-
bine, cytarabine, levamisole, arabinosylcytosine, carmustine, aspara-
ginase, and thiotepa (7,290,291), with methotrexate being the most
common and best described in children, usually those with acute
lymphocytic leukemia (292–294). Temozolomide injury is more com-
mon after treatment for malignant gliomas (295). The mechanisms
are not well understood but may include direct toxic effects (on axons,
oligodendrocytes, and progenitor cells) as well as secondary immu-
nologic reactions, oxidative stress, and microvascular injury (7). The
white matter abnormalities seen on imaging studies may be transient
or permanent and may be present with or without associated clinical
abnormalities (291,296,297). Temozolomide seems to cause necrosis
adjacent to tumor, which is thought to be due to endothelial cell dam-
age with consequent increased vascular permeability and some paren-
chymal necrosis (295).
Acute injury is seen in 3% to 10% of patients treated with intrath-
ecal methotrexate (292,298), with higher doses putting the affected
patients at higher risk for leukoencephalopathy (299). Affected patients
typically present with neurologic symptoms such as aphasia, weak-
ness, sensory deficits, or seizures (292,293,300). In these situations, the
imaging findings may be quite subtle on standard sequences such as
spin echo T2 and FLAIR (Fig. 3-24). Diffusion imaging shows reduced
diffusion in the affected area and may be useful in the recognition of
the abnormality (Fig. 3-24C). Typical findings are round to ovoid focal
areas of reduced diffusion in the central areas of the centrum semiovale
(deep to the central sulcus) that spare the subcortical U fibers (293,294).
Between 8 and 20 weeks after intrathecal methotrexate treatment, pro-
ton spectroscopy shows transient reductions in NAA, increases in cho-
line, and transient lactate peaks (Fig. 3-24D) (301). According to Chu
et al. (301), these metabolic abnormalities disappear by about 1 year
after treatment.
In contradistinction to the focal white matter abnormalities
seen in radiation-induced leukoencephalopathy and in acute che-
motherapeutic injury, T1 and T2 prolongation secondary to chronic
chemotherapy injury tends to be symmetric, widespread and, often,
diffuse (Figs. 3-22 and 3-25). The T2 prolongation is seen primarily
in the central and periventricular white matter, with relative sparing
of the subcortical U fibers (155,256,291,296,297); it is often more
severe in the prefrontal and parietal lobes, sparing the posterior fron-
tal lobes (Figs. 3-22B and 3-25). Occasionally, foci of T2 shortening
(hypointensity on T2-weighted images) are seen (302). The corpus
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 118 Pediatric Neuroimaging

FIG. 3-24. Focal acute white matter injury from methotrexate. A. Axial T2-weighted image shows faint hyperintensity (white arrows) in the left hemi-
spheric white matter. B. Axial FLAIR shows the same left hemisphere abnormality (white arrows) and an additional small area of hyperintensity in the
right hemisphere (white arrowhead). C. Axial diffusivity (Dav) map shows reduced Dav that is more severe in the left hemispheric (white arrows) than right
hemispheric (white arrowheads) lesion. D. Single voxel proton MRS from the left hemispheric lesion shows reduced NAA (downward-pointing arrow) and
the presence of lactate (upward-pointing arrow).

callosum, anterior commissure, and hippocampal commissure are
most often spared (256,260). When enhancement occurs after con-
trast administration, it tends to be multifocal, usually deep within
the centrum semiovale (256). The presence of foci of enhancement
and of T2 shortening tends to be associated with development of dif-
fuse necrotizing leukoencephalopathy (302) (see the section below).
Proton MRS of early chemotherapy-induced white matter change is
normal, suggesting that the T2 prolongation results from changes
in myelin, as opposed to axons (303). Hemorrhagic vasculopathy
is not seen in patients who have received chemotherapy without
radiation (263).
Combined Radiotherapy and Chemotherapy An important con-
cept is that the combination of chemotherapeutic agents and radio-
therapy often results in more severe injury than either chemotherapy
or radiotherapy alone (7,290,295,304). This combination may result
in severe edema, enhancement, and mass effect within the radiation
ports, typically developing 5 to 13 months after therapy (mean of 10
months) (290,304). Differentiation from recurrent tumor may be very
difficult, and is discussed in more detail in Chapter 7. In general, injury
occurs later than recurring tumor, is often multiple, and is often located
several centimeters away from the tumor resection site or even con-
tralaterally. The study by van Tassel et al. showed common locations

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 119

Diffuse Necrotizing Leukoencephalopathy When patients who

have received radiation and chemotherapy begin to rapidly deterio-
rate clinically in conjunction with diffuse white matter injury, the
condition is called diffuse necrotizing leukoencephalopathy (305).
This form of leukoencephalopathy is differentiated from other forms
by the presence of more extensive areas of white matter necrosis. On
imaging, the brain shows necrosis with areas of T1 and T2 shorten-
ing (Fig. 3-27). Lesions range from small rounded foci to large con-
fluent zones that may consist of noninflammatory demyelination or,
more commonly, frank necrosis (7). Injury to the blood–brain barrier
results in marked enhancement. If the patient survives, the necrotic
areas shrink and calcify (Fig. 3-27) and the volume of white matter
diminishes (256). The appearance of the white matter on imaging
studies does not always correlate well with the severity of the clinical
syndrome.

White Matter Disorders with Dysmyelination Initially

FIG. 3-25. Chronic methotrexate injury. Axial T2-weighted image shows
extensive white matter hyperintensity in both cerebral hemispheres. Note
the sparing of the subcortical white matter.
to be the corpus callosum and corticomedullary junctions (304).
Tumor was more often solitary and located immediately adjacent to
the surgical site. As stated above, correlation with radiation ports is
critical to making the correct diagnosis. More chronically, the changes
from combined radiotherapy and chemotherapy are widespread mul-
tifocal or diffuse cortical injury and diffuse deep cerebral and cerebel-
lar nuclear injury with calcification. Examination of the white matter
shows impaired myelination, diffuse injury with punctate calcifica-
tions, and volume loss (Fig. 3-26).
Affecting Subcortical Cerebral White Matter
Megalencephalic Leukoencephalopathy
with Subcortical Cysts (MLC)
Megalencephalic leukoencephalopathy with subcortical cysts (MLC,
OMIM 604004), also called leukoencephalopathy with macrocephaly
and mild clinical course, is an autosomal recessive disorder with onset
in infancy. This disorder is remarkable for its relatively mild early neu-
rologic signs and symptoms in the setting of a very abnormal imaging
study. Patients may present during first year of life with macrocephaly
or during the second year of life with delay in attaining developmental
milestones. A slow neurologic deterioration then ensues with gradu-
ally increasing spasticity, dysarthria, ataxia, and dementia. Head cir-
cumference stabilizes after the first year and then parallels the normal
curve. Most patients are wheelchair bound within 8 to 10 years (306),
although some can walk short distances with support at age 12 to
13 years. Seizures, usually responsive to medication, develop in a
minority of affected children (307). Slow cognitive deterioration is
noted from mid-childhood in older patients. Diagnosis is based upon a
combination of clinical and MR criteria.
About 80% of cases are caused by mutations of the MLC1 gene
at 22qtel; the gene encodes a plasma membrane protein of unknown

FIG. 3-26. Chronic injury from chemo/radiation therapy. A. Axial noncontrast CT scan shows calcification of the basal ganglia, deep frontal and occipital
cortex, and some volume loss in the left parietal lobe, where the subarachnoid spaces are enlarged. B. Parasagittal T1-weighted MR image shows better the
full extent of cortical calcification (white arrows). C. Axial T2-weighted image shows abnormal hyperintensity of white matter, indicating impaired myelina-
tion, enlargement of subarachnoid spaces, and focal cortical injury (white arrows) in the left parietal lobe.

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 120 Pediatric Neuroimaging
function that is mainly expressed in neurons and glia (308–310). How-
ever, 20% of patients, including a number of families, with a typical
MLC phenotype do not have MLC1 mutations, indicating genetic
heterogeneity of the disease. These 20% have been classified into two
groups, one with both clinical and MRI features identical to patients
with MLC1 mutations, and another with a less severe clinical course.
This second group has less pronounced white matter swelling, less
severe megalencephaly or normal head size, and less affected cerebellar
white matter on initial MR scans. No subcortical cysts are found out-
side of the anterior temporal lobes.
Pathology of MLC cases reveals a vacuolating myelinopathy in
which the outer layers of the myelin sheaths are separated, but the
inner layers are unaffected; axons are spared, but are widely separated
from adjacent axons by the vacuoles (311,312).
Neuroimaging studies are remarkable for a nearly complete
absence of myelin in the subcortical white matter; some central white
matter is spared, particularly in the corpus callosum, internal cap-
sules, brainstem, and the occipital lobes (Fig. 3-28A). The subcorti-
Barkovich_Chap03.indd 120
FIG. 3-27. Diffuse necrotizing leukoen-
cephalopathy. A. Noncontrast CT scan
soon after symptoms shows white matter
edema and multifocal cortical and subcor-
tical calcifications. B. Axial T2-weighted
image a few months later show damaged
white matter with areas of T2 hyper- and
hypointensity due to a combination of
edema, calcification, and necrosis. Mass
effect from the left hemisphere causes
midline shift. C and D. Pre- and post con-
trast T1-weighted images show marked
diffuse enhancement secondary to exten-
sive injury to the blood–brain barrier.
cal white matter appears swollen, with enlargement of the gyri in
affected regions (Fig. 3-28C). A characteristic feature is the presence
of subcortical cysts that initially develop in the anterior temporal lobes
(Fig. 3-28B) and may eventually arise in the frontal and parietal lobes
(Fig. 3-28D and E). The cerebellar white matter is less affected than the
cerebral white matter, but some degree of T2 prolongation is present
in the cerebellar white matter of most affected children (Fig. 3-28B and
C) (307). Mild cerebellar atrophy is usually present (306). Diffusion
studies show increased diffusivity in the cerebral white matter (dark on
diffusion-weighted images, bright on ADC maps) (313). Proton MRS
is remarkable for low NAA levels, manifest as decreased NAA/Cr ratios,
although MRS performed early in the course of the disease may be
nearly normal (67).
Group I phenotype of MLC without MLC1 mutations has imaging
findings essentially identical to that of patients with MLC1 mutations.
Group II has less subcortical swelling and better preserved cerebellar
white matter on initial MR scans; subcortical cysts are limited to the
anterior temporal lobes. On follow-up scans, MRI shows spectacular
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 121

FIG. 3-28. Megalencephaly with leukoencephalopathy and cysts. A–C. 16-month-old girl
with megalencephaly and mild developmental delay. Axial T1-weighted image (A) shows
marked absence of hyperintense myelin in the cerebral hemispheres. Some myelination is
present in the corpus callosum (white arrows) and internal capsules (isointense to basal gan-
glia). Axial FLAIR image (B) shows cysts (white arrowheads) in the anterior temporal lobes.
Note that the cerebellar white matter (which should be dark compared to gray matter at this
age) is abnormally hyperintense (white arrows). Coronal T2-weighted image (C) shows dif-
fuse abnormal hyperintensity of the white matter with the exception of the corpus callosum
(small white arrows) and hippocampal commissure (large white arrows). Cerebellar white
matter (white arrowheads) is abnormally hyperintense. Note that the cerebral gyri appear
large and rather swollen; there is no atrophy. D and E. Megalencephaly with leukoencepha-
lopathy and cysts; more advanced imaging findings. Parasagittal T1-weighted image (D)
shows subcortical cysts in right parietal (white arrowhead) and anterior temporal (white
arrows) lobes. The parietal lesion is confirmed as a cyst by the marked hypointensity (white
arrows) on the axial FLAIR image (E).

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 122 Pediatric Neuroimaging

improvement over the course of a few years with progression of myeli-
nation such that only a few minor signal abnormalities remain; subcor-
tical cysts in the temporal lobes regress and may disappear (personal
communication, Dr. Marjo van der Knaap).
Differentiation of this disorder from Canavan disease in particular
is made by clinical criteria (onset in first year for Canavan, second year
for MLC), lack of involvement of globus pallidus and thalamus (almost
always present in Canavan disease), the presence of subcortical cysts
(absent in Canavan disease), proton MR spectroscopy (large NAA peak
in Canavan disease, small NAA in MLC), and the diffusion character-
istics (reduced diffusivity in Canavan disease (11), increased diffusivity
in MLC (313) ).
typical MLC without MLC1 mutations is uncertain at this time. Typi-
cally, delayed motor development and subsequently delayed speech are
detected in the first 18 months of life. Motor dysfunction and cogni-
tive delay nearly always ensue. Occasionally, nystagmus, athetoid hand
movements, or dystonia develops (314,315).
MRI shows characteristic involvement of the subcortical supraten-
torial white matter and cystic lesions in the anteriormost part of the
temporal lobes (Fig. 3-29). The cysts do not communicate with the
ventricular system, which is typically enlarged (314,315). In our expe-
rience, peritrigonal white matter is also involved and this involvement
extends to the ventricular surface. Proton MRS is normal. The abnor-
mal white matter shows increased diffusivity.

Cystic Leukoencephalopathy Without Megalencephaly Aicardi-Goutières Syndrome

This recently described disorder seems to show autosomal reces- Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous
sive inheritance and has been found primarily in persons of central disorder that initially is manifested in infancy with irritability, poor
and eastern European descent (314). The genetic locus has not been feeding, progressive microcephaly, spasticity, and dystonic postur-
identified and the relationship of this disorder to those resulting in ing; profound psychomotor retardation ensues, often with death in

FIG. 3-29. Cystic leukoencephalopathy without megalencephaly. A. Parasagittal

T1-weighted image shows low signal intensity in the parietal white matter with
sparing of subcortical white matter (black arrows) and two cysts (white arrows)
anterior to the temporal horn of the lateral ventricle (white arrowhead shows
ventricular wall). B. Axial FLAIR image shows extensive hyperintensity of the
periventricular, deep, and subcortical white matter. C. Axial diffusivity (Dav) map
shows that the affected white matter has mostly increased Dav (hyperintensity).

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
early childhood (316). Findings of chronic CSF leukocytosis and basal
ganglia calcifications on CT raise the possibility of congenital infection,
but testing is negative. Recent studies have revealed that the disorder is
caused by mutations leading to cellular and immunological responses
that mimic congenital infections (317,318). New evidence suggests that
the nucleases defective in AGS are involved in removing endogenously
produced nucleic acids and that failure of this removal results in activa-
tion of the immune system (319). Currently, five different types of AGS
are described: AGS1 (OMIM#225750, an autosomal recessive disorder
caused by mutation of the TREX1 gene on chromosome 3p21), AGS2
(OMIM#610181, autosomal recessive caused by RNASEH2B on chro-
mosome 13q14-21), AGS3 (OMIM#610329, autosomal recessive caused
by RNASEH2C on chromosome 11q13.2, AGS4 (OMIM#606034,
autosomal recessive caused by RNASEH2A on 19p13.13), and AGS5
(OMIM#610905, an autosomal dominant form caused by mutation of
TREX1). These disorders were classified under the label of “pseudo-
TORCH syndrome” in previous editions of this book.
The finding of multiple punctate basal ganglia or white matter cal-
cifications in the proper clinical setting should raise the possibility of
AGS. The putamina are most commonly involved (Fig. 3-30A) but the
globi pallidi, thalami, deep and subcortical white matter and, some-
times, cerebellar dentate nuclei may also show punctate or globular
calcification (320); these may or may not be visible on MRI. The sub-
cortical and deep white matter typically are abnormally hypodense on
CT and show T1 hypointensity and T2/FLAIR hyperintensity on MRI
(Fig. 3-30B); subcortical white matter is involved early in the course of
the disease (321). Imaging studies also show ventriculomegaly, usually
progressive, secondary to progressively reduced volume of white mat-
ter in the cerebral hemispheres (Fig. 3-30B) (321). In later stages of the
disease, white matter may have signal intensity similar to CSF, particu-
larly in the frontal lobes (321). The cerebellum and brainstem may be
small, (322–324) but the cerebellar white matter is often spared. It is
important to remember that some patients with imaging findings that
are suggestive of TORCH infections have genetic/metabolic disorders.
Therefore, if TORCH screens are negative in such patients and, espe-
cially if there is a family history of neurodegeneration in childhood,
testing for AGS should be performed.
Cockayne Syndrome
Cockayne syndrome (OMIM 216400) is an autosomal recessive dis-
order that is characterized by cutaneous photosensitivity, dwarfism,
Barkovich_Chap03.indd 123
123
FIG. 3-30. Aicardi-Goutieres syn-
drome. A. Axial noncontrast CT scan
shows calcification of the basal gan-
glia (white arrows) with diffuse corti-
cal and white matter atrophy. B. Axial
T2-weighted image shows marked
ventriculomegaly and enlargement of
the subarachnoid spaces due to white
matter volume loss. The basal ganglia
show a few punctate hypointensities
(black arrows) secondary to calcifi-
cation. (This case courtesy Dr. Susan
Blaser, Toronto.)
pigmentary retinopathy, optic atrophy, cataracts, premature aging, and
progressive neurological dysfunction; joint contractures may develop.
It is caused by mutations in the ERCC8 gene encoding the group 8
excision-repair cross-complementing protein on chromosome 5q11
(325). Affected patients have impaired transcription-coupled repair
of damaged nuclear and mitochondrial DNA, which inhibits resump-
tion of replication and transcription (326). Affected patients typically
present with psychomotor retardation between the age of 6 and 12
months. Both development and growth progressively fall farther and
farther from the norm (327,328). Patients are further characterized
by accentuated thoracic kyphosis, lumbar lordosis, and characteristic
facies (160,327).
CT in Cockayne syndrome reveals brain calcification, most com-
monly in the basal ganglia (Fig. 3-31A), cerebellar dentate nuclei,
and subcortical white matter, as well as cerebral and cerebellar atro-
phy (160,329). MRI shows diffuse atrophy (involving both cere-
bral and cerebellar hemispheres) and T2 hyperintensity, initially in
the periventricular white matter, basal ganglia, and cerebellar nuclei
(330,331). The subcortical U fibers can be involved early in the disease
but are more commonly affected only in later stages (45). Suscepti-
bility-weighted, gradient-echo, and (sometimes) spin-echo or FLAIR
(Fig. 3-31B) images will show hypointensity within calcified deep cere-
bral and cerebellar nuclei (330).
Many other disorders have radiologic findings of cerebral calci-
fications and abnormal myelination. These include many mitochon-
drial disorders (332), GM1 gangliosidosis (333), biotinidase deficiency
(334), pseudo-TORCH syndromes (322), AGS (320), tuberous sclerosis
(see Chapter 6), congenital cytomegalovirus, congenital toxoplasmosis,
congenital rubella, and congenital AIDS (discussed in Chapter 11), and
many others. Some of these have a neuroimaging appearance similar
to those in Cockayne syndrome but without the characteristic clinical
findings. References for the other disorders are provided for interested
readers (316,335–337).
Galactosemia
Galactosemia (OMIM 230400) is an autosomal recessive disorder that
results from defective conversion of galactose to glucose by a path-
way catalyzed by several enzymes. It is most commonly the result of
galactose-1-phosphate-uridyl transferase deficiency due to mutation
of the GALT gene at chromosome 9p13, although other causes have
been reported (338). Affected patients present as newborns and young
5/6/2011 12:08:23 AM
 124 Pediatric Neuroimaging
infants with signs of increased intracranial pressure and vomiting.
If untreated, patients develop severe liver disease, profound mental
retardation, epilepsy, and choreoathetosis (339). Treatment is dietary
restriction of galactose; however, even compliant patients show some
neurologic and neuropsychologic abnormalities (340).
CT scans of patients with galactosemia are nonspecific, showing
extensive low attenuation in the cerebral white matter (59). MR stud-
ies seem somewhat more specific, showing delayed myelination (per-
sistent high signal) in the subcortical white matter and consequent
blurring of the cortical–white matter junction on T2-weighted images
(Fig. 3-32), although the same white matter seems to mature normally
on T1-weighted images (341,342). Cerebral and cerebellar atrophy is
seen in older patients. Focal white matter lesions are occasionally seen
and are of uncertain significance (341).
FIG. 3-32. Galactosemia in a 9-year-old girl. Axial T2-weighted image
show delayed myelination in the subcortical white matter with consequent
blurring of the cortical-white matter junction. Note the poor differentia-
tion of the cortex from the underlying white matter. (This image courtesy
Dr. Susan Blaser, Toronto.)
Barkovich_Chap03.indd 124
FIG. 3-31. Cockayne syndrome. A. Axial non-
contrast CT scan shows calcification of the basal
ganglia (white arrows) and low attenuation of
the white matter. The ventricles and sulci are
enlarged, compatible in this situation with
atrophy. B. Axial FLAIR image shows multiple
punctate areas of signal void (white arrows) in
the basal ganglia, which represent punctate cal-
cifications. Diffuse hyperintensity of the white
matter is present (black arrows).
Proton MR spectroscopy of the brain in patients with galactosemia
is reported to be normal by some authors (342), but others report reso-
nances at 3.67 and 3.74 ppm, corresponding to galactitol, in newborns
with very high urinary galactitol levels (343). These peaks are not spe-
cific for galactitol, as peaks with similar chemical shifts are present in
many sugars, and can represent glucose in diabetes mellitus, or arabitol
and ribitol in errors of polyol metabolism (344). Galactitol can be dis-
tinguished from myo-I, which precesses at nearly the same chemical
shift, but in the presence of J-coupling, which results in inversion of the
peak when using an echo time of 135 to 144 ms. Galactosemic patients
who have been following a galactose restricted diet for several years do
not have galactitol peaks (343).
Mitochondrial Disorders
Although mitochondrial encephalopathies can cause demyelination,
gray matter is almost always involved. Therefore, mitochondrial dis-
orders are discussed in the section “Metabolic diseases that affect gray
matter and white matter.”
White Matter Disorders Due to Hypomyelination
(Hypomyelinating Leukodystrophies)
A group of disorders have been described in recent years, in which
the primary white matter disorder is one of hypomyelination or,
in some cases, delayed myelination of the white matter; these have
become known as hypomyelinating leukoencephalopathies (345).
They are included as a separate group because the MR characteristics
of the white matter differ from that of myelin breakdown (demyeli-
nation), myelin vacuolization, or white matter breakdown (10). The
reduction of myelin is seen as persistent T2 hyperintensity, similar to
that normally seen in neonates and young infants. However, signal
intensity of hypomyelination may be nearly normal on T1-weighted
images, fractional anisotropy is only mildly reduced, and diffusivity
is only mildly increased compared to normal age-matched brains,
proton MRS is nearly identical, while magnetization transfer ratios
are low, similar to those of demyelination and myelin vacuolization
(10). Understanding these disorders will increase our knowledge of
the process of myelination and, perhaps, help intervene and stimu-
late myelination in affected patients. So far, these disorders include
Pelizaeus-Merzbacher disease (346), Pelizaeus-Merzbacher–like
disease (caused by GJA12 and MCT8 mutations and a mutation on
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
Xq (28,29,347,348) ), Cockayne syndrome type II (349), sialuria
(Salla disease) (350), Tay syndrome (351), 18q- syndrome (30,31),
leukodystrophy with trichothiodystrophy and photosensitivity
(352,353), congenital cataracts with hypomyelination (36), hypomy-
elination with atrophy of the basal ganglia and cerebellum (34), and
the very recently described cerebral hypomyelination with cerebellar
atrophy and callosal hypoplasia (354).
Pelizaeus-Merzbacher Disease
Pelizaeus-Merzbacher disease (OMIM #312080) (346) is a hypomyeli-
nating disorder caused by mutations of the PLP1 gene at chromosome
Xq22 (355,356), resulting in abnormal formation of proteolipid pro-
tein (PLP) and its isoform DM20, two of the major structural proteins
of myelin (356–360). The classic form of Pelizaeus-Merzbacher disease
shows X-linked recessive inheritance. Patients present in early life with
nystagmoid eye movements and slow motor development; they sub-
sequently develop involuntary movements and spasticity. The disease
course is protracted and can easily be misdiagnosed as static, leading to
a diagnosis of “cerebral palsy.” Death usually ensues in or early to mid-
adulthood. Patients with the connatal form of Pelizaeus-Merzbacher
disease show either autosomal or X-linked recessive inheritance; thus,
girls as well as boys may be affected (361,362). Affected patients pres-
ent at birth or in early infancy; in addition to abnormal nystagmoid
eye movements and extrapyramidal hyperkinesia, affected patients
develop spasticity, stridor, progressive contractures of the extremities,
optic atrophy, and seizures in the early stage. Progression is relatively
rapid, with death occurring in early childhood; pathologic exam shows
lack of myelin in the entire brain (360,363).
Most patients (60%–70%) with PMD have increased PLP1 due
to duplication of the genomic fragments containing the entire PLP1
gene (355). Patients with duplication of the gene typically have the
classic form of PMD (360,364). In these children, PLP is postulated to
accumulate in the endoplasmic reticulum and lysosomes while DM20
makes it to the cell surface; therefore, myelin molecules can be partly
formed. Other patients, with PLP1 point mutations or with three or
FIG. 3-33. Pelizaeus-Merzbacher disease, connatal form in a 2 month old. Axial T1 (A) and T2 (B)-weighted images show a complete absence of evidence
of myelination. In a normal infant of this age, one would expect to see T1 hyperintensity and T2 hypointensity in the posterior limb of both internal cap-
sules (see Chapter 2).
Barkovich_Chap03.indd 125
125
more copies of the PLP1 gene, typically have a more severe form of
the disease; misfolded proteins accumulate in the endoplasmic reticu-
lum and provoke an unfolded protein response, leading to apoptosis
(360,365–367). In connatal Pelizaeus-Merzbacher disease, both PLP
and DM20 proteins become trapped in the endoplasmic reticulum;
thus, myelin is more severely affected (368). Another form of Pelizaeus-
Merzbacher disease, resulting from a deletion of 19 base pairs in intron
3 of the PLP1 gene, has been described in which mild early develop-
mental delay is followed by progressive decline of acquired motor and
cognitive milestones (369). Still another disorder, known as spastic
paraplegia type 2 (SPG2, OMIM #312920), is caused by null mutations
of the PLP1 gene (360). Patients with SPG2 show normal motor devel-
opment in the first year of life and then develop progressive weakness
and spasticity of the lower limbs between the age of 2 and 10 years
(360). There may be symptoms that overlap with PMD, such as nystag-
mus, optic atrophy, ataxia, dysarthria, or impaired cognition, but they
are less prominent than in PMD (360).
On CT scans, Pelizaeus-Merzbacher disease appears as low atten-
uation in the white matter with progressive white matter atrophy; it
is therefore indistinguishable from most other white matter diseases
(370). The MR appearance of this disorder is one of a lack of myelina-
tion, without frank evidence of white matter destruction (27,46). In the
connatal form of the disease (Fig. 3-33), myelin is completely absent
and never develops. In the classic form, the brain typically retains the
appearance of a newborn, with high signal intensity only appearing
in the internal capsule, optic radiations, and proximal corona radi-
ata on T1-weighted images and a near complete absence of low sig-
nal intensity in the supratentorial region on the T2-weighted images
(Fig. 3-34). The amount of myelination and the volume of white matter
slowly diminish over time (27). The cerebellum may become markedly
atrophic (11) and cortical sulci show slowly progressive enlargement
(371,372). No relationship has been demonstrated between the degree
of myelination as determined by MR and the progression of the disease
or the clinical severity of the disease (373), other than the profound
lack of myelin in the connatal form (366,374).
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 126 Pediatric Neuroimaging
Reports of proton MRS are controversial; this is probably a result
of the fact that many of the reported patients have different mutations
of the PLP1 gene or no mutations of the PLP1 gene (and therefore have
PMD-like disease) and, thus, the reported patients are heterogeneous.
However, both Takanashi et al. (365) and Hanefeld et al. (375) have
recently studied patients with documented duplications of the PLP1
gene. Both groups have reported that NAA, Cr, Glu, and myo-I are
increased compared with age-matched controls (Fig. 3-34C) in white
matter voxels, while Hanefeld et al. have noted that Ch is reduced; spec-
tra are normal in gray matter voxels (basal ganglia and cortex) (375).
The increase in NAA is postulated to reflect either increased number of
axons per voxel (because of the lack of surrounding myelin sheaths) or
increased activity of oligodendrocyte precursors. The elevated Cr and
myo-I are postulated to result from reactive astrogliosis. Reduced Ch
is postulated to result from the severe reduction of choline contain-
ing myelin proteins and lipids caused by lack of normally functioning
Barkovich_Chap03.indd 126
FIG. 3-34. Pelizaeus-Merzbacher disease, classic form
in a 9-year-old. A. Axial T1-weighted image shows
some hyperintensity in the corpus callosum, internal
capsules, and optic radiations. However, a normal
9-year-old should have hyperintense white matter
throughout the brain. This is very delayed myelination.
B. Axial T2-weighted image shows profoundly delayed
myelination; all white matter should be hypointense
compared to gray matter at this age. C. Proton MRS
(TE = 144 ms) from the frontal white matter shows
increased NAA and creatine (Cr) compared to choline
(Ch), a common finding in the classic form of PMD
due to duplication of PLP1.
oligodendrocytes (375). Studies of patients with point mutations of
the PLP1 genes suggest that NAA is decreased, while Cho and Cr are
increased, using long echo proton MRS (376).
Pelizaeus-Merzbacher–like Disease
Some patients have been described with clinical presentation identi-
cal to that in patients with Pelizaeus-Merzbacher disease, but without
PLP1 mutations. These patients appear to have a different, Pelizaeus-
Merzbacher–like disease. An X-linked group has been reported with a
locus on Xq (347) and two autosomal recessive groups with mutations
of the GJA12 gene at 1q41-42 (29,348) and MCT8 at Xq13.2 (28).
GJA12 (OMIM 608804) encodes the gap junction connexin pro-
tein (Cx46.6), which is highly expressed in oligodendrocytes and
appears to play a role in a myelinogenesis (377). MRI and MR spec-
troscopy appear to be nearly identical to those in PMD due to PLP1
deletions (348).
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
MCT8 (OMIM 300095) encodes a thyroid hormone transporter
gene that is implicated in X-linked mental retardation with a wide
spectrum of clinical presentations. Mutations of this gene were found
in approximately 10% of a group of patients with clinical findings of
Pelizaeus-Merzbacher disease, but no mutations of PLP1 or GJA12
(28). This disorder is sometimes referred to as monocarboxylate trans-
porter 8 deficiency (378). Most affected patients have early-onset hypo-
tonia, nystagmus, ataxia, and choreoathetosis. Subsequently, spasticity
and generalized dystonia develop; motor and cognitive acquisitions
are delayed or absent (28). MRI shows essentially no myelination for
the first year of life (similar to connatal Pelizaeus-Merzbacher disease,
Fig. 3-33), but, unlike patients with PLP1 or GJA12 mutations, myelin
(T1 hyperintensity and T2 hypointensity of white matter) slowly
appears on MR scans after age 2 years. However, the volume of white
matter and the thickness of the corpus callosum remain diminished
(28). Experiments in mouse models suggest that the abnormal brain
development is due to deficiency to T3 hormone in the brain (379).
Leukodystrophies with Trichothiodystrophy
Trichothiodystrophy (brittle, sulfur-deficient hair) is a marker for a num-
ber of autosomal recessive neurocutaneous syndromes with neurologic
manifestations and mental retardation. At least six syndromes with tri-
chothiodystrophy have been described (351,352). Most affected patients
have ichthyosis, brittle sulfur-deficient hair, impaired intelligence,
decreased fertility (in some cases), and short stature (352). Other features
include nail and teeth dysplasia, retinal dystrophy, cataracts, increased
susceptibility to infections, endocrine dysfunction, cardiomyopathy, and
osteosclerosis (353,380,381). Major neurological features are mental
retardation, spasticity with pyramidal signs, hyperreflexia, spinocerebel-
lar signs such as nystagmus, dysarthria, tremor, and ataxia, peripheral
neuropathy, and neurosensory hearing impairment (351,382).
MR findings have been described in four syndromes with tri-
chothiodystrophy, and all seem to show diffuse hypomyelina-
tion, very similar to Pelizaeus-Merzbacher syndrome (Fig. 3-34)
(351,353,380,381,383–385). The hypomyelination was confirmed by
autopsy in one patient with PIBI(D)S syndrome (photosensitivity, ich-
thyosis, brittle sulfur-deficient hair, impaired intelligence, decreased
FIG. 3-35. Chromosome 18q deletion syndrome in a 7-year-old child. Axial T1-weighted image (A) appears normal but the T2-weighted image (B) and
diffusion weighted image (C) show indistinct separation of gray matter and white matter due to hypomyelination of the white matter. These findings are
characteristic of hypomyelination.
Barkovich_Chap03.indd 127
127
fertility, and short stature) (352). Ventriculomegaly was present in one
patient that we examined, possibly due to progressive atrophy of the
cerebrum and cerebellum (385). Osteosclerosis, when present, can be
identified by CT or MRI (381). One report described proton MRS find-
ings of reduced choline and elevated myo-I(386).
18q- Syndrome and Other Chromosome 18 Mutations
The chromosome 18 q deletion (18q-) syndrome (OMIM 601808) is
a recently described disorder caused by a deletion of the long arm of
chromosome 18 (30). Patients show a wide range of phenotypic varia-
tion, probably related to the extent and location of the deleted portion
of the chromosome. Some relatively constant manifestations include
mental retardation, developmental delay, short stature, impaired hear-
ing from aural atresia, craniofacial dysmorphism (midface hypoplasia,
frontal bossing, carp-like mouth), limb anomalies, oculomotor disor-
ders, and genital hypoplasia. Most of these characteristics are found in
patients with deletion of the most distal part of the long arm of the
chromosome, 18q22.3-ter (31). Neurologic manifestations may be
related to the fact that one of the myelin basic protein genes is located
on the long arm of chromosome 18 and is almost invariably included in
the deleted segment. Not surprisingly, other mutations of chromosome
18 have also been shown to have myelination defects (387). However,
individuals with deletions sparing the distal area seem to be less severely
affected, without abnormalities in the extremities, oculomotor defi-
ciencies, or short stature; their cognitive problems are milder (31).
MRI studies of patients with 18q- syndrome show findings of
delayed myelination, slower rate of myelination, and hypomyelination
compared with age-matched controls (30,388). In most cases, poor
differentiation between gray matter and white matter in the cerebral
hemispheres is reported on T2-weighted images (Fig. 3-35) (389),
probably due to abnormal myelin; this particular appearance appears
to be associated with mutations in the 18q22.3-q23 region (31). Inter-
estingly, the T1-weighted images have normal appearance (Fig. 3-35A)
(389) despite the fact that quantitative analyses show T1 prolongation
of white matter (388). Diffusion-weighted images show higher diffu-
sivity than age-matched controls (Fig. 3-35C). Small anterior lobes of
the pituitary gland have also been reported (390). Proton MRS at age
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 128 Pediatric Neuroimaging
FIG. 3-36. Sialuria (Salla disease). A. Sagittal T1-weighted image shows a markedly thin corpus callosum (white arrows), indicated markedly reduced white
matter volume. B and C. Axial T1 (B) and T2 (C)-weighted images show a small amount of T1 hyperintensity and T2 hypointensity in the posterior limbs
of the internal capsules (white arrows), suggesting the presence of some early myelination. (These images courtesy Dr. Susan Blaser, Toronto.)
30 months in a single patient revealed normal NAA, increased cho-
line on a long TE sequence in the parietal white matter, and increased
a-glutamate and myo-I on a short TE spectrum in the parietal white
matter. Of interest, these values nearly normalized within a year (391).
Sialuria
Sialuria, (OMIM 604369) also known as Salla disease, is an autosomal
recessive disorder caused by an error in sialic acid (N-acetylneuraminic
acid) metabolism (350); the genetic locus has been mapped to the
SLC17A5 gene at 6q14-q15 (392). A defect in the mechanisms of sialic
acid transport across the lysosomal membrane causes free sialic acid
to accumulate in the lysosomes of various tissues (393). There appear
to be two forms of the disease, and infantile form and an adult form
(394); while the adult form is seen predominantly in people of Finn-
ish descent (this is true Salla disease), the infantile form has no ethnic
prevalence (44). Sialic acid levels in the urine of affected infants are
usually about 20 times higher than in the adult form (394,395); urine
sialic acid levels may be normal in milder cases and require CSF analy-
sis to detect sialic acid (396). Affected children typically become symp-
tomatic between the age of 3 and 6 months, manifesting hypotonia,
ataxia, and often nystagmus. Head size is normal. Subsequently, devel-
opmental delay becomes apparent. The disorder is slowly progressive.
Most learn to walk and speak a few words, only to regress beginning in
the second and third decades (33).
MR studies of patients with Salla disease show reduced volume
of cerebral white matter and markedly diminished myelination. The
images resemble those of patients with Pelizaeus-Merzbacher disease.
The corpus callosum is extremely thin and unmyelinated (Fig. 3-36A).
In less severe cases, the ventricles are of normal size and some myelin
is seen in the peritrigonal white matter and the posterior limbs of the
internal capsules (Figs. 3-36B and C) (33). The subcortical white matter
never seems to myelinate. In patients with more severe symptomatol-
ogy, enlarged ventricles and subarachnoid spaces are seen (33). In some
patients, the cerebellar white matter is affected, as well (397,398). The
basal ganglia appear normal (Fig. 3-36) (399). As the disorder is slowly
progressive, it is difficult to know whether the myelination abnormality
and enlargement of the CSF spaces is progressive (33).
Barkovich_Chap03.indd 128
MRS of patients with Salla disease shows elevation of the Cr and
NAA peaks, diminution of the Ch peak in the white matter; spectra
in the basal ganglia show an enlarged Cr peak but normal NAA and
Ch peaks compared with controls (399). The reason for the increased
amplitude of the “NAA” peak appears to be that the acetyl protons from
N-acetylneuraminic acid resonate at the same frequency as the acetyl
protons from N-acetyl aspartate (399).
Hypomyelination with Congenital Cataracts
Hypomyelination with congenital cataract is a recently described dis-
order that is caused by deficiency of a membrane protein of unknown
function called hyccin, which is encoded by the DRCTNNB1A gene
located at chromosome 7p15.3 (36). Affected patients are first recog-
nized at birth, or during the first month after birth, when they are dis-
covered to have bilateral cataracts. Development is then normal until
the end of the first year of life, when delayed motor development is
detected. Affected infants learn to “cruise” (walk with support) but
never walk without help and gradually become wheelchair-bound (35).
Scoliosis slowly develops and progresses, along with hyperactive deep
tendon reflexes, extensor plantar responses, dysarthria, cerebellar signs,
and truncal ataxia (35). Cognition is impaired, with mild to moderate
impairment in all patients described to date (35).
No central nervous system pathology has been evaluated in these
patients. However, sural nerve biopsy shows reduced or absent myelin
as well as absence of compaction of the myelin sheaths of peripheral
nerves (35). Overall, the impression is that little myelin is actually
formed and that this is subsequently broken down such that the dis-
ease is probably best considered a combination of hypomyelination
and demyelination (400).
Neuroimaging with MRI shows more severe white matter abnor-
malities compared to other hypomyelinating disorders. On T1-weighted
images, cerebral and cerebellar white matter may be slightly hyperin-
tense, isointense, or slightly hypointense compared with gray matter;
white matter is hyperintense compared to gray matter on T2-weighted
images (35). Subcortical white matter may be partially spared early in
the course of the disease (Fig. 3-37) (400). Some patients have more
severe T1 and T2 prolongation in the periventricular and deep white
5/6/2011 12:08:26 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 129

FIG. 3-37. Hypomyelination with congenital cataracts in a 3-year-old child. A. Parasagittal T1-weighted image shows abnormal hypointensity of the deep
white matter with normal hyperintensity (white arrows) of the subcortical white matter. B. Axial T2-weighted image shows abnormal hyperintensity of deep
white matter (white arrows) with sparing of the periventricular and subcortical white matter. Note lens replacements (black arrows) in both ocular globes.
C. Coronal T2-weighted image shows abnormal hyperintensity of deep cerebral (white arrows) and cerebellar (white arrowheads) white matter; note spar-
ing of corpus callosum and of subcortical white matter in both compartments. D. Axial diffusivity (Dav) map shows increased Dav in the affected cerebral
white matter.

matter, which may show hypointensity on FLAIR images, suggesting
cavitation (400). These regions seem to start anteriorly and progress
posteriorly; they decrease in volume over time (35,400). There is no
enhancement after intravenous administration of paramagnetic con-
trast (400). Cerebellar white matter is less severely affected than cere-
bral white matter. The pons is moderately hypoplastic, sometimes
showing T2 or FLAIR hyperintensity in the corticospinal tracts and
transverse pontine fibers (400).
Diffusion-weighted imaging shows increased diffusivity
(Fig. 3-37D) in affected white matter, with slightly increased Dav values
in the unmyelinated white matter and higher values (by ∼20%) in the
cavitating white matter (400). Proton MRS with short echo time may
show an increased myo-I/Cr ratio and Cho/Cr ratios early in the course
of the disease; metabolite quantification in a single patient showed
elevated Cr and myo-I, with reduced NAA (400).
Fucosidosis
Fucosidosis (OMIM #230000) is a rare autosomal recessive lysosomal
storage disease, resulting from a deficiency of alpha-L-fucosidase (401).
Affected patients variably present with progressive neurologic deterio-
ration, coarse facial features, and dysostosis multiplex (401). Abnormal
hyperintensity is present in the white matter on T2-weighted and FLAIR
images of patients in late infancy and early childhood; this may be the only
finding in late infancy (402). However, because cortical and basal ganglia
involvement is common, the more complete discussion is in a later section
of this chapter on disorders involving both gray and white matter.

Barkovich_Chap03.indd 129 5/6/2011 12:08:27 AM

 130 Pediatric Neuroimaging
Hypomyelination with Atrophy of the Basal
Ganglia and Cerebellum (HABC)
Hypomyelination with atrophy of the basal ganglia and cerebellum
(OMIM 612438) is a hypomyelinating disorder that has involvement
of the basal ganglia and cerebellum as well as white matter. It is dis-
cussed in the section of this chapter on Disorders that involve Gray and
White Matter.
White Matter Diseases with Nonspecific Patterns
Nonketotic Hyperglycinemia (Glycine Encephalopathy)
Nonketotic hyperglycinemia, also called glycine encephalopathy
(OMIM #605899), is an autosomal recessive disorder of amino acid
metabolism in which large quantities of glycine accumulate in plasma,
urine, and CSF. It is caused by a disturbance in the breakdown of gly-
cine, which may result from mutations of several different genes in the
mitochondrial glycine cleavage system; loci for these genes have been
identified at 16q24, 9p22, 3p21, and 2p21.1 (44). In the classic form
of the disease, onset of clinical symptoms is in the neonatal period or
early infancy (70% in first 4 days of life (403) ) with myoclonic enceph-
alopathy (lethargy, hypotonia, and myoclonic jerks, progressing to
Barkovich_Chap03.indd 130
apnea and often death) (404,405). Those patients who recover sponta-
neous respiration develop seizures, dystonia, and pronounced develop-
mental delay (404). Milder clinical presentations have been reported,
including a childhood form with mild mental retardation and episodes
of delirium, chorea, and vertical gaze palsy during febrile illness, and
a late-onset form in which children present with progressive spastic
diplegia and optic atrophy but preservation of intellectual function
(156,404,406). A transient neonatal form has also been described
(407,408).
CT studies have revealed cerebral and cerebellar volume loss with
hypoattenuation of the periventricular white matter (409). Early MR
studies show severely delayed myelination and white matter edema
(Fig. 3-38A–D). Prenatal neurotoxicity may result in encephalomalacia
with thinning of the corpus callosum and cerebral cortical anomalies.
Studies later in the course of the disease show a nonspecific pattern
of decreased volume and T2 hyperintensity of the cerebral cortex and
cerebral hemispheric white matter with a consequently small corpus
callosum (Fig. 3-38F and G) (410,411). A few studies have reported
reduced diffusion in the dorsal brainstem and corticospinal tracts
(posterior limbs of internal capsules, central corona radiata) on dif-
fusion-weighted imaging (Fig. 3-38B and D), probably reflecting the
FIG. 3-38. Nonketotic hyperg-
lycinemia in a neonate. A and B.
Axial T2-weighted and diffusion
weighted images show T2 hyperin-
tensity (A) and reduced diffusivity
(B) in the cerebellar white matter
(black arrows) and central tegmen-
tal tracts (black arrowheads). C and
D. Axial T2-weighted and diffusion
weighted images at the level of the
basal ganglia show diffuse white mat-
ter hyperintensity with reduced dif-
fusivity in the posterior limbs of the
internal capsules (black arrows), the
myelinated part of the white matter.
E. Proton MRS (TE = 144 ms) shows
abnormally elevated glycine peak
(Gly) at 3.6 ppm. Myo-Inositol also
precesses at this frequency but is not
seen at echo times this long.
5/6/2011 12:08:28 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
known pathological finding of vacuolating myelinopathy in the acute
phase of the disorder; imaging at this stage can resemble that of maple
syrup urine disease (section IV.B.1.g), which is also due to a vacuo-
lating myelinopathy. Anisotropy of the white matter may be normal
(412,413). As atrophy develops over time, however, diffusion normal-
izes and then increases while anisotropy decreases, probably as a result
of the known axonal degeneration (413).
Proton MRS studies are critical for making the diagnosis, showing an
abnormal peak at 3.56 ppm (Fig. 3-38E), believed to represent glycine
(411,414). Abnormal spectra are reported in patients with normal MRI
studies. Moreover, the clinical course of the patients seems to correlate
more closely with the cerebral glycine level, as detected by MRS, than
to plasma or CSF concentrations of glycine (411,414). In order to sepa-
rate the glycine peak from that of myo-I, which has a similar chemical
shift, the spectra should be obtained with a long echo time (135-144 or
270-288 ms). The myo-I protons with that chemical shift have a short
T2 relaxation time and, therefore, disappear on the long echo time
spectra. Therefore, MRS is the most important study for the diagnosis
and for following patients with nonketotic hyperglycinemia (411).
Dihydropyrimidine Dehydrogenase Deficiency
Dihydropyrimidine dehydrogenase deficiency (DPD, OMIM 274270)
is caused by mutation of the DPYD gene located at 1p22 (415); DPD
is the rate-limiting enzyme in the three-step pathway of uracil and
thymidine catabolism and in the pathway leading to the formation
of beta-alanine (44). It has been reported mainly in patients of Euro-
pean or Turkish ancestry. Affected children have had a variable clinical
phenotype ranging from unaffected to severe neurologic involvement
(415,416). Because of the presence of unaffected individuals, including
asymptomatic siblings, with biochemical and molecular findings simi-
lar to affected patients, it appears that DPD deficiency is a necessary,
but not sufficient, prerequisite for the development of clinical abnor-
malities (415,417). Seizures and mental and motor retardation are
common features, affecting 45% of individuals (415). Ocular abnor-
malities (23%), autism (18%), growth retardation (18%), microceph-
aly (14%) and mild dysmorphic features (14%) are relatively frequent
findings (415). Ophthalmologic findings in DPD deficient patients
include megalocornea, optic atrophy, iris and choroidal colobomata,
and fundus hypopigmentation (415). The mechanism of neurologic
injury in DPD has not been clearly elucidated, although decreased
levels of the neurotransmitter-alanine and increased central nervous
Barkovich_Chap03.indd 131
131
FIG. 3-38. (Continued) F and
G. Follow-up MR images at age
18 months. Sagittal T1-weighted
image (F) shows a very small
corpus callosum (white arrows),
resulting from severe loss of
cerebral white matter. Axial
T2-weighted image (G) shows
enlarged ventricles and suba-
rachnoid spaces with hypomy-
elinated white matter, indicative
of atrophy from severe cortical
and white matter injury.
system concentrations of uracil and/or thymine may be contributing
factors (418).
Reported brain imaging findings consist of partial agenesis of
the corpus callosum, intracerebral hamartoma, T2 prolongation of
the white matter secondary to markedly delayed myelination, slight
white matter hyperintensity, “strong contrast between white and gray
matter,” and diffuse cerebral atrophy (415). The rare patient with
underlying DPD deficiency who undergoes cancer chemotherapy
with 5-fluorouracil may develop severe toxic side effects, including
a multifocal inflammatory leukoencephalopathy with hyperintense
white matter lesions on T2-weighted images (419). The T2-weighted
axial images show abnormally prominent CSF spaces. Abnormal T2
prolongation is present in the periventricular cerebral white matter.
In addition, abnormal T2 prolongation may be seen in the brain-
stem, specifically in the pontomedullary portions of the medial lem-
nisci and median longitudinal fasciculi, and in the inferior olivary
nuclei (420). The ventral superficial reticular area of the medulla
and the parvocellular reticular area of the pons may also be involved
(Fig. 3-39).
3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase Deficiency
HMG CoA lyase is an important compound in both the breakdown
of L-leucine and in fatty acid oxidation; the latter process is impor-
tant in the production of acetyl CoA and acetoacetate, both of which
are important compounds in energy production within the brain.
In addition, excess HMG CoA inhibits the process of gluconeogen-
esis. Deficiency of HMG CoA lyase (OMIM 246450) is characterized
by recurrent episodes of severe metabolic derangement, including
hypoglycemia, metabolic acidosis, and sometimes hyperammonemia
(421,422). It is caused by mutations of the HMGCL gene at chromo-
some 1pter-p33 (423). Patients typically present with their first crisis
as neonates or young infants. Diagnosis is suggested by abnormalities
in urinary organic acids (3-hydroxyisovaleric, 3-methylglutaconic,
3-methylglutaric acids and 3-hydroxy-3-methylglutaric acid) and con-
firmed by demonstration of deficient activity of HMG CoA lyase in
leukocytes and cultured fibroblasts (421,422).
CT of patients with HMG CoA lyase deficiency shows diffusely low
attenuation of the white matter (37). MRI usually reveals nonspecific
gray and white matter abnormalities. During infancy or childhood,
mild frontal atrophy and ventricular enlargement will be noted, with
multiple patchy or confluent white matter lesions. Deep gray matter
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 132 Pediatric Neuroimaging

FIG. 3-39. Dihydropyrimidine dehydrogenase deficiency. A. Axial T2-weighted image shows abnormal hyperintensity (black arrows) in the medullary
olives/reticular activating system. B. Axial diffusion weighted image at the same level as (A) shows reduced diffusivity (white arrows) in the lesions. C. Axial
T2-weighted image at the level of the pons shows hyperintensity in the medial lemnisci and median longitudinal fasciculi. D. Axial T2-weighted image at
the level of the lateral ventricles shows enlarged ventricles and subarachnoid spaces, as well as abnormal periventricular T2 hyperintensity (white arrows).
(This case courtesy Dr. Greg Enns, Stanford, California.)

abnormalities (basal ganglia and cerebellar nuclei) are subtle early,
becoming more obvious as myelination progresses; if the disease is
appropriately treated, these lesions may disappear on follow-up studies.
Later, as brain myelination progresses, white matter changes become
obvious. In most reported cases, the subcortical white matter is spared
(Fig. 3-40), but some cases have shown involvement of the subcortical
axons, as well (37,422). In patients who suffer episodes of severe hypo-
glycemia, the characteristic neuroimaging findings of hypoglycemic
brain injury (caudate and putaminal injury (424) see Chapter 4) may
be superimposed upon the baseline findings of the HMG CoA lyase
deficiency (422).
Proton MR spectroscopy of patients with HMG CoA lyase defi-
ciency shows reduced NAA/Cr, increased Ch/Cr, and increased myo-I/Cr
ratios, suggesting enhanced membrane turnover and gliosis in the
white matter of affected patients (422). Broad peaks are consistently
seen at 1.3 and 2.4 ppm during metabolic decompensation, possibly
due to accumulation of HMG CoA; however, the precise biochemical
explanation is not yet clear.
Congenital White Matter Hypoplasia/Familial
Spastic Paraplegia
Congenital white matter hypoplasia is a term used to describe children
in whom the volume of white matter in the cerebral hemispheres is
reduced without a known cause, such as white matter injury of pre-
maturity, twin-twin transfusion syndrome, metabolic disease, or
congenital infection (57). Affected children typically have primarily
delayed motor development and are classified as having cerebral palsy.
Seizures or cognitive disabilities are present in some. Congenital white

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
FIG. 3-40. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Axial
T2-weighted image shows abnormal hyperintensity of most of the centrum
semiovale with sparing of the subcortical white matter (black arrows).
matter hypoplasia is probably the end result of a number of processes,
including genetic disorders of white matter development and prena-
tal injury/infection. Genetic causes are sometimes classified as familial
spastic paraplegia (233,241,425) (see IV.B.1.n, earlier in this chapter);
many different genetic loci have been associated with these disorders
(426) and the pathophysiology is only beginning to be worked out
(233,427,428).
Imaging findings are similar in all cases. The volume of white mat-
ter in the cerebral hemispheres is reduced, but there is no evidence of
reactive astrogliosis such as from ischemic or infectious injury. The
corpus callosum is abnormally thin but fully formed. In severe cases,
the brainstem might be thin. Basal ganglia, cerebral cortex, and cer-
ebellum are normal. Diffusion imaging and proton spectroscopy are
normal or show slightly reduced diffusivity and NAA, respectively.
Idiopathic Inflammatory, Autoimmune, Infectious, and
Toxic Disorders Affecting White Matter
Idiopathic inflammatory diseases of the nervous system include a
wide range of clinical and histopathological entities that are classified
according to the pattern of involvement (monofocal or multifocal, with
possible involvement of brain, spinal cord, and nerve roots), sever-
ity (asymptomatic, mild, and severe), and disease course (monopha-
sic, multiphasic, relapsing-remitting, progressive, etc). Traditionally,
isolated optic neuritis and transverse myelitis have been considered
monofocal and monophasic diseases; recently, the term clinically iso-
lated syndromes (CIS) has been used to describe these entities. ADEM
is a multifocal, but usually monophasic and self-limiting process. MS
and neuromyelitis optica (NMO) are chronic (relapsing) multifocal
inflammatory diseases. Although inflammatory diseases of the CNS
in adults and children have many similarities, distinct differences have
been identified that have potential clinical relevance for treatment
Barkovich_Chap03.indd 133
133
and prognosis. Recently, clinical consensus definitions have been
developed specifically for the pediatric forms (occurring in patients
younger than 10 years) of inflammatory diseases of the CNS in an
attempt to create a uniform terminology and identify common clini-
cal and neuroimaging features associated with the proposed entities
in children (429–431).
As in adults, ADEM and MS are the most common idiopathic
inflammatory diseases of the brain in the pediatric patient popula-
tion, but their diagnosis is often complicated because no single clinical,
laboratory or imaging feature is specific to either disorder. Although
imaging findings may be suggestive, it is often impossible to confi-
dently diagnose inflammatory diseases of the CNS and in particular,
to differentiate them from many other pathological conditions of the
CNS (vascular, neoplastic, metabolic, etc.) solely by MRI.
Multiple Sclerosis
Although usually considered an adult disease, symptoms of MS
can begin during childhood. It has been estimated that up to 10%
of all patients with MS present during childhood (429,430), with
10,000 cases in the United States (432). The clinical presentation of
the disease in early childhood can range from school problems and
paresthesias to dramatic presentations suggesting diffuse encephal-
opathy with cerebral edema, meningismus, and impaired conscious-
ness (433). It is important to remember that 10% to 25% of children
initially diagnosed as having ADEM are ultimately diagnosed with MS
(8,434). Other presenting phenotypes include optic neuritis (25%),
transverse myelitis (11%), and CIS with single presenting symptom
other than optic neuritis, transverse myelitis, or ADEM (434). There-
fore, it is often not until the second attack of a neurologic episode that
the diagnosis of MS should be suggested. Recent studies suggest that
childhood-onset MS patients are more likely than adult-onset patients
to have a relapsing-remitting course and have a longer course before
the onset of secondary progression; however, they reach states of irre-
versible disability at a younger age than patients with adult-onset MS
(430).
New recommendations from an international panel of experts
have emphasized the importance of MRI in the diagnosis of MS in
adults (434,435). In particular, MRI is used to document dissemination
of lesions in space and in time. Unfortunately, these criteria are not as
useful in children as in adults (436). Currently, the most accurate cri-
teria for differentiating MS from other, nondemyelinating, neurologic
disorders are based on MRI and consist of at least two of the follow-
ing: ≥5 lesions on T2-weighted images; ≥2 periventricular lesions; or
≥1 brainstem lesion (434).
Standard MRI in MS Imaging findings in children with MS are not
significantly different from those in adults (Fig. 3-41). Sharply margin-
ated lesions are generally seen in the white matter T1 hypointense with
T2/FLAIR hyperintense (Figs. 3-41 and 3-42); often, on T2-weighted
images of active plaques, a central area of very high signal intensity is
surrounded by a peripheral area of moderately high signal intensity
(Figs. 3-41C and 3-42A). Plaques are common in the cerebral cortex
but these are small and, therefore, are not well shown by MRI at 1.5T
or 3T at this time. FLAIR sequences show abnormalities in MS patients
even when standard T2-weighted images are normal (437–439). How-
ever, FLAIR is somewhat limited in the detection of posterior fossa and
spinal cord lesions (15,440,441); therefore, we routinely acquire both
FLAIR and T2-weighted sequences in patients with known or suspected
MS. Enhancement (Fig. 3-41D) may or may not be seen, depending
on the acuity of the plaque; new lesions enhance for an average of 3
weeks (median 2 weeks) (442). Overall, children with MS tend to have
fewer lesions in general and fewer enhancing lesions than adults. In
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 134 Pediatric Neuroimaging

children, lesions in the juxtacortical and deep white matter are much
more common than those in the periventricular white matter or cor-
pus callosum (434). In addition, the incidence of tumefactive plaques
(Figs. 3-42) (443) and posterior fossa plaques (Fig. 3-41E) (444,445)
seems to be somewhat higher, and the disease activity (frequency of
onset of new lesions) seems to be greater (445). Tumefactive plaques
in the brainstem and spinal cord in children may be associated with
extensive swelling and MR signal changes suggestive of neoplasm (446).
Tumefactive plaques can sometimes be differentiated from tumors by
the presence of other, more typical plaques, lack of mass effect, location
adjacent to the ventricular surface, and an incomplete rim of enhance-
ment (Fig. 3-42C) as contrasted with a complete ring of enhancement
in tumors.
Diffusion-weighted images (Fig. 3-42B) may show reduced dif-
fusivity in the regions of active inflammation, resulting from the
inflammatory infiltrate; in our experience, reduced diffusivity is seen
earlier than enhancement in acute plaques. Single voxel proton MR
spectroscopy (Fig. 3-42D) may also be useful; short echo spectra dem-
onstrate elevated glutamate and glutamine in the lesion, while both long
and short echo spectra show elevated choline, elevated lactate, elevated
lipid, and decreased NAA (447). These diffusion and MRS findings are
similar to those seen in tumors; therefore, a search for other plaques,
serial clinical exams, and serial imaging exams may be necessary to
make a definitive diagnosis of MS in such children (446). Readers inter-
ested in further information concerning imaging findings in MS are
referred to any standard adult neurology or neuroradiology text.
The differential diagnosis for multiple white matter regions of T2/
FLAIR hyperintensity, some of which may or may not enhance, include
multiple small infarctions (as from antiphospholipid antibody syn-
drome, SLE, Takayasu disease, or even arterial dissection), monophasic

FIG. 3-41. Multiple sclerosis in a 15-year-old. Often, lesions in childhood are very similar to those in adults. A. Axial T2-weighted image shows multiple
lesions in both cerebral hemispheres (small white arrows), involving the periventricular, deep, and subcortical white matter. The large lesion in the middle
of the right hemisphere (large white arrow) is very hyperintense and is surrounded by edema (more moderate hyperintensity). B. Axial reformation of volu-
metric FLAIR sequence at the same level as (A) demonstrates that more subtle lesions are detectable than on T2-weighted images. C. Coronal T2-weighted
image shows the same large hyperintense, edematous lesion (large white arrows) in addition to a subcortical plaque (white arrowhead) and a plaque in the
left midbrain-pons junction (small white arrows). D. Coronal T1-weighted image after intravenous injection of paramagnetic contrast shows rim enhance-
ment of the large right hemispheric lesion (white arrows) and the subcortical plaque (white arrowhead). E. Coronal T2-weighted image shows bilateral cer-
ebellar lesions (white arrows) in addition to supratentorial lesions (white arrowheads). F. Sagittal T2-weighted image of the cervical spine shows a lentiform
hyperintense plaque (black arrows) in the dorsal spinal cord at the C1 level. Note that the dorsal surface of the cord bulges slightly outward, indicating mass
effect from an acute lesion.

Barkovich_Chap03.indd 134 5/6/2011 12:08:31 AM

 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 135

FIG. 3-41. (Continued) G. Axial T2-weighted image

through the C1 level shows the plaque (black arrows)
involving the dorsal columns of the spinal cord. H. Sagit-
tal T1-weighted image of the cervical spine after intra-
venous administration of paramagnetic contrast shows
enhancement (white arrows) of the plaque.

FIG. 3-42. Tumefactive multiple sclero-

sis. A. Axial T2-weighted image shows an
area of T2 hyperintensity (white arrows)
in the right parietal lobe. Note that the
lesion has little mass effect, is located
adjacent to a lateral ventricle, and has an
area of marked hyperintensity centrally.
B. Axial diffusivity (Dav) image shows
reduced Dav in the medial aspect; this
likely corresponds to the location of the
inflammatory infiltrate (white arrows).
C. Axial T1 postcontrast image shows an
incomplete rim of enhancement (white
arrows) at the posteromedial aspect of
the lesion. The dense enhancement of
the more anterior part is atypical. Biopsy
showed demyelination. D. Single voxel
proton MRS (TE = 144 ms) shows ele-
vated choline, low NAA and high lactate,
typical findings for a tumefactive demy-
elinating plaque.

Barkovich_Chap03.indd 135 5/6/2011 12:08:33 AM

 136 Pediatric Neuroimaging
demyelinating diseases (such as ADEM or acute transverse myelitis),
migraine, and infections/inflammatory disorders such as Lyme dis-
ease or neurosarcoidosis (431). When only a single lesion is identified,
tumor is the most concerning differential diagnosis; dynamic perfu-
sion imaging is the most useful technique in differentiating these two
entities (448) (see the beginning of Chapter 7). A search should also be
made for lesions within the cerebral cortex, or juxtacortical lesions at
the border between the cortex and the subcortical white matter, which
are becoming recognized as an important component of this disease
(434,449,450).
More Advanced MR Techniques in MS Although precontrast
and postcontrast T1, T2, FLAIR, and diffusion imaging are stan-
dard sequences for the evaluation of MS, many other MR techniques
may be useful in the evaluation of patients with MS, particularly in
the research setting. The use of magnetization transfer techniques
improves visibility of enhancing MS lesions by suppressing the T1
shortening effects of myelin. However, because some MS lesions have
high intensity on precontrast T1-weighted images, it is necessary to
obtain precontrast, as well as postcontrast, T1-weighted images if
magnetization transfer is used (437). Quantification of white mat-
ter injury can be accomplished via the calculation of magnetization
transfer ratios and diffusion tensor imaging (see Chapters 1 and 2)
(451–454). Although FLAIR is somewhat limited in the detection of
posterior fossa and spinal cord lesions (15,440,441), double inversion
recovery, in which the signals of both CSF and white matter are sup-
pressed through the use of two separate inversion pulses (455), seems
to be useful in these regions (456).
The ability of diffusion tensor imaging techniques to assess dam-
age to the microstructure of the brain makes it potentially the most
useful technique for assessing brain injury in this disorder (magneti-
zation transfer is more specific for myelin damage), as axonal injury
results in reduced average diffusivity and reduced fractional anisotropy
(454). Although these findings seem to be less severe in pediatric-onset
disease than in adult-onset MS (457), early results suggest that disease
in white matter pathways is widespread, with increased diffusivity and
reduced FA, even in normal-appearing white matter (458). Within the
plaques themselves, highest diffusivity values are found in T1 hypoin-
tense lesions, representing long standing destructive damage. Dif-
fusivity values in enhancing and nonenhancing plaques are variable,
although anisotropy is always lower in enhancing than in nonenhanc-
ing plaques, suggesting that the inflammatory effects have a more vari-
able impact on diffusivity than on anisotropy and that blood–brain
barrier breakdown probably varies during these active periods (454).
Magnetization transfer techniques are also useful in differentiating
the inflammation associated with MS (little reduction of magnetiza-
tion transfer) from actual demyelination (more marked reduction of
magnetization transfer) (459). Magnetization transfer ratios dimin-
ish more rapidly in the acute phase and are overall lower in secondary
progressive MS than in relapsing-remittingMS; this observation may
indicate a difference in the nature of these forms of the disease (460).
Detection of small lesions of the cerebral cortex can be improved by
increasing signal-to-noise with parallel imaging or higher field strength
(461), or by the use of sequences that suppress both the signal of white
matter and that of CSF (462).
Localized proton spectroscopy from white matter plaques of chil-
dren with MS shows a decrease in NAA and creatine and an increase
in choline and myo-I relative to age-matched controls (117). Adja-
cent white matter is normal, but adjacent cortical gray matter shows
reduced NAA. This data is supported by reports in the adult litera-
ture suggesting that acute MS plaques have increased choline and nor-
mal NAA (indicating inflammation but no cell loss), whereas chronic
Barkovich_Chap03.indd 136
lesions have decreased choline and decreased NAA (indicating reso-
lution of inflammation but loss of neurons or axons) (463). Reduced
NAA (464) and elevated lactate (464,465) may also be seen in acute
plaques (Fig. 3-42). The decreased NAA correlates with axonal damage,
whereas the increase in choline correlates with both local inflammation
and increased myo-I with reactive astrogliosis, while the lactate is likely
secondary to the inflammation (465). It should be noted that MRS of
a tumefactive MS plaque may be nearly identical to that of tumor, so
anatomic characteristics (see the section in the beginning of Chapter 7)
and other methods, such as dynamic perfusion imaging (which shows
increased blood volume in high-grade intraparenchymal tumors but
reduced blood volume in demyelinating plaques (448) ), are needed to
establish the diagnosis. The fact that decrease in NAA correlates with
axonal damage has led to the use of whole brain (“global”) proton MRS
to quantify whole brain NAA as a marker of total axonal/neuronal dys-
function. Such global analysis allows inclusion of disease in normal-
appearing white matter that might otherwise be missed (454).
Neuromyelitis Optica (Devic Disease)
NMO has been historically characterized by sequential or concomitant
optic neuritis and transverse myelitis; however, the spectrum of the
disease has recently been expanded to include patients with encephal-
opathy, seizures, intractable vomiting, and brainstem-mediated hiccups
(466). Indeed, in early stages, it may be clinically difficult to differenti-
ate from MS(466,467). Although it is most common in adults, it may
be encountered in children (age of onset 14–65 years). The disorder is
more common in women and in nonwhite populations (466–468). A
viral prodrome is present in up to 84% of patients. CSF studies reveal
intrathecal oligoclonal bands in 20% of patients, but, more importantly,
recently developed blood test may reveal the presence of a highly spe-
cific serum antibody, the so-called neuromyelitis optica-immunoglob-
ulin G (NMO-IgG) (466–468). Prognosis is better in children (complete
recovery in 77%) than in adults (18%). The disease, although initially
believed to be monophasic, may be multiphasic, with recurrences within
6 months to 5 years (466–468). In the acute phase, swelling of optic
nerves and the affected part of the spinal cord are seen, but ultimately
optic nerve atrophy and necrosis within the spinal cord develop.
Identification of lesions within the optic nerves or suprasellar
optic pathways may be challenging and requires high-resolution imag-
ing, including STIR sequence, which appears to be the most sensitive
technique to detect optic neuritis. If lesions associated with swelling
are located at the level of the proximal optic pathways, optic glioma
may be a differential diagnostic consideration, but differences in clini-
cal presentation and evolution usually allow a fairly confident differ-
entiation. Detection of spinal cord lesions is generally easy by MRI.
The T2 hyperintense lesion, often occupying almost the entire cross-
sectional area of the cord, is usually more extensive (3–17 segments)
than MS-related cord lesions, and signal enhancement after intra-
venous gadolinium injection may be seen in 20% of patients (469).
Lesions may be detected in brain parenchyma during the course of the
disease in up to 60% of patients (469,470). Although this contradicts
the initial presumption that the disease is limited to the spinal cord
and optic pathways, it does not rule out the diagnosis of the disease if
the currently proposed diagnostic criteria are otherwise met. Until a
few years ago, the diagnostic criteria of NMO required (beyond optic
neuritis and acute myelitis) at least two of three supportive criteria, two
of which relied on MRI, notably the presence of a contiguous spinal
cord lesion and a brain MRI study not satisfying the criteria of MS.
More recently, brain imaging findings have been dropped from the set
of supportive criteria (466–469). As spinal cord lesions may “split up”
into several, apparently distinct, smaller lesions during the recovery
period and brain lesions may increase in number with time (ultimately
5/6/2011 12:08:34 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
fulfilling the diagnostic imaging criteria for MS), specificity of the MRI
is highest if it is performed as early as possible after the initial clinical
presentation.
Acute Disseminated Encephalomyelitis (ADEM)
Children may develop acute encephalitis late in the course of a viral ill-
ness or after a vaccination; less commonly, encephalitis may occur after
a bacterial infection (particularly mycoplasma) or drug ingestion or
with no history of a preceding event (471,472). This disorder is called
acute disseminated encephalomyelitis (ADEM) or parainfectious
encephalomyelitis. The most common clinical presentation is the onset
of focal neurological signs a few days to several weeks after the clini-
cal onset of the viral infection. These are usually severe and indicate
multifocal involvement of the CNS. Headache of rapid onset is com-
mon, followed by vomiting (32%–35%), impairment of consciousness
(45%–69%), and seizures (13%–35%). Nuchal rigidity is often present.
Encephalopathy exhibiting behavioral changes (confusion, excessive
irritability) and/or alteration of consciousness is a virtually, “sine qua
non” diagnostic criterion. Sometimes the disease presents with isolated
acute psychosis. Focal neurological signs include long tract signs (85%,
with acute hemiparesis in 23%–77%), cerebellar ataxia (50%–65%),
cranial nerve palsy (44%–45%), and visual loss (13%–23%). Spinal
cord involvement is present in approximately 24% of patients (473).
CSF cultures are repeatedly negative for bacteria, fungi, or viruses and
typically (although not always) no oligoclonal bands are found; eleva-
tion of proteins and white cell count (pleocytosis) are frequent (473).
Measles, mumps, chickenpox, rubella, pertussis, mycoplasma, herpes,
cytomegalovirus, Campylobacter jejuni, and Group A streptococcus
are the organisms most often implicated in this disease; however, many
cases seem to occur “spontaneously,” or follow nonspecific infections
(474–476). Patients usually respond well to steroid therapy, and the
neurological findings evolve and then resolve over a period of weeks
(477). The majority of individuals make a complete recovery with no
neurological sequelae; 10% to 30% will have some permanent neuro-
logical damage (474,475).
Sometimes the disorder waxes and wanes over a period of months.
The International Pediatric MS Study Group has proposed operational
definitions to address this phenomenon (478). Monophasic ADEM is
defined as a multifocal clinical syndrome in patients without a prior
demyelinating event. Symptoms may evolve over a period of 3 months
after the clinical onset. Recurrent ADEM is characterized by a second
attack, involving the same anatomic areas, more than 3 months after
the initial event. Multiphasic ADEM is characterized by a second event
in a different anatomic area (a new focal neurologic deficit or a new
lesion on MRI) more than 3 months after the initial event. A significant
number of patients who receive an initial diagnosis of ADEM eventu-
ally receive a diagnosis of MS; this number could be as high as 25%
(5,434,479). The chances of a subsequent attack of demyelination is
higher in patients who are 10 years old or greater at the time of the
initial attack, have a pattern suggestive of MS (see paragraph on imag-
ing findings below) on the initial MRI, or have an optic nerve lesion.
Chances of a second attack are lower in patients with myelitis (symp-
toms of spinal cord involvement) or mental status changes (encephal-
opathy) (480).
ADEM is likely caused by an autoimmune response; it is postu-
lated that the precipitating illness induces a host-antibody response
against a central nervous system antigen. This postulate is supported
by the fact that the gross pathological and histological manifestations
of ADEM closely resemble those of experimental allergic encephalitis,
an experimentally induced autoimmune disease caused by antibodies
to myelin. Pathologically, a diffuse perivenous inflammatory process
causes confluent areas of demyelination. In the brain, cortical and deep
Barkovich_Chap03.indd 137
137
gray matter are involved, but to a lesser extent than white matter. In the
spine, both gray and white matter may be affected.
On imaging studies, moderate to large areas of demyelination
(low density on CT, T1 hypointensity and T2/FLAIR hyperintensity on
MRI) are seen in the subcortical and deep white matter of one or both
hemispheres, usually asymmetrically (Fig. 3-43) (481,482). CT, which
is often the first imaging modality used in the emergency diagnostic
workup of a child presenting with a severe acute neurological syndrome,
is often negative in patients who are later diagnosed to have ADEM.
MR examination of the brain is usually positive, but lesion patterns are
highly variable. Periventricular white matter is involved in about half
of patients with ADEM, in contrast to greater than 90% involvement
in MS and the corpus callosum is much more commonly involved in
MS than in ADEM; these criteria might be useful in differentiating
ADEM from an initial episode of MS(9,434,477). Other factors that
favor a diagnosis of MS are absence of a diffuse bilateral pattern and
the presence of black holes (sharply marginated regions of T1 hypoin-
tensity) (434). MRI reveals abnormalities of the deep cerebral nuclei
(Fig. 3-43B) in approximately 50% of affected pediatric patients (477,
483–485). The brainstem (Fig. 3-43A), spinal cord (Fig. 3-43D), and
cerebellar white matter (Fig. 3-43A) are each involved in about 30%
to 50% of affected patients (477,483,485); spinal cord lesions often
are located in the central gray matter (Fig. 3-43E). Petechial hemor-
rhage may be present within the lesions; this is best demonstrated by
T2-weighted gradient-echo images or susceptibility-weighted images.
In the subacute phase, the lesions will show various patterns of enhance-
ment (nodular, diffuse, a complete ring, or a partial ring) after infusion
of contrast (484,486). Diffusion images show increased diffusivity in
the foci of demyelination in both the acute and the subacute phases,
a factor that is useful in differentiating ADEM from vasculitis (lesions
from vasculitis show reduced diffusion in the acute phase). Perfusion
imaging will show normal or reduced blood volume. An important
point is that the T2 changes in the brain evolve over time, as does the
clinical syndrome. As a result, follow-up MR studies may show an
apparent worsening in spite of clinical improvement (487). Although
ADEM may recur, as mentioned earlier, under such circumstances the
clinical exam and CSF analyses are more indicative of the course of the
disease than the MR results.
Other disorders may present with neurologic and imaging findings
that resemble those of ADEM; these disorders include viral encephali-
tis, collagen vascular diseases, Whipple disease, neurosarcoidosis, and
MS(431,446,488–490). These alternative diagnoses must always be
kept in mind when patients present with acute neurologic deficit and
imaging findings compatible with ADEM.
Acute Hemorrhagic Encephalomyelitis
Acute hemorrhagic encephalomyelitis is a rare (2%), hyperacute variant
of ADEM in which the involved regions of brain undergo hemorrhagic
necrosis. It has been associated with herpes simplex and Epstein-Barr
virus infections, although the inciting infection is often not identified
(491,492). It is rarely iatrogenic (induced by melarsoprol, an organic
drug containing arsenic that is used to treat trypanosomiasis). At
autopsy, the brain is markedly swollen and numerous hemorrhagic
foci are seen in cerebral and cerebellar white matter and the brainstem
(pons). Microscopically, fibrinoid necrosis of vessel walls (both arter-
ies and veins) is found in conjunction with perivascular tissue necro-
sis and hemorrhages. Mixed perivascular infiltrates (neutrophils and
mononuclear cells) are also seen, with evidence of demyelination and
axonal fragmentation. Patients often progress rapidly into delirium
and coma and most die within the first few days to a week of onset
(474,493). The few survivors have serious neurologic sequelae (494).
Imaging findings are of multiple or large unilateral or bilateral lesions
5/6/2011 12:08:34 AM
 138 Pediatric Neuroimaging
of the cerebral white matter, most commonly involving the frontal and
parietal lobes. The basal ganglia, thalami, brainstem, cerebellum, and
spinal cord may be involved. Overall, the lesions are similar to those in
ADEM except that the lesions are larger, hemorrhagic, and have more
associated edema and mass effect (11,160,495).
Collagen Vascular Diseases/Systemic Lupus Erythematosus
Collagen vascular diseases are immunologically mediated syndromes
in which antigen-antibody complexes are found in various body tis-
sues, resulting in multiorgan dysfunction. The most common of these
disorders presenting with neurologic signs and symptoms in children
and adolescents is systemic lupus erythematosus (SLE).
The average age of patients at the time of diagnosis of childhood
SLE is 13 years but patients may present as young as age 8 years. Males
are more commonly affected in childhood (496); in adults, females
are more commonly affected with a ratio of approximately 3:1. The
average age at the onset of neurologic manifestations, which develop
in 13% to 45% of patients with SLE, is 14 years (488,497–502). In 32%
to 47% of affected patients, the neurologic manifestations either pre-
cede the diagnosis of SLE or are coincident with the diagnosis; another
30% manifest neurologic signs or symptoms within 1 year of time of
Barkovich_Chap03.indd 138
FIG. 3-43. Acute disseminated encephalomyelitis in a 2-year-old.
A. Axial T2-weighted image shows abnormal hyperintensity in the
left medullary pyramid (black arrow) and in the white matter of
both cerebellar hemispheres (white arrows). B. Axial T2-weighted
image at the level of the basal ganglia shows multiple lesions of vari-
able size involving the thalami and lentiform nuclei (white arrows),
as well as the cerebral white matter. C. Axial T2-weighted image at
the level of the bodies of the lateral ventricles shows asymmetrical
areas of hyperintensity of varying size in the deep and subcortical
white matter. D. Sagittal T2-weighted image shows multiple areas
of involvement (white arrows) in the thoracic and lumbar spinal
cord. E. Axial T2-weighted image through an involved area of the
thoracic spinal cord shows that the lesion (white arrows) is in the
central gray matter of the cord.
diagnosis (503). Therefore, the diagnosis may not be known at the time
of the initial neuroimaging study (488). Neurologic signs and symp-
toms include neuropsychiatric difficulties (most commonly depression;
also concentration or memory problems, or frank psychosis) in 40% to
48%, headache (22%–64%), seizures (usually generalized tonic-clonic
seizures, 20%), ischemic events (15%–28%), chorea (3%–28%), visual
loss (12%), peripheral neuropathy (5%), cranial neuropathy (8%),
vertigo (4%), and myelopathy (4%) (488,499,503). Neurologic events
commonly occur in SLE, potentially related to therapy, infection, com-
plications, or to functional problems related to the underlying disor-
der; the specific cause is, therefore, often difficult to pinpoint (502,504).
A variety of pathologic abnormalities have been identified in the brains
of patients with SLE, including cerebral atrophy, cerebral infarcts
due to emboli, vasculitis (often associated with the antiphospholipid
antibody syndrome (505,506) ), petechial hemorrhages, and areas of
demyelination; these are attributed to angiopathy, direct autoimmune
damage to brain, demyelination, and ischemia from thromboembo-
lism (507), all of which are believed to result from the action of cyto-
toxic antibodies that vary in their composition and antigenicity and,
thus, attack various vulnerable parts of the central nervous system
(501–504,506).
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
Imaging studies may show a variety of findings that vary with the
indication for imaging. In patients with neuropsychiatric disorders, CT
and MRI are usually negative or show large CSF spaces (488). In patients
with seizures, MRI/CT may show focal lesions (25%) or may be nor-
mal. The focal lesions are typically areas of low attenuation (CT) or T1
hypointensity and T2/FLAIR hyperintensity (MRI) in the white mat-
ter of the cerebrum, cerebellum, brainstem, or spinal cord (Figs. 3-44
and 3-45) (508). The basal ganglia may be involved; if so, angiogra-
phy should be performed to look for vasculitis (Fig. 3-44). Spinal cord
lesions may have moderate associated mass effect and edema (490).
The MR lesions are believed to represent either autoimmune cerebritis/
myelitis or parenchymal involvement secondary to small vessel vasculi-
tis. Depending on the underlying process, diffusion imaging may show
normal or reduced diffusivity. Some peripheral enhancement after
intravenous administration of paramagnetic contrast may be present
in the subacute phase. In adults, transmural angiitis may result in vas-
cular rupture and hemorrhage (509), but this has not been reported in
children. When lesions are in the cerebral hemispheres, affected areas
tend to involve subcortical white matter, with or without overlying cor-
tex (Fig. 3-45), and may revert to normal on subsequent scans. When
Barkovich_Chap03.indd 139
139
FIG. 3-44. Systemic lupus erythematosus vasculitis in
a 10-year-old girl. A. Axial T2-weighted image shows
abnormal hyperintensity in the caudate nuclei, anterior
lentiform nuclei, anterior limbs of the internal capsules,
and right posterior lentiform nucleus (white arrow).
These regions reverted to normal on subsequent scans.
B. Postcontrast T1-weighted image shows some promi-
nent curvilinear enhancement, presumed to be vessels.
C. Collapsed view from a 3D time of flight MRA of the
circle of Willis shows several areas of narrowing (white
arrows) of the M1 segments of the middle cerebral
arteries.
the lesions are paramedian in location, it is not clear whether they rep-
resent areas affected by SLE (vasculitis or cerebritis) or those that are
abnormal because of recent hypertension or seizure, both common
in SLE, with consequent cortical and subjacent white matter changes
(510,511) (these changes have, unfortunately, been given the name
“posterior reversible encephalopathy syndrome” (512) ). In general,
abnormalities secondary to seizures or hypertension are bilateral, sym-
metrical, paramedian, involve the cortex and subcortical white matter,
and are more prevalent in the posterior aspect of the brain (occipital
and parietal lobes more than frontal lobes) (510,513). Although theses
abnormalities are most often reversible, they can sometimes result in
permanent brain injury (510,514). It is important to perform diffu-
sion imaging in such cases; those areas with normal or increased diffu-
sion will completely reverse, while those areas with reduced diffusion
have suffered permanent injury and will atrophy (513). Other findings
in patients with SLE include infarcts, which are typically the result of
vasculitis, and may involve both superficial and deep gray matter. They
are typically asymmetric, which helps differentiate them from changes
that result from seizures or hypertension, and have reduced diffusion in
the acute phase. Vascular imaging may be helpful, showing angiopathy
5/6/2011 12:08:35 AM
 140 Pediatric Neuroimaging

FIG. 3-45. Multiple lesions

due to antiphospholipid anti-
body syndrome in a 14 years
old with systemic lupus ery-
thematosus. A. Axial FLAIR
image shows bilateral cerebel-
lar (white arrows) and temporal
lobe (white arrowheads) lesions
in a teenager who presented
with seizures. B. Coronal FLAIR
image shows that the cerebral
lesions (white arrowheads) are
subcortical in location.

(irregularity of arterial lumens), arterial occlusions, or venous occlu-
sions, as well as focal infarcts. Infarcted tissue will, obviously, not return
to a normal appearance. Proton spectroscopy has been shown to reveal
decreased NAA/Cr ratios in the basal ganglia of patients with major
symptoms, such as psychosis or seizures, as compared to those patients
with less severe signs and symptoms (515). The NAA/Cr ratios appeared
to correlate with the course of the disease in one study (516).
Osmotic Myelinolysis in Childhood
In adults, osmotic myelinolysis is seen primarily in the pons (central
pontine myelinolysis) and most commonly occurs among chronic alco-
holics in poor nutritional states. Both the poor nutritional condition
and an overly rapid correction of severe hyponatremic dehydration
seem to predispose them to the development of osmotic myelinolysis
in the central pontine region. Other patients with severe nutritional
disturbances and fluid/electrolyte imbalances are also at risk. The exact
cause and pathogenesis of this disorder have not been determined
(517,518); but current theory suggests a hyperosmotically induced
demyelination process resulting from rapid intracellular/extracellu-
lar to intravascular water shifts producing relative glial dehydration,
myelin degradation, and/or oligodendroglial apoptosis (519). In chil-
dren, central pontine myelinolysis has been reported to occur with
various disorders including fulminant hepatitis, liver transplantation,
diabetic ketoacidosis, chronic debilitation, treatment of hyperam-
monemia and craniopharyngioma, and malnutrition often associated
with severe fluid and electrolyte disturbances (520–525).
The imaging appearance of childhood myelinolysis is identical to
that in adults, with a focus of low attenuation (CT) or prolonged T1
and T2 relaxation times (MRI) in the central pons (Fig. 3-46A); the
corticospinal tracts are characteristically spared. Diffusion is reduced
in the affected area(s) (Fig. 3-46B) (526). Both the patient and the MR
scan may return to normal after slow treatment of nutritional and

FIG. 3-46. Central pontine myelinol-

ysis in a child with lymphoma.
A. Axial SE 2500/30 image shows T2
prolongation (arrow) in central pons.
B. Average diffusivity (Dav) image shows
reduced Dav, indicating acute cellular
injury (arrow).

Barkovich_Chap03.indd 140 5/6/2011 12:08:36 AM

 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
electrolyte abnormalities (525,527). It is important to remember that
osmotic myelinolysis can develop in other areas, including the basal
ganglia (528), thalami (529), cerebral cortex (usually at the cortical-
white matter junction) (519,530), and middle cerebellar peduncles
(531). (Relatively few disorders cause abnormalities of the middle cere-
bellar peduncles. In addition to Wallerian degeneration due to pontine
injury, it is seen in spinocerebellar ataxias types 2 and 3, Wilson disease,
and fragile X permutation (532,533) ).
Toxins
Several exogenous toxins can cause demyelination. Many of these
intoxications result in a spongiform leukoencephalopathy that initially
affects the peripheral white matter, including the subcortical U fibers.
Among the toxic substances that cause demyelination are triethyl tin,
hexachlorophene, cuprizone, actinomycin D, and isoniazid (160,534–
536). A similar pattern is described after ingestion of toxic heroin
(Fig. 3-47) (537–540). All of these disorders cause bilateral symmetric
white matter injury that involves the subcortical U fibers early in the
course of the clinical illness.
Lead Encephalopathy
Special mention must be made of lead encephalopathy. The typi-
cal clinical presentation of lead intoxication is abdominal cramping,
nausea, and vomiting. Neurologic signs and symptoms vary from
Barkovich_Chap03.indd 141
141
mild behavioral change to frank obtundation, with occasional ataxia,
aphasia, or psychological disturbance (534,541). The most common
imaging finding is edema (swelling and T2/FLAIR hyperintensity) in
the external and extreme capsules (Fig. 3-48) (542). Rarely, lead intoxi-
cation may lead to localized edema in the cerebellum causing hydro-
cephalus and presentation as a posterior fossa mass (541,543). CT and
MRI in these cases show localized cerebellar edema with mass effect
and mild enhancement after intravenous contrast infusion (541,543).
The appearance is identical to that of acute cerebellitis from viral ill-
nesses (see Chapter 11).
Solvent Abuse
Solvent abuse is a serious problem in some cultures, particularly in
adolescents and young adults. Toluene and other forms of organic
materials (trichloroethane, methylchloroform) are inhaled and rap-
idly absorbed into the blood stream, from where they can cross the
blood–brain barrier and involve the central nervous system. Patients
may present with acute encephalopathy or with chronic mental and
neurologic deterioration. Insomnia, forgetfulness, anosmia, and tin-
nitus are reported to be common (544). Neurologic exam reveals
cerebellar ataxia (50%), tremors of the extremities (35%), increased
deep tendon reflexes (25%), and rigidity (25%) (544). Pathologic stud-
ies of the brains of affected patients show neuronal and axonal loss
with associated demyelination: diffuse demyelination of the cerebral
FIG. 3-47. Acute leukoencephalopathy
from toxic heroin ingestion. A and B. Axial
T2-weighted images show abnormal hyper-
intensity in the pons (p), middle cerebellar
peduncles (m), and cerebral white matter
(w). Note that some of the subcortical white
matter is affected. C. Coronal FLAIR image
shows involvement of the corpus callosum
(white arrows) but sparing of the basal gan-
glia. D. Average diffusivity map shows mildly
reduced diffusivity in the deep cerebral white
matter. E. Proton MRS (TE = 26 ms) from
the cerebral white matter shows low NAA
due to neuronal injury, broad macromolecu-
lar peaks at 0.9 and 1.3 ppm from damage to
membranes and release of lipids, and a small
amount of lactate (arrows point to the dou-
blet at 1.3 ppm) due to impaired mitochon-
drial production of ATP.
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 142 Pediatric Neuroimaging
FIG. 3-48. Lead encephalopathy in a 9-year-old child. Axial T2-weighted
image shows hyperintense edema (black arrows) in the external and extreme
capsules.
and cerebellar white matter; degeneration and gliosis of ascending and
descending long fiber tracts, peripheral nerves, and axons of the corpus
callosum; and generalized cerebral and cerebellar atrophy (545,546).
MRI shows loss of gray-white discrimination, diffuse mild T2 pro-
longation of the cerebral and cerebellar white matter, often some T2
shortening of the putamina, and generalized atrophy of cerebrum and
cerebellum (540,545,546). In severe cases (associated with a longer
duration of abuse (544) ), T2 shortening may be seen in the thalami,
substantia nigra, and cerebral cortex (547).
Progressive Multifocal Leukoencephalitis
Progressive multifocal leukoencephalitis is a rare demyelinating disease
caused by a papovavirus; it is seen almost exclusively in immunocom-
promised patients. It causes a combination of isolated and confluent
areas of T2 prolongation, primarily in the white matter. Mass effect
and contrast enhancement are minimal, if present at all. This disease is
more fully discussed in Chapter 11.
Subacute Sclerosing Panencephalitis
Subacute sclerosing panencephalitis is a slow virus infection of the CNS
that develops secondary to measles infection. Imaging studies show a
nonspecific pattern of increased water in white matter with localized
cortical lesions in some cases. This disease is discussed more fully in
Chapter 11.
Metabolic Disorders Primarily Affecting
Gray Matter
A large number of conditions affecting the pediatric central nervous
system affect the gray matter, including ischemia, inflammation, infec-
tions, malformations, and injuries, in addition to inborn errors of
metabolism. Many metabolic gray matter disorders have nonspecific
imaging findings. In some disorders, such as some mucolipidoses,
Gaucher disease, and some forms of Niemann-Pick disease, the brain
appears normal. In others, the cerebral cortex may be thin; the cere-
bral white matter is often diminished in volume and has low attenua-
tion (CT) and prolonged T1 and T2 relaxation times (MRI) compared
Barkovich_Chap03.indd 142
to normal white matter. The T2 prolongation of white matter in gray
matter disease, however, is not as marked as in the leukodystrophies
(e.g., see Figs. 3-1 to 3-3), presumably because the white matter abnor-
mality results from Wallerian degeneration of the axons, rather than
from inflammation or destruction of oligodendrocytes or myelin. In
some instances, patchy, focal areas of white matter abnormalities may
also be present (in a primarily and dominantly gray matter disease);
the exact nature and pathogenesis of these findings are not yet fully
understood. In this section, gray matter disorders that have distinctive
abnormalities on neuroimaging studies are discussed.
Gray Matter Disorders Primarily Involving
the Deep Gray Cerebral Nuclei
Pantothenate kinase–Associated Neuropathy
(Neurodegeneration with Brain Iron Accumulation 1, Formerly
Hallervorden-Spatz Disease)
Pantothenate kinase–associated neuropathy (PKAN, also called neuro-
degeneration with brain iron accumulation 1 or NBIA1, OMIM 234200)
is a rare metabolic disorder that is characterized clinically by progressive
gait impairment, gradually increasing rigidity of all limbs, slowing of
voluntary movements, choreoathetotic or tremulous movement disor-
der, dysarthria, and mental deterioration (548,549). Optic atrophy or
retinitis pigmentosa may develop (549). Although the age of onset var-
ies considerably, most patients begin to show some neurological dete-
rioration during the last half of the first decade or first half of the second
decade of life (550); however, the age of onset can vary greatly (550). In
addition, all patients with PKAN do not have all of the manifestations of
the disorder, probably because more than one genetic disorder underlies
this disease. A number of families of diverse ethnic backgrounds have a
mutation on chromosome 20p12.3-p13 (551); this has been found to be
a novel pantothenate kinase gene (PANK2) (552), the protein product
of which localizes to mitochondria in animal models (553).
Two forms of PKAN have been defined (554). The classic form is
characterized by disease onset before the age of 10 years (mean 3.4 ±
3.0 years), manifest as extrapyramidal signs (dystonia, dysarthria, and
choreoathetosis, seen in >95%), pyramidal signs (spasticity, hyperre-
flexia, and extensor toe signs, seen in 25%), cognitive decline (29%),
and retinopathy (68%); most of these patients have mutations of
PANK2 (555). The atypical form is characterized by a slightly older
age of onset (13.7 ± 5.9 years), less common (73%), less severe, and
more slowly progressive extrapyramidal signs, and uncommon retin-
opathy (20%); pyramidal signs are about equally common (18%) as in
the classic form (555); these patients are less likely to have mutations
of PANK2 and are referred to as having Neurodegeneration with brain
iron accumulation (554).
The striking pathologic finding in affected patients is rust-brown
pigmentation of the globus pallidus and zona reticulata of the substan-
tial nigra. Iron is concentrated in these regions, where it is found in large
astrocytes, microglia, and neurons. Presumably as a result of the iron
deposition, one finds also symmetrical destruction of the globus pal-
lidus (particularly the internal segment) and substantia nigra (556).
Imaging studies reflect the underlying pathology. CT scans may
show low- or high-density foci in the globi pallidi. Although the cause of
this variability has not been proven pathologically, it is likely that the low
density lesions reflect tissue destruction, whereas the high-density foci
are a result of subsequent dystrophic calcification. MRI shows hypoin-
tensity in the globus pallidus on T2-weighted images (Fig. 3-49, more
pronounced hypointensity than is normally seen in the second decade,
see Chapter 2), resulting from iron deposition (557–559); this finding
may appear before clinical symptoms develop (560). The globus pallidus
hypointensity may not be apparent on low field strength scanners, even
if gradient-echo techniques are used; on higher field strength scanners
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 143

FIG. 3-49. Pantothenate kinase-associated neuropathy in a 14-year-old
with dystonia. Axial T2-weighted image shows the classic “eye of the tiger”
sign with T2 hyperintensity central to T2 hypointensity in the globi pallidi.
(3 T), the sign will appear on both T2-weighted spin echo and on FLAIR
images. Foci of T2 hyperintensity of variable size are typically present
within the area of T2 hypointensity (Fig. 3-49); these foci presumably
represent pallidal destruction and gliosis (558). This imaging sign, called
the “eye of the tiger sign” seems to be much more common in those cases
with PANK2 mutations (555) (but it is not always present (561,562) and
one report describes this characteristic sign disappearing during the
course of the disease (563) ). Patients without PANK2 mutations (i.e.,
those having neurodegeneration with brain iron accumulation (554) )
also have T2 hypointensity in the globi pallidi but are less likely to have
the central T2 hyperintensity (562). Although oculodigital dental dys-
plasia (564) has been shown to have similar globus pallidus changes to
those of PKAN, the associated white matter changes in that disorder and
the other obvious physical manifestations allow easy distinction of the
disorders. Therefore, the finding of T2 shortening in the globi pallidi during
the second decade should raise strong suspicion for the diagnosis of PKAN
rather than one of the many other disorders that affect the basal ganglia
in children (Tables 3-9 to 3-11). Diffusion imaging shows increased FA
and mean diffusivity in the globi pallidi and substantia nigra of affected
patients compared with age-matched controls (565).

TABLE 3-9 Childhood Diseases Involving the Deep Cerebral Nuclei

Acute Ethylmalonic acidemia L-2-hydroxyglutaric aciduria
Hypoxia Propionic academia Maple syrup urine disease
Hypoglycemia Succinic semialdehyde dehydrogenase Wilson disease
Toxins (carbon monoxide, cyanide) deficiency 3-Hydroxyisobutyric aciduria
Hemolytic-uremic syndrome Guanidinoacetate methyltransferase Hallervorden-Spatz disease
Osmotic myelinolysis deficiency Dentatorubral and pallidoluysian atrophy
Encephalitis Biotin dependent encephalopathy Degenerative Diseases
Parainfectious Encephalomyelitis Isovaleric acidemia Juvenile Huntington disease
Tegretol Toxicity Molybdenum co-factor deficiency Sequelae of acute insults
Chronic Mitochondrial ATP synthetase deficiency Basal ganglia calcification syndromes
Inborn errors of metabolism 3-Methylglutaconic aciduria (i.e., Cockayne syndrome, Fried syndrome)
Mitochondrial disorders Malonic acidemia Other Diseases
Canavan disease Alpha ketoglutaric aciduria Neurofibromatosis type 1
Glutaric aciduria types I and II 3-Ketothiolase deficiency Chronic liver disease of any cause
Methylmalonic acidemia Biotinidase deficiencies Aicardi-Goutières syndrome

TABLE 3-10 Disorders Resulting in Deep Cerebral Nuclear Calcification

Endocrine Organic acidurias Measles
Hypoparathyroidism Congenital or Developmental Chicken pox
Pseudohypoparathyroidism Familial idiopathic symmetric basal Pertussis
Pseudopseudohypoparathyroidism ganglia calcification Coxsackie B virus
Hyperparathyroidism Hastings-James syndrome Cysticercosis
Hypothyroidism Cockayne syndrome Systemic lupus erythematosus
Metabolic Lipoid proteinosis (hyalinosis cutis [568]) Acquired immunodeficiency syndrome
Mitochondrial disorders Neurofibromatosis Toxic
Aicardi-Goutières syndrome Tuberous sclerosis Hypoxia
Fahr disease (familial cerebrovascular Oculocraniosomatic disease Cardiovascular event
ferrocalcinosis) Methemoglobinopathy Carbon monoxide intoxication
Pantothenate kinase associated neuropathy Down syndrome Lead intoxication
Carbonic anhydrase deficiency type II Inflammatory Radiation therapy
Wernicke encephalopathy Toxoplasmosis Methotrexate therapy
Griscelli disease (566) Congenital rubella Nephrotic syndrome
Fried syndrome (567) Cytomegalovirus

Barkovich_Chap03.indd 143 5/6/2011 12:08:39 AM

 144 Pediatric Neuroimaging

TABLE 3-11 Anatomic Distribution of Some Diseases Affecting Basal Ganglia

Diagnosis Globus Pallidus Caudate Putamen White Matter
Acute Disorders
Hypoxia/ischemia-neonate + − + ±
Hypoxia/ischemia-older child + ++ ++ +
Hypoglycemia-neonate ± − − ++
Hypoglycemia-older child + + + +
Cyanide intoxication ++ + + −
Carbon monoxide intoxication ++ + + +
Hemolytic-uremic syndrome + + +
Osmotic myelinolysis + + + ++ pons
Viral Encephalitis + + + +
Chronic Disorders (with Possible Acute
Presentation During Metabolic Decompensation)
Leigh syndrome + + ++ +
Canavan disease ++ − − ++
GM2 Gangliosidoses − ++ − +
Juvenile Huntington Dz. + ++ ++ +
Wilson disease ++ + ++ +
Fried syndrome + ++ +
Glutaric aciduria type I − ++ ++ ++
Glutaric aciduria type II − + + +
Ethylmalonic encephalopathy + ++ ++ −
Molybdenum co-factor def. − ++ ++ +
Methylmalonic acidemia + − − +
Pantothenate kinase associated
neurodegeneration (Hallervorden-Spatz disease) ++ − − −
Propionic acidemia − ++ ++ +
Succinic semialdehyde dehydrogenase deficiency ++ − − −
Guanidinoacetate methyltransferase deficiency ++ − − −
Isovaleric acidemia ++ − − −
L-2-hydroxyglutaric aciduria ++ + + ++
Chronic liver disease ++ − − −
Kearns-Sayre syndrome ++ − − ++
Pyruvate dehydrogenase (E2) deficiency ++ − − −
3-ketothiolase deficiency − − ++ +
Alpha ketoglutaric aciduria + + ++ −
3-methylglutaconic aciduria (type 1 and 4) ++ ++ ++ +
HMG coenzyme A lyase deficiency − + + ++
Aicardi-Goutieres syndrome + + ++ ++
3-Hydroxyisobutyric aciduria + ++ ++ −
Dentatorubropallidoluysian atrophy ± − − +
++, characteristic lesion pattern element; +, occasional lesion pattern element; −, lack of involvement.

Barkovich_Chap03.indd 144 5/6/2011 12:08:39 AM

 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
Juvenile Huntington Disease
Huntington disease (OMIM 143100) is a chronic progressive degenera-
tive disease characterized by choreiform movements, mental deteriora-
tion, and an autosomal dominant transmission. The genetic defect is an
expanded, unstable segment of DNA with a repeating CAG segment in
the first exon of the HTT gene on chromosome 4p16.3 (569). The CAG
stretch on the gene is unstable when transmitted to the next generation,
with a propensity toward further expansion, particularly during sper-
matogenesis (570). Larger segments of CAG repeats are associated with
earlier onset; juvenile Huntington disease is usually associated with 80
to 100 CAG repeats (571). Less than 6% of patients present prior to
the age of 14 years (572). The clinical presentation in children varies
with the age of presentation. Children presenting before the age of 10
years most frequently manifest cognitive decline and seizures, whereas
those presenting at age 10 years or older most commonly present with
oropharyngeal dysfunction (573). Chorea was not a presenting sign
but developed later in the course of the disease and, with dystonia, was
more prevalent in the early age at onset group, whereas rigidity and
bradykinesia were more prevalent in the older age at onset group (573).
Patients in both groups developed gait, cognitive, and behavioral dis-
orders at some point during the course of the disease. Furthermore, a
slow and steady decline in IQ was observed on serial neuropsychologic
testing in patients from both groups (573). Presentation with progres-
sive myoclonus epilepsy has been described (574).
Imaging studies are normal early in the course of the disease. As
the disease progresses, the striatum atrophies and develops T2 hyperin-
tensity; atrophy of the caudate heads results in a characteristic enlarge-
ment of the frontal horns of the lateral ventricles, which become
convex laterally (Fig. 3-50) (572). Atrophy in the putamen, seen bet-
ter by MRI than by CT, is equal to or more severe that in the caudate
(573,575). Cortical atrophy is most prominent in the frontal lobes. As
in many other metabolic diseases, F-18 fluorodeoxyglucose PET scan-
ning is sensitive to decreased glucose uptake in the striatum before CT
or MR scans become positive (576). Comparisons of the sensitivity of
PET to that of MRI have not been published. A single report of proton
MRS found reduced NAA and increased myo-I on short echo (35 ms)
spectra in a voxel including the caudate head and anterior putamen;
the patient already had substantial atrophy of the corpus striatum at
the time the spectrum was obtained (577).
Barkovich_Chap03.indd 145
145
FIG. 3-50. Juvenile Huntington disease in a
7-year-old. Axial T2-weighted (A) and FLAIR
(B) images show small, hyperintense caudate
heads and putamina. Hyperintensity of the
caudates is more easily seen on the FLAIR
image. Early in the course of the disease, the
hyperintensity might be the only abnormality.
Isovaleric Acidemia
Isovaleric acidemia (also known as isovaleric acid CoA dehydrogenase
deficiency, OMIM 243500) is an autosomal recessive disorder caused by
mutation of the isovaleryl CoA dehydrogenase gene (IVD), located at
chromosome 15q14-15 (578,579). Two clinical forms, possibly allelic,
are recognized: the acute neonatal form, leading to massive metabolic
acidosis characterized by vomiting, dehydration, and restlessness from
the first days of life and rapid death, and a chronic form in which peri-
odic attacks of severe ketoacidosis (typically provoked by infection)
occur with asymptomatic intervening periods (580). The abnormali-
ties result from an accumulation of isovaleric acid, which is toxic to the
central nervous system.
Limited reports suggest that neuroimaging in the chronic form
reveals low attenuation on CT scans with both T1 hypointensity and
T2/FLAIR hyperintensity on MRI in the bilateral globi pallidi (581).
Succinic Semialdehyde Dehydrogenase Deficiency
Also known as 4-hydroxybutyric aciduria, succinate semialdehyde
dehydrogenase deficiency (OMIM 271980) is a rare autosomal reces-
sive disorder in the degradation pathway of gamma-amino butyric
acid (GABA) (582); the causative gene ALDH5A1 has been mapped
to chromosome 6p22 (583,584). The result is an increase in GABA
in the CSF and of 4-hydroxybutyric acid in the urine. Affected
patients manifest a slowly progressive encephalopathy character-
ized by delayed motor function, delayed to absent language develop-
ment, and mental retardation. These are variably accompanied by
ataxia, seizures, hypotonia, behavioral problems, autistic features,
hallucinations, and choreoathetosis (582,585,586). Rarely, presen-
tation may be in infancy with hypotonia, psychomotor delay, and
strabismus (587). EEG shows generalized and focal epileptiform dis-
charges, photosensitivity, and background slowing (586). MRI char-
acteristically shows T2 prolongation in the globi pallidi (Fig. 3-51A)
and, sometimes, dentate nuclei of the cerebellum (585,588). With
disease progression, diffuse cerebral cortical, basal ganglia, and thal-
amic atrophy ensues (589). MRS shows normal choline, creatine,
and NAA (Fig. 3-51B). It will be interesting to see whether MRS
sequences looking at GABA, glutamate, and glutamine show any
abnormalities.
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 146 Pediatric Neuroimaging
FIG. 3-51. Succinate semialdehyde dehydrogenase deficiency in a 2-year-old with language delay. Axial T2-weighted image (A) shows bilateral T2
hyperintensity (white arrows) of the globi pallidi. Proton MR spectrum (TE = 288 ms) of the basal ganglia (B) is normal.
Creatine Deficiency Syndromes
MR spectroscopy has allowed the discovery of several syndromes in
which the concentration of creatine is reduced within the brain. The
first of these syndromes to be described was guanidinoacetate methyl-
transferase (GAMT) deficiency (OMIM 612736), an autosomal reces-
sive inborn error of creatine synthesis (590) caused by mutations of
the GAMT gene at chromosome 19p13.3. The other creatine deficiency
syndrome is an autosomal recessive disorder caused by a deficiency of
L-arginine:glycine amidinotransferase (AGAT, OMIM 612718), another
enzyme important in creatine biosynthesis (591), caused by mutation
of the GATM gene at chromosome 15q15.3. Creatine and creatine
phosphate are essential for the storage and transmission of phosphate-
bound energy in muscle and brain. They are catabolized to creatinine.
For maintenance of the body pool of creatine, the daily urinary loss
of creatinine must be balanced by endogenous synthesis and dietary
intake of creatine (592). GAMT and AGAT deficiencies reduce creatine
synthesis. In both disorders, the severe depletion of creatine/phospho-
creatine causes developmental delay, followed by regression, muscle
hypotonia, extrapyramidal movement abnormalities, and intractable
epilepsy (590–595). GAMT deficiency is also characterized by severe
expressive language delay (596) and hyperactivity (593). These symp-
toms can be partially or completely reversed by dietary creatine supple-
mentation (597,598), so it is crucial to make the diagnosis in affected
patients. Indeed, we have seen a patient with AGAT deficiency improve
remarkably, initially manifesting moderate to severe delay but improv-
ing to well above the mean 18 months after beginning creatine supple-
mentation. Supplementation may work better in AGAT than in GAMT
deficiency (597).
The combination of MRI and, particularly, proton MR spectros-
copy can be used to strongly suggest this diagnosis. MRS shows a mark-
edly reduced or completely absent creatine peak; this is most easily
seen on long TE spectra (Fig. 3-52). In addition, short TE sequences
show a broad guanidinoacetate peak at 3.78 parts per million in chil-
dren with GAMT deficiencies. The creatine peak will slowly reappear
and the other peaks disappear after creatine supplementation is insti-
tuted. MRI is typically normal in patients with AGAT deficiency, but
in many cases of GAMT deficiency shows bilateral T2 prolongation
Barkovich_Chap03.indd 146
with reduced diffusivity of the globi pallidi (599) and mild myelina-
tion delay or T2/FLAIR hyperintensity of the cerebral white matter
(Fig. 3-52A) (590,592–594,598).
The X-linked mental retardation syndrome (OMIM 300352) is
another creatine deficiency syndrome in which MRS shows absence of
or severe reduction of the creatine peak in developmentally impaired
children (600,601). It is caused by a defect in formation of a creatine
transporter protein due to mutations of the SLC6A8 gene at chro-
mosome Xq28 (601). Affected children present with mild to moder-
ate global developmental delay and severe developmental language
impairment (602); hypotonia and seizures may be present (603).
Mutations of SLC6A8 have been found in up to 1% of patients with
mental retardation (604) and those with autistic spectrum disorders
(605). This disorder does not respond to creatine supplementation. It
can be separated from GAMT deficiency and AGAT deficiency by the
elevated plasma and urine creatine levels and normal guanidinoacetate
levels (601).
Wernicke Encephalopathy
Wernicke encephalopathy (OMIM 277730, also called Gayet-Wernicke
encephalopathy and alcohol-induced encephalopathy) is a degenera-
tive condition caused by a chronic deficiency of thiamine (vitamin B1).
Although a classical clinical triad of oculomotor abnormalities, men-
tal status changes, and ataxia has been described, few patients present
with the full triad. In pediatric patients, the most common presenta-
tion, seen in more than 80%, is one of altered mental status (confusion,
somnolence, stupor, or coma) (606). Ocular signs (ophthalmoplegia or
nystagmus) are present in about two thirds of patients at presentation,
but ataxia is uncommon (~20%) (606). Affected patients are typically
malnourished, most commonly from malignancy, gastrointestinal dis-
ease, or food allergy. A recent history of carbohydrate loading or par-
enteral nutrition is often obtained (606).
Pathologic examination shows symmetric hemorrhage secondary
to proliferation and dilation of capillaries in the gray matter around
the third ventricle, sylvian aqueduct, and fourth ventricle. In adults, the
most common MRI findings are T2/FLAIR hyperintensity and atrophy
of the medial thalami and mamillary bodies, with the periaqueductal
5/6/2011 12:08:39 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
area involved in about two thirds; about half show enhancement after
administration of intravenous contrast (540,607–609). Increased dif-
fusivity is seen in the affected areas (610). The few reported cases of
pediatric Wernicke encephalopathy show involvement (low attenuation
on CT, T2/FLAIR hyperintensity on MRI) of the medial thalami (most
common finding, Fig. 3-53), putamina, caudate nuclei, and frontotem-
poral cerebral cortex (606,608,611). Rapid atrophy may ensue (606).
Extrapontine Myelinolysis
The term extrapontine myelinolysis refers to osmotic myelinolysis in
regions other than the pons. Patients become symptomatic after rapid
shifts in fluids, usually the result of overly rapid treatment of hypona-
tremia; the causes are almost certainly similar to those of central
Barkovich_Chap03.indd 147
147
FIG. 3-52. Guanidinoacetate methyltransferase deficiency in an
8-month-old child. A. Axial T2-weighted image shows bilateral T2
prolongation (white arrows) of the globi pallidi. B. Single voxel
proton MRS (TE = 288 ms) of the basal ganglia shows normal
choline (Cho) and N-acetylaspartate (NAA) peaks but absence of
the creatine peak. C. Single voxel proton MRS (TE = 26 ms) of the
basal ganglia also shows absence of the creatine peak. The find-
ing is more subtle on the short echo time scan because of the less
stable baseline and the increased number of peaks. An abnormal
broad guanidinoacetate peak is present at 3.78 ppm.
pontine myelinolysis (612). Affected children may manifest a variety
of neurologic signs and symptoms, including akinesis, ataxia, catato-
nia, choreoathetosis, rigidity, dysarthria, dystonia, emotional lability,
mutism, myoclonus, myokymia, parkinsonism, and tremor (612). The
imaging abnormality consists of T2 prolongation in the claustrum and
putamen in children (Fig. 3-54), with the hippocampus sometimes
being involved (613); diffusion is reduced in the affected area(s) (526).
Extrapontine myelinolysis may occur with or without associated cen-
tral pontine myelinolysis (612).
Hemolytic-Uremic Syndrome
The hemolytic-uremic syndrome (HUS) is a multisystemic dis-
order, characterized by renal failure, thrombocytopenia, and a
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 148 Pediatric Neuroimaging
FIG. 3-53. Pediatric Wernicke encephalopathy in an anorexic 12-year-old.
Axial T2-weighted image shows abnormal T2 hyperintensity (white arrows)
of the medial thalami.
microangiopathic hemolytic anemia that follow a prodrome of acute
afebrile gastroenteritis, often with bloody stools. The central nervous
system is affected in 20% to 50% of patients; altered mental status,
personality changes, seizures, long tract signs, and loss of vision are
the most common manifestations (614,615). HUS is thought to be a
FIG. 3-54. Extrapontine myelinolysis in a 3-year-old girl. Axial
T2-weighted image shows T2 prolongation in bilateral claustra and lateral
putamina. These areas reverted to normal after slow correction of electro-
lyte abnormalities.
Barkovich_Chap03.indd 148
consequence of infection by Gram-negative organisms (most com-
monly verotoxin-producing E. coli). Histological studies have shown
that verotoxin produced by the bacteria binds to the endothelium of
small vessels that leads to thrombosis of vessels in affected organs
(616,617). The mutation of several genes that regulate the comple-
ment alternative pathway causes a variant of the disease called atypi-
cal hemolytic-uremic syndrome (OMIM 235400) (618), in which the
prodrome of enterocolitis and diarrhea is absent. Young children and
adolescents are principally affected; most patients are less than 5 years
old. Pathologic studies have found edema, hemorrhage, and isch-
emic injury in the basal ganglia, thalami, hippocampi, and cerebral
cortex.
On imaging studies, the deep cerebral nuclei are most commonly
affected, but the cerebral cortex is involved in severe cases. CT shows
abnormal attenuation (low or high) in the basal ganglia; cortical
hypointensity may be present. FLAIR and T2-weighted MR images
show hyperintensity in the affected areas of the deep gray cerebral
nuclei, particularly thalami, putamina, brainstem, cerebellar vermis,
and cerebral cortex (Fig. 3-55) (619,620). The adjacent white matter,
particularly the internal and external capsules in the case of putami-
nal involvement and the subcortical white matter in cases of cortical
involvement, may be involved (Fig. 3-55B) (617,620,621). T1-weighted
MR images may show hyperintensity in the basal ganglia (Fig. 3-55),
resulting from coagulative necrosis secondary to microthrombosis
without hemorrhage or calcification (617). These areas of T1 hyperin-
tensity may persist on follow-up imaging (Fig. 3-55E) (620) and may
continue to enhance for many weeks (Fig. 3-55F). When the cerebral
cortex is involved, similar signal characteristics are seen (617). Dif-
fusion images show reduced diffusivity in affected areas in the acute
phase and increased diffusivity in the subacute and chronic stages of
the disorder (Fig. 3-55C) (620).
Sydenham Chorea
Sydenham chorea, also called chorea minor, St. Vitus dance, or rheu-
matic encephalitis, is a presumed autoimmune phenomenon that results
from streptococcal infections. Most common in children between age
of 7 and 12 years, it may be isolated (20%–30%) or be associated with
other manifestations of rheumatic fever (carditis, migratory polyar-
thritis, subcutaneous nodules) (622,623). Affected patients develop a
hypotonic, hyperkinetic syndrome that is characterized clinically by
involuntary and uncoordinated movements, muscular weakness, fre-
quent falls, dysarthria, difficulty in concentrating and writing, slurred
speech, and emotional lability. In most patients, the symptoms resolve
within 2 years, but recurrences may occur. Psychiatric problems, such
as poor attention span (ADHD), aggressive behavior, obsessive-com-
pulsive disorder, anxiety, and depression may develop, as well (623).
Neuropathological studies have revealed degeneration of neurons and
alteration of blood vessels in the cerebral cortex, basal ganglia, and
cerebellum (624), as well as antibodies reactive against neurons of the
caudate nucleus (623).
Imaging findings may correlate with outcome. The basal ganglia
are by far the region in which abnormalities are most commonly rec-
ognized, in particular the caudate nuclei, putamina, and cerebral white
matter. Localized low attenuation is seen on CT, while T2 prolongation
is seen on MRI (625–627). These changes are rarely permanent; they
generally resolve within weeks or months (627). When MR changes are
permanent, they seem to be associated with prolonged clinical course
of disease and recurrent episodes of neurological impairment (625).
Reduced volume of the basal ganglia can be detected on volumetric
studies, even in patients with apparently normal MRI studies (628).
Proton MR spectroscopy shows elevated choline/creatine and reduced
NAA/creatine (629).
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 149

FIG. 3-55. Hemolytic-uremic syndrome, early (A–C) and late (D–F) subacute phases. A and B. Axial FLAIR image shows abnormal hyperintensity in the dorsal
brain stem (white arrowheads), cerebellar vermis (white arrow), external/extreme capsules (black arrowheads), internal capsules (black arrows) and globi pallidi (g).
C. Axial diffusivity (Dav) maps shows increased Dav in the external/extreme capsules (black arrows) and the internal capsules (black arrowheads). D. Axial FLAIR
image 2 weeks later shows residual hyperintensity (white arrows) in the putamina. E and F. Axial pre- (E) and postcontrast (F) images show persistent T1 hyperin-
tensity (white arrows) in the posterior putamina and globi pallidi. Contrast enhancement in (F) shows that the blood–brain barrier injury has not fully healed.

Chronic Liver Disease
As in adults, chronic liver disease causes T1 shortening in the globi
pallidi, cerebral peduncles, superior cerebellar peduncles, and pituitary
gland. This appears to result from just about any cause of hepatic fail-
ure including Crigler-Najjar disease type 2, congenital hepatic fibro-
sis, viral hepatitis, sclerosing cholangitis, Byler disease, biliary atresia,
Alagille syndrome, Wilson disease, or copper toxicosis (630).
Gray Matter Disorders Primarily
Involving Cortex
Neuronal Ceroid Lipofuscinosis
The neuronal ceroid lipofuscinoses (NCL) are among the most com-
mon progressive encephalopathies of childhood; they occur all over the
world with an incidence of about 1 in 25,000 live births. Ten main types
have been identified (Table 3-12): infantile (Santavuori-Haltia disease,
CLN1), late infantile (a genetically heterogeneous group that includes
classical Jansky-Bielschowsky (CLN2), variant (CLN6), Finnish vari-
ant (CLN5), and Turkish variant (CLN7) forms), juvenile (Batten or
Spielmeyer-Vogt disease, CLN3), early juvenile (CLN9), adult domi-
nant (Kufs disease, CLN4), adult recessive, progressive epilepsy with
mental retardation (northern epilepsy syndrome, CLN8), and cathep-
sin D deficient (CLN10) types (631,632).
Clearly, the different types of NCL represent different disease enti-
ties; they are grouped together because they have similar pathologic
findings and similar clinical presentations. In addition, studies with
animal models suggest that these disorders are due to mutations of
membrane proteins, and that at least some of the affected proteins are
involved in synaptic vesicle function (641).

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 150 Pediatric Neuroimaging
TABLE 3-12 Classification of Neuronal Ceroid Lipofuscinosis
Age at Onset Designation
Congenital or later CLN10
Infantile or later CLN1 (Classic)
Late infantile or later CLN2 (Classic)
CLN5 (Finnish)
CLN6 (variant)
CLN7 (Turkish)
CLN8
Juvenile CLN3 (Classic)
CLN9
Adult CLN4 (Kufs)
PPT1, palmitoylprotein thioesterase 1; TPP1, tripeptidylpeptidase 1
Clinical presentation depends upon the type of NCL and the age
of presentation (642,643). Infants with the congenital form are charac-
terized by primary microcephaly, neonatal (or prenatal) epilepsy, and
death in early infancy (644). Patients with infantile forms typically are
brought to attention because of deceleration of head growth and mus-
cular hypotonia after the age of 6 months. Ataxia and motor clumsiness
develop together with irritability, sleep disturbance, and visual failure
leading to a rapid developmental deterioration during the second year
of life. In late infantile forms, the first symptoms begin around the
third year of life, typically an unexpected delay of psychomotor devel-
opment or epilepsy of sudden onset. Seizures are generalized tonic-
clonic or partial, frequently of a severe myoclonic type; they may soon
become resistant to drug treatment. The first symptom of patients with
juvenile forms is usually failure of vision, followed after several years by
progressive dementia, seizures, and progressive impairment of speech
and motor function (645,646). Definitive diagnosis is made by genetic
testing or by electron microscopic analysis of lipopigments from the
skin, which shows characteristic ultrastructral characteristics (646).
For neonates with microcephaly and epilepsy, testing for deficiency of
cathepsin D may be an economical approach to diagnosis. Similarly, in
young children with unexplained epilepsy and acute cessation of devel-
opment, analysis for PPT1 and TPP1 activity (see Table 3-12) has been
recommended (643).
Findings on imaging studies (Figs. 3-56 and 3-57) are nonspecific;
therefore, imaging is best used to rule malformations, infection, or other
causes of encephalopathy. In the infantile form, the major findings are
variable cerebral and cerebellar atrophy associated with T2 hyperin-
tense rims around the ventricles (Fig. 3-56) and T2 hypointensity in
the thalami and globi pallidi (80,647–650). The T2 changes appear to
correlate with loss of myelin and gliosis of unknown origin (651); thal-
amic atrophy develops, suggesting that the thalamic T2 changes may
be primary, rather than secondary. Cortical hypoperfusion is shown by
SPECT (650). Atrophy of both cortex and deep structures appears to
develop more rapidly in the infantile form (Fig. 3-56) than in the late
infantile form and earlier in the late infantile form than in the juvenile
form (647,652). In the late infantile and progressive epilepsy with men-
tal retardation forms, cerebellar atrophy is an early finding (Fig. 3-57;
indeed, these patients often present with motor delay secondary to cer-
ebellar atrophy (632,653,654) ), whereas in the other forms, cerebellar
Barkovich_Chap03.indd 150
Chromosome Location Gene Product
11p15 (633) Cathepsin D
1p32 (634) PPT1
11p15.5 (635) TPP1
13q22 (636) partially soluble protein
15q21 (637) Membrane protein
4q28 (638) Membrane protein
8p23 (639) Membrane protein
16p12 (640) Membrane protein
unknown unknown
unknown unknown
and cerebral atrophy seems to progress at similar rates. In the juvenile
form, MRI is typically normal before the age of 10 years and, therefore,
is not useful for diagnosis. Variable atrophy and T2 hypointensity of
the thalami may be seen after the age of 14 years (647,651).
Proton MRS in the infantile form of the disease shows a complete
loss of the NAA peak, marked reduction of creatine and choline, and
elevation of myo-I and lactate in gray and white matter (650,655). In
the late infantile form, reduced NAA has been noted in gray and white
matter; myo-I, creatine, and choline are elevated in white matter (Fig.
3-57D) (653,655). On short TE spectra, the level of myo-I elevation is
reportedly concordant with the severity of disease (653). Lactate eleva-
tion is reportedly seen in some patients (655). In juvenile NCL, spectra
are reportedly normal (655). However, the patients reported thus far
were at different stages of their disease at the time their spectra were
performed. Thus, the MRS differences may have reflected differences in
the stage of the disease (amount of brain destruction) at the time of the
spectra more than differences in the diseases themselves.
PET and SPECT may be useful in establishing diagnosis in NCL. 18
FDG PET studies show severe reduction of metabolism in all the corti-
cal and subcortical structures. Regional analysis shows marked bilat-
eral hypometabolism, particularly in calcarine, lateral occipital, and
temporal cortices and in thalami (656). In infantile NCL, SPECT using
99m-Tc HMPAO showed bilateral anterior frontal, posterior tem-
poroparietal, and occipital hypoperfusion. Initially, hypoperfusion was
localized and symmetric, whereas atrophy on MRI was more general-
ized. Reduction in cerebellar perfusion and onset of cerebellar atrophy
occurred later. Perfusion of deep gray matter nuclei is well preserved
up to terminal stage in spite of apparent atrophy seen on MRI (657).
SPECT in juvenile NCL shows diffuse hypoperfusion, most severe in
the temporal lobes, and less so in the parietal, occipital, and cerebellar
regions. Interesting, epilepsy does not correlate well with involvement
of any region by SPECT (658).
Aspartylglucosaminuria
Aspartylglucosaminuria (OMIM 208400) is a hereditary lysosomal
storage disorder caused by defective activity of the enzyme aspartyl gly-
cosiminidase in various body tissues and fluids (659). The AGU gene
on chromosome 4q32-33 has been cloned and several mutations caus-
ing aspartylglucosaminuria have been identified (660). Characteristic
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 151

FIG. 3-56. Infantile neuronal ceroid lipofuscinosis; sequential imaging studies showing progressive atrophy. A. Sagittal T1-weighted image at age 8 months
shows slightly thin corpus callosum but is otherwise normal. B. Axial FLAIR image shows mild enlargement of the frontal horns. C and D. Follow-up sagittal
T1-weighted and axial FLAIR images 1 month later shows larger cerebellar vermian fissures and thinning of the corpus callosum (C) with enlarging ventricles
and cortical sulci (D), indicating interval volume loss. Rims of high signal have developed around the lateral ventricles. E and F. Six months later, the sagittal
T1-weighted image (E) shows marked thinning of the corpus callosum with volume loss of the brain stem and cerebellar vermis, while the axial FLAIR image
(F) shows marked enlargement of ventricles and sulci. (This case courtesy Dr. Lara Brandao, Rio de Janeiro, Brazil.)

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 152 Pediatric Neuroimaging

FIG. 3-57. Late infantile neuronal ceroid lipofuscinosis, advanced disease. A. Sagittal T1-weighted image shows thinning of the corpus callosum and mod-
erate to severe cerebellar atrophy. B. Axial T2-weighted image shows large cerebral ventricles and sulci and slight diffuse hyperintensity of the cerebral white
matter. C. Coronal T1-weighted reformation from volumetric data set shows marked prominence of CSF spaces and profound cerebellar atrophy. D. Single
voxel proton MR spectroscopy (TE = 25 ms) of the frontal white matter shows a small NAA peak and an abnormally large myo-inositol peak (arrow).

neurological manifestations are mildly dysmorphic facial features,
slowly progressive mental retardation, delayed speech, hyperkine-
sia, motor clumsiness, and slight truncal ataxia (660–662). A mental
decline typically begins during the second decade of life, and death
generally occurs during the fourth decade.
MRI studies of the brain show bilateral T2 hypointensity and T1
hyperintensity in the posterior thalami (pulvinar region) (663) and
poor differentiation between cortex and underlying white matter that
appears to result from increased signal intensity in the subcortical white
matter on T2-weighted images (661). It seems that this white matter
abnormality may be reversed by bone marrow transplant (664). As the
patients mature, cortical–white matter differentiation improves, but
cortical atrophy develops, manifested as shrunken gyri and enlarged
sulci (661).
Anti–N-Methyl-d-Aspartate Receptor (NMDAR) Encephalitis in
Children and Adolescents
Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis is a
recently described disorder with a well-defined set of clinical features
(19,665). Initially described in young women with teratomas of the

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 153

FIG. 3-58. N-methyl-D-aspartate receptor (NMDAR) encephalitis. A. Coronal

FLAIR image shows subtle hyperintensity (white arrows) of the right frontal cortex,
insula, and hippocampus when compared to the left hemisphere. B. Image from
pelvic ultrasound shows a hypoechogenic mass (white arrows) with a solid central
component (white arrowhead). C. Coronal postcontrast CT reformation shows the
low attenuation right pelvic mass (black arrows) with central calcification (white
arrowhead). (These images courtesy Dr. Ken Martin, Oakland.)

ovary who developed changes of mood, behavior, and personality,
resembling acute psychosis, it was soon found that the disorder also
develops in girls and women without teratomas, as well as in children
and men. This disorder is now recognized as a surprisingly common
cause of a syndrome of neuropsychiatric symptoms (agitation, para-
noia, disinhibition, focal seizures, speech dysfunction), movement
abnormalities (orofacial dyskinesias, dystonia, choreoathetoid, rigid-
ity), and autonomic dysfunction (hypertension, tachycardia, hyper-
tension, hyperthermia, sleep dysfunction, dilated pupils) in children
(19,666). Most affected patients are initially diagnosed as having viral
meningitis. The diagnosis is made by CSF analysis and detection of the
NR1 subunit of the NMDAR. Current recommendations are screening
of the abdomen and pelvis with ultrasound and MRI to look for a tera-
toma for at least 2 years (19). Treatment is by removal of the teratoma
(if present) or immunotherapy (665,667).
Neuroimaging may be normal or may show subtle T2/FLAIR
hyperintensity in the hippocampi, cerebral cortex, or cerebellum (Fig.
3-58); these areas may show reduced diffusivity if diffusion-weighted
imaging is performed early in the course of the disease. Enhancement
of the leptomeninges or multifocal parenchymal enhancement may
be detected after intravenous injection of paramagnetic contrast,
depending upon the stage of the disease at the time of imaging (19).
Prolonged disease without therapy results in atrophy. Results of pro-
ton MR spectroscopy have not been reported. If a pelvic teratoma is
present, it will usually appear as a cystic and solid mass with calcifica-
tion (Fig. 3-58B and C).
Infantile Neuroaxonal Dystrophy
Patients with the infantile form of neuroaxonal dystrophy (INAD,
OMIM 256600, also called Seitelberger disease) usually present during

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 154 Pediatric Neuroimaging
FIG. 3-59. Infantile neuroaxonal dystrophy. A. Sagittal T1-weighted image shows moderate cerebellar cortical atrophy, with shrunken folia and enlarged
fissures. B. Coronal T2-weighted image shows hyperintensity of the shrunken cerebellar cortex and enlarged cerebellar fissures (white arrows). (These
images courtesy Dr. Susan Blaser, Toronto.)
the end of the first year or the second year of life; the disease progresses
throughout childhood with death ensuing late in the first decade or
early in the second decade (668). Most cases of the disorder appear to
be caused by mutations of the PLA2G6 gene at chromosome 22q13.1
that encodes a calcium-independent phospholipase A2 enzyme that
catalyzes the hydrolysis of glycerophospholipids (669). Affected
patients develop regression of cognition and motor skills, followed
by nystagmus and progressive deterioration of posture, gait, speech
(if developed), and visual acuity; nystagmus and strabismus are com-
mon (668,670). About 30% present following an intercurrent illness
(668). Physical exam reveals axial hypotonia, four limb spasticity and
bulbar signs. Patients eventually develop ataxia, dystonia, optic atrophy
and blindness, muscular atrophy, severe dementia, and complete lack
of motor function. Epilepsy develops in some patients (668,670,671).
An atypical form of neuroaxonal dystrophy, also caused by mutations
of PLA2G6, has been described with later age of onset (average 4.4
years) and slower progression; details of this form of the disorder are
still being elucidated (670). Some authors consider INAD to be part of
a group of disorders called neurodegeneration with brain iron accu-
mulation, along with pantothenate kinase associated degeneration
(discussed above in section IV.C.1.a), aceruloplasminemia, and neuro-
ferritinopathy (670).
Pathology shows atrophy of the cerebellar and cerebral cortices,
with marked astrogliosis, extensive axonal swelling and spheroids in
the axoplasm of affected regions (671). MRI shows prominent sulci
in the cerebral and cerebellar cortices, diminished cerebral white mat-
ter, and marked T2 prolongation of the cerebellar cortex (Fig. 3-59).
Sequential scans will show progressive cerebellar atrophy in most
patients (668,672). Some patients show thinning of the optic nerves
and chiasm (672). Infants with mutations of the PLA2G6 gene often
show T2 hypointensity (corresponding to iron deposition) in the globi
pallidi (668); this is most notable in children with the atypical form of
the disease. Proton MRS shows progressive loss of NAA and slightly
elevated lactate in the basal ganglia (673).
Barkovich_Chap03.indd 154
Niemann-Pick Disease
Niemann-Pick disease is an autosomal recessive disorder that is charac-
terized by progressive hepatosplenomegaly, lymphadenopathy, edema,
and, in some patients, neurologic degeneration. The underlying prob-
lem is a deficiency of sphingomyelinase; as a result of the deficiency,
lipids (sphingomyelin, cholesterol, and lysobisphosphatidic acid)
accumulate throughout the reticuloendothelial system and, in some
forms of the disease, in the brain. Six clinical forms (A through F) of
the disease are described. Three of these forms, A (OMIM 257200),
C1 (OMIM 257220), and C2 (OMIM 607625) have neurologic mani-
festations, which consist primarily of loss of motor and intellectual
function. Onset in early infancy and rapid deterioration are charac-
teristic of Type A variant, which is caused by mutations of the SMPD1
gene at chromosome 11p15.1-4 (674). Onset in early childhood with
slower progression is seen in Type C1 (242), caused by mutation of the
NPC1 gene at chromosome 18q11-12 (675) and Type C2, caused by
mutation of NPC2 at 14q24.3, which have similar phenotypes (676).
These children come to attention in the latter half of the first decade
due to clumsiness and developing ataxia; as the disease progresses they
develop dysarthria, dysphagia, dystonia, dementia, and seizures (676).
Imaging findings (Fig. 3-60) reflect the pathologic descriptions of
nonspecific progressive gray matter atrophy. The cortical sulci and ven-
tricles are enlarged. The corpus callosum is thin. The underlying white
matter shows diffuse, hazy T2 hyperintensity and, to a lesser extent,
T1 hypointensity. Proton MRS shows progressive diminution in the
amount of NAA.
Rett Syndrome
Rett syndrome (OMIM 312750 (677) ) was established as an inter-
nationally defined syndrome in 1983 (678). It is a progressive neu-
rodevelopmental disorder that occurs sporadically, with prevalence
in girls reported at about 1/10,000. Recent work has shown that the
disorder is caused by mutation of the MECP2 gene on chromosome
Xq28 (679,680). Although the mutation is usually fatal in boys, some
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
boys have been reported to have Rett syndrome as a result of somatic
mosaicism, a condition in which only some cells have the mutated gene
(681), or an extra X chromosome (682).
Typically, affected patients have a normal prenatal and perinatal
history but have onset of progressive deterioration that begins in the
latter half of the first year of life. This is usually manifested as regres-
sion of purposeful hand use, cognitive functions, acquired language,
and social skills. Decline in growth rate of the head begins at age 2
to 4 months, dropping to less than 3rd percentile by age 4 years. By
age 3, profound intellectual disability is evident and patients develop
stereotyped repetitive hand movements with fixed position of the
hands. Subsequently, intellectual disability remains relatively static
while motor functions deteriorate (680). Seizures develop in up to 80%
of affected patients (683,684). Pathology shows global decrease in the
size of neurons with increased packing density, decreased melanin in
the large neurons of the pars compacta of the substantia nigra (685).
Rett syndrome is extremely uncommon in boys. When boys are
affected, they may have a typical presentation of a Rett Syndrome phe-
notype (seen with somatic mosaicism (686) or with X-inactivation in
an XXY karyotype (682,687,688) ). Alternatively, they may have severe
neonatal encephalopathy (687,689) or severe mental retardation with
progressive spasticity (690). Autopsy of one patient with a small dele-
tion in MECP2 who presented with neonatal encephalopathy showed
bilateral perisylvian polymicrogyria (691).
Although qualitative neuroimaging studies of girls with Rett Syn-
drome are usually normal or show mild diffuse atrophy, quantitative
neuroimaging studies show global reduction in gray and white matter
volumes, with the largest reductions in the prefrontal, posterior frontal,
and anterior temporal cortices and the caudate nucleus. White mat-
ter volumes are reduced uniformly through the brain (692). Proton
MRS shows decreased NAA in older patients, more pronounced in gray
matter than in white, with reduction of the glutamate/glutamine ratio
(693). Frontal and parietal lobes and insular cortex seem predomi-
nantly involved (694).
Toxins
Certain toxins affect primarily gray matter. Therefore, toxic exposure
should always be considered in children, particularly adolescents,
Barkovich_Chap03.indd 155
155
FIG. 3-60. Niemann-Pick disease,
type C in an 18-year-old. Axial
T2-weighted images (A and B) show
enlarged ventricles and subarachnoid
spaces and diffuse haziness of the cere-
bral white matter. These are character-
istic findings of a gray matter disease
involving primarily cortex.
with acute neurological symptoms and bilateral, symmetric gray mat-
ter involvement. Carbon monoxide poisoning (Fig. 3-61), cyanide
poisoning (Fig. 3-62), intoxication with drugs such as ecstasy (695),
and exposure to organic solvents (540,695) can all result in damage
to the deep gray matter (CO to the globi pallidi and substantia nigra
(696), cyanide to the globi pallidi and striatum) and, sometimes, to
the cerebral or cerebellar (particularly with cyanide, Fig. 3-62) cortex
(540,697,698). Delayed injury may develop in the cerebral white mat-
ter (“postanoxic encephalopathy”) by mechanisms that are unclear
(699,700). Most of these injuries will show reduced diffusion if MRI is
performed in the acute phase (696).
Progressive Cerebral Poliodystrophy (Alpers Disease)
Alpers disease is discussed in the Mitochondrial Disorders section.
Trichopoliodystrophy (Menkes Disease)
Menkes disease is discussed in the Mitochondrial Disorders section .
Metabolic Disorders That Affect Both Gray And
White Matter
Canavan Disease (Aspartoacylase Deficiency,
Spongiform Leukodystrophy)
Canavan disease (OMIM 271900) is an autosomal recessive disor-
der, most common in Ashkenazi Jews, that is caused by a deficiency
of aspartoacylase. The biochemical disorder results in accumulation
of NAA in the brain (701) and N-acetyl aspartic aciduria (702). The
ASPA gene has been cloned and localized to the short arm of chro-
mosome 17 (17pter-p13) (703). In rodents, aspartoacylase activity is
expressed only in oligodendrocytes (704), where it catalyzes the hydro-
lysis of neuronally derived NAA to acetate and aspartic acid, so it may
be postulated that deficiency of the enzyme results in accumulation of
NAA in oligodendrocytes with consequent intramyelinic edema, vac-
uolization, and oligodendrocyte failure in humans as well. However,
the biochemistry of NAA is complex (701) and is still being elucidated
(705). It has been suggested that myelin damage in Canavan disease is
related to a profound impairment of water homeostasis of brain result-
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 156 Pediatric Neuroimaging
FIG. 3-61. Carbon monoxide poisoning. A. Axial T2-weighted image shows hyperintensity in bilateral globi pallidi (large white arrows) and occipital
cortex (small white arrows). B. Coronal FLAIR image shows swelling and hyperintensity (arrows) of the globi pallidi and hippocampi.
ing in fluid imbalance between intracellular (axon-glial) and extracel-
lular (interlamellar) spaces within myelinated white matter. In brain,
NAA is synthesized in neurons and it is one of the most abundant low
molecular-weight parenchymal cellular metabolites, believed to have
a role in the molecular efflux water pump system. Indeed, NAA may
function as a water transporter and since the synthesis of NAA is intact
in Canavan disease, “overproduction” of NAA within neurons may lead
to increased water migration from the axon into the periaxonal space.
Normally, hydrolysis of NAA takes place in this space by aspartoacy-
lase. If NAA is not eliminated, excess water builds up in the periaxonal
space, leading to increased osmolar pressure, probably causing rupture
Barkovich_Chap03.indd 156
of the sealed interlamellar spaces and, hence, intramyelinic edema,
with resultant demyelination and loss of glial cells (706).
In the first few weeks of life, affected infants may show marked
hypotonia, with severe head lag. Soon, they may develop macroceph-
aly and seizures. Psychomotor development is delayed. With further
progression of the disease, spasticity, intellectual failure, and optic
atrophy develop. Death usually occurs in the second year of life (707).
Some patients have a more protracted clinical course with less severe
impairment of psychomotor development (708,709); indeed, some
may have developmental delay and problems with social interaction
but a normal neurologic exam (710). Presumably the mutations of
FIG. 3-62. Cyanide poisoning. Axial T2-
weighted image (A) shows abnormal hyper-
intensity (white arrows) of the globi pallidi.
Coronal FLAIR image (B) shows diffuse severe
swelling and hyperintensity of the cerebellar
cortex.
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
ASPA in these children have a less pronounced effect on the function
of aspartoacylase (710,711). Laboratory diagnosis of Canavan disease
is based on demonstration of increased urinary excretion of NAA.
In the newborn, imaging studies of the brain may be normal; how-
ever, proton MR spectra are already abnormal (see later comments
on proton MRS). In typical infantile onset patients, imaging studies
reveal diffuse, symmetric abnormalities of the cerebral white matter
without any focal predominance. When transfontanelle sonography
is performed with high frequency transducers in neonates, it shows
hyperechogenicity of the white matter, causing a reversal of the normal
pattern of cortical and white matter echogenicity (712). CT shows a
diffuse low density in the cerebral and cerebellar white matter and in
the globi pallidi. MRI reveals diffuse T1 hypointensity and T2/FLAIR
hyperintensity in the cerebral white matter (Fig. 3-63) (713). The
subcortical white matter is preferentially affected early in the course
of the disease (distinguishing this disorder from Krabbe disease and
metachromatic leukodystrophy) and may appear swollen (45,46). Less
severe cases with milder clinical courses may have nearly normal cere-
bral white matter, with T2/FLAIR hyperintensity being seen only in
the subcortical U fibers, corpus striatum, cerebellar dentate nuclei,
dorsal pons, and portions of the cerebellar peduncles (709,711). The
globi pallidi are nearly always affected (Figs. 3-63 and 3-64), with spar-
ing of the adjacent putamen; thalami are frequently involved, as well,
especially in more advanced stages (Fig. 3-64) (45,155,306,714). The
cerebellar dentate nuclei may be affected (714) and I have seen a case
involving the midbrain and dorsal pons. Contrast enhancement is not
reported. As the disease progresses, diffuse atrophy of the white matter
and, subsequently, cerebral cortex is seen (Fig. 3-64) (59). Diffusion-
weighted imaging shows characteristic reduced diffusion (compared
to normal age-matched white matter, Fig. 3-63B) in the entirety of
the affected white matter due to the myelin vacuolization (10,715);
the reduced diffusion is quite prolonged and may be detectable over
multiple follow-up studies. DTI shows markedly reduced fractional
anisotropy (10).
Patients with less severe mutations have fewer findings on MRI,
limited to some T2 hyperintensity in the basal ganglia (710) or even
a completely normal study. In such case, MR diagnosis is dependent
upon proton MR spectroscopy.
Proton spectroscopy (Fig. 3-64C) reveals elevated levels of the
NAA peak in both mild and severe cases (709,716), a finding that is
Barkovich_Chap03.indd 157
157
strongly suggestive of this disorder. The NAA is less elevated in milder
cases (717). Reduced glutamate/glutamine is found on short echo pro-
ton MRS (718).
Fibrinoid Leukodystrophy (Alexander Disease)
Alexander disease (OMIM 203450), also known as fibrinoid leu-
kodystrophy, was originally described as a disorder of infants, who
present during the first year of life (sometimes as early as the first few
weeks of life) with macrocephaly, failure to attain developmental mile-
stones, and progression to psychomotor retardation with death usu-
ally ensuing in infancy or early childhood (57,707,719,720). In the late
1990s, it was discovered that the disease is caused by mutations causing
gain of function of the gene for glial fibrillary acidic protein (GFAP),
an intermediate filament protein that is highly specific for cells of
astroglial lineage and is located at chromosome 17q21 (721,722). Since
the discovery of GFAP dysfunction as the cause, it has been shown that
Alexander disease has a large phenotypic spectrum. Typical infantile
Alexander disease, with onset before age 2 years, has onset in the first
year of life and rapid lethal course, as described above. The juvenile
form of Alexander disease is characterized by onset between age 2 and
12 years; head size is often normal. Affected children typically present
with ataxia, bulbar signs (sometimes recurrent vomiting) and spastic-
ity with a more slowly progressive course. Rarely, presentation may be
one of spinal cord dysfunction (gladder and gait disturbances (723) )
or weight loss and vomiting (724). The adult-onset form of Alexander
disease has predominantly symptoms of brainstem involvement,
beginning during adolescence or later (after age 12) with dysarthria,
dysphonia, dysphagia, pyramidal signs and ataxia; palatal myoclonus is
common. Many of these patients survive into adulthood (724–728).
The disease is caused by physiologic disruptions resulting from
mutation of GFAP proteins. It is speculated that the leukodystrophy of
Alexander disease is a secondary effect of impaired astrocyte functions
leading to deregulation of astrocyte-derived myelination signals (722).
Mutant GFAP precipitates in astrocytes in aggregates, together with
heat-shock proteins and alpha-B-crystallin, to form Rosenthal fibers
(eosinophilic inclusions in astrocyte cytoplasm), which disrupt astro-
cyte function (729). In addition, astrocytic density is increased and a
paucity of myelin is seen (730). No genotype-phenotype correlation
has been established and, indeed, some mutations have been associated
with all three forms of Alexander disease (728). It appears, therefore,
FIG. 3-63. Canavan disease, early MRI
findings. A. Axial T2-weighted image
shows diffuse white matter hyperin-
tensity, absence of any myelination in
the internal capsules, and abnormal
hyperintensity of the globi pallidi (white
arrows). The white matter volume is
normal; no atrophy is seen. B. Axial dif-
fusivity (Dav) image shows reduced Dav
diffusely in the cerebral white matter
and in the globi pallidi (white arrows).
5/6/2011 12:08:48 AM
 158 Pediatric Neuroimaging
that a molecular understanding awaits an understanding of the effects
of the specific mutation on the three-dimensional structure of the
GFAP molecule and its functions, as well as the effects of other genetic
or environmental factors. The diagnosis can be strongly suggested by
imaging findings (725,728), and confirmed by increased levels of GFAP
in the CSF (731) or analysis of the GFAP gene.
CT shows low density in the frontal white matter that typically
extends posteriorly into the parietal region and internal capsule. Low den-
sity may be seen in the caudate heads. Contrast-enhancement is often seen
near the tips of the frontal horns early in the disease (732,733). An expanded
cavum septi pellucidi is often seen and is of uncertain significance.
van der Knaap et al. have described five MRI criteria by which
the diagnosis of infantile Alexander disease can be made: (a) exten-
sive cerebral white matter changes with frontal predominance, (b) a
periventricular rim with high signal on T1-weighted images and low
signal on T2-weighted images, (c) abnormalities of the basal ganglia
and thalami, (d) brainstem abnormalities, and (e) contrast enhance-
ment of periventricular regions and lower brainstem (725). The MR
findings in the infantile form of the disease are those of T1 hypointen-
sity and T2 hyperintensity involving most of the frontal white matter
and extending posteriorly to the parietal white matter and the internal
and external capsules (Fig. 3-65). Subcortical white matter is affected
Barkovich_Chap03.indd 158
FIG. 3-64. Canavan disease, more advanced MRI find-
ings. A and B. Axial T2-weighted images shows diffusely
hyperintense white matter (isointense to the lateral ven-
tricles), with hyperintensity of the globi pallidi (g) and
thalami (t). Note the enlarged subarachnoid spaces and
cortical sulci, indicating more advanced white matter dis-
ease with volume loss. C. Single voxel proton MRS (TE =
288 ms) from the frontal white matter shows markedly
reduced choline (Ch) and elevated NAA. Creatine (Cr)
appears normal.
early in the course of the disease. A rim of short T1 and short T2 relax-
ation times typically persists immediately around the lateral ventri-
cles (Fig. 3-65A), particularly the frontal horns; this has been called a
periventricular “garland.”(723) The ependyma of the trigones may be
hyperintense on T1-weighted images; the relationship of this hyperin-
tensity to the “garland” is not understood. The basal ganglia are typi-
cally involved, particularly the caudate heads, and anterior putamina,
which are usually edematous early in the course of the disease and
may enhance (Fig. 3-65B). The globi pallidi and thalami are less com-
monly affected. In later stages of the disease and, particularly in the
juvenile and adult forms, the brainstem, particularly the periaqueduc-
tal region and the medulla, commonly show T2 prolongation and may
enhance after administration of contrast. In addition, cavities/cysts
may develop in affected regions of the brain as the disorder progresses
(155,725,734). Diffusion imaging shows increased diffusivity in the
affected regions (dark on diffusion-weighted images (Fig. 3-65D),
bright on ADC images). Proton MR spectroscopy shows reduced NAA
in affected areas and, sometimes, increased myo-Inositol (Fig. 3-65E).
Patients with the juvenile form of Alexander disease typically
have regions of T1 and T2 prolongation in the medulla, pons, and
middle cerebellar peduncles; enhancement is intense after intravenous
administration of paramagnetic contrast (726). Involvement of
5/6/2011 12:08:48 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 159

FIG. 3-65. Alexander disease, infantile form. A. Axial T1-weighted image shows low intensity in the frontal white matter, extending into the caudate
heads and the external and extreme capsules. Hyperintensity in and adjacent to the walls of the lateral ventricles (black arrows) is often present. B. Axial
T2-weighted image (different patient) shows marked hyperintensity in the frontal white matter, caudates and putamina, external and extreme capsules.
Note that the abnormal signal involves the subcortical white matter (small black arrows). C. Coronal FLAIR image shows involvement of subcortical parietal
white matter (small black arrows) and cerebellar white matter (large black arrows). D. Axial diffusion weighted image shows low diffusivity (hypointensity)
in the frontal lobes, characteristic of Alexander disease. E. Proton single voxel spectrum (TE = 26 ms) from frontal white matter of an affected 10 months
old shows low NAA, elevated choline (Ch) and elevated myo-inositol (myo-I).

supratentorial (predominantly frontal) white matter and basal ganglia
often develops a few years after presentation (Fig. 3-66). “Garlands” of T1
hyperintensity/T2 hypointensity are often seen around the lateral ven-
tricles (Fig. 3-66) (723). Of interest, the subcortical white matter may not
be involved in this form of the disease (726). Proton MRS of the cerebral
white matter shows marked reduction of NAA with elevation of myo-I,
choline, and lactate (730). DTI of affected white matter shows increased
diffusivity and decreased FA; magnetization transfer is reduced (730).
Patients with the adult-onset form of the disease are found to
have atrophy and abnormal signal intensity in the medulla oblongata,
extending caudally to the C1-2 levels of the spinal cord (728,735). The
signal changes are typically T1 and T2 prolongation; these may be dif-
fuse, or may specifically affect the medial lemniscus and corticospinal
tracts. Other areas that may be involved include the cerebellar pedun-
cles (inferior, middle, and superior), midbrain tegmentum, hila of the
deep cerebellar nuclei, and central spinal cord (735). Patchy enhance-
ment is inconsistently seen in these regions. Most patients will also have
some cerebral periventricular white matter T2 prolongation (735).
Diffusivity in the supratentorial white matter appears to be generally
increased. Spectroscopy of the supratentorial white matter typically
shows increased amplitude of the myo-I peak, with normal amplitudes
of other metabolites (728,735).
Mucopolysaccharidoses
The mucopolysaccharidoses are lysosomal storage disorders that
result from deficiency of specific lysosomal enzymes involved in the
degradation of mucopolysaccharides (glycosaminoglycans). Muco-
polysaccharide deposits in the lysosomes interfere with the degradation

Barkovich_Chap03.indd 159 5/6/2011 12:08:49 AM

 160 Pediatric Neuroimaging
of other macromolecules, resulting in the intralysosomal accumulation
of other materials in addition to mucopolysaccharides. Incompletely
degraded mucopolysaccharides accumulate in the tissues and are
excreted in the urine as dermatan sulfate, heparan sulfate and kera-
tan sulfate. Diagnosis is made by combining the clinical picture with
characteristic urinary mucopolysaccharides (736,737). Table 3-13 sum-
marizes the main genetic and biochemical aspects of the various muco-
polysaccharidoses. The clinical manifestations of these disorders vary.
Mucopolysaccharidoses are multisystemic diseases. Involvement
of the skeletal system (dwarfism, skull base abnormalities, bone and
joint dysplasias), liver, spleen (hepatosplenomegaly), heart (thickening
of the valves), eye (corneal opacities), and central nervous system (pri-
mary and secondary involvement) are characteristic (676). Obviously,
for the neuroradiologist central nervous system involvement is in the
focus of the diagnostic imaging workup. Involvement of the CNS may
be direct or indirect.
The most frequent imaging substrates of direct central nervous
system involvement are enlarged perivascular spaces and white mat-
ter abnormalities. Enlargement of perivascular spaces is likely related
to mucopolysaccharide deposition in leptomeninges, impairing out-
Barkovich_Chap03.indd 160
FIG. 3-66. Alexander disease, juvenile
form. A. Sagittal T2-weighted image shows
abnormal hyperintensity in the dorsal
medulla (black arrows) and cervical spinal
cord (white arrow) as well as the anterior
portion of the very thin corpus callosum.
B. Parasagittal T1-weighted image shows
abnormal hypointensity of the frontal white
matter (f) with more normal hyperinten-
sity of the parietal (p) and temporal white
matter. C and D. Axial T1 (C) and T2 (D)-
weighted images show the “garland” of
abnormal signal intensity (arrows) around
the lateral ventricles, hyperintense on the
T1-weighted image and hypointense on the
T2-weighted image.
flow of interstitial fluid from the parenchyma. Enlarged perivascular
spaces are therefore filled with interstitial fluid (and mucopolysac-
charides), as described in pathology texts (48). Cerebral white matter
lesions may represent demyelination secondary to accumulation of
macromolecules (mucopolysaccharides and others) within neurons
and oligodendrocytes. If the patient presents with macrocephaly due
to hydrocephalus, interstitial edema (see Chapter 8) may also play a
role in the development of white matter signal abnormalities.
Indirect CNS damage in mucopolysaccharidoses often results from
hydrocephalus or compression of the upper cervical spinal cord in the
cranial-cervical junction area. Hydrocephalus in mucopolysacchari-
doses is likely a result of impaired CSF resorption due to meningeal
mucopolysaccharide deposits and, possibly, increased venous pressure
due to bony overgrowth of the skull base and narrowing of venous
outflow pathways. As a result of hydrocephalus, most patients with
mucopolysaccharidoses have macrocephaly. Narrowing of the foramen
magnum-upper cervical spinal canal area is due to combined effects of
atlantoaxial instability (odontoid dysplasia in conjunction with liga-
ment laxity) and mucopolysaccharide deposits within synovial and
dural structures. Ligamentous hypertrophy may develop in response to
5/6/2011 12:08:50 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 161

TABLE 3-13 Mucopolysaccharidoses

Gene Type OMIM#/Eponym Inheritance Enzyme Deficiency Urinary GAG Neurologic Signs
IDUA 4p16.3 IH 607014/Hurler AR Alpha-L-Iduronidase Dermatan sulfate Marked
IDUA 4p16.3 IS 607016/Scheie AR Alpha-L-Iduronidase Heparan sulfate None
IDUA 4p16.3 IH/S 607015/ AR Alpha-L-Iduronidase Dermatan or Intermediate
Hurler-Scheie Heparan sulfate between IH and IS
Genetic Heterogeneity. II 309900/Hunter X-Linked Iduronate sulfatase Dermatan or Mild to moderate
Locus at Xq28 recessive heparan sulfate
SGSH 17q25.3 IIIA 252900/ AR Heparan Heparan sulfate Mental deterioration
Sanfilippo A N-sulfatase
MPS3B 17q21 IIIB 252920/ AR Alpha-N-acetyl- Heparan sulfate Mental deterioration
Sanfilippo B glucosaminidase
HGSNAT 8p11.1 IIIC 252930/ AR Acetyl CoA: alpha- Heparan sulfate Mental deterioration
Sanfilippo C glucosaminide
acetyltransferase
GNS 12q14 IIID 252940/ AR N-acetylglu- Heparan sulfate Mental deterioration
Sanfilippo D cosamine
6-sulfatase
GALNS 16q24.3 IVA 253000/ AR N-acetylgalac- Keratan sulfate and Secondary to skeletal
Morquio A tosamine-6- chondroitin- changes
sulfate sulfatase 6-sulfate
GLB1 3p21.33 IVB 253010/ AR Beta-galactosidase Keratan sulfate Secondary to skeletal
Morquio B changes
ARSB 15q11–13 VI 253200/ AR Arylsulfatase B Chondroitin Secondary to skeletal
Maroteaux-Lamy sulfate changes
GUSB 7q21.11 VII 253220/Sly AR Beta-Glucuronidase Dermatan sulfate Variable
Heparan sulfate
OMIM#, Online Mendelian Inheritance in Man disease number; AR, Autosomal recessive inheritance; GAG, glycosaminoglycan.

chronic subluxation at the C1-2 level, causing additional compression
on the upper cervical spinal cord.
Despite many similarities in the pathophysiologic processes, the
actual clinical manifestations of mucopolysaccharidoses vary as a
function of the different subtypes. In Hurler (MPS-I-H) and Hunter
(MPS-II) diseases, the clinical picture is usually dominated by cen-
tral nervous system involvement, including mental retardation. Some
degree of intellectual deficit may be present in Scheie (MPS-I-S) and
Hurler-Scheie (MPS-I-HS) diseases. Sanfilippo (MPS-III) disease pres-
ents with neurological abnormalities only (hepatomegaly or dysostosis
are lacking). Skeletal involvement with secondary CNS manifestations
dominate the clinical picture in Morquio (MPS-IV) and Maroteaux-
Lamy (MPS-VI) diseases, mainly as a result of vertebral subluxation,
which occurs most frequently at the atlantoaxial joint (676,736,737)
with resultant stenosis, cord compression and myelopathy.
Imaging studies of the brain in the mucopolysaccharidoses are
usually ordered when secondary CNS involvement due to hydroceph-
alus, craniocervical instability, or spinal cord compression is suspected
(738–741). CT and MRI usually reveal delayed myelination, atrophy,
varying degrees of hydrocephalus, enlarged perivascular spaces, and
white matter changes (742–744). In all types of mucopolysacchari-
doses, the white matter abnormalities are manifested as diffuse low
attenuation within the cerebral hemispheric white matter on CT and
as diffuse areas of T1 hypointensity and T2 hyperintensity on MR
studies (Figs. 3-67 to 3-70). In Hurler syndrome and, to a lesser extent
in Hunter (type II), Sanfilippo (type IIIa), and Maroteaux-Lamy
(type IV) syndromes, sharply defined enlarged perivascular spaces are
commonly present in the corpus callosum and basal ganglia, as well as
the cerebral white matter (Figs. 3-68 to 3-70) (59). With progression
of the disease, the lesions become larger and more diffuse and resem-
ble a leukodystrophy (Fig. 3-67) (745), reflecting the development of
infarcts and demyelination; if treated early, many of the lesions regress
after bone marrow transplantation. Diffuse white matter haziness is
seen on T2-weighted images in mucopolysaccharidoses types IH, II,
and III, resulting in diminished contrast between cortex and underly-
ing white matter (Fig. 3-70) (743,746). The atrophy and white matter
changes occur earliest in types I, II, III, and VII, usually becoming vis-
ible during the first few years of life. In mucopolysaccharidoses types
IV and VI, the white matter changes and atrophy may not become
apparent until the second decade of life (736,742–744); these patients
typically have normal intelligence (747) and present for medical
care with reduced exercise tolerance and myelopathy (748). Affected
patients are commonly macrocephalic, probably from a combina-
tion of hydrocephalus and mucopolysaccharide deposition within the
brain, meninges, and skull. This communicating hydrocephalus may
cause enlargement of subarachnoid spaces and optic nerve sheaths; if

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 162 Pediatric Neuroimaging

FIG. 3-67. Mucopolysaccharidosis 1H, Hurler syndrome. A. Sagittal T1-weighted image shows marked ventriculomegaly and frontal bossing (large white
arrows) due to hydrocephalus. The sphenoid bone is small, leading to a large, deep sella turcica. The basi-occiput (small white arrow) is small, as is the
odontoid process of C2 (white arrowhead). B. Axial T2-weighted image shows ventriculomegaly with diffusely hyperintense white matter due to myelina-
tion delay and interstitial edema. Mildly enlarged perivascular spaces are seen in the thalami and external capsules. C. Coronal reformat of T1-weighted
volumetric acquisition shows subcortical myelination (white arrowheads) and multiple slightly enlarged perivascular spaces (white arrows). D. Sagittal
T2-weighted image of the spine shows irregular endplates of the vertebral bodies and a gibbus deformity (focal kyphus) at T1 (white arrow) due to narrow-
ing of the anterior aspect of the vertebral body.

longstanding, the latter may result in optic nerve atrophy (Fig. 3-70E).
A high incidence of intracranial arachnoid cysts may also contribute
to the macrocephaly (742,749).
The spine abnormalities in the mucopolysaccharidoses con-
sist of characteristic vertebral body abnormalities that are described
well in pediatric and musculoskeletal radiology texts. Their spines
are usually imaged to determine the site and cause of cord compres-
sion (Fig. 3-70), which occurs frequently in mucopolysaccharidoses
types IV and VI (59,736,737,750). The most common location for the
cord compression is at the atlantoaxial (C1-2) joint (Fig. 3-70D and
F). Atlantoaxial instability may occur in these patients as a result of
laxity of the transverse ligament or because of hypoplasia or absence
of the odontoid (Fig. 3-70A and D). Flexion/extension views are
often necessary to demonstrate the laxity of the transverse odontoid
ligament. Ligamentous hypertrophy (Fig. 3-70A and D) may develop
in response to chronic subluxation at the C1-2 level, causing additional
compression on the upper cervical spinal cord. MRI of the craniocer-
vical junction in affected patients shows a shortened odontoid, with
a soft tissue mass of variable size. The soft tissue mass, which is of
intermediate signal on the T1-weighted images and low signal on the
T2-weighted images, probably represents a combination of unossified
fibrocartilage and reactive change (747). A small os odontoideum may
be present. The combination of the anterior soft tissue mass and the
indentation of the posterior arch of C1 may narrow the spinal canal
and compress the spinal cord at that level. No abnormal enhance-
ment is seen. Another cause of cord compression at the C1-2 level is
dural thickening resulting from intradural deposition of collagen and
mucopolysaccharides. This is seen as a thickening of the soft tissue

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 163

FIG. 3-68. Older child with mucopolysaccharidosis 1H, Hurler syndrome. A and B. Sagittal T1-weighted images show multiple well-defined focal
areas of hypointensity, probably mucopolysaccharide-filled perivascular spaces, in the cerebral white matter and corpus callosum. C. Axial T2-weighted
image shows well-marginated foci of hyperintensity superimposed upon some subtle, diffuse hyperintensity in the centrum semiovale.

FIG. 3-69. Mucopolysaccharidosis II, Hunter syndrome. A. Sag-

ittal T1-weighted image shows multiple small cysts (white arrows)
in the corpus callosum. B and C. Axial T2-weighted images show
dilated perivascular spaces and multiple cystic enlargements of
perivascular spaces (white arrowheads) throughout the cerebral
hemispheres.

Barkovich_Chap03.indd 163 5/6/2011 12:08:52 AM

 164 Pediatric Neuroimaging

FIG. 3-70. Mucopolysaccharidosis IIIA (Sanfillipo) and IV (Maroteaux-Lamy) syndromes.

A. Sagittal T1-weighted image of a patient with Sanfillipo syndrome shows two cysts (large white
arrowheads) in the body of the corpus callosum. Note that the basiocciput (small white arrows)
is small and the odontoid process of C2 (large white arrow) is absent. The ligaments connect-
ing the odontoid to the basiocciput (small white arrowheads) are hypertrophied. B and C. Axial
FLAIR image (B) and coronal T2-weighted image (C) of the same patient show the cysts in the
corpus callosum (white arrows) and show slight hyperintensity of the cerebral white matter, result-
ing in indistinct cortical-white matter junctions. D. Sagittal T1-weighted image of a child with
Maroteaux-Lamy syndrome shows an abnormally thick clivus (large white arrows) compressing
the pons. Abnormal soft tissue (t) surrounding the dens is probably a combination of mucopoly-
saccharide and hypertrophied ligaments. The vertebral bodies (small white arrows) are small and
pointed anteriorly, separated by large intervertebral discs. The calvarium is thick, the posterior fossa
is small, and there is a dilated perivascular space (white arrowhead) in the corpus callosum. E. Axial
T2-weighted image of the same patient as in (D) shows large sylvian fissures (s) and dilated optic
sheaths (white arrows) containing atrophic optic nerves due to increased intracranial pressure. F.
Axial T2-weighted image at the foramen magnum shows anteroposterior compression of the cervi-
comedullary junction (arrows) by the soft tissues surrounding the unstable dens. G and H. Sagittal
T1 (G) and T2 (H)-weighted images show spinal stenosis secondary to intervertebral disc enlarge-
ment, likely due to the deposition of mucopolysaccharides.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
posterior to the dens, resulting in narrowing the subarachnoid space
at that level. One final cause of cord compression in these patients is
gibbous formation in the thoracic spine. This results from the vertebral
deformities and abnormal enlargement of intervertebral discs (Fig.
3-70G and H) and is most common in Morquio disease (mucopolysac-
charidosis type IV) (59,736,737,750). Meningeal thickening may result
in cyst formation in mucopolysaccharidoses types 1H and II (59).
Proton MR spectroscopy results have been reported in a few of the
mucopolysaccharidoses (751). Affected patients tend to have multiple
resonances from glycosaminoglycans deposited in the brain; these are
seen from about 3.3 to 4.4 ppm, upfield from the normal creatine and
choline peaks (752). Care should be taken not to mistake these peaks
for a lack of water suppression. Other reports suggest a decreased NAA/
choline ratio and elevated glutamate, glutamine, and myo-Inositol.
Multiple Sulfatase Deficiency
Multiple sulfatase deficiency is rare autosomal recessive disorder that
has clinical and imaging features of both mucopolysaccharidoses and
metachromatic leukodystrophy (676); therefore, it is listed here as a
subcategory of mucopolysaccharidoses. As its name indicates, multiple
sulfatase enzymes (those involved in metachromatic leukodystrophy
and in the various forms of mucopolysaccharidoses) are deficient; the
residual enzyme activities vary considerably, explaining the significant
phenotypic variations. The most frequent form occurs in early child-
hood, but rare neonatal and juvenile forms also exist (676).
Clinically, facial dysmorphia (similar to that seen in mucopoly-
saccharidoses), hepatosplenomegaly, microcephaly (macrocephaly in
the neonatal form (753) ), delayed development, progressive spasticity,
blindness and deafness are usually found. Imaging findings in multiple
sulfatase deficiency represent the combination of abnormalities seen
in metachromatic leukodystrophy and mucopolysaccharidoses, nota-
bly variable patterns of white matter disease and diffuse brain atrophy;
occasionally, these are associated with enlarged perivascular spaces and
craniocervical junction abnormalities (754,755).
Peroxisomal Disorders
Peroxisomes are small cellular organelles that contain multiple com-
pounds that are essential for normal growth and development of the
organism. The biochemical functions that take place in peroxisomes
are beyond the scope of this book; more than 40 enzymatic func-
Barkovich_Chap03.indd 165
165
FIG. 3-70. (Continued)
tions have been identified in peroxisomes (756). Among the most
important are betaoxidation of a specific set of fatty acids and their
derivatives, synthesis of ether-phospholipids and plasmalogens, alpha-
oxidation of phytanic acid, and biosynthesis of cholesterol and bile
acids (49,50,757,758). Some authors classify peroxisomal disorders
into three major groups, based upon the severity of the enzyme dys-
function, whereas others divide them into two groups (Table 3-14),
Deficiencies in Peroxisomal Biogenesis and Single Peroxisomal Protein
Deficiencies (756,759), which are described below in greater detail.
Peroxisomal disorders show remarkable clinical phenotypic het-
erogeneity but dysmorphic features, hepatointestinal dysfunction
and CNS involvement are common in many of them; therefore per-
oxisomal diseases should always be suspected in a neonate presenting
with a polymalformative syndrome associated with severe neurologi-
cal disturbances. The imaging abnormalities in peroxisomal disorders
have a wide spectrum of patterns, but the most characteristic patterns
include neuronal migration disorders with abnormal myelination
(e.g., Zellweger syndrome, neonatal adrenoleukodystrophy) or sym-
metrical demyelination that most typically involves the corticospinal
tracts, corpus callosum, and posterior greater than anterior white mat-
ter structures (e.g., pseudoneonatal adrenoleukodystrophy, X-linked
adrenoleukodystrophy-adrenomyeloneuropathy complex). Classic
X-linked adrenoleukodystrophy has already been discussed in section
IV.B.1.c as a white matter disorder with central white matter involve-
ment. A group of peroxisomal disorders with generalized loss of perox-
isomal function, present at birth. A few of these disorders will be briefly
discussed, with focus primarily on imaging characteristics. Interested
readers are referred to review articles or texts in Child Neurology or
Metabolic Disease for further details (756,760,761).
Peroxisomal Biogenesis Disorders
Several disorders seem to result from deficient peroxisomal biogenesis,
including Zellweger syndrome, neonatal adrenoleukodystrophy, and
infantile Refsum disease. Common to all three are liver disease, vari-
able neurodevelopmental delay, retinopathy, and perceptive deafness
with onset in the first months of life. All of these disorders seem to
be inherited as autosomal recessive traits (762). The underlying prob-
lem appears to be mutations in peroxisomal biogenesis genes, which
code for proteins (peroxins) essential for peroxisome formation (763).
Mutations that completely destroy the protein’s function seem to cause
5/6/2011 12:08:55 AM
 166 Pediatric Neuroimaging

TABLE 3-14 Classification of Peroxisomal Disorders

Group A: Peroxisome Biogenesis Disorders
1. Zellweger spectrum disorders
a. Zellweger syndrome
b. Neonatal adrenoleukodystrophy (NALD)
c. Infantile Refsum disease
2. Rhizomelic chondrodysplasia punctata (RCDP)
3. Refsum disease secondary to PEX7 mutation
Group B: Loss of Single Peroxisomal Function (Peroxisomes Present)
1. Disorders of peroxisomal beta-oxidation
a. X-Linked adrenoleukodystrophy and variants
b. D-bifunctional protein deficiency
c. Acyl-CoA oxidase deficiency (pseudo-NALD)
d. 2-methylacyl-CoA racemase deficiency
e. SCPx deficiency
2. Disorders of etherphospholipid biosynthesis
a. Dihydroxyacetone phosphate (DHAP) acyltransferase deficiency
b. Alkyl dihydroxyacetone phosphate (DHAP) synthase deficiency
3. Disorders of fatty acid alpha-oxidation
a. Phytanoyl-CoA 2-hydroxylase deficiency
b. 2-Hydroxyphytanoyl-CoA lyase deficiency
c. Di-and trihydroxycholestanoic acidemia
d. Glutaryl-CoA oxidase deficiency (Glutaric aciduria type III)
e. Classic Refsum disease (Phytanoyl-CoA hydrolase deficiency)
4. Disorders of glyoxylate metabolism
a. Hyperoxaluria type 1 (AGT deficiency)
b. Acatalasemia
Modified from Raymond GV, Naidu S, Moser HW. Peroxisomal disorders. In: Swaiman KF, Ashwal S, Ferriero DM, eds.
Pediatric Neurology: Principles and Practive, 4th ed. Philadelphia, PA: Mosby Elsevier, 2006:735–758; Wanders RJ,
Waterham HR. Biochemistry of mammalian peroxisomes revisited. (Annu Rev Biochem) 2006;75:295–332, with permission.

the more severe (Zellweger) phenotype, while mutations that allow
some residual peroxin function permit some peroxisomes to form and
result in the less severe (neonatal adrenoleukodystrophy and infantile
Refsum disease) phenotypes (762).
Zellweger syndrome (also called cerebrohepatorenal syndrome,
OMIM 214100) results from a nearly complete absence of peroxi-
somes, resulting in a wide range of biochemical abnormalities, includ-
ing impaired catabolism of very long chain fatty acids, bile acid
intermediates, pristanic, phytanic, and pipecolic acids, as well as low
levels of plasmalogens due to impaired synthesis (764). This autosomal
recessive syndrome can be caused by mutations of any of a number of
genes involved in peroxisome biosynthesis including those on chro-
mosomes 7q21 (PEX1), 8q (PEX2), 6q (PEX3), 12 (PEX5), 6p (PEX6),
17 (PEX12), 1p36.2 (PEX14), and 22q11.21 (PEX26) (44); in addition,
a Zellweger syndrome locus on 7q11 is suspected on the basis of chro-
mosome aberrations (765). Affected patients have multiple congeni-
tal anomalies (craniofacial, eyes, liver, bones, brain) and are severely
hypotonic and weak from birth, may have severe psychomotor retar-
dation, dysmorphic facial features, hypotonia, seizures, periarticular
calcifications, and hepatomegaly with impaired liver function; survival
is typically less than 1 year (756).
Imaging findings in Zellweger syndrome (Fig. 3-71) (766) reflect
the pathologic characteristics (767,768). Patients have profound
hypomyelination (Fig. 3-71A), malformations of the cerebral cortex
(Figs. 3-71A and C and 3-72A), and subependymal germinolytic cysts
(most commonly near the foramina of Monro, Figs. 3-71B and 3-72B)
(766). The cortical malformation consists primarily of gyri that are
too numerous and too small (Fig. 3-71); pathology studies suggest
that these do not represent true polymicrogyria, but merely too many
gyri of decreased amplitude (769). On imaging, the appearance most
commonly looks like polymicrogyria in the region of the sylvian fis-
sures (Figs. 3-71A and C and 3-72A). Multiple small gyri (clearly not
polymicrogyria) are often found in the anterior frontal and tempo-
ral lobes (Fig. 3-71A). In addition, some patients have a malforma-
tion resembling pachygyria or band heterotopia (see Chapter 5),
with a thick layer of arrested neurons deep to a thin outer cortex, in
the perisylvian and perirolandic cortex (Fig. 3-72). Subependymal
germinolytic cysts, most commonly seen in the caudothalamic notch
(Fig. 3-71B) are identified best on sagittal and coronal T1-weighted
images. (Other conditions with germinolytic cysts include congeni-
tal viral infections, fetal circulatory disorders, D-2-hydrdoxyglutaric
aciduria, pyruvate dehydrogenase E1-alpha deficiency, and complex
mitochondrial dysfunction with pontocerebellar hypoplasia (770).
Proton MRS results have also been reported in Zellweger syndrome,
but are nonspecific. NAA is significantly reduced, even in the neona-
tal period (Fig. 3-71D). Lactate and lipid peaks are seen at long echo
times of 270 to 280 ms (771).
Neonatal adrenal leukodystrophy (NALD, OMIM 202370) differs
fundamentally from X-linked adrenal leukodystrophy radiologically
as well as clinically; the choice of name for this disorder is unfortu-

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 167

FIG. 3-71. Three-week-old neonate with Zellweger syndrome. A. Axial T2-weighted image shows an increased number of abnormally small gyri (white
arrows) in the frontal lobes and polymicrogyria (black arrows) in the sylvian fissures. Myelination is delayed. B. Axial T1-weighted image shows germinolytic
cysts (white arrows) near the caudothalamic notch of both lateral ventricles. Abnormally small gyri with shallow sulci are seen in the posterior sylvian
fissures (white arrowheads). C. Coronal T2-weighted image shows polymicrogyria (black arrows) in the walls of the posterior sylvian fissures. The cerebellum
is abnormally small and has abnormal foliation. D. Single voxel proton MRS (TE = 288 ms) from the basal ganglia shows abnormally small NAA peak.

nate and confusing (it results from the finding of adrenal atrophy and
cytoplasmic inclusions in the first case described (772). The distinction
of NALD from Zellweger syndrome is less clear; indeed, some authors
consider the two disorders to be parts of a continuum that includes
Zellweger (the most severe phenotype), NALD (intermediate pheno-
type) and infantile Refsum disease (OMIM 266510, least severe pheno-
type), as all result from mutations of the same gene and have significant
clinical overlap (107,756,766,768,773,774). It is postulated that less
severe mutations allow preservation of some peroxisomal function that
results in a somewhat less severe phenotype (756,762), but attempts to
differentiate them genetically (or biochemically) do not reliably pre-
dict the clinical course (756). Patients with milder forms of peroxi-
somal biogenesis disorders are typically born hypotonic at birth with
mild cranial dysmorphism (midface hypoplasia), poor feeding, and
hepatomegaly. Seizures and developmental delay developing during
infancy (775), and tremor, ataxia, hyperreflexia, sensory deficits, and
progressive auditory and visual dysfunction develop over time (776).
The head size is small and the corpus callosum extremely atrophic as
a result of the white matter atrophy. Patients usually die in late infancy
(775). Imaging results vary from nearly complete absence of myelin
in the cerebral white matter and severe loss of white matter volume
(47) to subtle polymicrogyria (45) to inflammatory demyelination of
the corticospinal tracts, cerebellum, and posterior cerebral white mat-
ter (similar to X-linked adrenoleukodystrophy (section IV.B.1.c) in
location and enhancement) (777,778). Distinction from X-linked ALD
is easy, however, as affected children present at younger ages (infancy
instead of the second half of the first decade) and include both boys
and girls.
Imaging Differential Diagnosis of Peroxisomal Biogenesis Dis-
orders Several disorders can have a similar neuroimaging appearance
to that of the peroxisomal biogenesis disorders. These include peroxi-
somal bifunctional enzyme defect (764,780) and peroxisomal thiolase
deficiency (pseudo-Zellweger) (781), which have hypomyelination

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 168 Pediatric Neuroimaging
FIG. 3-72. Zellweger syndrome with band heterotopia. A. Axial T2-weighted image shows bilateral perisylvian polymicrogyria (white arrows) as well as a
layer of gray matter several millimeters deep to the cortex (black arrowheads), representing a band heterotopia. B. Coronal T1-weighted image shows large
bilateral germinolytic cysts (large white arrows) at the caudothalamic notch of both lateral ventricles, as well as a faint band heterotopia (small white arrows)
just deep to the cortex over both posterior frontal convexities.
with perisylvian polymicrogyric-type cortical malformations, and acyl-
CoA oxidase deficiency (see next paragraph) (782), which has a similar
MRI appearance to infantile Refsum disease. In addition, patients with
these disorders have neonatal courses and phenotypic manifestations
that resemble those in peroxisomal biogenesis disorders (50). Other
differential considerations from a neuroimaging perspective include
the CMDs with brain malformations (see Chapter 5) and congenital
cytomegalovirus infections (see Chapter 11). All of these disorders
have hypomyelination associated with cortical malformations. Differ-
entiation is made by associated findings, which include brainstem and
cerebellar anomalies in CMDs (Chapter 5), and white matter gliosis
with diffuse or multifocal polymicrogyria (if present) in congenital
cytomegalovirus infection (Chapter 11).
Acyl-CoA-oxidase Deficiency
Acyl-CoA-oxidase deficiency (ACOX1, OMIM #264470) is an auto-
somal recessive disorder in which very long chain fatty acids accumulate
due to mutations of the ACOX1 gene at chromosome 17q25 (782,783).
Affected patients are dysmorphic and typically present during the sec-
ond or third year of life with hypotonia, generalized seizures with tonic
jerks, failure to thrive, poor response to visual and auditory stimuli, loss
of motor achievements, and hepatomegaly (784,785). Death often ensues
during the middle of the first decade (785). Brain MRI is character-
ized by abnormal T1 hypointensity and T2/FLAIR hyperintensity in the
corticospinal tracts, periventricular white matter, and corpus callosum
(Fig. 3-73) (784); the pattern is similar to that of X-linked adrenoleu-
kodystrophy and infantile Refsum disease. Characteristics of diffusion
imaging and proton MR spectroscopy have not been reported.
Rhizomelic Chondrodysplasia Punctata
Rhizomelic chondrodysplasia punctata is an autosomal recessive dis-
ease of peroxisome biogenesis, in which the main biochemical prob-
lem is a deficiency in the biosynthesis of plasmalogens. This disorder
Barkovich_Chap03.indd 168
appears to have several variants (Type 1 OMIM 215100, Type 2
OMIM 222765, Type 3 OMIM 600121), characterized by deficien-
cies in several peroxisomal proteins, including phytanoyl-coenzyme
A hydroxlyase, alkyl-DHAP synthetase, 3-ketoacyl-CoA thiolase,
and dihydroxyacetonephosphate acyltransferase (DHAP-AT) (786).
Patients with the DHAP-AT form of rhizomelic chondrodysplasia
punctata have mutations of the PEX7 gene, which is located on chro-
mosome 6q22-24 (787–789). Affected patients are short in stature,
with disproportionate shortening of the proximal parts of the extremi-
ties (rhizomelia). They have a characteristic facies, with frontal boss-
ing, flat nasal bridge, and small nares, and associated microcephaly,
cataracts, and ichthyosis (756). Development is marked by a severe
motor and cognitive delay. Plain X-ray shows severe shortening of
long bones, metaphyseal cupping and splaying, and disturbed ossifi-
cation of the humeri and femora, with stippling of the epiphyses of
the long bones (Fig. 3-74). MRI of the brain shows patchy T2 pro-
longation, sulcation abnormalities, and subependymal heterotopia
(Figs. 3-74 and 3-75). We have seen compression of the cervicomedul-
lary junction and tethering of the spinal cord (Fig. 3-74). Proton MRS
reportedly shows elevated levels of mobile lipids and the presence of
acetate and other ketone bodies, characterized by a peak at 1.9 ppm,
just upfield from NAA (790).
Nonrhizomelic Chondrodysplasia Punctata
Nonrhizomelic chondrodysplasia punctata is a disorder caused by
an isolated deficiency of dihydroxyacetonephosphate acyltransferase
(791). Affected patients present with failure to thrive and microcephaly;
subsequent examination shows axial hypotonia with limb spasticity,
a long philtrum, and thin lips. Epilepsy almost always develops, usually
starting as febrile seizures during the first few years of life. Radiologic
exam by skeletal survey shows chondrodysplasia punctata without rhi-
zomelia. MRI of the brain shows patchy T2 prolongation, predomi-
nantly in the deep white matter (792).
5/6/2011 12:08:56 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 169

FIG. 3-73. Acyl-CoA-oxidase deficiency. The MRI appearance of this disorder is similar to that to X-linked adrenoleukodystrophy and infantile Refsum
disease. A. Axial T2-weighted image shows abnormal hyperintensity in the pontine corticospinal tracts (black arrowheads) and cerebellar white matter
(white arrows). B. Coronal T2-weighted image shows abnormal hyperintensity in the cerebral white matter (white arrows), cerebellar white matter (white
arrowheads), and middle cerebellar peduncles (black arrows). C. Axial T2-weighted image shows abnormal hyperintensity in the callosal splenium and pari-
etal white matter with extension into the posterior limbs of the internal capsules (white arrows). D. Axial postcontrast T1-weighted image shows enhance-
ment in the callosal splenium (white arrowheads), peritrigonal white matter (white arrows), and posterior limbs of the internal capsules (black arrows).
(These images are courtesy of Erik Gaensler, San Francisco.)

Wilson Disease
Wilson disease, also known as hepatolenticular degeneration (OMIM
277900), is an autosomal recessive disorder in which a deficient trans-
port protein prevents the elimination of copper from cells (mainly
hepatocytes) and incorporation into ceruloplasmin in blood. As a
result, large amounts of copper accumulate in mitochondria, an caus-
ing free radical formation and oxidative damage in multiple organs
(liver, brain, kidney, eye) (793). The responsible gene is called ATP7B
and is located at chromosome 13q14.3-21.1 (794). Initial symptoms in
children are usually related to liver failure (jaundice or portal hyperten-
sion). When neurologic symptoms predominate, the appearance of the
illness is delayed until the end of the first decade or the second decade
and progression is slower than in the hepatic form (57). Several clinical
phenotypes have been identified. The classic form is characterized by
extrapyramidal signs (dystonia and Parkinson-like features). In other
patients, cerebellar signs (ataxia and wing-beating tremor) or bulbar
signs (swallowing difficulties, dysarthria) and seizures may dominate
the neurological picture (795). Deterioration in school performance
and behavior, intellectual impairment or emotional disturbances may
also be observed. In patients with neurologic presentations, the diag-
nosis is usually made from the presence of Kayser-Fleischer rings, rings
of green pigmentation in the cornea. However, when Wilson disease
presents with hepatic symptoms, Kayser-Fleischer rings may not yet
be present.

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 170 Pediatric Neuroimaging

FIG. 3-74. Rhizomelic chondrodysplasia punctata. A. Antero-

posterior radiograph shows irregularity and abnormal stippling
of multiple joints (white arrows), including shoulders, elbows,
hips, and costo-vertebral joints. B. Sagittal T2-weighted image
at the cranio-cervical junction shows an edematous upper cervi-
cal spinal cord (black arrows) that is compressed by the posterior
arch of C1 (white arrowhead). Foliation of the cerebellar vermis
appears abnormal and the ventral pons appears small. C. Sagittal
T2-weighted image of the thoracolumbar spine shows abnormal
appearing vertebrae resulting from the chondrodysplasia. The tip
of the conus medullaris is low and the filum terminale (white
arrowheads) is thick, suggesting a tethered spinal cord. D. Axial
T2-weighted image at the level of the lateral ventricles shows large
ventricles, abnormally hyperintense white matter, and irregular,
abnormal sulcation of the cerebral cortex.

FIG. 3-75. Rhizomelic chondrodysplasia punc-

tata. A. Axial T2-weighted image shows patches
of subcortical T2 prolongation (open white
arrows) and a periventricular nodular heteroto-
pion (open black arrow). B. Axial T2-weighted
image at a higher level shows asymmetrical
patchy white matter hyperintensities (arrows).
A venous malformation is present in the parietal
region. (This case courtesy Dr. Curtis Sutton.)

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
CT findings of Wilson disease consist of low density in the basal
ganglia and variable cerebral white matter atrophy (796). Brain MRI
in clinically symptomatic patients is usually, but not always, abnormal.
Indeed, in a small portion (27%) of patients with mild neurological
manifestations, conventional MRI may be normal; conversely, in about
one third of clinically asymptomatic patients subtle abnormalities may
be found (797,798). Patients presenting with hepatic failure in child-
hood are usually found to have bilateral, symmetric T1 shortening (high
intensity on T1-weighted images) in the globus pallidus (Fig. 3-76A)
and dorsal midbrain, secondary to the hepatic failure and portosys-
temic shunting (799,800). The T1 changes are believed to result from
abnormal accumulation of manganese; they may be conspicuous even
in clinically well-controlled patients who do not have other detectable
CNS abnormalities (on T2-weighted images). MR findings in patients
presenting with CNS signs and symptoms consist of T1 hypointensity
and T2/FLAIR hyperintensity in the putamina, caudate nuclei, globi
pallidi, dorsal mesencephalon, thalami, cerebral peduncles, superior
cerebellar peduncles, and claustra (Fig. 3-76) (801); some of the T2
Barkovich_Chap03.indd 171
171
changes may resolve after chelation therapy (795). Lesions of the claus-
tra are inconsistently seen but, when present, may be suggestive of Wil-
son disease. Reduced diffusivity may be seen in actively involved regions
(Fig. 3-76E). The presence of deep gray nucleus involvement seems to
correlate well with neurologic disability, striatal lesions with pseudo-
parkinsonism, and putaminal lesions with dystonia (802). Cortical and
white matter atrophy are present in up to 70% or patients as the disease
advances (Fig. 3-76D) (801) and, occasionally, focal areas of abnormal
signal intensity are seen in the cerebral hemispheric white matter, pri-
marily frontally and temporally (803,804); subcortical white matter is
typically affected more than deep white matter (801). Although cere-
bral involvement is most commonly bilateral and symmetrical, asym-
metric or unilateral involvement can occur (805). Proton spectra are
normal in treated patients (806–808). Untreated patients show slight
decrease in all metabolites; the mean values of NAA/Cho and NAA/Cr
were lower in patients with Wilson disease than in the control subjects
(Fig. 3-76F) (808). Myo-Inositol/creatine ratios were increased in the
basal ganglia on short echo spectroscopy (809).
FIG. 3-76. Wilson disease. A. Coronal
T1-weighted image shows abnormal hyper-
intensity of the globi pallidi (g) bilaterally. B.
Axial T2-weighted image shows abnormal
hyperintensity (white arrows) in the dorsal
midbrain. C. Axial T2-weighted image at
the level of the basal ganglia shows abnor-
mal hyperintensity (white arrows) in the
caudate heads and putamina. D and E. Axial
T2-weighted (D) and diffusion-weighted
(E) images 5 years later shows enlarged CSF
spaces and some new hyperintensity (white
arrows in D) in the thalami, compatible with
progression of disease. The reduced diffusiv-
ity (white arrows in E) in the lateral thalami
indicates active cellular injury. F. Proton MR
spectrum (TE = 288 ms) shows reduced
choline and creatine peaks.
5/6/2011 12:08:59 AM
 172 Pediatric Neuroimaging

FIG. 3-76. (Continued)

Mitochondrial Disorders (Respiratory Chain Disorders) weakness, hypotonia, delayed development, and cardiopulmonary
The mitochondrial disorders (Tables 3-15 and 3-16) are a group of dis- failure leading to early death. The other major multisystemic presenta-
eases characterized by disorders of mitochondrial function that result tion is that of Leigh syndrome; indeed, complex I deficiency seems to
in (a) elevated NADH/NAD+ ratio in cells, (b) impaired adenosine
triphosphate (ATP) production in affected cells, (c) increased super-
oxide radical formation, and (d) functional impairment of numerous
metabolic pathways (810–816). Mitochondrial disorders are relatively TABLE 3-15 Disorders of the
common metabolic disorders of childhood, with recent demonstration Respiratory Chain
of a birth prevalence of inherited mitochondrial disorders to be greater
than 1 in 5,000 (817). Single or multiple organs (brain, heart, muscles,
I. Complex I Deficiency
kidney, liver, endocrine glands, bone marrow) can be involved, with
A. Myopathy
the striated muscles and brain most commonly affected (810–814).
B. Multisystemic disorder
A mitochondrial disorder should be suspected in patients presenting
1. Fatal Infantile disorder
with an unexplained combination of neuromuscular and/or non-
2. Leigh syndrome
neuromuscular symptoms, a progressive course, and involvement of
seemingly unrelated organs or tissues (815), particularly if associated II. Complex II Deficiency
with certain “red flags” such as short stature, neurosensory hearing A. Succinate dehydrogenase deficiency
loss, progressive external ophthalmoplegia, axonal neuropathy, diabe- B. Coenzyme Q10 deficiency
tes mellitus, hypertrophic cardiomyopathy, or renal tubular acidosis 1. Myopathic form
(4). It should also be suspected in severely ill newborns when there is 2. Ataxic form
little evidence suggestive of an intrapartum hypoxic-ischemic insult 3. Infant encephalomyopathic form
or when MR features are unusual for hypoxic-ischemic injury (818). III. Complex III Deficiency
Classification of these disorders is difficult. Classification neither by A. Multisystemic disorders
phenotype nor by morphology has been satisfactory, particularly in 1. GRACILE syndrome (growth retardation, aminoaciduria,
children in whom classic “syndromic” findings tend to be absent (4). cholestasis, iron overload, lactic acidosis, early death)
Classification by metabolic pathway involved has been similarly unsat- 2. Leigh syndrome
isfactory. Therefore, the term mitochondrial disorder is becoming B. Myopathy
restricted to disorders of a single biochemical pathway, the respiratory C. Infantile histiocytoid cardiomyopathy
chain (819).
IV. Complex IV Deficiency
The respiratory chain contains five functional units, called com-
A. Myopathic forms
plexes I-V, that are embedded in the inner mitochondrial membrane
B. Multisystemic forms
(Table 3-15). Its function is to transfer electrons from reduced nucle-
1. Leigh syndrome
otides and flavoproteins to molecular oxygen with resultant oxidation
2. Alpers syndrome
of NADP and FAD. Almost all of these disorders are associated with
lactic acidosis and an elevated lactate/pyruvate ratio (819). Complex I V. Complex V Deficiency
(reduced NADP-CoQ reductase) is the largest complex of the respira- A. Multisystemic forms
tory chain. Patients with complex I deficiency can be subclassified as 1. Leigh syndrome
those with myopathy or multisystemic disorder (819). The myopathy, 2. NARP (Neuropathy, Ataxia, Retinitis Pigmentosa)
manifested as exercise intolerance and limb weakness, typically develops 3. Familial bilateral striatal necrosis
in childhood or early adult life. The multisystemic involvement can be 4. Fatal infantile multisystemic disease
manifested as a fatal infantile disorder with congenital lactic acidosis,

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
TABLE 3-16 Clinical Classification of
Mitochondrial Disorders
I. Exclusive or Predominant Muscle Involvement.
A. Fatal infantile myopathy
B. Benign infantile myopathy
II. Predominant Brain Involvement
A. Subacute necrotizing encephalomyelopathy (Leigh syndrome)
1. Pyruvate dehydrogenase complex
2. Respiratory chain complex (cytochrome c oxidase)
3. ATPase 6 subunit of complex V
B. Alpers syndrome
C. Myoclonic epilepsy with ragged-red fibers (MERRF)
D. Trichopoliodystrophy (Menkes disease)
E. Mitochondrial Encephalopathy with lactic acidosis and
stroke-like episodes (MELAS)
F. Glutaric Acidurias Types I and II
G. Familial Mitochondrial Encephalopathy with
macrocephaly, cardiomyopathy, and Complex I deficiency
H. Neonatal lactic acidosis, complex I/IV deficiency, and fetal
cerebral disruption
III. Other
A. Progressive external ophthalmoplegia
1. Isolated
2. With retinitis pigmentosa and other organ involvement
(Kearns-Sayre syndrome)
3. Encephalomyopathy in adults
4. Mitochondrial neurogastrointestinal encephalopathy (MNGIE)
be one of the major causes of Leigh syndrome (see discussion later in
this section) (819). Complex II (succinate-CoQ reductase) deficiency is
less common; it typically presents as an encephalomyelopathy. Succinate
dehydrogenase deficiency (see discussion later in this section) belongs
to this group, as does CoQ10 deficiency. The latter can cause a myopa-
thy characterized by recurrent myoglobinuria and CNS dysfunction
that includes seizures, ataxia, or mental retardation. When ataxia pre-
dominates, significant brainstem involvement or cerebellar atrophy may
be present (see section V.E.3.f on cerebellar atrophy in this chapter for
more details). Complex III (coenzyme Q-cytochrome-c oxidoreductase)
defects are divided into three forms. The first is a generalized multisys-
temic disorder manifested by limb weakness, exercise intolerance, and
various neurologic signs (819). The second is a tissue-specific syndrome
manifested as a pure myopathy with childhood onset (819). The third is
a pure cardiomyopathy manifested in early infancy (819). In addition,
a rapidly fatal infantile disorder called GRACILE (growth retardation,
aminoaciduria, cholestasis, iron overload, lactic acidosis, early death) has
been described in Finland (820). Complex IV (cytochrome c oxidase)
defects can also be divided into myopathic and systemic forms (821).
Myopathies include a fatal infantile syndrome and a benign infantile syn-
drome. The main multisystemic presentation is Leigh syndrome; Alpers
disease has also been associated with complex IV deficiency, but these
cases are not well characterized. Complex V (mitochondrial ATP syn-
thase) deficiencies are associated with clinical findings of both Leigh syn-
drome and NARP (neuropathy, ataxia, and retinitis pigmentosa), as well
as a milder condition known as familial bilateral striatal necrosis (819).
Major and minor diagnostic criteria for mitochondrial disorders
have been proposed (822,823), but no consensus has been reached.
However, certain clinical features are characteristic of many of the
Barkovich_Chap03.indd 173
173
mitochondrial disorders and may raise the possibility of the diagnosis;
these include seizures, hypotonia, peripheral neuropathy, ataxia, oph-
thalmoplegia, bulbar signs, short stature, mental deterioration, muscle
weakness, cardiomyopathy, cardiac arrhythmia, exercise intolerance,
and neurosensory hearing loss (4,811–813,824). When the classic symp-
tom complex of a specific mitochondrial disorder is found, a specific
diagnosis is rather straightforward. However, such findings are rare in
children. This blurring of symptom complexes has created controversy
concerning the classification of mitochondrial disorders. Some groups
(811,814,825) believe that certain clinical features are adequately clus-
tered in some patients to allow the identification of syndromes that
are useful in patient management. Other investigators believe that
the overlap of features among the “syndromes” is too great to make
the clinical classifications useful; they await a biochemical/molecular
genetic classification (3,4,812,813,816,826–828). Moreover, many dis-
orders of organic acid and fatty acid metabolism lead to abnormal
mitochondrial function (829), as do some neurodegenerative disorders
(830); should these be classified as mitochondrial disorders? Overall,
the classification has not become any clearer in the past 15 years; there-
fore, it remains sufficient to understand that mitochondrial disorders
and other metabolic disorders are not always clearly separate and distinct
entities, and that the disorders in this group, even when distinguishable,
have significant overlap.
Considering the considerable overlap among mitochondrial disor-
ders, it is not surprising that the imaging findings are not distinctive.
Some patients may have only delayed myelination or a nonspecific T2
prolongation in the white matter (831). Others may have white matter
cavitation or cortical malformations (832). Recently, it has been noted
that cerebellar atrophy is common in many mitochondrial disorders
(833). However, certain imaging characteristics should cause mito-
chondrial disorders to be included in the differential diagnosis. Disor-
ders of mitochondrial function should be considered in any infant or
child who has abnormalities of the deep cerebral gray matter or dorsal
brainstem, in particular if white matter disease or cerebellar atrophy
is present, as well. The finding of significantly increased lactate in the
brain parenchyma or CSF by proton MR spectroscopy also supports
the possibility of mitochondrial disease (834) (please note, however,
that mild elevation of lactate is common in the neonate and nonspe-
cific). MRS of CSF may be more sensitive than MRS of cerebral tissue,
as lactate is slowly cleared from brain tissue into the CSF before being
resorbed into the systemic circulation (835).
Certain mitochondrial disorders, such as MERRF (myoclonus, epi-
lepsy, ragged red fibers) and Leber hereditary optic neuropathy are seen
primarily in adults and, therefore, are not discussed in this book.
Mitochondrial Encephalomyopathy with Lactic Acidosis and
Strokelike Episodes (MELAS)
MELAS (OMIM 540000) refers to a group of disorders causing episodes
of throbbing headache, nausea, vomiting, and permanent or reversible
stroke-like events (hemianopsia and hemiparesis) in conjunction with
some of the signs and symptoms of generalized mitochondrial disease
(811,836–841). Patients can present at any age, most commonly in
the second decade (841). Serum and CSF lactate are usually elevated
at the time of presentation. Affected patients may have any of several
deletions of mitochondrial DNA (842), the most common mutation
being in the tRNALeu gene (815). The cause of the stroke-like events
is unknown. Currently, the disorder is believed to result from derange-
ments in cytochrome oxidase enzymatic function and consequent
effects on neuronal ATP levels (842).
Imaging studies in the acute phase show swelling and T1 hypoin-
tensity and T2/FLAIR hyperintensity in the affected areas of the brain
(Figs. 3-77 and 3-78), primarily the parietal and occipital cortex and
5/6/2011 12:09:00 AM
 174 Pediatric Neuroimaging

subcortical white matter (840,843,844) (but any cortical area may
be affected) and in the basal ganglia (Fig. 3-77) (845,846). In some
patients, the dorsal brainstem and spinal cord are involved (847);
cerebellar atrophy may develop in late stages of the disease (833,848).
Sequential scans may show resolution and subsequent reappearance of
the abnormal areas (840,843,849) or, more commonly, development
of new lesions (Fig. 3-78). Eventually, T1 hyperintensity may appear
in the affected cortex, indicative of permanent cortical damage, and
atrophy then ensues (850). The lesions are not restricted to a specific
arterial distribution (Fig. 3-78)—indeed, single lesions often cross
vascular boundaries—helping to distinguish MELAS from embolic or
thrombotic infarction. MR spectroscopy shows high lactate in affected
areas of brain (Fig. 3-78C) (845,851,852). However, as infarcts of any
cause seem to result in local increases in lactate (853), the presence
of lactate in the region of an acute cortical lesion is certainly not spe-
cific for MELAS; the presence of lactate in areas of the brain that are

FIG. 3-77. Mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS). This teenage girl with a history of short stature and devel-
opmental delay presented with acute blindness. A. Axial noncontrast CT scan shows low attenuation (white arrows) in the occipital lobes. Other areas of low
attenuation (black arrows) are seen in the corpus striatum. B. Axial FLAIR image from the following day shows additional lesions (regions of hyperintensity)
in the left occipital pole (smaller white arrows) and left cingulate gyrus (larger white arrow). Notice that the left occipital lesion crosses vascular boundaries, a
characteristic of the cortical lesions of MELAS. C. Axial post contrast T1-weighted image shows enhancement of the left occipital and cingulate gyrus lesions,
in addition to the posterior putamina (small white arrows) and left superior frontal gyrus (large white arrow). D. Diffusion weighted image (b = 1,000) shows
reduced water motion (manifested as hyperintensity) in the left occipital pole (small white arrows) and superior frontal gyrus (large white arrow).

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 175

FIG. 3-78. MELAS in a young child: sequential infarc-

tions. A and B. Axial T2-weighted image (A) and diffusion
weighted image (B) show hyperintensity (white arrows) in
the right parietal cortex, indicating subacute infarction.
C. Single voxel spectrum (TE = 288 ms) shows slightly
reduced NAA and a markedly enlarged lactate doublet
(Lac). D and E. Axial FLAIR (D) and diffusion weighted
image (E) 2 weeks later show new infarctions in the left
temporal lobe (white arrows) and pulvinar (white arrow-
head), regions with different vascular distributions.

Barkovich_Chap03.indd 175 5/6/2011 12:09:01 AM

 176 Pediatric Neuroimaging
not visibly abnormal on T2 or diffusion images is more suggestive of
mitochondrial disease. Short echo time MRS shows elevated glucose
and severely reduced NAA, glutamate, and creatine (854). Reports
describing the findings of diffusion imaging in MELAS are conflict-
ing. Some authors report reduced diffusion in some affected areas
(855,856), while others report increased diffusion (857). This dif-
ference may reflect the acuity of the lesion or its severity. In either
event, findings on diffusion images should not be used to differentiate
MELAS from other causes of cortical injury at this time. Of interest,
the size of the diffusion abnormality may increase over several weeks
on sequential studies (850). This progression and the crossing of vas-
cular boundaries may be useful in separating MELAS from embolic or
thrombotic infarcts. Perfusion studies show increased local blood flow
(858,859) but decreased local glucose uptake and oxygen extraction
fraction (860,861) in affected brain tissue in the acute phase.
Kearns-Sayre Syndrome/Progressive External
Ophthalmoplegia
Kearns-Sayre syndrome (OMIM 530000) and progressive external
ophthalmoplegia (OMIM 258450, also called ophthalmoplegia plus)
are discussed together because both are mitochondrial disorders char-
acterized by progressive external ophthalmoplegia with cardiac and
retinal manifestations. To establish the diagnosis of Kearns-Sayre syn-
drome, patients must have, as a minimum, external ophthalmoplegia,
retinitis pigmentosa, and onset of neurologic or muscular dysfunction
before the age of 20 years (811,814,838,839,862). Some authors require
elevated CSF protein (863), heart block (59,862), or cerebellar ataxia
(815) for clinical diagnosis. Patients may also have dementia, short
stature, sensorineural hearing loss, endocrine dysfunction, elevated
serum and CSF lactate, and muscle weakness (811,814,863,864). Many
different mitochondrial DNA deletions have been found in affected
patients (44,865). Progressive external ophthalmoplegia patients have
exercise-induced or permanent pareses, progressive external ophthal-
moplegia, peripheral neuropathy, hypoacusis, pyramidal and extrapy-
ramidal symptoms, cerebellar syndromes, and dementia (866,867).
FIG. 3-79. Kearns-Sayre syndrome, early disease phase. A. Axial T2-weighted sequence shows T2 prolongation (black arrows) in the dorsal mesencephalon.
B. Axial T2-weighted image at a higher level shows mild subcortical T2 prolongation (white arrows). Note that the subcortical U fibers are involved even at
this early stage. C. Diffusion weighted image (b = 1,000) shows reduced water motion (manifested as hyperintensity, arrows) in the subcortical white matter.
D. Coronal FLAIR image again shows involvement of subcortical white matter with sparing of periventricular white matter (arrows). Note that the globi
pallidi are not involved at this stage of the disease.
Barkovich_Chap03.indd 176
The disorder is associated with mutations of the nuclear-encoded
DNA polymerase-gamma gene (POLG) located at chromosome 15q25,
although many reported patients have had mutations of mitochondrial
DNA. There appears to be some overlaps of progressive external oph-
thalmoplegia with MNGIE (see following section).
The neuroimaging findings in Kearns-Sayre syndrome and oph-
thalmoplegia plus appear very similar. CT scans show cortical and
white matter atrophy, hypodensity of cerebral and cerebellar white
matter, and variable hypodensity or calcification of the deep cerebral
and cerebellar nuclei (59,868). It is not clear whether the calcification
is the result of the primary disorder or the associated hypoparathyroid-
ism that often accompanies the syndrome (869). MR scans (Figs. 3-79
and 3-80) show patchy T2 hyperintensity in the white matter, predomi-
nantly subcortical, with early involvement of the subcortical U fibers
(Fig. 3-79) and sparing of periventricular areas (845,867). Later the
deep cerebral white matter and the deep gray matter nuclei, particu-
larly the dorsal midbrain, medial and posterior thalami, and the globi
pallidi, show T2 hyperintensity (Fig. 3-80) (831,845,867,870,871). The
characteristic MR findings may not be present early in the course of
the disease (831). The affected white matter shows reduced diffusion
(Fig. 3-79) (11), which may persist over several years (Fig. 3-80) (872).
DTI in a single patient with Kearns-Sayre syndrome appeared to show
low fractional anisotropy and increased diffusivity compared to age-
matched normals (873). Proton MR spectroscopy of affected regions
shows increased lactate and reduced NAA.
Mitochondrial Neurogastrointestinal Encephalomyopathy
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE,
OMIM 603041) is a multisystemic disorder clinically characterized
by severe gastrointestinal dysmotility (often pseudoobstruction),
cachexia, progressive external ophthalmoplegia, peripheral neuropa-
thy, and leukoencephalopathy (874); the most common neurologic fea-
tures are peripheral neuropathy, ptosis, ophthalmoparesis, and hearing
loss (875). Average age at onset is 19 years, but varies from infancy to
the fifth decade (875). The disorder is caused by mutations in the gene
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 177

FIG. 3-79. (Continued)

FIG. 3-80. Kearns-Sayre syndrome, later disease phase. A and B. Axial T2-weighted images show abnormal hyperintensity in the midbrain (black arrows, A),
globi pallidi (white arrowheads, B) and subcortical white matter (white arrows, B). C. Axial diffusion weighted image shows abnormal hyperintensity in the sub-
cortical white matter (white arrows), indicated reduced diffusivity. D. Single voxel proton MR spectrum from the basal ganglia shows elevated lactate (Lac).

Barkovich_Chap03.indd 177 5/6/2011 12:09:03 AM

 178 Pediatric Neuroimaging
encoding thymidine phosphorylase (TYMP, located on chromosome
22q13.32-qter) (876). A form without leukoencephalopathy can be
caused by mutations of the DNA polymerase gamma gene (POLG)
at chromosome 15q25; this has led to the speculation that there is an
overlap of mitochondrial-induced progressive external ophthalmople-
gia (see previous section, V.D.6.b) and MNGIE (877). Mitochondrial
deletions may be associated with MNGIE, as well (878). This discussion
of Kearns-Sayre, PEO, and MNGIE nicely shows the difficulties associ-
ated with organizing mitochondrial disorders into distinct clinical/genetic
syndromes.
Neuroimaging shows the presence of diffuse leukoencephalopa-
thy in patients with mutations of TYMP (875,879), but not in patients
with POLG mutations (877). CT of patients with leukoencephalopa-
thy reveals diffuse hypodensity of cerebral and cerebellar white matter.
MRI shows diffuse high signal intensity of the periventricular and deep
cerebral white matter on T2-weighted and FLAIR images (Fig. 3-81);
subcortical U fibers and corpus callosum are typically spared. Thalami
and basal ganglia may show patchy T2 and FLAIR hyperintensity or
may be spared; in some patients, the hyperintensity extends caudally
into the internal and external capsules and brainstem (11,880).
Disorders Causing Leigh Syndrome
Leigh syndrome (OMIM 256000) refers to a symptom complex with
characteristic, but variable, clinical and pathologic manifestations
(338,881). Affected infants and children typically present toward the
end of the first year of life with hypotonia and psychomotor dete-
rioration. Ataxia, ophthalmoplegia, ptosis, dystonia, and swallowing
difficulties almost inevitably ensue. Classic pathologic abnormalities
include microcystic cavitation, vascular proliferation, neuronal loss,
and demyelination in the midbrain, basal ganglia, cerebellar dentate
nuclei, and, occasionally, cerebral white matter (338,882–884).
Although it has been known for some time that several biochemi-
cal and genetic abnormalities cause Leigh syndrome, the different
genetic causes are only now being elucidated. The disorder seems to
be the result of defective terminal oxidative metabolism from any of
FIG. 3-81. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) due to TYMP mutation.
Axial T2-weighted images (A and B) show diffuse leukoencephalopathy with relative sparing of corpus
callosum, internal capsules (arrows) and basal ganglia. Minimal thalamic involvement (white arrowheads)
is identified.
Barkovich_Chap03.indd 178
a number of causes that are likely to impair energy production (885).
Many disorders can result in Leigh syndrome; indeed, mutations of
both mitochondrial and nuclear DNA, involving genes coding for pro-
teins in respiratory chain complexes I, II, III, IV, and IV, mitochondrial
tRNA, pyruvate dehydrogenase complex, and Coenzyme Q10 have
been shown to cause Leigh syndrome (3,44,886). Four groups seem to
account for the large majority of cases; these and a few others of inter-
est will be discussed in some detail.
The first group is that with defects of the pyruvate dehydrogenase
complex; biochemical defects can involve any of the three catalytic
subunits of the enzyme complex or the activation of the complex by
pyruvate dehydrogenase phosphatase (887,888). Pyruvate dehydroge-
nase deficiency typically has the classic imaging findings described in
Leigh syndrome with T1 hypointensity and T2/FLAIR hyperintensity
of the corpus striatum (caudate and putamen) and cortex in addition
to delayed myelination (Fig. 3-82). Long echo time proton MRS shows
large lactate peaks and small NAA peaks in affected regions. Diffusion-
weighted images show reduced water diffusivity in acutely affected
regions and increased diffusivity in chronically affected regions, which
may show frank cavitation. However, cerebral dysgenesis can also be
seen, particularly in E1 alpha subunit (PDHA) deficiency, which is the
most common enzyme defect in PDH deficiency. This X-linked disor-
der (PDHA1 is located at Xp22.2-p22.1) is associated with dysgenesis
of the corpus callosum, absence of the medullary pyramids, ectopic
olivary nuclei, dysplasia of the cerebellar dentate nuclei, subcortical
heterotopia, and polymicrogyria (889,890).
The second group has cytochrome oxidase deficiency (COX, respi-
ratory chain complex IV); this is currently believed to be the most com-
mon cause of Leigh syndrome (891,892). The COX enzyme complex
is composed of 13 structural subunits, some of which are encoded by
mitochondrial DNA, some by mitochondrial tRNA genes, and some by
nuclear DNA (891). Leigh syndrome is caused by a defect that is inher-
ited as an autosomal recessive trait. Mutations of SURF1, a gene located
on nuclear chromosome 9q34 and important in the assembly and main-
tenance of cytochrome oxidase activity, are probably the most common
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 179

FIG. 3-82. Leigh syndrome due to pyruvate dehydrogenase deficiency. Axial FLAIR images show abnor-
mal in the corpus stratum (large white arrows in A), posteromedial thalami (white arrowheads in A), and
several regions of cerebral cortex (small white arrows in B).

cause of this form of the disease, being responsible for as many as one
third of the COX deficiency patients (891,893–895). Affected patients
present near the end of the first year of life with progressive enceph-
alopathy, hypotonia, ataxia, abnormalities of eye movement, swallow-
ing difficulties, and central respiratory problems (891,896). Mutations
of other genes needed for COX assembly are associated with clinical
variations of Leigh syndrome: SCO2 and COX15 genes with cardioen-
cephalopathy, SCO1 gene with hepatoencephalopathy, and COX10 with
nephroencephalopathy (819). Imaging features of a number of patients
with SURF1 mutation associated with COX deficiency have been
described (896–898). Early scans may be normal (898). As the disease
progresses, they develop characteristic T1 hypointensity and T2/FLAIR
hyperintensity in the subthalamic nuclei, medulla, inferior cerebel-
lar peduncles, inferior olives and nucleus of the solitary tract in the
medulla, central tegmental tract and reticular formation in the dorsal
pons, and periaqueductal gray matter of the mesencephalon in nearly
all cases (Fig. 3-83). Involvement of the substantia nigra, red nuclei, and
cerebellar dentate nuclei are seen less commonly, while involvement of
the medial thalami is seen in some cases but is uncommon (896–899).
The acutely affected areas show reduced diffusion (Fig. 3-83D). In our
experience, lactate is not always seen on proton MRS in these patients.
Of note, SURF1 mutation with COX deficiency has also been described
with exclusive white matter involvement (900); this observation empha-
sizes the remarkable phenotypic variations of mitochondrial disorders!

FIG. 3-83. Leigh syndrome secondary to SURF1 mutation in a 15-month old child. A–C. Axial T2-weighted images through the brain stem show involve-
ment of the inferior olives (large black arrows in A), central tegmental tracts (black arrows in B), dorsal midbrain (large white arrows in C), red nuclei (small
white arrows in C), and subthalamic nuclei (white arrowheads in C). D. Axial diffusion weighted image (b = 1000) shows reduced diffusion (hyperintensity)
in most of the affected area of the midbrain.

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 180 Pediatric Neuroimaging
A third group of mutations, which show maternal inheritance,
appear to arise from mutations to the mitochondrial ATPase 6 gene
(Complex V) (901–906). Mutations in this family may also be respon-
sible for clinically milder Leigh-like syndromes, such as bilateral stri-
atal necrosis (907,908) and NARP (neuropathy, ataxia, and retinitis
pigmentosa) (909). These patients seem less homogeneous than the
SURF1 group, but in limited experience have involvement of the ante-
rior putamina, dorsal mesencephalon, and dorsal pons (Fig. 3-84).
A fourth group, which may be responsible for a large group of
patients, is complex I deficiency (910–914). Few reports are available
regarding neuroimaging findings in this disorder, although extensive
white matter cavitation has been reported in a few cases (Fig. 3-85)
(832,914) and typical basal ganglia involvement in others (915). We
have noted callosal cavitation to be common (Fig. 3-85A), along with
cerebellar atrophy (Fig. 3-85A) and high lactate levels on proton MRS
(Fig. 3-85D). With the accumulation of more clinical and laboratory
data, more precise patterns of radiologic and clinical features will
emerge, along with refinements in classification.
A less common group is that of infants with thiamine deficiency.
Although very rare in developed countries, infantile thiamine deficiency
is an important cause of Leigh syndrome because it can be treated;
therefore, it should always be considered in the proper clinical setting,
particularly if the mamillary bodies are affected. Infants develop this
disorder when their diet is deficient in thiamine (vitamin B1) and they
have a mutation of the gene coding for one of the enzymes that use thi-
amine as a cofactor (611,916). The lack of thiamine is typically either
the result of being breastfed by mothers who were themselves thiamine
deficient or being fed infant formula lacking thiamine Affected infants
typically present in the first year of life with gastrointestinal symptoms
(vomiting or diarrhea) accompanied by apathy, apnea, or seizures.
Vertical nystagmus may be present of neurologic examination (917).
Analysis of the CSF and serum at the time of admission will typically
show elevated lactate. CT shows low attenuation of the frontal lobes or
basal ganglia (918). MRI shows the characteristic bilateral symmetrical
putaminal T2 hyperintensity of Leigh syndrome with frequent involve-
ment of the medial thalami, periaqueductal gray matter, and dorsal
brainstem, as well. What distinguishes thiamine deficiency from other
Barkovich_Chap03.indd 180
FIG. 3-83. (Continued)
causes of Leigh syndrome, however, is the nearly constant involvement
of the mamillary bodies and the frequent involvement of the frontal
cortex (917,919); the latter may be associated with poor prognosis
(919). Calculated Dav images will show reduced diffusivity in affected
areas in the acute phase. Proton MR spectroscopy reveals elevated lac-
tate and decreased NAA in affected regions of the brain (917).
Complex II deficiencies account for about 2% of mitochondrial
encephalomyopathies (920). Leukodystrophy and Leigh syndrome have
been among the wide range of presentations. Succinate dehydroge-
nase deficiency can present with either of these phenotypes (920,921).
Patients typically present with acute neuromotor deterioration late
in the first year or early in the second year of life. MRI shows either
basal ganglia disease typical of Leigh syndrome or T2/FLAIR hyper-
intensity of periventricular and deep cerebral white matter together
with cerebellar white matter (Fig. 3-86A–C). Diffusivity is reduced in
actively involved areas (Fig. 3-86D). Diagnosis can be confirmed by
proton MR spectroscopy, which shows a large singlet (succinate) at
2.4 ppm in white matter (Fig. 3-86E) but not in gray matter. We have
seen other disorders due to Complex II deficiencies with abnormalities
largely confined to the posterior fossa and sparing of supratentorial
structures.
In summary, the patterns of injury in patients with Leigh syn-
drome vary with the mutation that is the cause of the syndrome; these
patterns are described in the previous paragraphs and summarized in
Table 3-17. Diffusion characteristics and proton spectroscopic char-
acteristics vary depending upon the acuity of the lesion. In the acute
phase of injury, when mitochondrial function is acutely impaired and
ATP production acutely reduced, water diffusivity will be reduced. If no
permanent damage ensues, diffusivity may return to normal. However,
if significant astrogliosis or necrosis ensues in the injured area, diffusiv-
ity will be increased. MR spectroscopy has shown decreased NAA and
elevated lactate, with lactate elevation most pronounced in areas with
acute mitochondrial dysfunction (and consequent anaerobic glycoly-
sis) and in those areas most severely affected on the imaging studies
(845,851,852). As other disorders that involve the basal ganglia may
not have increased basal ganglia lactate (922), the presence of lactate in
a patient with a characteristic imaging pattern supports the diagnosis
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 181

FIG. 3-84. Neuropathy, ataxia, and retinitis pigmentosa (NARP).

A. Sagittal T2-weighted image shows abnormal hyperintensity (white arrows)
in the dorsal brainstem. B and C. Axial T2-weighted (B) and coronal FLAIR
(C) images shows abnormal diffuse and focal hyperintensity in the lentiform
nuclei (large white arrows), caudates (white arrowheads), and hypothalamus
(small white arrows). The extent of abnormality is better appreciated on the
FLAIR image. D and E. Axial diffusion weighted image (D) shows reduced
diffusivity in the cerebral peduncles (white arrowheads) and midbrain
tegmentum (white arrows), while axial postcontrast T1-weighted image
(E) shows enhancement (white arrows) in the areas that had reduced
diffusivity.

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 182 Pediatric Neuroimaging

FIG. 3-85. Leigh syndrome due to complex 1 deficiency. A. Sagittal T1-weighted image shows cavitation of the posterior body and splenium of the cor-
pus callosum (white arrows) and cerebellar vermian atrophy (white arrowheads). B. Axial T1-weighted image shows low signal intensity of periventricular
white matter (arrows and arrowheads), with more marked hypointensity, suggesting cavitation posteriorly (white arrows). C. Coronal FLAIR image shows
heterogeneous hyperintensity of periventricular and deep white matter, with some central areas of hypointensity (white arrows) indicating complete cavita-
tion. Cerebellar white matter (white arrowhead) is involved. D. Single voxel proton MRS from frontal white matter showing a low NAA peak and markedly
elevated lactate (Lac).

of Leigh syndrome. However, lactate is absent in up to 50% of patients
with Leigh syndrome at the time of MRI (3), and the presence of lactate
is not specific for mitochondrial disorders (ischemia, infection, inflam-
mation, and neoplasm can also cause elevated lactate).
Alpers Disease
Alpers disease (OMIM 203700) is a rare autosomal recessive, progres-
sive multisystemic disorder characterized by predominant involvement
of the cerebral gray matter and the liver (824,884,923–925). The disease
seems to be caused by mutations of the nuclear gene encoding mito-
chondrial DNA polymerase gamma, POLG1, located on chromosome
15q25 (926,927). Patients typically present with intractable seizures,
particularly myoclonic jerks, following some early developmental delay
or failure to thrive (824,884,925,928). Identification of the clinical tet-
rad of refractory seizures, episodic psychomotor regression, cortical
blindness, and liver disease with micronodular cirrhosis is often diag-
nostic (927). Onset is usually in the first few years of life, and may
be as early as the first few weeks. Overt evidence of hepatic disease is
variable, but abnormalities of hepatic chemistry may be detected early
(925,929). Pathologically, the brain shows spongiform cortical atrophy,
which is most pronounced in the occipital region, and atrophy of the
basal nuclei, particularly the thalami and globi pallidi (59,884,925).
Reports of imaging of patients with Alpers disease are few. CT find-
ings include focal hypodensities of both gray and white matter, followed
by diffuse atrophy (59,824). On MRI, authors note T2 hyperintensity
in cortex, subcortical white matter and basal ganglia, diminished white
matter, delayed myelination, and cortical thinning that is most severe
in the frontal, posterior temporal and occipital lobes (845,925,930);
progression of the disorder is often rapid (931). No reports of MRS in
Alpers disease have been published.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 183

FIG. 3-86. Leigh syndrome due to succinate dehydrogenase deficiency (complex

II). A–C. Axial T2-weighted images show extensive T2 hyperintensity in the middle
cerebellar peduncles and cerebellar white matter (white arrowheads, A), corpus cal-
losum (small white arrows, B), periventricular and deep cerebral white matter (large
white arrows, B and C). D. Axial average diffusivity (Dav) image shows reduced Dav
in the corpus callosum (small black arrows) and corticospinal tracts (black arrow-
heads) but increased diffusivity (hyperintensity) in the deep cerebral white matter.
E. Single voxel proton MRS from the frontal white matter shows reduced NAA and
a large singlet at 2.4 ppm representing succinate (Su). Succinate was not seen in gray
matter voxels. (This case courtesy Dr. Vernon Byrd, Charlotte.)

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 184 Pediatric Neuroimaging

TABLE 3-17 Causes and Imaging Characteristics in Leigh Syndrome

Cause
Pyruvate dehydrogenase complex deficiency
Cytochrome Oxidase deficiency with SURF1 mutation
Complex V deficiency with mtATPase6 mutation
Infantile thiamine deficiency
Succinate dehydrogenase deficiency
Complex I deficiency with MTND1 mutation
Other Complex I deficiencies
Imaging Characteristics
Involvement of corpus striatum and, in infants, thalami. White matter cavities.
Sometimes malformations.
Subthalamic nuclei, periaqueductal gray matter, central tegmental tract,
cerebellar nuclei, cerebellar peduncles, inferior olivary nuclei
Anterior putamina, globi pallidi, dorsal mesencephalon and pons
Frontal cortex, mamillary bodies, putamina, periaqueductal gray matter, dorsal
brainstem
Periventricular and deep white matter in all cerebral lobes and cerebellum.
Corpus callosum may cavitate. MRS shows large singlet at 2.4 ppm (succinate)
Subthalamic nuclei, corpus striatum, dorsal brain stem (especially medulla) (913)
Callosal and white matter involvement with cavitation. May have cerebellar atrophy.

Trichopoliodystrophy (Menkes Disease)
Trichopoliodystrophy (932) (OMIM 309400) is an X-linked recessive
mitochondrial disorder that results from impaired intestinal absorption
of copper with consequent impairment of cytochrome oxidase activity
in the mitochondria (cytochrome c contains two copper atoms (884) ).
The responsible ATP7A gene, which codes for a copper transporting
ATPase called Menkes protein (MNK), has been localized to Xq13.3
(933,934). Generically, the disease is related to a defect of “transmem-
brane copper transport mechanism,” which has several consequences
at different critical levels of copper trafficking within the organism.
Impairment of normal intestinal absorption of copper causes cop-
per deficiency in blood (ceruloplasmin level is also low) and copper
accumulation within the organelle-free cytosol of epithelial cells of the
small intestine. Transport of copper is impaired at the cellular level, as
well (MNK is localized to the trans-Golgi network and is required for
normal transport of copper within the cell); hence, copper cannot be
delivered to those enzymes requiring copper as an essential cofactor.
Therefore, even if copper is present within the cytosol, intraorganelle
(in particular intramitochondrial) copper concentration is severely
depleted. Specifically, from a neurologic perspective, copper in the
brain is trapped within endothelial cells of vessels and astrocytes, while
neurons are in a state of copper deficiency. Thus, oral or even intrave-
nous copper supplementation is ineffective in the disease.
Early diagnosis is difficult, but the decreased activity of dopamine-
b−hydroxylase causes elevation of the ratio of dihydroxyphenylacetic
acid to dihydroxyphenylglycol in plasma, which may aid early diagno-
sis and, hopefully, treatment (935). Affected patients are often born
prematurely and typically present in infancy with truncal hypotonia,
hypothermia, failure to thrive, and seizures (884,932). In milder cases,
prominent cerebellar ataxia, dysarthria, and moderate cognitive defi-
cit are noted, but seizures are absent (936). Head circumference at
birth may be normal or decreased; a reduction with respect to the
normal growth curve soon becomes evident. Patients have coarse,
stiff, sparse hair with broken, nodular, frayed ends (884,932); hence
the disease is referred to as “kinky hair disease.” Their skin is hypop-
igmented, hyperextensible, and their joints are hypermobile. Some
patients develop the “occipital horn syndrome,” in which a wedge-
shaped calcification forms within the tendinous insertions of the
trapezius and sternocleidomastoid muscles at their attachment to the
occipital bone (936,937). Most patients die before the third year of
life (938). Pathologic examination shows diffuse atrophy of cerebral
and cerebellar hemispheres with thin-walled, tortuous cerebral arter-
ies (884). Microscopic examination shows widespread spongiform
degeneration of the gray matter, sometimes exhibiting frank cavita-
tion. The volume of white matter is reduced and the white matter is
hypomyelinated (884).
Imaging findings in Menkes disease are nonspecific, but as a con-
stellation of findings are rather characteristic (939–942). Skeletal sur-
veys show bones that are osteoporotic with flared metaphyses of long
bones, rib fractures and Wormian bones in the skull (Fig. 3-87A). Rapid
progression of atrophy, with resultant subdural hematoma formation
and T1 hyperintensity/T2 hypointensity in the cerebral cortex, has
been observed by neuroimaging, (Fig. 3-87C) (845,942–944). Cerebral
arteries are elongated and tortuous (Fig. 3-87B). An important point
in this respect is that rapid brain atrophy in the presence of large bilat-
eral subdural hematomas and apparent cortical blood is not necessarily a
manifestation of asphyxic or physical trauma and that trichothiodystro-
phy should be a consideration in such cases.
Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase
Deficiency)
Glutaric aciduria Type I (GA1, OMIM 231670) is an autosomal reces-
sive disorder caused by deficiency of glutaryl-CoA dehydrogenase, an
enzyme located in mitochondria and involved in the metabolism of
L-lysine, L-hydroxylysine, and L-tryptophan. The responsible GCDH
gene is located at chromosome 19p13.2 and contains 11 exons. Muta-
tions of different exons can result in different phenotypes. It is proposed
that glutaric acid and 3-hydroxyglutaric acid, which accumulate in the
brain in this disorder, affect cell function and eventually lead to the
acute striatal damage that is commonly seen in this disorder (945), pos-
sibly due to excitotoxicity by overstimulation of N-methyl-D-aspartate
receptors (946). Patients may initially present with an acute encephal-
opathy, with macrocephaly, or with gradual neurological deterioration,
including hypotonia, progressive dystonia or choreoathetosis, and
tetraplegia (947). Regardless of initial presentation, most patients will
have an acute encephalopathic crisis by age 18 months (range: neonate
to 37 months), usually triggered by a febrile illness with some degree
of dehydration (946). Following the acute illness, most motor skills
have been lost and a severe dystonic dyskinetic movement disorder is
present (948). Intellectual function can be relatively unaffected (948).

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 185

FIG. 3-87. Trichopoliodystrophy (Menkes kinky hair

disease). A. Axial CT image (bone algorithm) at age
11 weeks shows multiple Wormian bones (white arrows)
in the posterior calvarium. B. Axial T2-weighted MR
image shows prominent CSF spaces and multiple tor-
tuous vessels (black arrows) in and around the circle of
Willis. C. Follow-up T1-weighted image at age 5 months
shows profound atrophy with enormous bilateral sub-
dural hematomas. (These images courtesy Dr. Susan
Blaser, Toronto.)

Rarely, patients remain asymptomatic into adulthood (949). Pathology
shows neuronal loss and astrogliosis of the basal ganglia in addition to
spongiform changes in the cerebral white matter (838,947).
Neuroimaging findings are important to suggest the diagnosis and
direct the biochemical analysis. Imaging findings include large bilateral
frontotemporal CSF spaces (open Sylvian fissures) that resemble bilat-
eral anterior sylvian/temporal arachnoid cysts (Figs. 3-88 and 3-89) but
are a result of hypoplasia of the frontal and temporal opercula (946).
These may be detected prenatally or in the early prenatal period by
ultrasound (950). T2/FLAIR hyperintensity is seen in the basal ganglia
(most obviously in the putamen and caudate, and less conspicuously in
the globus pallidus) and white matter (Figs. 3-88 and 3-89); the white
matter changes may not be seen early in course of the disease, and are
usually seen only after at least one acute event of clinical decompensa-
tion (Fig. 3-89) (946). Myelination is delayed (947,951–953). As the
disease progresses, the basal ganglia become atrophic and the corti-
cal sulci may enlarge. Abnormalities are often seen within the upper
midbrain with a pattern reminiscent of the so-called giant panda face
traditionally described in Wilson disease. During metabolic crisis, the
cerebellar nuclei may also be abnormal and present with T2/FLAIR
hyperintensity (954). Central tegmental tracts along the floor of the
fourth ventricle often show bilateral symmetrical T2 hyperintensity, as
well (954). Chronic subdural hematomas are seen in 20% to 30% of
affected patients, typically after relatively minor trauma, and are often
accompanied by retinal hemorrhage (947,948). Although it is impor-
tant to rule out child abuse in these children (especially if retinal hem-
orrhages are also present), it is also important to recall that patients
with large subarachnoid spaces or large arachnoid cysts are more likely
to develop subdural hematomas from relatively minor trauma (see
Chapter 8). Ultimately, diffuse cerebral atrophy with frontotemporal
predominance develops.
Although none of the above conventional imaging findings is
specific for glutaric aciduria type 1, the constellation of “open Sylvian
fissures” in conjunction with bilateral basal ganglia disease in a mac-
rocephalic child presenting with dystonia, is highly suggestive of the
disease. It is noteworthy that macrocephaly and Sylvian fissure abnor-
malities are present in both benign and malignant clinical phenotypes
(and are not affected by medical treatment). Therefore, the finding of
Sylvian fissure abnormalities in an infant with macrocephaly (even with-
out basal ganglia lesions), especially in ethnic groups with known high

Barkovich_Chap03.indd 185 5/6/2011 12:09:10 AM

 186 Pediatric Neuroimaging

FIG. 3-88. Glutaric aciduria Type 1 in a 5-day old infant. A–C. Axial T1 (A), T2 (B) and average diffusivity (C) images show abnormal signal intensity in the
posterior putamina (white arrows), compatible with acute/subacute injury. Note the enlarged sylvian fissures (f) due to hypoplasia of the frontal and tempo-
ral opercula. D. Coronal FLAIR image shows germinolytic cysts (black arrows) in addition to the abnormally hyperintense putamina (black arrowheads).

disease prevalence, should prompt a targeted laboratory work-up for GA1
in order to prevent the devastating consequences of a possible meta-
bolic crisis and the resultant neurological crippling from basal gan-
glia damage. Intervention and modificaiton of the course of disease
is usually in the form of special diets which limit intake of lysine and
tryptophan.
Advanced imaging techniques may have value in the diagnos-
tic imaging workup of GA1. Diffusion-weighted imaging may show
reduced diffusion in the white matter and reduced or increased dif-
fusion in the deep gray nuclei (955), dependent upon the stage of the
disease; reduced diffusion is seen after acute clinical decompensation,
whereas increased diffusion is seen in the more chronic phases of the
disease. Proton MR spectroscopy findings probably also vary with the
stage of the disease. Lactate is slightly elevated in the white matter
during and in the early subacute phase after decompensation (955).
In the late subacute phase, MRS shows increased choline and reduced
NAA (955). In the chronic phase, low NAA is found without lactate
(946).
18F-fluorodeoxyglucose PET scanning in glutaric aciduria type
1 shows diminished glucose uptake in the basal ganglia, thalami, the
insula, and the temporal opercular cortex (956). It is not clear what
relationship the diminished metabolic activity of the opercular region
has to the enlargement of the sylvian fissures and anterior middle
cranial fossa.
Glutaric Aciduria Type II (Multiple Acyl CoA Dehydrogenase
Deficiency)
Glutaric aciduria Type II, also known as multiple acyl CoA dehydro-
genase deficiency or MADD (OMIM 231680), results from a defect of
the mitochondrial electron transport chain at coenzyme Q. It can be
caused by mutations to at least three different genes: ETFA at 19q13.3,
ETFB at 15q23-25, and ETFDH at 4q32-qter. It differs from glutaric

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
aciduria type I in that multiple acyl-CoA dehydrogenase deficiencies
result in large excretion not only of glutaric acid but also of lactic, eth-
ylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids.
This disorder can result from deficiency of any one of three molecules:
the alpha and beta subunits of electron transfer flavoprotein and elec-
tron transfer flavoprotein dehydrogenase. It has been proposed that
these be called glutaric aciduria types IIa, IIb, and IIc, respectively
(957). Affected patients may present as neonates or infants, usually
with hypoglycemia, hypotonia, and acidosis; facial dysmorphism and
visceral anomalies may be present. Those presenting in infancy rarely
survive beyond a few weeks. Those presenting later in infancy are
managed by dietary means in an attempt to prevent the progression of
the disease (838,958). Some reports of adolescent or adult presentation
are published (959); these older patients are reported to have move-
ment disorders (960).
Imaging studies show basal ganglia involvement (838,960).
Patients we have seen with glutaric aciduria type II showed T2 pro-
longation in the caudate head, posterior putamen, and cerebral
hemispheric white matter. We have also seen T2 prolongation in the
periatrial white matter, middle cerebral peduncles, callosal splenium,
and corpus striatum; in one patient, reduced diffusion was present
only in the white matter sites, not in the corpus striatum (Fig. 3-90).
Other reports describe hypoplasia of the temporal lobes and, in one
instance, absence of the cerebellar vermis (961,962). Proton MRS
shows elevated lactate and high Ch/Cr (indicating dysmyelination)
(958,962).
Neonatal Lactic Acidosis, Complex I/IV Deficiency,
and Fetal Cerebral Disruption
Patients with neonatal lactic acidosis, complex I/IV deficiency, and fetal
cerebral disruption present in the neonatal period with seizures and
encephalopathy. They are usually small in stature and have small heads
(<3rd percentile) and dysmorphic features (770). Antenatal polyhy-
dramnios may be detected. TORCH infection may be suspected. Anal-
ysis of mitochondria shows severe combined deficiency of complexes
I and IV in muscle and liver. Imaging shows multiple anomalies includ-
ing subcortical heterotopia with callosal hypogenesis (see section on
subcortical heterotopia in Chapter 5), subependymal (germinolytic)
cysts, subcortical calcifications, and abnormally hyperintense (on
T2-weighted images) in the brainstem and cerebellum (770) ). These
Barkovich_Chap03.indd 187
187
FIG. 3-89. Glutaric aciduria Type
1 in an infant with developmental
delay and macrocephaly. A. Axial
T2-weighted image shows enlarged
sylvian fissures (black arrows) due to
hypoplasia of the temporal opercula
and abnormal hyperintensity of the
central tegmental tracts (black arrow-
heads). B. Axial T2-weighted image
shows abnormal hyperintensity of
the basal ganglia (black arrows) and
the periventricular and deep white
matter (white arrows), classic find-
ings when seen in conjunction with
the enlarged sylvian fissures.
finding suggest that abnormal mitochondrial function began during
the period of organogenesis.
Friedreich Ataxia
Friedrich ataxia is discussed in the section on Metabolic Disorders Pri-
marily involving the Cerebellum.
Ethylmalonic Encephalopathy
Ethylmalonic encephalopathy (OMIM 602473) is an extremely rare
autosomal recessive disorder. Only about forty cases have been identi-
fied worldwide, mostly in Mediterranean and Arab populations. It is
characterized by increases in ethylmalonic, methylsuccinic, and lactic
acids, which are found in the serum. The cause is mutations of a gene
called ETHE1, located at chromosome 19q13.32 (963). Most identified
mutations show loss of function of the protein product, ETHE1, which
is targeted to mitochondria and, after cleavage of a short leader peptide,
is internalized into the mitochondrial matrix (963). Although the exact
function of the ETHE1 protein is not known, the severe consequences of
its malfunction suggest that its function is critical for energy production.
Known clinical phenotypes include neonatal onset with acute metabolic
crisis, and early or late infantile onset with slowly progressive enceph-
alopathy with or without metabolic decompensation. Patients with the
slowly progressive phenotype present with neuromotor delay, pyrami-
dal and extrapyramidal signs, ataxia and dysarthria (964,965). The most
prominent systemic manifestation of the disease is vasculopathy (tortu-
ous retinal veins, usually not present at birth), cutaneous petechiae and
ecchymoses, orthostatic acrocyanosis, persistent microhematuria and
chronic diarrhea. The disease leads to death by early childhood in most
cases, the major cause of death is complications related to vasculopathy.
Few imaging reports of patients with ethylmalonic encephalopathy
have been published. Some affected patients appear to have patchy T2
and FLAIR hyperintensity in the basal ganglia, cerebral white matter,
and sometimes brainstem, findings typical of mitochondrial disorders
(963,966). Progressive atrophy is seen on sequential studies (967).
Another report found CNS malformations: tethered cord and Chiari
I malformation (968).
Nonspecific Mitochondrial Disorders
As discussed in the opening paragraph of this section, some brain disor-
ders that are associated with mitochondrial dysfunction do not fit into any
5/6/2011 12:09:11 AM
 188 Pediatric Neuroimaging
of the syndromes that have been described or have overlapping features
of multiple mitochondrial “syndromes.” These nonspecific mitochon-
drial disorders can present in patients of any age, from neonates to senior
citizens (3,4,816,969,970). Presenting signs and symptoms are variable,
as in all mitochondrial disorders (3,4,811,816,845), with seizures, short
stature, mental deterioration, muscle weakness, exercise intolerance, and
neurosensory hearing loss being the most common (811–813,824).
Barkovich_Chap03.indd 188
FIG. 3-90. Glutaric aciduria type II. A–D. Clockwise from upper
left, echo-planar T2 (EP T2), diffusion-weighted (DWI), diffusiv-
ity image (ADC), and diffusion weighted images (DI) show T2
prolongation and reduced diffusion in the lateral pons bilater-
ally. E–H. Echo-planar T2, diffusion-weighted, apparent diffusion
image, and diffusion images at the level of the lateral ventricles
show T2 prolongation in the basal ganglia, periventricular white
matter, and splenium of the corpus callosum. However, reduced
diffusion (dark on ADC, bright on DI) is only seen he at the
periphery (arrows) of the white matter lesions, suggesting that
most of the T2 prolongation is chronic, not acute.
Imaging findings are nonspecific with increased water (low attenu-
ation on CT, T1 hypointensity and T2/FLAIR hyperintensity on MRI)
in the brainstem, deep gray matter nuclei, cerebral/cerebellar white
matter, cerebral or cerebellar cortex (831), indistinguishable from the
images of the other disorders discussed in this section. Remember that
mitochondrial disorders can have a broad range of appearances, from
isolated brainstem involvement (Fig. 3-91) (899) to isolated cerebellar
5/6/2011 12:09:12 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
atrophy (Fig. 3-92) (971,972) to isolated white matter involvement that
may include small to moderate sized white matter cysts (832,914,973).
As illustrated many times in this section, diffusion imaging and spec-
troscopy may be useful to differentiate acute metabolic injury from
subacute or chronic injury.
Pyruvate Dehydrogenase Deficiency
The pyruvate dehydrogenase complex is a large multienzyme com-
plex that catalyzes the oxidative decarboxylation of pyruvate to acetyl
CoA in the mitochondrial matrix. It is composed of five enzymes,
containing three major subunits (E1, E2, and E3), all of which have
smaller subunits within them. It is becoming clear that mutations of
the alpha subunit of E1 (located on chromosome Xp22.1) are, by far,
the most common cause of human metabolic disease (974). However,
the clinical manifestations of the disease vary widely depending on
the precise mutation (and its effect on enzyme function) and, when
present in women, the degree of inactivation of the affected X chro-
mosome. Overall, symptoms seem to correlate pretty well with the
residual activity of the enzyme complex (974). Uncommonly, muta-
tions of the E2 (975) or E3 (976,977) binding protein component of
the pyruvate dehydrogenase complex can cause disease. As stated in
the previous section, pyruvate dehydrogenase deficiency, along with
Barkovich_Chap03.indd 189
189
FIG. 3-91. Nonspecific mito-
chondrial disorder with iso-
lated brain stem involvement.
Axial T2-weighted images show
abnormal hyperintensity (black
arrows) in the pons (A) and mid-
brain (B) with normal appearing
cerebellum.
mutations of other complexes in the respiratory chain, is a common
cause of Leigh syndrome (978). Clinical phenotypes can be divided
into three major presentations (neonatal, infantile, or benign) (979)
that, as stated earlier, depend on the residual enzyme activity (974).
Neonatal presentation is characterized by hypotonia, episodic apnea,
convulsions, weak suck, dysmorphic features (broad nasal bridge,
upturned nose micrognathia, posteriorly rotated ears, short fingers
and arms, hypospadias), lethargy, low birth weight, failure to thrive,
and coma (819). Some patients may have life threatening congenital
lactic acidosis or acute flaccid paralysis (980). The infantile pheno-
type usually has onset between ages 3 and 6 months with psycho-
motor retardation, hypotonia, convulsions, episodic apnea, ataxia,
pyramidal tract signs, decelerating head growth, ophthalmoplegia,
optic atrophy, peripheral neuropathy, dysphagia, and cranial nerve
palsies (819). Other infants and children have benign syndromes such
as intermittent weakness or ataxia (often associated with intermittent
lactic acidosis) or episodic dystonia (975), and still others may have
nonspecific signs or symptoms, such as failure to thrive, hypotonia,
or developmental delay (978). Most commonly, patients make little
or no subsequent developmental progress. Lactic acidosis is typically
found at the time of clinical presentation, with a normal lactate/
pyruvate ratio.
FIG. 3-92. Mitochondrial disor-
der resulting in isolated cerebellar
atrophy. Sagittal (A) and coronal (B)
T1-weighted images show shrunken
cerebellar cortex with widening of
cerebellar sulci.
5/6/2011 12:09:13 AM
 190 Pediatric Neuroimaging

Neuroimaging by MRI shows findings typical of Leigh syn-
drome (see examples in previous section on mitochondrial disorders,
particularly Fig. 3-82) in about half of affected patients (41,981). In
other patients, MRI shows atrophy of varying degrees with injury to
the cerebrum and cerebellum or, rarely, frank cerebral malformation,
the most common being callosal agenesis. (Pyruvate dehydrogenase
deficiency is one of the few inborn errors of metabolism that can result
in brain malformations). Correlations between the genetic defect and
the imaging appearance have not yet been fully established, although
patients with mutations limited to the E1a or E2 component of the
pyruvate dehydrogenase complex may have abnormalities limited to the
globi pallidi (975,980). Delayed myelination can be seen, as can frank
leukodystrophy (981). Studies in some patients show primarily white
matter disease involving cerebellum, posterior limb of the internal
capsule, and occipital white matter (41). Other patients have multiple
cysts in the cerebral white matter that may appear prenatally or post-
natally and seem to be the result of necrosis (982); ventriculomegaly
often ensues (983). Because damage often begins prenatally, diffusivity
of affected white matter is often increased at the time of imaging (983).
Proton MRS almost always shows elevated lactate (981,983) (and may
show a small pyruvate peak at 2.36 ppm (984) ); therefore, a finding of
callosal agenesis in a patient with severe lactic acidosis strongly sug-
gests a diagnosis of LDH deficiency.
Disorders of the Urea Cycle and Ammonia
Disorders of the urea cycle result from disruption of the major pathway
for the disposal of nitrogen in the body; they include ornithine carbamyl
transferase deficiency (ornithine transcarbamylase deficiency), carbamyl
phosphate synthetase deficiency, argininosuccinic aciduria (arginino-
succinate lyase deficiency), citrullinemia (argininosuccinate synthetase
deficiency), and hyperargininemia (arginase deficiency) (985,986). All
result in hyperammonemia and elevation of glutamine levels that may
be worsened by high protein intake or illness. Differentiation is made
by biochemical and genetic testing (Table 3-18). The timing of onset of
these disorders depends upon the nature of the molecular defect and
the degree to which the patient sustains some capacity for elimination
of nitrogen waste products (987). With severe disturbance of molecular
function, patients become symptomatic as neonates, within the first few
days of life, with progressive irritability, lethargy, poor feeding, hypo-
thermia, and seizures; neurodevelopmental outcome is related to the
duration of neonatal hyperammonemic coma (988). Those patients
with better molecular function present later (in childhood, adolescence,
or adulthood) and typically have intermittent neurologic dysfunction
that may present as movement disorders, seizures, ataxia, lethargy, or
confusion; in the mildest cases, the symptoms may be psychiatric ones
such as hyperactive behavior, mood disturbances, or psychosis (986).
Episodes can be triggered by anesthesia for minor surgery (988). In
ornithine carbamyl transferase deficiency, which is X-linked dominant
(Table 3-18), girls are variably affected and boys always severely affected
(989). Improved therapy has lead to better long term outcome, but most
survivors have developmental disabilities (986).
In our experience, similar patterns of injury are seen with OCTD,
CPSD, and citrullinemia (990), and possibly with argininosuccinic
aciduria and hyperargininemia. The CT pattern in affected patients is
nonspecific, with a pattern of diffuse edema (Fig. 3-94A), particularly
in infancy, as a result of hyperammonemia. Images later in the course
of the disease may show both focal and diffuse areas of hypodensity
on CT. On MRI, the appearance is somewhat more specific, as certain
regions of the cerebral cortex and deep gray matter show T1 hypoin-
tensity and T2/FLAIR hyperintensity; in particular, the insular cortex
(posterior more than anterior), perirolandic cortex, and basal ganglia
(particularly the globi pallidi) show early T2 hyperintensity and swell-
ing (Figs. 3-94 and 3-95). In affected neonates, T1 hyperintensity of
affected deep gray and cortical structures will appear within the first
few days of life (Fig. 3-96). Care should be taken not to misdiagnose
hypoxic-ischemic injury in these children; the differentiation can be
made by the predominant globus pallidus and putaminal injury in
urea cycle disorders, in contrast to the predominant thalamic injury
in neonatal hypoxia-ischemia. In older patients, the appearance of the
cerebral cortex in the acute phase shows T2 hyperintensity and swelling

TABLE 3-18 Differentiation of Urea Cycle Disorders

Disease/OMIM Number Gene/Locus Enzyme Defect Biochemical Features
CPTD/237300 CPS1 2q35 Carnitine palmityl transferase No citrulline in plasma
No orotic aciduria
OTCD/311250 OTC Xp21.1 Ornithine transcarbamylase Orotic aciduria
No citrulline in plasma
Citrullinemia types I ASS 9q34.1 Argininosuccinic acid synthetase High plasma citrulline, ammonia,
(neonatal) and III alanine. High urinary orotic acid
(infantile)/215700
Citrullinemia SLC25A13 7q21.3 Argininosuccinic acid synthetase High plasma citrulline, ammonia
type II/605814 in liver
Argininosuccinic ASL 7cen-q11.2 Arginosuccinase High plasma argininosuccinate.
Aciduria/207900 Moderate citrulline in plasma
Hyperargininemia/207800 ARG1 6q23 Arginase Elevated plasma arginine
OMIM, Online Mendelian Inheritance in Man; OCTD, ornithine carbamyl transferase deficiency; CPTD, carbamyl phosphate synthetase deficiency.

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 191

FIG. 3-93. Mitochondrial dis-

order with white matter cavita-
tion. Sagittal T1-weighted image
(A) shows hypointensity (black
arrows) indicating cavitation in
the posterior body and splenium
of the corpus callosum. Cavita-
tion in the periventricular and
deep white matter is verified by
the hypointensity of the affected
white matter (black arrows) on the
coronal FLAIR image (B). Cer-
ebellar atrophy is present, as well.

FIG. 3-94. Ornithine transcarbamylase

deficiency in a 7-year-old child. A. Axial
noncontrast CT scan shows diffuse edema
manifested as sulcal effacement and low
attenuation of the cerebral cortex resulting
in loss of cortical-white matter contrast.
B. Axial T2 weighted image shows edema
manifested as hyperintensity and thicken-
ing of the insula and frontal lobe cortex.
C. Coronal FLAIR image also shows hyper-
intensity of the insular cortex (white arrow-
heads), as well as temporal cortex (large
white arrows) and cingulate sulci (small
white arrows). D. Follow up study shows
development of diffuse cerebral atrophy.

Barkovich_Chap03.indd 191 5/6/2011 12:09:14 AM

 192 Pediatric Neuroimaging

FIG. 3-95. Citrullinemia in a 5-year-old child. A and B. Axial T2-weighted images show edema in the globi pallidi (white arrows), insular cortex and
underlying external and extreme capsules (white arrowheads), left cingulate cortex, and medial left frontal cortex. C. Axial diffusion weighted image shows
reduced diffusivity in the insulae (white arrowheads) and left cingulate cortex (white arrow). D. Single voxel proton MRS (TE = 30 ms) shows reduced NAA
and increased glutamate/glutamine (Glx, at 2.1–2.5 and 3.8 ppm) in the basal ganglia.

of the cortex (Figs. 3-94 and 3-95) (990); the insulae and cingulate gyri Methylmalonic and Propionic Acidemias
are most commonly affected and, in general, the frontal lobes seems
Both methylmalonic and propionic acidemia are autosomal recessive
more affected than the parietal, occipital, or temporal lobes. The peri-
disorders that cause ketoacidosis and excretion of the respective acids in
rolandic and occipital cortex seem to be specifically spared (990). As
the urine. Propionic acidemia (OMIM 606054) is caused by mutation in
the disease progresses, atrophy develops; it is often severe and may be
the genes encoding propionyl-CoA carboxylase, PCCA (at chromosome
multicystic. Two characteristics of brain involvement are noteworthy:
13q32) or PCCB (at chromosome 13q21-23) (994). Methylmalonic aci-
(a) the subcortical U fibers are not spared–the subcortical white mat-
demia (OMIM 251000) is caused by mutation of the gene (MUT) encod-
ter is involved severely and early (991) and (b) cerebral involvement is
ing methylmalonic CoA mutase, located at chromosome 6p21 (995),
often slightly asymmetric. Proton MRS in both of these disorders in
which functions with its coenzyme cobalamin (vitamin B12) to convert
the acute or subacute phase shows lactate (a doublet centered at 1.33
methylmalonyl-CoA to succinyl-CoA. Both diseases often present early
ppm) and of glutamine/glutamate resonances (at 2.1–2.5 ppm, just
in life with episodes of metabolic acidosis, vomiting, tachypnea, leth-
downfield from NAA, and at 3.75 ppm, also attributable to glutamine
argy, and seizures, often leading to coma and death. Survivors are typi-
(992,993) ). Because of the short T2 relaxation times, the glutamine/
cally small with small heads; they suffer from quadriparesis, movement
glutamate peaks are best seen with short echo time (20–30 ms) STEAM
disorders, and psychomotor retardation with episodic vomiting, keto-
sequences (Fig. 3-95) (992).

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 193

FIG. 3-96. Ornithine transcarbamylase deficiency in a neonate. A and B. Axial T1-weighted images show hyperintensity in the lentiform nuclei, particu-
larly the globi pallidi (small white arrows), insular cortex, and perirolandic cortex, in addition to hypointensity of the caudate heads (large white arrows).
C. Axial T2-weighted image shows diffusely abnormal hyperintensity of the white matter (which is isointense to CSF) and the basal ganglia, indicating dif-
fuse edema. D. Proton MR spectrum (TE = 288 ms) shows an abnormal lactate peak (Lac) and an abnormal glutamate peak (Glx).

sis, and coma (40,284,838,996). Other patients present with progressive
encephalopathy with central hypotonia of varying severity, sometimes
associated with movement disorders or dystonia (40,997,998). Neuro-
logic examination reveals central hypotonia with pyramidal tract signs
and symptoms at time of crises; dystonia and choreoathetosis are com-
mon sequelae of basal ganglia involvement (999).
CT and MRI reveal increased water (low attenuation and T1
hypointensity, T2/FLAIR hyperintensity), most commonly in the
white matter and globi pallidi in methylmalonic acidemia (Fig. 3-97)
and in the putamina and caudate nuclei in propionic acidemia (Fig.
3-98) (40,996,997,1000,1001). CT often shows calcification of the
basal ganglia in MMC (1001), and we have seen cystic changes of the
globi pallidi on MRI (Fig. 3-97B). Abnormal hypodensity (CT) and
T2 hyperintensity (MRI) is sometimes observed in the periventricu-
lar white matter (40,59,1000,1001); myelination delay is present early
and both cortical and white matter volume loss is often present in later
stages. In the acute phase of a clinical decompensation reduced diffu-
sivity may be seen in the affected regions, likely a result of mitochon-
drial dysfunction (1002).
Proton MR spectroscopy in propionic aciduria reportedly shows
decreased NAA and myo-I and increased glutamate/glutamine in the
basal ganglia (999); reduced NAA is also reported in MMC (1002).
Lactate elevation was present in one reported case (1002). PET studies
show increased uptake of 18-fluoro-2-deoxyglucose early in the course
of the disease (first year of life). Later, in the second and third years,
decreased uptake is noted in the basal ganglia (998).

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 194 Pediatric Neuroimaging
GM1 and GM2 (Tay-Sachs and Sandhoff Diseases)
Gangliosidoses
GM1 gangliosidosis (OMIM 230500) is a rare lysosomal storage dis-
ease characterized by a deficiency in the activity of lysosomal beta-
galactosidase. The result is an accumulation of GM1 ganglioside
and asialo-GA1 in the brain and of oligosaccharide in the abdomi-
nal viscera (1003). Three forms of the disease have been described
(1003,1004); all are the result of mutations of the GLB1 gene located
on chromosome 3p21.33 (1005). Of interest, mutations of this same
gene can cause Morquio type B disease (see section V.D.3); not surpris-
ingly, clinical overlap can be seen between the diseases (1006). Those
patients with the (most common) infantile form have dysmorphic
facial features, osseous dysplasias, hepatosplenomegaly, hypotonia,
FIG. 3-98. Propionic academia in a 22-month old child. Axial T2-weighted
image shows abnormal hyperintensity of the head of the caudate nucleus
and putamen, as well as reduced myelination of the cerebral white matter.
Barkovich_Chap03.indd 194
FIG. 3-97. Methylmalonic aciduria;
13-month-old child with developmen-
tal delay. A. Axial FLAIR image shows
abnormal hyperintensity of the deep
cerebellar nuclei (black arrows). B. Axial
T2-weighted image shows abnormal
hyperintensity in the globi pallidi (white
arrows). A small cyst (white arrowhead) is
present in the left globus pallidus.
mental retardation, and seizures. Those with the late infantile/juvenile
form have progressive psychomotor retardation beginning in early
childhood (typically between ages 1 and 5 years) with development of
seizures, spasticity, and a movement disorder; death ensues within a
few years. Children or adults with the chronic form have slowly pro-
gressive dystonia, dysarthria, ataxia, myoclonus, and extrapyramidal
signs (1003,1004). Patients with the late infantile and chronic forms
lack facial dysmorphism, hepatosplenomegaly and dysostosis.
GM2 gangliosidoses are autosomal recessive disorders of sphin-
golipid storage caused by a deficiency of hexosaminidase. The degra-
dation of GM2 ganglioside to GM3 ganglioside is dependent on the
enzyme lysosomal N-acetylhexosaminidase, which consists of two
major isoenzymes, A and B. A deficiency of isoenzyme A, coded by
the HEXA gene at chromosome 15q23-24, causes Tay-Sachs disease
(OMIM 272800) while deficiencies of the beta subunit of both isoen-
zymes A and B (coded for by the HEXB gene at chromosome 5q13)
cause Sandhoff disease (OMIM 268800) (1007). A third type of the
disease, called the AB variant of Tay-Sachs disease or the AB variant
of GM2 gangliosidosis (OMIM 272750) is caused by deficiency of the
GM2 activator protein, which mediates the interaction between the
water-soluble beta hexosaminidase A and its membrane-embedded
substrate, GM2 ganglioside (1008). All three of these disorders result
in an abnormal accumulation of GM2 ganglioside in the cytoplasm of
neurons; the resulting extensive neuronal loss and white matter degen-
eration lead to brain atrophy. Clinical and imaging findings are similar
in the diseases. In the most common infantile forms, patients present
with psychomotor retardation and hypotonia followed by neurologic
deterioration during the second half of the first year of life. Progressive
motor weakness, spasticity, dystonia, choreiform movements, ataxia,
blindness, macrocephaly, and seizures ensue (838,1009). After a period
of 3 to 10 years, the child becomes bedridden and demented (1010). In
the juvenile form of the disease, presentation is during the middle or
second half of the first decade, typically with gait disturbances, inco-
ordination, and developmental delay (1011), whereas patients with the
adult form typically present in middle age with progressively impaired
cognition (1012). In both of these disorders, the neuroimaging find-
ings are typically limited to cerebellar>cerebral atrophy, so they are
more fully discussed in the section on cerebellar disorders at the end
of this chapter.
5/6/2011 12:09:17 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
Neuroimaging findings in GM1 gangliosidosis, Tay-Sachs
and Sandhoff disease are nearly identical (1004,1009,1013,1014),
although there are some subtle differences. CT studies show high
attenuation in the thalami (Fig. 3-99A) and low attenuation in the
white matter in early stages, with cerebral and cerebellar atrophy in
later stages (1015). MRI shows some T1 hyperintensity in the thal-
ami (1009,1014). T2 hyperintensity is seen in corpus striatum (Fig.
3-100) and in posteromedial thalami in Tay-Sachs disease (1014).
One report of MRI in the late infantile form of GM1 gangliosido-
sis reported T1 hyperintensity, with hypointensity on both T2- and
T2*-weighed images in the acute phase, and generalized atrophy
with atrophic, T2 hyperintense putamina, and shrunken, profoundly
hypointense globi pallidi on T2-weighted and FLAIR images (1016).
The T2 hyperintensity in the basal ganglia of GM2 gangliosidoses
may render the basal ganglia isointense to surrounding white mat-
ter (Fig. 3-100), in contrast to the dramatic high signal of the basal
ganglia seen in organic acidemias and mitochondrial disorders. T2
hypointensity and relatively reduced diffusion are seen specifically
in the ventral thalamic nucleus in Tay-Sachs, which may be a distin-
Barkovich_Chap03.indd 195
195
FIG. 3-99. GM2 gangliosidosis (Sandhoff disease). A. Axial CT
image shows abnormal high attenuation of the thalami (white
arrows). Note that the normal gray matter attenuation of the
basal ganglia is not present. B and C. Axial T2-weighted images
show slight hypointensity of the thalami (small white arrows)
compared to the cerebral cortex, patchy hyperintensity (large
white arrows) of the basal ganglia, and hyperintensity (white
arrowheads) of the periventricular white matter.
guishing feature (Fig. 3-100). Diffuse, progressive T2 hyperintensity
in the white matter (Figs. 3-99B and C and 3-100) is seen in both Tay-
Sachs and Sandhoff diseases, occasionally presenting a leukodystro-
phy-like appearance; however, the corpus callosum usually remains
well myelinated. Atrophy and T2 shortening of the thalami is seen in
older patients with Sandhoff disease (59,1009). Eventually, cerebral
and cerebellar atrophy ensues.
Reports of short echo (30 ms) proton spectroscopy of the basal
ganglia in children with Tay-Sachs disease showed elevated myo-
Inositol and choline associated with reduced NAA compared with
age-matched controls (1017,1018). Short echo MRS of a patient with
Sandhoff disease showed reduced NAA with elevated choline and myo-
Inositol in addition to a peak at 2.07 ppm that has been attributed to
N-acetylhexosamine; the highest concentrations of N-acetylhexo-
samine are in white matter and thalami (1019).
Fucosidosis
Fucosidosis (OMIM #230000) is a lysosomal disorder caused by defi-
ciency of alpha-L-fucosidase, the enzyme that hydrolyzes fucose from
5/6/2011 12:09:18 AM
 196 Pediatric Neuroimaging
glycolipids and glycoprotein; it is classified as a glycoproteinosis. The
enzyme deficiency results in the accumulation of a variety of alpha-L-
fucose-rich storage products in many organs, such as the liver, spleen,
skin, heart, pancreas, thymus, thyroid, kidneys, and brain (1020). The
genetic locus for alpha-L-fucosidase has been assigned to 1p34.1-36.1,
and has been designated FUCA1 (1020). Clinically, this disease is divided
into two forms, infantile (type I) and juvenile (type II), although a con-
tinuous spectrum of the disease exists, dependent upon the severity of
the enzyme deficit (401). Affected patients have progressive neurologic
deterioration along with angiokeratoma corporis diffusum, tiny purple
or red raised cutaneous lesions that are initially found on the trunk,
nonprogressive hepatomegaly (40%) and splenomegaly (25%) (401).
Skeletal findings are of dysostosis multiplex, which shows characteris-
tic abnormalities of spine, pelvis, and hips (401,1021). Pathology shows
prominent neuronal loss in gray matter, especially the thalamus, hypo-
thalamus, cerebral cortex, and the Purkinje cells and dentate nuclei of
the cerebellum (1022).
Imaging studies show findings characteristic of diffuse gray mat-
ter loss. CT shows atrophy and hypodensity in white matter and globi
pallidi. MRI reports indicate variable findings (1020,1021). Abnor-
mal hyperintensity is present in the white matter on T2-weighted
Barkovich_Chap03.indd 196
FIG. 3-100. GM2 gangliosidosis (Tay-
Sachs disease) in a 14-month-old. A and
B. Axial T2-weighted images show hyper-
intensity of the basal ganglia and thalami,
with the exception of a rounded area (white
arrows) in the ventral thalamus, which is
hypointense. C. Axial T2-weighted image
at the level of the centrum semiovale
shows absence of normal hypointensity
from myelination at this age. D. Diffusion
image at the level of (A) shows abnormally
increased diffusion (black arrows) through
most of the deep gray nuclei, but reduced
diffusion (white arrows) in the anterior
thalami, where the T2 hypointensity was
seen in (A).
and FLAIR images of patients in late infancy and early childhood
(Fig. 3-101); this may be the only finding in late infancy (402). Asso-
ciated T2 shortening (manifested as hypointensity on T2-weighted
images and most easily seen on FLAIR images) develops in the medial
and lateral segments of the globi pallidi (Fig. 3-101). Hyperintensity
of the hypothalami may be seen (1020). These features are somewhat
reminiscent of findings in the GM2 gangliosidoses. In patients with
more longstanding disease, MRI shows diffuse atrophy with nonspe-
cific T2 prolongation in periventricular white matter and T1 and T2
shortening (T2 hypointensity) in the globi pallidi (1021). The appear-
ance is nearly identical to that in the neuronal ceroid lipofuscinoses.
Proton MR spectroscopy of the affected white matter shows the pres-
ence of a doublet centered at about 1.2 ppm (referred to, in error, as
lactate in the literature) and a broad “hump” corresponding to multiple
peaks from about 3.4-3.8 ppm (1023). The combination of imaging
and MRS findings is probably specific.
l-2-hydroxyglutaric Aciduria
L-2-hydroxyglutaric aciduria (OMIM 236792) is an autosomal recessive
disorder caused by mutations of the L2HGDH gene at chromosome
14q22 (1024). The gene encodes a putative mitochondrial protein,
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 197

which the authors dubbed “duranin,” with homology to FAD-

FIG. 3-101. Infantile fucosidosis. Axial T2-weighted image in a 13-month
old child shows abnormal hypointensity of the white matter, most notable
in the peritrigonal regions (black arrowheads). Note the marked absence
of myelin in the posterior limbs of the internal capsules (white arrows)
and the hypointensity of the globi pallidi (white arrowheads). (Courtesy of
Dr. Susan Blaser, Toronto.)
dependent oxidoreductases (1024). Affected patients present with a
slowly evolving moderate motor delay (mainly presenting as ataxia),
macrocephaly, and, sometimes, febrile seizures during the first year of
life (1025). Mental deficiency of variable severity typically becomes
manifest during the second year (1026–1029), sometimes followed by
dystonia and pyramidal signs. Rarely, the disease may have a fulmi-
nant course resulting in infantile death (1030). Pathologic analysis of
affected brains shows spongiform degeneration of cerebral and cer-
ebellar white matter with intense gliosis and vacuolation of the neu-
ropil. The subcortical white matter contains numerous hyperplastic
astrocytes and is severely demyelinated with cystic cavities. The basal
ganglia and cerebellum are less affected, with spongiosis but only mild
neuronal loss and no cavitations (1026–1028,1030–1032).
The MRI findings are virtually pathognomonic for the disease.
White matter abnormalities exhibit a very characteristic centripetal
and slightly anteroposterior gradient; subcortical U-fibers are most
severely affected with virtually total loss of normal signal intensity.
Conversely, periventricular white matter, and in particular central
cortical-spinal tracts and corpus callosum are spared (Fig. 3-102).
The extreme and external capsules, as well as the anterior limb and
genu of the internal capsules are abnormal. Cerebellar white matter
is usually spared. Although at first glance the disease seems to have a
leukodystrophy-like appearance, the basal ganglia are always at least

FIG. 3-102. L-2-hydroxyglutaric aciduria in an 11-year-old, early phase. A. Axial T2-weighted image
shows abnormal hyperintensity in the cerebellar nuclei (white arrows). B. Axial T2-weighted image
shows abnormal hyperintensity of the globi pallidi (white arrows) more than putamina and caudates.
Subcortical white matter hyperintensity (white arrowheads) is present. C and D. Axial FLAIR (C) and
coronal T2 (D) images better show subcortical white matter hyperintensity (white arrowheads). Note
hyperintensity of cerebellar nuclei (white arrows) in (D).

Barkovich_Chap03.indd 197 5/6/2011 12:09:20 AM

 198 Pediatric Neuroimaging
subtly abnormal (714,1026,1029,1033). The thalami are normal, but
the cerebellar nuclei are always abnormal and somewhat swollen
(Fig. 3-102) (714,1025,1026,1029,1033). Over time, more extensive
involvement of white matter is noted (Fig. 3-103) and affected struc-
tures tend to atrophy (714,1025,1029,1033). When patients present as
neonates, CT may show cerebellar hypodensity in the first few days
of life (1030). Eventually, this may evolve to mild to severe cerebellar
atrophy, particularly involving the vermis. Water diffusivity is reported
to be normal in most of the brain; it is reduced in acutely affected
white matter (11) and slightly increased in chronically affected sub-
cortical white matter (1034). Short echo time proton spectroscopy
is reportedly normal other than slightly reduced NAA and increased
myo-Inositol (1034).
As described above, when the disease course is relatively benign
and protracted, affected patients survive into adulthood. Lately, a
growing body of data suggests the increased incidence (at least 10%) of
brain tumors in patients with L-2-hydroxyglutaric aciduria (1035). The
explanation of this is yet unclear, but it is noteworthy that recently the
potential oncogenic role of 2-hydroxyglutarate (a product of tumor-
associated IDH mutants) has been advocated (1036).
Acute Necrotizing Encephalitis
The term acute necrotizing encephalitis (ANE) refers to an acute
encephalopathy with bilateral thalamotegmental involvement that
occurs in infants and children; infants between ages 6 and 18 months
are most commonly affected (1037–1040). A history of a mild anteced-
ent illness (fever and upper respiratory or gastrointestinal infection) is
elicited in more than 90% of affected patients. Then, after 0.5 to 3 days,
the patient has an acute onset of severe neurological symptoms. In more
severe cases, the patient develops convulsions (40%) or impaired con-
sciousness (28%) or vomiting (20%), and coma usually ensues within
24 hours. Recent reports suggest that the disorder may sometimes be
rather mild, with alterations of consciousness or motor signs as the
only symptoms (1041). Biochemical studies show elevated aspartate
aminotransferase in 82%, elevated alanine aminotransferase in 70%,
and elevated lactate dehydrogenase in 77%. CSF opening pressure is
elevated and analysis reveals elevated protein but no cells (1037–1040).
Although some reports have implicated influenza A and B viruses
(1042,1043) and human herpes virus 6 (1044,1045) in the pathogenesis,
it is now believed that the most likely cause is immune-mediated after
infection (1037,1042,1046). In support of this, an autosomal dominant
Barkovich_Chap03.indd 198
FIG. 3-103. L-2-hydroxyglutaric aci-
duria, later phase. Axial T2-weighted
images (A and B) show involvement of
globi pallidi (black arrows) more than
putamina and more extensive involve-
ment of white matter.
form of the disease has been identified; the causative gene (RANBP2)
encodes nuclear pore protein Ran Binding Protein 2 (1047) and maps
to 2q12.1-2q13 (1048,1049). When the disease affects multiple family
members or has recurrent episodes in an individual, mutations of this
gene should be suspected (1047).
Pathologic analysis of affected brains shows edema, causing necro-
sis of the neurons and glia, in the thalamus, brainstem tegmentum,
and cerebellar dentate nucleus. There is florid petechial hemorrhage
around small caliber intraparenchymal vessels. There may also be non-
hemorrhagic white matter lesions in the cerebral and cerebellar paren-
chyma. An absence of inflammatory cells, except a few extravasated
leukocytes, differentiates this disorder from ADEM and acute hemor-
rhagic encephalomyelitis (1037).
Neuroimaging studies in acute necrotizing encephalitis show bilat-
eral thalamic lesions, which are continuous with lesions in the lateral
putamina and external/extreme capsules (Fig. 3-104); these often cavi-
tate and become hemorrhagic, particularly in their central portions
(Fig. 3-105) (1050). Ring enhancement around the hemorrhagic areas
develops after a few days. The anterior putamina tend to be spared.
Most studies also show low attenuation and T2/FLAIR hyperintensity
in the tegmentum of the brainstem and, in some, the nuclei and deep
white matter of the cerebellum. In about half of affected patients the
cerebral hemispheres are involved, usually by patchy hypodensity and
T2 hyperintensity (Fig. 3-104); some cavitate, but no hemorrhage is
seen in these cerebral hemispheric lesions (1037). Reduced diffusivity
is reported in the affected regions of the brainstem, cerebellum, and
thalami during the first few days after onset of symptoms (1045,1051).
However, our experience has been that diffusivity is increased (Fig.
3-104), possibly because of the rapid tissue necrosis, unless the injured
area is hemorrhagic.
Hypomyelination with Atrophy of the Basal Ganglia
and Cerebellum
Hypomyelination with atrophy of the basal ganglia and cerebellum
(OMIM 612438, also called HABC and hypomyelinating leukodystro-
phy 6) is a newly described disorder of unknown cause. Clinical presen-
tation varies with the severity of the disease. Most affected children are
initially seen because of some difficulty learning to walk; subsequently,
they have frank motor deterioration with an extrapyramidal movement
disorder consisting of dystonia, choreoathetosis, and rigidity, increas-
ing spasticity, and ataxia (34,1052). Severely affected children are noted
5/6/2011 12:09:21 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 199

FIG. 3-104. Acute necrotizing encephalopathy (ANE). 3-year-

old with seizures after 1 day of fever, vomiting, diarrhea. A. Axial
noncontrast CT shows low attenuation in bilateral thalami (T)
and cerebral white matter. B–D. Axial T2-weighted images
show abnormal hyperintensity in the dorsal pons, cerebellar
white matter (B), thalami, posterior putamina and external/
extreme capsules (C), and cerebral white matter (D). E. Axial
average diffusivity image shows increased diffusivity (arrows)
in the thalami and external/extreme capsules. F. Single voxel
proton MRS (TE = 288 ms) from the thalamus shows low NAA
and markedly elevated lactate (Lac).

Barkovich_Chap03.indd 199 5/6/2011 12:09:22 AM

 200 Pediatric Neuroimaging

FIG. 3-105. Acute necrotizing encephalopathy with thalamic necrosis and hemorrhage. Axial SE T2-weighted images show edema extending into the
posterior putamina, external and extreme capsules (white arrows in A). Note the hypointensity (black arrows in A), indicating hemorrhagic necrosis, in the
thalami. More superior image (B) shows hyperintensity(white arrows in B) extending into the perirolandic white matter.

to have poor vision or oculogyric eye movements and absent motor
development when they are only a few months old (1053). Variable
nystagmus, decreased hearing, short stature, and microcephaly have
been reported (1052). Cognitive deficits are variable, but all affected
children appear to have learning difficulties and require special edu-
cation (34,1052). EEG reveals slowing of background activity in all
patients.
MRI shows diffuse hypomyelination, with hyperintense cere-
bral white matter compared to gray matter on T2-weighted images
(Fig. 3-106); progressive loss of myelin is seen on sequential scans (1052).
Sometimes, the anterior portion of the posterior limb of the internal
capsule may show slight T2 hypointensity. Of interest, the white matter
does become hyperintense compared to gray matter on T1-weighted
images (1052). These findings of hypomyelination, probably due to

FIG. 3-106. Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) in a 3-year-old. A. Sagittal T1-weighted image shows a thin cor-
pus callosum and cerebellar atrophy (white arrows). B. Axial T2-weighted image shows marked hypomyelination and nearly complete absence of caudate
heads and putamina. Globi pallidi (white arrows) can be seen.

Barkovich_Chap03.indd 200 5/6/2011 12:09:23 AM

 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 201

both lack of deposition and further myelin loss, have been confirmed
by histopathology (1052). The corticospinal tracts are most severely
affected and appear hyperintense in the pons and midbrain, highlighted
by the hypointensity of the surrounding structures (34). Depletion of
corticospinal tract axons in the brainstem was confirmed by histo-
pathology (1052). Volume of cerebral white matter is mildly reduced
(Fig. 3-106) and seems to diminish over time. In addition, the putamen
and, to a lesser degree the caudate nucleus, are small and show pro-
gressive atrophy on sequential scans; globi pallidi and thalami appear
to be spared. The cerebellum also undergoes progressive atrophy
(Fig. 3-106), with the vermis being more severely involved than the
hemispheres (34); histopathology shows the most severe involve-
ment to be in the internal granular layer of the cerebellar cortex
(1052). Proton MRS shows normal cortical spectra, but reveals
increased myo-Inositol and creatine peaks with normal NAA in the
white matter, representing white matter gliosis with preservation of
axons. Spectra of the basal ganglia are similar to those of white mat-
ter (34). The effects of this disorder on water diffusion, as measured
by diffusion-weighted imaging and diffusion tensor imaging, has not
been reported.

3-Methylglutaconic Aciduria
3-methylglutaconic aciduria (MGA) is a fairly common biochemical
disorder that is seen in several syndromes with diverse clinical features
(1054). It is usually divided into five categories based upon clinical and
laboratory findings (1055). Patients with the autosomal recessive type
I (OMIM 250950) typically present with neurologic signs and symp-
toms. These patients have mutations in the AUH gene (on chromo-
some 9), which encodes 3-methylglutaconyl-CoA hydratase (1056).
The phenotypic presentation varies, some patients manifesting delayed
development of language and hyperchloremic acidosis associated with
gastroesophageal reflux, while others have much more severe pheno-
type, including seizures, cerebellar findings, and atrophy of the basal
ganglia (582). In other types of 3MGA the deficient enzyme, hence
the source of excreted 3-methylglutaconic acid is yet unknown. As the
most commonly and severely affected organs in 3MGA are the brain,
heart, and sometimes the liver and skeletal muscles, it is possible that
increased excretion of 3-methylglutaconic acid is only an epiphe-
nomenon, or a biochemical marker for a group of unspecified energy
metabolism disorders. The primary defect is likely in the mitochondrial
respiratory chain.
Barth syndrome or type II 3-methylglutaconic aciduria (OMIM
302060) is caused by mutations of the TAZ gene at chromosome Xq28
(1057) and characterized by short stature, congenital cardiomyopa-
thy, neutropenia, and recurrent infections (1058,1059). In type III
3-methylglutaconic aciduria also called Costeff syndrome, Behr syn-
drome, or optic atrophy plus (OMIM 258501, caused by mutation
of the OPA3 gene at chromosome 19q13.2-q13.3) (1060), early onset
optic atrophy is accompanied by extrapyramidal signs and ataxia;
the condition is well known among Jews of Iraqi descent. Type IV, or
nonspecific, 3-methylglutaconic aciduria is a clinically heterogeneous
autosomal-recessive condition characterized neurologically by delayed
psychomotor development and slowly developing, worsening spastic-
ity. Neonatal hypoglycemia and lactic acidosis have been noted in some
cases (998,1061), as has presentation as Leigh syndrome (1062). Type V
3-methlylglutaconic aciduria (OMIM 610198, caused by muta-
tions in the DNAJC19 gene at 3q26.3) is characterized by early-onset
dilated cardiomyopathy with conduction defects, nonprogressive cer-
ebellar ataxia, testicular dysgenesis, and growth failure in addition to
3-methylglutaconic aciduria (1063).
Imaging findings in type II and type II 3MGA are usually unre-
markable, although occasionally atrophy may be found. In both type I
FIG. 3-107. 3-methylglutaconic aciduria, type I. Axial T2-weighted image
shows T2 prolongation in the caudate heads and the anterior halves of the
putamina.
and type IV 3MGA (and in the uncategorized phenotype with hyper-
methioninemia) the most characteristic imaging presentation is sym-
metrical bilateral basal ganglia disease (T2/FLAIR hyperintensity in
the caudate heads and anterior halves of the putamina) with cerebel-
lar atrophy (Fig. 3-107). In addition, myelination of the cerebral white
matter is delayed and, especially in advanced stages of the disease, dif-
fuse cerebral atrophy as well as focal white matter alterations may also
be present (41,998,1061).
Molybdenum Cofactor Deficiency
Molybdenum cofactor deficiency (OMIM 252150) is an autosomal
recessive disorder in which molybdenum cofactor, a component that
is essential to the function of three enzymes, is deficient. Molybdenum
cofactor deficiency can be caused by mutation of genes (MOCS1 at
chromosome 14q24 and MOCS2 at chromosome 6p21.3) that encode
enzymes essential for the two separate steps in the formation of molyb-
denum cofactor (1064). The clinical phenotype is identical in these two
groups (1064). A third type of molybdenum cofactor deficiency, called
type C, is caused by mutation in the gephyrin gene (GEPH at chromo-
some 5q11) (1065).
Patients with molybdenum cofactor deficiency present with
severe neurologic signs and symptoms in first few days of life;
this neonatal encephalopathy can mimic that of hypoxic-ischemic
injury. The leading symptom is drug-resistant epilepsy with a
burst suppression pattern on EEG (1066,1067). Other features can
include feeding difficulties, mental retardation, lens dislocations,
and myoclonic spasms (1068). Biochemical abnormalities include
elevated urinary sulfite, low plasma urate, and very low urinary uric
acid. Pathologic exam of affected brains shows severe diffuse brain
atrophy with diffuse myelin loss, cortical and central neuronal loss,
gliosis, and cystic changes that are most severe in the basal ganglia
(1069–1071).

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 202 Pediatric Neuroimaging
Neuroimaging studies show profound injury to the brain. In the
neonatal period, neuroimaging shows decreased attenuation (CT), and
T1 and T2 prolongation (hypointensity on T1-weighted images, hyper-
intensity on T2-weighted and FLAIR MR images) of the white matter
and caudate nuclei, suggestive of edema (1070,1072,1073). During the
first weeks after birth, ultrasound shows rapid cystic degeneration of
the white matter with enlargement of the ventricles and subarachnoid
spaces (1074). During the same period, reduced diffusivity in affected
areas can be detected by diffusion-weighted imaging (1074). In the
subacute phase, the basal ganglia may show T1 hypointensity and T2
hyperintensity, similar to that in profound neonatal hypotensive injury
(see Chapter 4) and urea cycle disorders (see section V.D.8). As the
changes evolve into the more chronic phase, the caudate and lentiform
nuclei show marked diminution in size (Fig. 3-108) and the white mat-
ter shows injury that may evolve into frank cystic changes (1072,1073).
Graf et al. have reported a patient in whom globus pallidus involvement
predominated (1075), whereas Teksam et al. have reported intracranial
hemorrhage (1076). Differentiation from severe neonatal hypoxic isch-
emic injury (1077) is made by the predominant thalamic involvement
in hypoxic-ischemic injury (see Chapter 4) and its relative absence in
this disorder.
Isolated Sulfite Oxidase Deficiency
Isolated sulfite oxidase deficiency (OMIM 272300) is a rare auto-
somal recessive disorder that leads to early neurologic deterioration
and, in many cases, early death. The causative gene, called SUOX,
has been mapped to chromosome 12q13.2-13.3 (1078). Sulfite oxi-
dase is a soluble mitochondrial enzyme, located within the inter-
membranous space, which catalyzes the oxidation of endogenous or
exogenous sulfite to sulfate. Sulfite oxidation is the final step in the
metabolism of sulfur derived from sulfur-containing amino acids
(830). The presentation is similar to that of molybdenum cofactor
deficiency (section V.D.17). Affected neonates typically feed poorly,
with frequent vomiting, are lethargic, and develop seizures in the first
few days of life. EEG shows diffuse slowing and, sometimes, bilat-
eral diffuse epileptiform activity. Lens ectopia is common (1079).
Barkovich_Chap03.indd 202
FIG. 3-108. Molybdenum co-factor defi-
ciency. A. Subacute phase. Axial T2-weighted
image shows T2 prolongation in the caudate
heads (solid black arrows) and white matter,
T2 shortening in the shrunken lentiform
nuclei (open black arrows) and thalami. B.
Chronic phase. Axial T2-weighted image
shows volume loss in the basal ganglia.
Diagnosis is made by detection of increased urinary excretion of
sulfite and S-sulphocysteine associated with low plasma cystine lev-
els. Decreased sulfite oxidase activity is found in cultured fibroblasts.
Molecular analysis shows deletions in the mitochondrial genome
(1079). If the children survive, they manifest progressive microceph-
aly with long tract signs, poor head control, truncal hypotonia and
appendicular spasticity (830).
Neuropathologic exam shows cystic encephalomalacia of the white
matter with marked astrogliosis, cortical atrophy, and shrunken, gliotic
basal ganglia (830,1080).
Imaging studies early in the course of the disease show edema in
the cerebral cortex, white matter, and basal ganglia (Fig. 3-109A–D)
(1081,1082). The hippocampi are relatively spared. T1 shortening is
seen at the cortical-white matter junction and in the basal ganglia
(Fig. 3-109A and B), followed by atrophy of the basal ganglia and
cystic degeneration of the white matter within the first month (Fig.
3-109H and I) (1082). After a few weeks, the brain degenerates into
cystic encephalomalacia (1081). Diffusion-weighted imaging shows
markedly reduced diffusion in the basal ganglia, cerebral cortex, and
subcortical white matter in the subacute phase (Fig. 3-109E and F)
(1080). Long echo (TE = 288 ms) proton MR spectroscopy shows
very low NAA and markedly elevated lactate in the subacute phase
(Fig. 3-109G) (1080).
Toxin Ingestions
It is important to remember that inborn errors of metabolism are
toxic exposures in which the toxins are intrinsic. It stands to reason,
therefore, that similar patterns of injury will result from exposure to
external toxins, such as drugs. Figure 3-110 is an example of brain
injury from ingestion of substances that had toxic effects. Notice
that both gray matter and white matter are involved; the imaging
features could be seen in an inborn error of metabolism. Toxic expo-
sure should always be considered if disease manifestations or disease
onset are in any way atypical, particularly the acute onset of neu-
rological signs and symptoms in a previously healthy adolescent or
teen.
5/6/2011 12:09:25 AM
 FIG. 3-109. Isolated sulfite oxidase deficiency. Newborn with seizures and vomiting. A and B. Axial T1-weighted images show blurring of the cortical-
white matter junction and abnormal hyperintensity in the lentiform nuclei (white arrows) as well as heterogeneous white matter with multiple foci of hyper-
intensity (white arrowheads). C and D. Axial T2-weighted images show abnormal heterogeneous hyperintensity of white matter (isointense to CSF) with
hyperintense basal ganglia (black arrows) and multiple areas of cortical edema (white arrows). E and F. Axial diffusivity (Dav) maps show reduced diffusivity
in the basal ganglia (black arrows) and multiple cortical regions (black arrowheads). G. Single voxel proton MRS (TE = 135 ms) shows reduced NAA and high
lactate (Lac) in the frontal white matter. H and I. Follow-up axial FLAIR images at age 6 months show severe atrophy with multicystic encephalomalacia.
Note the multiple layers of subdural hematomas (s) due to the atrophy.

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 204 Pediatric Neuroimaging
METABOLIC AND NEURODEGENERATIVE
DISORDERS PRIMARILY INVOLVING THE
CEREBELLUM
Differentiation of Cerebellar Atrophy from
Hypoplasia
A large number of metabolic diseases affect the cerebellum; how-
ever, relatively few of these affect the cerebellum predominantly
(Table 3-19). This section will discuss some disorders that affect
the cerebellum in childhood. Before discussing specific disorders,
however, it is important to discuss the difference between the imag-
ing appearance of cerebellar atrophy and cerebellar hypoplasia. The
Barkovich_Chap03.indd 204
FIG. 3-110. Ten-year-old girl after
ingestion of multiple drugs. Axial
noncontrast CT images (A–D) show
marked hypoattenuation and swell-
ing of the cerebellum, globi pallidi,
and cerebral white matter to involve
the subcortical U fibers. Early hydro-
cephalus is present.
term cerebellar atrophy will refer to a cerebellum that is small and
has enlarged cerebellar fissures (Fig. 3-111) or if it has been shown to
undergo progressive loss of volume. The pons is usually normal in cer-
ebellar atrophy, as the connections with the cerebellum are typically
well established before the atrophy begins; if atrophy begins in utero,
the pons will be proportionately small. The term cerebellar hypoplasia
will refer to a small cerebellum in which the fissures are of normal
size compared with the folia (Fig. 3-112); cerebellar hypoplasia is usu-
ally associated with pontine hypoplasia. For a reference, the normal
cerebellar vermis extends from the inferior colliculi to the obex on
the midline sagittal MRI of a neonate and from the intercollicular sul-
cus in an older infant or child. Note that these imaging appearances
are fairly consistent, regardless of the specific cause of the hypoplasia
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 205

TABLE 3-19 Childhood Disorders with Significant Cerebellar Involvement

A. Cerebellar Atrophy p. Ataxia with selective vitamin E deficiency
1. With Ataxia as an Early Clinical Sign q. Abetalipoproteinemia
a. Friedrich ataxia r. Cayman ataxia
b. Late-onset Tay-Sachs disease s. Dentatorubropallidoluysian atrophy
c. Pontocerebellar hypoplasia 2. Without Ataxia as an early sign
d. Mitochondrial disorders (particularly disorders of a. Congenital disorder of glycosylation 1a
respiratory chain complex I and coenzyme Q) b. Infantile neuroaxonal dystrophy
e. Cerebrotendinous xanthomatosis c. Infantile olivopontocerebellar atrophy
f. DNA polymerase gamma disorders (mitochondrial d. Progressive encephalopathy with edema, hypsarrhythmia,
recessive ataxia syndrome and optic atrophy (PEHO) syndrome
g. Neuronal ceroid lipofuscinoses (all types, cerebellar e. Langerhans cell histiocytosis
findings most pronounced in late infantile form and f. Wolfram syndrome
progressive epilepsy/mental retardation form) g. Hypomyelination with atrophy of the basal ganglia and
h. Ataxia-telangiectasia (see Chapter 6) cerebellum (discussed in previous section)
i. Ataxia telangiectasia-like disorder h. 3-methylglutaconic aciduria type I and IV
j. Ataxia with oculomotor apraxia, types 1 and 2 B. Cerebellar Hypoplasia
k. Autosomal recessive ataxia of Charlevoix-Saguenay 1. Marinesco-Sjögren syndrome
l. Infantile onset spinocerebellar ataxia 2. X-linked nonprogressive congenital cerebellar hypoplasia
m. Mevalonic kinase Deficiency 3. Höyeraal-Hreidarsson syndrome
n. Marinesco-Sjögren syndrome 4. Revesz syndrome
o. Spinocerebellar ataxias

or atrophy. As it seems pointless to show multiple cases with indis-
tinguishable features, this section will illustrate only disorders with
somewhat distinctive features.
Cerebellar Ataxias
Many genetic disorders cause cerebellar ataxia as an early sign of neu-
rologic disease. These can roughly be divided into two major groups;
those presenting in before the age of 20 years are traditionally clas-
sified as “autosomal recessive” ataxias, while those presenting at later
ages are grouped as “autosomal dominant” ataxias. Although the age
of onset in all of these disorders can be variable, this traditional group-
ing is quite useful for the purposes of this book. Table 3-20 lists the
autosomal recessive ataxias with their genetic characteristics, main
clinical features, and imaging findings. More details are included in the
descriptions of the disorders that follow.

FIG. 3-111. Cerebellar atrophy. Axial (A) and coronal (B) T1-weighted images show a small cerebellum with shrunken cortex, diminished white matter,
and very enlarged fissures. The pons is of normal size, indicating that atrophy occurred after early infancy.

Barkovich_Chap03.indd 205 5/6/2011 12:09:28 AM

 206 Pediatric Neuroimaging

FIG. 3-112. Cerebellar hyp-

oplasia. A. Moderate hypopla-
sia. The vermis (white arrows)
is small, not extending superi-
orly to the intercollicular sulcus
or inferiorly to the obex. Fis-
sures are not enlarged, how-
ever, indicating that no atrophy
has occurred. The pons (white
arrowheads) is small. B. Severe
hypoplasia. The vermis (white
arrow) is tiny, but has normal
lobulation and fissures are not
enlarged. Not the pons (white
arrowheads) is extremely small.

Cerebellar Atrophy mapped to chromosome 9q13, with no evidence of genetic heteroge-

Friedreich Ataxia
Friedreich ataxia (OMIM 229300) is the commonest form of hered-
itary ataxia, with a prevalence of 2.1 × 10−5. This is an autosomal
recessive disorder; the genetic locus of the FXN gene has been
neity (1083). The function of the encoded protein (called frataxin) is
unknown, but it is known that frataxin is located at the inner mito-
chondrial membrane and its mutation seems to trigger deficiency
of iron-sulphur cluster-containing enzymes, such as mitochondrial
respiratory chain complexes I-III (815). Deficiency of frataxin is gen-

TABLE 3-20 Cerebellar Ataxia Presenting in Childhood and Adolescence

Disorder Gene Locus Protein Function Clinical S/Sx Imaging
Friedreich Ataxia FXN 9q13 Mitochondrial iron Ataxia, nystagmus, weakness, amyotrophy, Normal Cb Spinal cord
metabolism unstable gaze fixation, Babinski, deaf- atrophy
ness, cardiomyopathy, diabetes, scoliosis
Late-Onset HEXA 15q23-24 Glycosphingolipid Ataxia, nystagmus, weakness, amyotro- Cb atrophy
Tay-Sachs metabolism phy, saccadic ocular pursuit, spasticity,
hypotonia, tremor, myoclonus, dystonia,
impaired cognition, epilepsy
Cerebrotendinous CYP27 2q33-ter Bile-acid synthesis Ataxia, weakness, amyotrophy, spasticity, Cb atrophy, cerebral atrophy,
xanthomatosis myoclonus, dystonia, Parkinsonism, diffusely increased FLAIR
impaired cognition, epilepsy, cataracts, and T2 white matter
tendon xanthomas signal intensity
Mitochondrial COQ2 9p13.3 Not known Hypotonia, motor delay, ataxia, or seizures Cb atrophy (vermis and
CoQ10 deficiency APTX 6q21 hemispheres)
PDSS1 10p12.1
PDSS2 4q21-q22
CABC1 1q42.2
Mitochon- POLG 15q22-26 Mitochondrial Ataxia, nystagmus, weakness, amyotro- Mild vermian atrophy,
drial DNA DNA repair and phy, ophthalmoplegia, saccadic ocular increased FLAIR and T2
polymerase replication pursuit, Babinski, tremor, myoclonus, white matter signal inten-
gamma choreoathetosis, impaired cognition, sity in Cb white matter,
disorders epilepsy, impaired hearing, hepatic thalami. In some variants,
failure T2 hyperintensity in
occipital lobes, brain stem.
Spinocerebellar Many Many Many Ataxia, weakness, amyotrophy Cb atrophy, spinal cord
ataxias 1–27 atrophy in some, pontine
atrophy in some

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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 207

TABLE 3-20 Cerebellar Ataxia Presenting in Childhood and Adolescence (Continued)

Disorder Gene Locus Protein Function Clinical S/Sx Imaging
Dentatorubropal- ATN1 12p13.31 Unstable CAG Myoclonus, cerebellar ataxia, and mental Cb and midbrain atrophy,
lidoluysian repeat retardation cerebral atrophy, white
atrophy matter volume loss.
Ataxia- ATM 11q22-23 DNA damage Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy
Telangiectasia response oculomotor apraxia, Babinski, tremor,
myoclonus, dystonia, choreoathetosis,
diabetes, oculocutaneous telangiectasias,
radiosensitivity, immunodeficiency
Ataxia- MRE11 11q21 DNA damage Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy
Telangiectasia- response oculomotor apraxia, dystonia, chore-
like disorder oathetosis, radiosensitivity, immuno-
deficiency
Ataxia with oculo- APTX 9p13 DNA repair, Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy, mostly in
motor apraxia possibly RNA oculomotor apraxia, ophthalmoplegia, vermis.
type 1 processing gaze fixation instability, hypotonia,
tremor, dystonia, choreoathetosis,
impaired cognition, scoliosis, optic
atrophy
Ataxia with oculo- SETX 9q34 unknown Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy, mostly in
motor apraxia oculomotor apraxia, saccadic ocular vermis.
type 2 pursuit, strabismus, Babinski, tremor,
myoclonus, dystonia, choreoathetosis,
impaired cognition, scoliosis
Ataxia of SACS 13q11 Protein folding Ataxia, nystagmus, weakness, amyotro- Cb vermian atrophy, spinal
Charlevoix- phy, saccadic ocular pursuit, spasticity, cord atrophy.
Saguenay Babinski, tremor, myoclonus, dystonia,
choreoathetosis, impaired cognition
Infantile-onset C10orf2 10q24 DNA replication Ataxia, weakness, amyotrophy, ophthal- Cb atrophy, spinal cord atro-
spinocerebellar moplegia, hypotonia, choreoathetosis, phy, brain stem atrophy.
ataxia impaired cognition, epilepsy, impaired
hearing, optic atrophy, hypogonadism
Cayman ataxia ATCAY 19p13.3 Neurotransmitter Ataxia, nystagmus, hypotonia, tremor, Cb atrophy
metabolism psychomotor delay
Marinesco- SIL1 5q31 ? Protein folding Ataxia, nystagmus, weakness, amyotro- Mild Cb atrophy
Sjögren phy, strabismus, hypotonia, tremor,
syndrome psychomotor delay, impaired cognition,
scoliosis, skeletal deformities, cataracts,
hypogonadism
Ataxia with Vit E TTPA 8q13.1- Vit E homeostasis Ataxia, amyotrophy, Babinski, tremor, RP, Normal or mild Cb atrophy
Deficiency 13.3 cardiomyopathy
Abetalipopro- MTP 4q22-24 Lipoprotein Ataxia, nystagmus, amyotrophy, RP, car- Normal
teinemia metabolism diomyopathy, acanthosis
Refsum Disease PHYH 10 pter- Fatty acid oxidation Ataxia, amyotrophy, RP, cardiomyopathy, Normal Cb
PEX7 p11.2 Peroxisomal skeletal deformities, renal failure,
6q22-q24 protein elevated CSF protein
importation
Autosomal SYNE1 6q Not known Dysarthria, ataxia, dysmetria, Cb vermian and hemispheric
recessive Cb hyperreflexia, nystagmus atrophy
ataxia Type 1

S/Sx, signs and symptoms; Cb, cerebellum; RP, retinitis pigmentosa; Vit, Vitamin.

Barkovich_Chap03.indd 207 5/6/2011 12:09:29 AM

 208 Pediatric Neuroimaging
erally caused by expansion of the GAA triplet within the first intron
of the FXN gene; normally there are 33 or fewer GAA triplets, while
in pathological expansions, there are from 67 to more than 1,000
triplets (1084). The disease shows considerable variability in age of
onset, rate of progression, severity, and extent of disease involvement
(1085). Although the disease can present at nearly any age, onset is
before the age of 10 years in 35% to 40%. Gait and stance ataxia and
lower limb areflexia are constant findings. Dysmetria, dysarthria,
lower extremity areflexia, Babinski signs, scoliosis, and decreased
vibratory sensation are present in the majority of affected patients;
hypertrophic cardiomyopathy is present in nearly half (1085). A
high incidence of diabetes mellitus (25%) is present in childhood
onset cases (1083). The main pathologic features are early loss of
large sensory neurons in the dorsal root ganglia, followed by degen-
eration of the posterior columns of the spinal cord, spinocerebellar
tracts, and pyramidal tracts (1086). MRI is most often normal but
may show atrophy of the superior vermis (Fig. 3-113), inferior cer-
ebellar hemispheres, spinal cord, and, occasionally, brainstem (Fig.
3-113) (1083,1087). Recently, DTI using tract based spatial statistics
has been used to study this disorder, finding increased diffusivity in
the cerebellum and decreased fractional anisotropy in the superior
cerebellar peduncles (1088).
Ataxia-Telangiectasia
Ataxia telangiectasia is a fairly common cause of ataxia and cerebel-
lar atrophy in children, with prevalence as high at one per 40,000 in
the United States. Some classify it as a phakomatosis. This disorder is
discussed in Chapter 6.
Late Onset GM2 Gangliosidosis
The “classic” infantile forms of GM2 gangliosidosis (Tay-Sachs dis-
ease and Sandhoff disease) were described in section IV.D.10 on dis-
eases involving gray and white matter. Some patients have less severe
involvement, probably because they are compound heterozygotes,
with one severe and one mild mutation (1089); as a consequence, the
FIG. 3-113. Friedreich ataxia. A. Sagittal T1-weighted image shows a small cerebellar vermis with think folia and prominent fissures (white arrows) in the
superior vermis. The cisterna magna is abnormally large. The pons is normal. B. Axial T2-weighted image though the pons shows a large fourth ventricle
and abnormal hyperintensity (white arrows) in the dorsal pons.
Barkovich_Chap03.indd 208
build-up of ganglioside within neurons and glia is slower, the onset of
symptoms later, and the progression of the disease more protracted
(1011). Patients with the juvenile form of the disease typically present
in the middle or end of the first decade with gait disturbances, incoor-
dination, speech problems, and developmental delay; muscle wasting,
proximal weakness, and bladder/bowel incontinence ensue during the
following decade (1011). Patients with the adult onset of the disease
present in middle age with progressive cognitive disability (1012);
most patients also suffer from psychotic episodes and bipolar disorder
(1089,1090).
Unlike the infantile form, patients with late onset GM2 gan-
gliosidosis typically have little or no white matter or basal ganglia
abnormalities on neuroimaging. Instead, their studies show pro-
gressive cerebellar greater than cerebral atrophy (1011,1012,1091).
Proton MR spectroscopy (TE = 144 ms) shows reduced NAA in the
thalami and cerebral white matter compared with age-matched con-
trols (1092).
Ataxia with Oculomotor Apraxia, Types 1 and 2
Ataxia with oculomotor apraxia type 1 (OMIM 208920) is an early
onset autosomal recessive cerebellar ataxia with peripheral axonal
neuropathy, oculomotor apraxia, and hypoalbuminemia. It is caused
by mutation of the APTX gene at 9p13 (1093), the protein product
of which is thought to play a role in DNA, and possibly RNA, repair
(1094). Affected patients typically present with cerebellar ataxia, senso-
rimotor neuropathy (with dorsal column involvement and areflexia),
ocular movement disorders (nystagmus, fixation instability, oculomo-
tor apraxia), extrapyramidal signs, and mild cognitive impairment
(1095–1097). MRI shows cerebellar atrophy with predominantly verm-
ian involvement (1096).
Formerly known autosomal recessive spinocerebellar ataxia, ataxia
with oculomotor apraxia type 2 (OMIM 606002) is an autosomal reces-
sive disorder caused by mutations (missense, in frame deletion or splice
mutations, or truncations) of the SETX gene at chromosome 9q34-qter
(1098) and characterized by the onset of gait ataxia during the second
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 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
decade, associated with oculomotor apraxia (∼50%), peripheral neu-
ropathy (>95%), impaired smooth pursuit (100%), and gaze-evoked
nystagmus (90%). Pyramidal signs are present in approximately 20%,
tremor and extrapyramidal signs in 10% to 15%, and cognitive changes
are found in some populations (1099,1100). MRI is similar to that in
type 1, with cerebellar atrophy that is largely confined to the vermis
(1099–1101).
Autosomal Recessive Spastic Ataxia
(of Charlevoix-Saguenay)
Autosomal recessive spastic ataxia (OMIM 270550) is a disorder that
was initially described in Quebec (1102), but has since been found
to be fairly widespread (1097,1103). Molecular genetic analyses have
mapped the responsible gene, named SACS, to chromosome 13q12
(1104). The protein product of the gene, called sacsin, is thought to
be involved in protein folding, and is expressed in a variety of regions
within the central nervous system, including the cerebral cortex, the
granular layer of the cerebellar cortex, and the hippocampus (1103).
Affected patients present in the third or fourth year of life with gait
unsteadiness after a delay in walking. Later, examination shows spastic
ataxia, slurred speech, increased deep tendon reflexes, abnormal plantar
responses, nystagmus, retinal striations (due to hypermyelinated reti-
nal axons), defects in ocular pursuit movements, and often mitral valve
prolapse (1102). EMG shows axonal neuropathy, with absent sensory
action potentials and mildly reduced motor conduction. Intelligence is
usually normal. Imaging typically shows cerebellar vermian atrophy; in
addition, some cases show diminished cerebral white matter and a thin
corpus callosum (1103,1105).
Mitochondrial Disorders Causing Cerebellar Atrophy
Coenzyme Q10 Deficiency
Deficiency of coenzyme Q10 (ubiquinone, a component of the mito-
chondrial respiratory chain) can result in phenotypes of encephalomy-
opathy, multisystemic organ failure, isolated myopathy, Leigh syndrome
with growth retardation, and progressive ataxia with cerebellar atrophy
(OMIM 607426). Mutations of several genes that code proteins involved
FIG. 3-114. Mitochondrial complex I deficiency with cerebellar atrophy. A. Sagittal T1-weighted image shows cerebellar atrophy with prominent fissures
(white arrows) in the markedly hypointense superior vermis. Note cavitation (white arrowheads) in the callosal genu, suggesting possible complex I or com-
plex II deficiency. B and C. Axial FLAIR images show hyperintensity of the superior cerebellum, indicating active disease, and hypointensity (supporting
cavitation) in the callosal genu and deep frontal white matter (white arrows).
Barkovich_Chap03.indd 209
209
in synthesis of CoQ10 can cause the syndrome (1106). In this section,
only the ataxia/cerebellar atrophy form (971,972) will be discussed; in
one report, this deficiency was present in 13% of patients with undiag-
nosed cerebellar ataxia and atrophy (971). It has been postulated that,
because CoQ10 has lower concentration in the cerebellum than other
regions of the brain that the cerebellum is particularly susceptible to
injury in mitochondrial disorders (1107). However, a recent study
indicates that cerebellar volume loss can be seen in many mitochon-
drial disorders, including complex I deficiency (Fig. 3-114), complex
II deficiency, complex IV deficiency, mutations of the catalytic subunit
of mitochondrial DNA polymerase g, MELAS syndrome, MGNIE syn-
drome, and those with multiple respiratory chain deficiencies (833). In
addition, some patients with coenzyme Q10 deficiency have a different
clinical syndrome, with infantile encephalomyopathy and nephropathy
(1108), while others have a predominantly myopathic form with recur-
rent myoglobinuria and CNS involvement (1109). Therefore, although
the presence of cerebellar atrophy in children should raise suspicion for
a mitochondrial disorder, the evaluation of mitochondria should not
be restricted to coenzyme Q10.
Initial symptoms of coenzyme Q10 deficiency are quite variable.
Encephalopmyopathic forms, infantile encephalopathy, Leigh syn-
drome, and infantile multiorgan disease have been reported as well as
the ataxic encephalopathy with cerebellar atrophy (971,1110–1112).
The ataxic encephalopathy form typically is initially manifested as
hypotonia and motor delay, ataxia, or seizures; all seem to have their
onset in the first decade. Ataxia becomes apparent by age 10 years and
affects the trunk, limbs, and speech. Long tract signs (hyperreflexia,
Babinski signs, spasticity) are found in about half of affected patients.
Other findings include myoclonus and ophthalmoparesis (971). Imag-
ing studies show progressive atrophy of the cerebellar vermis and
hemispheres (971).
SANDO Syndrome
The so-called SANDO (sensory ataxic neuropathy, dysarthria, and
ophthalmoparesis) syndrome (OMIM 607459) is caused by muta-
tions of the catalytic subunit of mitochondrial DNA polymerase g,
which is believed to function in both the replication and repair of
5/6/2011 12:09:30 AM
 210 Pediatric Neuroimaging
the mitochondrial genome (1113). Affected patients present in child-
hood or adolescence, usually with sensorimotor ataxia, headaches, or
seizures. Dysarthria, external ophthalmoplegia, or myoclonus may
ensue (1113,1114). MRI shows T2 and FLAIR hyperintensity of the
cerebellar white matter with progressive cerebellar atrophy. Some cases
have also been reported with hyperintensity in the thalami, occipital
white matter, and brainstem (1114).
Infantile Onset Spinocerebellar Ataxia
Still another mitochondrial disorder causing cerebellar ataxia is infan-
tile onset spinocerebellar ataxia (OMIM 271245), a disorder that has
been described mainly in Finland (1115). The disorder is caused by
mutation of the C10orf2 gene on chromosome 10q24; the protein
product is involved in DNA replication (1115,1116). Affected patients
present during the first 2 years of life with a progressive course that
includes cerebellar ataxia, hypotonia, sensory neuropathy with areflexia,
ophthalmoplegia, optic atrophy, epilepsy, and (in females) primary
hypogonadism (1115,1116). MRI is normal at the time of clinical pre-
sentation but shows progressive atrophy of the cerebellum, brainstem,
and spinal cord, starting at approximately 6 years of age (1116,1117).
Infantile Olivopontocerebellar Atrophy
Autosomal dominant inheritance, onset during adulthood, and a
slowly progressive course characterize most cases of olivopontocer-
ebellar atrophy. Infantile olivopontocerebellar atrophy is extremely
rare and is characterized by rapid degeneration and death within a few
months or years of the onset of disease (1118). Neuroimaging by MRI
or CT shows classic findings of a small cerebellum and small pons,
with marked diminution in the size of the middle cerebellar peduncles
(1119). This is a not a well-defined entity. Most cases are better clas-
sified as congenital disorders of glycosylation (section IV.E.3.i). Oth-
ers may represent a recently described X-linked congenital cerebellar
ataxia (1120).
Pontocerebellar Hypoplasia
Cerebellar hypoplasia is frequently associated with pontine hypoplasia,
probably for two reasons: (a) many cerebellar nuclei establish axonal
connections with ventral pontine nuclei and vice versa (these axons
form a significant amount of the bulk of the ventral pons) and (b) the
decussation of the middle cerebellar peduncles forms the most ventral
Barkovich_Chap03.indd 210
portion of the pons. As a result, abnormal development of the pon-
tine nuclei, cerebellar nuclei, or the cerebellar cortex, or injury to these
structures during the developmental period (with subsequent degen-
eration of axons coursing through the middle cerebellar peduncles)
result in hypoplasia of the cerebellar hemispheres and the pons. Thus,
pontocerebellar hypoplasia is a heterogeneous disorder and most of
the entities that make up the disorder have genetic causes (1121). Five
specific clinical syndromes have been defined in which the pons and
cerebellum are hypoplastic in infancy; these are referred to as the pon-
tocerebellar hypoplasias types 1 to 5 (1122). These disorders are also
included in Chapter 5, but are principally discussed here, as their clini-
cal courses are progressive.
Patients with type 1 pontocerebellar hypoplasia (PCH1, OMIM
607596, caused by mutations of the VRK1 gene at chromosome 14q32)
typically present with progressive microcephaly, central hypotonia,
visual impairment, abnormal eye movements, and delayed psychomo-
tor development (1123,1124). They are often myopathic from involve-
ment of the anterior horn cells of the spinal cord, and may be born
with contractures of the extremities (1125). Both the cerebellum and
pons are small at birth and show further atrophy on subsequent stud-
ies; therefore, PCH1 is best considered a form of cerebellar atrophy that
begins prenatally. A characteristic feature is that there is relative sparing
of the vermis (Fig. 3-115), which is different from most cerebellar atro-
phies (in most, the vermis is equally or more affected compared to the
cerebellar hemispheres). Associated anomalies of the cerebral cortex
and corpus callosum are commonly seen.
Type 2 pontocerebellar hypoplasia, as described by Barth et al.
(1126,1127) is inherited as an autosomal recessive trait. It is genetically
heterogeneous, with PCH2A (OMIM 277470), caused by mutations of
the TSEN54 gene at chromosome 17q25.1, PCH2B (OMIM 612389)
caused by mutations of TSEN2 gene at chromosome 3p25.1, and
PCH2C (OMIM 612390) caused by mutations of the TSEN 34 gene at
chromosome 19q13.4. These genes encode noncatalytic (TSEN54) and
catalytic (TSEN2 and TSEN34) subunits of the tRNA splicing endonu-
clease (1128). All have similar clinical characteristics. Affected patients
are characterized by progressive microcephaly, epilepsy, and severe
neurological compromise, including early onset chorea and extrapyra-
midal dyskinesias that are progressive (1129,1130); there is essentially
no developmental progress (1126). Pathologically, it is characterized
by a reduced number of folia in the cerebellum and an undersized
FIG. 3-115. Pontocerebellar hyp-
oplasia type 1. Sagittal T1-weighted
image (A) shows a small pons and
slightly hypoplastic cerebellar ver-
mis. The callosal splenium is too
small. Axial T2-weighted image
(B) shows that the vermis (black
arrows) is relatively spared com-
pared with cerebellar hemispheres.
5/6/2011 12:09:31 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
ventral pons. Histologic examination shows loss of both afferent and
efferent cerebellar axons, marked reduction in the density of Purkinje
and granule cells, and marked reduction in the number of neurons in
the cerebellar nuclei. The pons shows reduced density of ventral pon-
tine neurons and diminished number of myelinated axons within the
basis pontis (1131). In addition, segmental focal lesions are seen in the
cerebellar cortex, dentate nuclei, and inferior olives (1132). On imag-
ing, the pons is quite small, but may have a slight ventral bulge; the cer-
ebellum is variable in size, ranging from mildly to severely hypoplastic
(Fig. 3-116) (1129–1131,1133,1134). As with type 1 PCH, the vermis is
relatively spared compared with the cerebellar hemispheres. Supraten-
torial structures are reported to be essentially normal, but the suba-
rachnoid spaces may be enlarged and white matter may have abnormal
T1 hypointensity/T2 hyperintensity (Fig. 3-116).
This well-defined entity should be differentiated from other
reports of “PCH2,” which clearly describe a different disorder: onset is
in utero (polyhydramnios, profound microcephaly), the neonates are
profoundly affected, and imaging shows severe cerebral, as well and
brainstem and cerebellar, atrophy (1134). Both the pons and cerebel-
lum are much more severely affected in these cases.
A third form of PCH (PCH3, OMIM 608027) was proposed by
Rajab et al. (1121), whose clinical, imaging and genetic studies demon-
strated a similar disorder to PCH2, except for the absence of dyskinesias
and the presence of optic atrophy, with linkage to chromosome 7q11-21.
Unfortunately, no pathological information is available for this entity.
Additional PCH types were proposed by Patel et al. (1135), who sug-
gested that PCH cases with severe olivary hypoplasia (“C-shaped” infe-
rior olives), also known as congenital olivopontocerebellar hypoplasia,
should be distinguished as PCH4 if the vermis is relatively preserved, or
PCH5 if the vermis is not spared. However, Barth et al. performed patho-
logic examinations on two patients with PCH4, finding features nearly
identical to those in PCH2, only of greater severity (1132). In review-
ing this data, Hevner suggested that PCH2 and PCH4 are likely related
lesions, with their differences likely reflecting different mutations in the
same gene or mutations of genes involving the same developmental path-
way (1122). Clearly, the understanding of these disorders is evolving.
Congenital Disorders of Glycosylation
Congenital disorders of glycosylation are a group of disorders result-
ing from defects in nine genes of the N-linked glycosylation pathway
Barkovich_Chap03.indd 211
211
(1136), in which enzymes catalyze the synthesis and processing of
asparagine (N)-linked glycans or oligosaccharides on glycoproteins.
These glycoconjugates play critical roles in metabolism, cell recogni-
tion and adhesion, cell migration, protease resistance, host defense, and
antigenicity, among others (1137). These disorders are divided into two
main groups and many (the number keeps increasing) subgroups that
are likely to change as the disorders become better understood. Most of
them do not involve the cerebellum and will not be further discussed.
The most common type of congenital disorder of glycosylation is
Type 1a (OMIM 212065), formerly known as carbohydrate deficient
glycoprotein syndrome. This autosomal recessive disorder is caused by
mutation in the PMM2 gene, located at chromosome 16p13.3-p13.2
(1138,1139). The underlying biochemical deficit is a reduction of
phosphomannomutase activity, impeding the conversion of mannose-
6-phosphate to mannose-1-phosphate, which is necessary for synthe-
sis of dolichol-pyrophosphate-oligosaccharides (1138,1140). Due to
increased understanding and more readily available testing, this disor-
der is being discovered more frequently and is now understood to have
a variable clinical expression, ranging from severe to very mild. The
most severe form referred to as the neurologic multivisceral form, is
characterized by failure to thrive, inverted nipples, abnormal distribu-
tion of subcutaneous fat, hepatomegaly, episodes of ascites, and peri-
cardial effusion. Infants generally present with severe encephalopathy
consisting of hypotonia, abnormal eye movement, and peripheral neu-
ropathy; examinations reveal cerebellar hypoplasia, retinitis pigmen-
tosa, and pronounced psychomotor retardation (1141). Older children
have ataxia, peripheral neuropathy, and moderate mental retardation
(1142). About 20% die in the first year of life from severe infection,
liver failure, cardiac insufficiency, or status epilepticus (1141). Those
that survive show considerable motor and cognitive delay (1141,1143),
usually noted at the age of 4 to 5 months. Motor impairment is wors-
ened by the presence of cerebellar, extrapyramidal, and peripheral
nerve dysfunction with resultant axial hypotonia, muscle weakness
(especially in lower extremities), dyskinesia, ataxia, dysmetria, and
tremor (1144). Progressive microcephaly and retinopathy are present
in about 80% of cases (1144). A second group, with findings restricted
to the nervous system, has a more benign prognosis. Patients in this
group present with psychomotor retardation, strabismus, and retinitis
pigmentosa; they make developmental progress until adolescence, after
which the neurologic condition becomes static (1145). Diagnosis is
FIG. 3-116. Pontocerebellar hyp-
oplasia type 4. Sagittal T1-weighted
image (A) shows microcephaly with
disproportionately small cerebel-
lum and brain stem. The posterior
corpus callosum is too thin. Axial
T2-weighted image (B) shows
prominent CSF spaces and abnor-
mally hyperintense cerebral white
matter.
5/6/2011 12:09:31 AM
 212 Pediatric Neuroimaging
FIG. 3-117. Congenital disorder of glycosylation, type 1a. Sagittal
T1-weighted image shows a small cerebellar vermis with atrophy of the
anterior vermis (white arrows). This is thought to represent atrophy that
begins before birth.
made by isoelectrofocusing of serum transferrin, which reveals marked
increase of asialo- and disialotransferrin, with marked decrease of
tetra- and pentasialotransferrin (1146).
Neuroimaging studies show marked global cerebellar hypopla-
sia and superimposed atrophy (Fig. 3-117) that likely begins in utero
(1147) and progresses in infancy (1148,1149) but seems to stabi-
lize (1144). The anterior vermis is reportedly most severely affected
(1150,1151). Associated imaging features include brainstem hypopla-
sia, pontine hypoplasia, and supratentorial white matter hypoplasia or
atrophy (1144,1152).
Mevalonic Kinase Deficiency (Mevalonic Aciduria)
Mevalonic kinase deficiency (OMIM 610377) is a disorder of choles-
terol biosynthesis, resulting from a deficiency of mevalonate kinase,
the first enzyme after HMG CoA reductase in the biosynthesis of cho-
lesterol and nonsterol isoprenes. The MVK gene encoding mevalonate
kinase is located on chromosome 12q24; the mutations thus far iden-
tified seem to cluster in the C-terminal end of the protein (1153).
Affected children present with varying degrees of severity of clinical
illness, which does not seem to be related to the level of activity of the
enzyme. All patients suffer from recurrent crises consisting of fever,
lymphadenopathy, hepatosplenomegaly, vomiting, diarrhea, arth-
ralgia, and a morbilliform rash; these may be triggered by infection.
Severely affected children have dysmorphic features (wide irregular
fontanelles, low set and posteriorly rotated ears), cataracts, hepa-
tosplenomegaly, lymphadenopathy, and anemia. They are severely
developmentally delayed and may be stillborn or die in infancy. Less
severely affected patients have psychomotor retardation, hypotonia,
myopathy, and ataxia. Neuroimaging studies show selective and pro-
gressive cerebellar atrophy involving both hemispheres and vermis
(1153–1155).
Progressive Encephalopathy with Edema,
Hypsarrhythmia, and Optic Atrophy (PEHO)
PEHO syndrome (progressive encephalopathy with edema, hypsar-
rhythmia, and optic atrophy, OMIM 260565) is a recessive disorder
Barkovich_Chap03.indd 212
that was originally described in Finland (1156), but has since been
described in populations all over the world (1157). Affected patients
present in infancy with hypotonia, hyperreflexia, poor feeding, micro-
cephaly, and delayed motor milestones and speech. Infantile spasms
develop during the first year of life. Deep tendon reflexes are initially
reduced, but become brisk as spastic quadriparesis ensues. No appar-
ent visual contact is appreciated, and ophthalmologic exam reveals
optic atrophy. Facial dysmorphisms include large earlobes, gingival
hyperplasia, and swelling of the face and the dorsum of hands and feet.
Electroencephalographic evaluation shows hypsarrhythmia, a pattern
of abnormal interictal high amplitude waves, and a background of
irregular spikes.
On pathology, cerebral and pronounced cerebellar atrophy is seen,
the essential histopathological lesions being confined to the cerebellar
cortex and the optic nerve. Severe neuronal loss is present in the inner
granular layer of the cerebellum. The Purkinje cells are relatively pre-
served in number although reduced in size, deformed and slightly mis-
aligned (dendrites were horizontally oriented). The molecular layer is
reduced in volume. The optic nerves are atrophic. Myelination appears
normal (1157,1158).
Neuroimaging studies during the first year of life are often nor-
mal, other than thinning of the corpus callosum (1159). Subsequent
studies show reduced volume of cerebral white matter along with pro-
gressive cerebellar atrophy, involving the entire cerebellum (Fig. 3-118)
(1159). The reduced cerebral white matter volume results in progres-
sive thinning of the corpus callosum (Fig. 3-118D) (1157,1160). Serial
neuroimaging studies showed that the disease process is operative dur-
ing the postnatal period, although a prenatal onset cannot be excluded
(1158). Short echo proton MRS, not surprisingly, shows progressive
reduction of NAA throughout the brain, along with the presence of
small amounts of lactate (1159).
Dentatorubral and Pallidoluysian Atrophy
Dentatorubral and pallidoluysian atrophy (OMIM 125370) is an auto-
somal dominant disorder resulting from an unstable expansion of a
CAG trinucleotide on the ATN1 gene on chromosome 12p13.31. The
greater the number of CAG repeats, the earlier the onset and the greater
the severity of the patient’s condition (1161,1162). The incidence of
this disorder varies with race, with the highest incidence, by far, found
in Japanese; this incidence seems to parallel the frequency of CAG
repeats (1163). Age of onset ranges from the first to seventh decades;
as most patients present in adulthood, this disorder is discussed only
briefly. Clinical symptoms are variable, even within a single affected
family. Most childhood-onset patients have a progressive myoclonic
epilepsy syndrome consisting of myoclonus, cerebellar ataxia, and
mental retardation (1164). Adult-onset patients usually have cerebellar
ataxia, choreoathetosis, and dementia; thus, they can be misdiagnosed
as having Huntington disease (1164,1165).
Neuroimaging studies of patients with the juvenile form show T2/
FLAIR hyperintensity in globi pallidi and mild atrophy of cerebrum,
cerebellum, and mesencephalon (1166). According to Miyazaki et al.
(1167), however, the characteristic MR findings in the childhood-onset
form of the disease are atrophy of the cerebellum and brainstem teg-
mentum (especially midbrain and superior pons), and periventricu-
lar and/or deep white matter hyperintensity on T2-weighted images
(Fig. 3-119). T2/FLAIR hyperintensity of the white matter (correspond-
ing to diffuse myelin pallor on histology (1168) ) is common, with the
number of lesions correlating with increasing age (1168). Noteworthy
in this report is the absence of definitive abnormalities involving the
globus pallidus, subthalamic nucleus (also known as the nucleus of
Luys, from which the name of this disorder derives), and red nucleus in
the childhood form of the disease.
5/6/2011 12:09:32 AM
 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders 213

FIG. 3-118. Progressive enceph-

alopathy with edema, hypsarrhyth-
mia, and optic atrophy (PEHO).
A. Sagittal T1-weighted image at
age 15 months shows thinning of
the corpus callosum (small white
arrows) with small cerebellum
(large white arrow) and brain stem.
B and C. Coronal T1-weighted
image (B) and axial T2-weighted
image (C) show that both cerebel-
lar hemispheres (white arrows in B)
are small and the volume of cerebral
white matter is reduced. D. Follow-
up sagittal T1-weighted image at
age 10 years shows further thinning
of the brain stem (white arrow) and
corpus callosum, and thickening of
the calvarium (white arrowheads, a
sign of further cerebral atrophy).
(These images courtesy Dr. Junichi
Takanashi, Chiba, Japan.)

Neuronal Ceroid Lipofuscinoses
These disorders have already been discussed in a previous section of
this chapter on Gray Matter Disorders. It is important to remember that
cerebellar atrophy is an important component of these disorders. More
importantly, in some forms (in particular the late infantile (CLN2) and
progressive epilepsy with mental retardation (CLN8) forms), the pre-
senting signs (both clinical and imaging) are those of cerebellar atrophy.
Langerhans Cell Histiocytosis
Langerhans cell histiocytosis (LCH, OMIM 604856) is a rare systemic
granulomatous disease of the dendritic system with a variable clini-
cal course that may be encountered at any age. The annual incidence
in children aged younger than 10 years has been reported as 0.2 to 2
per 100,000 children (1169). Typically, children with LCH present with
either systemic disease (involving skin, bone, liver, spleen, lung, and
hematopoietic system) or focal brain or calvarial lesions (1170–1172) as
described in Chapter 7. Uncommonly, patients with LCH may develop a
neurodegenerative pattern in the cerebellum with loss of Purkinje cells
and gliosis (1169). The patients may have signs of neurodegeneration
in childhood or it may be detected incidentally on brain MRI obtained
for other causes; neurologic symptoms from neurodegeneration are
more common in the third or fourth decade (1173). The posterior
fossa is involved in more than 90% of affected patients, showing cer-
ebellar atrophy associated with symmetrical T2 hyperintensity of the
cerebellar white matter and, often, a rim of T1 hyperintensity in the
periphery of the cerebellar dentate nuclei (Fig. 3-120) (1169,1173). T2
hyperintensity is also frequently seen in the white matter of the pontine
tegmentum, often associated with involvement of the pontine corti-
cospinal tracts (Fig. 3-120). The cerebrum is typically involved, as well,
showing foci of T2 hyperintensity in the cerebral white matter along
with discrete symmetrical T1 hyperintensity in the globus pallidus.
Diffuse cerebral cortical atrophy with thinning of the corpus callosum
may be present, but is uncommon (1169,1173).
Hypomyelination with Atrophy of the Basal
Ganglia and Cerebellum (HABC)
Hypomyelination with atrophy of the basal ganglia and cerebellum
(OMIM 612438) is a hypomyelinating disorder that has involvement

Barkovich_Chap03.indd 213 5/6/2011 12:09:32 AM

 214 Pediatric Neuroimaging

FIG. 3-119. Dentatorubropallidoluysian atrophy (DRPLA), childhood form. A and B. Sagittal T1-weighted image (A) and axial T2-weighted images (B)
at age 2 years are essentially normal. C. Sagittal T1-weighted image at age 6 years show thinning of the midbrain (white arrowheads) and atrophy of the
cerebellum (shrunken folia and enlarged fissures, white arrows). D. Axial T2-weighted images show enlarged ventricles due to white matter volume loss and
atrophy of caudates, abnormal peritrigonal hyperintensity (white arrowheads), absence of the low signal intensity of the red nuclei (white arrows, compare
to B), and enlarged cerebral cortical sulci. Note that atrophy of the globus pallidus and subthalamic nucleus is not common in the childhood form of the
disease. (These images are courtesy of Dr. Hiroshi Oba, Tokyo, Japan.)

of the basal ganglia and white matter as well as cerebellar atrophy. It
is discussed in the section of this chapter on Disorders Involving Gray
and White Matter.
Cerebellar Atrophy with Adolescent/Young
Adult Onset
The following disorders may be detected in children, but more com-
monly present toward the end of the second decade or in adulthood.
As some patients may initially present in childhood, they are briefly
discussed here.
Spinocerebellar Ataxias
The spinocerebellar atrophies are a group of phenotypically and geno-
typically heterogeneous group of dominantly inherited disorders. At the
time of the writing of this book, at least 27 have been described (1174),
including dentatorubropallidoluysian atrophy (DRPLA) (1175). Most
of these disorders have their onset in adults and differentiation is

Barkovich_Chap03.indd 214 5/6/2011 12:09:33 AM

 Chapter 3 • Metabolic, Toxic, and Inflammatory Brain Disorders
difficult, depending on a combination of clinical features, radiologic
features, and genetic testing (1175). Some (SCA1-3, 7, 13, and DRPLA)
have radiologic features of olivopontocerebellar atrophy, some (SCA
12, 17, and 19) have both cerebral and cerebellar atrophy, and others
(SCA 14 and 15) have atrophy limited to the cerebellar vermis (1175).
A full discussion is well beyond the scope of this chapter. Interested
readers are referred to an increasing number of excellent works on the
subject (1174–1177).
Cerebrotendinous Xanthomatosis
Cerebrotendinous xanthomatosis is a disorder of the hepatic bile acid
synthesis pathway caused by mutations of the CYP27 gene on chro-
mosome 2q33-qter (1097,1178). Mutation of the protein product,
the mitochondrial sterol 27-hydroxylase, results in increased serum
cholestanol and bile alcohols; the deposition of these metabolites in
the central nervous system probably causes the clinical phenotype.
Neurologic symptoms typically begin during the late second decade or
early third decade and include ataxia with pyramidal or extrapyrami-
dal signs, sensorimotor peripheral neuropathy, and seizures (11,1178).
Psychiatric problems and early dementia may ensue. Associated find-
ings include early juvenile cataracts, atherosclerosis, tendon xanthomas,
and chronic diarrhea. MRI shows generalized cerebral and cerebellar
atrophy in addition to diffuse T2/FLAIR hyperintensity of the white
matter (11,1097,1178). Calcifications are often present in the affected
cerebellar white matter.
Wolfram Syndrome
Wolfram syndrome was originally described as a combination of dia-
betes mellitus and bilateral optic atrophy (1179). It was later called
DIDMOAD for prominence of diabetes insipidus, diabetes mellitus,
optic atrophy, and deafness (1180). In more than 90% of affected
patients, the disorder (OMIM 222300) is caused by mutations of the
WFS1 gene located at chromosome 4p16.1 (1181); a second form of
the disease (WFS2, OMIM 604928) is associated with mutations of
CISD2 at chromosome 4q (1182). Affected patients can also have anos-
mia, ataxia, and central apnea. Pathologic analysis of the brain showed
severe degeneration of the optic nerves, chiasm and tracts as well as
severe loss of neurons from the lateral geniculate nuclei, ventral pons,
and the hypothalamic paraventricular and supraoptic nuclei. In addi-
tion, there was widespread axonal dystrophy with axonal swellings in
Barkovich_Chap03.indd 215
215
FIG. 3-120. Langerhans cell histocy-
tosis involving the cerebellum. Axial
T2-weighted image (A) shows abnor-
mal hyperintensity (white arrows)
pons in the region of the corticospinal
and corticopontine tracts. Coronal
T2-weighted image (B) shows abnor-
mal hyperintensity in the cerebellar
white matter (white arrows) and in
the hila of the cerebellar nuclei (black
arrowheads). Note the prominent sulci
in the cerebrum, suggesting mild cere-
bral cortical atrophy.
the pontocerebellar tracts, the optic radiations, the hippocampal for-
nices and the deep cerebral white matter (1183). Two reports of MRI
in Wolfram syndrome noted striking brainstem and cerebellar atro-
phy in addition to atrophy of the optic system and hypothalamus
(1184,1185); both were adults at the time of the scan. However, another
report described normal cerebellum and brainstem other than T2 pro-
longation in the substantia nigra (1186). Thus, the disease is apparently
heterogeneous; whether the imaging differences reflect differences in
the disease or just different stages of the disease (related to age, per-
haps) remains to be clarified.
Cerebellar Hypoplasia
Marinesco-Sjögren Syndrome
Marinesco-Sjögren syndrome (OMIM 248800) is a rare autosomal reces-
sive disorder characterized clinically by congenital cataracts, cerebel-
lar ataxia, hypogonadotropic hypogonadism, and mental retardation
(1187,1188). The causative gene (called SIL1) has been localized to chro-
mosome 5q31 (1189) (another, very similar disorder of congenital cata-
racts, facial dysmorphism, and neuropathy, or CCFDN, has been mapped
to 18q23 (1190) ). Cerebellar ataxia (with Purkinje and granule cell loss)
and childhood-onset cataracts are the most prominent signs of the
Marinesco-Sjögren syndrome, but muscular lesions are also commonly
present (1191,1192). The most characteristic MR finding is a very small
cerebellum in a small posterior fossa (1193,1194), but this is not, appar-
ently, an invariable finding (1195). In addition, the anterior pituitary lobe
may be small and the posterior lobe may be small or absent (1195).
X-Linked Nonprogressive Congenital
Cerebellar Hypoplasia
X-linked nonprogressive congenital cerebellar hypoplasia (OMIM
302500, also called X-linked spinocerebellar ataxia type 1) is an
X-linked disorder localized to an interval on chromosome Xp11.21-
q21.3. Affected boys first present with a marked delay of early develop-
mental motor milestones. A neurologic syndrome becomes evident by
age 5 to 7 years and includes cerebellar ataxia, dysarthria, and external
ophthalmoplegia. There are no symptoms of mental retardation, spas-
tic paraparesis, or sensory loss. Neuroimaging studies reveal hypoplasia
of the cerebellar hemispheres and vermis. The disease shows no pro-
gression beyond early childhood (1120,1196).
5/6/2011 12:09:34 AM
 216 Pediatric Neuroimaging
Höyeraal-Hreidarsson Syndrome
Höyeraal-Hreidarsson syndrome (OMIM 300240) is a multisystemic
disorder affecting males and characterized by prenatal onset of growth
failure, psychomotor retardation from an early age, microcephaly,
ataxia, spasticity, immunodeficiency, and thrombocytopenia and then
progresses to pancytopenia (1197–1199). It is caused by mutation of
the DKC1 gene at chromosome Xq28 (1200); this is the same gene that
causes X-linked dyskeratosis congenita. Neuropathological findings are
of delayed myelination and hypoplasia of the cerebellar granule cell
layer without loss of Purkinje cells (1197,1198,1201). Fetal imaging
may show cerebellar hypoplasia. Postnatal imaging shows a small cer-
ebellum (with slightly enlarged fissures but no progression on succes-
sive scans) and small pons, usually with reduced cerebral white matter,
a thin corpus callosum, and delayed myelination (1202,1203). Radio-
graphs may show distal metaphyseal flaring of the long bones (1203).
Revesz Syndrome
Revesz syndrome (OMIM 268130) is a variant of dyskeratosis congen-
ita, a rare disorder characterized by bone marrow failure and integu-
ment abnormalities, such as abnormal skin pigmentation, dystrophic
nails, and leukoplakia (1204). It is caused by mutations of the TINF2
gene at chromosome 14q12 (1205). In Revesz syndrome, patients pres-
ent with leukocoria due to a Coats disease–like retinopathy (1206). In
addition, patients can have aplastic anemia, ataxia with cerebellar hyp-
oplasia, and multiple cerebral parenchymal abnormalities (1206,1207).
Mental retardation is found in up to 25% of patients (1204). Imag-
ing studies are characterized by the presence of leukocoria, cerebellar
hypoplasia, multiple cerebral calcifications, and the presence on MRI
of multiple foci of T2 prolongation, sometimes enhancing, that are
reported to represent gliosis (1207).
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 CHAPTER
Brain and Spine Injuries
4 in Infancy and Childhood
ERIN SIMON SCHWARTZ AND A. JAMES BARKOVICH
Introduction
Basic patterns of brain destruction
Porencephaly
Hydranencephaly
Encephalomalacia
Hypoxic-ischemic brain injury
Localized infarctions
Diffuse ischemic or inflammatory brain injury
CNS injury in multiple pregnancies
Ischemic brain injury in multiple pregnancies
INTRODUCTION
In this chapter, destructive processes of the brain and spine are
discussed. This is an important group of disorders in that the injuries
discussed in this chapter are responsible for more than 90% of cases
of cerebral palsy (the other 9% is caused by malformations (1). In a
strict sense, it is difficult to separate the brain injuries discussed in this
chapter from many of those discussed in Chapter 3, as many metabolic
and demyelinating disorders are, in fact, destroying brain cells while
hypoxia, hypoglycemia, and hyperbilirubinemia might be considered
metabolic disorders. However, inborn metabolic, toxic, and idiopathic
(autoimmune) disorders are usually progressive, whereas those result-
ing from physical, hypoxic-ischemic, hypoglycemic, and hyperbiliru-
binemic trauma are usually static, resulting from one or two (usually)
well-defined events. Therefore, separation of the disorders into two
chapters seems to make sense from a theoretical perspective and keeps
the chapters at reasonable length.
BASIC PATTERNS OF BRAIN DESTRUCTION
Before considering specific patterns of brain injury from specific
causes, it is useful to consider the imaging appearances that result from
severe diffuse brain injury in the neonate and infant. Diffuse insults to
the brain, causing widespread destruction, result in different radiologic
and pathologic appearances, depending upon the cause, the maturity
of the brain at the time of insult, as well as the severity of the insult.
The imaging appearances seen in the acute and subacute stages after
injury are discussed in subsequent sections. Specific end-stage patterns
of tissue reaction to severe global injury are described by the terms
porencephaly, multicystic encephalomalacia, and hydranencephaly. An
understanding of these terms will be useful in further discussions in
this and subsequent chapters.
240
Barkovich_Chap04.indd 240
Neonatal hypoglycemia
Bilirubin encephalopathy (kernicterus)
Brain injury associated with congenital heart disease
Hypernatremic dehydration
CNS trauma in infancy and childhood
Birth trauma
Postnatal trauma
Nonaccidental trauma (child abuse)
Before discussing specific destructive patterns, it is necessary to
understand how the developing brain reacts to injury. The immature
brain responds to an insult in a different manner than the mature
brain. The fetal brain has limited capacity for astrocytic reaction;
therefore, necrotic tissue is completely reabsorbed (liquefaction necro-
sis), resulting is a smooth-walled, fluid-filled cavity (porencephaly,
also called a porencephalic cyst). In contrast, the mature brain reacts
to injury by significant astrocytic proliferation; the resulting lesion
contains soft brain (“encephalomalacia”) consisting of astroglial cells
and an irregular wall composed primarily of reactive astrocytes. The
neonatal and infant brains fall somewhere in between. The ability to
mount an astrocytic response to injury seems to begin sometime dur-
ing the late second or early third trimester and progressively increases;
the neonatal brain has about 15% of the astrocytic response to injury
as the mature brain (2,3). Thus, the postinjury residual evolves from
(a) a pure cyst in the second trimester fetus to (b) a cyst with astroglial
septae in the last months of gestation and the neonatal period to (c)
pure astrogliosis with no appreciable cystic component in the mature
brain.
Porencephaly
The term porencephaly has many different definitions. Pathologists
use the term to describe focal cavities with smooth walls and mini-
mal surrounding glial reaction (2,4,5). Those cavities resulting from
focal brain destruction prior to approximately the 20th gestational
week are often lined by dysplastic gray matter and accompanied by
anomalies of the overlying cortex, usually polymicrogyria (5,6). Used
in this sense, porencephaly is essentially synonymous with schizen-
cephaly, an anomaly that results from destruction of a portion of the
germinal matrix and surrounding brain before the hemispheres are
fully formed (see Chapter 5). Other authors have designated lesions
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 241

developing early in the second trimester as encephaloclastic poren-
cephalies, smooth-walled cavities without any surrounding gliosis, in
order to differentiate them from agenetic porencephalies and from
cystic encephalomalacia (see discussion below), a condition charac-
terized by shaggy-walled cavities with considerable astroglial reaction
and resulting from late gestational, perinatal, or postnatal injuries
(2,7,8).
On imaging studies, (encephaloclastic) porencephalies appear as
smooth-walled cavities that are isointense to CSF on all sequences,
including diffusivity maps (Fig. 4-1). The cavities have no internal
structure, and the surrounding brain is of normal signal intensity.
Many regions of porencephaly (Fig. 4-2) are impossible to differen-
tiate from ex vacuo enlargement of the lateral ventricles secondary
to complete liquefaction and absorption of surrounding white mat-
ter; indeed, the “cyst” may be completely integrated into the adjacent
ventricle.
Hydranencephaly
Hydranencephaly is a condition in which most of the brain mantle
(cortical plate and hemispheric white matter) has been damaged, liq-
uefied, and resorbed (9); it can be considered as porencephaly of nearly
the entire cerebrum. The cerebral hemispheres are largely replaced
by thin-walled sacs containing cerebrospinal fluid (CSF) (2,5). The
membranes of the sacs are composed of an outer layer of leptomen-
ingeal connective tissue and an inner layer of remnants of the cor-
tex and white matter along with astrogliosis. Although some people
consider hydranencephaly a congenital anomaly, it is included in this
chapter on destructive disorders because the presence of remnants of
hemispheric tissue and reports of association with twin-twin transfu-
sion (10) and congenital infection (11,12) clearly imply a destructive
process. A similar condition has been induced in laboratory animals
by the occlusion of both carotid arteries in utero. In all likelihood,
any of a number of diffuse insults to the developing brain, at a time
when the brain reacts by liquefaction necrosis, can result in hydra-
nencephaly (2,12). Clinically, affected patients may be microcepha-
lic, normocephalic, or macrocephalic, depending upon the presence
and degree of associated hydrocephalus (13). Because of the nearly
complete lack of cortical tissue, the children reach few developmental
milestones (13).
Imaging studies of patients with hydranencephaly show that the
cerebral hemispheres are nearly completely replaced by CSF (2,14,15).
The thalami are usually preserved. The inferior medial aspects of the
frontal lobes and the inferior medial aspects of the temporal and occip-
ital lobes may also be preserved (Fig. 4-3). The brainstem is usually
atrophic; the cerebellum is almost always normal.
The diagnosis is best established by sonography or magnetic reso-
nance imaging (MRI), both of which will show the thin rim of cerebral
tissue around dilated ventricles; MRI is probably best for fetal diag-
nosis, as it is not subject to shadowing or reverberation artifacts (10).
It is sometimes difficult to differentiate hydranencephaly from severe
hydrocephalus on computed tomography (CT) scans because the rim
of tissue may be obscured by artifact generated by the overlying cal-
varium, particularly if a low radiation dose is used, as is common in
pediatric studies. This distinction is significant because some hydro-
cephalic children, even when the condition is extremely severe, respond

FIG. 4-1. Focal porencephaly. A. Axial T2-weighted image shows a sharply defined, homogeneously hyperintense cavity in
the posterior limb of the right internal capsule (black arrow). B. Axial Dav (average diffusivity) map at the same level shows very
high diffusivity, compatible with freely moving water molecules in a cyst.

Barkovich_Chap04.indd 241 5/25/2011 11:38:22 AM

 242 Pediatric Neuroimaging
well to CSF diversion procedures and develop normal cognitive and
motor function if shunting is performed at an early age. In contrast,
children with hydranencephaly will not improve intellectually after
shunting. In practice, this distinction may be purely academic because
an abnormally enlarging head in infants with either entity dictates CSF
diversion. Although CSF diversion will not improve development in
infants with hydranencephaly, it will prevent the development of the
grotesquely enlarged head size that would otherwise result from the
increased intracranial pressure. Maintenance of normal head size aids
patient management.
Encephalomalacia
Encephalomalacia, in contradistinction to porencephaly and hydra-
nencephaly, is characterized pathologically by astroglial proliferation
and, often, septations within the area of damaged brain. MRI shows the
reactive astrogliosis and tissue injury as areas of T1 hypointensity and
T2 or FLAIR hyperintensity compared with myelinated gray and white
matter (Fig. 4-4). In infants, images obtained in the subacute phase
after injury will often show T1 hyperintensity and T2 hypointensity of
injured cortex and white matter (Fig. 4-5); the precise cause of these
Barkovich_Chap04.indd 242
FIG. 4-2. Porencephaly secondary to presumed
venous infarction. A. Parasagittal transfontanelle
sonogram shows a large cavity (white arrows) extend-
ing from the left lateral ventricle (black arrows) into the
left frontal lobe. No internal structure is seen within
the cavity. B. Follow-up axial proton density image
shows the large cystic area (white arrows) in the left
frontal lobe at the site of prior hemorrhagic infarction.
The left basal ganglia are absent, having been destroyed
by the infarction. Diminished white matter and abnor-
mal hyperintensity (white arrowheads) is seen around
the ventricular trigones secondary to white matter
injury of prematurity. C. Coronal reconstruction of
3D-FLAIR image shows hypointensity within the cyst
(white arrows), the complete suppression of the con-
tents confirming its cystic nature. Note the difficulty
in differentiating this destructive lesion from ex vacuo
enlargement of the ventricle. Hyperintensity of the
contralateral white matter (black arrow) results from
white matter injury of prematurity.
signal changes are poorly understood. The inherently poorer contrast
resolution of CT limits reliable differentiation of porencephaly from
cystic, and even noncystic, encephalomalacia (Fig. 4-4A). Ultrasound
is the most sensitive modality in the detection of glial septa but is less
useful in the overall evaluation of the brain.
Multicystic encephalomalacia results from a diffuse insult to the
brain late in gestation, during birth, or after birth (2,5). Multiple cys-
tic cavities of variable size, separated by glial septations, form in the
necrotic area (Figs. 4-4 to 4-7) (5). The location of the lesions varies
with the nature of the insult. If caused by thrombotic or embolic infarc-
tion (Figs. 4-4 and 4-6), the affected area will be in the distribution of
a branch of a major cerebral artery. In contrast, injury resulting from
mild to moderate hypotension will tend to be located in the inter-
vascular boundary zones (see “watershed areas,” Fig. 4-5). When very
severe, only the immediate periventricular white matter may be spared
(Fig. 4-7). Profound hypotension results in injury to the deep cerebral
nuclei and a variable amount of cortex; the precise distribution varies
with postconceptional age (16–18). Neonatal hypoglycemia causes dam-
age in the parietal and occipital lobes (19,20). When injury is the result
of an infection, the site of the encephalomalacia is nonspecific, reflecting
the region of the brain injured by the infection. Other than location,
5/25/2011 11:38:22 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
the imaging appearance does not characterize the cause. Ultrasound
will show increased echogenicity between the second and fifth day after
injury, with cystic degeneration developing between the 7th and 30th
day after injury in term infants (21). The variation in the time to cavi-
tation is presumably related to the severity of the injury, as well as the
maturity of the brain. CT initially shows diffuse hypoattenuation in the
affected regions of the brain; this appearance eventually evolves to one
of hypodense tissue containing cysts of various sizes (Fig. 4-8). Septa-
tions are often seen within the damaged region, and calcification may be
present (2). On MRI, the affected area appears as an ill-defined area of
T1 hypointensity and T2/FLAIR hyperintensity containing loculations
of fluid (hypointense on T1, FLAIR, and diffusion-weighted images,
hyperintense on T2 images and average diffusivity (Dav) images (Figs.
4-4, 4-6, and 4-7). Some heterogeneity is often present, as a result of the
combination of variably sized glial septae and CSF within the lesion.
The heterogeneity is often most apparent on the FLAIR sequence or the
first echo of the T2-weighted sequence, in which the glial strands are
Barkovich_Chap04.indd 243
243
FIG. 4-3. Hydranencephaly. A. Sagittal T1-weighted
image shows absence of most of the cerebrum. Portions
of the inferomedial temporal and occipital lobes (white
arrows) are present. B. Axial T2-weighted image shows
complete absence of the cerebral hemispheres with the
exception of the thalami (small black arrowheads) and
some portions of the medial temporal lobes (black arrows)
and occipital lobes. The anterior falx cerebri (large black
arrowhead) is present, surrounded by a small amount of
residual frontal lobe. C. Axial T2-weighted image shows
presence of the falx (black arrows) at the level of the upper
cranial vault.
quite hyperintense in contrast to the CSF spaces, which are isointense
to the ventricular CSF. If the routine images are not definitive, diffusion
sequences can be used to determine diffusivity, which will be highest in
cystic regions, lower in microcystic regions, and still lower in noncystic
encephalomalacia; all damaged tissue will have higher diffusivity than
normal brain.
HYPOXIC-ISCHEMIC BRAIN INJURY
This section covers injuries of brain that are believed to be mediated by
hypoxia or ischemia. Much has been written to suggest that ultimately
the injury in many of these disorders, including localized infarctions,
is initiated by inflammatory factors. The authors do not dispute that
this may, indeed, be true in many cases. Nonetheless, hypoxia or isch-
emia are likely involved in the brain injury at some level, whatever the
initiating factors; therefore, hypoxia-ischemia seems to be a good title
under which to organize these disorders.
5/25/2011 11:38:23 AM
 244 Pediatric Neuroimaging
Localized Infarctions
Stroke is an important cause of morbidity and mortality in childhood.
Indeed, it is one of the top ten causes of childhood death (22,23).
Approximately 25% of all pediatric strokes occur in neonates, and
approximately 50% occur in children less than 1 year of age (22,23);
Barkovich_Chap04.indd 244
FIG. 4-4. Encephalomalacia in 12-year-old secondary to
remote MCA infarction. A. Axial noncontrast CT scan shows
heterogeneous hypodensity (white arrows) in the right posterior
temporal lobe, as well as some ex vacuo enlargement of the right
lateral ventricle. B. Coronal T1-weighted image shows better
detail of the encephalomalacic area (black arrows). Shrunken
hypointense gyri are seen separated by reduced volume of
less hypointense encephalomalacic white matter. C. Axial
T2-weighted image shows the area of encephalomalacia (white
arrows) as mostly hyperintense with residual, more normal, tis-
sue (small black arrows) as more hypointense. D. Coronal FLAIR
image shows hyperintense encephalomalacia. The central areas
of hypointensity (black arrows) are regions of fluid secondary
to cavitation.
fetal MRI has demonstrated that many infarcts occur before birth. The
reason for this high incidence of strokes in fetuses and infants is not
known. Despite these numbers, the misconception prevails that stroke
is a rare and relatively unimportant illness in childhood. Fortunately,
the medical community has recently become more aware of this entity
and its importance in pediatric health (22,24–33).
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 245

FIG. 4-5. Encephalomalacia secondary to moderate hypotension. Axial SE T1 (A) and axial T2-weighted (B) images show cortical
thinning with abnormal T1 and T2 prolongation in the frontal watershed areas and volume loss with some T1 and T2 shortening in
the occipital lobes. T1 shortening is seen in the lateral thalami.

Manifestations and Causes of Infarctions in Children
Focal ischemic infarction has a variable clinical presentation in the
pediatric age group. Presenting signs and symptoms depend upon
the region of brain affected and the age of the patient at the time of
the infarct (32,34–37). Perinatal/prenatal stroke is much more com-
mon than generally recognized, with a prevalence of 1 in 2300 to 5000
live births (38). Perinatal stroke has been deemed important enough
that the term ischemic perinatal stroke is now defined as “a group
of heterogeneous conditions in which there is a focal disruption
of cerebral blood flow secondary to arterial or cerebral venous
thrombosis or embolization between 20 weeks of fetal life through
the 28th postnatal day, confirmed by neuroimaging or neuropatho-
logic studies” (38). Risk factors for presumed perinatal ischemic
stroke (PPIS) are listed in Table 4-1. When presenting acutely after

FIG. 4-6. Multicystic encephalomalacia secondary to arterial infarction. Axial SE T1 (A) and T2-weighted (B) images show a sharply
defined area of T1 and T2 prolongation in the left MCA distribution. Thin septae (arrowheads) are present within the cavity.

Barkovich_Chap04.indd 245 5/25/2011 11:38:25 AM

 246 Pediatric Neuroimaging
FIG. 4-7. Severe macrocystic encephalomalacia. Coronal T1-weighted
image shows large cystic spaces of the cerebral cortex and white matter with
sparing of only a small region of periventricular white matter. Large cysts
are separated by septae.
infarction, neonates and young infants typically manifest seizures,
decreased level of consciousness, hypotonia, irritability, lethargy, or
poor feeding (38); in this regard, it is important to remember that up
to 5% of encephalopathic neonates, who were presumed on clinical
grounds to have a diffuse brain injury, may be symptomatic from
acute focal infarction (39). However, when neonatal infarctions are
clinically cryptic (29,40) or if the infarct occurs in utero (41–45),
presentation may be one of early hand preference in infancy (infants
do not usually show hand preference prior to the age of 1 year) or
congenital hemiplegia; such infarcts are currently referred to as PPIS
(32). Indeed, it is estimated that approximately 30% of patients with
congenital hemiplegia are the result of PPIS (38). Older infants and
children who suffer strokes present in a manner similar to adults,
with an abrupt onset of neurological deficit (31,34–36). Because the
clinical presentation of stroke in neonates and infants can be quite
subtle, imaging is often the most revealing component of the diag-
nostic work-up.
As many as 50% of focal brain infarctions in the pediatric popu-
lation are “idiopathic”; that is, the cause of the stroke is never found
(46,47). In our experience and that of others (40), this number is
even higher in neonatal infarctions. Many strokes are associated
with coagulopathies or metabolic disorders. A study by Ganesan et
al. (48) indicates that as many as 40% of pediatric stroke patients
in western populations are anemic; 21% either had elevated total
plasma homocysteine or were homozygous for the methylene tetra-
hydrofolate reductase mutation. Another study showed that 63% of
children with stroke had at least one prothrombotic risk factor and
28% had at least two risk factors; plasminogen activator inhibitor,
which forms a complex with tissue-type plasminogen activator to
inhibit fibrinolysis, was the most common abnormality, seen in 27%
(49). In a multicenter case-control study of term newborns with
symptomatic ischemic stroke, 62 of 91 stroke patients (68%) had at
Barkovich_Chap04.indd 246
least 1 prothrombotic risk factor compared with 44 control subjects
(24%): Factor V G1691A mutations, protein C Type I deficiency,
and elevated lipoprotein (a) levels were found more frequently in
cases than controls, while prothrombin and methylenetetrahydro-
folate reductase mutations were not significantly different between
the groups (50). In another cohort of 24 newborns with perinatal
cerebral infarction confirmed by neonatal MRI, 10 newborns (42%)
had at least 1 prothrombotic state, including heterozygosity for fac-
tor V Leiden in 5 and high factor VIIIc concentrations in 6 (51).
These prothrombotic states, in particular, the factor V Leiden muta-
tion, were associated with adverse neurodevelopmental outcomes
(51). In patients with no underlying metabolic disorders, trauma
and previous varicella zoster infection were significantly more com-
mon. A significant association was found between cerebral arterial
abnormalities and systolic blood pressure greater than 90th percen-
tile; a trend was identified for an association with varicella within
the previous year. Genetic or acquired conditions causing throm-
bophilia were rare causes of stroke in their series. In 79 children
with unilateral ischemic stroke, Braun et al. (52) found that arte-
riopathy, diagnosed by MR arteriography (MRA), CTA, or catheter
angiography, was most commonly stable after the initial inflamma-
tory period (which lasted for months). Outcome was much better
in patients in whom the arteriopathy stabilized or improved than in
those in whom it progressed (52). They postulate that this subset of
arteriopathies (those that eventually stabilize) are inflammatory in
nature (indeed, many are seen within a year of varicella infections)
and propose the term transient cerebral arteriopathy to describe this
condition (52). In east Asian populations, the incidence of child-
hood brain infarction is similar to that in western populations, but
the underlying causes differ (31,53); congenital heart disease, CNS
infection, vascular diseases (particularly moyamoya), and hemato-
logic disease (leukemia, thalassemia) are the most common predis-
posing causes (31,53), although metabolic causes are seen in up to
20% (31).
Long-term prognosis of children with focal infarctions and no
underlying disorder varies with the location of the infarction and the
age of the patient at the time of the injury (54). Poor motor outcome
is associated with basal ganglia involvement and with periventricular
venous infarction (32). Seizures, poor cognition, and delayed develop-
ment are associated with cortical involvement (32,52). Patients with
larger infarctions or infarctions involving eloquent regions of cortex
obviously have larger residual deficits than those with smaller infarcts
and those involving less eloquent regions (28,55). Among children
with infarcts of similar size or location, younger patients typically
have smaller clinical deficits; in neonates, hemiparesis typically does
not ensue unless the cortex, basal ganglia, and internal capsule are all
affected, whereas later in childhood, hemiparesis may ensue even if
only one or two of those sites are affected (54). Compared with adults,
prognosis is generally good unless epilepsy develops, because children
with negative workups are unlikely to have another stroke and because
the pediatric brain retains significant plasticity. Thus, in the absence of
epilepsy, many functions normally performed by the injured regions of
brain will be taken over by other regions that have been spared (56).
When epilepsy develops, however, cognitive recovery is impaired (56).
Outcome in East Asian populations is similar to that in western series,
with death in 15% to 20%, persistent neurological deficits in 30% to
40%, and normal outcome in 35% to 50% (31,53). Follow-up of a large
number of children with neonatal or infantile stroke from a study in
Marseille showed no residual deficit in 28%, mild to moderate deficit
in 48%, and need for significant long-term care (severe deficit) in only
24% (57). However, it appears that children (but not infants [54]) have
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 247

FIG. 4-8. Encephalomalacia secondary to moderate hypoten-

sion. A. Contrast-enhanced CT image in the acute phase shows
low attenuation in the frontal and temporo-occipital (solid
arrows) white matter and the caudate heads (open arrows). B. In
the subacute phase (1 week after injury), the injured regions show
contrast enhancement. C. In the chronic phase (2 months after
injury), the cerebral cortex is shrunken away from the calvarium,
resulting in an increased amount of extraparenchymal fluid. The
ventricles have enlarged secondary to atrophy of white matter
and the caudate heads. Abnormal lucency (arrows) representing
encephalomalacia is present in the frontal and temporo-occipital
white matter.

a higher incidence of persistent dystonia after basal ganglia infarction
(28,58) and a higher (25%–50%) incidence of epilepsy after ischemic
stroke (59) than adults.
As alluded to earlier, disorders of coagulation may be identified
in neonatal strokes (48–51,60–66), including deficiencies of proteins
C and S (60–66), G20210A prothrombin mutations (66), and factor V
Leiden (51,61,62), as well as the presence of anticardiolipin antibodies
(63,67–69). Other causes are listed in Tables 4-2 and 4-3.
Choice of Radiologic Study in Pediatric Stroke
The choice of radiologic study depends on the age of the patient. As
neonates generally present with seizures or nonspecific symptoms,
ultrasound is the first study performed at most institutions. When
properly performed with high frequency probes and when the studies
are performed after day 4, ultrasound detects up to 87% of neonatal
strokes involving the basal ganglia and large supratentorial vascu-
lar territories (40). However, ultrasound is not very sensitive in the

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 248 Pediatric Neuroimaging

TABLE 4-1 Risk Factors for PPIS

Maternal factors/conditions Twin-to-twin transfusion syndrome
Thrombotic disorders Fetal/neonatal polycythemia
Infertility and infertility treatment Congenital heart disease
Preeclampsia Neonatal hypoglycemia (in preterm infants)
Prolonged rupture of membrane (>24 h) Persistent fetal circulation and extracorporeal membrane
Chorioamnionitis oxygenation therapy
Maternal autoimmune conditions and autoantibodies (platelet Intrauterine growth restriction
alloantigen-1) Fetal/neonatal infections and meningitis
Antiphospholipid syndrome Nonspecific factors
Fetal/neonatal disorders Ethnicity and race (higher incidence in black infants compared
Mutations in COL4A1 (gene for procollagen IVa1) with non-Hispanic white infants)
Inherited thrombophilia Infant gender (higher incidence in boys)

TABLE 4-2 Some Causes of Pediatric Stroke

Cardiac causes Infection (viral [80,83–86], bacterial meningitis [34], aspergillus
Cyanotic congenital heart disease [35,47] if immunosuppressed [87])
Cardiomyopathy [70] Coagulopathies (deficiencies of protein C or protein S [60–64],
Vascular dissection [70] factor V Leiden [61,62], methylene tetrahydrofolate reductase
Mitral valve prolapse [70] [88,89], lipoprotein (a) [88,89], or presence of antiphospho-
Cardiac tumors [71] lipid antibodies [63,67–69])
Thrombosis Maternal drug abuse (90,91)
Polycythemia [34] Migraine (47,92)
Trauma [72] Metabolic disorders (see Table 4-3)
Vasculopathies (sickle cell disease [73], moyamoya disease [74,75], Vascular malformations (35,72,93)
Kawasaki disease [72], PHACE syndrome [76], COL4A1 muta- CNS tumors by compression of vessels (35,72,93)
tions [45,77,78], postinfectious/inflammatory [52,79,80], Vasculitis (94–96)
fibromuscular disease [72], neurofibromatosis Type 1 [72],
radiation-induced [72], spontaneous dissection [81,82])

TABLE 4-3 Metabolic Causes of Stroke in Childhood

Organic acidurias Lysosomal storage disorders
Hyperhomocysteinemia Fabry disease
Propionic aciduria Cystinosis
Methylmalonic aciduria Urea cycle defects
Isovaleric acidemia Ornithine carbamyl transferase deficiency
Glutaric aciduria Type I Carbamyl phosphate synthetase deficiency
Glutaric aciduria Ty pe II Other
3-Methylcrotonyl-CoA carboxylase deficiency Progeria
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency Sulfite oxidase deficiency
Mitochondrial disorders Hyperlipoproteinemia
Mitochondrial myopathies Phosphoglycerate kinase deficiency
Leigh disease Congenital disorders of glycosylation
MELAS syndrome L-carnitine deficiency
Cytochrome oxidase deficiency Disorders of cholesterol and triglyceride metabolism
From (47,97–103) (see also Chapter 3).

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
detection of small white matter infarctions, small cortical infarctions
over the cerebral convexities, or those in the posterior fossa. There-
fore, we typically perform MRI with MRA or MR venography
(MRV) to supplement the sonogram, as MRI will find both ischemic
and hemorrhagic lesions throughout the brain and allows excellent
assessment of both the anterior and posterior cerebral circulations.
Indeed, even if ultrasound finds an infarction, MRI often detects
additional parenchymal lesions and MRA/MRV can detect vascular
thromboses as well as many medium and large vessel vasculopathies
(38, 104). Moreover, diffusion-weighted imaging increases the
sensitivity of detecting infarction, and it allows detection of early
Wallerian degeneration, manifested as reduced diffusion only a few
days after the injury; when seen along the corticospinal tracts, this
finding is highly predictive of subsequent hemiplegia (105). Finally,
we generally avoid CT in infants (and children) because of the ion-
izing radiation and because venous thrombosis may be difficult to
detect on routine CT images (because of the high attenuation of
blood in scans of neonates and infants). Overall, MRI should be
the study of choice in neonates and infants with suspected cerebral
infarction.
In older children, MRI with MRA/MRV is the first study of choice,
if available. As stated in the prior paragraph, we try to avoid CT in
infants and children. (Nevertheless, CT venography is very accurate
in the detection of venous sinus thrombosis and should be performed
if an infant or child is suspected of having venous thrombosis, and
MRI is inconclusive, difficult to perform, or contraindicated [106].)
Catheter angiography is performed if the cause of the infarction is
not diagnosed by laboratory or imaging studies, as it is more sen-
sitive than CT or MRI to the presence of vasculopathy in medium
and small vessels (26). It is important to keep in mind, however, that
even high-resolution catheter angiography is often normal in small
vessel vasculitis, as in systemic lupus erythematosus. At some insti-
tutions, perfusion imaging is routinely performed in infants and
children suspected of ischemic brain injury, whereas in others, it is
reserved for patients with known vasculopathy, such as moyamoya
disease (see Chapter 12), usually when revascularization procedures
such as bypass or synangiosis are being considered. When perfusion
is assessed, susceptibility-weighted perfusion MRI (see Chapter 1) is
the study of choice.
Imaging Appearances of Arterial Infarctions
in Children
Although the appearance of the infarct on imaging studies is indepen-
dent of the cause of the infarct, some types of infarcts have predilec-
tions for certain regions of the brain. Knowledge of these predilections
may aid in narrowing the differential diagnosis of the cause of infarc-
tion. For example, posterior circulation infarctions are unusual in chil-
dren; an infarct in this location should raise suspicion for a traumatic
injury to the vertebrobasilar circulation (27,107,108) or, less likely,
vasospasm secondary to migraine (109), or even MELAS (if not in a
strict vascular distribution, see Chapter 3 [110,111]). Thalamic infarcts
typically occur in the setting of meningitis (infectious vasculitis), con-
genital heart disease, migraine, or trauma (112).
Although cranial ultrasound is less sensitive than CT or MRI in
the detection of infarcts in neonates and infants (113), ultrasound
is usually the first brain imaging study performed, and knowledge
of the findings is important. Cerebral infarction appears as an ill-
defined region of hyperechogenicity (Figs. 4-9 and 4-10) that slowly
develops for several days after the event. Differentiation of hemor-
rhagic from bland infarction may be difficult; however, focal areas
Barkovich_Chap04.indd 249
249
of marked hyperechogenicity within the echogenic zone should
suggest hemorrhage. Cystic degeneration develops over 2 to 4 weeks
with associated ex vacuo enlargement of the ipsilateral ventricle
(114). Infarcts of the deep cerebral nuclei (Fig. 4-9) and larger corti-
cal infarctions, such as those secondary to occlusion of the internal
carotid artery or the main trunk of the middle cerebral artery (MCA)
(Fig. 4-10), are more easily detected than smaller infarctions that are
restricted to the cerebral cortex or white matter (114). Posterior fossa
infarctions are difficult to detect unless quite large; imaging through
the posterolateral fontanelle improves sensitivity. The use of color
Doppler and power Doppler sonography, which show changes in
regional cerebral blood flow after infarction (115), improve the sen-
sitivity of sonography.
On CT, cerebral infarction in the neonate has a similar appearance
to that in the older child or adult. When the infarction involves the
cerebral cortex, CT shows a well-defined, often wedge-shaped, region
of hypoattenuation that initially seems restricted to gray matter but
after the first 24 hours is seen in both the gray and white matter in
an arterial distribution (Fig. 4-11). Some caution must be used, how-
ever, as certain areas in the posterior temporal and occipital cortex
normally have low attenuation on CT of infants and are difficult to
assess. Areas of hemorrhage are unequivocally detected as regions
that are hyperdense compared to normal parenchyma on noncontrast
scans. The administration of iodinated contrast is rarely necessary to
establish the diagnosis. Contrast administration will result in enhance-
ment of the infarcted region of cortex starting about 5 days after the
injury; enhancement will slowly disappear starting 4 to 6 weeks after
the injury.
On MRI, the best way to identify infarctions in the first few
days is by the use of diffusion imaging (Figs. 4-9 to 4-11), which
shows reduced diffusivity within hours of the infarction. The acute
infarct is seen as hyperintense signal on diffusion-weighted images
(DWIs) and as hypointense signal on calculated diffusivity (also
called apparent diffusion coefficient, or ADC) images; these abnor-
malities are easily recognized and are identical to the appearance of
acute infarction in adults. Diffusivity decreases within hours (116)
and remains reduced for about 6 days before pseudonormalization
occurs (117); diffusivity increases above normal around day 12 (118).
Note that none of these numbers are absolute; they vary somewhat
from individual to individual. Evaluation of white matter tracts dur-
ing the acute phase can show early evidence of Wallerian degenera-
tion (manifested as reduced diffusivity, Fig. 4-10D) (105,119), which
may be predictive of persistent neurologic impairment (105,120).
Therefore, if available, diffusion images should be obtained in chil-
dren with an acute onset of unexplained neurologic deficits or infants
with unexplained seizures. If the deficit is more than a 24 hours old,
the use of diffusion imaging is less critical as routine CT or MRI can
identify the infarct; nonetheless, reduced diffusion in a vascular dis-
tribution increases confidence in the diagnosis. In contrast to CT,
the spin echo and FLAIR MR appearance of focal bland (nonhemor-
rhagic) infarction in a neonate is very different than in older children
and can be quite subtle (Figs. 4-9 to 4-11). In newborns, the acutely
edematous, infarcted cortex becomes isointense with the underly-
ing unmyelinated white matter on routine spin-echo sequences. We
look for infarcts by trying to identify the entire circumference of the
hypointense cerebral cortex on T2-weighted images. If a segment of
the cortex appears to be “missing,” it probably represents focal infarc-
tion (the “missing cortex sign,” showed nicely in Figs. 4-10, 4-11). The
internal capsules should also be carefully examined, as high signal
intensity of the posterior limb of the internal capsule on T2-weighted
5/25/2011 11:38:28 AM
 250 Pediatric Neuroimaging

FIG. 4-9. Basal ganglia infarction in a neonate with congenital heart disease.
A. Transfontanelle sonogram shows increased echogenicity (arrows) in the left
corpus striatum. B. Axial T2-weighted image shows hyperintensity (arrows) in
the left caudate head and anterior left putamen. C. Axial diffusion-weighted
image (b = 700 s/mm2) shows hyperintensity, indicated reduced diffusion, in
the infarction.

images may be associated with the development of contralateral
hemiplegia (105). It should be noted that FLAIR images can be mis-
leading in neonates/infants and will often not allow identification of the
infarction (Fig. 4-11D). In the subacute phase (4–6 days after birth),
infarcted gray matter may show high signal intensity on T1-weighted
images and low signal intensity on T2-weighted images (Fig. 4-12),
probably because of petechial hemorrhage, release of myelin lipids,
astroglial reaction (causing reduced amount of free water), or cal-
cification. The MR appearance of infarctions in older children and
adolescents is identical to the appearance of similar injuries in adults,
as is the MR appearance of hemorrhagic infarcts in children of any
age. If intravenous paramagnetic contrast is administered (this is not
usually necessary), it results in an enhancement pattern (Fig. 4-12)
and temporal evolution similar to that described in the preceding
paragraph for CT.
Infarction of the deep gray matter nuclei in neonates and young
infants is seen on sonography as subtle hyperechogenicity. Although
it has been reported that deep infarcts do not become detectable by
sonography until the end of 1 or 2 weeks when the hyperechogenic-
ity becomes prominent (114), high-resolution sonograms will detect

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 251

FIG. 4-10. MCA infarction. A. Sonogram in the coronal plane shows mild hyperecho-
genicity (white arrows) in the white matter in the MCA distribution. Note the slightly
increased echogenicity in the left basal ganglia and compression of the left frontal horn
(small black arrow), consistent with early infarction. B. Axial T2-weighted image shows
the infarct involving the entire MCA cortex (white arrows) that is hyperintense com-
pared with the remainder of the gray matter, and isointense with underlying white mat-
ter. The left caudate (black arrows) is also abnormally hyperintense. C. Axial diffusivity
map (b = 700 s/mm2) shows reduced diffusivity (hypointensity, white arrows) in the
infarcted MCA territory. Note the involvement of the basal ganglia, confirming what
was seen on the T2-weighted image (B). D. Axial diffusivity map (b=700 s/mm2) at the
level of the pons shows reduced diffusivity (black arrow) in the left pons, as a result of
Wallerian degeneration in the corticospinal tract. E. Collapsed image from TOF MR
arteriogram shows lack of flow-related enhancement in the middle portion of the left
MCA (arrow), a thrombus that is the cause of the infarct.

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 252 Pediatric Neuroimaging

FIG. 4-11. Missing cortex sign, utility of CT and FLAIR in cerebral infarctions of neonates. A. Axial CT scan shows hypoden-
sity (black arrowheads) in the left parietal lobe. B. Axial T2-weighted image shows absence of the normal cortical hypointensity
in the infracted area. A region of “missing cortex” suggests cortical injury in a neonate or infant. C. Calculated ADC image
shows reduced diffusion (hypointensity, white arrows) in the infarcted area. D. Coronal FLAIR image through the infarct shows
the subtlety of infarct detection with FLAIR imaging in neonates and infants. We do not use FLAIR in children during the first
year of life.

subtle changes (Figs. 4-9A and 4-10A) in the first few days after injury.
Basal nuclei infarctions can be very subtle on CT, as well, particularly
if the infarction is bilateral and associated with cerebral edema. This
appearance is discussed and illustrated later in the chapter in the sec-
tion on “profound hypotension.” The point to be stressed is that isch-
emic injury to the basal ganglia may be overlooked on ultrasound or CT
(of neonates or older children, Fig. 4-13A) unless the radiologist specifically
assesses the deep gray matter echogenicity or attenuation, respectively.
The MR appearance of infarcted basal ganglia is variable, depending
on the MR sequences used, the stage of the infarction, and the amount of
hemorrhage present. The infarction is readily identified as a hyperintense
region in a vascular distribution on DWIs (Fig. 4-9C) or as a hypoin-
tense region on a calculated diffusivity (ADC) image (Fig. 4-13B). On
spin-echo imaging, the acutely infarcted basal ganglia will appear nor-
mal for the first 8 to 12 hours (Fig. 4-9B) unless hemorrhage is present
(unusual in the acute phase). In subacute basal ganglia infarction, some

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 253

FIG. 4-12. MCA infarction secondary to embolus.

A. Axial T1-weighted image shows hyperintensity in
the right lentiform nucleus (arrows) and poor differ-
entiation of the cerebral cortex from the underlying
white matter in the right MCA distribution. B. Axial
T2-weighted image shows hyperintensity of the cortex
in underlying white matter in the right MCA distribu-
tion. C. MR angiogram shows an embolus (arrow) in
the supraclinoid segment of the right internal carotid
artery. D. Axial T2-weighted image shows abnormal
hypointensity in the right lentiform nucleus and cere-
bral cortex in the MCA distribution. E. Postcontrast
T1-weighted image from follow-up scan performed
1 week after event. Marked enhancement is seen in
the injured regions of brain. (This case courtesy of
Dr. Chip Truwit, Minneapolis, MN.)

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 254 Pediatric Neuroimaging

FIG. 4-13. Infarct of putamen due to vasculitis. A. Axial noncontrast CT shows low attenuation of the left putamen
(white arrows). Compare to normal gray matter signal of right putamen.B. Axial Dav map shows reduced diffusivity (low inten-
sity, white arrows) in the affected putamen. C. Axial collapsed view of 3D TOF MR angiogram shows narrowing of the left MCA
(arrows). D. Axial postcontrast T1-weighted image shows enhancement (arrows) in the walls of the left MCA. Enhancement of
the wall of the blood vessel strongly suggests inflammatory vasculopathy. (This case courtesy of Dr. Susan Blaser, Toronto, ON.)

hemorrhage, calcium, or myelin degradation will typically be present in
the infarcted nuclei, resulting in a heterogeneous signal on both T1- and
T2-weighted images (Figs. 4-12). As with cortical infarctions, FLAIR is
often falsely negative in basal nuclear infarctions in the neonate.
Evidence in adults suggests that perfusion imaging, either with
a bolus of intravenous contrast or using arterial spin labeling (ASL,
see Chapter 1) may be of some value in determining how much
brain tissue can be saved by intervention (by looking at the extent of
perfusion-diffusion mismatch). There is not yet any evidence that per-
fusion imaging is useful in the assessment of infarctions in children.
Moreover, both bolus administration and ASL are difficult in young
infants and neonates. Therefore, perfusion imaging is not universally
used in pediatric strokes at this time; it is routinely used at Children’s
Hospital of Philadelphia, but not at UCSF.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
Close scrutiny of the cerebral blood vessels is important when
examining an MR scan of an infant or child who has suffered a cere-
bral infarction. Therefore, some type of vascular imaging study should
be obtained in all infants and children with unexplained ischemic
infarction (Figs. 4-10, 4-12, and 4-13). Although vascular injury or
inflammation can sometimes be detected on routine anatomic imag-
ing by the detection of vessel wall thickening or enhancement (see Fig.
4-13D) (104), vascular injury is better detected by MRA, which gives
an excellent depiction of the intracranial carotid, vertebral, and basilar
arteries and their proximal branches (Figs. 4-10E and 4-13C). Indeed,
between 64% and 74% of arterial defects in pediatric ischemic infarc-
tions are located in the supraclinoid carotid artery or the proximal
(M1 segment) MCA (26). Therefore, if infarction is suspected clini-
cally or on the basis of the anatomic images, MR angiography should
be performed to carefully evaluate the blood vessels for evidence of
dissection, thrombosis, stenosis, or dysplasia (the techniques for this
are described in Chapter 1). In particular, dissection appears to be far
more common than previously suspected in childhood stroke (25,26).
The appearance of dissection in children is not different from that in
adults. It is suggested on MRI by the presence of a crescent of meth-
emoglobin (bright on fat-suppressed T1-weighted images) in the wall
of the lumen of affected vessels and on MRA by the presence of an inti-
mal irregularity, a double lumen, a pseudoaneurysm, a tapering arterial
occlusion, or an elongated area of tight, irregular, and tapering stenosis
or occlusion (26). Catheter angiography is no longer necessary unless
subtle abnormalities of branch vessels or vasculitis of small-to-middle
sized arteries is suspected; however, these locations are unusual ones
for arterial abnormalities in children (26).
As of this writing, there is no evidence to support the routine use
of proton MR spectroscopy (MRS) in children with acute localized
infarction. MRS is more useful in the evaluation of patients with dif-
fuse ischemic injury, to be discussed later in this chapter.
Infarction Secondary to Venous Occlusion
Venous infarcts secondary to venous thrombosis are fairly common,
both prenatally and in childhood (106). At present, best estimates are
that the incidence of venous thrombosis is 0.67 cases per 100,000 chil-
dren per year (106). Of these, up to 40% suffer venous infarction, of
which about 70% are hemorrhagic (106). In addition, a significant
number of cases of congenital hemiplegia appear to result from pre-
natal periventricular venous infarctions (41,42). Venous thrombosis
should be suspected in any child who, in the absence of trauma or
infection, has an unexplained hemorrhage or a brain injury that does
not fit an arterial vascular distribution (in particular, anterior tempo-
ral lobe hemorrhage, frontal or parietal involvement, and absence of
caudate involvement favor venous infarction [121,122]). If family his-
tory is present, consider hemorrhage due to Collagen IV A1 (COL4A1)
mutation (77), which looks identical to hemorrhagic venous infarc-
tion on MRI (45,78). Hemorrhage due to COL4A1 mutations can
range from mild to very severe and, in the most severe fetal cases,
can even cause hydranencephaly (Dr. Linda de Vries, personal com-
munication). Whatever the cause, affected infants commonly present
with seizures and diffuse neurologic signs, whereas older children
more commonly manifest alteration of consciousness, headache, or
focal neurologic signs (106). Risk factors are age-dependent: peri-
natal complications in neonates, head and neck infections (otitis
media, mastoiditis, or sinusitis) in preschool children, and trauma or
chronic diseases such as connective tissue disorders in older children
(106,121,123).
As will be discussed in a later section of this chapter, venous
thrombosis is a common cause of spontaneous cerebral hemorrhage
in neonates, both intraparenchymal (30) and, rarely, epidural (124).
Barkovich_Chap04.indd 255
255
Parasagittal injuries, often hemorrhagic, are seen most commonly in
association with superior sagittal sinus thrombosis (Figs. 4-14 and
4-15), temporal lobe hematomas are usually associated with transverse
sinus thrombosis (and consequent vein of Labbé thrombosis, Fig. 4-16),
and thalamic hemorrhage is usually associated with vein of Galen/
straight sinus thrombosis (Fig. 4-17). Occluded venous sinuses are not
commonly seen in association with frontal polar hematomas; however,
all frontal hematomas and parasagittal frontal infarcts should lead to
evaluation of the patency of the superior sagittal sinus (Fig. 4-18).
It is important to remember two facts when venous thrombosis is
identified in neonates and children. The first is that all patients with
spontaneous venous thrombosis should be evaluated for disorders
of coagulation, such as partial deficiencies of clotting factors (fac-
tor V Leiden (61,62) or proteins C and S (60–64), high coagulation
factor VIII (121), G20210A prothrombin mutations (66), thermo-
labile methylenetetrahydrofolate reductase polymorphism (88,89),
increased lipoprotein A (88,89), and the presence of anticardiolipin
antibodies (63,67,68). The second is that venous thrombosis often
resolves in neonates without aggressive therapy and without neuro-
logic residua (125–127). The best current estimates are that 77% of
affected neonates and 40% to 50% of affected infants and children are
neurologically normal after a mean of 2.1 years (106,121). The role of
intervention, such as intravascular thrombolysis, is not clear at this
time; caution is advised in this regard, as nearly 70% of pediatric venous
infarcts are hemorrhagic (106).
Duplex Doppler sonography is very useful for the diagnosis of
sinovenous thrombosis in neonates and young infants. Echogenic clot
is seen in the affected sinus, and Doppler analysis shows absence of, or
alterations in, flow. In older infants and children, MRI is the imaging
modality of choice. Routine T1- and T2-weighted spin-echo images
should be obtained (and FLAIR in children older than 1 year), in addi-
tion to diffusion-weighted images, gradient-recalled echo images, and
MRV. If the venous thrombosis is acute (<7 days old), it will exhibit
marked hypointensity with apparent expansion of the affected sinus
(due to susceptibility effects) on gradient-recalled echo images with
long echo time (TE = 25–30 milliseconds) (128). Often, the sagittal
T1-weighted images are diagnostic by themselves, as they show sub-
acute clot (high signal intensity) in the sagittal, straight, or transverse
sinuses (Fig. 4-14); this appearance is diagnostic. CT may also be
used; indeed, CT venography is the most sensitive study for the detec-
tion and diagnosis of venous thrombosis (129), showing thrombi as
hypodense areas within the affected venous structure. However, subtle
brain injury is more difficult to detect on CT, especially in neonates
and young infants. On CT, venous infarcts are usually poorly delim-
ited, hypodense or mixed attenuation areas involving the subcortical
white matter and producing a slight mass effect (Fig. 4-15A). The low
attenuation is probably due to localized cerebral edema, whereas high
attenuation areas usually represent hemorrhage. Following contrast
administration, linear or round gyral enhancement frequently over-
lies the hypodensity. The thrombosed vein may be seen overlying the
infarction as a curvilinear region of high attenuation. On MRI, early
venous infarcts may be identified by visualization of prolonged T1 and
T2 relaxation times in characteristic regions (most commonly fron-
toparietal parasagittal [Figs. 4-14 and 4-15] and temporal [Fig. 4-16]).
Another early imaging sign is visualization of thrombus in the deep
medullary veins (Fig. 4-17); this usually indicates thrombosis of both
the superficial and deep venous systems. Of note, diffusion images may
show reduced, normal, increased, or a mixture of diffusivity in areas of
venous infarction (130–132). This probably results mainly from the
fact that venous sinus occlusion initially reduces venous outflow, with
consequent interstitial (“vasogenic”) edema, which causes increased
diffusion. If adequate collateral venous outflow is not established,
5/25/2011 11:38:33 AM
 256 Pediatric Neuroimaging

FIG. 4-14. Venous infarction secondary to superior sagittal sinus thrombosis. A. Axial noncontrast CT scan shows
mixed high and low attenuation in the left frontal lobe. Note the high attenuation (arrows) in the superior sagittal sinus.
B. Sagittal SE 550/16 image shows hyperintensity (large arrows) in the superior sagittal sinus, indicating methemoglobin and
subacute thrombus. C and D. Axial T1- and T2-weighted images show a mixture of hemorrhage (bright in C, dark in D) and
edema (dark in C, bright in D) characteristic of venous infarction.

frank venous infarction will occur. The net diffusion characteristics
of the region are roughly additive; thus, the diffusion characteristics
will depend upon the degree of increased water motion resulting from
interstitial edema and the degree of decreased water motion secondary
to the infarct. The frequent presence of blood (Fig. 4-18), the para-
magnetic effects of which makes diffusivity values unreliable, may also
contribute to this heterogeneity of diffusion characteristics. Many (up
to 70%) venous infarcts are hemorrhagic; hemorrhagic infarcts have
an imaging appearance that varies from large subcortical hematomas
(Fig. 4-18) to petechial hemorrhages within edematous brain paren-
chyma (Figs. 4-14 and 4-16) (106,133). The hemorrhages are generally
subcortical and often multifocal with irregular margins. They are occa-
sionally linear in nature, indicating hematoma in and around the vein;
this appearance is quite specific.
Finally, although CT venography is the most definitive method
for establishing the diagnosis of venous thrombosis (129), we use MRI
as our first choice for making the diagnosis in infants because of the
lack of ionizing radiation; MRV with contrast is useful to better evalu-
ate areas where flow-related enhancement is diminished due to rapid
flow or flow is parallel to the imaging plane on two-dimensional (2D)
time-of-flight (TOF) sequences. Venous sinus thrombosis is discussed
further in the section on this chapter on “Venous Thrombosis/Venous
Infarction” and in Chapter 11, in the section on “Complications of
Meningitis.”
Diffuse Ischemic or Inflammatory Brain Injury
Diffuse brain injury has many causes in neonates and children, includ-
ing metabolic disease, complications of prematurity, complications of
the birth process, and infection. This section will cover disorders that
are generally considered to be ischemic or inflammatory (white matter
injury of prematurity might be either or both). A number of terms are

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 257

FIG. 4-15. Extensive sinus thrombosis in a child with seizures. A. Axial noncontrast CT scan shows areas of low attenuation (white
arrows) in the right frontal and left parietal parasagittal white matter. B. Coronal FLAIR image shows abnormal cortical hyperintensity
(white arrows), representing ischemic injury in the parietal cerebral convexities. C. Axial diffusivity map shows low signal intensity
(white arrows) representing reduced diffusivity in the parasagittal regions of the hemispheres. D. Anteroposterior maximum intensity
projection of 2D TOF MR venogram shows near complete absence of flow related enhancement in the major dural venous sinuses. Only
the right transverse (white arrow) and sigmoid sinuses and the right jugular vein (arrowheads) are patent. Sagittal sinuses, straight sinus,
vein of Galen, and left transverse/sigmoid sinuses are occluded.

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 258 Pediatric Neuroimaging
used to describe diffuse ischemic brain injury in the neonate, including
perinatal asphyxia, neonatal encephalopathy, hypoxic-ischemic enceph-
alopathy, and asphyxia neonatorum. The causes of this type of injury
have been widely debated. Although some authors have postulated that
obstetric factors are the most important (134,135), many others have
questioned this assumption (136) and have suggested the importance
of prenatal and perinatal infection (137–141), placental pathology
(142), or underlying metabolic disorders (143), among other factors.
Barkovich_Chap04.indd 258
FIG. 4-16. Temporal lobe hemorrhagic venous infarct sec-
ondary to transverse sinus thrombosis. A. Axial noncontrast
CT shows hypoattenuation in the anterior right temporal lobe
(white arrowheads) and hyperattenuation (white arrow) in the
right sigmoid sinus, suggesting venous infarction secondary to
sigmoid sinus thrombosis. B. Axial T2-weighted image shows
areas of hypointensity (white arrows), suggesting hemorrhage,
in the infarction. C. Postcontrast axial T1-weighted image
shows slow flow and filling defects in the right transverse sinus
(white arrows), confirming thrombosis. Compare with normal
signal void in left transverse sinus (black arrows).
Such factors should be actively investigated unless obvious causes such
as umbilical cord or uterine rupture, large placental abruption, or car-
diocirculatory arrest are found.
The physiology of brain injury resulting from hypoxia and isch-
emia is rather complex and not completely understood. Asphyxia,
defined as impaired exchange of oxygen and carbon dioxide, results in
diminished oxygen content in the blood (hypoxia), increased carbon
dioxide in the blood (hypercarbia), acidosis, and decreased systemic
5/25/2011 11:38:36 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 259

FIG. 4-17. Total deep and superficial venous sinus thrombosis. A. Sagittal T1-weighted image shows hyperintensity consistent with subacute blood
(methemoglobin) in the superior sagittal sinus (large white arrows) and vein of Galen/straight sinus (small white arrows). B and C. Axial T2-weighted
images show hypointensity extending radially from the ventricular walls (small arrows) suggestive of thrombus in the deep medullary veins. D. Phase-
contrast MR venogram shows absence of moving protons (no flow) in the superior sagittal sinus and straight sinus.

blood pressure. The hypercarbia and hypoxia cause a loss of the normal
vascular autoregulation in the brain of the term neonate (144,145),
resulting in so-called pressure-passive flow. (In the noncompromised
term neonate, blood vessels of the brain constrict when blood pres-
sure increases and dilate when blood pressure decreases. This process,
known as autoregulation, maintains constant cerebral blood flow. Loss
of autoregulation results in pressure passive flow. In preterm neonates,
pressure passive flow is present even in the absence of asphyxia or
other disease [145].) The combination of decreased blood pressure
and pressure-passive flow results in decreased perfusion of the brain
(146,147) and may result in ischemic injury in term infants (probably
mediated by excitotoxicity (148), discussed in subsequent sections),
and in germinal matrix hemorrhage, or white matter injury in preterm
infants (147,149–151). The newborn brain is quite resistant to hypoxia
in the setting of normal cerebral blood flow because glucose and other
energy substrates, notably ketone bodies, minimize or prevent brain
damage (152). Thus, most hypoxic-ischemic brain injury in neonates is a
result of cerebral hypoperfusion.
The duration of the hypoperfusion is a critical factor in determin-
ing whether brain damage results from an episode of hypoperfusion
(17). Neonatologists and obstetricians have found that babies suffering
short periods of hypotension suffer no long-term effects. In support
of this, our anecdotal experience is that neonates and children who
have been quickly resuscitated after respiratory or cardiac arrests show

Barkovich_Chap04.indd 259 5/25/2011 11:38:36 AM

 260 Pediatric Neuroimaging

FIG. 4-18. Obtunded neonate with blown pupil. A. Noncontrast CT shows large left frontal hemorrhage (white arrows) with
left to right subfalcine herniation. Coronal sutures are wide (white arrowheads) and there is a suggestion of subdural blood
(black arrowheads) over the left convexity. B. Axial T2-weighted image again shows large left frontal hematoma and confirms
subdural hemorrhage (white arrows). C. DWI shows the complexity of hemorrhagic venous infarcts on diffusion imaging. Sus-
ceptibility effect of acute or subacute blood can mask diffusion characteristics of water molecules. D. Collapsed view of 2D TOF
MR venogram shows no flow related enhancement of sagittal or straight sinuses.

no abnormalities on their subsequent imaging studies. Animal models
support this, as well. In asphyxiated neonatal sheep, selective neuronal
necrosis is seen only after 10 minutes of perfusion arrest (153,154), and
in monkeys damage is detected only after 7 minutes of perfusion arrest
(155), with basal ganglia injury seen after 8 to 12 minutes and severe
injury of the entire brain after 20 minutes (156,157). Although it is
difficult, in most cases, to know the precise time of onset of an arrest,
our anecdotal experience suggests that longer arrests, in the range of
15 to 25 minutes, result in brain injury. The amount of time to brain
injury from less severe hypotension is more variable, depending upon
the amount of energy substrate reaching the cells (158).
Although hypoperfusion is the primary cause of neonatal asphyxic
brain injury, hypoxia does have a role. In addition to its effect on auto-
regulation, hypoxia reduces cardiac contractility/cardiac output and

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
alters capillary permeability. Reperfusion of the weakened capillaries
(particularly those within the germinal matrices of premature infants,
which are structurally weaker than the capillaries in the remainder of
the premature brain [159]) can cause rupture of cerebral blood vessels
and result in intracranial or intraventricular hemorrhage (151,160).
Secondary Energy Failure
A useful concept in understanding imaging results after hypoxic-
ischemic injury is that of secondary energy failure (Fig. 4-19). During
hypoxia-ischemia, significant changes occur in the brain on magnetic
resonance studies. 31P spectroscopy shows depletion of phosphocre-
atine or NTP (nucleotide triphosphates, including ATP) (161), pro-
ton spectroscopy shows elevated lactate (162), and diffusion-weighted
imaging shows reduced diffusivity (163,164). These findings then
normalize in the early recovery period (6–18 hours), only to revert to
abnormality again around 24 hours after the injury. This reversion to
abnormality has been called secondary energy failure (162). It is pos-
tulated to be the result of structural damage to intracellular molecular
structures that are important to cellular metabolism, particularly high-
energy phosphate reserves; the structural damage accumulates during
the “early recovery period” and, as this accumulation takes place, cel-
lular metabolism deteriorates (165).
Patterns of Diffuse Hypoxic-Ischemic Brain Injury
A number of different patterns of brain injury can be seen as a result of
hypoxic-ischemic episodes in neonates, infants, and children (16,166–
174). These patterns can be best understood if interpreted as being the
result of three primary factors: (a) severity of hypotension, (b) matu-
rity of the brain at the time of injury, and (c) duration of the event.
Severity of Hypotension
When blood flow to the brain is mildly or moderately reduced (mild to
moderate cerebral hypotension with impaired autoregulation), blood
flow is shunted from the anterior to the posterior circulation in order
to maintain adequate perfusion to the brain stem, cerebellum, and
basal ganglia (175). As a result, damage is limited to the cerebral cortex
and the intervascular boundary zones (both cortex and white matter
[176]) of the cerebral hemispheres (Fig. 4-20). However, when reduc-
tion of cerebral blood flow is severe (profound cerebral hypotension),
resulting in complete or nearly complete cessation of cerebral blood
Barkovich_Chap04.indd 261
261
FIG. 4-19. Secondary energy failure. During hypoxia-ischemia,
significant changes occur in the brain on magnetic resonance
studies. 31P spectroscopy shows depletion of phosphocreatine or
NTP (including ATP), proton spectroscopy shows elevated lactate,
and diffusion-weighted imaging shows reduced diffusivity. These
diffusion and spectroscopy findings may normalize in the early
recovery period, only to revert and become abnormal again after
about 24 hours. Secondary energy failure is postulated to result
from structural damage to intracellular molecular structures that
are important to cellular metabolism, particularly high energy
phosphate reserves. Structural damage accumulates during the
“early recovery period” and, as this accumulation takes place,
cellular metabolism deteriorates. Don’t be fooled during latency
period into thinking that there has been no brain damage!
flow, shunting of blood is no longer adequate to save the deep struc-
tures from damage.
In profound hypotension, the location of injury is initially to
the deep cerebral nuclei (thalami and basal ganglia), posterior brain
stem, and the most active regions of the cerebral cortex (the senso-
rimotor region). Damage to the remainder of the cortex and white
matter occurs only later in the course of the hypotensive episode
(16,166,170,173,174,177–179). The location of injury is probably
related to the state of maturity of the brain (17,148,180,181). Positron
emission tomography studies of glucose uptake in the developing brain
(182), which reflect metabolic activity; SPECT studies, which show rela-
tive regional perfusion (183,184); and proton spectroscopy (185), which
reflects biochemical maturation, all show excellent temporal and topo-
logical correlation with the process of myelination (Fig. 4-21) (186). In
addition, the regions affected in profound hypotension are connected
by circuits that use glutamate as their neurotransmitter (187). Imma-
ture NMDA receptors have heightened excitability and can be opened
in hypoxia-ischemia. This, combined with impaired removal of gluta-
mate by energy-dependent transporters, is an important cause of cell
injury in severe hypoxia-ischemia (148). As these areas have the most
advanced myelination, highest perfusion, increased synaptic plasticity,
and greatest glucose uptake, they would seem to be at highest risk for
injury in the absence of glucose and oxygen (which provide energy to
the cell). Indeed, the pattern of brain injury detected on MR studies of
newborns who have suffered profound hypotension corresponds quite
closely to the patterns of myelination, perfusion, and glucose uptake at
the time of injury (16,17,170,180–182). These correlations suggest that
the most metabolically active and mature regions of the brain, those
that have the most advanced myelination, biochemical composition,
perfusion, and glucose uptake, are the regions that suffer damage first
in the setting of a nearly complete cessation of brain perfusion.
Maturity of the Brain
The patterns of injury secondary to mild to moderate hypotension and
those secondary to profound hypotension both change with the post-
conceptional age of the child.
Premature infants who suffer mild to moderate hypotension typi-
cally sustain injury to the periventricular and deep white matter with
sparing of the subcortical white matter and cerebral cortex. In contrast,
term infants who suffer similar degrees of hypotension sustain injury
5/25/2011 11:38:38 AM
 262 Pediatric Neuroimaging
FIG. 4-20. Intervascular boundary zones. Axial SE T1-weighted images (A and B) show the intervascular boundary zones between
the ACA distribution and MCA distribution anteriorly and between the PCA distribution and the MCA posteriorly.
in the watershed portions of the cerebral cortex and in the underlying
subcortical and periventricular white matter. Classically, this change in
injury pattern has been attributed to a changing location of the inter-
vascular boundary zones (“watershed regions”). Van den Bergh (188),
Takashima and Tanaka (189), and deReuck (190) postulated that the
ventriculofugal blood vessels in the brain (those coursing outward into
the cerebrum from the intraventricular and periventricular regions) are
poorly developed during the first two trimesters of gestation. Almost
all of the blood supply to the cerebral white matter and cortex, there-
fore, was postulated to come from the ventriculopetal blood vessels
coursing inward from the surface of the brain. This explanation, and
the existence of ventriculofugal arteries, has been disproved (191–193).
In addition, new information better explains the observed findings.
The cerebral vessels in the premature infant have a relatively limited
vasodilatory capacity, resulting in an inability of the brain to accept
increased blood flow; this limitation in vasodilatory capacity exacer-
bates the ischemia. Superimposed upon the reduction of blood flow is
the fact that the periventricular white matter of a premature infant is
a site of oligodendrocyte proliferation in preparation for myelination.
The developing cerebral white matter in this region responds to oxy-
gen deprivation by utilizing anaerobic glycolysis, an inefficient mecha-
nism of glycogen metabolism that results in depletion of high-energy
phosphates and in localized lactic acidosis. Late oligodendrocyte pro-
genitors are very susceptible to lactic acidosis from hypoxia-ischemia
(194), probably because their AMPA glutamate receptors lack GluR2
subunits, allowing them to flux high amounts of calcium (toxic to
the cells [195,196]); in addition, they do not have proper enzymes to
detoxify nitric oxide and other oxygen free radicals (197). The time at
which late oligodendrocyte progenitors are present in the brain coincides
with the period of vulnerability of periventricular white matter injury in
the fetal brain (198). Thus, as a result of the state of immaturity of the
premature brain and its vascular supply, the periventricular and deep
white matter areas are the regions at highest risk when autoregulation
Barkovich_Chap04.indd 262
is compromised in prematurely born neonates. White matter damage
of prematurity (sometimes called periventricular leukomalacia) is,
therefore, a fairly common brain injury in prematurely born children.
Three different types of white matter injury are described by Volpe
(147): diffuse injury, which has the mildest clinical manifestations;
focal/multifocal noncavitary injury, which has intermediated clinical
severity; and focal/multifocal cavitary injury, which has severe clinical
manifestations. All three types can be identified and distinguished by
MRI and are described in the next section, on imaging of brain injury
in premature neonates. White matter injury is particularly common
in those with respiratory distress syndrome, antepartum placental
abruptions, hypocapnia, twin pregnancy, septicemia, or ischemia dur-
ing delivery (167,168,172,199,200). In contrast to the premature brain,
the term neonate (38–42 postconceptional weeks) and postterm neo-
nate (43–46 postconceptional weeks) have normal GluR2 expression in
the oligodendrocytes, but reduced GluR2 expression in the neocortex
(196); thus, the cortex becomes selectively vulnerable to mild-moder-
ate ischemia as the neonate approaches term. Thus, due to matura-
tion of the brain, and (likely) its vascular system, the pattern of injury
begins to change between the 34th and 38th postconceptional weeks, as
the regions at highest risk for injury extend peripherally to include the
subcortical white matter and cerebral cortex in the interarterial bound-
ary zones; note that white matter involvement frequently still occurs
and this can be seen on good quality imaging studies (176). These so-
called watershed areas are almost always involved if mild to moder-
ate hypotension of sufficient duration takes place after 36 weeks (18).
In some patients, the damage extends medially and laterally from the
watershed zones to involve larger areas of the cerebrum.
Pontosubicular necrosis, in which the subiculum and fascia den-
tata of the hippocampus and ventral pons are selectively involved (5) is
seen almost exclusively in premature infants, typically in the setting of
hypocarbia and hyperoxemia (201–203). Although the precise cause is
not known, the fact that pontosubicular necrosis is almost always seen in
5/25/2011 11:38:39 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 263

FIG. 4-21. 18FDG PET scans showing changing glucose uptake with maturity. A. Highest glucose metabolism at birth is in the
posterior fossa, thalami (arrows), and sensorimotor regions of the cerebrum. B. Proton magnetic resonance spectroscopic image of
a neonate shows that the highest NAA concentration is in the thalami (black arrows), confirming that this is the earliest part of the
cerebrum to mature. Note similarity to (A). C. By age 3 months, the basal ganglia (black arrowheads) have similar metabolism to the
thalami and the visual cortex (white arrows) has much greater activity. D. By age 8 months, the cerebral cortex metabolism is the
highest in the brain, greater than that in the thalami and similar to that of the basal ganglia. This relative activity will be similar at
subsequent ages. (A and D are courtesy of Prof. Harry Chugani, Detroit.)

the setting of periventricular leukomalacia added to the fact that the fascia The pattern of injury from profound hypotension evolves as brain
dentata seems to undergo apoptotic cell death (204) suggests that the regions mature, because the increased metabolic demand combined
hypocarbia and hyperoxemia exacerbates cellular injury from hypoxia- with the stage of maturity of the glutamate receptors changes the pat-
ischemia in the pons and hippocampus in the premature infant. terns of vulnerability of the brain (16). The process of maturity involves

Barkovich_Chap04.indd 263 5/25/2011 11:38:40 AM

 264 Pediatric Neuroimaging
changes in neurotransmitters used as well as the maturity of the
receptors (148,196), in local glucose uptake (182), in relative regional
blood flow (183,184), in levels of metabolites (185), and in myelina-
tion (170,181). The thalami and brainstem have the highest metabolic
activity in the early third trimester; from the middle of the third tri-
mester through 40 postconceptional weeks, the brain stem, thalami,
basal ganglia, and perirolandic region have the highest metabolic activ-
ity (16,17,182,205). By the end of the first postnatal month (44 post-
conceptional weeks), the visual cortex becomes more metabolically
active (Fig. 4-21) (182). After the third or fourth postnatal month, the
remainder of the cerebral cortex and the basal ganglia become increas-
ingly metabolically active (Fig. 4-21D) and the regions more likely to
be damaged shift from the thalami and perirolandic cortex to the basal
ganglia and the entire cerebral cortex (170).
Duration of the Injury
Duration of the event is another important factor in interpreting an
imaging study of an asphyxiated child. It is not possible to know the
precise duration of an arrest or of a hypotensive injury in most cases,
particularly in a neonate who may have been hypotensive prior to deliv-
ery. In addition, there is almost certainly variability among infants in
the ability to tolerate reduced energy substrates to the brain. In general,
however, as discussed earlier in this section, short episodes of hypoten-
sion do not seem to cause brain injury; this has been found in animal
models, as well (153–155). Moreover, mild degrees of hypotension are
usually compensated by autoregulation. However, in the setting of
pressure-passive cerebral blood flow or in hypotension too severe for
autoregulation to compensate, the longer the hypotension persists the
more likely it is to result in brain damage and the more extensive the
brain damage is likely to be.
Injury in the Premature Neonate
Neurologic Sequelae of Brain Injury in the
Prematurely Born Neonate
Neuroimaging assessment of premature infants is becoming increas-
ingly important as the number of premature births increases (11% of
all live births in the United States in 2000 [206]) and survival rates of
very low-birth weight (<1500 g) infants increase (207), but the sur-
vivors remain at great risk for the neurodevelopmental impairments
(208–212). Recent studies suggest that the rate of cerebral palsy has
decreased (to 9% (212)) but neurologic disability is still seen in 40%,
with a rate of 50% in those born from 24 to 28 gestational weeks
(211–214). Indeed, among infants born at 25 or fewer weeks, up to
90% are stillborn or die before hospital discharge. Of survivors, half
have neurodevelopmental disability and, of these, half have severe dis-
ability (215). In childhood, children born at weights of less than 1000 g
have significantly more functional limitations and dependency needs,
requiring significantly more services than closely matched controls
(212,213). At the age of 5 years, children born at 33 weeks or less have
significantly higher incidence of neuromotor dysfunction including
learning disabilities (212,216). When they reach adulthood, people
born at very low birthweight (infants weighing <1500 g at birth) or
born moderately or severely premature have less chance of finishing
high school, lower mean IQ, lower academic achievement scores, higher
rates of neurosensory impairments, and subnormal height (217,218).
Special healthcare resources are needed by 42% of children born at 24
to 28 weeks and by 31% of those born at 29 to 32 weeks (217,218).
Looking at the data in another way, infants who weigh less than 2500 g
account for 11% of all births in the United States, but more than 90%
of neonatal deaths, while those who weigh between 500 and 1500 g
account for 1% of all live births but more than 60% of all neonatal
deaths (219).
Barkovich_Chap04.indd 264
Although there are many conditions that result in brain injury in
the premature neonate, the two most widely accepted pathogenetic
mechanisms are maternal-fetal infection and impaired cerebrovascular
autoregulation with resultant ischemia (220). Definitive proof for either
mechanism is lacking and a full discussion of the controversy as to which
mechanism predominates is beyond the scope of this book. However, cur-
rent work seems to support the ischemia hypothesis (148,196,220,221). For
all of the reasons discussed in the previous section, ischemic injury tends
to occur in different regions of the brain in preterm infants than in term
infants. Autoregulation is often absent in premature neonates (145), and,
because of the relatively high incidence of lung immaturity (with resul-
tant hypoxia), patent ducti arteriosi, and sepsis, mild cerebral hypoperfu-
sion is relatively common. Because of the presence of late oligodendrocyte
progenitors, which are very susceptible to lactic acidosis from hypoxia-
ischemia (194) (probably because their AMPA glutamate receptors lack
GluR2 subunits, allowing them to flux high amounts of calcium—toxic
to the cells (195,196)), the cerebral white matter is the part of the brain
most sensitive to ischemic injury in this age group (194,198,221); thus, it
is the most common location for injury (146,147,222–224).
The motor and visual pathways course though regions of white
matter that are commonly injured; therefore, motor and visual impair-
ment are the most common neurologic sequelae of periventricular white
matter injury, although the incidence of these sequelae are decreasing
(225). Because the lower extremity axons course medially to the upper
extremity axons, they are more affected by periventricular injury and
motor function is more severely affected in the lower extremities than
the upper extremities. This condition, called “spastic diplegia,” is a com-
mon syndrome in neurologically impaired premature neonates, with
an incidence of 5% to 15% (225,226). Visual impairment is common
among prematurely born children with spastic diplegia, with an inci-
dence as high as 70% (227–229). This correlation probably reflects the
fact that the geniculocalcarine tracts (optic radiations) and the visual
association pathways course through the posterior periventricular white
matter; therefore, the same white matter injuries that cause motor dis-
abilities may also cause visual impairment (227–229). Indeed, presence
of visual impairment correlates well with sonographic evidence of PVL
(230), with MR evidence of damage to the occipital lobes and cerebel-
lum (the cerebellum has an important role in oculomotor function)
(231), and with changes in fractional anisotropy (FA) on diffusion ten-
sor imaging (DTI) (232,233). The visual impairment is characterized by
low acuity, visual field defects, disorders of conjugate gaze, abnormal eye
movements, and oculomotor disturbances; visual-spatial perceptions
are affected as well (231,234–236). Of interest, the ophthalmologic dys-
function of prematurely born neonates differs significantly from that in
term neonates who suffer injury to the visual pathways (235).
Even premature infants (<33 weeks gestation) with normal neu-
rologic outcomes have a high incidence of cognitive impairment when
examined at age 8 years (237,238). Cognitive impairment is identified
in nearly 50% of preterm children with no sonographic abnormalities
(noncystic white matter injury) (215,225,239–241), although the inci-
dence of severe impairment is less than 5% (237,238). The incidence of
severe cognitive impairment increases significantly if hydrocephalus or
loss of cerebral parenchyma can be detected by sonography (238). The
cognitive impairment is suspected to be the result of injury to com-
missural tracts and intrahemispheric association pathways, especially
the posterior corpus callosum, which functions to transfer cognitive
information (238,242–244), with a possible contribution from injuries
to the cerebellum (245,246).
Types of Brain Injury in Premature Neonates (and Fetuses)
Several types of brain injuries may occur secondary to hemody-
namic alterations in premature infants, including white matter injury,
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 265

TABLE 4-4 Brain Injury in Premature Neonates

Type of Injury Location Pathology
Germinal matrix hemorrhage Walls of lateral ventricles (may extend into Hemorrhage secondary to rupture of thin
ventricle and cause hydrocephalus) walled capillaries in germinal matrix
Cerebellar cortex
White matter injury Deep cerebral white matter (may be multifocal Focal/multifocal necrosis, which forms
or diffuse) astroglial scar.
May cavitate.
Venous infarction Cerebral basal ganglia, deep and periventricular Infarction often hemorrhages.
white matter May liquefy, leading to porencephaly
Cerebellar atrophy Cerebellar vermis and hemispheres Unknown

germinal matrix hemorrhage, intraventricular hemorrhage, periven-
tricular hemorrhagic infarction (PVHI), and cerebellar infarction
and atrophy (Table 4-4) (147, 247). Of note, all of the types of injury
described in prematurely born infants can develop in fetuses of the same
postconceptional age. In our examinations of fetuses with sonography
and MRI, we have seen germinal matrix hemorrhage, intraventricu-
lar hemorrhage, white matter injury, and PVHI. Others have reported
similar findings in the literature (248–251). Indeed, in the series of de
Vries et al., 16% of PVHI was present at birth, with another 3% already
evolved into a porencephalic cyst (252). Takanashi et al. found PVHI
to be a common cause of congenital hemiplegia in term infants, again
suggesting prenatal injury as the cause (41,42).
Periventricular and Intraventricular Hemorrhage As stated earlier,
when tissue is hypoperfused and subsequently reperfused, especially
in the presence of increased venous pressure, the weakened capillar-
ies may rupture, resulting in hemorrhage (151,253,254). This type of
hemorrhage is most frequently seen in the ventricular/subventricular
zones (also called the germinal matrix), the area within the ventricular
wall in which the cells that compose the brain are generated (255,256).
It is thought that the hemodynamic instability associated with birth is
related to these germinal matrix hemorrhages, as 40% have their onset
within 5 hours of birth (257) and 90% within the first 4 days (151). The
germinal matrix is extremely vascular but the vessels have very thin
walls and are sensitive to changes in oxygen supply and blood flow. The
germinal zones are most active between approximately 8 and 28 weeks
of gestation; neurons are the primary cells produced in early stages,
whereas glial cells are produced in later stages of germinal zone activ-
ity (258). Toward the end of the second trimester, the germinal zones
diminish in activity and begin to involute; as involution progresses, the
incidence of subependymal hemorrhage decreases. The last areas of the
germinal matrix to involute are the regions around the frontal horns.
One area near the posterior aspect of the caudate heads, the ganglionic
eminence portion of the germinal zone, seems to hemorrhage most fre-
quently. Another area seems to cap the anterior tips of the frontal horns
and can be seen for several weeks after birth (see Chapter 2).
The external granular layer of the cerebellum is a germinal zone as
well (259), and hemorrhages in this germinal zone are also common
(260,261) and increasingly recognized in prematurely born neonates,
with a prevalence of about 20% (262). Cerebellar hemorrhage is more
common in infants weighing less than 750 g at birth; other risk fac-
tors include emergent cesarean section, patent ductus arteriosus, and
low 5-day minimum pH (263). Neonatal mortality and morbidity are
higher among preterm neonates with cerebellar hemorrhage compared
with preterm controls (263). Germinal matrix hemorrhage is unusual
after 34 weeks of gestation (3,222,264). The choroid plexus also fre-
quently bleeds in premature infants, often in association with germinal
matrix hemorrhage.
Periventricular and intraventricular hemorrhage in the premature
neonate has been divided into four grades, related to its severity (265).
Grade I (Fig. 4-22) refers to germinal matrix hemorrhage with no or
minimal intraventricular hemorrhage. Grade II bleeds extend from the
subependymal germinal zone into the ventricles (which remain normal
in size). In Grade III bleeds (Figs. 4-23 and 4-24) intraventricular hem-
orrhage is associated with ventricular enlargement. This ventricular
enlargement can result from parenchymal injury (ex vacuo ventricular
enlargement) or, in some cases, communicating hydrocephalus.
Venous Infarctions Grade IV bleeds of Papile et al. (Fig. 4-25) were
at one time thought to be extensions of germinal matrix bleeds into
the surrounding parenchyma. Currently, they are thought to result
from venous infarction (266) and are termed PVHI (267). Approxi-
mately 15% of all infants with intraventricular hemorrhage will
develop PVHI (267), with 80% to 90% developing within the first
96 hours after delivery (252). Bilaterality of PVHI and more exten-
sive hemispheric involvement by the injury are predictive of poorer
outcome (268). When PVHI are bilateral, or if there is a family his-
tory of PVHI, some consideration should be given to a genetic cause.
Familial porencephaly has been reported in several families, caused by
a microangiopathy resulting from mutations to the gene for COL4A1,
located at chromosome 13q34 (78). The mutations compromise the
structural integrity of the vascular basement membrane, rendering the
vessels susceptible to disruption, especially at times of increased stress
(78). Hemorrhage from COL4A1 may occur at any age, from fetus to
adulthood (45,78).
Ventricular enlargement in Grade III hemorrhages is often asso-
ciated with damage of periventricular tissue; therefore, it is an excel-
lent prognosticator of the short- and long-term neurological outcome.
Only 26% of patients with Grade III/IV hemorrhages survived in one
large study of 484 infants, whereas 67% of infants with Grade I/II hem-
orrhage survived (269). Patients with mild hemorrhage and normal
ventricular size have less than a 10% incidence of long-term neuro-
logical sequelae (270). Patients with enlarged ventricles associated with
intraventricular hemorrhage have approximately a 50% incidence of
neurological sequelae. PVHI (266,271) is associated with significant
permanent brain injury; 50% to 90% of affected patients have serious

Barkovich_Chap04.indd 265 5/25/2011 11:38:42 AM

 266 Pediatric Neuroimaging
neurological sequelae that are related to the location and extent of the
parenchymal injury (223,252,269,272,273).
White Matter Injury Another type of injury commonly seen in pre-
term infants is white matter injury of prematurity. This injury is most
commonly called periventricular leukomalacia, or PVL. However, it is
important to remember that this “white matter injury” is frequently
accompanied by neuronal and axonal disease that affects the thalami,
basal ganglia, cerebral cortex, brain stem, and cerebellum (224); there-
fore, it is better considered an encephalopathy of prematurity (224).
In addition, nearly any part of the white matter (periventricular, deep,
or subcortical) can be affected, and, in our experience, injury is most
common in the deep white matter of the hemisphere, some distance
from the ventricular wall. In addition, use of the term PVL for white
Barkovich_Chap04.indd 266
FIG. 4-22. Papile Grade 1 hemorrhage with cerebellar hem-
orrhage. A. Coronal sonogram from anterior fontanelle shows
echogenic hemorrhage (white arrow) compressing the body of
the left lateral ventricle in a premature neonate with adjusted
age of 29 weeks. No intraventricular extension was seen. B. Axial
T2-weighted MR image shows the hemorrhage as a focus of
marked T2 hypointensity (black arrows) in the wall of the body
of the left lateral ventricle. C. Axial T2-weighted image through
the lower cerebellum shows one large (white arrow) and several
smaller (white arrowheads) foci of hypointensity, representing
cerebellar germinal matrix hemorrhages.
matter injury in premature neonates has resulted in the assumption by
many that all periventricular white matter injury is a result of preterm
hypoxic-ischemic injury, which is clearly not the case. Infections, meta-
bolic diseases, hydrocephalus, and the presence of complex congenital
heart disease, to name a few, can cause injury to periventricular white
matter (see Chapter 3, 8, and Refs. 274,275). To avoid these pitfalls and
the confusion generated by them, the term white matter injury of pre-
maturity will be used in this chapter, keeping in mind that nearly all
parts of the brain are, to some extent, involved.
Thirty years ago, white matter injury was demonstrated pathologi-
cally in 85% of infants with birth weights between 900 and 2200 g who
survived beyond 6 days (276); with advances in neonatology, that num-
ber has dropped considerably (277–280). Although sonography stud-
ies report incidences of PVL to be in the 5% to 10% range (281), this
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 267

FIG. 4-23. Papile—Grade 2 hemorrhage. A. Intraventricular hemorrhage is shown as hyperechogenic regions (arrows) in the
enlarged frontal horns of the lateral ventricles. B. Sagittal plane sonogram shows hemorrhage (arrows) layering in the occipital horn
of the lateral ventricle. C. Axial T1-weighted image of a different patient shows subacute hemorrhage, manifested as homogeneous
hyperintensity in the left ganglionic eminence (the site of hemorrhage, large white arrow), and in the trigones and occipital horns
of the lateral ventricles (small white arrows). D. Axial T2-weighted image shows that the subacute hemorrhages are homogeneously
hypointense.

technique is much better at detecting cavitary (“cystic”) injury than
noncavitary injury. Autopsies and MR studies, which show noncavitary
as well as noncavitary injury, reveal white matter injury in about 50%
of preterm neonates (280,282–284). Thus, it seems that ultrasound
underestimates the prevalence of this type of injury (147,280,283). In
view of the fact that 25% to 50% of prematurely born infants with
white matter injury have cognitive and learning disabilities (285), this
is an important factor supporting the use of MRI. The occurrence of
white matter injury is likely related to many different factors includ-
ing intrauterine infection, postnatal infection, hypoxia, premature
rupture of membranes, maternal chorioamnionitis, and hypotension
with impaired autoregulation (176,267,274,278,286,287), as well as
secondary effects on brain development (147,224). As discussed pre-
viously, recent data suggest that the injury may result from effects of
ischemia upon late oligodendrocyte progenitors, which show selective
vulnerability to hypoxic ischemic injury due to the immaturity of their
receptors and cellular metabolism (147,194–197,221). Another poten-
tial cause is injury to the neurons of the subplate, a transient deep layer
of the cortex that acts as a way station for axons that will ultimately
connect with permanent cortical layers (288). Moreover, the time at
which late oligodendrocyte progenitors are present in the brain and
the time at which the subplate is present coincide with the period of

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 268 Pediatric Neuroimaging

FIG. 4-24. Papile scale—Grade 3 hemorrhage, acute and sub-

acute stages. A. Coronal sonogram from anterior fontanelle
shows bilateral large echogenic masses (white arrows), represent-
ing ganglionic eminence hemorrhages that have extended into
the lateral ventricles. B. Parasagittal sonogram shows the extent
of the intraventricular hemorrhage, extending from the body
of the lateral ventricle (white arrowheads) through the trigone
to the temporal horns (white arrows). C. Coronal SPGR image
shows moderately dilated ventricular system, with subacute
hyperintense clot in the inferior frontal horns (white arrows)
and the inferior temporal horns (white arrowheads). D. Axial
T2-weighted image shows subacute/chronic blood products
lining the ventricular walls with more hyperintense clot (black
arrows) adherent to the choroid plexuses. E. Axial diffusivity
(Dav, ADC) map shows the subacute blood as very hypointense
signal in the ganglionic eminences and choroid plexuses. No
acute parenchymal injury is identified.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 269

FIG. 4-25. Evolution of PVHI. A. Coronal transfontanelle sonogram of a 1-week-old prematurely born neonate (born at 25 week of
gestational age) shows echogenic hemorrhage in the left lateral ventricular germinal matrix (white arrowhead) and in the periventricular
white matter (large white arrows), the latter representing hemorrhagic infarction. The ventricle is compressed. Incidental Grade 1 hem-
orrhage (small white arrow) is seen in the germinal matrix of the right lateral ventricle. B. Axial T2-weighted image from an MR scan
performed several days after (A) shows the hypointense hemorrhage extending from the ventricle into the periventricular white matter
(white arrows). C. Coronal SPGR performed 2 weeks after (B) shows marked ventriculomegaly and evolving hyperintense hemorrhages.
The parenchymal hemorrhage (white arrows) shows some central hypointensities, representing breakdown and resorption of the blood
products. D. Axial T2-weighted image shows the hypointense margins of the hemorrhagic infarction (white arrows) and the central hyper-
intensity, confirming the central breakdown and resorption of hemorrhage and infarcted tissue.

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 270 Pediatric Neuroimaging

FIG. 4-25. (Continued) E. Coronal SPGR obtained at 35 weeks shows some reduction in ventricular size, but the region of the
hemorrhagic infarction has evolved into a porencephalic cavity (white arrows) with smooth walls and a communication with the left
lateral ventricle. F. Axial T2-weighted image obtained at the same time as (E) is slightly degraded by motion, but shows the persistent
enlargement of the lateral ventricles and the left frontal porencephaly (black arrows). Some hemorrhage in the wall of the right lateral
ventricle (white arrow) can still be seen.

vulnerability of the fetal brain for white matter injury of prematurity
(198). The amount of injury correlates with duration of ischemia, and
the location correlates with the location of late oligodendrocyte precur-
sors (221). All three different types of white matter injury described by
Volpe (147) (diffuse white matter injury, which has the mildest clinical
manifestations; focal/multifocal noncavitary white matter injury, which
has intermediated clinical severity; and focal/multifocal cavitary white
matter injury, which has severe clinical manifestations) can be identi-
fied and distinguished by MRI. The diffuse and noncavitary lesions
have stable appearances on MRI, but cavitary white matter lesions
evolve, with the injured regions undergoing necrosis followed by liq-
uefaction and then shrinkage of the cavity with resultant focal enlarge-
ment of the adjacent ventricle (264,289). On pathology studies, the
two most common locations are the posterior periventricular white
matter adjacent to the lateral aspect of the trigone of the lateral ven-
tricles and the frontal white matter adjacent to the foramina of Monro
(5,199,200,290); however, MRI studies indicate a propensity for the
lesions to occur in the peritrigonal region and in the deep (as opposed
to periventricular or subcortical) white matter at the level of the bodies
of the lateral ventricles (280,282,283). The incidence of white matter
injury seems to increase with very low gestational age. A prospective
ultrasound study showed a 25% incidence in very premature (24 weeks)
neonates as compared with 5% in 26 to 27 week premature infants
(279). Another study showed an incidence of 9.2% among 802 infants
born between 24 and 32 weeks gestational age (278). In contrast, de
Vries et al. found no difference in the incidence of cystic white matter
injury between a group born at 32 gestational weeks or less (5%) and
a group born at 33 to 36 weeks (6%) (281). Although percentages with
white matter injury are almost certainly low, as ultrasound is known
to be insensitive to noncavitary white matter injury (280,283), it seems
clear that cystic white matter injury is most common in very prema-
turely born neonates.
Inder et al. have developed a grading system for overall white
matter abnormality in prematurely born infants. They developed a
score based upon 5 white matter parameters: (a) foci of T1 shorten-
ing in the white matter, (b) reduced white matter volume, (c) ven-
triculomegaly, (d) thinning of the corpus callosum, and (e) impaired
myelination. The white matter is evaluated and a score from 1 to 3 is
assigned for each variable, with the overall grade determined by add-
ing the individual scores (291). Using this method, they found that
motor and cognitive outcome at age 2 years are strongly associated
with the severity of white matter injury (292). Sie et al. (293) proposed
a different grading system, based only on white matter injury: Grade
1—normal; Grade 2—punctate T1 shortening; Grade 3—T1 and T2
shortening with six lesions or less; Grade 4—more than six lesions with
T1 and T2 shortening; Grade 5—extensive white matter changes with
hemorrhage and/or cavitation; and Grade 6—diffuse signal changes
in periventricular and subcortical white matter with hemorrhage and
cavitation.
Cerebellar Injury It has recently been discovered that late cerebel-
lar growth is impeded in children born prematurely, particularly those
with associated brain injuries. Normally, the cerebellar volume increases
rapidly during the last trimester of pregnancy, more rapidly than the
cerebral or mean brain volumes (294). In prematurely born neonates,
mean cerebellar volume at term equivalent age is significantly smaller
than the volume of term born infants. This cerebellar growth impair-
ment is strongly correlated with associated cerebral injury, particularly
intraventricular hemorrhage, even in the absence of direct cerebellar
injury (245,246,294,295). As signaling between the overlying leptom-
eninges and the developing cerebellum is crucial to development of
the cerebellum, it is very possible that the subarachnoid blood some-
how interferes with this signaling. Cerebellar hypoplasia may also be,
in part, due to cerebellar hemorrhage, a finding being discovered with

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
increasing frequency in prematurely born infants, particularly those
born at weights less than 750 g (261), and in part due to transsynaptic
degeneration of cerebellar tracts and neurons resulting from supraten-
torial brain injuries (263).
Imaging Findings and Clinical Correlations in Premature
Neonates
It is apparent from the above discussion that much of the brain injury
in premature infants is manifested in the deep areas of the brain. For
example, germinal matrix hemorrhage occurs mostly at the caudotha-
lamic notch and parenchymal damage in the periventricular and deep
white matter. In addition, the degree of enlargement of the ventricles
themselves has significant prognostic value. These are areas seen
well by sonography (Figs. 4-22 to 4-25). Moreover, sonography can
be performed in the neonatal intensive care unit, using the anterior
and posterolateral fontanels as sonographic windows. Maintenance
of body temperature is vital in these infants and it is difficult to pro-
vide adequate warmth and monitoring outside of the neonatal ICU
unless an MR compatible incubator is used (296). Therefore, initial
imaging evaluation of these infants by sonography is recommended
despite the known superior sensitivity and added information with
MRI (280,283,292,297).
Periventricular and Intraventricular Hemorrhage Sonograms
show germinal matrix hemorrhage as a region of increased echogenic-
ity. Images acquired in the coronal plane show a well-defined area of
increased echogenicity adjacent to the ventricular wall. The most com-
mon location is at the “caudothalamic notch,” inferior to the floor of
the posterior part of the frontal horn (Figs. 4-22 and 4-23). The sagittal
plane is often very useful in differentiating germinal matrix hemor-
rhage from the echogenic choroid plexus because the choroid plexus
does not extend anterior to the foramen of Monro, whereas the caudate
heads and the adjacent ganglionic eminence hemorrhage lie immedi-
ately anterior to the foramen. MRI shows germinal matrix hemorrhage
as round to ovoid regions that are hypointense on T2-weighted images
(Figs. 4-22 and 4-23). When subacute, they are also hyperintense on
T1-weighted images (Fig. 4-23). Both ultrasound and MRI also fre-
quently show hemorrhages of variable size in the cerebellar cortex,
likely as a result of bleeding within the transient external granular
layer, a germinal zone for the cerebellar cortex (260). Limperopoulos
et al. found such hemorrhages unilaterally in the cerebellar hemisphere
in 71%, isolated to the vermis in 20%, and involving both vermis
and hemisphere in 9% (263); they were isolated to the cerebellum in
23%, with the rest being associated with supratentorial lesions (263).
These cerebellar hemorrhages have the same appearance (Fig. 4-22)
as do supratentorial germinal matrix hemorrhages, but do not result
in hydrocephalus. When cerebellar hemorrhages are large, significant
atrophy may ensue (Fig. 4-26).
Intraventricular hemorrhage results in filling of a portion or, some-
times, all of the ventricular system with echogenic material. When
acute, the intraventricular hemorrhage is extremely echogenic (Fig.
4-24) and may be difficult to differentiate from the normally echogenic
choroid plexus. Power Doppler, which shows vascularity within the
choroid but not within clot, may be useful to make this differentia-
tion (298). Over the first few weeks after the acute event, the intraven-
tricular clot organizes and becomes well defined and less echogenic. At
this stage, it appears as a relatively sonolucent mass within the lateral
ventricle, usually in the body or the atrium. At this time, the clot is less
echogenic than the choroid plexus, which is situated adjacent to the
thalamus. Hemorrhage can also be detected by CT, on which it appears
hyperdense in the acute phase and becomes isodense at 7 to 10 days
after the bleed. Conventional spin-echo and gradient-echo or suscep-
Barkovich_Chap04.indd 271
271
tibility-weighted MR sequences are the methods of choice to look for
hemorrhage in the neonate. Neonatal intraparenchymal hematomas are
isointense to slightly hypointense on T1-weighted images and markedly
hypointense on T2- and T2*-weighted images in the acute stage (first 3
days); they are not seen well on FLAIR images. They gradually develop
increased signal intensity on T1-weighted images (while remaining low
in signal intensity on T2- and T2*-weighted images) over the next 3 to
7 days (Figs. 4-23 and 4-25) (299). Between 7 and 14 days, the hema-
toma gradually increases in signal intensity on T2-weighted images
and remains so while slowly turning isointense to CSF on T1-weighted
images over the next several months (Fig. 4-25) (299).
In the acute phase after intraventricular hemorrhage, ventricular
dilatation results from blockage of the CSF pathways by hemorrhagic
particulate matter; this acute hydrocephalus often resolves and is of
no prognostic value. When the hemorrhage is severe, however, it can
cause an obliterative arachnoiditis that usually occurs in the basilar cis-
terns. The arachnoidal adhesions block the normal flow of CSF and
necessitate permanent CSF diversion. Superimposed upon this sec-
ondary hydrocephalus is the fact that patients with posthemorrhagic
ventricular enlargement have an increased incidence of periventricular
white matter injury, pontosubicular injury, and olivocerebellar injury
(300). Tissue loss secondary to cavitary white matter injury results in
ventricular enlargement that usually appears towards the end of the
second week. As one does not want to divert CSF in a patient with ex
vacuo ventricular enlargement, it is essential to know the baby’s head size
and to look for signs of hydrocephalus (such as dilation of the anterior
recesses of the third ventricle, see Chapter 8) before making a diagnosis
of communicating hydrocephalus in these patients. Whatever the cause,
the development of this secondary ventricular enlargement implies a
poorer developmental prognosis for the premature infant (225). Such
ventricular dilatation is well demonstrated by transfontanelle sonogra-
phy or MRI (Fig. 4-24); the patient should be scanned approximately
1 week after initial documentation of the hemorrhage in order to
exclude subsequent ventricular enlargement.
Periventricular Hemorrhagic Infarctions PVHIs are ischemic
parenchymal injuries with associated hemorrhage that typically occur
in the periventricular white matter adjacent to the lateral ventricle. Size
of the infarct varies markedly depending upon the area of drainage of
the occluded vein and the amount of collateral drainage by other veins.
The location depends upon the vein that has been occluded; hemor-
rhage adjacent to the frontal horn implies occlusion of the transverse
caudate vein, adjacent to the ventricular body implies occlusion of the
terminal vein or striate vein, while hemorrhage adjacent to the trigone
implies occlusion of the lateral atrial vein (more superior injury) or the
inferior ventricular vein (more inferior injury) (301). PVHIs are seen
on sonography as globular, crescentic, or fan-shaped areas of mixed
hyper- and hypoechogenicity (Fig. 4-25A). It is difficult to determine
how much hemorrhage is present based solely on the sonogram. CT
shows large areas of periventricular hypodensity, often with high den-
sity hemorrhage within it. Acutely, MRI shows regions of hemorrhage
(dark on T2-weighted images), often surrounded by nonhemorrhagic
venous infarct (hyperintense on T2-weighted images) (252). As the
lesion evolves, the blood oxidizes to methemoglobin (Fig. 4-25B)
and is slowly resorbed, resulting in liquefaction of the infarcted areas
(Fig. 4-25C and D). Ultimately, the affected brain region liquefies. It
may then shrink, so the adjacent ventricle expands (ex vacuo) into the
affected region of the hemisphere or the cyst may remain, usually in
communication with the adjacent ventricle (Fig. 4-25E and F). Cysts
associated with PVHI are unlike the cysts in periventricular leukomal-
acia, which are typically multiple and small. Color Doppler ultra-
sound studies of these hemorrhages show that the vein draining the
5/25/2011 11:38:47 AM
 272 Pediatric Neuroimaging

FIG. 4-26. Cerebellar germinal matrix hemorrhages with volume loss. A and B. Axial T1-weighted images show residual hyperintense
hemorrhage (white arrows) at the periphery of the left cerebellar hemisphere. Note that the affected hemisphere is small. C. Different
patient. Sagittal T1-weighted image shows small cerebellar vermis with foci of T1 shortening (white arrows) and small pons (white arrow-
head). D. Coronal gradient-echo 500/35 image shows marked hypointensity (black arrows) representing substantial hemosiderin in the
periphery of the shrunken cerebellar hemispheres, secondary to extensive germinal matrix hemorrhage.

affected region into the lateral ventricle (typically the thalamostriate
vein anteriorly, the lateral atrial vein in the periatrial region, and the
inferior ventricular vein in the temporal horn [302]) is nearly always
completely occluded (302,303), adding to the accumulating evidence
that these are venous infarctions. DTI studies show increased diffusiv-
ity and delayed development of anisotropy of white matter, in addi-
tion to delayed loss of anisotropy in cortex within affected regions of
the brain (304).
White Matter Injury of Prematurity When the cerebral white mat-
ter is investigated by cranial ultrasound, high frequency transducers
(up to 10 MHz) should be used for optimum evaluation, and multiple
sequential exams should be obtained, as abnormalities may be tran-
sient (305). White matter injury of prematurity should be suspected
on ultrasound studies when increased echogenicity is present in the
periventricular regions (306); however, edema also causes increased
echogenicity and edema can resolve without any subsequent brain
damage (307). In addition, increased echogenicity can be seen in
this region in the absence of injury or edema (308), probably due to
specular reflections from the normal bundles of axons. Moreover, nor-
mal scans have been reported in infants subsequently proven to have
white matter injury at autopsy (309,310). Therefore, the appearance of
hyperechogenicity in itself is not enough to make a diagnosis of white
matter injury. The best early sonographic sign of periventricular white
matter injury is the periventricular “flare,” an area that shows loss of
the normal regularly spaced parenchymal echoes (the normal tissue

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 273

architecture); instead, the damaged tissue has an indistinct, “globular”
appearance (Fig. 4-27A). In addition to the loss of normal tissue archi-
tecture, heterogeneity of the hyperechogenic white matter should be
sought, as heterogeneity (likely representing tissue hemorrhage or
breakdown) correlates best with poor neurodevelopmental outcome at
2 years (305); the more severely damaged tissue has echogenicity equal
to or greater than that of the choroid plexus. If prolonged (>2 weeks)
periventricular flares are seen, the incidence of spastic diplegia or tet-
raplegia is 50% (311). However, flares have a low sensitivity and posi-
tive predictive value for the presence of white matter injury (280) and
for long-term outcome (312,313). Definitive diagnosis of white matter
injury by sonography requires demonstration of heterogeneity (called
heterogeneous flares [293] and caused by necrosis or hemorrhage)
and the subsequent formation of parenchymal cavities (sometimes
called echolucencies or hypoechoic lesions) from liquefaction of the
injured white matter (Fig. 4-27) (306,314–317). The timing of cavita-
tion varies, depending on the extent and severity of the injury, but it
typically appears on ultrasound 2 to 4 weeks (usually <3 weeks) after
injury (281,317,318). The size of cavities varies over time, as the injured
tissue undergoes necrosis (cavitation starts), the cavities coalesce (this
causes enlargement), and then shrinkage/astrogliosis ensues (causing
contraction).
White matter injury can be graded by the characteristics of the
periventricular white matter on sonography (319). Grade I is defined
as periventricular and deep white matter areas of increased echogenic-
ity present for 7 days or more (prolonged periventricular flare). Grade
II has areas of increased echogenicity that evolve into small, localized
frontoparietal cysts (Fig. 4-27C). In Grade III, periventricular areas

FIG. 4-27. Evolution of cystic white matter injury of prematurity (cystic PVL). A
and B. Coronal (A) and parasagittal (B) transfontanelle sonograms at 1 week of age
show periventricular “flares” (white arrows), regions of increased echogenicity with
loss of normal echogenic texture of the white matter near the trigones of the lateral
ventricles. The echoes are less evenly spaces and in some areas some of the echoes
seem to coalesce. C. Coronal transfontanelle sonogram at age 18 days shows areas of
reduced echogenicity (white arrows), representing cavitation and areas of increased
echogenicity (white arrowhead), representing necrosis (probably hemorrhagic) as the
damaged white matter evolves.

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 274 Pediatric Neuroimaging

FIG. 4-27. (Continued) D. Coronal transfontanelle sonogram at age 25 days shows increasing bilateral cavitation (white arrows) of
the damaged white matter. E and F. Coronal (E) and sagittal (F) T1-weighted MR images obtained a few days after (E) shows the
cavitary white matter lesions (white arrows) in the periventricular and deep white matter. Some noncavitary white matter lesions
(white arrowheads in E) can also be identified. G. Axial T2-weighted MR image shows abnormal white matter hyperintensity that
are nearly isointense to the regions of cavitation (black arrowheads), making the cavities difficult to identify. H–J. Sagittal T1 (H),
parasagittal T1 (I), and coronal FLAIR (J) images obtained at age 6 months show changes of chronic white matter injury. At this
point, the cavities have shrunk into small glial scars and the volume of white matter has been markedly reduced. The corpus callo-
sum (white arrows in H) is extremely thin. Cortical sulci reach (black arrows in J) and indent (arrowheads in I) the lateral ventricles
due to loss of white matter. Ventricles have enlarged (ex vacuo) due to the loss of white matter.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 275

FIG. 4-27. (Continued)

of increased echogenicity evolve into extensive periventricular cystic
lesions involving occipital and frontoparietal white matter (Fig. 4-27D).
Dammann has suggested that Grade I white matter injury can be fur-
ther divided into “brief flares” that resolve within 6 days, “intermedi-
ate flares” that last for 6 to 13 days before resolution, and “prolonged
flares” that resolve after 14 days (320). Sie et al. (293) have suggested
that “heterogeneous flares” (Fig. 4-27A and B) have a worse prognosis
and that they should be classified as Grade 1b (with Grade 1a being
applied to homogeneous flares). In general, the long-term outcome
of affected patients is more dependent on the location and extent of
injury than on the sonographic grade.
Of note, white matter cavitation is much less common than
noncavitary white matter injury and seems to be becoming progres-
sively less common (280,283,292). Noncavitary white matter injury is
detected by MRI in about 50% of premature neonates as small foci that
are hyperintense on T1-weighted images and mildly hypointense on
T2-weighted images (280,282,283). At most institutions, CT and MRI
do not currently play a major role in the early diagnosis of white matter
injury of prematurity because of the difficulty involved in transport-
ing and caring for sick premature neonates. However, the institutions
that use MRI have found many signal abnormalities in the white mat-
ter early in the course of the injury. No sonographic abnormalities are
seen that consistently correspond to these MR findings in the majority
of reports (280,283,321); although Leijser et al. have reported hetero-
geneous hyperechogenicity in affected regions (305), they found MRI
to be much more reliable than ultrasound in the detection of mildly
and moderately abnormal (i.e., noncavitated) white matter (322). In
our experience, punctate areas of T1 hyperintensity are seen as early
as 3 to 4 days after birth (Fig. 4-28); mild T2 hypointensity can usu-
ally be seen, as well, in the larger lesions. Reduced diffusivity is seen

FIG. 4-28. Noncavitary white matter injury of prematurity. A. Axial T1-weighted image shows multiple foci of T1
hyperintensity (black arrows) in the deep white matter of both cerebral hemispheres. The lesions, which typically appear
during the first week to 10 days, are of uniform intensity, with no regions of hypointensity to suggest cavitation. B. Axial
DWI shows hyperintensity (black arrows), indicating reduced diffusivity (acute injury) in the two largest lesions.

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 276 Pediatric Neuroimaging

if imaging is performed in the first week (Fig. 4-28). The T1 and T2
abnormalities may represent reactive astrogliosis (323), possibly due
to microglial activation (324). They typically remain visible in the
white matter for several weeks to months after injury (321), although
some disappear after a few weeks (282,283). They should be differ-
entiated from hemorrhage, which has much shorter T2 relaxation
time and, therefore, much lower signal intensity on T2-weighted and
susceptibility-weighted images (see, e.g., Fig. 4-19B). When extensive
(involving more than one lobe), these white matter lesions are asso-
ciated with reduced FA, higher radial diffusivity, and higher average
diffusivity (Dav) in much of the cerebral white matter (325). FA may
be reduced at term equivalent age, even in the absence of white matter
hyperintensities at that time (326) (although it is not known whether
the foci of T1 hyperintensity disappeared or never developed); reduced
FA at term equivalent age is associated with impaired neurodevelop-
mental outcome at age 2 years (326).
Larger areas of white matter hyperintensity may undergo necro-
sis, resulting in the development of T1 hypointensity either within or
adjacent to the areas of T1 hyperintensity, and sometimes T2 hyperin-
tensity within the areas of T2 hypointensity (Fig. 4-29). If the area of
damage is large, small cavities may coalesce into larger ones, resulting in
the presence of frank cavities within the white matter (Fig. 4-27E–G).
The process of cavitation decreases the area of T1 hyperintensity. This
process, combined with evolution of the reactive astrogliosis and sub-
sequent increasing T1 hyperintensity caused by myelination, causes
these lesions to disappear on MRI over the 3 to 4 months after injury.
As the cavities shrink over the subsequent 3 to 4 weeks, the cerebral
hemispheres show diminished volume of white matter (Fig. 4-27H–J),
characteristic of what has been called “end stage periventricular
leukomalacia” (199).
Sie et al. have looked at the MR evolution of white matter lesions
on sequential MR studies of premature neonates (327). They report
that the small white matter T1 hyperintensities become small areas of
gliosis (hyperintense on T2-weighted spin-echo and FLAIR images)
with the same size and location on follow-up studies performed after
the white matter myelinates. As mentioned earlier, regions of cavitation
tend to shrink into small foci of gliosis. Therefore, when cavitation of
the white matter in the premature neonate is mild, mild ex vacuo ven-
tricular dilatation will develop along with focal gliosis and focal thin-
ning of the corpus callosum; this constitutes end stage white matter
injury. Extensive white matter injury often cavitates; the MR appear-
ance evolves into diffuse white matter gliosis with diffuse callosal
thinning and moderately to markedly dilated lateral ventricles. The
white matter changes vary in severity; extensive lesions throughout the
white matter (periventricular, deep, and subcortical) result in almost
total white matter loss with severe ventricular dilatation, irregular
ventricular margins, and diffuse callosal thinning and shortening; a
shorter corpus callosum is associated with poorer neurodevelopmental
outcome (328).
Correlations have been shown between the severity of white matter
injury and clinical outcome at ages 18 (327) and 24 months (231,292).
Of interest, clinical outcome correlated more with the extent and loca-
tion of injury than the type (cystic, noncystic, hemorrhagic) of injury
(231,305,327). Neonates with a few scattered white matter lesions were
normal at 18 months but, as the authors point out, further follow-up
is necessary to determine whether these patients might develop mild
neurodevelopmental deficits later in childhood (327).
The Hammersmith group has described the presence of diffuse
high signal intensity, without focal injuries, in the white matter of
prematurely born neonates at term equivalent age, which they call
DEHSIs (diffuse excessive high signal intensities, Fig. 4-30) (329).
They believe that this represents a diffuse white matter injury, as
described in the pathology literature (147), and they have shown
that it is associated with increased white matter diffusivity and worse
outcomes (284). Others, however, have described T2 hyperintense
“caps” in the deep white matter anterior to the frontal horns and T2
hyperintense “arrows” in the deep parietal white matter posterior to
the trigones in prematurely born neonates (330) and in fetuses of
equivalent gestational ages (331,332). The precise anatomic substrate
of these regions has not been definitively determined and, indeed,

FIG. 4-29. Mild cavitation of white matter injury demonstrated by MR. A. Axial T1-weighted image shows several foci of T1 shortening (open white
arrows) in the cerebral white matter. Two of the posterior foci have some hypointensity within them, suggesting cavitation/necrosis. A small subependymal
hemorrhage (solid black arrow) is seen in (A) and (B). B. Axial T2-weighted image shows abnormal hyperintensity in the periventricular and deep white
matter. Very faint T2 hypointensity (open black arrows) is seen within the hyperintense white matter around the ventricular trigones. C. Axial T1-weighted
image shows multiple foci of T1 hyperintensity in the deep cerebral white matter. Two of these foci (white arrows) show central hypointensity, indicative of
cavitation/necrosis.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
FIG. 4-30. DEHSI of white matter. A and B. Axial T2-weighted images at two levels show white matter intensity that is
almost the same as the CSF in the lateral ventricles (the subcortical white matter is somewhat spared).
the underlying substrate may differ at different gestational ages
(330–333). Whatever the underlying substrate, all agree that the T2
hyperintensity of white matter is abnormal in some prematures and
the use of diffusion imaging should be used for this differentiation.
As the diffusivity of normal white matter changes both temporally
(different diffusivity at different gestational ages in the same loca-
tion) and topologically (different diffusivity in different regions of
the developing brain at the same gestational age), comparison with
normal values for a neonate of equivalent postconceptional age (334)
should be performed.
The value of diffusion imaging and proton spectroscopy has not
been fully established in the evaluation of the premature brain, but some
results are promising. Diffusion imaging shows reduced diffusion in the
periventricular white matter in the first few days after injury (Fig. 4-31),
before ultrasound or conventional MR sequences show any abnormal-
ity (335), but the diffusivity changes normalize quickly (usually within
6 days) (117,119). An important point is that it is crucial to look at cal-
culated Dav values in all scans of neonates, as the DWIs may be falsely
negative due to the very long T2 values of the neonatal brain (remember
that DWIs have contribution from both diffusion and T2). In the pre-
mature neonate without brain injury, Dav decreases by 0.021 mm3/s/wk
(336); therefore, sequential studies can detect abnormal white matter
development even if imaging is not obtained immediately after injury.
FA, determined by DTI, is also useful to evaluate white matter injury,
but requires sequential imaging. It was found that preterm neonates
without white matter injury show progressively increased FA (by 0.008
per week) of the white matter on sequential scans, but those with white
matter injury have stable or decreased anisotropy (297) (also unpub-
lished results, Dr. Sonia Bonifacio). The relationship of these early
changes in anisotropy to long-term outcome has not been completely
established; however, the presence of reduced FA later in infancy (at
term equivalent age) seems to be associated with impaired neurodevel-
opment (326,337), suggesting that the earlier microstructural changes
Barkovich_Chap04.indd 277
277
may be a harbinger of impaired development, as well. Reduced FA in the
corticospinal tracts prior to term equivalent age correlates with motor
outcome (338); reduced FA in the optic radiations prior to (232,233)
and at term equivalent age (339) correlates with impaired visual func-
tion. Spectroscopy may also prove useful in early evaluation of white
matter injury, as the lactate peak enlarges and NAA peak diminishes in
affected areas before standard imaging sequences become abnormal.
MRI and CT are both useful for the diagnosis of end stage white
matter injury (“end stage periventricular leukomalacia”) in later infancy
and childhood after the fontanels have closed. CT and MRI are also
useful in making a diagnosis in mild cases of white matter injury where
nonspecific ventriculomegaly is the only detectable abnormality on
sonography. The CT findings of end stage white matter injury are (a)
irregular outline of the body and trigone of the lateral ventricles; (b)
reduced quantity of white matter, always at the trigones but in severe
cases involving the whole centrum ovale; and (c) deep, prominent sulci
that abut or nearly abut the ventricles with little or no interposed white
matter (199). MR scans show these same abnormalities (Fig. 4-27 H–J).
In addition, MRI shows abnormally increased signal intensity in the
periventricular white matter on FLAIR and T2-weighted images, most
commonly observed in the peritrigonal regions bilaterally (Fig. 4-27J)
(18,200,340), and delayed myelination (341,342). In general, lower
birth age correlates with more severe myelin deficit (343). The midline,
sagittal MR image will show thinning of the corpus callosum, most
commonly the posterior body and splenium, resulting from degenera-
tion of transcallosal axons (Fig. 4-27H) (18,344,345). MR volumetry
has shown that the white matter volume is reduced (346) and ventri-
cles enlarged (347) in end-stage white matter injury. DTI studies have
shown increased water motion (348), smaller size of the retrolenticular
internal capsule and the posterior thalamic radiations (349,350), and
reduced anisotropy in the corticospinal tracts (348,351). These findings
also seem to be useful for predicting the severity of neurodevelopmen-
tal deficits in affected patients (232,326,339,352). These sophisticated
5/25/2011 11:38:51 AM
 278 Pediatric Neuroimaging
techniques are not necessary, however, to make the diagnosis of end
stage white matter injury.
The signal abnormalities of end-stage white matter injury (end
stage periventricular leukomalacia) have a superficial resemblance to
the normal areas of slow myelination dorsal and superior to the trigo-
nes (see Chapter 2 and Fig. 4-32). The normal regions of unmyelinated
white matter, however, are separated from the ventricular wall by a
thin band of myelinated white matter in the splenium of the corpus
callosum and tapetum, whereas the abnormal signal attributable to
injured white matter directly abuts the ventricular wall. The differen-
tiation is best seen on coronal, T2-weighted sequences; axial views may
not depict this finding (340). Moreover, loss of volume of the cerebral
white matter is not present on normal scans (353) and the ventricular
contour in normal patients is smooth, not irregular.
Barkovich_Chap04.indd 278
FIG. 4-31. Acute white matter injury in a 4-day-old 28-week
gestational age premature infant. A. Axial T1-weighted image
shows slight hyperintensity (arrows) of the deep white matter.
B. Axial T2-weighted image is essentially normal. C. Axial Dav
map shows reduced diffusion (arrows) in the deep white matter,
compatible with acute injury. (These figures courtesy Dr. Joel
Cure.)
One final comment should be made regarding abnormal periven-
tricular signal in infants and children. A finding of periventricular
hyperintensity and volume loss on FLAIR or T2-weighted images is not
specific for white matter injury of prematurity. In fact, periventricular
tissue damage can be caused by many different disorders, such as
ventriculitis (a common sequel of meningitis in infants, see Chapter
11), inborn errors of metabolism (see Chapter 3), hydrocephalus (see
Chapter 8), and in utero events (354,355). The diagnosis is best made
in conjunction with a thorough past medical history.
Cerebellar Injury in Premature Neonates Studies have shown
that a small but significant number of premature neonates (in the
range of 8%–20%) suffer either focal or diffuse cerebellar injury
(247,262,295,356–358). Focal cerebellar injury is usually due to
5/25/2011 11:38:52 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
FIG. 4-32. Normal immature periventricular white matter. SE 2500/70 (A) and FLAIR (B) images show T2 prolongation in the
periventricular white matter (large arrows) is not accompanied by any loss of white matter volume. A stripe of normally myelinated
white matter (small arrows in B) is present in the immediate periventricular region.
cerebellar hemorrhage. When ultrasound is performed through the
posterior or the mastoid fontanelle (which improves visualization
of the cerebellum), evidence of cerebellar hemorrhages is found in
up to 9% of premature neonates (260,262,358); detection sensitivity
seems to be increased by use of the mastoid fontanelle (262). Only
half of these hemorrhages are associated with supratentorial hemor-
rhage (Fig. 4-22) and nearly all of the smaller ones are clinically silent
(260). MRI shows a higher incidence of hemorrhage (∼20%), seen as
marked T2 shortening in the periphery of the cerebellum, often mul-
tifocal (Fig. 4-22C) (262). In those patients with moderate to large
hemorrhages in whom subsequent MR scans were obtained, focal or
diffuse (Figs. 4-26 and 4-33) cerebellar atrophy is found (260). There-
fore, it is likely that small cerebellar bleeds, probably originating in the
germinal matrix (external granular layer), are the cause of focal cer-
ebellar injury in a substantial number of premature neonates. Diffuse
cerebellar volume loss is found in a group of prematurely born infants
at term equivalent age or later, usually in those of extremely low birth
weights. The mechanism of volume loss is unknown (295,356,357),
although Volpe suggests that it is a form a selective neuronal necrosis
(147). Other possibilities include diaschisis due to cerebral white mat-
ter injury or interference with trophic influences from surrounding
posterior fossa leptomeninges (245,246,359).
Profound Hypotension or Circulatory Arrest in Premature
Infants A different pattern of brain injury is seen in premature infants
who have suffered profound hypotension or cardiocirculatory arrest;
outcome in these patients is typically very poor (360). In these infants,
injury is predominantly in the deep gray matter nuclei and brainstem
nuclei (those areas that are most mature and have highest metabolic
rates in the premature and term neonate, Fig. 4-18), although white
matter injury and germinal matrix hemorrhage may develop as well
(5,16,177,361). More specifically, the dorsal brain stem, anterior cer-
ebellar vermis, and thalami are the regions most commonly injured,
but the lentiform nuclei (globus pallidus and putamen, particularly
posterior putamen) and the precentral and postcentral gyri are
Barkovich_Chap04.indd 279
279
frequently involved (16). The remainder of the cerebral cortex is usu-
ally spared. The postulated reasons for this pattern were discussed in
an earlier section. Ultrasound acquired in the first day or two may be
normal; however, by the second or third day, hyperechogenicity may
be detected in the basal ganglia and thalami (Fig. 4-34). CT shows
hypodensity of the thalami and basal ganglia (often isodense to white
matter instead of gray matter, Fig. 4-34). MR images acquired in the
first 2 days after injury will show reduced diffusion of dorsal mid-
brain and thalami (Fig. 4-35A and B), and the thalami will typically
be hyperintense on the T2-weighted sequence. As in term infants (see
next section), premature infants who suffer prolonged (>20 minutes)
profound hypotension may suffer injury to the entire brain; in this
situation, diffusivity is diffusely reduced, and the diffusion images
may appear qualitatively normal. Therefore, in the setting of suspected
brain injury, Dav values should be calculated and compared to age-
matched norms. By the second or third day after injury, T1-weighted
images will show faint, diffuse hyperintensity (Fig. 4-35C) in the
injured regions. T2 hypointensity does not develop until the end of the
first week (5–6 days, Fig. 4-35D). By the middle of the second week,
the T1 hyperintensity becomes more globular in appearance and more
localized within the dorsal brainstem (if affected), ventrolateral thal-
ami and posterior putamina (Figs. 4-35 and 4-36). In patients who
are injured prior to about 28 weeks postconceptional ages, damage
to the basal ganglia seems to result in liquefaction; follow-up scans
show cavities in the location of the lentiform nuclei (Fig. 4-37) (16).
Imaging 1 to 3 weeks after injury may show white matter abnormal-
ity, typically mild, diffuse T2 hyperintensity associated with small foci
of T1 hyperintensity scattered throughout the centrum semiovale.
Imaging studies obtained in the chronic phase, after injured tissue has
undergone liquefaction and astrogliosis, will reveal small, shrunken,
often calcified thalami (Figs. 4-35F, G and 4-37), small brainstem and
cerebellum, small or absent basal ganglia, and reduced cerebral white
matter volume (16). The reduction of cerebral white matter is pre-
sumably the result of loss of the thalamocortical, corticothalamic, and
corticoputaminal axons.
5/25/2011 11:38:53 AM
 280 Pediatric Neuroimaging

FIG. 4-33. Large cerebellar hemorrhage in premature neonate. A. Coronal reformation of SPGR image shows large hem-
orrhage (white arrows) involving nearly the entire right cerebellar hemisphere, the vermis, and extending into the medial
aspect of the left cerebellar hemisphere. B. Axial T2-weighted image shows the subacute hematoma with black hemosiderin
rim (white arrows) and necrotic, hyperintense center. The right cerebellar hemisphere will be extremely small.

FIG. 4-34. Ultrasound and CT of profound hypoten-

sive injury in a 28-week premature infant. A and B.
Sagittal (A) and coronal (B) sonograms at age 4 days
show marked hyperechogenicity (open arrows) in the
thalami and basal ganglia. C and D. Axial noncontrast
CT images at age 5 days show absence of normal gray
matter attenuation in the basal ganglia. Note that some
germinal matrix hemorrhage is present in the walls of
the right lateral ventricle.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 281

FIG. 4-35. MRI of profound hypotensive injury in a 2-day-old, 28 weeks gestational age infant. A–E are from age 5 days. F and G
are from age 3.5 weeks. A and B. Dav maps show reduced diffusivity (hypointensity) in dorsal pons (black arrows in A), ventrolateral
thalami (black arrows in B) and optic radiations (black arrowheads in B). C. Axial reformation of 3D SPGR sequence shows abnormal
hyperintensity in the ventrolateral thalami (black arrows) and posterolateral putamina (black arrowheads). D. Axial T2-weighted
image shows the ventrolateral thalamic nuclei to have very abnormal, sharply-defined hypointensity (black arrows). The putamina
(black arrowheads) and caudate heads are abnormally hyperintense (compare to other gray matter).

Barkovich_Chap04.indd 281 5/25/2011 11:38:54 AM

 282 Pediatric Neuroimaging

FIG. 4-35. (Continued) E. Proton MR spectrum (288 millisec-

onds) from basal ganglia shows abnormally low NAA at 2.0 ppm,
slightly elevated lactate (Lac) at 1.33 ppm, and the presence of
propan-1,2-diol (arrowhead) at 1.1 ppm. Propan-1,2-diol is a
base used in Phenobarbital (used for treatment of seizures, see
Chapter 2). F. Axial reformation of 3D SPGR sequence acquired
at age 3.5 weeks shows the thalami (white arrows) are shrunken
and hyperintense, probably representing gliosis and calcifica-
tion. G. Axial T2-weighted image acquired at the same time as
(F) also shows small, calcified thalami (black arrows). Note areas
of abnormal hyperintensity in posterior putamina (black arrow-
heads).

An important concept is that both hypoxia/ischemia and anoxia/
arrest can occur in utero (Table 4-5 and Fig. 4-38A). The pattern of
brain damage seen in infants who have suffered in utero injury is, by
imaging criteria, identical to that seen in postnatal infants of the same
gestational age (Fig. 4-38B and C) (16,18).
Imaging Choices in Premature Neonates
Premature infants are often hemodynamically unstable and, therefore,
transporting them is somewhat risky. Transfontanelle ultrasound can
be performed in the neonatal intensive care unit without moving the
neonate and is, therefore, the initial imaging study of choice in all pre-
mature neonates with definite or suspected neurologic impairment.
Techniques such as color Doppler, quantitative sonographic feature
analysis (362), examination through posterolateral fontanelles (260),
and use of high frequency transducers (363) may ultimately result in
improved detection of parenchymal injury by ultrasound and make
utilization of other techniques unnecessary. At present, however,
sonography is not very sensitive to the detection of nonhemorrhagic,
noncavitary parenchymal injury (280,283,364) or to brainstem or cer-
ebellar injury. Therefore, if the neurologic status of a child is worse
than can be explained by ultrasound findings, another imaging study is
usually necessary. In our experience, CT is not significantly more sensi-
tive than ultrasound for the detection of nonhemorrhagic brain injury
in premature neonates. The low contrast sensitivity of CT and the high
water content of the premature brain make white matter injury (the
most common brain injury in premature neonates) very difficult to
identify. Moreover, it is best to avoid the use of ionizing radiation in
children and in neonates in particular. Therefore, we generally use MRI

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
as the neuroimaging study of choice after ultrasound. Standard MRI
has much higher contrast resolution and can detect brain injury (man-
ifest as T1 shortening of affected brain parenchyma) within 2 to 3 days
of injury. Proton spectroscopy shows metabolic disturbances within
hours of injury (365). Diffusion imaging may miss injuries if performed
in the first few hours after injury and will underestimate the extent of
injury if performed within the first 24 hours (117,119,365,366), but
is highly sensitive from 2 to 5 days after injury (117,119). In addition,
DTI can be used to assess the size and integrity of white matter path-
ways (232,338,339,367,368). Moreover, MRI can be performed safely
if chemical blankets or MR compatible incubators (now commer-
cially available) are used to keep the neonate warm and nonmagnetic
or properly shielded life support and monitoring equipment is used
(see Chapter 1).
Injury in the Term Neonate
Neonatal encephalopathy in term infants is an important patient care
issue and carries medical/legal implications, as well. Although some
degree of hypoxia or ischemia is fairly common during the birth
Barkovich_Chap04.indd 283
283
FIG. 4-36. Profound hypotensive injury in a
32-week neonate. Imaging performed at age
20 days. A. Axial T1-weighted image shows T1
shortening (arrows) in the dorsal pons. B and
C. Axial T1- and T2-weighted images show T1
> T2 shortening in the midbrain and amygdalae
(arrows). D and E. Axial T1- and T2-weighted
images show T1 shortening and T2 prolonga-
tion in the lateral thalami, globi pallidi, and lat-
eral putamina.
process, the incidence of moderate to severe neonatal encephalopathy
seems to be falling, with recent estimates of 1 to 3 per 1000 live term
births (369–372). Approximately 0.3 per thousand live term births
(15%–20% of those with encephalopathy) have significant neurologi-
cal residual (225). Patients may manifest spastic or dyskinetic motor
impairment (it is estimated that 8% to 15% of cerebral palsy is caused
by perinatal hypoxic-ischemic injury [287,373,374]), delayed develop-
ment (225,375), cognitive impairment (225,376,377), or visual impair-
ment (378); not surprisingly, the clinical outcome seems to be related
to the pattern, as well as the severity, of injury (176,225,375,377,379). It
is, therefore, important to understand both the pathophysiology of the
brain damage in these situations and the pathological sequelae. More-
over, a considerable amount of work is being done to find therapies
for asphyxiated neonates (380–382). Therefore, early identification of
those children who have suffered brain injury may soon become vital.
Cortical/Subcortical Injury
As discussed in the previous section, the regions of the brain most
susceptible to ischemic damage change as the infant matures. In term
5/25/2011 11:38:56 AM
 284 Pediatric Neuroimaging

FIG. 4-37. Profound in utero hypotensive injury at 28 weeks of gestational age. A and B. Axial CT images 3 weeks after injury show cavitation
(solid arrows) of the thalami with surrounding blood or calcium. The basal ganglia (open arrows) are markedly hypointense. C. Different patient, imaged
approximately 3 weeks after injury. Axial T1-weighted image shows cavitation (arrows) of the basal ganglia.

infants, mild to moderate hypotension results in injury to the cerebral reactive astroglial cells that form scar tissue, although far less scar tissue
white matter and cortex, particularly in the intervascular boundary is formed in the neonate than in the mature brain (2,3,383). Patients
zones (also called “parasagittal zones” or “watershed areas,” Fig. 4-20), with parasagittal injuries tend to present with seizures and/or hypoten-
which lie in the regions between the regions perfused by the anterior sion. Eventually, the neurological exam evolves to proximal extremity
and middle cerebral arteries, and those between the middle and pos- weakness and spasticity (225). Cognitive outcome is variable but seems
terior cerebral arteries, but more extensive injury may occur. Another worse when the frontal watershed zones are involved (375,384); our
change that has occurred in the infant brain since the sixth and seventh data indicate that this cognitive impairment becomes more apparent
month of gestation is the onset of glial response to injury. The brain as the child matures (375,377,385). Disproportionate disturbances in
of the second trimester fetus responds to trauma by liquefaction and development of language or visual-spatial abilities may also be noted
resorption of the damaged tissue without accompanying astrogliosis; (225,376).
the more mature brain of the term infant responds by production of Pathologically, most prolonged mild to moderate hypotensive
events in term infants result in discrete, sometimes multicystic, infarc-
tions in the intervascular boundary zones.
Detection of watershed ischemic injury is difficult by ultra-
TABLE 4-5 Some Causes of Fetal Brain sonography (114) because the affected areas of the brain lie close to
the inner table of the skull near to the midline and angling the trans-
Injury ducer to visualize these regions can be difficult. Using state-of-the-
art techniques with high frequency transducers, the affected areas
Maternal origin
can be seen and will show increased echogenicity of the parasagittal
Maternal shock
white matter, reflecting edema in the subcortical watershed regions
Maternal hypoxia
(Fig. 4-39A) (363). In severe cases, the cortex will also become edem-
Maternal thrombophlebitis
atous; the resulting increase in cortical echogenicity results in blur-
Maternal abdominal trauma
ring of the cortical-white matter junction and effacement of sulci
Maternal hypo/hypertension
with consequent inability to see the extremely echogenic leptom-
Feto-maternal transfusion
eninges. Detection by CT in the acute phase is also difficult because
Fetal origin the frontal and parietooccipital white matter is normally of low
Fetal infection (arteritis, hypotension) attenuation in the newborn (see Chapter 2) and the cortex may be
Fetal arteriopathy (COL4A1 mutations) partially obscured by beam hardening artifacts from the overlying
Hydrops fetalis calvarium (Fig. 4-39B). Beam hardening is less severe with modern
Fetal embolism (placenta, other) CT scanners but the price one pays for good visualization of the
Feto-fetal transfusion cortex is the use of fairly high (radiation) dose techniques. Finally,
even if the parasagittal cortex is edematous, it is not clear that edema
Placental origin augurs permanent damage (307). Evaluation with MRI is, therefore,
Premature placental separation optimal.
Excessive placental infarction If it is possible to obtain MRI during the first 24 to 48 hours of
life, diffusion-weighted imaging and proton spectroscopy are the

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 285

FIG. 4-38. MRI of prenatal profound hypoxic-ischemic injury. A.

Axial SSFSE image of 27-week fetus whose mother had suffered an
arrest at 25 weeks gestational age. Thalami are small and abnormal
hypointensity is seen in the lateral thalami (white arrows). Postero-
lateral right putamen is abnormally hyperintense (white arrowhead).
B. Sagittal T1-weighted image 2 days after elective cesarean section
shows abnormal hyperintensity (white arrows) in the dorsal brain-
stem, indicating injury with gliosis and probable calcification in that
region as a result of the prenatal injury. C. Axial T1-weighted image
shows small thalami and abnormal hyperintensity in the ventrolateral
thalami (white arrows) and posterior putamen (small white arrow-
head). The lateral thalamus is abnormally hypointense (large arrow-
head), indicating injury to that structure, as well.

most sensitive MR techniques for the identification of brain injury;
diffusion-weighted imaging is better for determining the pattern of
injury. In mild-moderate hypotensive injury, diffusion imaging shows
extensive involvement of the cortex and underlying white matter in
the intervascular boundary zones (watershed zones, Fig. 4-39D and E),
but sometimes the area of reduced diffusivity is confined to subcor-
tical white matter and the cortex appears normal, while other times
the entirety of the cerebral cortex is involved, well beyond the inter-
vascular boundary zones (Fig. 4-40); the basal ganglia and posterior
fossa structures are relatively spared (Fig. 4-40). Sometimes (usually in
patients who are born before 40 gestational weeks), the white matter
injury is isolated (174,176), but it is usually associated with cortical
injury. The reason for the variability in topology of injury is not fully
understood but likely is related to the severity and the duration of the
hypotension, and possibly accompanying metabolic factors such as
hypoglycemia (which is known to exacerbate hypoxic-ischemic injury
[386]). Diffusion-weighted imaging can give false-negative results if
performed in the first few hours after injury (prior to secondary energy
failure [117,163,164,365,366,387]) and will underestimate the extent of
injury if performed in the first 24 hours (119,365). Increased sensitivity
is gained by assessing calculated Dav images or the Dav values themselves
(119,388), rather than the DWIs, to compensate for the very long T2

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 286 Pediatric Neuroimaging

FIG. 4-39. Watershed injury in a term neonate at age 2 days. A. Transfontanelle sonogram
using high frequency transducer shows increased white matter echogenicity and blurring
(arrows) of the junction between cortex and white matter. B. Axial noncontrast CT scan
shows subtle cortical and subcortical hypodensity (white arrows) in the intervascular bound-
ary zones (watershed zones). C. Axial T2-weighted image shows hyperintensity of the cortex
(white arrows) in the intervascular boundary zones. The hyperintense cortex becomes nearly
isointense to underlying white matter. D and E. Axial ADC images (b = 700 s/mm2) shows
reduced diffusion (low signal intensity, white arrows) in the intervascular boundary zones;
note that both cortex and subcortical white matter are affected.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 287

FIG. 4-39. (Continued) F. Proton MR spectrum (TE = 288 milliseconds) in the basal ganglia is essentially normal. G. Proton MR spectrum (TE =
288 milliseconds) in the frontal intervascular boundary zone shows the presence of lactate (Lac) at 1.33 ppm, indicating cellular injury and anaerobic
metabolism. Notice the doublet (two peaks) at 1.1 ppm from 1,2-propanediol.

values of the neonatal brain (remember that signal intensity on DWIs
is determined by both T2 and diffusivity factors). In the acute phase,
proton MRS shows elevation of lactate and, in severe cases, reduction
of NAA (119,365,389,390) in the cerebral cortex (most notably in the
watershed zones) and subcortical white matter, more so than in the
deep gray matter (Fig. 4-39F and G). Between 24 hours and 8 days,
diffusion imaging, the pattern of injury seen on the Dav maps evolves,
with diffusivity normalizing in some regions and becoming abnormal
in others (119). The reason for this is not certain, but it is likely either
Wallerian degeneration along white matter tracts or spreading excito-
toxic injury. Proton MRS remains abnormal, with lactate levels peak-
ing at 3 to 5 days after injury, then slowly declining, while NAA levels
start to decline about 3 days after injury (119). On T2-weighted images,
affected cortex will be hyperintense compared with adjacent normal
cortex beginning within 24 hours of injury (Figs. 4-39C and 4-40C).
The first echo (60 ms) of the T2-weighted images is often more sensi-
tive to edema than the second echo (120 ms) in the first 2 days after
injury (391). On T1-weighted images, edematous brain will appear as
areas of low signal intensity in the cortex and subjacent white matter
when compared with normal white matter (392,393); the most obvious
finding, when present, is loss of gray matter-white matter distinction
(Fig. 4-40B), but this is mainly seen in very severe injury. The multi-
planar imaging capacity of MR also aids detection of ischemic brain
damage; the coronal and sagittal planes are best for assessing high con-
vexity regions, while the anterior and posterior poles of the cerebrum
are better assessed in the axial and sagittal planes.

FIG. 4-40. Severe cortical-subcortical injury in 4-day-old neonate. A. Coronal transfontanelle sonogram shows diffuse hyper-
echogenicity of the white matter with blurring of the cortical-white matter junction. Note that the deep structures (thalami [T]
and basal ganglia [B]) are relatively spared. B. Coronal T1-weighted SPGR image shows low intensity of the cerebral white matter
with marked blurring of the cortical-white matter junction, compatible with diffuse edema and cortical injury.

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 288 Pediatric Neuroimaging
As the injury evolves, spectroscopy and diffusion images undergo
pseudonormalization (from about 6–10 days) and then begin to show
evidence of more chronic brain injury, with increased diffusivity on Dav
maps and decreased NAA on proton MRS (117,119,388). On anatomic
images, cortical thinning and cystic degeneration of the underlying
white matter is seen in the parasagittal vascular boundary zones. After
3 to 4 weeks, the cavitary areas shrink into glial scars (Fig. 4-41). Ex
vacuo dilatation of the adjacent lateral ventricles can be seen, particu-
larly in the trigones and occipital horns. The parasagittal white matter
shows abnormal T2 and FLAIR hyperintensity, although the abnormal
Barkovich_Chap04.indd 288
FIG. 4-40. (Continued) C. Axial T2-weighted image shows
diffuse hyperintensity of the white matter and cortex. The
normal hypointensity of the cortex and its sharp margin
with underlying white matter is gone, replaced by diffuse
blurring of cortex. Basal ganglia (B) and thalami (T) are
relatively spared. D and E. Axial Dav maps show marked
hypointensity (reduced diffusivity) throughout the cere-
brum, most marked in the cortex. Again, note relative spar-
ing of basal ganglia and thalami (in D).
signal intensity of the white matter may not be apparent until the end
of the first year when T2 hypointensity, secondary to myelination,
appears (394).
A correlation has been shown between the severity of the cortical
damage and the severity of the subsequent spastic paresis (166,391,395)
and cognition (375–377,384) of the patient. The shrunken cortex has a
peculiar pattern in which the deep portions of the gyri are more affected
than the superficial portions, creating mushroom-shaped gyri known
as ulegyria (5). These peculiarly shaped gyri form because of the unique
vascular supply to the gyri in the infant brain. Takashima and Tanaka
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
(396) have shown that, in the newborn, there is greater perfusion to the
apices of the gyri than to the cortex at the depths of sulci. Therefore,
when a hypoxic-ischemic event occurs, the tissue loss is greater in the
depths of the sulci, resulting in the characteristic “mushroom” shape.
MRI can identify ulegyria because of the characteristic gyral pattern
and the underlying tissue loss and gliosis (Fig. 4-42). Probably the most
important reason to identify this entity is to differentiate it from poly-
microgyria, which is a malformation of neuronal organization and is
seen in a number of inherited syndromes. In myelinated brain, polymi-
crogyria (see Chapter 5) appears on MRI as an area of thickened cortex
with irregularity of the cortical-white matter junction and, often, para-
doxically smooth pial surface. It is not associated with perinatal brain
injury or with neonatal encephalopathy.
Profound Hypotension
As discussed in an earlier section, a different pattern of brain injury
is seen in neonates who have suffered profound hypotension or
Barkovich_Chap04.indd 289
289
FIG. 4-41. Chronic watershed injury at age 5 months. A. Sagit-
tal T1-weighted image shows an abnormally think corpus cal-
losum (white arrows) secondary to white matter injury in the
cerebral hemispheres. B. Axial T1-weighted image shows abnor-
mal cortical hyperintensity in the affected watershed regions
(white arrows). The hyperintensity is likely a result of astrogliosis
causing increased amount of bound water in this (still) imma-
ture brain. C. Axial T2-weighted image at age 5 months shows
loss of hypointensity of the cortex and abnormal hyperintensity
of underlying white matter (white arrows) at the areas of injury.
cardiocirculatory arrest, as compared to mild or moderate hypoxia/
hypotension (Table 4-6) (5,17,119,156,170,177,379,397). This group
of patients shows injury primarily in the lateral thalami, posterior
putamina, subthalamic nuclei, hippocampi, and corticospinal tracts
on MR studies (170,180,181,388,398), locations corresponding to
those regions of brain most metabolically active (182), with the highest
blood flow (184), and highest degree of synapse construction (187,399)
at the time of birth. Some patients will, in addition, show injury in the
lateral geniculate nucleus and optic radiations. The cortex is relatively
spared, other than the perirolandic gyri (170,180,181,379). The most
severely injured patients in this group have injury to brainstem nuclei
(119,379,400); the majority of these brain stem-injured patients likely
die before they are imaged and, therefore, are represented more in
pathologic (5,177,180,181,361,401) than in the radiologic literature.
Patients with the profound hypotension pattern appear to have
different neonatal courses and different subsequent neurologic deficits
than those with the moderate hypoxia/hypotension pattern. Patients
5/25/2011 11:39:00 AM
 290 Pediatric Neuroimaging

FIG. 4-42. Ulegyria. A. Coronal T1-weighted image shows shrunken left parietal cortex with hypointensity of the underlying white
matter (white arrows), and an enlarged ipsilateral ventricle. The overlying gyri are shrunken, with the deeper portions of the cortex
being more severely involved than the superficial portions. B. Coronal T2-weighted image shows abnormal hyperintensity in the
parietooccipital white matter and of the depths of the sulci (black arrows), reflecting tissue damage. Note that the superficial aspects
of the cortex are less involved, giving the gyri a mushroom-shaped appearance.

with the profound pattern of injury have lower 1 minute Apgar
scores, usually 3 or below (397,402), or a postnatal cardiocirculatory
arrest (379,403). Clinical manifestations depend upon the severity of
the injury. Patients with very severe brain injury often die in infancy
(379,397,402) or develop choreoathetosis in addition to quadripare-
sis, severe seizure disorders, microcephaly, and mental retardation
(375,397,403–406). Patients with moderate injury almost always have
spastic and dyskinetic motor impairment (398,402,403). Patients with
mild injury may initially develop normally after mild neonatal enceph-
alopathy or may be mildly delayed (173,179,400,402,407). It is impor-
tant to remember that many children who develop choreoathetosis
may not manifest extrapyramidal signs until after the first year of life
(225,403). The large majority develops choreoathetosis between the
ages of 1 and 4 years (408,409); however, some patients do not develop
abnormal movement until as late as 7 to 14 years (225,408–410). More-
over, nearly half of the patients with late onset of choreoathetosis have
a history of normal neurologic development until the extrapyramidal
signs and symptoms develop (408–410) (of interest, such children
seem to have injury to the subthalamic nuclei [398]). Finally, many
children who appear normal at age 1 or 2 years go on to have cognitive
delay (375) and learning difficulty when they reach school age (407).
Therefore, even mild imaging abnormalities may have significant con-
sequences on long-term outcome.
On pathologic studies, the patients are found to have moderate
to severe destruction in the hippocampi, putamina, inferior colliculi,
central gray matter of the midbrain, other brainstem nuclei, and the
ventro-lateral nuclei of the thalami (156,361,401,406). Positron emis-
sion tomographic studies of patients with athetoid cerebral palsy show

TABLE 4-6 Patterns of Injury in Diffuse Hypoxic-Ischemic Injury

Age of Child
Premature Neonate (up to 32
postconceptional weeks
Term neonate (∼34–56
postconceptional weeks)
Older child (more than 4–6
postnatal months)
Mild to Moderate Hypotension
Periventricular/deep white matter injury
Cortex and white matter injury (white matter exclu-
sively in mild injury; parasagittal watershed cortex
and white matter in moderate injury; entire cortex
and underlying white matter in severe injury)
Parasagittal watershed injury (cortex and white
matter)
Profound Hypotension
Thalamic, basal ganglia, and brainstem injury
Dorsal brainstem, anterior cerebellar vermis,
thalamus, basal ganglia, corticospinal tracts,
and perirolandic cortex injury. In severe
injury, all supratentorial structures affected.
Basal ganglia and diffuse cortical injury;
perirolandic and thalamic sparing

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 291

TABLE 4-7 Findings and Effective Times for Imaging Techniques in Perinatal
Hypoxic-Ischemic Injury
Technique Findings Timing Comments
Ultrasound Increased echogenicity 2–10 d Poor assessment of deep structures and of cerebral convexities
X-ray CT Low attenuation 1–7 d Temporal lobes difficult to assess. Ionizing radiation.
Anatomic MRI T2 hyperintensity 24 h
T1 hyperintensity 2–3 d–mo
T2 hypointensity 6–7 d–mo
Tissue loss (atrophy) 10–12 d
Proton MRS Increased lactate 1–15 d Relatively mild elevation until secondary energy failure (>24 h).
Decreased NAA Day 3 or later
DWI Reduced diffusivity 1–5 d Minimal during first 24 h. Maximizes at 3–4 d. Pattern evolves over 8–10 d.
Pseudonormalization 5–10 d
Increased diffusivity >10 d

CT, x-ray computed tomography; DWI, diffusion-weighted imaging of the patient; MRI, magnetic resonance imaging; MRS, proton magnetic resonance spectroscopy.

normal cortical activity, but diminished metabolism in the thalami and
lentiform nuclei (405), consistent with the MR and pathologic findings.
Timing of Appearance of Imaging Findings The time of detection
of imaging abnormalities varies with the technique utilized (Table 4-7)
and the severity of the injury; the most severe injuries can be detected
during the first 16 to 24 hours after injury, whereas the milder inju-
ries are not visible on imaging studies (other than diffusion-weighted
MRI) for several days. The imaging findings evolve continuously for
many weeks, so it is important to either image the neonates at a con-
sistent time after the injury or be aware of how the imaging findings
evolve. If no intervention (which might necessitate earlier imaging) is
planned, the optimal time for early imaging is 3 to 4 days after the injury
(Figs. 4-43 and 4-44). Sonograms will show hyperechogenicity of the
affected structures, CT will show reduced attenuation of affected struc-
tures, anatomic MRI will show T1 and T2 hyperintensity, diffusion-
weighted MRI will show reduced diffusion, and proton MRS will show
elevated lactate and diminished NAA peaks.
In the first 2 to 3 days after profound hypotension, ultrasound may
show hyperechogenicity in the thalami, globi pallidi, putamina, periven-
tricular white matter, and perirolandic cortex (Figs. 4-43 to 4-45). This
hyperechogenicity can easily be overlooked if the sonographer is not

FIG. 4-43. Profound neonatal hypotension of moderate severity; evolution at ages 17 hours, 4, and 8 days. A. Axial T1-weighted
image shows a nearly normal appearance. Note that the posterior limbs of the internal capsules (white arrows) are bright at this
age despite the injury. B. Axial T2-weighted image at age 17 hours shows slightly increased signal intensity of white matter but is
otherwise normal.

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 292 Pediatric Neuroimaging

FIG. 4-43. (Continued) C. Axial Dav map at age 17 hours shows

minimal reduced diffusivity in the ventrolateral thalami (white
arrows). D. Proton MRS (TE = 288 milliseconds) at age 17
hours from basal ganglia region shows normal height of NAA
peak. Minimal elevation of lactate (Lac) is seen at this stage of
injury. E and F. Parasagittal and coronal sonograms performed
at age 3 days show increased echogenicity (arrows) in the thalami.
G. Axial CT image performed at age 4 days shows hypodensity in
the basal ganglia and thalami.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 293

FIG. 4-43. (Continued) H. Axial T1-weighted image at age 4

days shows absence of the normal spot of hyperintensity in the
posterior limbs of the internal capsules. The lentiform nuclei
and the ventral thalami show faint, diffuse hyperintensity.
I. Axial T2-weighted image at age 4 days shows diffusely hyper-
intense white matter (nearly as bright as CSF) and slightly bright
posterior thalami. The hypointensity in the ventrolateral thal-
ami (white arrowheads) is normal. J. Axial Dav map at age 4 days
shows hypointensity (reduced diffusivity, white arrowheads) in
the ventral thalami and posterior putamina. K. Proton MRS (TE
= 288 milliseconds) from basal ganglia region at age 4 days shows
decreased height of NAA peak and increased height of lactate
(Lac) compared with initial spectrum (D). L. Axial T1-weighted
image on day 8 after birth shows that the hyperintensity in
the basal ganglia and thalami is more localized in the ventro-
lateral thalami (white arrowheads), posterolateral putamina
(white arrows) and medial putamina (black arrowheads).

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 294 Pediatric Neuroimaging
actively searching for it (363,411); the finding of thalamic hyperecho-
genicity portends a poor neurologic outcome (173,412). With very
severe injury, increased echogenicity is seen diffusely throughout the
cortex, white matter, and basal ganglia (Fig. 4-44). Initially, it will be
more apparent in the white matter and the differentiation between
hyperechoic white matter and hypoechoic cortex becomes more pro-
nounced than usual. However, over the first few days after the event, the
cortex becomes increasingly edematous and hyperechogenic, resulting
in a loss of cortical-white matter differentiation (Fig. 4-44A, B and
4-45A). Transcranial Doppler shows decreased resistive index in the
first days after injury, probably because of impaired autoregulation.
(Normal resistive indices [RI, peak systolic minus end diastolic veloc-
ity divided by peak systolic velocity] of the major intracranial vessels
are between 0.71 and 0.75 with a standard deviation between 0.07 and
0.08 [413].) Fluctuations in RI have also been reported, likely reflecting
impaired autoregulation (363).
CT shows hypoattenuation of the thalami and basal ganglia
(Fig. 4-43C), with these gray matter structures become isodense with
Barkovich_Chap04.indd 294
FIG. 4-43. (Continued) M. Axial T2-weighted image at age
8 days shows persistently hyperintense thalami and basal gan-
glia, but no focal abnormalities. N. Axial Dav map at age 8 days
shows that the reduced diffusivity (hypointensity) has shifted
largely to the posterior putamina (white arrows). The diffusiv-
ity in the ventrolateral thalami (white arrowheads) has nearly
completely disappeared. O. Proton MRS (TE = 288 millisec-
onds) from basal ganglia region at age 4 days shows continued
decreased height of NAA. Lactate (Lac) is decreasing and will
be gone by the end of the second week.
surrounding white matter (170); this finding can be easily overlooked,
as can they hypointensity of the cerebral cortex (particularly perirolan-
dic) and superior cerebellar vermis. It is, therefore, essential to specifi-
cally assess gray matter structures (cortex, thalami and basal ganglia) to
be sure that the attenuation values are similar to other gray matter struc-
tures. The presence of low attenuation in the thalami on postnatal days
2 to 4 is highly predictive of poor neurological outcome (397). In very
severe brain injury, the CT shows diffuse hypodensity on the first day
of life, involving basal ganglia, white matter, and cortex (Fig. 4-46A);
the cerebellum is often spared.
Anatomic MRI will typically be normal if performed on the day
of birth. Proton spectroscopy may show elevation of lactate within a
few hours of birth (365,389,390), although it is important to realize
that the lactate level may nearly normalize from approximately 6 to
18 hours before rising again due to secondary energy failure. In some
patients with severe injury, reduced NAA may be seen within the first
24 hours of life (365,389,390), although it usually takes 48 to 72 hours.
Diffusion imaging will typically show reduced diffusion in the lateral
5/25/2011 11:39:04 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 295

FIG. 4-44. Very severe profound neonatal hypotensive injury: acute (3 days), subacute (15 days) and chronic (8 months) imaging.
A and B. Coronal (A) and parasagittal (B) transfontanelle sonograms at age 3 days show increased echogenicity in the basal gan-
glia and white matter, as well as blurring of the cortical-white matter junctions. C. T1-weighted image at age 3 days shows diffuse
hyperintensity of the basal ganglia (white arrows) and thalami and diffuse hypointensity of the white matter. The normal hyperin-
tensity of the posterior limb of the internal capsule is not seen. D. T2-weighted image at age 3 days shows slight hyperintensity of
the posterior thalami and the cerebral white matter. The hypointensity normally seen in the posterior limb of the internal capsule
is absent, confirming severe, diffuse edema.

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 296 Pediatric Neuroimaging

FIG. 4-44. (Continued) E and F. Dav maps at age 3 days show

extensive hypointensity (reduced diffusivity) in the basal ganglia
(B), thalami (T), cerebral cortex (C), and subcortical white mat-
ter (W). The extent of reduced diffusivity suggests a severe injury.
G. Proton MRS (288 milliseconds) at age 3 days shows reduced
NAA and markedly elevated lactate (Lac). Both of these findings
suggest severe injury. H. Axial T1-weighted image at age 15 days
shows markedly abnormal hyperintensity (white arrows) of the
basal ganglia, thalami, and posterior perisylvian cortex and central
cavitation (C) within the putamina and thalami. The white matter
is abnormally hypointense. I. Axial T2-weighted image at age 15
days confirms the cavitations (C) of the deep gray nuclei and the
abnormal edema (hyperintensity) of the white matter.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 297

FIG. 4-44. (Continued) J and K. Axial T2-weighted images at age 8 months show that the basal ganglia cavities have largely shrunk
and the basal ganglia are consequently small. The white matter volume has markedly diminished and is abnormally hyperintense,
and the cortex is very thin (black arrows) in multiple areas. This is the end result of very severe profound neonatal hypotension.

FIG. 4-45. Profound neonatal hypotension of moderate sever-

ity, evolution from 2 days to 2 years. A. Coronal sonogram at
age 3 days shows mildly increased echogenicity of thalami (T),
lentiform nuclei (B) and deep white matter. Some blurring at
the cortical-white matter junction (white arrowheads) is seen.
B. Axial T1-weighted image at age 2 days shows diffusely
increased signal intensity in the basal ganglia (white arrows).
C. Axial T2-weighted image at age 2 days shows diffuse hyper-
intensity of the thalami, white matter (almost isointense with
CSF), and cortex, highly suggestive of diffuse edema.

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 298 Pediatric Neuroimaging

FIG. 4-45. (Continued) D–F. Axial Dav maps at age 2 days show hypoin-
tensity (reduced diffusivity) in the dorsal midbrain (white arrows, D),
basal ganglia (white arrowheads, E), ventrolateral thalami (white arrows,
E), and corticospinal tracts (black arrows, F). These are the most com-
mon location of early findings on diffusivity maps. G. Proton MRS
acquired from the basal ganglia/thalami at age 2 days shows a small
NAA peak and elevated lactate (Lac). H. Axial T2-weighted image at age
12 months shows T2 prolongation (white arrows) and sulcal enlargement
in the cerebellar vermis.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 299

FIG. 4-45. (Continued) I. Axial T2-weighted image at age 12 months shows small
basal ganglia and hyperintensity in the thalami (open arrows) and putamina (solid
arrows). J. Axial T2-weighted image at age 12 months at the level of the frontopari-
etal convexity shows abnormal hyperintensity (arrows) along the perirolandic gyri.
K. Axial T2-weighted image at age 2 years shows T2 hyperintensity and volume loss
in the lateral thalami (white arrowheads) and posterior putamina (white arrows). L.
Axial T2-weighted image at age 2 years shows T2 hyperintensity and volume loss in the
perirolandic white matter and cortex (white arrows).

thalami within the first 24 hours of life (Fig. 4-43C) (119,365,366).
(Remember that sensitivity is improved by using calculated average dif-
fusivity (Dav) images or Dav values instead of unprocessed DWIs, which
underestimate injury because of the very long T2 relaxation values of
neonatal brain.) However, diffusion imaging may yield false negative
results in the early hours of life (163,365,366) and will nearly always
underestimate the amount of damage if performed in the first 24 hours
of life (before secondary energy failure) (117,119,365). Dav values of
less than 0.8 × 10−3 mm2/s in the thalami or posterior limb of the inter-
nal capsule and less than 1.1 × 10−3 mm2/s in the white matter at ages
1 to 4 days seem to be associated with permanent injury (388,414). It
should be noted that metabolite ratios (on MRS) and Dav values (on
DTI) change continuously over the first week of life (see Fig. 4-43) and
pseudonormalize in neonates by the fifth or sixth day (117,119). By day
3 after injury, T1- and T2-weighted images become definitely abnor-
mal, although findings are subtle (119,169). T2-weighted sequence
show that the basal nuclei, particularly the posterior thalami, are isoin-
tense with white matter (instead of normal hypointensity); this hyper-
intensity is best seen on the first (60 milliseconds) echo but will be seen
with longer echoes, as well (Fig. 4-43I). During days 3 to 5, diffusion
abnormalities will be at their maximum; both diffusion-weighted/Dav
images and T1-weighted images will show abnormal signal intensity
in the lateral thalami and posterior putamina (Fig. 4-43H and J) and
along the corticospinal tracts up to the perirolandic cortex (119). If the
brainstem is injured, reduced diffusivity is seen in the dorsal midbrain
or pons (Fig. 4-45D). In severely injured patients, Dav values may drop
to less than 50% of normal in the thalami, basal ganglia, and dorsal
brain stem during this time period, with values as low as 0.4 × 10−3
mm2/s (119). Reduction of Dav by more than 25% to 35% is associ-
ated with poor long-term outcome (119,337,388,414,415) (for normal
neonatal Dav values see Bartha et al. [334]). Extensive cortical injury,
if seen (Figs. 4-44E, F and 4-46D, E) portends a very poor neurologic
outcome (379,395). The second echo T2-weighted images may be
normal or show symmetric absence of the normal spot of hypointen-
sity in the posterior limb of the internal capsule (Fig. 4-44D). When
severely injured, the basal ganglia will show T2 hyperintensity, becom-
ing isointense with white matter on T2-weighted images (Fig. 4-43M
and 4-46C). On proton MRS, NAA is reduced by up to 40% by day
3 to 4, while the size of the lactate peak maximizes during this time
period (119,415). In very severe brain injury, the T1-weighted images

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 300 Pediatric Neuroimaging

FIG. 4-46. Value of physiological imaging in two patients. A–F. Extremely severe profound hypotensive injury; images
obtained 1 day after birth. A. Axial noncontrast CT shows extensive brain swelling with hypoattenuation of the basal gan-
glia, thalami, white matter, and cortex. The ventricles are compressed and the cranial sutures are widened (“split”). B. Axial
T1-weighted image shows compressed lateral ventricles and diffuse hypointensity of the cortex, white matter, and basal gan-
glia. The ventrolateral thalami (white arrows) stand out as relatively hyperintense, possibly because they are more cellular
and myelinated than the other portions of the cerebrum. C. Axial T1-weighted image shows diffuse hyperintensity, with near
isointensity of gray and white matter due to massive edema. Ventrolateral thalami stand out as hypointense, probably for the
same reason as their T1 hyperintensity in (B). D and E. Axial Dav maps show marked hypointensity (reduced diffusion) of
nearly all parts of the brain with the exception of the frontal white matter (F) and cerebellum (C). F. Proton MRS (TE = 288
milliseconds) from basal ganglia/thalami shows enormous lactate peaks (Lac). Note that the NAA peak is already lowered.
G–J. Perfusion imaging of acute, severe profound hypotensive injury associated with meconium aspiration. G and H. Axial
Dav maps show markedly reduced diffusivity in the deep gray nuclei and perirolandic cortices. I. Relative cerebral blood flow
map from arterial spin labeled perfusion imaging demonstrates hyperperfusion of damaged deep gray nuclei and perirolan-
dic cerebral hemispheres. J. Axial T2-weighted image shows marked enlargement of the deep perforating arteries in the basal
ganglia and thalami.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
are nearly uniformly hypointense and T2-weighted images nearly
uniformly hyperintense due to the diffuse edema, while the Dav maps
are nearly uniformly hypointense due to the extent and severity of
injury; proton MRS shows an enormous lactate peak and small NAA,
even on the first day after birth (Fig. 4-46). Limited experience with
perfusion imaging in the subacute phase shows hyperperfusion of
injured regions (Fig. 4-46G–J).
By 7 to 10 days after the injury, ultrasound shows better definition
of the hyperechogenic areas and some increase in ventricular size as
the edema resolves. CT scans also show resolution of edema and may
begin to show high signal, probably representing hemorrhage or calci-
fication, in the affected gray matter nuclei (170,178). On MRI, Dav has
nearly normalized in the thalami, basal ganglia, and corticospinal tracts
(Fig. 4-43N), although it may be reduced in locations that were initially
normal (119); the new areas of reduced diffusion may represent Walle-
rian degeneration or spread of excitotoxic injury. On proton MRS, the
size of the lactate doublet is decreasing during this time and the NAA
and choline peaks have decreased (Fig. 4-43O) (119). On anatomic
images, the high signal seen in the deep gray matter on T1-weighted
images becomes heterogeneous, with small areas of marked focal
hyperintensity in the globi pallidi, the ventrolateral thalami, and in the
posterior putamina (Fig. 4-43L). Heterogeneous high and low signal is
seen in the basal nuclei on the T2-weighted images, probably the result
of astrogliosis and mineralization (323). The extent of injury is vari-
able, being limited to the lateral thalami and posterior putamina in the
least severely injured patients, and progressively involving the periro-
landic cortex, hippocampi, superior cerebellar vermis, the remainder of
the deep cerebral nuclei, the central mesencephalon, and the remainder
of the cerebral cortex as the injury becomes progressively more severe.
In the most severely injured patients, the entire cerebral cortex, all the
deep cerebral nuclei, the cerebellar vermis, and many brainstem nuclei
are injured (166,169,170,395). The extent of involvement is most likely
related to the duration and severity of the hypotensive incident, possi-
bly superimposed upon genetic predisposition. The T1 hyperintensity
and T2 hypointensity slowly fade (Fig. 4-44) as atrophy of the injured
tissues develops and myelination progresses.
In the chronic phase, weeks to months after the injury, the affected
areas of brain may undergo cavitation (Fig. 4-44H–K); or they become
Barkovich_Chap04.indd 301
301
FIG. 4-46. (Continued)
shrunken and show T2 hyperintensity compared to normal myelinated
brain tissue (Fig. 4-45H–J). In mild-moderately affected patients,
abnormalities are most commonly seen (>90%) in the ventrolat-
eral thalami, posterior putamina, and corticospinal tracts from the
internal capsule up through the perirolandic cortex (Fig. 4-45H–L);
in 50% to 60% of patients, the anterior cerebellar vermis is affected
(Fig. 4-45H) (416,417). Involvement of the subthalamic nuclei may
be seen in children with dyskinesia (398). In more severely affected
patients, more extensive involvement is seen until, in the most severely
affected patients, multicystic encephalomalacia may involve most of
the brain (Fig. 4-47). The T2 prolongation may not become evident
in the cerebral white matter until myelination is well under way (Fig.
4-45 H–J). It may be seen at ages as young as 8 months (394) or not
until 13 to 14 months, depending on the location of the injury and the
degree of associated myelination delay. MRI is much more sensitive
than CT to the damage in the deep cerebral nuclei and corticospinal
tracts (170,418) and to the myelination delay that almost invariably
accompanies diffuse ischemic brain injury (18,341).
Effects of Brain Cooling
In the past few years, brain cooling (to 34°C for 3 days) has begun to be
used as an immediate treatment for neonatal hypoxic-ischemic brain
injury. Few definitive results have been published. Our experience is
that cooling seems to reduce the amount of injury in mild or moderate
brain injury detected by MRI if the MR scan is performed within 2 days
of the time the cooling has ended. It appears to have little or no effect
on severely brain-injured babies. The pattern of injury also appears to
be affected, as we have seen less basal ganglia injury and more white
matter injury than we were accustomed to seeing in noncooled neo-
nates with similar clinical pictures at birth. These results remain very
preliminary at the time of publication of this book.
Notes on MRS in Asphyxiated Term Infants
Proton MRS is extremely valuable in the assessment of encephalo-
pathic neonates. Although early work focused upon phosphorus (31P)
MRS (161,419–422), the limited availability and long acquisition time
of 31P MRS on most clinical scanners and the improvements of much
faster proton MRS (117,365,366,384,389,390,423–427) has resulted in
5/25/2011 11:39:10 AM
 302 Pediatric Neuroimaging

FIG. 4-47. Severe cystic encephalomalacia of most of the brain in a 4-month-old infant who suffered extremely
severe profound hypotension at birth. Basal ganglia, white matter, and cortex are severely damaged. A. Axial
T1 weighted image at the level of the basal ganglia shows diffuse volume loss. The basal ganglia are shrunken
and hyperintense. The white matter shows marked volume loss and multiple cysts of varying size. The cortex is
thinned, especially centrally. B. Axial T2 weighted image at a higher level shows decreased volume of abnormal,
hyperintense white matter, with multiple cysts of variable size.

proton MRS becoming established as a key sequence in the evaluation
of these neonates. Proton MRS is particularly useful in the assessment
of neonates in the first hours after birth, when the imaging studies
are normal or subtly abnormal and diffusion studies are unreliable
(117,119,365,366,390). Lactate elevation, resulting from anaerobic
glycolysis secondary to mitochondrial dysfunction, is detected on long
echo proton MRS by identification of the characteristic lactate doublet
(two sharp peaks) centered at 1.33 ppm (Figs. 4-43 to 4-46). Elevated
lactate can be detected by proton MRS as early as 4 to 8 hours after
birth (365), although lactate levels remain relatively low until the onset
of secondary energy failure, about 24 hours after the injury (119).
It appears that the most important metabolite values in the assess-
ment of brain injury are NAA and lactate. Cheong et al. looked at abso-
lute concentrations of metabolites and found increased lactate and
decreased NAA, choline, and creatine after neonatal hypoxic-ischemic
injury (428). Of these metabolites, the decreased NAA was the most
prognostically accurate in distinguishing normal/mildly injured neo-
nates from severely injured neonates (428). However, calculation of
absolute metabolite concentrations is impractical in the acute clinical
setting, so the ratios of peak areas (which depend upon both concen-
tration and T2 relaxation time) are more commonly used. We have
found Lac/NAA to be the most useful ratio. In our experience, initial
lactate elevation (in the first few hours after injury) usually dimin-
ishes and remains at low levels until 18 to 24 hours when it begins to
increase; this delayed elevation is thought to relate to delayed energy
failure (429). Hanrahan et al. (389) found that lactate to creatine ratios
(Lac/Cr) correlated well with a reduction of high energy phosphates as
detected by 31P MRS and with stormy neonatal courses. They found that
Lac/Cr greater than 1 in the first 18 hours of life had a high predictive
value (87%) of either neonatal death or abnormal neurodevelopmental
outcome at age 12 months (390). Amess et al. (427) found that thal-
amic Lac/NAA more than 2 standard deviations above the mean
neonatal value predicted adverse outcome at age 12 months with a
specificity of 93% and a positive predictive value of 92%. In their data,
Lac/NAA was more predictive than Lac/Cr or Lac/Cho. Barkovich et
al. found that the basal ganglia Lac/Cho ratio was most predictive of
12-month outcome (384). Penrice et al. found that normal control
neonates have Lac/NAA ratios less than 0.3 in the thalami, but asphyxi-
ated neonates generally have values above 0.4 and seriously injured
infants above 0.5; they found that elevated Lac/NAA ratios were asso-
ciated with poor long-term prognosis (429). Others have also found
correlations between brain lactate levels in the first few days of life and
neurologic outcome (424,426). In general, the presence of a detectable
lactate peak in the first few days after birth is a sign of significant brain
injury and is predictive of subsequent neurologic impairment; higher
lactate predicts worse prognosis. (CAUTION: lactate can be present in
the CSF of normal neonates (430,431). Therefore, make certain that your
voxel does not contain CSF when acquiring your spectra!) Reduced NAA
and creatine in the subsequent few days to weeks is also evidence of
significant brain damage and emphasizes the poor prognosis of the
affected child (384,425,432). It is important to recognize, however, that
the presence of lactate is normal in the immature white matter ([433]
and Chapter 2) and that the quantity of NAA in the brain varies with
maturity (434,435). Moreover, different regions of the brain mature at
different rates (see Chapter 2) (185). Therefore, it is crucial to know the
postconceptional age of the infant and the region of the brain from which
the spectrum was obtained before interpreting the proton spectra.
Some authors have investigated the importance of glutamate levels,
as determined by in vivo proton MRS, in perinatal asphyxia (436–438).
Both Groenendaal et al. and Zhu et al. studied glutamate levels in the

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 303

first 2 days after birth using short echo time (~30 milliseconds) proton
MRS at 1.5 T (they are not elevated at the end of the first week [437]).
Both the alpha glutamate peak at 3.75 ppm and the beta and gamma
glutamate peaks (at 2.0–2.5 ppm) were elevated, although the elevation
of alpha glutamate did not reach significance (probably because of the
minor contribution of alpha glutamate to total glutamate signal). In a
larger series, Zhu et al. (438) report elevation of the alpha glutamate
peak, as well, and found correlations between the Glu/Cr ratios and
outcome.
Another important detail in the evaluation of encephalopathic
neonates by spectroscopy is to carefully determine the chemical shift at
which the lactate doublet is located. The methyl protons in lactate reso-
nate at 1.33 ppm. Propane-1,2-diol (propylene glycol), a solvent that is
used as the injection vehicle for administration of phenobarbital and
diphenhydantoin, crosses the blood–brain barrier and accumulates in
the brain. The methyl protons of propan-1,2-diol resonate as a doublet
at 1.15 ppm (see Chapter 2 and Fig. 4-39), immediately upfield from
lactate. It is critical to carefully assess the chemical shift of the peaks so as
not to mistake the propan-1,2-diol doublet for that of lactate; the prog-
nostic implications of lactate accumulation in the brain are important,
whereas the presence of propan-1,2-diol is not.
Parenchymal and Intraventricular Hemorrhage in the
Term Neonate
In contrast to premature infants, in whom germinal matrix hemor-
rhage fairly commonly extends into the lateral ventricles, intraventric-
ular hemorrhage is uncommon in term infants. Documented sources
of intraventricular hemorrhage in this age group include the choroid
plexus, residual germinal matrix, genetic disorders, vascular malfor-
mation, tumor, extension of hemorrhagic cerebral infarction (usually
thalamic), and coagulopathy (30,78,160,439–442). The most impor-
tant reasons for differentiating the various sources of neonatal hemor-
rhages are that (a) choroid plexus and thalamic hemorrhages are most
commonly seen in stressed infants; (b) patients with thalamic hemor-
rhages have a high incidence of neurologic sequelae, such as spastic
paraparesis, hydrocephalus, and seizures (439); and (c) patients with
coagulation disorders, such as alloimmune thrombocytopenia, have
a good prognosis if properly treated (441–443). When intracranial
hemorrhage, of whatever cause, results in dilation of the fourth ven-
tricle, the outcome is usually very poor (444).
It seems that venous thrombosis is the most common cause of neo-
natal thalamic (straight sinus thrombosis, Fig. 4-48), choroid plexus
(straight sinus thrombosis), parasagittal (superior sagittal sinus throm-
bosis, Fig. 4-49), and temporal or occipital lobe (vein of Labbé, trans-
verse sinus, or sigmoid sinus thrombosis, Fig. 4-50) hemorrhage (30),
possibly as a result of injury to the immature neonatal venous system
due to changing positions of the cranial bones during delivery (445).
Venous infarctions have already been discussed in an earlier section of
this chapter on localized infarctions. When checking for coagulopathy,
it is a good idea to look for COL4A1 mutations, which can result in
hemorrhage due to congenital vascular wall weakness (77,78). Lobar
hemorrhages can be seen in many locations in the neonatal brain.
Lobar hemorrhages are presumed to have many causes; however, in
most neonates, the cause is never identified (446). In general, neonates
with lobar hemorrhages of unknown cause have a good prognosis; a
poorer outcome is associated with lobar hemorrhages in the setting of
low Apgars, perinatal hypoxia-ischemia, or respiratory distress (446).
Another disorder to consider when large parenchymal hemor-
rhages are seen in fetuses or neonates is neonatal alloimmune thrombo-
cytopenia. In this disorder, fetal platelets that carry paternally derived
antigens cross the placenta and enter the maternal circulation where
they induce the production of maternal antibodies. When these mater-
nal antibodies cross the placenta and enter the fetal circulation, fetal
platelets are destroyed and their function impaired (443,447). Affected
infants typically present with widespread petechiae or purpura that
develop within a few hours of birth. Intracranial hemorrhage is seen
in up to 30% of cases; as many as half of these occur before birth
(448,449). The diagnosis is made by demonstrating maternal alloan-
tibodies directed against a paternal platelet antigen. The rate of recur-
rence in subsequent pregnancies is quite high (448). Imaging acutely
shows large parenchymal hemorrhages or choroid plexus hemorrhages.
Subdural blood may be present, as well. The regions of hemorrhage
subsequently undergo liquefaction and, if imaged in the late subacute
or chronic phase, large cyst-like regions of porencephaly or macrocys-
tic encephalomalacia are present, usually with ex vacuo enlargement of
the adjacent ventricle (447).

FIG. 4-48. Thalamic hemorrhage in a neonate. A. Axial noncontrast CT shows left thalamic hemorrhage (arrows) with intraventricular extension.
B. Sagittal SE 550/11 image shows subacute hemorrhage in the lateral, third, and fourth ventricles. High signal intensity (open white arrows), presumably
thrombus, is present in the proximal straight sinus. C. Phase-contrast MR venogram (Venc = 20 cm/s) shows flow (high intensity, solid white arrows) in the
vein of Galen and the distal straight sinus, but occlusion of the proximal straight sinus at the site of the thrombus in B.

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 304 Pediatric Neuroimaging

FIG. 4-49. Hemorrhagic left frontal infarct secondary to

sagittal sinus thrombosis. A. Sagittal T1-weighted image
shows complex hematoma in left frontal lobe. Note hyper-
intense methemoglobin (black arrows) and isointense
deoxyhemoglobin (black arrowheads) within the hema-
toma. B. Axial T2-weighted (SE 3000/120) image shows
the markedly hypointense hematoma (black arrows). Note
the enlarged superior sagittal sinus (black arrowheads), sug-
gesting thrombosis. C. Sagittal maximum intensity projec-
tion from 2D TOF venogram shows absence of flow related
enhancement along the course of the superior sagittal sinus
(black arrows).

FIG. 4-50. Acute occipital lobe hemorrhage in a neo-

nate. A. Axial T2-weighted image (SE 3000/120) shows
large acute hemorrhage (black arrows) in the right
occipital lobe. B. Maximum intensity projection from
2D TOF venogram shows lack of flow related enhance-
ment in the right transverse sinus (white arrows), con-
sistent with acute thrombosis.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
The imaging appearance of intraventricular blood was described
in the section on premature infants.
Timing of Studies
The subject of optimal timing of imaging studies after neonatal hypoxic-
ischemic brain injury warrants special mention. In catastrophic injury,
severe abnormality is seen immediately by nearly any imaging modality.
For less than catastrophic injury, however, timing is best understood in
the context of secondary energy failure, discussed at the beginning of the
section on Diffuse Ischemic and Inflammatory Brain Injury. As discussed
in that section, brain metabolism transiently normalizes for 18 to 24 hours
after an ischemic injury (162,165). At 18 to 24 hours, it is thought that suf-
ficient structural damage to membranes and molecules accumulates such
that the electron transport chain in the mitochondria ceases to work and
normal metabolic processes start breaking down (162,165). As a result of
this 18 to 24 hour window of somewhat normal cellular function after the
injury, spectroscopy and diffusion images can be falsely negative during the
first hours after injury in asphyxiated neonates and, even when positive, will
generally underestimate the extent of brain injury (117,119,162,366). This
clinical experience correlates with findings in animal experiments, indicat-
ing that diffusivity and spectroscopy may be transiently abnormal (mild
injury), biphasic (moderate injury—abnormal during hypoxia-ischemia,
followed by transient normalization during the “latency period,” followed
by permanently abnormal), or severely and permanently abnormal (early
cell necrosis) (164,387). The animal experiments indicate that transiently
reduced diffusion is associated with selective neuronal death, whereas
both the biphasic and permanently abnormal situations are associated
with widespread cell death in affected areas (164,387); energy produc-
tion in animals with biphasic diffusion metrics follows a similar bipha-
sic pattern (165). Humans are not imaged during hypoxia-ischemia. In
catastrophic injury, reduced diffusivity, low NAA and high lactate are seen
almost immediately; these finding persist and outcome is terrible. In less
severely affected patients, imaging during the first 24 hours shows find-
ings of the “latency period,” with nearly normal diffusivity and metabo-
lite levels (119). By 12 to 24 hours, CT shows diffuse low attenuation in
FIG. 4-51. Profound hypotensive injury in a 12-month-old infant. A. CT image obtained 36 hours after arrest
shows edema with low attenuation in the basal ganglia and cerebral cortex. B. Axial T2-weighted (SE 2500/80) MR
image 10 days later shows abnormal hyperintensity of the basal ganglia, posterior thalami, and cerebral white matter
diffusely.
Barkovich_Chap04.indd 305
305
injured regions, whereas MRI shows T2 prolongation of affected gray
and white matter (seen best on first echo of T2-weighted sequence); both
typically show diminished ventricular and sulcal size. After 24 to 48 hours,
diffusivity becomes markedly reduced, NAA decreases, and lactate mark-
edly increases in injured areas, correlating with secondary energy failure;
these findings portend poor neurological outcome (388). At this time,
standard imaging studies cannot determine whether brain damage and
neurological sequelae will be severe or minimal unless other associated
features such as focal hemorrhages are present. Therefore, the best time
to image patients is at 3 to 4 days after injury; edema (seen on anatomic
MRI, CT, and sonography), reduced diffusivity, and metabolite abnormali-
ties (reduced NAA, elevated lactate and glutamate) are present and near
maximum at these times. The worst possible time to image is 1 week after
injury. At 1 week, diffusivity has pseudonormalized, lactate has nearly dis-
appeared, and edema has resolved, but significant tissue loss is not yet
apparent; therefore, an imaging study at 1 week may look nearly normal,
even if significant damage has occurred. If interpreted as normal, the cli-
nician and parents may be led to falsely believe that the infant has suf-
fered no significant brain damage. If follow-up scans are to be performed
to assess the extent of brain injury, therefore, they should be obtained a
minimum of 3 weeks (best 4 months [450]) after the injury. The repeat
scan (preferably an MR, which is considerably more sensitive to detection
of white matter and deep gray matter damage) will show a return to near-
normal in those patients who will have relatively mild deficits, whereas
cystic or hemorrhagic parenchymal degeneration and progressive atro-
phy indicate a more guarded prognosis.
Injury in Older Infants and Children
When older children are encephalopathic after hypoxia, ischemia, or
circulatory arrest (e.g., after drowning), findings are generally similar
to those in adults. If the injury is caused by profound hypotension, low
attenuation is seen in the basal ganglia on CT (Fig. 4-51) and reduced
diffusivity with T2 hyperintensity is seen in basal ganglia and cortex
on MRI (Fig. 4-51 and 4-52). If injury is caused by mild to moder-
ate hypotension, watershed injury is seen (Fig. 4-53). MRI is the ideal
5/25/2011 11:39:12 AM
 306 Pediatric Neuroimaging

FIG. 4-52. Drowning injury in a 4-year-old boy. A. Axial SE 600/9 image shows blurring of the cortical-white matter junction in
the occipital lobes. B. Axial SE 2500/70 image, somewhat degraded by motion, shows hyperintensity of the frontal and parietooc-
cipital cortex. C and D. Axial DWIs (b = 1000 s/mm2) shows reduced water motion in the corpus striatum (caudate nucleus and
putamen) and in most of the cerebral cortex and white matter with the exception of the perirolandic regions (white arrows).

study if it can be done quickly and diffusion-weighted imaging is avail-
able. Findings are similar to those in adults. DWIs will show reduced
diffusivity in the cerebral cortex and corpus striatum within the first
24 hours of injury (Fig. 4-52), while spectroscopy will show glutamate
and glutamine elevation if short echo times are used; lactate is not con-
sistently seen (451). In severe injury, a “reversal sign” may be seen on the
Dav images, with markedly reduced diffusivity of cerebral white matter
compared with cortex and basal ganglia, by the third and fourth day
after injury (Fig. 4-54) (452). If diffusion imaging is abnormal, MRS can
be used for prognostication (426). The presence of lactate or reduced
(by 25% or more) NAA, Cr, or NAA/Cr correlates strongly with poor
outcome (451). However, as NAA levels remain normal for several
days, the use of this criterion may result in false negative results if the
study is performed less than 3 days after injury (451). Standard MRI
findings of asphyxic injury in a child are very subtle in the first 24 to
72 hours, consisting of subtle swelling with mild T1 and T2 prolonga-
tion in the basal ganglia and insular cortex and with blurring of gray
matter-white matter interfaces (Figs. 4-52 and 4-54) (451). On spin-
echo T2-weighted images, an early finding that may be very helpful is
the appearance of a curvilinear stripe of T2 prolongation (Fig. 4-55) at
the cortical-white matter junction, particularly at the depths of sulci in
the watershed region (18,451,453), which corresponds to blurring of the
cortical-white matter junction on T1-weighted images. This sign, which
may represent cortical laminar necrosis, indicates significant cortical

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 307

damage. Of note, Christophe et al. (453) found these signs to be both
sensitive and specific, with a positive predictive value of poor outcome
of 82% when the imaging was performed in the first 3 days after injury.
If MRI is not quickly available or if adequate monitoring/support
cannot be performed on the MR scanner, CT can be performed, as the
unstable child is easily monitored within the CT scanner. Initial CT
images (<24 hours) will show subtle hypoattenuation of the basal gan-
glia and insular cortex; sometimes, the cisterns around the midbrain
are effaced. Subsequent scans (24 to 72 hours) will show diffuse cere-
bral edema, with decreased gray matter-white matter differentiation,
effacement of sulci and cisterns, and decreased attenuation of the basal
ganglia and cortex (Fig. 4-51A) (454,455). Hemorrhage may become
apparent in the basal ganglia or cortex by 4 to 6 days after the injury.
An ominous finding is the so-called CT reversal sign in which the cere-
bral hemispheric white matter becomes hyperdense compared to cor-
tex (Fig. 4-54A) (456,457). This reversal sign is believed to result from
an accumulation of venous and capillary blood in the white matter
secondary to impaired venous drainage. The prognosis of children
with this sign is dismal (456,457).
Note that the pattern of brain injury from hypoxic/ischemic injury
in older infants and children differs from that seen in neonates. This
difference seems to be related to the physiological and biochemical
changes that occur in the brain with maturation; there are different
patterns of regional activity at different ages in the maturing brain
(see Fig. 4-21) (182–185). The changes are most apparent in injury
from profound hypotension; older infants, children, and adults show
involvement of the basal ganglia, with relative sparing of the thalami,
and significant cortical involvement with relative sparing of the periro-
landic regions (Figs. 4-52 and 4-55) (170,453). In chronic stages, severe
atrophy of the entire cerebrum may be seen (Fig. 4-55C and D). In
injury from mild to moderate hypotension, the differences from the
pattern of injury seen in neonates are minor (18).

FIG. 4-53. Watershed injury in 4–month-old

infant. A and B. Axial T2-weighted (SE 3000/120)
image 5 days after injury shows abnormal hyper-
intensity (white arrows) of the cerebral cortex and
subcortical white matter in the intervascular bound-
ary zones. C. Dav map shows hypointensity (reduced
diffusivity, white arrows) in intervascular boundary
zones.

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 308 Pediatric Neuroimaging

FIG. 4-54. Reversal signs. A. CT image shows the cerebral

white matter in the left hemisphere and much of the right hemi-
sphere is hyperintense compared to the gray matter of the cere-
bral cortex. B and C. MR reversal sign in a 2-year-old scanned
after a drowning accident. Axial T2-weighted image (B) shows
faint hyperintensity of white matter and blurring of the cortical-
white matter junction. Axial Dav map (C) shows hypointensity
(reduced diffusivity) in the white matter with, paradoxically,
relatively normal gray matter signal intensity.

CNS INJURY IN MULTIPLE PREGNANCIES
Ischemic brain injury in twin gestation is an important subject and deserv-
ing of some discussion. Twin pregnancies represent 1.2% of spontaneously
conceived pregnancies (458). Multiple pregnancies can be caused by either
of two mechanisms. Monozygotic (identical) twins result from splitting of
a single zygote into two or more embryos. These twins may share the same
amniotic sac and chorion (monoamniotic monochorionic), may share
the placenta but have his or her own amniotic sac (diamniotic monocho-
rionic), or may each have their own amniotic sac and placenta (diamni-
otic dichorionic; these fetuses are in the same situation as dizygotic twins).
When more than one ovum is present and each is fertilized by a different
sperm, dizygotic (fraternal or nonidentical) twins result. In this situation,
each embryo develops its own chorion and placenta; they are no more
alike than any other two siblings born to the same parents.
Ischemic Brain Injury in Multiple Pregnancies
The incidence of prenatal mortality is high in twins; up to 80% of twin
pregnancies diagnosed by routine sonography in the first trimester
are singletons by the time of birth (459,460); the surviving fetus has
one chance in five of neurological impairment (461). The incidence of
brain injury in twin pregnancies that continue to delivery is also rela-
tively high, being estimated at 30% in monochorionic twins (about ten
times more than in age-matched controls); by contrast, the incidence
in dichorionic twins is about 3% (5,147,462–466).

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 309

FIG. 4-55. Profound childhood hypotensive injury in a 2-year-old. Acute and chronic phases. A. Axial proton density image
(SE 2500/30) shows hyperintensity of the putamina and caudates compared with the thalami. The cortex-white matter junc-
tion is indistinct. B. Axial T2-weighted (SE 2500/70) image shows a stripe of hyperintensity (arrows) between the cortex and
underlying white matter. This can be a useful sign in evaluating asphyxiated children in the first few days after injury. C and D.
Follow-up images at age 3 years. Marked diffuse atrophy of the cerebrum is present.

Part of the neurologic morbidity is related to the high prevalence
of premature birth in twin gestations, but comparisons between single-
tons and twins matched for gestational age show an increased risk for
death and developmental impairment in twins (467,468). Although
other factors (disseminated intravascular coagulation, hypotension,
or thromboembolism due to death of cotwin) are often factors (147),
most ischemic brain injury seems to result from the presence of placen-
tal vascular anastomoses (artery to vein is the most important type),
which are nearly always present in monochorionic placentas (469). In
most cases, the anastomoses are balanced, but in 10% to 15%, they are
unbalanced; the process in unbalanced anastomoses has been termed
“twin-twin transfusion” and the spectrum of disorders is referred to as
the “twin-twin transfusion syndrome (TTTS).” If TTTS is untreated,
the prognosis is very poor with overall mortality in the range of 80%
to 100% (470). As a result of the abnormal placental anastomoses, one
twin (called the donor) loses blood to the other (called the recipient);
the donor becomes hypovolemic with associated oliguria, oligohy-
dramnios, and growth restriction while the recipient becomes hyperv-
olemic with polyuria, polyhydramnios, and cardiac dysfunction (458).
Although laser therapy has been used in an attempt to close the anas-
tomoses, they are difficult to cure and the treatment is associated with
significant fetal morbidity (471).

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 310 Pediatric Neuroimaging

The type of ischemic brain injury is dependent upon the age of
the fetuses at the time of the transfusion. Injuries reported from events
during the second half of pregnancy include intraventricular hemor-
rhage, localized cerebral infarctions (single or multiple), porencephaly,
hydranencephaly, multicystic encephalomalacia, periventricular leu-
komalacia, and polymicrogyria (5,147,458,462–465). Mechanisms of
injury that have been elucidated include (a) disseminated intravascular
coagulation caused by transfer of thromboplastin material from the
dead twin, (b) embolism from the dead fetus or placenta, (c) severe
hypotension and cerebral ischemia resulting from transfusion of blood
from the surviving fetus to the dead fetus, (d) placental circulatory
stasis resulting in impaired umbilical cord blood flow or embolism,
and (5) venous hypertension (147,458,462,463). Mechanism (4) is
currently believed to be the most common (469). Norman et al. (472)
make the point that monoamniotic twins are particularly prone to
umbilical cord entanglement.
Although the diagnosis of TTTS is made by sonography, which
will show the oligo- or polyhydramnios, the small or distended urinary
bladder, and the presence of cardiomegaly, fetal MRI best detects brain
injury (458). In particular, one should look for hemorrhage, infarc-
tions, polymicrogyria, porencephaly, hydranencephaly, multicystic
encephalomalacia, and cavitary white matter injury (Fig. 4-56). If the
diagnosis is made after birth, the appearance of these injuries in twins
is identical to that of singletons with similar injuries at similar postcon-
ceptional ages; all have been discussed and illustrated in earlier sections
of this chapter.
NEONATAL HYPOGLYCEMIA
Neonatal hypoglycemia is probably under recognized, since common
symptoms, such as stupor, jitteriness, and seizures, may be lacking or
inconspicuous in many affected neonates; thus, hypoglycemia may
remain undetected until seizures develop (473). The definition of hypo-
glycemia in infants varies with the maturational state of the infant, as
less mature infants tolerate lower glucose levels than more mature ones
and mature infants tolerate lower levels than older children and adults.
Currently accepted levels defining significant hypoglycemia in the new-
born are below 30 to 35 mg/dL in the first 24 hours and below 40 to
45 mg/dL after 24 hours in term infants (473–475). Volpe, and others,
make the point that absolute values are not useful, as other factors, such
as rate of cerebral blood flow, cerebral utilization of glucose, duration
of hypoglycemia, and association with exacerbating factors (hypoxia,

FIG. 4-56. Fetal MRI manifestations of injuries from twin-

twin transfusion syndrome. A. Sagittal SSFSE image shows
periventricular hemorrhage (white arrows) in 22 week fetus
due to presumed hypotension/ischemia. B. Coronal SSFSE
image shows parenchymal loss (black arrows) in 23-week
fetus from infarction in right frontal lobe. Postnatal scan
showed polymicrogyria. C. SSFSE image shows normal brain
of normal cotwin (N on left of image) and injury resulting
in schizencephaly (white arrows) and periventricular nodular
heterotopia (black arrowheads) affected cotwin.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
FIG. 4-56. (Continued) D. SSFSE shows twin demise of smaller fetus (black arrows) with nearly complete resorption of brain tissue.
Larger cotwin is normal. E. SSFSE image shows hydranencephaly of surviving cotwin (this case courtesy Dr. Joel Cure).
hyperbilirubinemia) all impact on whether or not brain injury will
occur (473,476). Indeed, up to 8% of low-risk infants suffer an episode
of hypoglycemia using the blood glucose level criteria, typically at 3 to
4 hours after delivery (474). Reasons for tolerance of low glucose levels
by infants include (a) the ability of the newborn brain cells to utilize
lactate as an energy source (477,478), (b) low energy requirements of
the immature neurons resulting from the low level of neuronal activity
(473), (c) the relatively minor effect of hypoglycemia upon cardio-
vascular function of the newborn (479), and (d) marked increase in
cerebral blood flow provided by even moderate hypoglycemia (473).
It should be noted that the presence of hypoglycemia exacerbates
hypoxic-ischemic injury, but that this condition has characteristics of
hypoxia-ischemia and not hypoglycemic brain injury (386,473).
Volpe (473) describes four major causes of neonatal hypoglyce-
mia. Transitive-Adaptive hypoglycemia is the term he uses to describe
a heterogeneous, relatively common condition in which the onset is
very early after birth, the duration is brief, the degree is mild, and the
response to glucose is prompt. Included in this group are infants of dia-
betic mothers, infants with erythroblastosis, and preterm infants who
suffer hypoxia-ischemia. Infants in this group are rarely symptomatic.
Secondary-associated hypoglycemia describes infants with hypoglyce-
mia secondary to associated illnesses, such as hypoxia-ischemia, intrac-
ranial hemorrhage, sepsis, and congenital anomalies. Affected neonates
typically present at the end of the first day of life, duration of hypogly-
cemia is brief, degree is fairly mild, and response to glucose therapy is
prompt. About half of infants in this category exhibit neurologic symp-
toms. Classical transient neonatal hypoglycemia includes principally
small for gestational age term infants who have suffered intrauterine
malnutrition; it is significantly less common than the first two groups.
Most affected infants are symptomatic, typically presenting toward the
end of the first day of life. The degree of hypoglycemia is relatively
severe, duration may be prolonged, and large amounts of glucose
are required as therapy. Severe recurrent hypoglycemia is the final and
least common category; most infants in this group have primary dis-
orders of glucose homeostasis. Causes include Beckwith-Wiedemann
syndrome, beta cell nesidioblastosis, beta cell hyperplasia, endocrine
deficiencies, and inborn errors of metabolism. In our experience at
Barkovich_Chap04.indd 311
311
UCSF, the most common cause of neuroimaging-apparent brain dam-
age secondary to neonatal hypoglycemia is hyperinsulinism secondary
to congenital tumors or hyperplasia of pancreatic beta cells. As Inder
points out, three principles are important in relation to hypoglycemic
brain injury in the newborn. First, prolonged and severe, rather than
transient or minor, hypoglycemia seems to be required. Second, the
injury involves primarily neurons of the upper cortical layers (layers 2
and 3) in the parietal and occipital cortex, as well as the hippocampi,
caudates, putamina, brain stem, and cerebellum. Finally, mild hypogly-
cemia combined with mild hypoxia causes injury, whereas either of the
two conditions in isolation does not (386).
Imaging studies of patients who have suffered damage from peri-
natal hypoglycemia reflect the pathological findings (480–482) of dif-
fuse brain damage, with the most severe injury localized primarily to
the parietal and occipital cortex of the brain and the underlying white
matter (19,20,483); hippocampi, corpus striatum, and cerebellum are
involved to a lesser extent. In the acute phase, reduced diffusivity is seen
along with edema of the cerebral cortex and underlying white matter
(Fig. 4-57), including the callosal splenium; T1 hypointensity and T2
hyperintensity in the affected cortex results in lack of distinction between
the cortex and subcortical white matter on T1- and T2-weighted images
(Fig. 4-57). MRI shows short T1 hyperintensity and T2 hyperintensity,
probably secondary to necrosis, in the cortex in the subacute phase.
As in ischemic injury, imaging in the subacute phase shows hyperin-
tensity and some damage to affected cortex, while diffusion imaging
shows reduced diffusivity in the white matter beneath the cortex, rather
than in cortex itself (Fig. 4-58) In the chronic phase (Fig. 4-57D and E),
the cortex and underlying cerebral white matter initially show cystic
encephalomalacia and, ultimately, become shrunken and atrophic.
The only reported proton MRS studies were performed with a short
echo time of 30 milliseconds. Large peaks were seen from 0.9 to 1.6
ppm (484). Although the authors suggested that lactate was present, no
intermediate or long echo spectrum was performed to unequivocally
demonstrate the presence of lactate. It is likely that the macromolecular
peaks were the result of massive cellular necrosis with release of macro-
molecular lipids. Although it is not unreasonable to suppose that some
lactate was present, verification will require further MRS studies.
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 312 Pediatric Neuroimaging

FIG. 4-57. Neonatal hypoglycemia, acute and chronic phases. A. Axial CT

scan shows parietal edema (arrowheads). Note that the low attenuation of
white matter seems to continue to the inner table of the skull. B. Axial T2
weighted image shows abnormal high signal intensity in the cerebral cortex,
primarily in the parietal and occipital lobes (arrows). C. Axial ADC image
(b = 700 s/mm2) shows reduced water motion (hypointensity, arrows) in the
posterior cortex. D and E. Follow-up sagittal and axial 3 weeks after injury
shows marked necrosis and atrophy (arrows) in the parietal and occipital
cortex.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
BILIRUBIN ENCEPHALOPATHY
(KERNICTERUS)
Although the relationship between serum levels of unconjugated bili-
rubin and brain damage is complicated, it is generally accepted that
sustained or pronounced neonatal hyperbilirubinemia results in brain
damage (485,486). Hyperbilirubinemia may be the result of a number
of predisposing factors. Red blood cell hemolysis (secondary to blood
group incompatibility, intrinsic defects of the red cell membrane or of
hemoglobin, or degradation of blood from hematoma formation) is
the most common cause. Other causes include polycythemia, inherited
or acquired defects of bilirubin conjugation, disorders of gastrointesti-
nal transit, prematurity, and hormonal disturbances (485,486).
Neonates with bilirubin encephalopathy manifest stupor and
hypotonia in the first few days of life; seizures occur in a minority
of affected patients. By the middle of the first week, hypertonia, with
backward arching of the neck or back, develops. Delayed development
Barkovich_Chap04.indd 313
313
FIG. 4-58. Neonatal hypoglycemia, subacute phase. A.
Sagittal T1-weighted image shows abnormal hyperintensity
(black arrows) of the parietal and occipital cortex. B. Coronal
T2-weighted image shows abnormal hyperintensity (small white
arrows) of the parietooccipital cortex and underlying white
matter. Note that the more anterior parietal cortex (large black
arrows), superiorly, has normal signal intensity. C. Axial Dav map
shows hypointensity (reduced diffusivity, white arrows) in the
occipital white matter.
becomes apparent during the first postnatal year. Extrapyramidal signs
(especially athetosis), abnormalities of vertical and horizontal gaze,
and hearing deficits typically develop after the age of 1 year (406,485).
It is not clear precisely how the bilirubin gets into the brain. It
appears that bilirubin can be transported across an intact blood–brain
barrier; it also appears, however, that disruption of the blood–brain
barrier, whether by hyperosmolarity, hypercarbia, hypoxia-ischemia,
or acidosis, facilitates the transport (485). A group of transporter mol-
ecules in neurons, glia, and capillary endothelial cells usually export the
bilirubin from brain cells to the extracellular space and then across cap-
illary walls into the blood. Disturbance in the action of these transport-
ers, either due to genetic causes or due to depletion of energy sources,
may play an additional role in neuronal injury by bilirubin (485). In
any event, the presence of high cellular bilirubin in neurons results in
injury, most prominent in certain locations of the brain. Pathologic
studies of children with chronic bilirubin encephalopathy have dem-
onstrated damage to the globus pallidus, subthalamic nucleus, and
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 314 Pediatric Neuroimaging

the CA2 and CA3 regions of the hippocampus (5,406). Of interest,
sick, acidotic, and edematous preterm infants with low serum albu-
min levels can develop pallidal injury and hearing loss from bilirubin
encephalopathy, even in the setting of clinically acceptable serum bili-
rubin levels, possibly because they have a less mature blood–brain bar-
rier or because their low albumin level results in higher free bilirubin
levels (485,487,488).
No specific CT or ultrasound findings have been described in bili-
rubin encephalopathy. In our experience, transfontanelle sonograms
inconsistently show hyperechogenicity of the globi pallidi (Fig. 4-59A)
(488,489). On MRI, neonates with acute bilirubin encephalopathy
show inconsistent T1 shortening and, rarely, T2 prolongation in the
affected regions (Fig. 4-59B and C) (488,490,491). Proton MRS with
TE of 144 milliseconds in the acute phase shows elevated myo-inositol/
Cr and Glx/Cr but no lactate (492). In the chronic phase, T2 prolonga-
tion and atrophy can be seen in the globi pallidi, subthalamic nuclei,
hippocampi, and cerebral white matter (Fig. 4-59D), while proton
MRS shows reduced NAA (493).

FIG. 4-59. Kernicterus. Acute and chronic stages. A. Coronal transfontanelle sonogram in a 2-week-old neonate with bilirubin
encephalopathy shows hyperechogenicity (white arrows) in the globi pallidi. B. Axial T1-weighted image in a 9-day-old infant with
bilirubin encephalopathy shows abnormal hyperintensity (black arrows) in the globi pallidi. C. Axial T2-weighted image in same
infant as (B) shows hyperintense white matter but normal appearing globi pallidi. It is not know why globi pallidi often appear nor-
mal acutely after injury. D. Coronal T2-weighted image in a 17-month-old infant shows evidence of kernicterus injury; abnormal
hyperintensity of the globi pallidi (white arrowheads), hippocampi (small white arrows), and right subthalamic nucleus (large white
arrow).

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 315

BRAIN INJURY ASSOCIATED WITH
CONGENITAL HEART DISEASE
Neurological deficits have been described in a large proportion of neo-
nates with complex congenital heart disease (494–497). It is not clear,
however, what proportion of these deficits are the result of the underlying
disease as compared to resulting from the surgical correction of the dis-
ease (33,498). Ultrasound studies have suggested the presence of cerebral
parenchymal disease in affected children prior to surgery (499) and this
has recently been confirmed by MRI (33,498). Recently, MRI and MRS
studies at UCSF (498) and other institutions (494) have shown that cere-
bral infarctions (Fig. 4-60A), cerebral white matter injury (presumably
ischemic, Fig. 4-60B–D), and abnormally elevated lactate are seen in the
brains of approximately 25% of children with congenital heart diseases
before they undergo reparative surgery. Additional injuries (infarctions
in ~20%, white matter injury in ~40%, and parenchymal hemorrhage
in ~10%) seem to be acquired between the preoperative MR studies and
postoperative studies obtained within 2 weeks of the surgery (494,498).
The presence of predominantly white matter injury (Fig. 4-60B–D) is
somewhat surprising as, outside of the spectrum of children with con-
genital heart disease, isolated white matter injury is usually seen in pre-
mature infants and not in term infants. The white matter injury may be
due to chronic hypoxia (163, 176) or, perhaps, to other factors, associ-
ated with heart disease, that delay brain maturation (498).

FIG. 4-60. Brain injuries associated with congenital heart disease include infarction,
ischemic cerebral white matter injury and, in the chronic phase, atrophy. A. Axial DWI
shows hyperintensity (white arrows) indicating an acute infarction in the left caudate
head and anterior putamen. B. Axial Dav map prior to heart surgery in a child with
transposition of the great vessels shows hypointensity (black arrows) behind the ventric-
ular trigones, indicating reduced diffusivity and acute injury. C. Axial inversion recov-
ery image shows abnormal T1 hyperintensity (black arrows) in the same regions that
had reduced diffusivity in (B). D. Sagittal T1-weighted image better shows the extent of
white matter injury (black arrows). The white matter injury is likely the result of chronic
mild to moderate hypoxia.

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 316 Pediatric Neuroimaging
HYPERNATREMIC DEHYDRATION
Young infants and, especially, premature infants are susceptible to
hypernatremia resulting from their relatively large surface area com-
pared to body weight (and thus increased insensible water loss through
the skin) and the inefficiency of water conservation secondary to their
renal immaturity (500). The most common cause of hypernatremia
dehydration is severe diarrhea (500,501). Affected infants typically
are extremely lethargic, yet hyperirritable to stimuli. Other signs and
symptoms include muscle rigidity, hyperreflexia, and, occasionally, sei-
zures (500,501). Brain damage is common, often with significant neu-
rologic sequelae (501).
Neurologic injury in hypernatremic dehydration results from the
elevation of sodium concentration in the extracellular spaces. Fluid
moves from intracellular to extracellular space, resulting in cellular
shrinkage. The brain pulls away from the calvarium, resulting in tear-
ing of bridging veins. In addition, the hyperosmolality within the blood
may cause capillary enlargement; superimposed upon shrinkage of the
vascular endothelial cells, this may predispose the affected patient to
capillary rupture and intraparenchymal hemorrhage (502). Finally,
dural venous sinus thrombosis can develop, with associated venous
infarctions (503).
Neuroimaging studies in hypernatremic dehydration reflect the
pathologic findings of interstitial edema and focal hemorrhages. On
sonography, the interstitial edema is seen as hyperechogenicity with
normal echo texture. Hyperacute hemorrhages are seen as focal, well-
demarcated regions of hypoechogenicity with a finer echogenic struc-
ture than normal brain tissue; as the hemorrhages coagulate, they
become hyperechoic. On CT and MRI, the interstitial edema is seen
as decreased attenuation and prolonged T1 and T2 relaxation times,
respectively, in the cerebral and cerebellar white matter. Reduced diffu-
sion is seen acutely in the lateral thalami and globi pallidi (504). Focal,
well-defined hemorrhages are seen in the cerebrum and cerebellum in
the cortex and the cortical-white matter junctions (505).
CNS TRAUMA IN INFANCY AND
CHILDHOOD
Pediatric trauma can be divided into two distinct groups. Birth trauma
is composed of those injuries that occur during and as a result of the
birth process. This form of trauma is unique in its pathological and
radiographic manifestations because of the immaturity of the CNS and
of the surrounding calvarium and spinal canal. Birth trauma will there-
fore be dealt with in some detail in this section. Trauma that occurs
later in life (postnatal trauma) results in pathological and radiological
exams that are similar to those in the adult. Since most neuropathol-
ogy and neuroimaging textbooks discuss the adult type of trauma, only
those aspects unique to children, such as nonaccidental trauma, will be
discussed in detail. Hypoxic-ischemic injury is sometimes considered
a form of birth trauma. However, as hypoxic-ischemic injury was dis-
cussed earlier in this chapter, it will not be duplicated here.
Birth Trauma
Ultrasound is the initial imaging modality of choice for the evalua-
tion of birth trauma because the scans can be obtained in a rapid fash-
ion without moving the patient; as a result, the patient can be closely
monitored during the exam. If the neonate has neurologic signs that
are unexplained by the ultrasound findings, further imaging should
be obtained. Although CT is adequate for assessment of injury, it has
the disadvantage of radiation exposure. Therefore, MRI is the study of
Barkovich_Chap04.indd 316
choice if available. MRI better demonstrates acute cerebral ischemia
than CT or sonography, as well as more accurately revealing posterior
fossa pathology such as retrocerebellar subdural hematomas, brain-
stem injury, and small cerebellar hemorrhages or infarctions. Although
it has been argued that oxyhemoglobin, the hemoglobin form seen
in hyperacute hemorrhage, is difficult to detect by MRI, hyperacute
hematomas are seen by MRI as space-occupying masses; their hem-
orrhagic nature can be confirmed by the very low signal intensity on
T2 gradient-echo or susceptibility-weighted sequences. It is difficult
to detect acute subarachnoid hemorrhage by MRI, although there is
some evidence that FLAIR sequences can be more sensitive than CT
[506,507]); however, the identification of subarachnoid hemorrhage is
rarely critical in the neonate. Similarly, the difficulty of distinguishing
the signal void of intracranial air (pneumocephalus) from that of over-
lying cortical bone is not a problem in the neonate, as pneumocephalus
rarely accompanies birth trauma. Nonetheless, in the acutely ill neonate,
the overriding factors are speed and safety, often making CT the second
imaging study of choice after ultrasound. When CT is obtained in the
acutely ill newborn, the patient should be scanned with 3 mm slice
thickness without the use of IV contrast. At this stage, the major goal is
to rule out large, space-occupying hematomas; small subdural hema-
tomas (particularly at the falcotentorial junction) are common after
vaginal deliveries and are of no clinical significance (508,509). Acute
interhemispheric and posterior fossa subdural hematomas are seen
on transfontanelle sonography as mildly echogenic fluid collections,
and on CT as hyperdense, extra-axial collections. Convexity subdural
hematomas are sometimes difficult to see on sonography because of
the difficulty in angling the transducer adequately. Cerebral edema and
infarcts appear as areas of increased echogenicity in the hemispheric
white matter on sonography and as areas of hypoattenuation on CT.
After the patient has stabilized, or if injury is not adequately revealed
by CT or ultrasound in the setting of strong clinical suspicion of injury,
magnetic resonance is the preferred imaging modality for assessing the
full extent of damage to the brain. MRI has been proven to be more
sensitive than CT in the detection of small extra-axial fluid collections
and white matter injuries (510–516). Brainstem injuries, important
for determining prognosis, are better detected by MRI (514). In order
to detect hemorrhage with maximal sensitivity, T2 gradient-echo or
susceptibility-weighted images should be obtained in all trauma or
suspected trauma cases. Diffusion imaging can also be useful to detect
acute injury in the watery neonatal brain; ADC images should always
be calculated to detect subtle injuries to the parenchyma.
Spinal Cord Injury
Various anatomical differences increase the susceptibility of infants to
spinal cord injury. The interspinous ligaments, posterior joint capsule,
and cartilaginous end plates are elastic and can be redundant, making
the pediatric spine more deformable than the more rigid adult spine.
Moreover, the planes of the facet joints are horizontally oriented (in
contrast to the more vertically oriented adult facet joint), creating
more mobility and less stability. Thus, infants are more susceptible to
hyperextension injury, which is most common in the cervical region
(517–521). Ligamentous laxity also makes the pediatric spinal cord
more susceptible to distraction injuries, as the neonatal spinal column
can be stretched 2 inches without structural disruption, whereas the
spinal cord ruptures after being stretched 0.25 inches (522); as a result,
the neonatal spinal cord may rupture but the spinal column remains
intact (523). Distraction injuries are most common in breech deliver-
ies and tend to occur in the lower cervical and thoracic regions (Figs.
4-61 and 4-62) (522,524–526). In cephalic delivery, injury to the upper
or midportion of the spinal cord is more common (5,523,527,528)
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 317

although injury at any level is possible and the involvement of multiple
levels is not uncommon. Spinal cord injuries that have been attributed
to birth injury include contusions, infarctions, lacerations, transections
(Fig. 4-61), dural disruption (Fig. 4-62), and subdural and epidural
hematomas (Figs. 4-63 and 4-64) (522,524,529).
The clinical presentation depends upon the level and extent of
injury. Severe injuries at the cranio-vertebral junction cause death
immediately. Incomplete injuries may allow survival. Mildly or mod-
erately injured patients may have low Apgar scores, respiratory distress,
or hypotonia. Prognosis is related to the severity and level of the injury;
high cervical cord injuries carry the worst prognosis because of the
effect on diaphragmatic motion and, consequently, ventilation (530).
Differential diagnosis includes amyotonia congenita (Oppenheim dis-
ease) or infantile spinal muscular atrophy (Werdnig-Hoffman disease).
When injury to the spinal canal or spinal cord is suspected, MRI
is the imaging modality of choice in the acute, subacute, or chronic
stage (531,532), although in experienced hands, sonography may be
useful (533,534). Sagittal, T1-weighted images should be obtained with
no greater than 3 mm slice thickness; these images will show subacute
blood and any structural deformity of the spinal cord or canal (Fig.
4-63 to 4-66). Sagittal, T2-weighted images should also be obtained;
fast/turbo spin-echo images are optimal because they are fast and
will usually show blood (Fig. 4-66). It is a good idea to acquire a T2
gradient-echo sequence to look for subtle hemorrhage, the presence
of which suggests a guarded prognosis. The T2-weighted images will
help to identify areas of edema or ischemia, which will have long T2
relaxation times, and areas of hemorrhage, which will have short
T2 relaxation times (Fig. 4-66). The worst prognosis for subsequent

FIG. 4-61. Birth trauma secondary to difficult breech delivery; sequential scans. A. Sagittal T2-weighted image shows abnor-
mal hyperintensity (white arrow) of the spinal cord at the C-2 level and retropharyngeal edema (white arrowheads). B. Axial
T2-weighted image more clearly shows hyperintense edema (arrows) in the spinal cord. C. Sagittal T1-weighted image several
days later shows narrowing of the cord at C-2 and hypointensity developing ventrally (arrows). D. Sagittal T2-weighted image
at the same time as (C) shows central hypointensity (black arrow), indicating hemorrhage within the spinal cord.

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 318 Pediatric Neuroimaging
FIG. 4-62. Birth trauma with spinal injury. A. Sagittal T2-weighted imaging shows the fracture-dislocation (large white arrow) through the C-5 vertebrae,
with spinal cord compression and complete ligamentous disruption. B. Axial T2-weighted imaging shows the abnormal T2 prolongation in the spinal cord and
the marked subcutaneous and deep soft tissue injury. C. Axial T2 gradient-echo image shows hypointense intramedullary hemorrhage (low intensity, arrow).
spinal cord function is in patients who have intramedullary hemor-
rhage; the next most severe is in those with edema extending over more
than one segment. The best prognosis is in those patients without hem-
orrhage or edema and in those with edema involving one segment or
less (535–539). MRI performed in the chronic phase, several months
after the event, can be helpful to determine the full extent of spinal
FIG. 4-63. Birth trauma. Spinal and intracranial extraparenchymal hema-
tomas. Sagittal T1-weighted image shows hyperintense extraparenchymal
blood in the dorsal spine (open white arrows), posterior fossa subdural
space (small solid black arrows) and interhemispheric subdural space (open
curved black arrows). (This case courtesy Dr. Chip Truwit, Minneapolis,
MN.)
Barkovich_Chap04.indd 318
cord damage (Figs. 4-63 and 4-64). Sonography will show injury as
hyperechogenicity and swelling of the cord in the acute and subacute
phases; regions of hemorrhage are more echogenic than regions of
edema (533,534). In the chronic phase, atrophy will be detected by
focal narrowing or, in severe cases, complete interruption of the spinal
cord. The importance of sonographic findings with respect to long-
term outcome has not been established.
Nerve Root and Brachial Plexus Injuries
Injuries to the nerve roots as they exit the spinal cord are relatively com-
mon, occurring in 0.3 to 3.6 of every 1000 live births (540); although
these are generally categorized as brachial plexus injuries, the injury most
commonly occurs to the roots that form the trunks of the plexus (541).
Injuries range in severity from mild stretching of the nerve, resulting in
transient neurologic dysfunction, to complete avulsion from the spinal
cord with resultant permanent deficit. The precise nature of the injury
depends upon the precise direction of the traction; most result from
traction of the shoulder while delivering the head of an infant in the
breech presentation or from turning the head away from the shoulder
in a difficult cephalic presentation of a large infant (542,543). Shoulder
dystocia and birth weight of greater than 3500 g are present in more
than half of cases (542) (cesarean deliveries have a lower rate of brachial
plexus injuries than do vaginal deliveries [544]). Clinically, Erb palsy
(adducted and internally rotated shoulder, extended, pronated elbow,
and flexed wrist resulting from injury to C-5, C-6, and C-7 roots) is
the most common presentation, with Klumpke palsy (extended wrist
and fingers, often associated with ipsilateral Horner syndrome resulting
from injury to C-8 and T1) considerably less common (530,541). The
majority of children with birth-related brachial plexus injury improve.
Although older studies suggest that up to 10% will go on to surgery
(545), more recent work indicates lower spontaneous improvement
rates and 10% to 15% permanent disability rate (546,547). At UCSF
and CHOP, these infants are monitored for 6 months; if no improve-
ment is seen or if improvement plateaus, surgery is performed.
The brachial plexus is most sensitively assessed by MR neurog-
raphy, looking for disruption of the individual roots and trunks of
the plexus (540,548,549). Coronal and axial STIR sequences, precon-
trast T1-weighted spin-echo images, and postcontrast fat-suppressed
T1-weighted spin-echo sequences are acquired (see Chapter 1 for
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
exact technique). Abnormalities seen include pseudomeningoceles,
enhanced, thickened nerves suggesting neuroma or scar, and low-lying,
“sagging” nerve roots suggesting avulsion without pseudomeningocele
formation (540) (Fig. 4-65). Avulsion of the roots may be seen on neu-
rography as abruptly terminating, thickened roots within a pseudo-
meningocele. Avulsed roots may also be seen on fat-suppressed RARE
images (Fig. 4-66) or by CT myelography, which demonstrate empty
(without a nerve root) small pseudomeningoceles at the site of the
avulsions. However, conventional myelography has essentially no role
in the modern radiologic evaluation of these patients. Thin section T2-
or T2*-weighted MR images, obtained in the coronal or axial planes,
will show the pseudomeningocele as an ovoid mass of hyperintensity
extending from the surface of the spinal cord to or through the affected
neural foramen; as little CSF motion will be present in the pseudo-
meningocele, thin section (2–3 mm) RARE sequences demonstrate
the pathology well (Fig. 4-66). Identifying a pseudomeningocele with
MRI or MR myelography has been reported to have a low sensitiv-
ity but a high specificity for nerve root avulsion although it cannot
Barkovich_Chap04.indd 319
319
FIG. 4-64. Spinal epidural hematoma from birth
trauma. A. Sagittal T1-weighted image shows abnormal
heterogeneous hyperintensity within the spinal suba-
rachnoid space. B. Sagittal T2-weighted image shows
an irregular layer of hypointensity (black arrows) in the
dorsal aspect of the spinal canal, strongly suggestive of
acute hemorrhage. Note the presence of edema (white
arrows) in the spinal cord. C and D. Axial T2-weighted
images show the hypointense dorsal subdural hematoma
(open black arrows) compressing the edematous spinal
cord (solid black arrows). (This figure courtesy Dr. Erik
Gaensler, San Francisco, CA.)
image well the exiting nerve (550). Identification of a posttraumatic
neuroma has a high sensitivity and specificity in determining lateral-
ity of injury but cannot reveal the exact area (i.e., trunk or division)
involved (550). Thus, MRI, which reliably shows the brachial plexus
and pseudomeningocele sac, in combination with MR neurography
and/or CT myelography, which shows the presence or absence of the
individual nerve roots, is the study of choice in affected patients.
Head Trauma
Extracranial Birth Trauma
Caput succedaneum is one of the three major varieties of extracranial
hemorrhage, the other two being subgaleal hemorrhage and cephalo-
hematoma. Caput succedaneum refers to a hemorrhage and edema
within the skin that is observed very commonly after vaginal delivery.
This edema is soft, superficial, pitting in nature, and crosses suture
lines. The lesion steadily resolves over the first few days of life. Radiog-
raphy is neither diagnostic nor necessary (551).
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 320 Pediatric Neuroimaging

FIG. 4-65. Neurogram of brachial plexus injury due to shoulder dystocia.

A and B. Coronal STIR images show edematous right C-7 and T-1 nerve
roots (bright and enlarged roots, white arrows). C. Axial STIR image shows
the edematous roots/trunks (arrows) as they course through the neck.

FIG. 4-66. Nerve root avulsion in a neonate. A. Coronal fat-suppressed T2-weighted image shows a pseudomeningocele
(arrows) at the right lateral spinal canal. B. Axial fat-suppressed postcontrast T1-weighted image shows the hypointense,
nonenhancing pseudomeningocele (black arrow) extending toward the right C-7 to T-1 neural foramen.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 321

Subgaleal hemorrhage refers to hemorrhage subjacent to the aponeu-
rosis covering the scalp beneath the occipitofrontalis muscle. Subgaleal
hematomas present as firm, fluctuant masses that increase in size after
birth; they sometimes dissect into the subcutaneous tissue of the neck.
Although patients can become symptomatic from these lesions second-
ary to blood loss, the lesion usually resolves over 2 to 3 weeks; imaging
of subgaleal hematomas is almost never necessary (551).
The term cephalohematoma refers to a traumatic subperiosteal
hemorrhage; because the blood is beneath the outer layer of perios-
teum, it is confined by the cranial sutures (Fig. 4-67). Cephalohemato-
mas occur in approximately 1% of live births; the incidence increases
markedly with the use of forceps and even more significantly with
vacuum-assisted deliveries (552). Cephalohematomas usually increase
in size after birth and present as a firm, tense mass; they are rarely
of clinical significance, unless a complicating intracranial lesion is
present. Resolution occurs in a few weeks to months (551). When
seen on CT or MRI, cephalohematomas appear as crescent-shaped
lesions adjacent to the outer table of the skull; they are hyperdense
on CT and show T1 and T2 shortening on MRI when imaged in the
subacute stage (Fig. 4-67). The hematoma does not cross the cranial
sutures. A few may eventually calcify; these gradually disappear over
many months of skull growth and remodeling. Occasionally, infants
are imaged at age 3 to 4 months when the parents or pediatrician
discover a firm mass (the calcified hematoma) on the skull. A CT at
this stage will show both an inner rim (calvarium) and an outer rim
(calcified elevated periosteum) of calcification (Fig. 4-67D). The MR
appearance of these lesions is usually that of subacute blood with high
signal intensity on T1- and long T2-weighted images that does not
cross a suture; when imaged more acutely, hypointensity may be seen
on T2-weighted images.

FIG. 4-67. Cephalohematoma. A. Axial CT scan shows soft tissue density overlying the skull between the lambdoid suture and
the coronal suture. Cephalohematomas do not cross sutures. Note that the outer wall of the cephalohematoma is periosteum,
which may calcify (arrows). B and C. Sagittal T1-weighted and axial T2-weighted MR images show the appearance of the acute
cephalohematoma. D. Axial CT at age 2 months show that the outer periosteal layer of the cephalohematoma has calcified.
Parents may bring these children to medical attention because of the “lump” on their head.

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 322 Pediatric Neuroimaging
Skull Fractures
The importance of skull fracture in the setting of head trauma is
unclear. While older studies indicate very little prognostic value for
fractures predicting neurological damage that results from trauma
(553,554) and some authors reporting that skull fractures may actually
diminish injury to the underlying brain (by dispersing the force from
the trauma) (555), more recent, larger studies indicate that the pres-
ence of a skull fracture increases the likelihood that the child has suf-
fered a clinically significant traumatic brain injury (556). Certainly, the
absence of a skull fracture by no means excludes brain damage. Docu-
mentation of fractures may be useful in the overall documentation of
trauma, however (especially nonaccidental trauma in older infants;
see section later in this Chapter). When documentation is desired, ref-
ormations in the coronal plane or 3D reformations using bone algo-
rithms may be valuable to detect fractures in the horizontal plane, can
be difficult to detect on routine CT scans. Alternatively, fractures can be
confirmed by obtaining skull x-rays or by close examination of the lat-
eral “scout” view from the CT scan; remember that the “scout” view may
be extremely valuable for the identification of skull fractures and should
carefully studied in all head trauma cases.
Barkovich_Chap04.indd 322
The most common skull fractures are linear and are most often
localized to the parietal or frontal bones. When the bone is not dis-
placed, the fracture heals spontaneously and no treatment is indicated.
In infants, skull fractures may heal in less than 6 months. In older chil-
dren, fractures generally heal within a year while in adults a healing
time of 2 to 3 years is common. As fractures heal, the fracture line on
radiographs becomes less and less distinct until, eventually, the fracture
may be difficult to differentiate from a vascular groove (557).
An important difference between infants and older children and
adults is the fact that the middle meningeal artery is not embedded
in the calvarium of the infant. Therefore, one need not be overly con-
cerned about a developing epidural hematoma when an infant sustains
a linear fracture of the squamous temporal bone (57).
Depressed skull fractures may result from pressure of the head
against the pelvis during the birth process or may be induced by appli-
cation of forceps (558,559). Whereas plain films may adequately visu-
alize linear fractures of the cranial vault, CT more accurately defines
the amount of displacement in a depressed fracture. Most importantly,
CT identifies space-occupying hematomas and assesses damage to
the underlying brain (Fig. 4-68), whereas plain radiography does not.
FIG. 4-68. Fracture and parenchymal injury secondary to
birth trauma, forceps delivery. A. Axial noncontrast CT scan
shows left parietal fracture (black arrows) and underlying
subdural hematoma (S) and small parenchymal hematoma
(white arrow). A large amount of scalp swelling and hemor-
rhage are also present. B. Axial proton density image shows
left medial parietal lobe contusion (black arrow) and periven-
tricular injury. C. Axial DWI shows reduced diffusion, mani-
fest as hyperintensity in the affected cortex.
5/25/2011 11:39:23 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
Depressed skull fractures are most often elevated, treated surgically or
noninvasively (560).
Occasionally, skull fractures are associated with tears of the under-
lying dura. When dural tears occur, meninges and brain tissue can her-
niate into the diastatic fracture site. The interposition of the meninges
between the diastatic bones prevents the osteoblasts from migrating
across the fracture site and inhibits healing of the fracture. Moreover,
the constant CSF pulsations upon the fracture cause enlargement of the
fracture and extracranial extension of meninges. This situation has been
called a “growing fracture” or a leptomeningeal cyst (557,561,562). Lep-
tomeningeal cysts are seen in 0.6% of all fractures, with 90% occurring
in patients less than 3 years old (561,562). On imaging studies leptom-
eningeal cysts have distinct bony margins at the fracture site (512,557),
simulating a lytic calvarial lesion if the associated abnormalities of the
subarachnoid space and underlying brain are not appreciated (563).
Intracranial tissue or CSF may be seen extending between the edges of
the bone at the fracture site (Figs. 4-69 and 4-70); this finding may be
useful to make the diagnosis early in the course of the injury, before the
fracture begins to progressively enlarge (564). Encephalomalacia of the
underlying brain is usually present, in our experience, appearing as an
area of low attenuation on CT (Fig. 4-70) and as an area of prolonged
T1 and T2 relaxation time on MRI (Fig. 4-70).
Traumatic Intracranial Hemorrhage in the Newborn
Mechanical trauma to the infant’s brain during delivery is some-
times seen in association with prolonged or precipitous delivery,
vaginal breech delivery, instrumented delivery, use of forceps or ven-
touse extraction (565). Most typically, the result is subdural hemor-
rhage; epidural, subarachnoid, and intraventricular hemorrhage may
also occur, but are almost always in conjunction with subdural blood
(551,566). Epidural hematoma is quite rare and usually is associated
with a large cephalohematoma and a subjacent skull fracture (567).
Patients typically present with increasing intracranial pressure/bulg-
ing anterior fontanel (551). Intraventricular hemorrhage is common
in the premature neonate, in which it is almost always the result of
germinal matrix hemorrhage that ruptures into the ventricular system,
as was discussed in the section on brain injury in prematurely born
FIG. 4-69. Leptomeningeal cyst. A. Plain film shows a well marginated lucency (arrows) with a sclerotic border at the site of a
previous skull fracture. B. Axial CT image shows brain herniating through a dural defect and causing erosive changes in the bone at
the fracture site. Encephalomalacia (arrows) is present in the underlying brain.
Barkovich_Chap04.indd 323
323
neonates. Subarachnoid hemorrhage is common in the neonate. When
seen in premature neonates, it is almost always the result of germi-
nal matrix hemorrhage that ruptures into the ventricular system. In
term neonates, it is almost always found in association with subdural
hemorrhage, but the pathogenesis is unknown; clinical consequences
are rare unless the hemorrhage is extensive, in which case it may lead
to hydrocephalus (551). Intraparenchymal hemorrhage is less common
than extraparenchymal hemorrhage and is typically associated with
venous injury or venous thrombosis.
Subdural hemorrhage is common in vaginally delivered neonates,
and is probably caused by lacerations of subdural veins near the fal-
cotentorial junction that result from molding of the head. MRI has
greatly increased the knowledge concerning the frequency and sever-
ity of subdural hemorrhage in newborns. Whereas it was previously
believed that posterior fossa subdural hematomas in infants were
rare and often life threatening, we now know that small falcine and
posterior fossa subdural hematomas are common in the postnatal
period (Fig. 4-71), reported in 26% to 63% of uncomplicated vaginal
deliveries (508,509,568). They are usually small (<3 mm) and are rarely
of clinical importance (508,509). Indeed, most resolve by the end of the
first postnatal month and nearly all resolve by 3 months. There are no
developmental sequelae unless they are associated with parenchymal
injury (i.e., venous infarction due to venous thrombosis) or result in
sufficient compression to impair CSF flow or brainstem function; in
the latter cases, they are surgical emergencies (569,570). There are four
major categories of neonatal subdural hemorrhage: (i) tentorial lacera-
tion, (ii) occipital osteodiastasis, (iii) falx laceration, and (iv) rupture
of bridging superficial cerebral veins.
Tentorial Laceration and Occipital Osteodiastasis
These two injuries are discussed together because both result in pos-
terior fossa subdural hemorrhage. Large tears of the tentorium result
in rupture of the vein of Galen, straight sinus, or transverse sinus;
the resulting subdural hemorrhage tends to be massive. The rapidly
expanding subdural collection can cause compression of the brain-
stem and result in death (569). Lesser degrees of infratentorial sub-
dural hemorrhage may result from smaller tentorial tears or rupture of
5/25/2011 11:39:23 AM
 324 Pediatric Neuroimaging

FIG. 4-70. Leptomeningeal cyst. A. Axial SE T1-weighted image shows encephalomalacia (curved black arrows) in the left temporal lobe with a well-
demarcated defect (curved white arrows) in the adjacent bone. B. Axial T2-weighted image better demonstrates CSF extending into the fracture site (arrows).
C. Bone window of a CT image shows the heaped-up bone edges (arrows) at the fracture site. (This case courtesy Dr. Chip Truwit, Minneapolis, MN.)

FIG. 4-71. Small posterior subdural hematomas in neo-

nates. A. Sagittal T1-weighted image shows an incidental
small retrocerebellar subdural hematoma (white arrow).
B and C. Sagittal (B) and axial (C) T1-weighted images
of a different patient show slightly more extensive benign
hemorrhage, shown as hyperintense subdural blood pos-
terior to the cerebellum (curved arrows) and along the
tentorium cerebelli (small solid arrows) and posterior
falx cerebri (open arrow).

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
smaller infratentorial veins without tentorial tears (Fig. 4-71). As stated
above, these small subdural collections are being recognized more fre-
quently as a result of the increased sensitivity of MRI and are usually
of no clinical consequence. The falx cerebri or supratentorial veins may
be torn at the same time, resulting in simultaneous supratentorial and
infratentorial subdural hematomas (Fig. 4-71) (508,570,571).
Occipital osteodiastasis consists of traumatic separation of the
squamous portion of the occipital bone and the exoccipital portion of
the occipital bone (at a site called the posterior occipital or supraoc-
cipital-exoccipital synchondrosis) during birth. This can be seen on
lateral radiographs or on CT with bone windows (572). In severe cases,
the dura and occipital sinuses are torn; the result is cerebellar lacera-
tion and a massive posterior fossa subdural hemorrhage (541,573).
The posterior fossa subdural hematoma lies under the tentorium and
extends laterally between the dura and arachnoid overlying the cerebel-
lar hemisphere.
On sonography, the hematoma is seen as mildly to moderately
echogenic material lying superior to the cerebellum on the sagittal
and coronal images (Fig. 4-72A and B). Both the fluid collection lying
beneath the tentorium and the hydrocephalus resulting from compres-
sion of the fourth ventricle and aqueduct can be detected (Fig. 4-72).
The CT appearance of these hemorrhages in the acute phase is that of
a high density thickening of the affected tentorial leaf with the high
density extending inferiorly, posterior to the cerebellar hemisphere
(Fig. 4-72C and D). These lesions are usually seen well on coronal and
sagittal views; the high density hematoma is seen immediately beneath
the tentorium (557,574). When some supratentorial veins or the falx
cerebri are also torn, a supratentorial interhemispheric subdural
hematoma may also be present. In the anemic infant, the acute sub-
dural hematoma may be isodense or even hypodense to brain because
of the relatively low protein content of the subdural collection. The
MR appearance of subdural hematomas varies with their chronicity. A
hyperacute hematoma is isointense to slightly hyperintense compared
with CSF on T1-weighted images, isointense or mixed iso/hypointense
compared to CSF on T2-weighted images, hyperintense on DWIs, and
hypointense on calculated ADC images. An acute subdural hematoma
is isointense to brain on T1-weighted spin-echo sequences, hypoin-
tense to brain on T2-weighted spin-echo and gradient-echo sequences
(Fig. 4-72 and 4-73), and hypointense on both DWI and ADC images;
FIG. 4-72. Tentorial and retrocerebellar subdural hematoma in a newborn. A and B. Sagittal (A) and coronal (B) sonograms
show the subdural hematoma as a hyperechogenic region (white arrows) within the tentorial incisura and below the tentorium,
pushing the cerebellum downward.
Barkovich_Chap04.indd 325
325
this appearance results from the presence of deoxyhemoglobin in the
red blood cells (575–578). RARE sequences are less sensitive to the
presence of blood products but they will usually be hypointense (Fig.
4-72G). As the hematoma evolves, it develops high signal intensity that
starts in the periphery on the T1-weighted spin-echo sequences and
progresses centripetally toward the center of the hematoma. The high
signal intensity, which appears first on T1-weighted spin-echo images
and later on T2-weighted spin-echo images, results from the conver-
sion of deoxyhemoglobin to methemoglobin. The hematoma remains
largely hypointense on DWI and ADC images at this stage (578). A
fluid-fluid level may be seen at this phase of hematoma evolution, as
the intact red blood cells remain in a dependent position (intermediate
signal on T1-weighted images, dark on T2-weighted images) with free
methemoglobin in the more superior supernatant liquid (bright on
both T1- and T2-weighted images) (579). Finally, as the blood break-
down products are reabsorbed, signal intensity on the T1-weighted
spin-echo images diminishes until eventually the subdural collection
is isointense with CSF on all sequences. It is important to evaluate the
size of the ventricles in these patients because acute hydrocephalus may
develop as a result of compression of the fourth ventricle or aqueduct.
It is important to remember that spine injury may occur in con-
junction with brain injury (Fig. 4-73). The possibility of injury to the
cervical spine should always be kept in mind when studying patients with
traumatic delivery and either a severe skull base injury or a worse neuro-
logic exam than can be explained by the amount of intracranial injury.
Falx Laceration and Superficial Cerebral Vein Rupture
These two injuries are discussed together because both result in
supratentorial subdural hematomas. Laceration of the falx cerebri is
much less common than, and usually occurs in conjunction with, lac-
eration of the tentorium. It usually occurs near the junction of the falx
with the tentorium, the source of bleeding most commonly being the
inferior sagittal sinus. The cause of both falx and tentorial tears seems
to be excessive vertical molding of the head with frontaloccipital elon-
gation. When laceration of the falx occurs, the subdural hematoma is
usually located in the inferior aspect of the interhemispheric fissure
over the corpus callosum (551).
Rupture of superficial cortical veins that bridge the dura results
in hemorrhage over the cerebral convexity. In contradistinction, an
5/25/2011 11:39:25 AM
 326 Pediatric Neuroimaging

FIG. 4-72. (Continued) C and D. Noncontrast CT image shows

interhemispheric subdural hematoma (arrows). Axial CT image
at the level of the fourth ventricle (C) shows the high attenu-
ation of the subdural hematoma in the left side of the poste-
rior fossa (large arrow) and behind the cerebellar hemispheres
(small arrows). Axial CT at a higher level (D) shows the subdural
hematoma (arrows) along the left leaf of the tentorium cerebelli.
E–G. Sagittal T1 (E), coronal postcontrast T1 (F), and axial
T2-weighted (G) MR images show the hematoma (white arrows)
within the tentorial incisura, pushing down on the cerebellum
and brainstem.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 327

FIG. 4-73. Birth trauma. A and B. Coronal sonograms show slight hyperechogenicity of the thalami, suggesting hypoperfusion injury (later confirmed).
Increased echogenicity (solid white arrows) suggesting hemorrhage is present at the tentorial incisura. Hypoechogenicity (open white arrows) is present
behind the cerebellum. C and D. Axial T2-weighted images show acute retrocerebellar (open black arrows), falcotentorial junction (solid black arrows), and
supratentorial convexity (small white arrows) subdural blood. E and F. Axial T1-weighted images shows abnormal hyperintensity of the globi pallidi and
the perirolandic cortex, as well as a subgaleal fluid collection (open white arrows). G. Sagittal T2-weighted image shows fracture dislocation of the mid-level
cervical spine (large white arrow) with prevertebral edema (small white arrows). Note the hypointense hemorrhage (black arrowheads) at the falco-tentorial
junction.

interhemispheric subdural hematoma results from lacerations of the falx
or falcine veins. In contrast to subdural hematomas occurring later in
infancy, which are more commonly bilateral, convexity subdural hemato-
mas in the newborn are usually unilateral and accompanied by subarach-
noid blood. An underlying cerebral contusion may be present (580).
The ultrasound, CT, and MR appearances and evolution of
supratentorial subdural hematomas (Fig. 4-74) are identical to those
previously described for infratentorial subdurals. As with infratentorial
subdural hematomas, coronal views are often helpful in assessing the
true size and extent of subdural collections. Whereas interhemispheric

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 328 Pediatric Neuroimaging

FIG. 4-74. Birth trauma. A. Coronal sonogram shows a left sided sub-
dural collection (open white arrows) with mass effect on the left lateral
ventricle. The brain parenchyma looks relatively unaffected. B and C.
Axial noncontrast CT images show subdural hemorrhage along the left
leaf of the tentorium (large white arrow), in the interhemispheric fissure
near the falco-tentorial junction (small white arrow), along the left cere-
bral convexity subdural space, and in the subcutaneous and subgaleal
spaces. Note the severity of the cerebral cortical involvement, which is
not detected by the sonogram (A).

subdural collections can be seen relatively easily on sonography, con-
vexity hematomas are more difficult to visualize because of the dif-
ficulty involved in angling the transducer to see the convexity region.
Importantly, sonography can be performed in the neonatal ICU and,
therefore, does not necessitate transporting very ill patients.
Postnatal Trauma
Although traumatic brain injury in infants and children is very similar
to that in adults, the causes are very different. Severe accidental head
trauma, common in older children and adults, is rather uncommon
in infants less than 2 years old. In fact, nonaccidental injury (child
abuse) is 10 to 15 times more common than accidental head trauma
in infants less than 1 year old (581) and nonaccidental trauma is the
leading cause of subdural hemorrhage at autopsy in children less than
1 year of age (582). Thus, when findings of severe head trauma are
found on imaging studies of infants, the suspicion of nonaccidental
trauma should always be raised. The imaging findings of trauma in
adults are described in a number of publications (512); therefore, those
characteristics in children that are similar to those in adults will be
only briefly discussed in this book. The differences in imaging findings
between children and adults will be emphasized.
CT is the initial imaging study of choice for acute head injury, to
detect herniation, large hematomas, or pneumocephalus that portends
fracture of the skull base; consideration should be given to including
the upper cervical spine (occiput to C-3), an area that is highly suscep-
tible to injury in young infants (583). After the patient has stabilized,
magnetic resonance is the preferred imaging modality for assessing the
full extent of damage to the brain. MRI has been proven to be more sen-
sitive than CT in the detection of small extra-axial fluid collections and
white matter shearing injuries (510–516). Brainstem injuries, which
have important prognostic significance, are better detected by MRI
(514). Moreover, MRI is extremely sensitive to the presence of hemo-
siderin from old hemorrhage (575); the presence of old CNS injuries in
association with newer ones may be important evidence in the diagnosis
of nonaccidental trauma. In order to detect hemorrhage with maximal
sensitivity, T2 gradient-echo images or susceptibility-weighted images
(584) should be obtained in all trauma or suspected trauma cases.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 329

Spinal Trauma Although neurological function at presentation is the single best

Vertebral column fractures and spinal cord injuries in children are less predictor of long-term neurological outcome (595,596), children have
common than in other age groups; however, they are not rare and have a significantly greater recovery of function after spinal cord injury than
received increasing attention in the medical literature since the advent do adults (597). MRI is a useful adjunct in the evaluation of spinal
of modern imaging techniques. As discussed in the section on birth trauma, especially in children who have abnormal findings on radio-
trauma, the pediatric spinal column has anatomic characteristics that graphs or CT; unexplained instability after normal studies in the acute
create different patterns of susceptibility to injury among children, as phase; persistent or delayed symptoms; disturbances of consciousness;
compared with adults. These include increased elasticity of ligaments or distracting injuries (598–601). In addition to demonstrating spinal
and soft tissues, open epiphyses, lack of development of ossification cord injury or extramedullary hematomas, MRI may show swelling of
centers, and changes in osseous strength, shape, and size (524,585,586). prevertebral soft tissues, injury (seen as abnormal T2 prolongation) to
For example, epiphysial plates are still open in the vertebral bodies of interspinous soft tissues (Fig. 4-75) or the posterior longitudinal liga-
younger children; they start to fuse at many levels by age 8 years. Facet ment, or traumatic disc herniations, in addition to cord injury (602).
joints are relatively horizontal in infancy, becoming more vertical with These findings may affect management in patients who need surgical
ossification between ages 7 and 10 years. Another factor concerns the stabilization (596,598). In addition, as discussed in the section on neo-
large head size and the relatively poorly developed paraspinous mus- natal spinal injury, MR findings are a sensitive indicator of the severity
cles in infants. This combination, coupled with the increased elasticity of spinal cord injury. T2-weighted images will help to identify areas
of ligaments, creates a relative hypermobility that leads to a predispo- of edema or ischemia, which will have long T2 relaxation times, and
sition for cervical spinal cord injury without plain film radiographic areas of hemorrhage, which will have short T2 relaxation times. The
abnormality (519,520). The greatest amount of motion in the cervical worst prognosis for subsequent spinal cord function is in patients
spine is at C-2 to C-3 in infants and young children; thus, injury is who have intramedullary hemorrhage (539); therefore, it is recom-
most common at this level. The fulcrum of movement moves to C-3 to mended that sagittal or axial T2 gradient-echo images be obtained (see
C-4 by the age of 5 to 6 years, and to C-5 to C-6, the same as in mature Figs. 4-61 and 4-62 in neonatal spine injury section). The next most
adults, by about age 15 years (519,524,587,588). Taking children as a severe MRI sign is the presence of edema extending over more than
whole, approximately 30% of injuries involve the upper cervical spine, one segment; this is best identified on sagittal T2-weighted images. The
15% involve the lower cervical spine, 30% involve the thoracic spine,
and 20% to 25% involve the lumbar spine (587,589–591). The causes
of spinal injury also vary with age. Cervical injuries in infants and tod-
dlers usually result from falls, motor vehicle accidents, and nonacci-
dental trauma; those in children aged 3 to 10 years result from falls,
bicycle accidents, and auto-pedestrian accidents; and those after age
10 years are most often the result of sports and automobile accidents
(588). As populations spend more time in motor vehicles, the causes
and location of cervical spine injuries change. A recent study in the
United States has revealed that the majority of spinal cord injuries in
the pediatric population are due to unrestrained children in motor
vehicles accidents (592). In such groups, more fractures and cervical
spinal cord injures in young children are found in the lower cervical
spine (593). The reason for this change is not known.
As infants and young children have a propensity for spinal cord
injury, an MRI should be obtained in all infants and children in whom
spinal injury is suspected, even in the absence of plain film radiologic
abnormalities. If radiographs are obtained, the radiologist should be
aware that findings in children, especially in the cervical spine, differ
from those in adults and that films taken in the “neutral” position can
be normal despite significant injury. The mobility of the cervical spine
in children is manifest by the large atlantodental space, which can be
as wide as 5 mm in children, and “pseudosubluxation,” a term refer-
ring to the up to 4 mm of anterior motion of C-2 on C-3 and C-3 on
C-4 in up to 40% of children under the age of 8 years (594). As a key
distinguishing feature, alignment of the spinolaminar line is preserved
with pseudosubluxation but misaligned with true subluxation. The
size of the prevertebral soft tissues also differs in children, as compared
with adults. In children less than 15 years old, the retrotracheal space
normally averages 3.5 mm and the retropharyngeal space averages 7 to
9 mm. In general, the prevertebral soft tissues should not exceed two
thirds of the width of the vertebral body of C-2 (524,594), although
this can be greatly affected by the phase of inspiration and patient posi-
tioning. In the adult, the prevertebral distance is normally 5 to 6 mm
at the C-3 level (524). Edema can be seen ventrally (usually a result of FIG. 4-75. Interspinous ligament injury. Sagittal STIR through the mid-
fracture) or dorsally (as a result of ligamentous injury) and, in either line in a 3-month-old infant shows T2 prolongation in the interspinous lig-
location, local soft tissue swelling (T2 hyperintensity and mass effect) aments of the midcervical spine (arrowheads). Focal subcutaneous edema
is most worrisome. and epidural fluid are also present posteriorly.

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 330 Pediatric Neuroimaging
best prognosis is in those patients without hemorrhage or edema and
in those with edema involving one segment or less (535–539). Keep
in mind that spinal cord edema increases by about one vertebral level
during the first day or two after injury with the maximum extent being
reached 48 to 72 hours after injury (603).
A great deal of literature has been concerned with the concept
of spinal cord injury without radiologic abnormality (SCIWORA) in
children (519,520). We don’t feel that classification of SCIWORA as a
separate entity is justified, as long as the radiologist and treating physi-
cian recognize the underlying concept that the immature spinal column
allows significant spinal cord injury to occur without plain radiograph
abnormalities and that other studies, such as MR, should be obtained to
look for soft tissue injury in appropriate clinical settings. SCIWORA will
not be addressed as a separate entity in this text.
Injuries in Young Children
It is important to remember that young children, through the age of
about 8 years, tend to sustain soft tissue injuries without incurring
radiologically apparent fractures. Thus, dislocations, ligamentous avul-
sions, subluxation without fracture, growth plate injuries, and epiphy-
sial separations are common. Most spinal injuries in this age group
involve the cervical spine, particularly the upper segments. Injuries,
including fatalities caused by automobile air bags, fall into this cat-
egory, particularly when children are improperly restrained (604,605).
Upper cervical injuries include atlanto-occipital dislocations, which
are frequently fatal (606) but, with improvements in on-scene resus-
citation, immobilization, and transportation techniques, have shown
increased rates of survival (607), and atlantoaxial dislocations, which
tend to be less serious because of the more capacious spinal canal at
C-1 (606). A combination of atlanto-occipital dislocation and atlanto-
axial dislocations can also be encountered. It is important to remem-
ber that the synchondrosis between the dens and the body of C-2 does
not normally fuse until the age of 7 or 8 years; therefore, trauma to
the odontoid in young children most commonly results not in a frac-
ture through the bony dens, but in a disruption of this synchondro-
sis, resulting in separation of the ossification center of the odontoid
Barkovich_Chap04.indd 330
from that of the body of C-2 (608,609). Plain radiographs in active
(not passive!) flexion and extension (performed carefully under phy-
sician supervision) will establish the diagnosis, but may be difficult
because of patient cooperation and rotation or superimposition of
structures; therefore, focal CT with coronal and sagittal reformations
has become the study of choice for upper cervical spine and atlanto-
occipital injuries in children (Figs. 4-76 and 4-77) (610). As discussed
in Chapter 1, newer CT technologies (such as automated dose modula-
tion algorithms) allow spine CT to be performed at doses lower than
previous standards (611). It is also important to remember that only
MRI will reliably show an associated spinal cord or brainstem injury
(Figs. 4-76 and 4-77) (518,536,538,612). As discussed in the section
on neonatal injury, the MRI may show edema, hemorrhage, or atro-
phy, depending upon the severity and chronicity of the injury (532).
Long segments of edema, extensive intramedullary hemorrhages, and
persistent compression of the spinal cord all are predictive of poor neu-
rologic outcome (595,613). Diffusion-weighted imaging and/or DTI in
the acute setting may be valuable in the evaluation of traumatic spinal
cord injury (Fig. 4-77) (614,615).
Rotary subluxations accompany rupture of the transverse liga-
ments and can become fixed. Diagnosis of fixed rotary subluxations is
made by performing CT scans with the head in a neutral position and
then turned 45° to the left and then 45° to the right (see section below
on torticollis/rotational injuries of C-1 to C-2). Fractures of the atlas
and axis are uncommon in younger children.
Fractures involving the thoracic or lumbar spine are uncommon
in children; they tend to involve the T-11 to L-2 levels, where the more
rigid thoracic spine joins the more mobile lumbar segments. Clinical
examination for thoracolumbar fracture is reported to be reasonably
sensitive and specific, but fractures can be missed (616). Soft tissue
injuries, involving the ligaments, cartilage, or growth plates, are more
common. Soft tissue injuries can be identified with flexion/extension
radiography or, more reliably, with MRI using sagittal T2-weighted
images with fat saturation; on the MR sequences, soft tissue damage is
seen as areas of high signal on T2-weighted images (617). Spinal cord
injury is, of course, best seen on MRI (Figs. 4-78 and 4-79). Seat belt
FIG. 4-76. Upper cervical injury in a 19-month-old infant. A.
Sagittal reformation of C-2 fracture shows fracture (large white
arrow) at the synchondrosis between the dens and body of C-2.
Note also the anterior position of the posterior arch of C-1 (small
white arrows), narrowing markedly the upper cervical canal and
the craniocervical junction. B. Sagittal T2-weighted image after
partial reduction of the fracture shows hyperintensity (white
arrow) at the fracture site. This image also shows a parenchymal
injury (black arrow) at the pontomedullary junction.
5/25/2011 11:39:28 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 331

FIG. 4-77. Atlanto-axial dissociation. A. Midline sagittal CT reformation shows an abnormally widened atlantodental interval
(small double arrowed line) and the increased distance between the dens and the clivus (large double arrowed line). B. Sagittal
STIR demonstrates abnormal T2 prolongation in the atlantodental interval with stretching of the tectorial membrane (small black
arrow), which allows the tip of the dens to contact the ventral surface of the cervicomedullary junction, disruption of the inters-
pinous ligament at C-1 to C-2 (large black arrow), and abnormal T2 prolongation in the lower cervical spinal cord (white arrow).
C. Sagittal diffusion-weighted imaging shows reduced diffusivity (white arrows) at the site of the traction injury in the lower cer-
vical spinal cord, with a more superior curvilinear hyperintense artifact. D. Sagittal ADC map confirms the abnormally reduced
diffusion in the spinal cord.

injuries, secondary to flexion-distraction (fortunately uncommon in Adolescent Injuries

the current era of shoulder and lap belt systems for all passengers),
tend to occur at the L-2 to L-4 levels (Fig. 4-78), lower than in older
patients (618). Thirty to fifty percent of patients are reported to have
associated visceral injury (618,619). These primarily horizontal inju-
ries may be difficult to identify on axial CT images (620,621); routine
reformations in the sagittal and coronal planes will increase detec-
tion. Burst fractures are uncommon in the pediatric population, with
thoracic level lesions having a higher incidence of neurologic injury
than lumbar lesions (622). The combination of flexion-extension plain
radiographs and MRI is the most useful combination in the diagnosis
of spinal trauma.
Adolescents from ages 9 to 16 years sustain spinal injuries at a rate
ten times that of younger children. The incidence is even higher in the
16- to 24-year-old age group; in fact, patients from age 16 to 24 years
have the highest incidence of spine trauma of any age group (623). As
children get older, they more often injure bone rather than exclusively
soft tissues; these injuries tend to be evenly distributed through the cer-
vical levels. The C-5 to C-6 level is most frequently injured in adoles-
cents (623). Although spinal cord injury can be present without plain
radiographic abnormalities in adolescents, bone abnormalities are seen
more commonly than not. Moreover, the severity of spinal cord injury
in adolescents without radiographic abnormalities tends to be less than

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 332 Pediatric Neuroimaging

FIG. 4-78. Spinal cord injury secondary to motor vehicle accident. Plain films
were normal. A. Sagittal T1-weighted image shows no significant abnormality. B.
Sagittal T2-weighted image shows diffuse abnormal hyperintensity of the spinal
cord. Abnormal hyperintensity is present between the spinous processes of L-2
and L-3 (arrows), indicating ligamentous injury at that site.

in those with radiograph abnormalities (524). Noncontiguous second
level injuries occur in the adolescent population at a rate similar to that
of adults (∼6%) (624).
The radiologic evaluation of adolescents with spine trauma is
essentially identical to that of adults with a few exceptions. The treating
physicians should remain aware of the possibility of soft tissue injury
without associated bone injury and, therefore, should obtain flexion-
extension films, especially in younger adolescents. Sagittal T2-weighted
MRI with fat saturation and STIR may be used to detect soft tissue
injury if flexion-extension views are judged too dangerous or difficult;
areas of soft tissue injury are seen as regions of high signal on these
images (512,617). Also, the radiologist should be aware that traumatic
disc herniation in adolescents is frequently associated with fracture
of the adjacent vertebral endplate, a finding that is much more easily
appreciated on CT and MRI than on plain radiographs (625). This
finding is important in surgical planning (626). Although plain radio-
graphs and CT are adequate for evaluation of bone injuries, MRI is
essential to determine the extent of spinal cord injury (Fig. 4-79) and,
thus, to establish a prognosis (627,628). The presence of hemorrhage
(short T2 relaxation time) or long segments (more than one vertebral
level) of edema (long T2 relaxation time) implies a poor prognosis for
recovery of function (535–538,627,628).
Another syndrome that is relatively unique to children and ado-
lescents is posttraumatic spinal cord infarction (629–631). Typically,
patients have onset of neurological signs several hours to several days
after the injury. Paraparesis or quadriparesis and dissociated sensory
loss then ensue; prognosis is variable. Radiographs and myelography
are normal (630,631). MRI will show anterior spinal artery infarction,
manifest as T2 prolongation in the anterior half to two thirds of the
spinal cord (Fig. 4-80A and B) or as hyperintensity in the ventral gray
matter of the cord. Diffusivity will be reduced in the acute/subacute
phase (Fig. 4-80C). Imaging in the subacute phase may show enhance-
ment of the infarcted region.
Patients with certain genetic abnormalities are predisposed to spi-
nal cord injury as a result of ligamentous laxity, spinal stenosis, spinal
kyphosis, or stenosis of the foramen magnum. Included in this group
are patients with Down syndrome (see Chapter 5), mucopolysacchari-
doses (especially Morquio syndrome, see Chapter 3), achondroplasia
(see Chapter 8), Klippel-Feil syndrome (see Chapter 9), and spondy-
loepiphyseal dysplasia. These patients should be observed for neuro-
logic dysfunction and neck pain in a longitudinal fashion and should
be carefully examined after even minor neck trauma (530,632,633).

Torticollis/Rotational Deformities of C-1 to C-2

FIG. 4-79. Spinal cord injury secondary to motor vehicle accident in a
10-year-old. Radiographs were normal. Sagittal T2-weighted image shows Torticollis is a common problem of childhood. Most cases have no
focal hyperintensity (white arrow) of the lower spinal cord, indicating a radiologic abnormalities and resolve spontaneously when treated con-
contusion. No osseous or ligamentous injury was present. servatively. Rarely, the deformity persists, due to anatomic derangements

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
that can be divided into two groups. The first group includes disorders
of the sternocleidomastoid muscle and locally painful neck conditions.
Fibromatosis colli, also called congenital fibrosis of the sternocleido-
mastoid, is a common cause of torticollis in infants that may be the
result of injury to the muscle during birth and subsequent scarring and
shortening of the muscle (634,635). This condition is discussed further
in Chapter 7. Benign paroxysmal torticollis of infancy is a disorder of
uncertain etiology (possibly migraine-related) that consists of brief,
repeated episodes, but is self-limited; episodes may be preceded by cry-
ing, agitation, vomiting, or pallor (636). Affected infants have a strong
family history of migraine headache and have shown a high incidence
of gross and fine motor delays (637). Locally painful neck conditions
that cause torticollis include lymphadenitis and other cervical inflam-
matory processes, Chiari I malformations, and tumors of the cervical
spine and posterior fossa (591).
The other major cause of torticollis in childhood is rotatory fixation
of the atlanto-axial joint. Rotation of the head largely relies on motion
at the atlanto-axial joint; indeed, 50% of total neck rotation occurs at
this level (638,639). In rotatory fixation of C-1 to C-2, the normal rota-
tion becomes limited, possibly due to inflammation of the synovium or
Barkovich_Chap04.indd 333
333
FIG. 4-80. Spinal cord infarction; this
child developed quadriparesis after a
sibling walked on his back. A. Sagittal
T2 image on third day after onset of
symptoms shows central hyperintensity
(white arrows) in the cervical spinal cord.
B. Axial T2 image shows hyperintensity
in the ventral gray matter. C. Axial ADC
map shows the reduced diffusivity in the
region of ischemia.
spasm of the sternocleidomastoid muscle. Most cases occur in children
below the age of 13 years (639). Patients with rotatory fixation typically
present with sudden onset of torticollis without antecedent symptoms.
Sometimes, there is a history of minor trauma.
Diagnosis is made by CT (640,641). Plain films are difficult and
confusing because of the inability of the patient to straighten the neck
(591). The patient is initially scanned with the head in neutral position.
The scan is then repeated, first with the head rotated maximally (up
to 45°) in one direction, and then with the head rotated maximally in
the other direction. If rotatory fixation is present, there will be no sig-
nificant motion of C-1 on C-2 in one direction. If the torticollis is due
to other causes, some rotation will be present. Sedation may be valu-
able, as muscle spasm may preclude significant motion, and the muscle
is relaxed by the sedation. If rotatory fixation is found, the patient is
treated with traction and muscle relaxants; surgery may be necessary if
the deformity persists, or if neurological deficits are present (642).
Fielding and Hawkins have divided rotatory fixation into four cat-
egories for the purposes of prognostication (642). Type I is the most
common and has the lowest incidence of neurological impairment.
Rotatory fixation is present without displacement of C-1. In Type II,
5/25/2011 11:39:30 AM
 334 Pediatric Neuroimaging
rotatory fixation is associated with anterior displacement of 3 to 5 mm
of C-1. In Type III, anterior displacement of C-1 is more than 5 mm.
In Type IV, posterior displacement of C-1 is present; this is necessarily
associated with deficiency of the odontoid.
Back Pain in Children
Although back pain is a common problem in adults, it is uncommon
in children and may be a manifestation of a serious underlying prob-
lem. Back pain may result from infectious (Chapter 11), congenital
(Chapter 9), neoplastic (Chapter 10), and traumatic causes. Most of
these causes are discussed in other chapters.
Acute traumatic causes of pediatric back pain are discussed earlier
in this chapter. Nonacute causes include spondylolysis and spondylolis-
thesis, intervertebral disc herniation, intervertebral disc degenera-
tion, and Scheuermann disease. Spondylolysis and spondylolisthesis
are identical in children and adults and will not be discussed here.
Scheuermann disease is a poorly understood phenomenon that is dis-
cussed in both pediatric radiology and bone radiology texts and, simi-
larly, will not be discussed here.
Intervertebral disc herniations in children are similar to those in
adults with three exceptions. (a) The size of disc herniations is larger in
children than in adults (643–645). (b) When traumatic, disc herniation
in adolescents is frequently accompanied by fracture of the adjacent
vertebral endplate, a finding that is much more easily appreciated on
CT and MRI than on plain radiographs (625). This finding is impor-
tant in surgical planning (626). (c) Pediatric disc herniations may be
calcified (646–648), possibly because of accompanying discitis (647);
the true incidence is likely underestimated (649). The presence of a
calcified disc does not change treatment, which is almost always con-
servative. It is important to remember two facts when a disc hernia-
tion is seen in children. First, most children with disc herniations are
asymptomatic (649,650). Second, the vast majority of these patients
recover completely without surgical intervention.
Intervertebral disc degeneration turns out to be a fairly common
finding in children with low back pain, being seen in 30% to 50% of
symptomatic patients, as compared with 20% of asymptomatic patients
(650,651). MRI shows loss of disc height and diminished signal on
T2-weighted images. Adjacent endplate changes have been reported to
have a high association with low back pain (651). Although the inci-
dence of disc degeneration is higher in adolescents with low back pain,
the 20% incidence in asymptomatic adolescents is notable. The finding
of disc degeneration has no impact on treatment.
Head Trauma
In general, CT is the initial study of choice for older children who
have suffered head trauma, because CT is fast and easily obtained; it
is sensitive in detection of intraparenchymal and extraparenchymal
hematomas, mass effect, and fractures; and it can be used to image
the spine, chest, and abdomen for traumatic imaging at the same sit-
ting as the head scan. We obtain 2.5 to 3 mm thick sections from the
vertex to the C-3 vertebral body in all pediatric trauma patients. The
reason for obtaining images in the upper cervical spine is the high inci-
dence of cervical spine injury that accompanies head injury in chil-
dren (521,583,608,609). Given the special concerns regarding radiation
exposure in children, groups have attempted to create a decision rule
by which those children with a lower risk of clinically significant brain
injuries could be identified, obviating the need for routine scanning
in children who do not meet criteria (556,652). While the US trial has
been validated, the Canadian trial has not yet been validated at the time
of this writing. Much work is also being done to identify a biomarker
for pediatric brain injury; however, a sensitive and specific marker or
panel of markers has yet to be discovered (653–655).
Barkovich_Chap04.indd 334
As with neonates, MRI (of both brain and pertinent regions of
the spine) should be obtained in all pediatric trauma victims in whom
the CT findings do not fully explain the extent of neurologic deficit
(532,536,612,617,627). Indeed, magnetic resonance more sensitively
assesses the full extent of damage to the brain (656). MRI has been
proven to be more sensitive than CT in the detection of small extra-
axial fluid collections and white matter shearing injuries (510–516).
Brainstem injuries, which have important prognostic significance, are
better detected by MRI (514,657). Moreover, MRI is extremely sensi-
tive to the presence of hemosiderin from old hemorrhage (575,584);
the presence of old CNS injuries in association with newer ones pres-
ents important evidence in the diagnosis of nonaccidental trauma. In
order to detect hemorrhage with maximal sensitivity, T2 gradient-echo
images or susceptibility-weighted images (584,658) should be obtained
in all trauma or suspected trauma cases. DTI shows reduced water dif-
fusivity in the acute and subacute phase and increased water diffusiv-
ity with reduced FA of white matter pathways in the chronic phase;
it should always be considered when MRI is performed in trauma
cases (659–662). When performed with many (more than 25) diffu-
sion-encoding directions, DTI finds many more injuries than FLAIR
or susceptibility-weighted images (661) and may contain important
prognostic information (663–665); DTI may also be valuable for cog-
nitive outcome prediction (666,667). Proton MRS can also be useful
in the subacute and chronic phases to determine the severity of paren-
chymal injury (660,668). Magnetoencephalography (MEG) studies in
children and adults with traumatic brain injury show abnormal slow
wave (theta and delta) activity, which has been shown to correlate with
neurologic function (669–671).
Extraparenchymal Hematomas
Epidural hematomas are uncommon in infants and increase slowly
in incidence throughout childhood to reach peak incidence in adults
(530). Epidural hematomas in younger children differ from those in
adults primarily in pathogenesis and clinical manifestations; prognosis
also appears to be better in children than in adults (672) and in younger
children than in adolescents (673). In young children, epidural hema-
tomas are more commonly the result of tears in the dural veins than
of laceration of the middle meningeal artery (very rarely, they may be
caused by venous thrombosis [124]); in older children and adolescents,
arterial causes are far more common (530). The difference in clinical
presentation results from two factors: (a) the pediatric skull is more
pliable than the adult’s and can expand as a posttraumatic hematoma
accumulates (674) and (b) intradural injury is uncommon (673). As a
result, the clinical presentation does not evolve as rapidly. Moreover,
in contradistinction to adults, in whom the head injury characteristi-
cally induces a loss of consciousness, children more commonly are only
stunned by the injury. This necessitates consideration of early imag-
ing in the pediatric trauma patient because the clinical manifestations
of significant trauma may initially be mild or transient. Although the
morbidity and mortality associated with epidural hematoma were his-
torically high, the outcome and prognosis following epidural hema-
toma are generally very good after rapid radiological identification and
surgical decompression (675).
The findings of epidural hematomas in children on CT and MRI
are identical to those of adults. CT will usually reveal a lentiform
hyperdense extraparenchymal collection that does not cross cranial
sutures (Figs. 4-81 and 4-82). Skull fractures and soft tissue swelling
are often present overlying the hematoma. Contusions may be pres-
ent in the subjacent brain parenchyma or in a contralateral location
(contre-coup injury). If the fracture extends into the mastoid air cells
or a paranasal sinus, pneumocephalus may be present (Fig. 4-82). If
the fracture is in the frontal bone and extends into the orbital roof, a
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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 335

FIG. 4-81. Epidural hematoma. A. Axial CT image in a 3-year-old child shows a lentiform extraparenchymal collection of high
attenuation blood (arrows) in the right anterior cranial fossa. Note that the collection does not cross the metopic or coronal
suture. B. Bone window image shows frontal bone fracture (arrow).

subperiosteal orbital hematoma may develop. Orbital hematomas may
cause acute proptosis and result in loss of vision unless the hematoma is
expediently decompressed. On MRI, the hyperacute hematoma is dark
on T1-weighted images and bright on T2-weighted images. The acute
hematoma is bright on T1-weighted images and dark on T2-weighted
FIG. 4-82. Epidural hematoma with pneumocephalus secondary to mas-
toid fracture. Axial CT image shows a lentiform high attenuation collection
of epidural blood (small arrows) overlying the left posterior temporal and
occipital lobes. The presence of extraparenchymal air (large white arrow)
suggests a basilar skull fracture.
images. As with subdural hematomas, a fluid-fluid layer may be present
secondary to layering of blood cells; the upper layer will be bright on
T1- and T2-weighted images and the lower level will be isointense to
brain on T1-weighted images and dark on T2-weighted images (579).
Subdural hematomas are most common in infants and elderly
adults and are less common in older children and adolescents (676).
They result from tears of cortical veins bridging the subdural space on
their way to the dural sinuses. The soft consistency of the unmyeli-
nated brain results in increased brain distortion during trauma and
puts increased stress upon these veins (530). In contrast to adults, in
whom traumatic subdural hematomas are usually unilateral, traumatic
subdural hematomas are bilateral in 80% to 85% of infants and are
typically located over the frontoparietal convexity. A history of trauma
is usually elicited. The presence of recent unreported physical trauma
or a history of mild trauma that is inconsistent with the severity of the
injury suggests child abuse (530,674,677–682). Other factors predis-
posing to hematomas include blood dyscrasias and prematurity (683).
Infants with benign enlargement of the subarachnoid spaces may be
at increased risk for subdural hematoma; however, this remains con-
troversial (684–686). Infants with subdural hematomas may present
with seizures, vomiting, hyperirritability, lethargy, or progressive head
enlargement (681,687). Older children typically present with signs
of increased intracranial pressure, such as depressed consciousness,
increased systemic blood pressure with a decreased pulse rate, irregular
respiration, pupillary asymmetry, and hemiparesis (688,689). If chil-
dren have normal level of consciousness and no motor weakness or
pupillary asymmetry, the hemorrhage may be subarachnoid; if so, it
will resolve spontaneously within a few days (690).
Imaging studies of subdural hematomas in children are identical
to those in adults. In the acute phase, CT will show a high attenuation
extraparenchymal crescentic fluid collection over the frontoparietal
convexity that typically crosses cranial sutures (Fig. 4-83). Within 1 to
3 weeks after the hemorrhage, the blood becomes isodense with brain

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 336 Pediatric Neuroimaging

FIG. 4-83. Acute traumatic subdural hematoma and parenchymal contusions (from child abuse). A. Axial noncontrast CT image shows
large extraparenchymal high attenuation collection (white arrows). This acute subdural hematoma crosses cranial sutures and lies both
lateral and medial to the left cerebral hemisphere. B. Coronal FLAIR image shows the subdural hematoma (hyperintense crescentic col-
lection, arrows) but shows no evidence of parenchymal injury in the left frontal lobe. C. Axial T2-weighted image shows the subdural
hematoma to be hypointense (white arrows). Parenchymal injury is seen as cortical and white matter hyperintensity (black arrows) in the
left frontal lobe. D. DWI (b = 1000 s/mm2) shows reduced diffusivity, manifested as high intensity (black arrows) in the left lateral frontal
lobe and left posteromedial parietal lobe.

tissue. At this stage, compression of the ventricles and medial displace-
ment of the gray-white junction with compression of the white matter
will indicate presence of the extra-axial fluid collection (Fig. 4-84A). If
intravenous contrast is given, the inner and outer membranes of the
subdural hematoma will enhance (Fig. 4-84B) (512). It is essential to
recognize shift of the ventricles, medial displacement of the corticome-
dullary junction, and medial displacement of the cortical sulci at this
state (557,691). Patients with visible subarachnoid spaces on the side of
the subdural hematoma may have a better prognosis (692). After 2 to 3
weeks, the density of the hematoma will be lower than that of brain and
closer to that of CSF. At this stage, it is usually called a chronic subdural
hematoma. Because of the development of fibrovascular granulation
tissue in the periphery of the subdural collection, the outer and inner
membranes of subacute or chronic subdural hematomas enhance
rather intensely after IV contrast is administered (557). On MRI, the
signal intensity of the extra-axial fluid collection will evolve as those
described for the epidural hematoma in the previous section (Figs.
4-81 and 4-83). The changes in signal intensity result from the loss of
oxygen from hemoglobin followed by the oxidation of hemoglobin to
methemoglobin and subsequent breakdown to diamagnetic materials
(576). Fluid-fluid layers are often present as a result of layering of the
blood cells in the dependent portion of the subdural collection (Fig.
4-83). MRI is also useful in the identification of injury to the under-
lying parenchyma (such as axonal shearing injuries, contusions, and
infarctions, see subsequent section) that commonly accompanies trau-
matic subdural hematomas (Fig. 4-83 and 4-85) (555,678–680,689).
Unlike intraparenchymal hematomas, in which the blood–brain
barrier inhibits their resorption, hemosiderin and ferritin are not
deposited within the wall of the chronic subdural hematoma (512,575).
Therefore, the absence of subdural hemosiderin does not imply that a
subdural hematoma is acute or that a prior subdural hematoma has
not been present.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 337

FIG. 4-84. Subacute (isodense) subdural hematoma. A. Axial noncontrast CT image shows compression of the right
lateral ventricle and right hemispheric white matter in addition to medial displacement of the gray matter-white
matter junction (arrows). B. After administration of iodinated contrast, part of the inner membrane of the subdural
hematoma enhances. In addition, many of the dural veins are medially displaced by the subdural collection.

Subarachnoid Hemorrhage hemorrhage may be the harbinger of more severe underlying brain
damage (677,691). Routine T1- and T2-weighted MR sequences are
Subarachnoid hemorrhage often accompanies intraparenchymal
not sensitive for the diagnosis of acute subarachnoid hemorrhage,
damage in both the child and the adult. In the acutely injured child,
probably because the hemoglobin is less concentrated than in clotted
CT is the imaging study of choice to detect the hyperdense subarach-
blood and the high oxygen tension of CSF inhibits the conversion of
noid blood. In the acute phase after injury, when nonhemorrhagic
hemoglobin to deoxyhemoglobin and methemoglobin (575,693,694).
parenchymal lesions are difficult to identify by CT, subarachnoid
FLAIR, T2 gradient-echo, and susceptibility-weighted sequences may

FIG. 4-85. Subarachnoid hemorrhage and cerebral infarction secondary to nonaccidental trauma. A. Axial CT image shows
the high attenuation of blood (small arrow) in the right occipital lobe secondary to contusion. The MCA distribution of the
left hemisphere (arrows) is hypodense secondary to infarction. B. Axial CT at higher level shows bilateral cerebral infarctions
(large arrows) and a thick irregular linear hyperdensity (small arrows) representing subarachnoid blood in the posterior
interhemispheric fissure.

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 338 Pediatric Neuroimaging

be sensitive to both acute and subacute hemorrhage (506,507,695,696)
and should be utilized to search for subarachnoid blood if an MRI is
obtained. Subarachnoid hemorrhage appears as high signal intensity
in the subarachnoid spaces on FLAIR images, whereas CSF is of low
intensity; on T2 gradient-echo and susceptibility-weighted imaging,
subarachnoid hemorrhage will appear hypointense, in comparison
with the hyperintense CSF (696). It is important to remember, how-
ever, that rapidly flowing CSF (such as that around the foramina of
Monro, the aqueduct of Sylvius, and the prepontine cistern) will com-
monly have high signal intensity on FLAIR images; rapidly flowing CSF
should not be mistaken for subarachnoid hemorrhage. CT shows acute
subarachnoid hemorrhage as increased attenuation in the subarach-
noid space. Traumatic subarachnoid hemorrhage is most commonly
seen in the posterior interhemispheric fissure, adjacent to the falx cere-
bri (Fig. 4-86), or layering along the tentorium cerebelli (Fig. 4-87);
sometimes, this increased attenuation is the only abnormality seen on
the CT scan. Blood along the tentorium is best demonstrated by imag-
ing in the coronal plane. When blood is located along the posterior
falx cerebri, the increased density within the interhemispheric fissure
is thicker and more irregular than the falx itself; a helpful finding is
extension of the blood into the cerebral sulci along the medial aspect
of the hemisphere (697) (Fig. 4-87). This thick, dense high signal in
the interhemispheric fissure has been called the “falx sign.” The reader
should note that, even in children, the falx can have a high attenuation
on CT. The falx itself, however, should be thin and regular in contour,
and no extension of the high attenuation into the cortical sulci should
be seen.
Injury to the Brain Parenchyma
In the acute phase after either physical trauma or asphyxia, generalized
cerebral swelling is seen more commonly in children than in adults with
similar types of head injury (698). This generalized cerebral swelling
probably results from a combination of edema and a decrease in cere-
brovascular autoregulation, resulting in vasodilatation and increased
cerebral blood volume (530,699). If an imaging study is obtained in
the first 12 hours after trauma, it may not demonstrate the edema. By
about 24 hours, CT and MRI of the brain show decreased distinction
between gray and white matter with compressed, slit-like lateral ven-
tricles (170,677,691); focal injury may be seen by diffusion-weighted
imaging at this time (Fig. 4-86) (700,701). In addition, the cerebral sulci

FIG. 4-86. MRI of severe head trauma; brain CT was normal. A. Cor-
onal fat-suppressed FLAIR image shows two right frontal cortical con-
tusions (white arrows) and bilateral deep white matter axonal shearing
injuries (white arrowheads). B. Axial GRE T2 image shows low inten-
sity foci (arrows) in the bifrontal regions of white matter injury. These
regions also demonstrated reduced diffusion. C. Axial Dav map shows
marked hypointensity (white arrow), indicating reduced diffusivity, in a
contusion of the splenium of the corpus callosum.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
and perimesencephalic cisterns are compressed. Transtentorial hernia-
tion of the temporal lobe may cause infarction of the posterior cerebral
artery (PCA) territory by compressing the PCA against the free edge
of the tentorium in the ambient cistern. Stretching of the thalamoper-
forating arteries during transtentorial herniation may cause thalamic
infarcts (702). Subfalcine herniation may cause infarcts in the territory
of anterior cerebral artery (ACA) branches (512).
Parenchymal lesions resulting from head trauma include cere-
bral contusions and white matter shearing injuries (561,703). Cerebral
contusions are bruises of the brain most commonly caused by decel-
eration injuries in which the brain forcibly contacts the rough edges
of the skull in the anterior temporal and orbito-frontal regions (Fig.
4-87) (555,704). They may also result from direct impact transmitted
Barkovich_Chap04.indd 339
339
FIG. 4-87. Traumatic injury with subarachnoid hem-
orrhage, and parenchymal injury. A. Axial CT image
shows subarachnoid blood in the ambient cisterns
(large solid black arrows), interpeduncular cistern
(white arrow) and along the tentorium cerebelli (small
solid black arrows). Parenchymal hemorrhage (open
arrow), probably secondary to axonal shear injury, is
present in the left temporal lobe. B. Image at the level
of the corpus callosum shows a large hemorrhage
(arrows) at the callosal splenium. C. Image at the level
of the frontoparietal convexities shows subarachnoid
blood in medial hemispheric sulci (curved arrows) and
a widened interhemispheric fissure (straight arrows),
possible secondary to a dural rent or an adjacent
subdural hematoma.
through the skull (Figs. 4-86 and 4-88). Shearing injuries result from
rotational forces on the skull. When the skull is rapidly rotated, the
brain lags behind, causing axial stretching and disruption of nerve
fiber tracts (512). Because the unmyelinated brain is less rigid than
the mature brain (and consequently more susceptible to distortion)
and because the subarachnoid spaces are more capacious, shear-
ing injuries are a more common consequence of rotational injury in
infants and young children. Shearing injuries most commonly occur
at the junction of the gray and white matter, in the deep white mat-
ter of the centrum semiovale, in the corpus callosum, the internal
capsule, the basal ganglia, and the brainstem (Figs. 4-86 and 4-87)
(513,555,561,678,703). Many of the brainstem lesions will be missed
unless MRI is obtained (657); as the presence of brainstem injuries
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 340 Pediatric Neuroimaging

FIG. 4-88. Trauma in a 10-month-old boy; television fell on his head. A. Axial CT scan shows hyperattenuating blood
(white arrow) in the right cerebellopontine angle cistern and hypoattenuating air (black arrow) in the left cerebellopon-
tine angle cistern. The presence of air suggests a basilar skull fracture. The temporal horn of the right lateral ventricle is
enlarged due to obstructive hydrocephalus from intraventricular hemorrhage. B. Coronal TSE T2 image shows periph-
eral and deep right cerebellar hemisphere contusions, as well as bilateral cerebellar tonsillar contusions (small white
arrowheads). An extradural hematoma overlies the lateral right cerebellar surface (white arrow). A large occipital bone
fracture is evident (large white arrowhead). C. Axial Dav map shows reduced diffusivity (hypointensity, white arrows) in
cerebellar contusion. D. Axial GRE T2*-weighted image shows a hematoma anterior to the cervicomedullary junction
(white arrow) and hemorrhage within the right tonsillar contusion (white arrowhead).

strongly correlates with duration of coma and with outcome, as
indicated by the Glasgow Coma Scale, MRI should be considered in
all children with severe head injury or coma (657). As discussed below,
DTI might be the best way to assess for shearing injuries in the chronic
phase, as the microstructural changes alter both mean diffusivity and
FA (660,661,700,705,706). Indeed, the number of damaged white
matter structures, as quantified by DTI, is significantly correlated
with mean reaction time on simple cognitive tasks and the presence
of abnormal slow waves on MEG; no such correlation with traumatic
microhemorrhages was found (661,669).
CT is sensitive in the diagnosis of hemorrhagic cerebral contusion
in the acute phase because it is sensitive to the presence of large areas
of acute blood within the brain (Figs. 4-86 and 4-88) (678,704) and to
the accompanying extra-axial hematomas (Figs. 4-81 and 4-82) or air
(pneumocephalus) that may be present (Figs. 4-82 and 4-88A), and
the patient is easily monitored during a CT scan. Thus, as stated ear-
lier, it is the imaging study of choice for the evaluation of head injury
in the acutely ill and unstable patient. However, as also stated, CT is
less sensitive than MRI in the detection of contusions (hemorrhagic
or nonhemorrhagic, Figs. 4-86, 4-88, and 4-89) and axonal shearing

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
injuries, particularly in the subacute and chronic phases of injury
(678). Therefore, MRI is the imaging modality of choice for assessment
of parenchymal injury. In the acute phase, diffusion images are most
sensitive for the detection of contusions and shearing injuries (Figs.
4-86 and 4-88) (700, 701). Hyperacute hemorrhage (in the first hours
after injury, when blood largely remains in the oxyhemoglobin con-
figuration) will appear on diffusion images as hyperintensity and on
Dav images as hypointensity, whereas acute hemorrhage (in which
blood is mostly in the deoxyhemoglobin form) will appear on both
types of images as hypointensity (578). In the subacute and chronic
phases, T2-weighted scans or a combination of FLAIR and T2 gradi-
ent-echo or susceptibility-weighted images are the best choices; these
methods are sensitive to both the nonhemorrhagic and hemorrhagic
injuries that are present at the site of prior contusions and shear inju-
ries (511,516,678,704). Gradient-echo studies with long-echo times
(20–30 milliseconds) and susceptibility-weighted images (584,658)
are even more sensitive than T2-weighted spin-echo studies for detect-
ing products of hemorrhage (Figs. 4-88D and 4-90) and, therefore, are
an essential adjunct in the MR examination of trauma victims. Lower
numbers of lesions on susceptibility-weighted images seem to cor-
relate well with better neurological outcome (660). RARE (fast/turbo
spin echo) and FLAIR sequences are relatively insensitive to the pres-
ence of intraparenchymal blood (Fig. 4-89) at 1.5 T and should not be
relied upon to exclude parenchymal hemorrhage in the setting of trauma.
FLAIR is useful to assess the full extent of white matter injury in older
children but, in neonates and young infants, FLAIR may be insensi-
tive to parenchymal injuries of all kinds (Figs. 4-83 and 4-90). If the
MRI is performed at 3 T, acute and subacute blood may be seen as
hypointense on RARE and FLAIR sequences (707); therefore, it is pos-
sible that gradient-echo sequences may be unnecessary if the scans are
performed at 3 T, but further work is necessary before these sequences
are eliminated. Subacute hemorrhagic injuries will often show areas
of high intensity on both T1- and T2-weighted images because of the
presence of methemoglobin and edema, respectively. Chronic injuries
will appear as hyperintense areas on FLAIR images; on T2-weighted
spin-echo images, they may show high signal intensity (astrogliosis,
which has more water than normal brain), low signal intensity (resid-
ual blood breakdown products from previous hemorrhage, Fig. 4-89),
or both. Both subacute and chronic hemorrhagic injuries have low sig-
nal intensity on gradient-echo scans with long-echo times (Fig. 4-90)
and on susceptibility-weighted images (584). Lesions in characteristic
locations, such as the orbitofrontal surface of the frontal lobes and the
anterior temporal lobes, are strongly suggestive of prior trauma. More-
over, the location and number of injuries within the brain may be of
prognostic value in terms of how much recovery of normal brain func-
tion can be expected. (Prognosis is probably predicted best by the use
of advanced imaging methods, as described below.)
Severe swelling of the brain suggests a guarded prognosis (708,709)
as does the presence of the “reversal sign” in which cerebral white mat-
ter has a higher attenuation than cerebral gray matter (Fig. 4-54)
(456,457). It is difficult in this acute phase to detect axonal shearing
injuries by CT. Therefore, one cannot determine whether diffuse cere-
bral swelling is the result of increased blood volume or axonal shearing
injuries (530,710). Proton MRS and DTI may have a role in making this
determination (see the last paragraph of this section); in their absence,
follow-up scans are necessary. Atrophy will develop if the brain has
suffered significant injury but the swollen brain will return to a normal
appearance if significant neuronal damage has not occurred (530,710).
Follow-up standard MR scans of children with mild head injury will
be normal at 3 months after the injury. Of children with moderate to
severe closed head injury, and, therefore, a poorer prognosis, 71% will
have parenchymal lesions on MR, predominantly in the frontal lobes,
Barkovich_Chap04.indd 341
341
if imaged at least 3 months after the injury. Interestingly, children with
frontal lobe lesions were found to be more frequently neurologically
and psychologically disabled than those with diffuse injury (711).
When imaged in the chronic phase, 3 months after injury, the finding
of brainstem injury (T2 prolongation from astrogliosis or T2 shorten-
ing from hemosiderin) portends a poorer prognosis (712).
As indicated in the previous paragraphs, recent evidence sug-
gests that MR DTI, MRS, and susceptibility-weighted imaging may
have a role in the acute phase to differentiate swelling from acute
axonal shear injury (660). Indeed, in the chronic phase, DTI and
MRS correlate better with clinical outcome than any anatomic imag-
ing sequences (661,705). Diffusion imaging (Figs. 4-83 and 4-88)
demonstrates reduced water diffusion in injured regions of brain
(increased intensity on diffusion images and decreased intensity on
Dav images) in the first hours after injury, whereas interstitial edema
and increased blood volume show increased diffusion (decreased
intensity on diffusion images and increased intensity on Dav images).
Diffusion imaging may detect abnormalities (manifested as reduced
diffusion) more than 2 weeks after injury (659). In addition, stud-
ies suggest that reduced FA, as assessed by DTI, may be an early and
more sensitive method of detecting axonal injury (661,700,705,713).
In the chronic phase of injury, the presence of reduced anisotropy in
specific white matter tracts correlates with the Glasgow Coma Scale
(705) and measures of learning and cognitive performance (661,706).
Proton MRS may be useful in differentiating swelling secondary to
increased blood volume from swelling secondary to shearing injury.
Proton MRS is nearly normal in the absence of parenchymal injury
but shows decreased NAA and increased choline, lactate and gluta-
mate/glutamine within the first 2 to 4 days after injury if significant
neuronal injury has occurred (714–718). Indeed, animal studies indi-
cate that NAA is reduced as early as 1 hour after injury (719,720).
NAA/Ch levels seem to correlate well with cognitive outcome, par-
ticularly when the frontal lobes are sampled (721) and lower NAA/
Ch ratios, higher Ch/Cr ratios, and the presence of lactate all cor-
relate with poor outcome (660,718,722). Indeed, proton MRS shows
reduced area under the NAA peak even in patients with mild brain
injury and normal MRI studies (668). Susceptibility-weighted images,
a high spatial resolution, 3D gradient-echo technique in which alter-
ations of phase are amplified (723) is even more sensitive to blood
products than standard gradient-echo images, showing tenfold more
hemorrhagic lesions in one study (584,658) and correlations have
been shown in small groups between number of lesions detected by
susceptibility-weighted images (SWIs), location of lesions, and clini-
cal outcome (658,660). SWI may become the sequence of choice for
initial assessment of shearing injuries.
Sequelae of Trauma
The sequelae of trauma include infarction from severe brain edema
and vascular injury, infections, leptomeningeal cysts, inflammation,
and hydrocephalus (674,689,724). The imaging appearance of these
conditions is discussed elsewhere in this book and will not be discussed
extensively here.
Infarctions from severe brain edema and leptomeningeal cysts
secondary to skull fractures are described earlier in this chapter.
Hydrocephalus frequently develops after head injuries, possibly as
a result of inflammation and subsequent adhesions caused by suba-
rachnoid blood. In children, it is sometimes impossible to differenti-
ate communicating hydrocephalus from cerebral atrophy, which can
also result from trauma, by imaging. Both can appear as dilatation
of the cerebral ventricles and sulci on imaging studies and both can
result from severe cerebral injury (725). Differentiation can sometimes
be made by careful analysis of the contours of the third ventricle (see
5/25/2011 11:39:34 AM
 342 Pediatric Neuroimaging

FIG. 4-89. Trauma in a 3-year-old boy; value of T2-weighted images, FLAIR, and diffusion imaging in detecting hemorrhagic injury.
A. Axial CT scan shows areas of hypoattenuation (white arrows) in the orbital surface of the right frontal lobe. Blood is identified
only in the right temporal lobe contusion (white arrowhead). B. Axial FLAIR image shows more contusions and blood (low intensity,
arrow) in the large injury in the right orbital surface. C. Axial T2-weighted image shows many more foci of low attenuation hemor-
rhage bilaterally in the frontal lobes. D. Axial diffusivity (Dav) image shows little damage, probably because of distortion due to sus-
ceptibility artifact from the skull base and blood.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 343

FIG. 4-90. Child abuse in a 2-month-old infant; value of gradient-echo images. A. Axial T1-weighted image
shows large bilateral subacute subdural hematomas with an area of more acute blood clot (curved white arrow). No
definite parenchymal injury is seen. B. Axial FLAIR image is not very useful for identifying brain injury in infants.
C. Axial RARE (FSE/TSE) image shows some evidence of blood (white arrows) in the left posterior temporal
lobe. Note the fluid-fluid layer (black arrows) in the posterior right subdural space. D. Axial gradient-echo image
(TE = 25 milliseconds, q = 15°) image shows multiple foci of hemosiderin (open black arrows), unequivocal
evidence of prior injury.

Chapter 8). Alternatively, diagnosis can be made by monitoring intrac-
ranial pressure or by a radionuclide flow study with 99mTc DTPA. The
technetium compound is injected into the spinal subarachnoid space
via lumbar puncture. If flow of the radionuclide upward over the cere-
bral convexities is not seen by 24 hours after its injection, or if the radi-
onuclide is seen within the lateral ventricles at 24 hours after injection,
there is very likely a block to CSF flow and hydrocephalus (726,727).
Of course, the most important features are clinical: an enlarging head
size and sutural splitting indicate hydrocephalus, whereas a decreas-
ing head circumference (compared to the normal distribution on head
growth charts) suggests atrophy. Identification of hydrocephalus in
this setting is important, as up to 75% of patients with posttraumatic
hydrocephalus will show neurologic improvement after placement of
a shunt (674).
Vascular complications of head injury include carotid-cavernous
fistulas, arterial dissections, and venous sinus occlusions. Signs and
symptoms of carotid-cavernous fistulas include pulsating exophthal-
mos, deficient ocular motility from multiple cranial nerve palsies, and,
sometimes, blindness or subarachnoid hemorrhage. Catheter angiog-
raphy is necessary for both diagnosis and treatment (see Chapter 12).
Arterial dissections can present with obtundation, mono- or hemipare-
sis, dysphasia, or Horner syndrome (see Chapter 12). T1-weighted MRI
of the skull base with fat saturation is very sensitive in establishing the
diagnosis of dissection. A crescentic rim of hyperintensity, presumably

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 344 Pediatric Neuroimaging
methemoglobin, will be seen in the vessel wall. MRA or CTA may show
intimal irregularities that allow the diagnosis to be established. In some
clinical settings, MR diagnosis of dissection may obviate the need for
catheter angiography. CT or MRI is essential to diagnose associated
cerebral infarction. Venous sinus occlusion can be diagnosed either by
MRV, CT venography, or intravenous digital subtraction angiography,
as described in Chapter 1 on techniques and Chapter 11 (“Complica-
tions of Meningitis” section).
Infection is an uncommon complication of brain injury. When
infection does occur, it is usually in the form of meningitis, second-
ary to bacterial seeding from basilar skull fracture, or cerebritis/abscess
from penetrating injuries. The latter is extremely rare in children and
is diagnosed from post contrast CT or MR examinations (see Chap-
ter 11). To diagnose a CSF leak from a basilar skull fracture, 3 to
5 mL of nonionic iodinated contrast is injected into the subarachnoid
space via lumbar or C-1 to C-2 puncture with the patient prone. The
patient is then kept prone and tilted 45° (with head down) for 60 to
90 seconds. The patient is maintained in the prone position while being
transported to CT, where direct coronal less than 2 mm sections are
obtained from the frontal sinuses through the temporal bones. If the
patient is actively leaking, contrast will be seen exiting through a defect
in the bone of the skull base. Alternative methods of detection of CSF
leakage, including noncontrast 3D-steady state MRI (CISS, FIESTA)
and intrathecal contrast-enhanced MR cisternography, are less mature
techniques and have not been widely used in children, but have the
advantage of not requiring ionizing radiation and, for the 3D-steady
state technique, being entirely noninvasive (728,729).
The role of inflammation in contributing to the neurologic seque-
lae of traumatic brain injury is not well understood. Evidence suggests
that inflammation can have both detrimental and beneficial effects fol-
lowing trauma. While the initial inflammatory cascade can result in
vascular leakage and dilation, edema, local hypoxia, and apoptotic cell
death, the anti-inflammatory and wound healing factors induced by
the initial inflammatory response may account for some of the benefits
(724). In the future, targeted anti-inflammatory agents may aid in the
prevention of secondary insults following traumatic brain injury, but
they are not currently in clinical practice.
Nonaccidental Trauma (Child Abuse)
Clinical, Mechanistic, and Epidemiological Aspects
Nonaccidental trauma (child abuse) is an increasing problem in pedi-
atric health care, with an estimated 1.5 million cases reported in the
United States in 1993 (730). Three million cases of suspected abuse
were reported in the year 2000, and 3.6 million in 2006 (731). Of these,
nearly half result in disfigurement, permanent neurological or psycho-
logical deficit, or death (732). In the year 2002, approximately 896,000
children were determined to be victims of child abuse or neglect (733).
In 2007, an estimated 1,760 children died from abuse or neglect. Head
trauma is the leading cause of morbidity and mortality in the abused
child, especially in patients under the age of 2 years (734–736). One
prospective study of head injuries in 100 children under the age of
22 years revealed that 24% were victims of abuse (737). This study and
others (738,739) have shown that children who have been abused have
a higher risk of permanent brain damage and death than those suffer-
ing truly accidental injuries. Radiologists have traditionally played an
important role in the diagnosis of child abuse by maintaining a high
index of suspicion in children who have multiple instances of unex-
plained trauma. Although the diagnosis has classically been made by
the use of bone radiographs, which demonstrate multiple fractures
of different ages (740–742), brain imaging can make an important
contribution. Brain imaging is especially important in the so-called
Barkovich_Chap04.indd 344
“shaken baby syndrome” (741–743), characterized by retinal hemor-
rhages, subdural or subarachnoid hemorrhage, cerebral contusion, and
diffuse cerebral edema with minimal evidence of external trauma. The
American Academy of Pediatrics recommends use of the term “abusive
head trauma,” rather than describing a single injury mechanism, in the
medical record when encountering the constellation of findings that
can result from inflicted injury (744).
Mechanisms of Injury
The injuries in child abuse victims can be the result of direct trauma,
shaking injuries, strangulation, or a combination thereof (735). How-
ever, the precise mechanisms by which the injuries occur and the forces
needed to produce them are not entirely clear due to the lack of a sat-
isfactory model and the lack of good data in describing mechanisms of
injury in identified cases (745,746). Indeed, most studies have been ret-
rospective, lacking controls, and no definition of nonaccidental trau-
matic brain injury or shaken baby syndrome for research studies has
yet been identified (745,746). Nonetheless, a few basic facts seem to be
generally accepted. Direct trauma can result in skull fractures, subdural
hematomas, and cerebral contusion of the coup-contre-coup variety.
Vigorous shaking probably causes contusions of the brain (from bang-
ing of the brain against the rough edges on the inner surface of the
calvarium) as well as associated subarachnoid and subdural hemor-
rhage (from rupture of bridging veins at their weak points) (582,678–
680,691,742,743,746–748). Damage to the lower brainstem and upper
cervical spine can be easily overlooked and likely are underreported
(749) (the cervical spine is particularly at risk in infants—see sections
on “Spinal Trauma” and “Injuries in Young Children,” earlier in this
chapter—and should be carefully evaluated if neck injury is detected
or any question of injury to the structures of the neck is raised [750]).
Such injuries may result in damage to the respiratory centers and may
be associated with subdural and epidural hematomas at the cervicome-
dullary junction that cause further injury; apneic episodes and subse-
quent hypoxia may ensue (745,751). Some axonal injuries, classically
thought to be diffuse axonal (“shearing”) injuries, have been hypoth-
esized to result from diffuse secondary hypoxia and edema that may
be triggered by an apneic episode (750,752,753); this theory remains
controversial.
Presentation
The clinical presentation of the abused child is variable. The most
common presentation is that of an irritable or abnormally subdued
child, refusing meals, perhaps vomiting or having apneic or cyanotic
attacks (743). The child may present with recurrent encephalopathy,
raising suspicion for metabolic disease or encephalitis; anemia is often
present and the weight of the child is frequently below 50th percen-
tile (681,687,754). Another common presentation is seizures; the child
may have an isolated seizure secondary to abusive head injury or may
present in status epilepticus. If the child presents with a history of head
trauma, the severity of the reported traumatic incident, typically a fall
off of a table or down several stairs, may not match the severity of the
injury detected on the imaging study; epidemiologic studies suggest
that serious injury with neurologic deficit is very unlikely from falls
of less than 1.2 m (about 4 ft) (681,750,755,756). A prior history of
abuse may be discovered (681,755,756). It is important to remember
that children with other developmental problems are at higher risk for
abuse (Fig. 4-91). Other risk factors include young parents, unstable
family situations, low socioeconomic status, and prematurity of the
child (735,745,757).
Outcome of abused children is variable, but often poor, and their
outcomes are significantly worse than those of children injured in acci-
dents (739). The estimated mortality rate ranges from 15% to 38%
5/25/2011 11:39:36 AM
 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 345

FIG. 4-91. Child abuse in a child with tuberous sclerosis. A. Axial T2-weighted image shows a left subdural hema-
toma with a focus of acute hypointense blood (solid arrows) within it. Note the right frontal tubers (open arrows).
B. Coronal GE T2* image shows more fully the extent (arrows) of the subdural hematoma.

(757), while 30% to 50% of survivors suffer cognitive or other neu-
rological deficits (758). In the first 4 months after the event, the most
notable sequelae are blindness, visual impairment, hemi- or tetraplegia,
and slowing of head growth (751,754,759,760). By age 18 months, psy-
chomotor retardation may be revealed by deficits in the emergence
of language, constructional ability, and spatiotemporal exploration.
Between ages 3 and 6 years, major behavioral disorders may become
apparent along with a lowering of IQ (761).
Choice of Radiological Exams
Skull radiographs are still useful in establishing the diagnosis of abusive
head trauma, in that the incidence of skull fractures in affected patients
is 45% (679). Multiple fractures, stellate fractures, bilateral fractures,
fractures more than 5 mm wide at presentation, and depressed fractures
should raise suspicion for abusive head trauma (681). Bone scintigra-
phy is not particularly useful in the diagnosis of linear skull fractures,
as the osteoblastic response is limited. Moreover, as mentioned earlier,
axial CT sections may miss linear skull fractures if they are parallel to
the plane of section. Therefore, it is essential to look at the scout view of
all CT scans obtained in the setting of trauma (Fig. 4-92).
Both CT and MRI can be of considerable assistance in the assess-
ment of an abused child, both by confirming the diagnosis and by
allowing appraisal of the extent of brain injury (678–680,691). With
increasing concerns regarding radiation exposure in children, the
American College of Radiology now recommends brain MRI over CT
for children aged 2 years of younger who are suspected to have suffered

FIG. 4-92. Use of scout film and identification of subtle subdural hemorrhage in nonaccidental trauma. A. Scout view
shows horizontal linear fracture (black arrows) in the frontal bone. B. Axial noncontrast CT image shows subdural blood
along the falcotentorial junction (small white arrows) and layering along the right wall of the superior sagittal sinus (white
arrowheads).

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 346 Pediatric Neuroimaging

abusive head trauma—so long as they have no focal signs or symptoms. If
a child up to age 5 years is suspected to have suffered physical abuse and
has neurologic signs, symptoms, or a seizure, then brain CT is recom-
mended as the most appropriate initial study (762). CT has advantages
in the acute setting, as it is sensitive in the detection of subdural (Fig.
4-92) and subarachnoid blood and calvarial fractures (Fig. 4-92), and
is more easily performed on an unstable, acutely injured child. Usually,
CT provides most of the necessary information. MRI is most useful
when CT has not confirmed a strong clinical suspicion of abuse, and
MRI shows best the full extent of neurological injury (brain and spine),
which is useful for prognostication of outcome. MR exams should
include diffusion images for the detection of nonhemorrhagic shear
injury and hypoxic-ischemic injuries, and susceptibility-weighted
images, for detection of small intraparenchymal hemorrhages, in addi-
tion to standard T1- and T2-weighted images. Ultrasound has signifi-
cant limits in the detection of subarachnoid hemorrhage and some
subdural hematomas, and is less sensitive in the detection of cerebral
parenchymal injury; it has no role in the diagnosis of abusive head
trauma, but may have some use in monitoring the progression of,
for example, subdural hematomas in infants receiving intensive care
(763).
Most investigators agree with the ACR position regarding CT as
first line imaging as soon as the child with suspected abusive head
trauma can be stabilized (762,764,765). The utility of MRI is clear when
the CT is abnormal or when the child’s neurological status is abnormal
in the setting of a normal CT. When the CT is normal and the child is
without neurological signs or symptoms, the necessity of MRI is less
well substantiated. Some favor the utilization of MRI for medical-legal
documentation purposes, including aiding in the timing of hemor-
rhages (762,764,765). Others suggest that the high sensitivity of MRI
with diffusion imaging can detect clinically significant injury when CT
findings are subtle (766). Follow up CT or MR scanning (around the
10 day postinjury window) may be valuable to check for the devel-
opment of hydrocephalus or change in subdural hematomas, and to
assess for evolution of parenchymal injuries. If the early MRI showed
brain parenchymal injury or if neurologic abnormality persists, then a
follow-up MRI is recommended after 2 to 3 months to look for enlarg-
ing subdural collections, hydrocephalus, or a developing leptomenin-
geal cyst (764).
Imaging Findings
Subdural hemorrhage is the most common intracranial manifestation
of abuse and its presence in any young child without an appropriate
history is strongly suggestive of abusive head trauma. In one series of
93 children, aged 3 years and less, with extraparenchymal hematomas,
47% with subdural hematomas were ultimately diagnosed as having
been abused (682). In contrast, only 6% of patients with epidural
hematomas were ultimately diagnosed as having been abused (682).
Subdural hematomas are particularly suggestive if seen in conjunction
with acute and subacute, acute and chronic, or subacute and chronic
intraparenchymal hemorrhages (because the presence of injuries of
different ages suggests repeated trauma) or if the hematoma is mul-
tiloculated or shows a fluid-fluid layer in the acute phase (suggesting
hemorrhage into a preexisting subdural hematoma, Fig. 4-90); subdural
hematomas in association with severe retinal hemorrhage, particularly
absent signs of impact have been reported to be highly specific, albeit
not very sensitive, for abusive head trauma (767).
It is sometimes difficult to differentiate bilateral chronic subdural
hematomas from benign infantile enlargement of the subarachnoid
spaces, a condition in which the extra-axial CSF spaces are enlarged as a
(presumed) result of immaturity of the arachnoid villi (see Chapter 8).
When blood products are present in the subdural collections, the diag-
nosis of trauma (but not necessarily abusive head trauma) can confi-
dently be made. However, when the extra-axial fluid is nearly isointense
with CSF on multiple pulse sequences, differentiation is aided by the
presence of associated parenchymal injuries (Figs. 4-90 and 4-94).
Subdural hematomas, subarachnoid hemorrhage and acute cerebral
contusions can be visualized by CT (Figs. 4-92 and 4-93). Contusions

FIG. 4-93. Nonaccidental trauma; use of diffusion imaging and spectroscopy. MRI was performed 2 days after the
injury. A. Axial noncontrast CT shows subdural blood layering along the walls of the superior sagittal sinus (black
arrowheads) and over the cerebral convexity (white arrows). A small amount of blood lies in the left occipital horn
(black arrow). Hypodensity of the brain parenchyma is seen in the frontal lobes and left temporal lobe. B. Axial SE
3000/120 image shows the large bilateral subdural collections and the areas of parenchymal hyperintensity in the
bilateral frontal lobes and left temporal lobe.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 347

FIG. 4-93. (Continued) C. Axial ADC image (b = 1000 s/mm2) shows reduced dif-
fusion (low signal intensity) in the regions of parenchymal injury. D. Proton MRS
(TE = 288) shows marked reduction of NAA and elevation of lactate (Lac) in the
injured temporal lobe. E. Follow up CT scan 2 months later shows severe encepha-
lomalacia in the injured brain regions.

may be seen as ovoid areas of low attenuation or as accumulations of
intraparenchymal blood (high attenuation) with surrounding edema
(Fig. 4-94A). However, small subdurals near the base of the brain and
vertex and small contusions in the anterior temporal lobes and in the
orbital surface of the frontal lobes may be difficult to detect on CT. As
mentioned earlier in the chapter, hemorrhage becomes more difficult
to detect by CT after approximately 1 week, as the blood becomes pro-
gressively isodense with brain (Table 4-8).
MRI is much more sensitive than CT in diagnosing subacute hema-
tomas, both subdural and intraparenchymal, at the vertex (Fig. 4-94)
and in transversely oriented locations (subfrontal, along the tentorium)
in the middle and posterior cranial fossae (678). While some general
concepts from the known evolution of intraparenchymal hemorrhage
can be extrapolated to extra-axial hemorrhage, caution should be exer-
cised in trying to date hemorrhages. The MR appearance of hemato-
mas varies with location, size, and stage of degradation; moreover, the
rate of degradation varies with size and location of the blood collection
(Table 4-9) (680,767,768). It remains to be determined if this general
evolution scheme developed from 1.5 T imaging is equally applicable
for 3.0 T imaging.
In addition, subdural hematomas resulting from abusive head
trauma are often of mixed density on CT (768–770). These may result
from single events in which early acute blood mixes with hyperacute
hemorrhage; single events in which acute hyperdense hemorrhage
mixes with hypodense serum and/or CSF; or two or more events with
acute and chronic hemorrhage combining to appear as a mixed den-
sity collection (768). Indeed, the only CT features that seem to support
a combination of two temporally distinct traumatic events are mem-
branes within a collection, large low density collections associated with
expanded underlying subarachnoid spaces (impaired absorption of
CSF due to old blood products obstructing immature arachnoid gran-
ulations), and a history of slowly enlarging head circumference (746).

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 348 Pediatric Neuroimaging

FIG. 4-94. Nonaccidental trauma. A. Noncontrast CT shows

hypodense chronic bilateral subdural hematomas, with super-
imposed acute hemorrhage over the left temporal lobe (white
arrow) and along the left tentorial leaf (white arrowhead), with
hemorrhagic contusion (black arrow) in the right frontal lobe.
The quadrigeminal plate cistern is effaced. B. Noncontrast CT
near the vertex shows the more acute, hyperdense bilateral sub-
dural hematomas (a) and the more hypodense chronic subdural
hematomas (c) containing posteriorly layering blood products
(arrows). Soft tissue swelling overlies the left parietal bone frac-
ture and intact right parietal bone. Note the marked parenchy-
mal edema. C. Axial T2-weighted image shows the right anterior
frontal and left posterior deep white matter hemorrhagic injuries.
The chronic subdural hematomas show predominately hyperin-
tense signal, while T2 hypointensity (black arrows) indicates the
more acute hemorrhages over the medial parietal lobes.

Although abusive head trauma is, by far, the most common cause of findings. It has also reported that infants with benign enlargement
subdural hematomas in infants, it is important to keep in mind that of the subarachnoid spaces (see Chapter 8) may develop subdural
metabolic diseases can also cause bilateral subdural hematomas. In hematomas after relatively minor trauma (685). However, all infants
particular, Menkes kinky hair disease, glutaric aciduria Type 1, and and children with subdural hematomas and no satisfactory explana-
Hermansky-Pudlak syndrome can cause both subdural hematomas tion should be referred to pediatricians subspecializing in child abuse,
and retinal hemorrhages (771). These diseases, although very rare, when available, or child protective services, for thorough evaluation, as
should be kept in mind when evaluating infants with such imaging a traumatic cause will very commonly be found (772,773). Radiologists
should be aware that all 50 United States have mandatory reporting
statutes for suspected child abuse and neglect.
Edema and parenchymal injury of the cortex and white matter is
TABLE 4-8 General Evolution of commonly present and is more sensitively detected by MRI than by
Subdural Hematomas on CT CT; in the early phase of injury, diffusion images make the lesions
more conspicuous (766). Common locations for the contusions
include the anterior temporal lobes and anterior frontal lobes (Figs.
Stage Appearance Estimated Age Range
4-93 and 4-94). Noncontusional cerebral cortical/subcortical injury
Hyperacute Isodense <3 h can also occur in child abuse, although the precise mechanism is not
Acute Hyperdense Few Hours to 11 d always elucidated (735,774). These lesions are typically not in classic
vascular territories and they often cross vascular territories; therefore,
Subacute Isodense 1 ½–3 wk it is not certain that they represent infarcts. Single large areas or mul-
Chronic Hypodense More than 3 wk tiple noncontiguous areas may be involved (Figs. 4-93, 4-95, and 4-96).
When large areas of cortical injury are seen in conjunction with sub-
(Adapted from References 767 and 768)
dural or subarachnoid hemorrhage in an infant, the possibility of abu-
sive head trauma should be raised (774). If the MR study is performed

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood 349

TABLE 4-9 General Evolution of Subdural Hematomas on MRI

Stage T1 Intensity T2 Intensity FLAIR Intensity Estimated Age Range
Hyperacute Iso or hypo Hyper Hypo <24 h
Acute Iso or hypo Hypo Hypo 1–4 d
Early subacute Hyper Iso or hypo Any 2–3 d to 1–2 wk
Late subacute Hyper Hyper Iso to hyper 1–2 wk to 1–2 mo
Chronic (subdural membrane) Iso Hypo Unproven, likely iso Few weeks to years
Chronic (subdural contents) Hypo but brighter Hyper Unproven, likely hypo Few weeks to years
than CSF but brighter than CSF
Note: When sedimentation of blood products occurs, the signal from the sediment is felt to be more accurate for timing of hemorrhage, particularly for T1 and
FLAIR sequences.
(Adapted from References 767 and 768)

soon after the event (during the first day), the injured tissue may be
difficult to detect by routine sequences. Diffusion imaging is invalu-
able in this setting, as the injured areas will show reduced diffusivity
(Figs. 4-93, and 4-96), often in areas that appear normal on standard
sequences (775,776). On routine sequences, the signal intensity of the
injured tissue varies, depending upon the age of the injury and the
presence or lack of associated blood. As described in prior sections,
acute hemorrhage is isointense with brain on T1-weighted spin-echo
sequences and hypointense on T2-weighted spin-echo and gradient-
echo sequences with 1.5 T imaging. Subacute blood develops high sig-
nal intensity, first on T1-weighted and then on T2-weighted sequences.
Old hemorrhage within the brain can be identified by the presence of
old blood products, predominantly hemosiderin and ferritin, which
appear as ill-defined areas of very low signal intensity on T2-weighted
spin-echo or gradient-echo sequences (see Fig. 4-90). Gradient-echo
or susceptibility-weighted images (SWI) are especially useful in sus-
pected abusive head trauma cases because of their sensitivity to regions
of different magnetic susceptibilities, especially when long (>30 mil-
liseconds) echo times are used for GE (Fig. 4-90 and 4-96C). Areas of
old hemorrhage can be seen on these images as areas of hypointensity
that are larger and much more apparent than on the T2-weighted spin-
echo images. These images are obtained in addition to T2-weighted
spin-echo images, not substituted for them. The information they
provide is complementary to that from spin-echo, RARE, or FLAIR
images; significant parenchymal injury may be missed when GE or
SWI sequences are employed exclusively. As stated earlier, RARE (fast/
turbo spin echo) and FLAIR sequences, which are relatively insensitive
to paramagnetic substances (Figs. 4-89, 4-90, and 4-96), should not be
used as primary sequences at 1.5 T static field strength in trauma cases, as
the presence of old and new hemorrhage is of critical importance. If 3 T
scanners become common enough that they are used for acute trauma,
it may be necessary to rethink this algorithm, as acute and early sub-
acute blood seems to be more easily detected as low signal intensity on
FLAIR and RARE sequences at 3 T (707).

FIG. 4-95. Nonaccidental trauma. A. Axial noncontrast CT image shows right-to-left subfalcine shift, right subdural hematoma (open arrows) and
hypodensity of the posterior cerebral hemispheres bilaterally (solid arrows). B. CT image at higher level shows hypodensity of the entire right cerebral
hemisphere and the anterior and posterior portions of the left hemisphere. C. Bone windows of a CT image superior to (B) shows a depressed skull fracture
(open arrow) and splitting of the coronal sutures (solid arrows).

Barkovich_Chap04.indd 349 5/25/2011 11:39:39 AM

 350 Pediatric Neuroimaging

FIG. 4-96. Nonaccidental trauma. Hemorrhage and hypoperfusion

injury in a 3-month old brought to the emergency department because of
seizure. A. Axial fat-suppressed FLAIR shows subdural hematomas over
both cerebral hemispheres (white arrows) that are largely lower in signal
intensity than parenchyma and have a gradient (with posterior more
hyperintense), while more acute subdural blood along the tentorium
(white arrowheads) is significantly more hyperintense than parenchyma.
B. Coronal T2-weighted image shows the heterogeneity of the various
ages of subdural hemorrhage, with hypointense more acute blood over
the medial right parietal cortex (black arrowheads) and hyperintense more
chronic blood over both convexities. Note the membrane in the left sided
chronic subdural hematoma (black arrow). C. Susceptibility-weighted
image demonstrates the intraventricular hemorrhage that layers within
the occipital horns of the lateral ventricles (black arrowheads). This was
not seen on other sequences. D. Axial T1-weighted image near the vertex
shows the subdural hematomas of varying ages, including a very hyper-
intense focus within the posterior interhemispheric fissure, and the loss
of gray-white differentiation in a watershed distribution (white arrows).
E. Axial Dav map shows markedly reduced diffusivity (low signal intensity)
in a watershed distribution, confirming hypoperfusion injury.

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 Chapter 4 • Brain and Spine Injuries in Infancy and Childhood
Injury to the spine and spinal cord is commonly seen in pathologic
examinations of abused children. The cervical spine is particularly
affected by shaking injury and should always be examined if other evi-
dence of shaking injury is identified. As discussed earlier, infants may
suffer significant spinal cord injury in the absence of radiologically
apparent injury to the spinal column. Therefore, MRI is the examina-
tion of choice for imaging of the spine. Both sagittal and axial T1- and
T2-weighted images should be obtained to look for spinal cord injury
(even cord transection), subdural and epidural hematomas, injuries to
the vertebral bodies, and paraspinous hemorrhage due to the vertebral
body injuries.
Proton MRS obtained in the subacute phase may be useful to assess
prognosis in shaken babies (Fig. 4-93). In particular, the presence of
elevated lactate or the reduction of NAA on MRS studies obtained 5 to
7 days after the injury indicate significant damage; preliminary stud-
ies suggest that these patients will have a poor prognosis (777). This
observation has been confirmed on a larger patient cohort, and made
even more sensitive and specific when correlated with age, initial GCS
score, and presence of retinal hemorrhage (778).
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 CHAPTER

Congenital Malformations
5 of the Brain and Skull
A. JAMES BARKOVICH AND CHARLES A. RAYBAUD

Basic concepts of brain development Anomalies of the craniocervical junction (the Chiari
Concepts: causes, classification, and basic embryology malformations)
Early brain development Chiari I malformations
Anomalies of dorsal prosencephalon development Chiari II malformations
Anomalies of the cerebral commissures Chiari III malformations
Malformations of cerebral cortical development Anomalies of the mesenchyme (meninges and skull)
Anomalies of ventral prosencephalon development Cephaloceles and other calvarial and skull base defects
Holoprosencephaly Intracranial lipomas
Arrhinia/arrhinencephaly Arachnoid cysts
Septooptic dysplasia Craniosynostosis
Isolated absence of the septum pellucidum Chromosomal anomalies
Anomalies of the hypothalamic-pituitary axis Trisomy 21
Anomalies of the eyes Trisomy 18
Anomalies of midbrain-hindbrain development Trisomy 13
Overview of midbrain and hindbrain development Fragile X syndrome
Classification of midbrain-hindbrain malformations Inversion duplication of short arm of chromosome 8
Wolf-Hirschhorn syndrome

bnormal brain development, leading to dysplasia or BASIC CONCEPTS OF BRAIN DEVELOPMENT

A malformation, is a common finding in the neuroimaging stud-
ies of children with developmental delay, mental retardation, Concepts: Causes, Classification,
or epilepsy (1–3). This chapter discusses brain malformations, includ- and Basic Embryology
ing the essential embryology and genetics involved in the development
As will become evident in the sections that follow, most structures
of the malformation, the clinical findings, the optimal imaging tech-
of the brain form at about the same time. Therefore, events leading
niques to aid in diagnosis, and imaging findings. In addition, it discusses
to malformation of the developing brain often result in anomalies of
basic embryology of the brain, the disturbance of which results in mal-
more than one structure. For example, malformations of cerebral cor-
formations. This information should allow the reader to diagnose most
tex development may have associated cerebellar anomalies, cephaloce-
disorders of brain development.
les often have associated gray matter heterotopia or anomalies of the
The organization of this chapter has changed from that in the prior
corpus callosum, and holoprosencephalies frequently have associated
editions of this book. In order to help the reader locate the malforma-
anomalies of the corpus callosum and the cerebral cortex. The reader
tion, it is only necessary to figure out what part of the brain or skull is
should keep this high incidence of multiple anomalies in mind when
affected. If the malformation involves the cerebral hemispheres or the
reviewing imaging studies; as a wise radiologist once said, the hardest
commissures connecting them (corpus callosum, anterior commissure,
brain malformation to find is the second one.
hippocampal commissure), it will be found in “Anomalies of Dorsal
Classification of brain malformations is also difficult. One reason
Prosencephalon Development.” If it primarily involves the basal ganglia,
for this, pointed out by Norman et al. (4), is that no two brain mal-
hypothalamus-pituitary axis, the olfactory structures, or the orbits, it will
formations are exactly the same. Indeed, differences are seen even in
be found in “Anomalies of Ventral Prosencephalon Development.” If it
the malformations of siblings with identical chromosomal mutations,
mainly involves the brain stem or cerebellum, look in “Anomalies of Mid-
probably as a result of epigenetic (5) and environmental (6) factors. It
brain-Hindbrain development.” The Chiari malformations are discussed
is, nonetheless, important to try to put similar malformations into a
in “Anomalies of the Craniocervical Junction.” Anomalies of the calva-
single group whenever possible; without some sort of organization, it
rium, skull base, subarachnoid space (lipomas and cysts), and leptom-
would be extremely difficult to assemble information about prognosis,
eninges are discussed in “Anomalies of the Mesenchyme.” Hopefully, this
optimal therapy, and the chances that future siblings will be similarly
organization will facilitate navigating this chapter. Before discussing the
affected. Another difficulty in classifying brain anomalies results from
anomalies themselves, it is important to understand the basics of brain
the aforementioned frequency of multiple anomalies. Should a cepha-
development. This knowledge will help the reader to recognize malfor-
locele with heterotopic gray matter and callosal agenesis be classified as
mations and to distinguish them from distortion of normal brain.
367

Barkovich_Chap05.indd 367 5/6/2011 8:58:32 PM

 368 Pediatric Neuroimaging
a disorder of neural tube closure, a malformation of cerebral cortical
development, or a disorder of commissuration? Or are there enough
patients with that combination of findings to define it as a malforma-
tion syndrome? These questions have no easy answers and, as a result,
this chapter mainly describes anomalies of the various structures of the
brain (i.e., corpus callosum, cerebral cortex, cerebellum) and its cover-
ings; we discuss the embryology of those structures but do not propose
an overall classification of the disorders, as is done on anomalies of the
spine in Chapter 9. A framework for classification based upon mor-
phology, genetics, and embryology is introduced for malformations
of cortical development (7) and malformations of the midbrain and
hindbrain (8–10). When these disorders have malformations of mul-
tiple structures, all are discussed together whenever possible.
One final important concept concerns the causes of brain anoma-
lies. The time during which specific structures of the brain are formed
is usually known. An injury (of any type) to the brain at the time a par-
ticular structure is forming will result in an anomaly of that structure; a
mutated gene can cause an identical anomaly if the protein product of
the gene functions in the formation of that same structure at the same
time. In addition, one protein may be involved in many pathways and,
thus, be necessary for the formation of different structures at differ-
ent times; as a consequence, a single mutation may cause anomalies of
several structures that form at different times. Finally, some of the same
chemicals responsible for promoting cell growth or guiding cell/axon
migration in utero have functions regulating brain metabolism after
birth; therefore, some patients with inborn errors of metabolism may
have brain malformations. Although only a few such associations are
described in the literature, more are likely to be discovered. One exam-
ple of this is the presence of callosal dysgenesis in patients with pyru-
vate dehydrogenase complex deficiency (11). Other examples include
the presence of abnormal sulcation in the Zellweger syndrome (12,13)
and the presence of cerebellar hypoplasia in mitochondrial respiratory
chain dysfunction (14) and adenylosuccinate lyase deficiency (15).
Early Brain Development
On about the 15th day of life, ectodermal cells proliferate along the sur-
face of the embryo to form a plate of tissue, the primitive streak. A rap-
idly proliferating group of cells, known as Hensen node, forms at one
end of the primitive streak and defines its cephalic end. From Hensen
node, cells that will form the notochord migrate rostrally and allow dif-
ferentiation of dorsal midline ectoderm into neuroectoderm. This plate-
like condensation of neuroectoderm is known as the neural plate.
At approximately seventeen days of gestation, the lateral portions
of the neural plate begin to thicken bilaterally, forming the neural folds;
the process of bending elevates these folds and brings them to the dor-
sal midline (16). At about 20 days, these folds meet in the midline at the
level of the rhombencephalon. This junction of the neural folds begins
the formation of the neural tube (17–19).
As the neural tube closes, the neuroectoderm, which will form the
central nervous system, separates from the overlying ectoderm, which
will become the skin. Until recently, most experts believed that neural
tube closure proceeds cranially and caudally in a zipper-like fashion.
More recent evidence, however, suggests that neurulation begins sepa-
rately at two, or possibly three, different levels in humans, when cellular
protrusions (possibly cilia) project medially from the most dorsal cells
of the neural folds on either side. Cell recognition and adhesion occur
under the influence of many molecules (20), closing the tube at each
point. This information may provide a unifying concept for certain
developmental malformations, such as cephaloceles. The cephalic end
of the neural tube, the anterior neuropore, closes at about 25 days of
Barkovich_Chap05.indd 368
gestation. The caudal end of the neural tube, the posterior neuropore,
closes at about 27 to 28 days of gestation.
At the time of closure of the anterior neuropore, three brain ves-
icles develop secondary to focal dilations in the rostral cavity of the
neural tube. These three early subdivisions are the prosencephalon
(forebrain), the mesencephalon (midbrain), and the rhombencepha-
lon (hindbrain) (Fig. 5-1). The rhombencephalon is separated from
the mesencephalon by the cephalic flexure and from the cervical spi-
nal cord by the cervical flexure. The prosencephalon divides into the
caudal diencephalon, which forms the pretectum, thalami, substan-
tial nigra-ventral tegmental area, and the prerubral tegmentum, and
the more rostral protosegment, from which the hypothalamus, optic
vesicles, and telencephalon (which will form the cerebral hemispheres)
arise (21). The cells that compose the brain arise primarily within the
germinal zones in the walls of the ventricles (22–28). Many secondary
germinal zones (e.g., the subventricular zone (SVZ) in the cerebrum,
the external granular layer [EGL] in the cerebellum) form when some
daughter cells migrate a short way before stopping and duplicating
again (27,29).
At the time of closure of the anterior neuropore, the optic vesicles
have already begun to bud from the protosegment; these will interact
with overlying ectoderm to form the optic nerves and ocular globes
(which are really rostral extensions of the diencephalon). As the tel-
encephalon develops, the cerebral hemispheres grow posteriorly to
cover the diencephalon, mesencephalon, and portions of the rhomb-
encephalon (Fig. 5-1); accompanying this growth of the hemispheres,
the corpus callosum seems to grow from anterior to posterior (see sec-
tion “Anomalies of the Cerebral Commissures”). Further details of the
development of the telencephalon are discussed in sections “Anomalies
of the Cerebral Commissures” and “Malformations of Cerebral Corti-
cal Development.”
The rhombencephalon will eventually divide into the myelenceph-
alon, which will form the pons and cerebellum (a dorsal extension of
the pons), and the metencephalon, which will form the medulla oblon-
gata. This process of development is discussed further in the section
“Anomalies of Midbrain–Hindbrain Development.”
ANOMALIES OF DORSAL
PROSENCEPHALON DEVELOPMENT
Anomalies of the Cerebral Commissures
The cerebral commissures are bundles of axons that arise from corti-
cal neurons and connect the two cerebral hemispheres by traversing
the developing hemisphere and crossing the midline. Alterations of
their morphology, as assessed by imaging, may be identified in many
hemispheric disorders, destructive or developmental, that impair cel-
lular migration, axon guidance, or crossing of the midline. As they can
be altered by so many processes, abnormalities of the cerebral com-
missures are among the most common developmental brain anoma-
lies, being found in 1.8 per 10,000 live births (30). The incidence is
increased in prematurely born children and in children born to moth-
ers of advanced age, as well as in children with chromosomal disorders
(17.3%), those with accompanying somatic disorders (musculoskeletal
33.5% and cardiac 27.6%), and those with other CNS malformations
(49.5%) (30). As many as 3% to 4% of patients referred for cognitive
or motor delay are found to have commissural anomalies, most often
of the corpus callosum (31). Commissural anomalies were identified
in 33% of fetal brain malformations found on MRI by Raybaud et al.
(32); this figure may be low, as mild commissural anomalies may be
missed by prenatal ultrasonography and, therefore, not referred for
5/6/2011 8:58:32 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 369

FIG. 5-1. Early development of the nervous system. A.

At the time of closure of the anterior neuropore, three
brain vesicles develop in the rostral cavity of the neural
tube. These three subdivisions are the prosencephalon,
mesencephalon, and rhombencephalon. The rhomben-
cephalon is separated from the mesencephalon by the
cephalic flexure and from the cervical spinal cord by
the cervical flexure. B. The pontine (rhombic) flexure,
which is the site of the future fourth ventricle and is
very important in the development of the cerebellum,
develops after the cervical and cephalic flexures. C. As
the telencephalon develops, the cerebral hemispheres
grow posteriorly to cover the midbrain and portions of
the hindbrain. The cerebellar hemispheres grow from
the dorsal, rostral portion of the hindbrain, which sit at
the cranial edge of the developing fourth ventricle (the
site of the pontine flexure).

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 370 Pediatric Neuroimaging

MRI (32). Although a few affected patients have normal cognition or
normal neurological examinations, the vast majority has neuromotor
and cognitive impairment (31,33). Therefore, it is important to analyze
the cerebral commissures in all patients referred for fetal or postnatal
imaging.
Anatomy and Embryology
The cerebral commissures include the anterior commissure, which
connects the olfactory cortex (paleocortex) and the lateral and inferior
temporo-occipital neocortex of the two hemispheres; the hippocam-
pal commissure (psalterium), which connects the fornices and, thus,
the hippocampal cortex (archicortex); and the corpus callosum, which
connects most of the hemispheric neocortex (principally neurons in
the intermediate cortical layers, Fig. 5-2). The corpus callosum, an evo-
lutionary acquisition of placental mammals (34), develops by second-
ary fusion of the hemispheres in the midline at the site of the cavum
septi pellucidi (35). Although the corpus callosum is the main pathway
through which neocortical commissural fibers cross the midline, some
neocortical axons (from the lateral and inferior temporo-occipital
lobes) also cross via the anterior commissure (36). The septum pellu-
cidum is central to this process. It is surrounded by the three commis-
sures, being formed by the midline juxtaposition of the layer of white
matter that forms the medial border of each lateral ventricle, anterior
to the hippocampal commissure. It contains myelinated, presumably
septocingulate, axons but no gray matter (37,38). The septum pellu-
cidum is distinct from the septal area, also called the septum verum or
septum granulosum, a gray matter structure that is connected to the
hypothalamus and located below the rostrum of the corpus callosum,
anterior to the lamina terminalis. The septum pellucidum is located
above the rostrum and forms the medial wall of the anterior parts of
the lateral ventricles.
The corpus callosum is the largest and most easily visualized of
the commissures. It is composed of five sections: the rostrum (lamina
rostralis), genu, body, isthmus, and splenium (Fig. 5-2). The isthmus
connects the precentral and postcentral gyri as well as the primary
auditory cortices (Fig. 5-3). It contains large, heavily myelinated axons.
Anterior to it, the body, genu, and lamina rostralis contain the small
myelinated commissural axons of the frontal lobe association areas:
premotor cortex/supplementary motor area and prefrontal cortex.
Posterior to the isthmus, the splenium contain axons from the parietal,
medial occipital, and medial temporal cortices. The midline portion of
the hippocampal commissure is fused to the inferior, concave aspect
of the splenium, behind the body of the fornix (Fig. 5-2); it cannot be
distinguished from the callosal splenium on midline sagittal images.
The anterior commissure is located in the upper portion of the lamina
terminalis (the anterior wall of the third ventricle), very close to the
junction of the lamina rostralis and the lamina terminalis (Fig. 5-2)
and the bifurcation of the fornix (where it divides into precommissural
[septal] and postcommissural [mamillary] tracts). The septum pellu-
cidum is bounded superiorly by the callosal body, anterior-inferiorly
by the lamina rostralis, and posterior-inferiorly by the body of the
fornix (Fig. 5-2) (38).
In order to understand commissural anomalies, it is essential to
understand the basics of commissural development. During the sev-
enth week of gestation, the upper portion of the lamina terminalis (at
the rostral end of the neural tube) thickens to become the lamina reu-
niens or commissural plate (Fig. 5-4A); it corresponds to the future
septum or septal area (35), and it establishes continuity between the
two hemispheres. The pioneer axons of the anterior commissure cross
the midline through cellular glial tunnels in its ventral portion dur-
ing the eighth week (Fig. 5-4B) (39). During weeks 9 to 10, the lamina
reuniens develops a groove, the sulcus medianus telencephali medii
(SMTM, Fig. 5-5A) in its dorsal surface. The lips of this groove con-
tain the early axons of the fornix that connect the septal area with the
future hippocampus; some of these forniceal axons cross the midline
in week 11, either within the dorsal lamina reuniens itself (35) or
along its surface under the meningeal covering (40), to form the early
hippocampal commissure (Fig. 5-4C). Then the walls of the SMTM

FIG. 5-2. The normal cerebral commissures. Sagittal T1-weighted image (A) shows the anterior commissure (white asterisk) in the upper portion
of the anterior wall of the third ventricle (lamina terminalis). The hippocampal commissure (black asterisk) connects the columns of the fornices
and blends with the callosal splenium in the midline. The parts of the corpus callosum are the lamina rostralis or rostrum (small white arrow), genu
(large white arrow), body (large black arrow), isthmus (double white arrow), and splenium (triple white arrow). Coronal image (B) better shows the
separation between the callosal axons (cc) connecting the cerebral hemispheric white matter and the hippocampal commissure (hc) connecting the
fornices.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 371

FIG. 5-3. Callosal defect secondary to parenchymal injury (history of neonatal hypoxic-ischemic injury at term). A. Axial FLAIR
image demonstrates encephalomalacia in the depth of the central sulcus and underlying white matter bilaterally. B. Sagittal midline
T2 image demonstrates focal atrophy (white arrow) of the corpus callosum at the level of the isthmus (destruction of the sensorimo-
tor commissural axons). This example illustrates that the rostrum, genu, and body contain frontal commissural fibers, while the
splenium contains parietal, occipital, and temporal fibers.

LR
LT

A. 7 w
FIG. 5-4. Development of the lamina reuniens and of the corpus
LR callosum, sagittal midline. A. During week 7, the upper portion of
the lamina terminalis (LT), which connects the hemispheres across
AC
LT the midline, thickens and forms the lamina reuniens (LR) of His. B.
In the following week, olfactory commissural fibers cross the mid-
B. 8 w line through the ventral aspect of the lamina reuniens to form the
anterior commissure (AC). C. In the following weeks, fibers develop
B between the anterior mediobasal cortex (septal nuclei) and the
future hippocampus to form the ipsilateral fornix (FO); about week
11, some forniceal fibers cross the midline in the dorsal portion of
HC the lamina reuniens and form the hippocampal commissure (HC).
FO D. During week 12, the corticoseptal boundary becomes defined at
the medial edge of the future neocortex and a glial sling forms along
this boundary (see Fig. 5-5B). E. By week 13, three commissural sites
have been established: anterior commissure, hippocampal commis-
LR sure, and glial sling. Depending on their origins, early neocortical
AC commissural fibers cross the midline along the anterior commissure
C. 11 w
(temporo-occipital fibers), the glial sling (frontal fibers) or the hip-
pocampal commissure (parietooccipitotemporal fibers). F. The cor-
HC pus callosum grows by addition of further commissural fibers and
FO
forms a single continuous structure stretched between the anterior
commissure and the hippocampal commissure; it circumscribes the
glial sling future septum pellucidum. Later, the prominent development of the
frontal lobes results in posterior growth of the anterior callosum,
which displaces the hippocampal commissure and the splenium
AC D. 12 w
backward above the velum interpositum (roof above the third ven-
tricle), stretching the body of the fornix.

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 372 Pediatric Neuroimaging

C D

HC and posterior
callosum
HC
FO
AC FO

AC
glial sling and anterior
callosum

septum pellucidum
corpus callosum

septum pellucidum

FIG. 5-4. (Continued)

come into contact in the midline along a line (called the corticoseptal
boundary, Fig. 5-5A) that marks the limit between the developing cor-
tical plate at one end and the septal area and the fornix at the other
(41–44). Specialized cells that originate from the SVZ of the germinal
matrix migrate toward this line, pierce the brain surface and invade
the developing subarachnoid space (meninx primitiva) (Fig. 5-4) to
form an interhemispheric bridge across the midline, which is called the
“glial sling” (41,45–47), or “midline glial zipper” (42,48,49). The cells
that compose the sling express surface molecules and secrete chemicals
into the extracellular space that help to guide axons across the midline
(39,47,50–53). Within the developing hemispheres, two specialized
glial structures secrete chemical signals that direct the commissural
axons toward the midline and the glial sling. One, located just above
the corticoseptal boundary is the indusium griseum glia, and the other
located just below it at the dorsomedial aspect of the lateral ventricle is
called the glial wedge (Fig. 5-5B) (43,44,53).

FIG. 5-5. Midline glia, corpus callosum, and cavum septi pellucidi coronal
diagrams. A. A deep sulcus (sulcus medianus telencephali medii, SMTM)
develops in the superior aspect of the lamina reuniens. A clear demarcation
(the corticoseptal boundary) appears between the banks of this sulcus and
the neocortical plate. B. Specialized glial structures develop in the vicinity
of the corticoseptal boundary; the glial sling (or midline zipper glia) forms
a bridge between the hemispheres; on each side of the midline, the indu-
sium griseum glia and the glial wedge form above and below the corticoseptal
boundary. C. The pioneer commissural fibers are channeled from the cingu-
late gyrus toward the midline by the repelling effect of the indusium griseum
glia and the glial wedge, and guided across the midline by the glial sling.
At the same time, the ipsilateral fornix and septocingulate (septum pellu-
cidum) fibers develop in the banks of the SMTM, which become the leaves
of the septum pellucidum (not shown); the space within the SMTM becomes
enclosed superiorly by the developing corpus callosum to form the cavum
septi pellucidi.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
The first callosal axons to cross along the glial sling arise from the
developing cingulate gyri (Fig. 5-5C) (47,54,55). These cingulate axons
act as pioneer fibers, guiding later axons from neocortical neurons. At
this stage, three separate sites of commissuration can be recognized
(Fig. 5-4D and F): the ventral lamina reuniens (forming the anterior
commissure), the dorsal lamina reuniens (forming the hippocampal
commissure), and the glial sling (composed of pioneer corpus cal-
losum axons bridging the interhemispheric fissure at the level of the
corticoseptal boundary). Later formed neocortical commissural axons
will use these commissural sites to cross the midline by a process called
fasciculation (by recognizing chemical signals on the axons that have
already crossed, rather than signals from the developing brain, their
migration is much less complex). As the number of neocortical axons
crossing at the more posterior hippocampal commissure and at the
more anterior corticoseptal boundary grows, these structures eventu-
ally meet in what will become the posterior body of the corpus cal-
losum. Therefore, the anterior and the posterior callosum originally
are separated (40) but eventually unite to form a single structure.
Because of the disproportionate growth of the frontal lobes in humans,
the hippocampal commissure, although initially in the lamina reu-
niens, is pushed posteriorly (stretching the forniceal columns) and
becomes located under the splenium (35). This apparent front-to-back
progression is generally interpreted as a front-to-back growth of the
corpus callosum but is in fact the front-to-back relative displacement
of the hippocampal commissure (and of the splenial axons attached
to it) that results from the back-to-front growth of the frontal lobes
and the corresponding accumulation of crossing axons in the anterior
callosal segment. Therefore, while the initial pioneer axons are begin-
ning to cross in the region of the interventricular foramina of Monro
[35]), the glial “sling” is just beginning to form in the anterior body,
while the SMTM is forming in the posterior body (56,57). The genu,
lamina rostralis, and body appear to form in rapid succession and all
are present at week 15 (Fig. 5-6) (53,58); the hippocampal commis-
sure develops earlier, but the splenium (using hippocampal commis-
sure axons as guides for fasciculation to cross the midline) does not
become prominent until weeks 18 to 19 (53). So although the anterior
corpus callosum (including the lamina rostralis) appears after the hip-
pocampal commissure, it enlarges and becomes grossly visible first; the
FIG. 5-6. Early fetal development of the commissures. A and B. Midline sagittal T1 images of anatomic specimens estimated at 13 to 14 weeks. The corpus
callosum is short (white arrows) and the splenium has not developed yet although the hippocampal commissure is apparent. C. In an 18-week specimen,
the splenium can be identified, and the anterior corpus callosum has grown posteriorly as the frontal lobes expand, pushing the hippocampal commissure
and attached splenium dorsally.
Barkovich_Chap05.indd 373
373
splenium forms over the hippocampal commissure after the anterior
corpus callosum and it enlarges later (35,58,59).
The septum pellucidum forms in close association with the anterior
corpus callosum. Its lower margin contains the early axons (week 10) of
the fornix between the septal area and the hippocampus, (week 11). The
fibers that connect the medial septal nucleus with the ipsilateral cingu-
late cortex develop in the septal leaves at the same time as the pioneer
callosal axons in the rat; they cross the glial sling and the corpus cal-
losum along the way. Because the septum pellucidum develops in the
walls of the SMTM, it becomes circumscribed by the lamina rostralis,
genu, and body of the corpus callosum (Fig. 5-4F). The interhemispheric
space between the septal leaves becomes the cavum septi pellucidi (Fig.
5-5C) (35,60); when the cavum extends posteriorly between the corpus
callosum and the hippocampal commissure, this extension is called the
cavum Vergae. Initially thought to be a meningeal space (35), recent evi-
dence suggests that it is the space that is left after the disappearance of
the glial sling (46), explaining why no meningeal epithelium is found on
the medial aspect of the septal leaves in a premature infant with cavum
septi pellucidi (37). The cavum becomes apparent about 20 weeks and
usually disappears within 3 months after birth, its lumen becoming pro-
gressively effaced from the back to the front (61,62).
Spectrum of Commissural Abnormalities
If the normal developmental process is disturbed, the development
of all three of the cerebral commissures or any combination of the
cerebral commissures may be affected; this results in a spectrum of
commissural anomalies (Fig. 5-7). The corpus callosum itself may be
completely absent (agenetic) or partially formed (hypogenetic). As
discussed in section “Anatomy and Embryology,” the corpus callo-
sum originates in two independent portions, with axons crossing by
way of a glial sling anteriorly and the hippocampal commissure pos-
teriorly. The hippocampal commissure forms at week 11, before the
anterior callosum at week 13; later callosal growth (through fascicu-
lation) is mostly anterior prenatally, pushing the hippocampal com-
missure and associated posterior callosum posteriorly. Knowledge
of this sequence of development helps to differentiate the variants
of commissural malformation: (a) complete tricommissural agen-
esis (global failure of the midline crossing processes, Fig. 5-8); (b)
5/6/2011 8:58:38 PM
 374 Pediatric Neuroimaging

ant post

cc
s
s hc
A. a-commissural B. normal anatomy

Probst Probst FIG. 5-7. Schematic representations of various commissural and sep-
tal disorders. A. With complete absence of commissures, the leaves of
s hc
the septum pellucidum (s) border the medial edge of the limbic lobe.
C. global commissural agenesis D. isolated callosal agenesis B. During normal development, the anterior corpus callosum (blue, left)
at the corticoseptal boundary, the hippocampal commissure (violet)
and the splenium (blue, right) between the fornices, cross the midline.
ant post
C. In classic commissural agenesis, the commissural fibers do not cross
the midline. Callosal axons run parasagittally within the pellucidal leaves
(forming Probst bundles, blue ellipses) instead and fornices (violet ovals)
are not connected. D. In isolated callosal agenesis, the hippocampal com-
cc missure (hc, violet line between fornices) is present. E. In isolated agenesis
cc
of the hippocampal commissure, the corpus callosum (cc) is present, but
s hc fornices are not connected. F. In septooptic dysplasia, both callosal and
hippocampal commissures are present but the leaves of the septum pel-
E. agenesis of hippocampal commissure F. septo-optic dysplasia
lucidum are missing.

complete agenesis of corpus callosum, which almost always involves
both the callosal and the hippocampal commissures (Fig. 5-9); (c)
posterior agenesis, which may relate to a failure of the hippocampal
commissure (and therefore of the posterior callosum) to form (Fig.
5-10); (d) insufficient commissuration, with failure of the anterior
callosum to grow and push the hippocampal commissure poste-
riorly (Fig. 5-11); or (e) failure of the posterior callosum to grow
(Fig. 5-12). Rarely, the hippocampal commissure may form in the
absence of a corpus callosum (Fig. 5-13); more rarely still, only an
intermediate segment is missing between anterior callosal axons and

FIG. 5-8. Complete (tricommissural) agenesis. A. Midline sagittal T1-weighted image shows absence of the anterior, callosal
and hippocampal commissures, with a high-riding third ventricular roof, radial pattern of the medial hemispheric sulci, and
normal posterior fossa contents. B. Coronal T2-weighted image shows widely spaced lateral ventricles bordered medially by
heavily myelinated Probst bundles (white arrows) in the septum pellucidum (resulting in the crescentic appearance of the
ventricular lumen). Note the abnormally shaped hippocampi, caused by extension of the temporal horns into the parahip-
pocampal gyri (black arrows) where the white matter tract (ventral cingulum) is hypoplastic or absent.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 375

FIG. 5-8. (Continued) C. Axial T2 image shows a wide interhemispheric fissure with prominent ventricular
atria (colpocephaly, black arrows), likely because of the poorly developed posterior white matter. D. Axial
T2-weighted image shows the parallel bodies of the lateral ventricles, separated from the interhemispheric
fissure by Probst bundles (b) and the medial hemispheric cortex.

a well formed splenium/hippocampal commissure (63,64). Callosal
anomalies in classic holoprosencephaly are atypical, as the splenium
may be present without a normal genu or body, or the callosal body
and splenium may be present in the absence of a genu (63,65). In
the middle interhemispheric (MIH) variant of holoprosencephaly,
the genu and splenium may be present without a normal callosal
body (66). Examples are shown in the section “Holoprosencephaly”
of this chapter. In classic semilobar or lobar holoprosencephalies, the
frontal lobe is undivided, and no midline corticoseptal boundary can
develop to allow formation of an interhemispheric glial sling and
FIG. 5-9. Classic “callosal” agenesis. Midline sagittal T1 image shows a
normal-looking anterior commissure. The appearance otherwise is similar to
that of Figure 5-8A; both callosal and hippocampal commissures are missing.
subsequent crossing of anterior callosal axons; also, absence of septal
cortex precludes formation of a distinct fornix (hippocamposeptal
fibers). Yet, on the posterior cortical margin along the single ven-
tricle, forniceal fibers are present, allowing development of a hip-
pocampal commissure, and the callosal fibers of the posterior part
of the hemispheres may fasciculate along them to form a splenium,
or a splenium and body depending on the severity of the failure of
interhemispheric fissure formation (64,67). In the interhemispheric
variant of holoprosencephaly, the presence of the posterior corpus
callosum/hippocampal commissure may have the same explanation;
the anterior corpus callosum may be present because the septal area
developed normally with a normal anterior corticoseptal boundary,
a normal glial sling, indusium and glial wedge and, therefore, nor-
mal anterior callosum; the posterior body does not form because the
interhemispheric continuity has impaired formation of the corti-
coseptal boundary and prevented the eventual fusion of the anterior
and posterior callosal segments (38).
Specific callosal changes may be observed when the region of brain
that sends axons through a specific region of the corpus is destroyed
(e.g., porencephalies and schizencephalies). Those patients who have
had corpus callosotomies for seizure surgery (68) or transcallosal sur-
gical approaches to the lateral or third ventricles (69) have callosal
defects that may mimic congenital callosal defects if the surgical his-
tory is not known.
As stated above, the anterior commissure and hippocampal com-
missure are typically affected when the corpus callosum develops
abnormally (70). Most commonly, the anterior commissure will be
small and the hippocampal commissure absent in the setting of callosal
agenesis (64,70). Occasionally, however, the hippocampal commissure
will be enlarged in patients with hypogenesis or agenesis of the corpus
callosum (57): the enlarged commissure may mimic a section of cal-
losum on midline sagittal images; analysis of coronal images will show
that this commissure connects the fornices, not the cerebral hemi-
spheres (Fig. 5-13). An enlarged anterior commissure may be seen in
callosal agenesis, but this was rarely observed in large reported series
(64,71,72) and appears to be quite unusual.

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 376 Pediatric Neuroimaging

FIG. 5-10. Callosal hypogenesis (partial agenesis) in three patients; sigmoid bundle and tractography. A–C. Classic Probst bundles. Midline sagittal
T1-weighted image (A) shows a short segment of corpus callosum (white arrows) above the anterior commissure, in front of the foramen of Monro;
the lamina rostralis, the fornix, and the hippocampal commissure are not seen. Coronal T2-weighted image (B) shows an anterior callosal remnant
(black arrows) in the location of the genu, while a more posterior image (C) shows the typical appearance of commissural agenesis, with Probst bundles,
abnormal hippocampi, and medial extension of temporal horns. D and E. Sigmoid bundle. Midline sagittal T1-weighted image (D) shows a small cal-
losal remnant (white arrow) and an anterior commissure (white arrowhead). Axial T2-weighted image (E) shows a “sigmoid bundle”: a bundle of axons
starting in the right forceps minor (small white arrows), crossing the midline (black arrow, this is the callosal “remnant” seen in D), and extending into
the contralateral hemisphere in the location of a Probst bundle (large white arrow). White matter injury is present in the left hemisphere. F–H. Homo-
topic and heterotopic bundles identified by diffusion tensor imaging. Sagittal T1-weighte d image (F) shows callosal hypogenesis with small inferior
genu, absent rostrum, posterior body, and splenium. Fiber tracking of callosal axons superimposed on a color FA map shows homotopic bundles in the
forceps minor (blue), central cerebrum (orange), parietal lobe (purple), and forceps major (green). The yellow, heterotopic “sigmoid” bundle, crossing
from the left frontal lobe to the right occipital lobe, is seen with the other crossing fibers in (G) and is isolated in (H). (Figures F, G, and H are courtesy
Michael Wahl, San Francisco.)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 377

FIG. 5-10. (Continued)

FIG. 5-11. “Classic” posterior callosal hypogenesis (partial agenesis). A. Midline sagittal T1-weighted image shows a short,
but otherwise complete commissural plate. The anterior commissure is tiny or absent. B. Coronal T2-weighted image
through the amygdalae shows incomplete fusion of the septum pellucidum leaves. In this case, the posterior callosum is miss-
ing, but the fornix is abutting the undersurface of the posterior callosum (in A), which appears to be a normal splenium. This
malformation might result from a failure of the anterior callosum to grow normally and to displace the hippocampal com-
missure and splenium posteriorly. Note the small septum pellucidum between the fornix and the corpus callosum in A.

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 378 Pediatric Neuroimaging

FIG. 5-12. Callosal tapering, with mild posterior callosal hypogenesis. On this
midline sagittal T1-weighted image, the anterior commissure and anterior cal-
losum look normal, with a normal junction of the fornix suggesting a normal
hippocampal commissure. The splenium is less well developed suggesting a pos-
terior callosal commissural defect. As is commonly seen with splenium hypopla-
sia, the rostrum is absent.

Associated Anomalies and Syndromes
The formation of the corpus callosum and its precursors occurs
between about 8 weeks and 20 weeks of gestational age (35,73). This
corresponds to the period of the bulk of neuronal migration in the
forebrain, and most of the cerebrum and cerebellum also form at the
same time. Therefore, in addition to anomalies of the other telenceph-
alic commissures, anomalies of the corpus callosum are often associ-
ated with other anomalies of the cerebrum and cerebellum, such as
the Chiari II malformation, cerebellar hypoplasias, the Dandy-Walker
spectrum (Fig. 5-14), malformations of cortical development (Fig.
5-15), cephaloceles, hypothalamic malformations, and midline facial
anomalies (57,74,75). Although it is reported that isolated callosal agen-
esis may be asymptomatic, in the experience of most neurologists and
neuroradiologists, incidental detection of callosal agenesis is very rare.
More typically, affected patients present with seizures, macrocephaly,
delayed development, mental retardation, or hypothalamic dysfunc-
tion (Fig. 5-16) (30,33,64,76,77). Those who are cognitively and neu-
rologically normal often suffer from behavioral and neuropsychiatric
problems, leading to learning difficulties (78), sleep disorders (79),
language and social communication disorders (80), and visuospatial
attention deficits (81).
Callosal anomalies are a part of many syndrome complexes
(74,77,82–84); a 2010 search on OMIM (Online Mendelian Inheritance
in Man) retrieves 187 syndromes in which “corpus callosum agenesis”
is a significant feature. The most frequently mentioned of these is the
Aicardi syndrome (82). Aicardi syndrome is an X-linked dominant dis-
order consisting of infantile spasms, multiple cerebral malformations
(most commonly callosal agenesis, gray matter heterotopia, and poly-

FIG. 5-13. Callosal agenesis with hippocampal commissure mimicking a splenium. A. Midline sagittal T1-weighted image shows
apparent formation of the splenium in the absence of the anterior callosum. B. Coronal T1-weighted image shows that the commissure
connects the fornices and, therefore, is a hippocampal commissure, not a splenium (Reprinted from Barkovich AJ. Apparent atypical
callosal dysgenesis: analysis of MR findings in six cases and their relationship to holoprosencephaly. Am J Neuroradiol 1990;11:333–340,
with permission.).

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-14. Commissural agenesis with posterior fossa cyst. Midline sagit-
tal T2-weighted image shows that the anterior commissure (black arrow) is
present, but not the hippocampal or the callosal commissures. The poste-
rior fossa is large with high insertion of the tentorium, hypoplastic rotated
vermis, small pons, and a huge cistern magna.
microgyria [PMG]), chorioretinopathy, and an abnormal EEG pattern
(hypsarrhythmia). The syndrome occurs almost exclusively in females
(affected patients must have two X chromosomes, so patients with
Klinefelter syndrome [47XXY] can also have it [85]) with no family his-
tory of ophthalmologic or neurologic disease. The mutation results in a
spontaneous balanced translocation of the X chromosome. Prevalence
rate is 2 to 15 per 100,000 girls (86). Affected patients typically have
severe global developmental delay and early-onset, medically refrac-
tory epilepsy (86,87). Intracranial anomalies (Fig. 5-17) include callosal
agenesis or hypogenesis (often associated with interhemispheric cysts),
FIG. 5-15. Commissural agenesis with polymicrogyria. A. Midline sagittal T1-weighted image shows that the anterior
commissure is present, but not the hippocampal or callosal commissures; a persistent craniopharyngeal canal (white
arrows) is present. B. Axial T2-weighted image shows bilateral frontal polymicrogyria.
Barkovich_Chap05.indd 379
379
rarely callosal hypoplasia, periventricular nodular and subcortical het-
erotopia, PMG, posterior fossa and other extraparenchymal cysts, cer-
ebellar hypoplasia, choroid plexus papillomas, and microphthalamia.
Ophthalmologic exam reveals characteristic chorioretinal lacunae,
which result from retinal dysplasia, and ocular colobomata. Myelination
may be delayed (82,88–90). Callosal agenesis is also the most common
brain anomaly seen in the fetal alcohol syndrome, although patients
with this disorder more typically have normal neuroimaging studies;
the diagnosis is established by history and recognition of characteris-
tic facial and neurologic features. Patients with severe facial anomalies,
such as midline craniofacial dysgenesis (see section on “Cephaloceles
and Other Calvarial and Skull Base Defects”) or large midline clefts
have a high incidence of callosal anomalies. Other commissural abnor-
malities seen on neuroimaging studies include ventriculomegaly and
cavum septi pellucidi et Vergae (91).
The septum pellucidum may also be too small (surface area dispro-
portionately small in relation to the corpus callosum) with apparently
normal fornices. In hemimegalencephaly (HME), the septum may be
too thick and eccentric toward the dysmorphic hemisphere. Rarely,
the septum may be abnormally thick as an isolated anomaly; possible
causes include the presence of too many axons, an aberrant white mat-
ter fascicle in the midline, or the persistence of residual cellular mate-
rial, possibly glial or neuronal, in the lumen of the cavum. This finding
has not been associated with any clinical condition (92).
A complete list of syndromes with commissural anomalies is
beyond the scope of this text. Table 5-1 includes a listing of some of
the most common associated syndromes. Many of these syndromes are
discussed in this chapter or other portions of this book.
Anatomic Sequelae of Callosal Anomalies
The imaging findings in patients with callosal anomalies vary with the
cause of the callosal anomaly. If the problem is lack of formation or
destruction of the callosal axons, the result is a marked reduction of
cerebral white matter; in such cases, the commissures are often abnor-
mal, with portions either too thin or completely missing (Fig. 5-3).
When the problem is an abnormality within the interhemispheric
fissure, with an inability of the axons to cross the midline, the axons
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 380 Pediatric Neuroimaging

FIG. 5-16. Posterior tapering of the corpus callosum with hypothalamic

hamartoma, pituitary stalk agenesis, and posterior pituitary ectopia. The cor-
pus callosum is short with posterior tapering (large white arrows), but the junc-
tion with the fornix is normal; this suggests global callosal hypoplasia. Note the
hypothalamic hamartoma (small white arrow) associated with the absence of
the anterior commissure and the ectopic location of the hyperintense posterior
pituitary lobe (white arrowhead).

that would normally course into the contralateral hemisphere through
the corpus instead turn at the interhemispheric fissure and run parallel
to that fissure, forming the U-shaped longitudinal callosal bundles of
Probst (Figs. 5-8B and 5-18) that form intrahemispheric rather than
interhemispheric connections (98). These callosal fibers are best con-
sidered heterotopic; they connect different areas within one hemisphere
rather than symmetrical areas of opposite hemispheres, resulting in a
significant variant of normal functional anatomy. The Probst bundles
lie lateral to the cingulate gyri and medial to the medial walls of the
lateral ventricles; their inferomedial borders merge with rudimentary
fornices. Because of their location, the bundles of Probst invaginate
the medial borders of the lateral ventricles, giving the ventricles a
crescentic shape, which is most pronounced frontally (Figs. 5-8B and
5-19) (35,56,57). In either case, the third ventricle is located higher
than normal, between the lateral ventricles, and the foramen of Monro
tend to be enlarged. When the callosal body is absent, the bodies of
the lateral ventricles are straight and parallel, away from the midline
and separated from it by the medial walls of the hemispheres (Fig.
5-8D). Rarely, hypertrophy of the hippocampal or anterior commis-
sure accompanies callosal agenesis or hypogenesis (Fig. 5-13) (63). The
formation of the corpus callosum seems to be associated with medial
and upward rotation of the cingulate gyrus with consequent forma-

FIG. 5-17. Aicardi syndrome. A. Midline sagittal T1-weighted image shows hypogenetic corpus callosum with a large interhemispheric cyst
and cerebellar vermian hypoplasia. B. Axial T1-weighted image shows the large interhemispheric cyst, multiple subependymal/subcortical
heterotopia and dysplastic cortex in both hemispheres.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
TABLE 5-1 A Partial List of Syndromes
Associated with
Commissural Anomalies
Aicardi syndrome
Apert syndrome
Chiari II malformation
CRASH syndrome (Chapter 8)
Dandy-Walker malformation
Fetal alcohol syndrome
Frontonasal dysplasia (93)
Inversion-duplication of short arm of chromosome 8
Median cleft face syndrome
Morning glory syndrome (usually with sphenoidal cephalocele)
Mowat-Wilson syndrome (94)
Neu-Laxova syndrome (95)
Nonketotic hyperglycinemia (Chapter 3)
Pyruvate dehydrogenase deficiency (Chapter 3)
Oro-facial-digital syndromes
Rubinstein Taybi syndrome (96)
Shapiro syndrome (hypothalamic-pituitary dwarfism and
paroxysmal hypothermia) (97)
Walker-Warburg syndrome
tion of the cingulate sulcus. When the corpus callosum does not form,
the cingulate gyri do not rotate and are small due to hypoplasia of the
cingulum (99,100); thus, the cingulate sulci remain unformed (57) and
the medial hemisphere sulci radiate all the way to the third ventricle
(Fig. 5-8A). In addition, the medial hemispheric sulci have a rather dis-
organized appearance, probably secondary to disorganization of the
white matter tracts in and near the midline (Figs. 5-8 to 5-11). This
abnormal appearance of the medial hemispheric sulci is one of the
hallmarks of absence of the corpus callosum; this finding is especially
helpful when evaluating newborns, in whom the corpus is thin and
often difficult to see (see Chapter 2).
The corpus callosum is the most tightly packed bundle of axons
in the brain. This compactness makes the corpus a very firm structure
and gives the adjacent lateral ventricles their shape; the firmness of the
corpus also helps the ventricles to maintain their normal size, espe-
cially posteriorly. The firm caudate heads and lentiform nuclei keep
the size of the frontal horns relatively small, even in the absence of
the corpus callosum (although, when the genu is absent, the frontal
horns are convex laterally instead of concave, as in the normal case)
(Figs. 5-8B and 5-10C). Posteriorly, however, only loose white matter
surrounds the ventricles when the callosal splenium is absent. More-
over, multiple white matter tracts (including the dorsal cingulum,
within the cingulate sulcus, and the ventral cingulum, within the para-
hippocampal gyrus) are often hypoplastic or absent when the corpus is
hypogenetic, including those coursing around the ventricular trigone
and temporal horn (64,99). In callosal hypogenesis, therefore, the tem-
poral horns, trigones, and occipital horns of the lateral ventricles often
Barkovich_Chap05.indd 381
381
FIG. 5-18. Formation of the parasagittal bundles (of Probst). Because of
the lack of induction by the midline glia, the commissural axons fail to cross
the midline; instead when they reach the corticoseptal boundary they turn
and course parallel to the interhemispheric fissure within the septal leaves,
indenting the medial walls of the lateral ventricles. Broken lines represent
fibers of the corpus callosum in the normal brain. Solid lines represent the
fibers that fail to cross in callosal agenesis. (Modified from Rakic P, Yakovlev
PI. Development of the corpus callosum and cavum septae in man. J Comp
Neurol 1968;132:45–72, with permission.).
enlarge, with the temporal horns extending inferomedially into the
parahippocampal gyri, where the hypoplastic ventral cingulum would
normally be found (Figs. 5-8B and 5-10C) (100–102). This ventricular
configuration is known as colpocephaly.
Imaging of Callosal Anomalies
Agenesis of the corpus callosum can be detected on images obtained
in the axial plane, although the sagittal and coronal planes better
demonstrate the associated anatomic deformities (Fig. 5-10). The
characteristic lateral convexity of the frontal horns, parallel lateral
ventricles, colpocephaly, and upward extension of the third ventricle
into the interhemispheric fissure between the lateral ventricles can all
be identified in the axial plane (Fig. 5-8). Milder callosal anomalies,
however, are difficult to identify with axial images. MRI, ultrasound,
and modern multidetector CT all allow images to be easily obtained
in or reformatted into the coronal and sagittal planes, but the tissue
discrimination and the spatial definition of MRI are much superior
to those of other modalities. In addition, DTI and tractography may
allow a better understanding of the abnormal intrahemispheric and
interhemispheric connectivity (Fig. 5-10G and H). The severity of cal-
losal hypogenesis or dysgenesis is assessed well on the midline sagit-
tal images (Figs. 5-8 to 5-12). As mentioned earlier, when the corpus
is hypogenetic, the posterior portions and the inferior genu and ros-
trum are usually absent. Therefore, a hypogenetic corpus callosum
may include the posterior genu; posterior genu and anterior body;
genu and entire body; or entire genu, body, and hypoplastic splenium.
Other times, the hypogenetic corpus callosum may be mistaken for
hypoplastic (Fig. 5-20); a disproportionately small or absent splenium
helps to make the diagnosis of hypogenesis. Other MR findings in the
absence of a corpus callosum include lack of inward folding of the cin-
gulate gyri (with the medial hemispheric sulci extending all the way
5/6/2011 8:58:48 PM
 382 Pediatric Neuroimaging
FIG. 5-19. Schematic drawing illustrating the findings in callosal agen-
esis (compare with Fig. 5-8B). The lateral ventricles have a crescentic shape
secondary to the medially located bundles of Probst. The third ventricle
expands upward between the lateral ventricles into the interhemispheric
fissure. The cingulate gyri remain everted and the cingulate sulci do not
form. (Reprinted from Barkovich AJ. Apparent atypical callosal dysgenesis:
analysis of MR findings in six cases and their relationship to holoprosen-
cephaly. Am J Neuroradiol 1990;11:333–340, with permission.)
to the third ventricle), crescent-shaped lateral ventricles (caused by
an impression upon the medial walls of the ventricles by the medially
positioned bundles of Probst), incomplete rotation of the hippocampal
formation in the medial temporal lobes, inferomedial extension of the
temporal horns of the lateral ventricles (due to hypoplasia of the ven-
tral cingulum [100]), and extension of the roof of the third ventricle
into the interhemispheric fissure (Figs. 5-9 to 5-11).
FIG. 5-20. Hypogenesis mimicking hypoplasia. All the commissures are
small, but present. The round commissure (white arrowhead) above the
posterior third ventricle is the hippocampal commissure. Although this
might easily be mistaken for callosal hypoplasia, absence of the inferior
genu and hypoplasia of the splenium suggest that this is hypogenesis.
Barkovich_Chap05.indd 382
Diffusion tractography has added to our knowledge about white
matter pathways in the setting of callosal anomalies. In patients with
complete callosal agenesis, the axons running through the Probst bun-
dles connect anterior regions of the hemisphere with more posterior
regions, with the axons exhibiting a topographic organization (98).
In patients with hypogenesis of the corpus callosum, axons running
through the callosal remnant course not only to the expected areas but
also to all regions of the brain, both symmetrically (homotopic con-
nectivity) and asymmetrically (heterotopic connectivity) via so-called
sigmoid bundles (Fig. 5-10) (98,99).
Callosal Agenesis with Interhemispheric Cyst
Agenesis of the corpus callosum with interhemispheric cyst is a special
condition that may have a different cause than other types of callosal
agenesis. ACC with IHC can be divided into two major groups, one
in which the interhemispheric cyst is a diverticulum of the ventricu-
lar system and thus communicates with the ventricles (Type 1) and
one in which multiple, cysts are present that do not communicate with
the ventricles (Type 2, see Table 5-2) (103). Type 1 cysts are isointense
to CSF (Fig. 5-21), whereas Type 2 cysts are usually slightly hyperin-
tense to CSF on T1-weighted images and isointense to hyperintense
on T2-weighted images (Figs. 5-22 and 5-23). Type 2 ACC with IHC is
often associated with subcortical heterotopia or PMG and the Type 2b
cysts are frequently found in Aicardi syndrome. Pavone et al. (104) have
shown that large portions of the corpus callosum may be present and
that affected patients frequently have severe neurological and develop-
mental disorders. Of note, as with all types of cysts, the cysts associated
with callosal agenesis may not develop or become apparent on imaging
until late in gestation (105,106). As such cysts are frequently associated
with macrocephaly or frank hydrocephalus at birth, repeat sonographic
examination before delivery is recommended (105,106).
Type 2 cysts are often multiloculated. Under these circumstances,
it is important to establish which of the loculations communicate with
one another and with the ventricles, in order to properly plan which
compartments should be shunted and in what order. A CT cystogram
or ventriculogram is performed after nonionic iodinated contrast is
introduced into the cyst(s) to establish which of the CSF collections
communicate.
Patients with Type 1 interhemispheric cysts are most commonly
boys who present with macrocephaly or cranial deformity. Patients
with Type 1a and Type 2d cysts have the best prognosis in our experi-
ence, while those with Types 1c, 2b, and 2c have the worst prognoses.
Some studies indicate that developmental delay and focal neurologic
deficits are common in Type 1 cysts, but are uncommon and less severe
in Type 2 cysts (64,107); however, this has not been verified in a pro-
spective series. Seizures develop in less than half of affected patients.
Shunting or fenestration is usually necessary in Type 2 cysts; if the
cysts are adequately decompressed, many of these patients may ulti-
mately have normal neurologic exams and normal school performance
(64,70), although epilepsy may become a problem.
Diagnosis of Callosal Agenesis/Dysgenesis in the Fetus
Fetal ultrasound is performed in virtually every pregnancy in indus-
trialized countries, and the diagnosis of a major malformation such as
a commissural agenesis is usually suggested on the basis of this exam;
in particular, ventriculomegaly (especially bilateral colpocephaly, with
posterior dilatation of the lateral ventricles) and absence of a normal
cavum septi pellucidi suggests the diagnosis, especially if associated with
a large interhemispheric fissure or interhemispheric cysts (108,109).
However, ultrasonography may fail to demonstrate the malformation
itself, either because the surrounding tissues obscure the fetal head or
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 Chapter 5 • Congenital Malformations of the Brain and Skull 383

TABLE 5-2 Classification of Callosal Agenesis with Interhemispheric Cyst

Cyst Type Sex Age, Reason of Presentation Cyst Characteristics Associated Anomalies
Type 1 Communicate with Ventricles
1a M Neonate, macrocephaly Isointense to CSF. Hydrocephalus.
Unilocular.
Communicates with ventricles.
1b M>F Neonate, macrocephaly Isointense to CSF. Thalamic fusion without
Unilocular. subcortical heterotopia.
Communicates with third ventricle.
1c M Neonate, seizures, Isointense to CSF. Small ipsilateral cerebral
microcephaly Unilocular. hemisphere.
Communicates with lateral and third ventricle.
Type 2 No communication with ventricle
2a M Neonate, macrocephaly Isointense to CSF. Hydrocephalus.
Multilocular.
No communication with ventricles.
2b F Infant, neurodevelopmental Multiloculated. Subependymal heterotopia.
disorders (severe), seizures, No communication with ventricles. Polymicrogyria.
micro/macrocephaly Hyperdense on CT, hyperintense on T1MR. Deficient falx cerebri.
2c M Childhood seizures, delay Isointense to CSF. Subcortical heterotopia.
Multilocular.
No communication with ventricles.
2d ? Macrocephaly Arachnoid cyst. None.
Isointense to CSF.
Unilocular.
No communication with ventricles.

Adapted from Barkovich AJ, Simon EM, Walsh CA. Callosal agenesis with cyst: a better understanding and new classification. Neurology 2001;56:220–227,
with permission.

because the malformation is mild (e.g., in mild callosal hypogenesis).
If possible, endovaginal ultrasonography may significantly improve
the diagnostic efficacy, but depending on the obliquity of the head, it
may be limited by the small range of lateral motion of the probe (109).
Also, ultrasound may fail to demonstrate associated brain abnormali-
ties that significantly worsen the prognosis. At many institutions, fetal
MRI is used to confirm the diagnosis of callosal agenesis/hypogenesis
and to look for associated malformations because the diagnostic yield
is typically much superior (32,108–110). Fetal MRI may also be useful
to diagnose commissural agenesis in fetuses referred for nonspecific
ventriculomegaly or to rule out brain anomalies in fetuses where the
cavum septi pellucidi could not be identified on ultrasound. How-
ever, if abnormalities are mild and are missed on ultrasonography, no
fetal MRI will be performed, probably explaining the lower incidence
of partial relative to complete agenesis in prenatal, as compared with
postnatal, series of commissural anomalies (32).
MRI is the optimal modality to assess the fetal brain parenchyma
after 18 to 20 weeks gestational age. Any assessment obviously should
be with full knowledge of normal morphologic and size milestones
for the gestational age (see Chapter 2). Commissure malformations
in young fetuses are most easily seen on coronal images and are eas-
ily inferred from the ventricular morphology on the axial cuts; it may
be more difficult to ascertain that the corpus callosum is really absent
(rather than hypoplastic or atrophic) on the midline sagittal cut alone
(Figs. 5-24 and 5-25). Interhemispheric cysts are easily recognized in all
three planes (Fig. 5-26), whereas malformations of the posterior fossa
(brainstem, cerebellum) are better identified and characterized on sag-
ittal and axial images. Other commonly associated abnormalities better
shown by MRI include delayed sulcation and/or shallow sylvian fissure,
gray matter heterotopia, PMG, lissencephaly (with thick cortex), schi-
zencephaly, and choroid plexus cysts (32,108–111). The remainder of
the fetus should be examined, if possible, for extraneural abnormalities
of the skeleton, heart, and trunk.
Malformations of Cerebral Cortical Development
As a result of a greater awareness of their presence and of steadily
improving imaging techniques, malformations of cerebral cortical
development are being discovered with increasingly greater frequency
on imaging examinations of children with developmental delay or
partial epilepsy. Several studies have now shown that malformations
of cortical development are the cause of 23% to 26% of intractable
epilepsies in children and young adults (112–120), and 15% of lesions
resected for intractable epilepsy (121). This number emphasizes the
point that cortical malformations must be ruled out in essentially every
pediatric patient with developmental delay or epilepsy. Moreover, it
is becoming increasingly clear that many malformations of cortical

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 384 Pediatric Neuroimaging

FIG. 5-21. Two examples of callosal hypogenesis and Type 1 interhemispheric cyst. A. Sagittal T1-weighted image shows absence of the
commissures and a large interhemispheric cyst (black arrows) in a microcephalic patient; note the associated malformations of the brainstem
and vermis. B. Coronal T1-weighted image shows that the cyst is continuous with the third and lateral ventricles and straddles the falx; no
septum pellucidum or Probst bundles can be identified. C. Sagittal T1-weighted image in a different patient reveals an enlarged head with a
small meningocele (white arrow) at the vertex. Only the genu of the corpus callosum is present. A large CSF-intensity region is seen rostral and
dorsal to the genu. The cerebellum and tentorium cerebelli are pushed down by the cyst. D. Axial T1-weighted image shows that the cyst is in
communication with the enlarged lateral ventricles.

development are caused by chromosomal mutations (122–132); thus,
the presence of cortical malformations is important for proper coun-
seling of parents of affected children.
Embryology of the Cerebral Cortex
An understanding of the normal development of the cerebral cortex
is essential to understanding malformations of cortical development.
Initially, after initial formation of the cerebral hemispheres from the
developing prosencephalon, each cerebral hemisphere consists of
a thick basal (ventral) portion, called the subpallium, and a thinner
dorsal portion (the pallium, which will become the cerebral mantle).
The subpallium initially appears as bumps on the basal ventricular
wall, between the developing third and lateral ventricles, known as the
subpallium germinal zone, ventral germinal zone, or the ganglionic
eminences (Fig. 5-27). The cells proliferating here will form the dien-
cephalon, the basal ganglia, and the GABAergic (neurons that make
gamma-aminobutyric acid (153) as their neurotransmitter) interneu-
rons of the cerebral cortex, as discussed more completely in the fol-
lowing paragraph (133,134). Cells that will become the glutamatergic
(neurons that make glutamate as their neurotransmitter) neurons
of the cerebral cortex and glial cells are generated in the walls of the
developing lateral ventricles, in proliferative zones called the pallial or
dorsal germinal zone (Fig. 5-28). Cell divisions begin in the dorsal ger-
minal zones during the seventh week of gestation. During the eighth

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 Chapter 5 • Congenital Malformations of the Brain and Skull 385

FIG. 5-22. Callosal agenesis with Type 2a interhemispheric cyst. A. Sagittal

T1-weighted image shows absence of the corpus callosum with a large midline CSF
collection inferiorly displacing the interthalamic adhesion (white arrows). B. Coronal
T1-weighted image shows the interhemispheric fluid collection extending on both
sides of the falx cerebri. The lateral ventricles (open white arrows) and third ventricle
(solid white arrow) are displaced by the interhemispheric cyst. C. Axial T2-weighted
image shows that the collection in fact is composed of multiple loculations.

gestational week, the first young neurons begin to migrate radially
outward from the germinal matrix in the walls of the lateral ventricles,
ultimately forming the cerebral cortex (27,29,135). Movement of neu-
rons from the dorsal germinal zone to their final location is initially a
simple process. Cells in the germinal zone elongate, with the nucleus
moving to the end of the cell that is farthest removed from the ventricu-
lar surface. Contact with the ventricular surface is then terminated and
the remainder of the cell joins the nucleus at some distance from the
ventricular surface (136). Under the influence of certain genes, some
neuroepithelial cells are induced to become specialized radial glial cells
(RGCs) that span the entire thickness of the hemisphere from the ven-
tricular surface to the pia (Fig. 5-28) (27). The RGCs have two func-
tions: (a) they are stem cells, which divide asymmetrically to produce
daughter cells (neurons and glia), and (b) their elongated fiber-like
bodies act to guide migrating neurons (Fig. 5-29) when the hemispheres
enlarge. As different transcription factors start to be expressed, other
types of neurogenic progenitors form, called intermediate precursor
cells (IPCs), neuroepithelial cells, and short neural precursors (27,137).
IPCs migrate to a transient SVZ between the ventricular zone and the
intermediate zone (the developing white matter), where they divide
symmetrically into a pair of neurons that subsequently migrate to the
developing cortex (29,138–142). Neuroepithelial cells and short neural
precursors, in contrast, divide asymmetrically at the ventricular surface
to produce only a single neuron or single IPC.
RGCs tend to be grouped in fascicles that consist of four to ten
cells, all of which guide the migrating neurons. The fascicles supply
necessary metabolites to the migrating neurons; they also organize the
vertical lamination of the developing neocortical plate (143). Neuronal

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 386 Pediatric Neuroimaging

FIG. 5-23. Type 2c callosal agenesis with interhemispheric cyst. A. Sagittal T1-weighted image shows absence of the corpus callosum
with a dorsal interhemispheric fluid collection of CSF intensity and a second collection (white arrows) that is hyperintense compared
to CSF. B. Axial proton density image shows several loculations between the hemispheres. The posterior one is hyperintense compared
to CSF. C. Postcontrast T1-weighted image shows enhancement of the walls of the posterior interhemispheric loculation. D. Axial
T1-weighted image shows subcortical heterotopia (black arrows) in both hemispheres.

migration along RGCs seems to be dependent upon (a) recognition
of the glial cell by the neuron, (b) attachment of the neuron to the
glial cell, and (c) calcium entry into neuron; blocking calcium chan-
nels or blocking N-methyl-D-aspartate receptors inhibits cell migration
(144,145). Recent studies of neuronal migration indicate that a diverse
family of genes and transcription factors cooperate in orchestrating the
multistage, interrelated events involved in cortex development: control
of mode of cell proliferation, fate determination, establishment of
polarity within the young neuron, detachment from the local substrate
to attach to the fascicle, and migration to the proper cortical layer and
final position in the cortex (137,146–152). As migration nears comple-
tion, many of the RGCs begin to produce astrocytes, while others may
transform into astrocytes (27).
In contrast to the generation of glutamatergic neurons in the dor-
sal ventricular zones, GABAergic neurons seem to be generated pre-
dominantly in the subpallium ventricular zones (the medial [MGE]
and lateral [LGE] ganglionic eminences and the preoptic area [POA],
Fig. 5-27) (133,134). These zones have been divided based on the

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 Chapter 5 • Congenital Malformations of the Brain and Skull 387

FIG. 5-24. Commissural agenesis in a 24-week GA fetus. A. Coronal image shows the characteristic appearance of commis-
sural agenesis. Note the bundles of Probst (black arrows) in the medial walls of the lateral ventricles, between the dark signal
layers of both the germinal matrix and medial cortex. B. On this midline sagittal image, the absence of corpus callosum is
difficult to confirm; complementary axial and coronal images are necessary to make the diagnosis in young fetuses.

FIG. 5-25. Commissural hypogenesis in a 24-week GA

fetus. A. Coronal image shows a rudiment of corpus cal-
losum bridging the hemispheres, but the general morphol-
ogy is similar to that in Figure 5-24A. B. On this sagittal
image, the corpus callosum is poorly visualized, just as in
Figure 5-24B. C. Axial image shows the typical appearance
of commissural hypogenesis with a wide interhemispheric
fissure and colpocephaly; the callosal rudiment (black
arrow) is well shown anteriorly.

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 388 Pediatric Neuroimaging

FIG. 5-26. Commissural agenesis with interhemispheric cyst in a 29-week GA fetus. A. Midline sagittal image shows the roof of the
third ventricle is pushed down by a midline cyst that appears separate from the third ventricle, suggesting a type 2 cyst. B. Axial image
shows wide separation of the hemispheres by a multiloculated interhemispheric CSF collection that is centered at the level of the
foramen of Monro; no commissure is seen, and the lateral ventricles have the characteristic morphology of posterior colpocephaly.
The right cerebral hemisphere seems dysmorphic, suggesting a Type 2c ACC with cyst.

expression patterns of several transcription factors, suggesting that
specific features of the interneurons may be programmed very early
during the developmental process (28,154–157). Progenitors in the
ganglionic eminences produce postmitotic neurons with distinct
migratory trajectories and fates: LGE progenitors produce striatal
projection neurons and olfactory bulb interneurons, whereas MGE
progenitors produce cortical and hippocampal interneurons, and the
FIG. 5-27. This schematic demonstrates the ganglionic eminences, the
germinal zones of the subpallium (thick basal [ventral] portion of the
developing cerebrum) where GABAergic neurons (those that secrete
gamma aminobutyric acid—GABA—as a neurotransmitter) are generated,
and the migration of those neurons. Neurons generated in the ventricular
zone (VZ) and subventricular zone (SVZ) of the medial (MGE) and lateral
(LGE) ganglionic eminences migrate locally to form the globus pallidus
(GP), the striatum (Str) and migrate tangentially to become GABAergic
interneurons in the cerebral cortex (CTX). Neurons generated in the pre-
optic area (POA) contribute to the POA, the amygdala and the globus palli-
dus, as well as some cortical interneurons. Also labeled is the thinner dorsal
portion (the pallium), which will become the cerebral mantle.
POA progenitors produce neurons that migrate to the POA, amygdala,
globus pallidus, and cortex (158–163). It appears that the subtype
identity of the interneuron can be predicted by its time and place of
origin (154,156,159,161,164). POA-derived neurons destined for the
cerebral cortex initially migrate to the developing cortical layer 1 and
then migrate inward to deeper cortical layers (161,165,166) whereas
cortical interneurons from the MGE migrate tangentially to the SVZ
of the dorsal pallium germinal zone (133,167–173) from where they
attach to a radial glial cell, along which they migrate radially outward
to the developing cortex (27,29,174). Other GABAergic cells are gener-
ated in the SVZ of the dorsal germinal zones (152, 170) but (as some
GABAergic neurons migrate through the SVZ) it is not entirely certain
whether the dividing cells originated in the dorsal ventricular zone, the
dorsal SVZ, or the ganglionic eminence (27). The distinct molecular
characteristics of neurons arising from different germinal zones may
also serve distinct roles in modulating cortical activity (133,164). Loss
of these neurons, either by lack of generation or abnormal migration,
causes significant neurologic dysfunction (175).
The cortical layer in which a neuron will eventually reside can be
predicted by the known sequence of neuronal development and migra-
tion (147,176). The level at which the migrating neuron disengages
from the radial glial cell seems to be determined by short range inter-
actions with other cells during the last mitotic cycle while the neuron
is still in the germinal zone (177,178). This disengagement requires
secretion of a glycoprotein (called reelin) by neurons in layer 1 (179).
Reelin seems to be involved in the final stages of neuronal migration,
as well as disengagement of the migrating neurons from the RGCs
(180–182). In general, neurons migrate from the germinal zone to the
cortex in an “inside out” sequence. Those destined for the transient
deepest cortical layer (layer 7, also known as the “subplate” [183–187])
migrate early, followed by those destined for layer 6, layer 5, layer 4,
layer 3, and, finally, layer 2. The exception to the “inside out” rule of
neuronal migration is that those neurons destined for the molecular
layer (layer 1) seem to be the first to arrive in the cortex (136,188,189).

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-28. This schematic demonstrates the dorsal (pallial) germinal
zone, where glutamatergic cerebral cortical neurons (those that secrete glu-
tamate as a neurotransmitter) are generated, and the migration of those
neurons. Some of the cells generated in the ventricular and subventricular
zones become radial glial fibers (rgf), which act as guides along which neu-
rons migrate radially to the developing cerebral cortical plate.
After their arrival in the cortex, neurons become arranged in discrete
horizontal layers and establish synaptic contacts with local and dis-
tant neurons in a process known as cortical organization (7,190,191).
The subplate (transient layer 7 of the cortex, which nearly disappears
by term) is believed to play a large role in this organizational process
(183–187,192–194).
Regional specification of the cerebral cortex (remember that dif-
ferent regions of the cortex have different layering patterns and differ-
ent functions) is thought to be determined by a combination of genetic
factors and connections with other portions of the nervous system
(152). It appears that early specification is the result of a cascade of
genetic effects: morphogens and growth factors secreted by signalling
centers in the embryonic forebrain regulate expression of transcrip-
tion factor gradients across the developing cerebrum. The expression
of these transcription factors then impacts the expression of others,
and so on, until the final cellular phenotypes develop. This subject is
currently under active investigation (150–152).
Causes of Malformations of Cortical Development
Any abnormality that inhibits neuronal or glial proliferation, neuronal
migration, or subsequent cortical organization can result in a malfor-
mation of cortical development. These abnormalities may include (a)
gene mutations that interfere with cell proliferation, radial glial fascicle
development, the ability of the neurons to migrate, or the ability to
disengage within the developing cortex and subsequently grow neu-
rites and form synapses (7,195); (b) destructive events, such as infec-
tions or ischemia that damage the germinal matrix, the radial glial
fibers, the molecular layer, or the overlying “pial limiting membrane”
(191,196,197); or (c) the presence of exogenous toxins, such as drugs
or alcohol from ingestion of toxic substances, or endogenous toxins
from metabolic disorders, such as pyruvate dehydrogenase deficiency
or nonketotic hyperglycinemia (see Chapter 3), that may interfere with
one or more of the steps of cortical development (6,198). In malfor-
mations secondary to abnormal migration and those secondary to
abnormal late migration and cortical organization, the neurons tend
to be histologically normal. Therefore, the cortex usually has normal
signal intensity on imaging studies; that is, their signal is isointense to
Barkovich_Chap05.indd 389
389
FIG. 5-29. Illustration of the relationship of the migrating neurons to
fibers of the radial glial cells. A migrating neuron is seen ascending the radial
glial fiber. Abnormal development of the neuron, damage to the radial glial
fiber, or alteration of the molecules on the surface of either the migrating
neuron or the radial glial cell will cause an arrest of cell migration.
normal gray matter. Abnormal T2 hyperintensity in the white matter
is common in some of the malformations secondary to abnormal stem
cell development and in dystroglycanopathies; these findings will be
discussed in the appropriate sections.
Classification of Malformations of Cerebral
Cortical Development
Malformations of cortical development are divided into three cat-
egories based upon the step at which cortical development was likely
first disturbed: (a) stem cell proliferation or apoptosis, (b) neuronal
migration, and (c) late migration and cortical organization (Table 5-3)
(7). We will present the malformations in this order. Developmental
anomalies of the cerebral neocortex occur in a number of different
syndromes, many of which are listed with appropriate references in
Table 5-4 (199). The details of most of these syndromes will not be
elaborated upon in this chapter, as they are more appropriately dis-
cussed in a genetics text. Only a few well-known, common, or particu-
larly instructive syndromes will be elaborated upon.
Special Imaging Techniques for Cortical Malformations
Proper imaging technique and a high index of suspicion are crucial for
the identification of cortical malformations. MRI is the imaging study
of choice, as its high contrast resolution allows a much better analy-
sis of the cerebral cortex than any other neuroimaging technique. CT
misses the abnormality in more than 30% of affected patients (279).
Our protocol includes (a) T1-weighted volumetric three-dimensional
Fourier transformed (3DFT) spoiled gradient-echo sequences using
1.0 mm partition size (and reformatting in three orthogonal planes),
5/6/2011 8:58:56 PM
 390 Pediatric Neuroimaging

TABLE 5-3 Malformations of Cortical Development

I. Malformations due to abnormal neuronal and glial proliferation
or apoptosis
A. Decreased proliferation/increased apoptosis or increased pro-
liferation/decreased apoptosis—abnormalities of brain size
1. Microcephaly with normal to thin cortex
2. Microlissencephaly (Extreme microcephaly with thick
cortex)
3. Microcephaly with extensive polymicrogyria
4. Macrocephalies
B. Abnormal Proliferation (abnormal cell types)
1. Non-Neoplastic
a. Cortical hamartomas of tuberous sclerosis
b. FCD Type II
c. HME
2. Neoplastic (associated with disordered cortex)
a. DNET
b. Ganglioglioma
c. Gangliocytoma
II. Malformations due to abnormal neuronal migration
A. Lissencephaly/subcortical band heterotopia spectrum
B. Cobblestone complex/pial limiting membrane anomalies/con-
genital muscular dystrophy syndromes
C. Heterotopia
1. Subependymal (periventricular)
2. Subcortical (other than band heterotopia)
3. Marginal glioneuronal
III. Malformations due to abnormal cortical organization (including
late neuronal migration)
A. Polymicrogyria and schizencephaly
1. Bilateral polymicrogyria syndromes
2. Schizencephaly (polymicrogyria with clefts)
3. Polymicrogyria or schizencephaly as part of multiple
congenital anomaly/mental retardation syndromes
B. FCD Types I, III
C. Microdysgenesis
IV. Malformations of cortical development, not otherwise classified
A. Malformations secondary to inborn errors of metabolism
1. Mitochondrial and pyruvate metabolic disorders
2. Peroxisomal disorders
B. Other unclassified malformations
1. Sublobar dysplasia
2. Others

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
Chromosome Anomalies
Deletion 1p36.3 — Polymicrogyria Atrophy, leukoen- Clinodactyly, mid- Chrom (200)
cephalopathy, thin face hypoplasia,
corpus callosum flat nasal bridge,
cardiac defects
Inversion 2p12–q14 — Pachygyria Holoprosencephaly, Trigonocephaly, Chrom (201)
microcephaly ptosis, coloboma,
hearing loss (see
Baraitser-Winter
syndrome)
Duplication 3q — Polymicrogyria, — Hypertrichosis Chrom (202)
microcephaly, hyp-
oplasia of olfactory
bulbs
Deletion 4p– — Heterotopia, Microcephaly Prominent Chrom (1183,1184)
microgyria glabella, down-
turned mouth,
preauricular pit,
cardiac defects
Deletion 4q — Heterotopia, Microcephaly, wide Flat malae, promi- Chrom (203)
pachygyria ventricles nent lower lip,
Fallot tetralogy

(Continued)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 391

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions (Continued)
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
Trisomy 9p — Band heterotopia Corpus callosum Enophthalmia, full Chrom (204,205)
agenesis, cerebellar nasal tip, down-
hypoplasia, wide turned mouth,
ventricles brachytelepha-
langy
Trisomy 13 — Heterotopia Holoprosencephaly, Polydactyly, Chrom (206)
microcephaly, cer- scalp defects,
ebellar hypoplasia microphthalmia,
cleft lip/palate
Miller-Dieker 247200 Lissencephaly Type I Corpus callosum Brachycephaly, fur- Chrom (207)
syndrome (del agenesis, midline rowed forehead,
17p13.3) calcifications short upturned
nose, long thick
upper lip
Ring 17 — Heterotopia Wide Vventricles, Broad face, Chrom (208)
peripheral prominent chin,
neuropathy full lips
Trisomy 18 — Heterotopia Corpus callosum Prominent occiput, Chrom (1185,1186)
agenesis micrognathia,
clenched fingers,
cardiac defects
Trisomy 19 mosaic — Heterotopia Microcephaly Growth retardation, Chrom (1187,1188)
hypertelorism, mosaicism
pointed short
nose, small
mouth, limb
anomalies
Trisomy 21 — Heterotopia Microcephaly, Brachycephaly, short Chrom (1189,1190)
Alzheimer plaques stature, cardiac
defects, short
broad hands
Deletion 22q11 — Polymicrogyria, Microcephaly, cer- Cleft palate, Chrom (209–213)
heterotopia ebellar hypoplasia, prominent nose,
cysts dysplastic ears,
cardiac defects
69, XXX — Heterotopia Macrocephaly, wide Growth retarda- Chrom (1191–1193)
ventricles, corpus tion, asymmetry,
callosum agenesis syndactyly
Dysmorphic syndromes
Cornelia de Lange 122470 Heterotopia Microcephaly, cer- Hirsutism, Unknown (214)
syndrome ebellar hypoplasia, synophrys, long
mental retardation philtrum, thin
upper lip, upper
limb deficiencies
(Continued)

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 392 Pediatric Neuroimaging

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions (Continued)
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
Sotos syndrome 117550 Neuronal heterotopia Large ventricles, Macrocephaly, over- Unknown (215)
prominent trigone; growth syndrome
less often: persis-
tent midline cava,
macrocephaly,
open operculum,
absent corpus cal-
losum
Metabolic disorders
(1) Peroxisomal disorders
Zellweger syndrome 170955 Pachygyria, mainly Wide ventricles, Typical facial dys- AR (1194–1196)
perirolandic and germinolytic morphism, hepa-
occipital; polymi- cysts, delayed tosplenomegaly,
crogyria, mainly myelination, liver dysfunction,
frontal and perisyl- muscle hypotonia, failure to thrive,
vian distribution seizures retinopathy,
on MRI sensory deafness,
± cataract
Neonatal adreno- 202370 Polymicrogyria may Progressive Hepatosplenom- AR (216,217)
leukodystrophy be present leukodystrophy, egaly, failure to
muscle hypotonia, thrive, retinopa-
seizures thy, sensory deaf-
ness, ± cataract
Peroxisomal bifunc- 261515 Polymicrogyria Muscle hypotonia, Mild dysmor- AR (218,219)
tional protein Seizures phism, enlarged
deficiency fontanelles
(2) Mitochondrial disorders
PDHC E1a 312170 Polymicrogyria, Delayed myelination, Mental retardation, X-linked, (1197,1198)
deficiency subependymal atrophy-link gyral spastic prob-
heterotopia changes, olivary quadriparesis ably fatal
dysplasia in male
embryos
Familial respiratory — Polymicrogyria, Leigh syndrome Lactic acidosis AR? (220)
chain disease with leptomeningeal
cerebral calcifica- heterotopia,
tions and neocor- clustered
tical dysplasia heterotopia
Voltage-dependent 604492 Single case with Hydrocephalus Unknown (221)
anion channel perisylvian cortical
deficiency dysplasia
Glutaric aciduria 231680 Leptomeningeal Renal cysts AR (222)
Type II heterotopia
Fumaric aciduria 136850 Polymicrogyria Uncovered sylvian Fumaric aciduria, AR (223,224)
fossae, hypoplasia external dysmor-
of cerebral white phism
matter

(Continued)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 393

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions (Continued)
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
(3) Organic acidurias
3-hydroxyisobutyric, 236795 Polymicrogyria Cerebral calcifica- External dysmor- AR (225)
acidemia tions, cerebellar phism
hypoplasia
D-2-hydroxy-glutaric Occipital agyria in Delayed gyral and D-2-hydroxyglutaric AR (226)
aciduria minority of cases opercula develop- aciduria, elevated
ment, subependy- GABA in CSF,
mal cysts cardiomyopathy
(4) Disorders of the cholesterol biosynthesis
Smith-Lemli-Opitz 268670 Polymicrogyria (rare, Microcephaly, delayed Failure to thrive, AR (1199–1202)
syndrome not yet confirmed myelination cleft palate, 2/3
in cases with con- syndactyly, heart
firmed biochemical malformations,
abnormality) typical facial
dysmorphism,
increased 7-dehy-
drocholesterol in
serum
Transcriptional regulation
Rett syndrome/ 312750 Nodular heterotopia, Neonatal encephalop- XL-D (227)
MECP2 mutation perisylvian cortical athy with postural
dysplasia abnormality
Genetic brain disruptions
Pseudo-TORCH 251290 Polymicrogyria Micrencephaly, Small for gestational AR (228)
(infection-like) intracranial cal- age, corneal
syndrome cifications, small clouding, microg-
brainstem nathia, throm-
bocytopenia, bile
duct hypoplasia
Early embryonic brain malformations
Encephalocele — Heterotopia Unknown (229)
Holoprosencephaly 236100 Leptomeningeal het- Variable (230,231)
erotopia
Craniotelencephalic 218670 Polymicrogyria, Absent olfactory Trigonocephaly, pan- AR (232)
dysplasia periventricular nerves, anterior craniosynostosis,
heterotopia, focal encephalocele, microphthalamia,
lissencephaly optic nerve hyp- small nose, preau-
oplasia, aqueductal ricular pit
stenosis, cysts
in frontal lobes,
absent septum pel-
lucidum
Meckel-Gruber 249000 Microgyria Posterior encephalo- Sloping forehead, AR (1203–1205)
syndrome cele, molar-tooth polydactyly;
hindbrain mal- polycystic kidneys,
formation, corpus hepatic fibrosis,
callosum agenesis, cleft lip/palate
holoprosencephaly
(Continued)

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 394 Pediatric Neuroimaging

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions (Continued)
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
Joubert syndrome many Polymicrogyria Hypoplastic cerebellar Polydactyly, Variable (233–235)
and related vermis, Absent SCP retinal dystrophy,
disorders decussation nephronophthisis
Multi-Organ syndrome
(1) Neurocutaneous disorders
Neurofibromatosis 162200 Polymicrogyria, Tumors, macroceph- Café au lait spots, AD (236,237)
Type I heterotopia aly, foci of long T2 Lisch nodules,
on MRI neurofibromas
Linear nevus seba- 601359 Ipsilateral pachygyria, Wide ventricles, por- Linear verrucous AD See Chapter 6
ceous, epidermal glial hyperplasia, encephaly, mental lesions, ichthyosis
nevus hemimegalencephaly retardation hystrix, café-au-
lait spots, heman-
gioma
Tuberous sclerosis 1911100 Heterotopia, hemi- Subependymal nod- Hypopigmentation, AD (238–241)
megalencephaly ules, tumors angiofibroma,
shagreen patches,
renal angioli-
poma, dental pits
Hypomelanosis of Ito 146150 Heterotopia, polymi- Macrocephaly Linear depigmenta- Chrom (242,243)
crogyria tion, asymmetry, mosaicism
cataract
Encephalo-cranio- 176920 Heterotopia Porencephaly, mac- Abnormal pigmen- Unknown (244)
cutaneous rocephaly, wide tation, epibulbar
lipomatosis ventricles, cerebral dermoid, facial
atrophy asymmetry
Oculo-cerebro- 164180 Polymicrogyria, Corpus callosum Orbital cysts, Unknown (245–247)
cutaneous syn- heterotopia agenesis, cerebellar microphthalmia,
drome (Delleman hypoplasia focal skin defects
syndrome)
Incontinentia 308300 Heterotopia, Microcephaly Whorled hyper- XL-D (248,249)
pigmenti polymicrogyria pigmentation,
eye anomalies,
hypodontia
Sturge-Weber 185300 Polymicrogyria asso- Leptomeninges Glaucoma/buphthal- Unknown (250)
syndrome ciated with vascular angiomatosis, mos, vascular skin
impairment perivascular calci- changes in trigem-
fications, cortical inal distribution
necrosis
Klippel-Trénaunay 149000 Hemimegalencephaly Polymicrogyria Cutaneous heman- Unknown (251,252)
syndrome giomas, enlarged
bones
Neu-Laxova 256520 Polymicrogyria, Micrencephaly, Small for gestational AR (95,253,254)
syndrome lissencephaly corpus callosum age, ichthyosis,
agenesis, cerebellar proptosis, hyp-
hypoplasia oplastic eyelids,
short neck,
arthrogryposis
(Continued)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 395

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions (Continued)
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
(2) Connective tissue disorders
Ehlers-Danlos syn- many Heterotopia Abnormal vascular- Hypermobility, Unknown (255,256)
drome, Many types ization emphysema,
aneurysms Val-
salva
(3) Neuromuscular disorders
Merosin-negative 156225 Occipital agyria; Cerebral white matter Muscular dystrophy AD (257–260)
congenital muscu- leptomeningeal affected
lar dystrophy heterotopia in one
case report
Myotonic dystrophy 160900 Polymicrogyria Macrocephaly, Myotonia, cataract, AD (261)
progressive atro- frontal balding,
phy, peripheral hypogonadism,
neuropathy, white ECG anomalies
matter lesions
Dystroglycanopathies 236670, Cobblestone cortex, Dysmyelination, Retinal dysplasia, AR (257,260,262)
(Walker-Warburg, 253800, subpial heterotopia cerebellar dysplasia, persistent hyper-
Fukuyama CMD, 253280 ventral pontine plastic primary
MEB disease) hypoplasia, col- vitreous
licular fusion
(4) Skeletal dysplasias
Thanatophoric dys- 187600 Polymicrogyria Megalencephaly, Short limb dwarfism, AD (1206,1207)
plasia mesial temporal narrow thorax,
lobe anomalies cloverleaf skull
Fontaine-Farriaus — Periventricular het- Generalized cranio- Unknown (263,264)
craniosynostosis erotopia synostosis, facial
dysmorphism,
brachydactyly and
anonychia
Osteogenesis imper- 166210 Agyria, glial hyper- Perivenous microcal- Fractures, deforma- AD (265)
fecta Type II plasia cifications, white tions
matter lesions
(5) Oculo-cerebral syndromes
Aicardi syndrome 304050 Heterotopia, Corpus callo- Chorioretinopathy, XL (85,266,267)
polymicrogyria sum agenesis, hemivertebrae
glioependymal
cysts, infantile
spasms
MICRO syndrome 600118 Polymicrogyria Corpus callosum Microphthalmia, AR (268–270)
agenesis (incon- cataract, optic
stant) atrophy, motor
neuropathy
(6) Reduction defects
Adams-Oliver 100300 Polymicrogyria Thin ventricular Aplasia cutis con- AD (1208,1209)
syndrome white matter, genita of the skull,
patchy gliosis terminal trans-
verse limb defects,
constriction
(Continued)

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 396 Pediatric Neuroimaging

TABLE 5-4 Syndromes Featuring a Neocortical Neuronal Migration Disorder

with Extracerebral Lesions (Continued)
McKusick Other Brain Extracerebral Pattern of
Entity Number Cortical Dysplasia Anomalies Symptoms Inheritance References
(7) Urogenital abnormalities
Galloway Mowat 251300 Leptomeningeal het- Microcephaly, cer- Nephrotic syndrome AR (1210–1213)
syndrome erotopia, indistinct ebellar granular
cortical layering, atrophy, absence
polymicrogyria, of dentate gyrus,
periventricular myelin deficiency
heterotopia
Oligohydramnios — Abnormal lamination Contractures, facial Variable (271)
sequence (Porter of cerebral cortex, dysmorphism,
syndrome) white matter het- hypoplastic
erotopia, meningeal kidneys
and molecular
zone neuronal-glial
ectopias
(8) OFD syndromes
Oro-facial-digital 311200 Polymicrogyria, Corpus callo- Lobulated tongue, XL-D (272,273)
syndrome I heterotopia sum agenesis, multiple frenula,
wide ventricles, syndactyly
Dandy-Walker
cyst, midline glio-
ependymal cysts
Oro-facial-digital 277170 Polymicrogyria, Molar tooth mid- Hexadactyly, cleft AR (274,275)
syndrome VI heterotopia hindbrain mal- lip/palate, congen-
(Varadi-Papp formation, tuber ital heart disease,
syndrome) cinereum hamar- bifid toes
toma
(9) Other monogenic disorders
Baraitser-Winter 2433310 Classical lissencephaly Microcephaly Trigonocephaly, AD? (201,276,277)
syndrome (prob- ptosis, coloboma,
ably identical hearing loss,
to Ramer-Lin mental retarda-
syndrome) tion; 2p12-q14
inversion in some
patients
X-linked 307000 Polymicrogyria, Corpus callosum Contractures, men- XL-R (278)
hydrocephalus pachygyria agenesis, hypoplas- tal retardation,
tic medullary pyra- spasticity
mids, aqueductal
stenosis
AD, autosomal dominant; AR, autosomal recessive; XL-D, X-linked dominant; XL-R, X-linked recessive; Chrom, chromosomal.
(Adapted from Reference 199).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 397

(b) T2-weighted 3D (volumetric) Fast Spin Echo (3DFSE) volumetric
acquisition (using 1 mm partition size and multiplanar reformation) or
2 to 3 mm spin-echo or fast spin-echo sequences in two planes (usually
axial and coronal), and (c) 3D FLAIR using 1 mm partition size and
multiplanar reformation or 2 to 3 mm FLAIR sequences in coronal and
axial planes in all children with developmental delay or epilepsy. Param-
eters (repetition time, echo time, inversion time) should be adjusted to
optimize contrast between gray matter and white matter; this varies with
the age of the patient (see Chapter 1). The FLAIR sequence is important,
as subtle white matter abnormalities may give important clues to the
presence of the cortical malformation (especially in focal cortical dys-
plasias (FCDs) [280,281]). The use of parallel imaging, with an 8- or
16-channel coil, allows high signal/noise on thin imaging sections in a
clinically reasonable imaging time. Even small/subtle lesions are usually
detectable using this technique, especially when performed at 3 T.
When children have extratemporal partial epilepsies that do not fit
into the classification of benign epilepsies of childhood (282), it is espe-
cially important to search for malformations of cortical development
(112,282,283). It is essential to know the seizure semiology and the
location of any abnormal electrical activity on EEG when interpreting
such studies, as the abnormalities can be extremely subtle and are easily
missed if the general area (hemisphere or quadrant) of affected brain
is not known. If no MRI abnormality can be identified in spite of this
knowledge, the cause is usually a small FCD. Diffusion tensor imaging
(DTI), SPECT, positron emission tomography (PET), and magneto-
encephalography (MEG) may be helpful to find these small and subtle
lesions; PET, MEG, and SPECT should be coregistered to MRI images
(281,284–294). If MEG is available, it has the advantage of not requir-
ing radioactive tracers; however, it requires a large team of scientists,
technologists, and psychologists, as well as neurologists, neurosur-
geons, and neuroradiologists to make it work (292). Subtle anatomic
lesions can sometimes be detected in the regions of abnormal electrical
activity (Fig. 5-30) (290) and sometimes the actual focus of ictal onset
can be directly identified (291,292). PET studies are usually performed
with 18F-fluorodeoxyglucose (18F-FDG) or 11C flumazenil, while SPECT
uses 99mTc HMPAO or 123I iodoamphetamine. PET is more sensitive for
temporal lobe than for extratemporal epilepsy (295). However, the sen-
sitivity and specificity of 18F-FDG PET for extratemporal lesions can be
improved dramatically (50% to >90%) when quantitative analysis with
a region of interest template (284) or coregistration with MRI (293) is
used (Fig. 5-31). 11C flumazenil PET shows changes in GABAA/benzo-
diazepine receptor binding; decreased 11C flumazenil binding has been
observed in patients with FCD (285). In one study, abnormalities were
found on 11C flumazenil PET in 72% of patients with partial epilepsy
and normal conventional MRI studies (296,297); however, these results
have not been reproduced (297). Another compound, 11C methionine,
has also been shown to be useful in the detection of small cortical dys-
plasias by PET (298,299). Increased uptake is seen in the dysplasia. The
mechanism by which the 11C methionine is concentrated in the area of
the dysplasia is not known. As with 18FDG PET, 11C methionine PET is
nonspecific, and can be concentrated by tumors and abscesses as well
as dysplasias. Ictal SPECT may be sensitive to extratemporal foci of
cortical dysplasia, especially in the frontal lobes (289,300,301), but is
used less as PET becomes more available. The timing of radionuclide
injection is critical in ictal SPECT because variable and evolving pat-
terns of perfusion may make localization much more difficult if the
isotope is not administered as closely as possible to the time of seizure
onset. Postictal studies are not reliable in localizing extratemporal foci
(301). Even better is digital subtraction of ictal and interictal SPECT
studies followed by colocalization of the difference image with MRI
(302,303), which has high interrater reliability and a high rate of local-
ization of the epileptogenic focus. Overall, PET and SPECT are use-
ful adjunctive examinations but must be correlated with MRI, which
remains the most useful neuroimaging exam in the work-up of epi-
lepsy (281,293,304).
Some evidence has been presented that proton MR spectroscopic
imaging may be useful in localization of epileptogenic foci (305–307);
this technique is most useful in the temporal lobe, particularly in
hippocampal sclerosis. Woermann et al. (307) have shown abnormal
metabolite levels in nearly 90% of patients with malformations of

FIG. 5-30. Use of MSI in detecting focal cortical dysplasia. Axial (A) and sagittal (B) images of volumetric
T1-weighted volumetric data set show subtle focal blurring of the cortical white matter junction (black arrows).
This would be impossible to detect without the “spikes” (white triangles), which represent abnormal focal activity
detected by MEG and coregistered to the MR image. Histology after resection showed focal cortical dysplasia.

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 398 Pediatric Neuroimaging
cortical development; however, the abnormalities were inconsistent,
with the metabolite levels varying among patients. In addition, the
spectroscopic abnormalities have been far more widespread than the
lesion (308,309), suggesting that the MRS findings reflect secondary
changes rather than the primary epileptogenic focus. Li et al. (310) have
shown that the NAA/Cr ratio is reduced in malformations secondary
to abnormal stem cell formation (in which the neurons are dysplastic
or immature), is variably normal or reduced in heterotopic gray matter
(in which neurons are of variable maturity and have variably reduced
synapses), and is normal in PMG (in which the neurons are mature).
This suggests that the low NAA values present in some cortical malfor-
mations result from dysplastic or immature neurons in the malforma-
tion; however, these results have not been reproduced.
Finally, DTI has been used to detect cortical malformations that
result in epilepsy. Studies have shown that the white matter underly-
ing the cortical malformation has increased diffusivity (manifest as
Barkovich_Chap05.indd 398
FIG. 5-31. Use of 18FDG PET in imaging of malforma-
tions of cortical development. Note reduced uptake in
the left frontal lobe (black arrows in A) on this PET scan
coregistered with a T1-weighted MR image. MRI veri-
fies the abnormality, showing impaired myelination in
the subcortical white matter (white arrows in B and C).
Histology after resection showed focal cortical dysplasia
Type IIb. PET shows decreased uptake of 18FDG in epi-
leptogenic lesions on interictal studies; it is most useful
when coregistered with MRI.
increase in the apparent diffusion coefficient) and decreased anisotropy
compared with the same area of the brain in age matched controls
(294,311,312); these findings may reflect the changes in the brain that
cause of seizures, may be a result of the seizures, or both. The changes in
diffusivity of the white matter may help to determine the extent of the
dysplasia better than signal alterations on standard imaging and, in this
way, may aid surgical resection (294). Although neither the diffusion
changes nor the spectroscopic changes are specific for malformations
of cortical development, they may at times serve the same function
as PET and SPECT in localizing the region of abnormality such that
reinvestigation with MRI might better locate the lesion.
Overall, MRI remains the cornerstone of the imaging evaluation of
malformations of cortical development (280,313–315). Even if the epi-
leptogenic focus is identified by another technique, the focus is always
coregistered with an MR image before any intervention is planned.
Therefore, this section deals primarily with MRI.
5/6/2011 8:58:59 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 399

Malformations Secondary to Abnormal Stem Cell Proliferation
or Apoptosis
Microcephalies Microcephalies are divided into primary micro-
cephalies, which usually have a genetic cause and are the result of
either impaired proliferation of neuronal precursors or impaired
apoptosis (316–319), and secondary microcephalies, which result
from late prenatal, perinatal, or postnatal injury (the latter are not
described in this chapter). It is likely that many of the causative genes
are involved in DNA repair or cell cycle regulation and, thus, regula-
tion of cell proliferation (320); some have already been identified,
while others will likely be found soon, as the interest in this process
is rapidly increasing (318,319,321–323).
Currently, genes have been identified for very few microcepha-
lies and the patterns seen on imaging studies show a wide variation
(Table 5-5). Using purely morphologic characteristics, microcepha-
lies can be segregated into five major categories: gyral patterns, corti-
cal thickness, presence or absence of heterotopia, callosal anomalies,
and relative size of the forebrain, hindbrain, and ocular structures.
The gyral pattern can be normal, simplified (sulci are too few and
too shallow but cortical thickness is normal, Fig. 5-32), microgyric
(Fig. 5-33), or pachygyric (sulci are too few and too shallow with
thick cortex, Fig. 5-34). Heterotopia may be present (Figs. 5-32 and
5-35) or absent. The corpus callosum can be absent, hypoplastic, or
hypogenetic (see earlier section on callosal anomalies and Figs. 5-34
and 5-35). The forebrain can be large compared with the hindbrain
(Fig. 5-34), commensurate in size with the hindbrain, or small com-
pared with the hindbrain (Fig. 5-33). Similarly, the ocular globes can
be commensurate with cerebral size or large (Fig. 5-35). It is important
to note that most of these characteristics can be identified on MRIs
of the fetus (Fig. 5-33), as well as on postnatal studies. Although the
work of classifying microcephalies is in its infancy, ultimately the
imaging analysis of them will depend on these characteristics. It is
the hope of the authors that a better system of classifying these dis-
orders by imaging characteristics will be developed before the next
edition of this book.
Microcephaly with Simplified Gyral Pattern and Microlissencephaly.
Microcephaly with simplified gyral (MSG) pattern is the term that has
been proposed to describe malformations in which children are born
with head circumferences of 3 or more standard deviations below the
norm and their imaging studies show too few gyri and abnormally
shallow sulci (<1/2 the depth of normal sulci) (324,325). This is the
only classification that has been based on imaging characteristics.
Primary and secondary sulci are formed but tertiary sulci are not.
The volume of white matter in the cerebral hemispheres is reduced.
A number of genes have been identified that, when mutated, result
in MSG pattern (see Table 5-5). Unfortunately, simplified gyral pat-
terns seem very common in microcephaly; therefore, it is likely that
simplified sulcation is a more general consequence of diminished
cell proliferation (and consequent diminished white matter volume)
and not one that will allow segregation of specific genetic disorders.
However, it is likely that microcephalic patients with thickened cor-
tex in addition to simplified sulcation (a malformation that we call
microlissencephaly) have different pathoembryogenesis and clearly
different disorders. These patients are separated into Group 6, while
patients with MSG are in the other groups and can be separated by
differences in associated anomalies of the brain or other viscera. MSG
and microlissencephaly are both heterogeneous groups, but affected

TABLE 5-5 Genetic Causes of Microcephaly with Known Imaging Findings

Gene Chromosome OMIM No. Protein Inheritance Description
MCPH1 8p23 607117 Microcephalin AR Simplified gyral pattern
Microcephaly, PVNH
Good clinical function
ASPM 1q31 608716 Spindle-like microcephaly protein AR Simplified gyral pattern
Microcephaly, PVNH, HCC
ARFGEF2 20q13.13 608097 ARFGEF2 AR Mild microcephaly
Notable PVNH
Callosal hypoplasia
Myelin delay
CDK5RAP2 9q34 608201 CDK5 regulatory subunit-associated protein 2 AR Simplified gyral pattern
CENPJ 13q12.2 609279 Centromeric protein J AR Simplified gyral pattern
SLC25A19 17q25.3 607196 Mitochondrial deoxy-nucleotide carrier AR Simplified sulcation, early death,
2-ketoglutaric aciduria
EIF2AK3 2p12 226980 eIF2 akinase 3 AR Simplified sulcation in
Wolcott-Ralston Syndrome
PNKP 19q13.33 605610 Polynucleotide kinase 3’ phosphatase AR Normal sulcation.
Proportional cerebrum, cerebel-
lum. Decreased WMV
AR, autosomal recessive; PVNH, periventricular nodular heterotopia; HCC, hypogenesis of the corpus callosum; WMV, white matter volume.

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 400 Pediatric Neuroimaging

FIG. 5-32. Microcephaly with simplified gyral pattern,

moderate and severe. A and B. Moderately simplified gyral
pattern. Sagittal T1- (A) and axial T2- (B) weighted images
show too few gyri, shallow sulci (about 1/2 of normal), nor-
mal myelination, and a normal thickness of cerebral cortex.
C–E. Extremely simplified gyral pattern with hypoplastic
corpus callosum, proportional cerebellum, and hetero-
topic gray matter. Sagittal T1-weighted image (C) shows
extreme microcephaly with a very thin corpus callosum
(white arrows). Cerebellum and brainstem are proportion-
ate to the cerebrum. Axial T2-weighted image (D) shows an
extremely simplified gyral pattern with too few, too shallow
sulci. Coronal T1-weighted image (E) shows periventricu-
lar nodular heterotopia (white arrows) protruding into the
ventricular trigones.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 401

FIG. 5-33. Microcephaly with polymicrogyria in a 23-week fetus with biparietal diameter more than 3 standard deviations
below mean for gestational age. Axial (A) and coronal (B) SSFSE images show extensive polymicrogyria of the cerebrum (the
cortical surface should be smooth at this age, see Chapter 2). Note that the cerebellum is much larger than the cerebrum on
the coronal image (B).

patients in both are almost certainly microcephalic because of reduced
proliferation of neurons or glia.
Group 1. Group 1 includes patients who are products of normal preg-
nancies, have normal deliveries, normal neonatal courses, and normal
neonatal exams, notable only for their very small head sizes. Poor feeding
and poor weight gain may characterize the neonatal courses. All manifest
corticospinal tract signs during the first year of life, ranging in severity
from mild spasticity to multiple beats of clonus and bilateral Babinski
signs. The imaging studies of all patients in this group show a simpli-
fied gyral pattern with too few gyri, shallow sulci (about 1/2 of normal),
normal myelination, and a normal-appearing cerebral cortex (normal
cortical thickness and normal appearing cortical-white matter junction,
Fig. 5-32A and B). Almost all patients in this group show progressively
more severe developmental delay as they grow and reach school age.
One cause of MSG Group 1 appears to be the Nijmegen breakage
syndrome, an autosomal recessive disorder belonging to the family of
DNA repair disorders (326). Affected patients also have immunodefi-
ciency, X-ray hypersensitivity, and predisposition to cancer.
Group 2. The patients in group 2 are commonly products of breech
presentations and manifest abnormal neonatal reflexes and limb

FIG. 5-34. Microcephaly with absent corpus callosum, frontal pachygyria, and pontocerebellar hypoplasia. Sagittal T2-weighted
image (A) shows callosal agenesis and small pons and cerebellum compared with cerebrum. Axial T2-weighted image (B) shows
pachygyria of both frontal lobes (black arrows). Note the abnormal enlargement and shape of the lateral ventricles.

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 402 Pediatric Neuroimaging
spasticity that begin in the neonatal period. Affected patients have
difficulty suckling and recurrent vomiting and, therefore, manifest poor
weight gain. They develop generalized tonic seizures during the first
few days of life. MRI shows a very simplified gyral pattern with too few
gyri, shallow sulci (about 1/3 of normal), and delayed myelination. The
cerebral cortical thickness and gray-white junction appear normal.
Group 3. Patients in group 3 are typically born at term after uncom-
plicated deliveries. They have abnormal neonatal courses, manifest-
ing absence of neonatal reflexes, spasticity, seizures, and poor feeding.
MR scans in these patients show fewer gyri and shallower sulci than
groups’ 1 and 2, as well as periventricular nodular heterotopia (PVNH)
(Fig. 5-32C–E); they may have arachnoid cysts, and have normal
myelination. MCPH1 and ASPM mutations may belong in this group
(322,327,328). Cortical thickness and gray matter-white matter junc-
tion appear normal.
Group 4. Patients in group 4 have significant prenatal or neonatal
problems, such as polyhydramnios, congenital arthrogryposis, jejunal
Barkovich_Chap05.indd 402
FIG. 5-35. Microcephaly with thin corpus callosum, dis-
proportionately large eyes, and slightly disproportionately
large cerebellum. A. Sagittal T1-weighted image shows
microcephaly with very thin corpus callosum; the brainstem
and cerebellum are slightly large compared with cerebrum.
B. Axial T2-weighted image shows disproportionately
large ocular globes; they are as big as basal ganglia and
thalami combined. Gyral pattern is simplified. C. Coronal
T2-weighted image shows the cerebellum to be dispropor-
tionately enlarged compared with cerebrum. Heterotopia
(white arrows) protrude into the ventricular trigones.
atresia, hypertonicity, cortical thumbs, microphthalmia, optokinetic
nystagmus, and abnormal neonatal reflexes, and neonatal seizures.
These patients are sometimes described as having the “apple peel syn-
drome” (OMIM 243605) (329–331). MR scans are identical to group 1
(Fig. 5-32A and B), showing too few gyri, shallow sulci, and age-appro-
priate myelination; the cerebral cortex has a normal appearance.
Group 5. Patients in group 5 are profoundly microcephalic (4–5 stan-
dard deviations below normal) and profoundly abnormal from the
time of birth. All are profoundly hypotonic, have abnormal neonatal
reflexes, and develop myoclonic seizures during the first week of life.
Suck and swallow are weak, requiring gastrostomy for feeding. All show
minimal neonatal development. MRI of these patients show large sub-
arachnoid spaces surrounding extremely small brains with impaired
myelination, reduced volume of white matter, and very simplified
gyral patterns with no more than about 5 gyri in each hemisphere and
sulci less than one-third the depth of normal. The cerebral cortex may
appear abnormally thin. Patients are severely debilitated and die within
the first months of life.
5/6/2011 8:59:04 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull
Group 6. Patients in group 6 have findings of complete or nearly
complete agyria, with thickened cortex (Fig. 5-36). Many have asso-
ciated agenesis or hypogenesis of the corpus callosum and cerebellar
hypoplasia. Some have PVNH. Most are hypotonic at birth, develop
seizures in the first week of life, and achieve few developmental mile-
stones. One disorder in this group, sometimes called Amish lethal
microcephaly, is caused by mutations of the SLC25A19 gene at 17q25.3,
which encodes a nuclear mitochondrial deoxynucleotide carrier (332).
Affected patients are profoundly microcephalic at birth with moderate
micrognathia. Neurologic exam is mostly normal at birth, but feeding
becomes more difficult after the first 2 months and irritability increases
markedly; deterioration increases until death, usually during the first
year (332). Imaging shows profoundly small, smooth cerebrum and
cerebellum with small brainstem. The corpus callosum is typically
hypogenetic. A few PVNH may be present.
Group 7. Group 7, also called leukodysplasia, microcephaly, and
cerebral malformation, has been recently described and is linked to
chromosome 2p16 (333). Affected patients are severely microcephalic
(head circumference 3 or more standard deviations below normal) at
birth, show severe failure of postnatal brain growth, develop intrac-
table seizures during the neonatal period, do not show developmental
progression, and die within the first 3 years of life (333). Imaging shows
a cortex of normal thickness, simplified gyral pattern, lack of opercula-
tion, markedly reduced volume of white matter with callosal hypopla-
sia and ventriculomegaly, pontine hypoplasia, and cystic lesions in the
subcortical white matter of the temporal lobes (Fig. 5-37) (333).
Many of the patients with MSG were formerly classified as having
“microcephalia vera” (334,335), or “radial microbrain” (190,336,337).
However, the exact meaning of those terms was rather murky and
they were defined differently in different publications. This classifi-
cation better organizes these profoundly microcephalic patients and
helps in understanding the underlying developmental abnormalities
(324). As the causes and prognoses of secondary microcephalies are
quite different, it is important to rule out known causes of profound
microcephaly, such as prenatal infection (TORCH infections, see
FIG. 5-36. Microlissencephaly. Sagittal (A) and axial (B) images show a profoundly microcephalic brain (compare size of brain to size of face) that is
completely smooth, with a thick cortex. The corpus callosum is hypogenetic (small splenium, absent inferior genu and rostrum). Microlissencephaly is
probably better classified as a lissencephaly rather than a type of microcephaly.
Barkovich_Chap05.indd 403
403
Chapter 11), ischemia, inborn errors of metabolism, and prenatal
exposure to toxins or radiation, before classifying patients as having
microlissencephaly.
Focal Cortical Dysplasia with Dysplastic Neurons (Focal Trans-
mantle Cortical Dysplasia, Focal Cortical Dysplasia Type II)
First described by Taylor et al. (338) in 1971, FCDs are the single most
important cause of medically refractory focal epilepsy in childhood.
FCD is the third most common histologic diagnosis (after hippocam-
pal sclerosis and epilepsy-associated tumors) in children who undergo
epilepsy surgery, found nearly 15% to 20% of children who have
surgery for intractable epilepsy (280,339–341); the majority of these
are FCD Type II (121). FCDs appear to be mainly sporadic, with few
familial cases reported. The wide spectrum of these disorders has only
recently begun to be recognized. Although previous classifications of
FCDs have been proposed (342), they suffered from poor interobserver
and intraobserver reproducibility among pathologists (343) and have,
therefore, been revised. They are currently divided into four groups
(344). Mild malformations of cortical development (mMCD) are char-
acterized by normal cortical architecture and abundant ectopic neurons
located in or adjacent to cortical layer 1 or in the subcortical white mat-
ter. These are currently believed to result from late prenatal, perinatal,
or early postnatal (as yet undefined) processes. Type 1 FCDs are associ-
ated with architectural disturbances of the radial arrangement (FCD
Type Ia) or tangential arrangement (FCD Type Ib) of cortical neurons
or both (FCD Type Ic); these are also suspected to result from late pre-
natal, perinatal, or early postnatal disturbances. When changes of FCD
Type I are associated with other pathology, they are diagnosed as FCD
Type III (IIIa with hippocampal sclerosis, IIIb with glial or glioneu-
ronal tumors, IIIc with vascular malformation, IIId with scarring from
traumatic injury, porencephaly, or infection). Type II FCDs have more
pronounced architectural and cytoarchitectural disturbances such as
dysmorphic neurons (FCD Type IIa) and balloon cells (FCD Type IIb)
(344); they are also characterized by overabundance of GABAergic
neurons (personal communication, Dr. Roberto Spreafico). Type II
FCD is thought to be due to earlier, prenatal, disturbances to cortical
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 404 Pediatric Neuroimaging

FIG. 5-37. Leukodysplasia, microcephaly, and cerebral malformation (Micro-

cephaly with simplified gyral pattern group 7). Sagittal T1-weighted image
(A) shows thin corpus callosum (white arrows) and small cerebellum. Axial
T2-weighted images (B and C) show simplified gyral pattern with normal corti-
cal thickness, very large subarachnoid spaces, reduced white matter, ventriculom-
egaly, and lack of operculation.

development, possibly genetic (7,280). Because they are thought to
arise from an early disturbance, Type II FCDs are discussed in this sec-
tion. mMCD and FCD Types I and III are discussed in a later section,
“Malformations Secondary to Abnormal Cortical Late Migration and
Cortical Organization.”
FCD Type II is an important cause of epilepsy, both in children
and in adults (7,280,315,340,342). This malformation is referred to by
many names, including Taylor type of FCD, focal transmantle corti-
cal dysplasia (345), and forme fruste tuberous sclerosis (because many
FCD II lesions are histologically and radiologically identical to corti-
cal hamartomas of patients with tuberous sclerosis (68,346) and some
show a loss of heterozygosity at the TSC1 [347] or the TSC2 gene locus
[348,349]). The term FCD Type II is preferred and should be used. As
with tuberous sclerosis, studies of molecular markers of the dysplastic
neurons and balloon cells suggest that FCD Type II derive from RGCs
(350). Because of the overlap with tuberous sclerosis, patients with
radiologic or histologic findings of this malformation should be seen
by a geneticist or child neurologist in order to be screened (skin, kid-
neys, heart, etc.) for tuberous sclerosis (346).
Almost all affected patients have epilepsy, which typically becomes
clinically apparent during the first decade of life, sometimes as early
as the first few days (120,280,315,345). Compared with FCD Type I
and Type III, patients with Type II FCD come to medical attention
at younger ages, have higher seizure frequencies, and are much more
commonly extratemporal in location; seizure outcome after surgery is
generally better (280,315). The seizure type seems to vary with patient
age (120). The epilepsy of most patients is highly refractory to medica-
tion secondary to the high intrinsic epileptogenicity of these lesions
(117,351), which seems to be related primarily to the dysplastic, large
neurons within the lesions (339). Therefore, many of these patients
are helped by surgical resection of the dysplasia if the epileptogenic
focus can be found. The presence or absence of other neurologic signs
and symptoms of affected patients depends upon the size and location
of the malformation. When larger regions of cortex or eloquent areas
are involved, patients may have neurologic signs/symptoms. When
only small regions of cortex are involved, as is often the case, affected
patients may have normal neurologic examinations (280,345). EEG is
characterized by total absence of background activity and a distinctive

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 Chapter 5 • Congenital Malformations of the Brain and Skull
pattern of repetitive, high amplitude, fast spikes followed by high
amplitude slow waves interspersed with relatively flat periods.
On histologic exam, the normal six-layered appearance of the
cerebral cortex is disturbed. In addition, abnormal cells are seen in the
cerebral cortex and in the underlying white matter; these cells typically
include large neurons, dysplastic neurons, atypical glia, and balloon
cells, admixed with normal neurons (342,344,352,353). Glial prolifera-
tion and reduced myelination are seen in the affected white matter, and
may contribute to the T2 prolongation that is nearly always seen in the
subcortical white matter in FCD IIb (352,354). The affected regions of
cortex have an increased number of excitatory neurons and a decreased
number of inhibitory neurons, along with impaired GABA-mediated
neuronal inhibition, probably explaining the intrinsic epileptogenicity
of the affected cortex (355–358). Developmental lineage studies sug-
gest that the abnormal cells derive from the neocortical (dorsal) ven-
tricular and SVZs, possibly from RGCs, and are likely glutamatergic
(excitatory transmitters) (350).
Publications describing neuroimaging studies of patients FCD
Types I and II are confusing, largely because there is inconsistency in
Barkovich_Chap05.indd 405
405
histologic diagnosis of these disorders (343). Recent work suggests that
MRI findings in FCD Type II are characteristic (no consistent differ-
ence has been found yet between Type IIa and Type IIb, so both are
discussed together) (280,345,359). When the involved region of brain
is large, the cortical gyral pattern may be abnormal, with expanded gyri
and, occasionally, irregular sulci (Fig. 5-38). Abnormal signal intensity
(typically hyperintense on FLAIR and T2-weighted images) is seen in
subcortical white matter; the cortical-white matter junction typically
appears sharp on both T1- and T2-weighted images (Fig. 5-31), but is
often indistinct on FLAIR images. In some patients, a linear or curvilin-
ear focus of abnormal signal intensity extends from the cortical-white
matter junction to the ventricular surface (Fig. 5-39); this is referred to
as the transmantle sign and appears to be specific for FCD Type II when
seen (280,315). The signal intensity of this focus varies with the age of
the patient. In neonates and young infants, it is bright on T1-weighted
images and somewhat dark on T2-weighted images (Fig. 5-40); this
may be caused by intrinsically abnormal tissue or stimulation of myeli-
nation by the electrical activity of the seizures (360). Between the ages
of about 12 and 30 months, while the brain is actively myelinating,
FIG. 5-38. Large to medium FCD IIb. Sagittal T1 (A), axial FLAIR
(B), and coronal T2 (C) images show a large cortical and subcor-
tical lesion (white arrows) in the orbital surface of the left frontal
lobe and underlying white matter. The cortex is normal thickness
or thin, with blurring of parts of the cortical-white matter junction.
The affected white matter (white arrows) has transmantle extension
(from pia to ependyma) and shows hypointense T1 and hyperin-
tense T2/FLAIR signal, reflecting hypomyelination.
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 406 Pediatric Neuroimaging

FIG. 5-39. Axial (A) and coronal (B) T2-weighted images in a child with medially refractory partial epilepsy show a hyperin-
tense “transmantle sign” (white arrows) extending from the bottom of a right frontal sulcus to the superolateral margin of the
lateral ventricle. This is a specific sign for FCD IIb.

dysplasias may be difficult to detect by MRI using any standard
sequences; therefore, if EEG studies continue to show focal epilepto-
genesis, the T1 hyperintensity of myelinated white matter should be
suppressed with a magnetization transfer pulse (361) or a repeat MRI
should be performed after age 3 years. After the white matter myeli-
nates, the tract is seen as hyperintensity on T2-weighted and, especially,
FLAIR images, particularly when the image is parallel to the track (Fig.
5-39) (362). This track of T2 hyperintensity correlates well with the
location of the balloon cells (362,363), but the abnormal signal is more
likely due to gliosis and hypomyelination of the white matter. The
tract is difficult to see on T1-weighted images unless a magnetization
transfer pulse is used to suppress the hyperintensity of the white mat-
ter (361). Some of the affected cortex may also be T2 hyperintense and
long-standing dysplasias may erode the inner table of the calvarium
(Fig. 5-41) like cortical tubers of tuberous sclerosis (see Chapter 6).
On occasion, T2 hyperintensity is seen extending for several millime-
ters along the cortical-white matter junction on one or both sides of
the tract from the cortex to the ventricle; this may be caused by the
malformation but is more likely caused by the seizures it produces.
The cortical-white matter junction may be blurred on high resolution
T1-weighted images (Fig. 5-41), presumably due to incomplete myeli-
nation or astrogliosis in the subcortical white matter. The acquisition
of thin section, high resolution images is extremely useful in detecting
the smaller, subtler foci (345,364–366).
A group of patients with calcified FCD Type II lesions have been
reported (349). These look like calcified cortical tubers of tuberous

FIG. 5-40. FCD IIb in young infant. Coronal T1- (A) and T2- (B) weighted images show abnormal signal (white arrows) radiating
to the superolateral margin of the lateral ventricle from the depth of the affected sulcus. Note that in the unmyelinated brain, the
abnormal signal is hyperintense on T1-weighted images and hypointense on T2-weighted images.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 407

FIG. 5-41. FCD II resembling a tuber of tuberous sclerosis. Axial T1 (A)

and FLAIR (B) images and coronal T2 image (C) shows a focally expanded
gyrus (arrows) in the left temporal lobe, causing remodeling of the overlying
calvarium. The dysplasia (cortex and underlying white matter) is hypoin-
tense in (A) and hyperintense in (B) and (C). The cortical-white matter
junction is more indistinct in (A) and (B) than in (C).

sclerosis (see Chapter 6), with subcortical calcification (very hyperatten-
uating in CT, hypointense on T1- and T2-weighted MR images) and vol-
ume loss, resulting in enlarged subarachnoid spaces around the lesion.
Our experience with diffusion imaging in FCD Type II is similar
to that in the literature (294). The white matter under the lesion has
increased diffusivity and decreased fractional anisotropy. It is not clear
how much of this effect is the result of the lesion itself and how much is
the result of recurrent seizure activity and its effect on the tissue.
The few reports of proton MRS in transmantle dysplasias suggest
that there is a significant reduction of the NAA/Cr ratio compared with
normal controls and with normal areas in the affected brain (305,310).
The choline peak is normal to slightly increased. On short echo spec-
tra (TE = 20–30 milliseconds), myo-inositol is increased. Our limited
experience with perfusion imaging suggests that these lesions have
normal or reduced blood volume compared to normal white matter.
Hemimegalencephaly (Unilateral Megalencephaly) HME, first
described in 1835 (367), is the name given to a hamartomatous over-
growth of all or part of a cerebral hemisphere with defects in neuronal
proliferation, migration, and organization within the affected hemi-
sphere (368–372). The many different radiologic (369,370,373) and
pathologic (371,374,375) appearances suggest that HME is a heteroge-
neous malformation, with several different disorders (likely with sev-
eral causes) included under a single heading. The brain can be affected
in isolation, in association with cutaneous abnormalities (about 1/3
[376]), or with hemihypertrophy of part or all of the ipsilateral half
of the body; overall, about half of affected patients have other associ-
ated anomalies (377). Rarely, involvement of the cerebral hemisphere is
associated with enlargement and dysplasia of the ipsilateral cerebellar
hemisphere and brainstem, a condition referred to as total HME (378).
All cases seem to be sporadic and, of interest, only one pair of monozy-
gotic twins with HME has been reported (379). Affected children typi-
cally have macrocephaly at birth and in early infancy; this may be the
reason for initial referral for imaging, even though affected patients do
not have clinical signs of increased intracranial pressure. More com-
monly, affected infants come to attention because of an intractable sei-
zure disorder that begins at a very early age (usually before the first
birthday), hemiplegia, and severe developmental delay (369–371,374).

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 408 Pediatric Neuroimaging
Earlier onset of epilepsy seems to correlate with more severe motor
impairment (376). Seizures tend to be more severe when the mega-
lencephaly is localized to the frontal lobe (380). A high incidence of
HME seems to occur in patients with the epidermal nevus syndrome
(see Chapter 6 [376,381–383]). Other associated conditions include
Proteus syndrome (sometimes considered a form of epidermal nevus
syndrome [384]) (385,386), unilateral hypomelanosis of Ito (376,387),
neurofibromatosis Type I (388), Klippel-Trenaunay-Weber syndrome
(251), and tuberous sclerosis (241,389). No difference has been found
between the syndromic and nonsyndromic types of HME (378).
Pathologically, HME is a disorder reflecting abnormalities in pro-
liferation, migration, maturation, and differentiation of neurons (375);
thus, many suspect this disorder to be the result of abnormal stem
cell lineage, differentiation, and proliferation (7,372). Affected hemi-
spheres contain areas of pachygyria, PMG, and heterotopia, as well as
dyslamination, dysplastic neurons, immature neurons, balloon cells,
hypomyelination, and astrogliosis of the hemispheric white matter
(371,374,375,379). Interestingly, studies show an increased number
of glial cells on the affected side compared to the contralateral side
(390); it is not known whether this increase is developmental or reac-
tive. Reports conflict on the number of cortical neurons in the affected
hemisphere (379,390).
On CT and MRI, part or all of a hemisphere may be affected; the
frontal and occipital lobes are involved in nearly equal frequency in
localized megalencephaly (Fig. 5-42) (380). The involved region may
be moderately to markedly enlarged. Although the appearance of the
large hemisphere varies considerably, the most typical appearance
shows the cortex to have an abnormal gyral pattern with broad gyri,
shallow sulci, blurring of the cortical-white matter junction, and cor-
tical thickening (Fig. 5-43); however, the gyral pattern may appear
grossly normal or may be frankly agyric or polymicrogyric (Fig. 5-44)
(369,370). The white matter is of abnormally low signal on CT and
often shows heterogeneous signal intensity (some T2 hyperintense
and some isointense to myelinated white matter) on MR studies, rep-
resenting heterotopia and dysplastic neurons and glia (Figs. 5-43 and
5-44). The configuration of the ipsilateral lateral ventricle is usually
FIG. 5-42. Localized megalencephaly. Axial (A) and coronal (B) T1-weighted images show enlargement of the left
occipital lobe (black arrows) with broad gyri, shallow sulci, and poor differentiation of cortex and underlying white mat-
ter. The coronal image better shows abnormal white matter signal intensity and poor cortical white matter differentiation
in the megalencephalic region (arrows).
Barkovich_Chap05.indd 408
quite characteristic; it is enlarged, usually in proportion to the enlarge-
ment of the affected hemisphere, with the frontal horn being abnor-
mally straight and pointing superiorly and anteriorly (Figs. 5-43 and
5-44) (369). In occasional patients, however, the ipsilateral ventricle
is small (373). Rarely, the affected portion of the brain has a bizarre,
hamartomatous appearance (Fig. 5-45) (369,370); in this situation, the
characteristic enlargement of the affected brain and ipsilateral ventricle
allows diagnosis. In a minority of cases, the cerebellar hemisphere and
brainstem ipsilateral to the affected cerebral hemisphere are enlarged
(Fig. 5-44) (378).
It is important to recognize that the radiologic appearance of
the HME brain may change over time. Wolpert et al. (391) reported
a patient in whom the affected hemisphere atrophied during the first
year of life and was smaller than the contralateral (normal) hemi-
sphere when imaged at age 1 year. An analogous change was seen on
SPECT imaging, where the tracer uptake in the affected hemisphere
diminished over time (392). We have seen reduction in hemispheric
size of affected patients after episodes of status epilepticus. Salamon
et al. (379) reported that the “normal” hemisphere is often smaller than
age-matched controls and suggest that it is not normal at all; indeed,
they report that children with small “normal” hemispheres have poorer
neurodevelopmental outcomes after hemispherectomy.
Proton MR spectroscopy in HME shows reduction of the gluta-
mate and NAA peaks in white matter. Reduced NAA has also been
reported in cortical tubers of tuberous sclerosis (see Chapter 6) and in
cortical dysplasias with balloon cells (305,310) and probably relates to
the immaturity of the involved neurons.
The affected portion of the hemisphere has reduced metabolic
activity, and 18FDG PET scans show markedly reduced glucose uptake
in affected regions (Fig. 5-43) (393). Anatomic hemispherectomy,
functional hemispherectomy, or hemidecortication may, therefore,
be indicated if the seizure disorder is intractable and the contralateral
hemisphere is normal (394,395). However, hemispherectomy is con-
traindicated if the contralateral hemisphere has cortical malforma-
tions; therefore, careful assessment of the contralateral hemisphere is
crucial in affected patients.
5/6/2011 8:59:09 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 409

FIG. 5-43. Typical hemimegalencephaly. Axial T2-weighted (A) and FLAIR (B) images in an epileptic teenager show an
enlarged left hemisphere with fewer, broader gyri than the normal right hemisphere, and abnormally hyperintense white
matter. The cortical-white matter junction is blurred, particularly in the posterior aspect of the hemisphere (white arrows).
Coronal T2-weighted image (C) shows uplifting of the left frontal horn (white arrows) as well as abnormal white matter and
blurring of the cortical-white matter junction in the medial left convexity. Axial image from a PET study (D) shows reduced
uptake of 18F-FDG in the affected left hemisphere, most notably in the posterior hemisphere (white arrows).

Malformations Secondary to Abnormal Neuronal Migration
Malformations with Too Few or Too Shallow Sulci Smooth brains
can result from many causes, including congenital infection (especially
cytomegalovirus, see Chapter 11) and diminished cell proliferation
(“Microcephaly with Simplified Gyral Pattern and Microlissencephaly,”
see previous section), in addition to abnormal neuronal migration.
Careful attention to factors such as brain size (more than 3 standard
deviations below normal at birth suggests MSG pattern), cortical thick-
ness (diminished thickness should suggest in utero infection, dimin-
ished cell proliferation), and smoothness of the cortical-white matter
junction (irregularity of the junction indicates PMG from mutation
or midgestational injury) are essential to proper classification. The
most important malformations with too few or too shallow sulci due
to abnormal neuronal migration are those due to overmigration of
neurons resulting from abnormal pial basement membrane formation
(cobblestone malformations) and those due to diffuse arrest of neu-
ronal migration (lissencephalies).
Malformations Due to Abnormal Pial Basement Membrane
Formation
Background: Why do we find CNS abnormalities in patients with
Congenital Muscular Dystrophies? Malformations secondary to
abnormal pial basement membrane formation are a group of disor-
ders that are typically characterized by anomalies of the brain, eyes,
and muscles. They were initially discovered as a result of the observa-
tion that many children with congenital muscular dystrophies (CMD)

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 410 Pediatric Neuroimaging

FIG. 5-44. Hemimegalencephaly with more severe anomaly. Axial T2-weighted images (A and B) show polymi-
crogyria (black arrows) in the left frontal lobe and subcortical heterotopia (white arrows in B) in the white matter
more posteriorly. The ipsilateral ventricle (v) is large. Axial diffusivity image (C) shows minimally reduced diffu-
sivity in the affected hemisphere. Coronal T2-weighted image (D) shows enlarged, uplifted lateral ventricle (black
arrows), enlarged ipsilateral cerebellar hemisphere (white arrows), and abnormally hypointense white matter.

had associated anomalies of the brain and ocular globes; the first such
diseases described were Fukuyama congenital muscular dystrophy
(FCMD) (396,397), muscle-eye-brain (MEB) disease (398,399), and
the Walker-Warburg syndrome (WWS) (400,401). It was subsequently
discovered that the muscular abnormalities in these patients were the
result of abnormal linkage of the muscle fibers to the muscle basal
lamina; without proper linkage, the muscles were unable to contract
properly (402–404). Subsequent studies showed that similar linkages
are important in the development of the cerebral and cerebellar corti-
ces (where the same molecules link RGCs to the basement membrane
of the developing cortex), as well as the retina (linkage of glial guide
cells to the retinal limiting membrane) (402–404). The molecular
mechanisms shared by these different linkages were the “missing link”
in the connection between muscle, eye, and brain disease. The pre-
cise mechanisms that are impaired in these processes are not yet fully
understood. It seems that abnormalities of molecules involved in these
linkages result in a lack of connection of the RGCs to the pial base-
ment membrane in addition to the development of abnormal gaps in
that membrane. These defects result in a lack of normal detachment of
migrating glutamatergic neurons from RGCs and, consequently, lack
of normal laminar organization of the cortex; some neurons detach
early and remain in the subcortical white matter while others overmi-
grate through the gaps in the pial limiting membrane into the subpial
and subarachnoid spaces (402–405). Once the molecules involved in
the linkage mechanisms were discovered, neuroscientists began to look
for mutations of genes encoding these molecules; many such muta-
tions were found in patients with this spectrum of disease. Responsible
genes discovered so far in humans include POMT1, POMT2, FCMD,
FKRP, LARGE, POMGnT1, and GPR56 (125,405–412). Zic2 and Foxc1
have been implicated in such defects in animal models (413,414).

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-45. Hemimegalencephaly with bizarre, hamartomatous enlargement of the left hemisphere. The cortex is thick and
convoluted. Myelination appears abnormally advanced.
Mutations of genes coding for other proteins involved in the linkage of
the radial glia to the limiting membranes include laminin and merosin
(a form of laminin), mutations of which cause merosin-deficient
CMD (see Chapter 3) (415–421); CMD with leukoencephalopathy and
occipital agyria (258,422,423); CMD with severe mental retardation,
microcephaly, abnormal white matter, partial merosin deficiency, and
cerebellar hypoplasia (424); and CMD with partial merosin deficiency,
mental retardation, dysmyelination, and cerebellar cysts (425).
A number of studies have shown that several of the four major
phenotypes of congenital muscular dystrophy with malformations of
cortical development—WWS, FCMD, MEB, or limb-girdle muscular
dystrophy (which has no CNS involvement)—can be produced by
mutations of any of the genes involved in linkage of the RGCs to the
pial basement membrane (406–411,426) with those mutations having
the most severe effect on protein function causing WWS and those
with the least severe effect causing classic FCMD or limb-girdle muscu-
lar dystrophy. This should be kept in mind as these major phenotypes
and their imaging findings are described below.
Walker-Warburg Phenotype The Walker-Warburg phenotype
(WWP) is the most severe in this group of malformations. Affected
patients are obviously abnormal at birth, manifesting hypotonia that
is usually profound and unchanging, in addition to ocular abnormali-
ties (retinal dysplasia, colobomas, persistent hypoplastic primary vitre-
ous, congenital glaucoma or microphthalmos, optic nerve hypoplasia
[427]) and progressive macrocephaly due to congenital hydrocepha-
lus; they may have posterior cephaloceles and testicular defects as well
(400,401,428–430). Most patients have complete lack of psychomotor
development and die in the first year of life secondary to recurrent aspi-
ration and respiratory illnesses. As discussed above, this phenotype has
been seen in mutations of multiple genes (406–411). While the WWP
is seen in all ethnic groups, a striking difference has been observed
Barkovich_Chap05.indd 411
411
in the geographic distribution of mutations; POMT1 appears to be
more commonly mutated in Middle Eastern WWP populations, while
FCMD mutations seem to be common in European and American
WWP patients, particularly in Ashkenazi Jewish families (125).
On imaging studies, patients with WWP have a thickened cortex
with only a few shallow sulci and a distinctive cortical appearance,
ocular anomalies (which may be unilateral or bilateral), hydrocepha-
lus, callosal hypoplasia, and profound hypomyelination (Fig. 5-46)
(260,431). An occipital cephalocele is present in about 10% (Fig. 5-47).
The cerebral cortex (Fig. 5-46) is composed of multiple small bundles
of disorganized cortical neurons that project through the pia on the
outer cortical surface and into the underlying white matter on the
inner cortical margin (190); this appearance has been called a “cobble-
stone” cortex (432). Small nodules of gray matter may be seen a few
millimeters deep to the projections from the inner cortical margin (Fig.
5-46). The bundles of neurons are separated by fibroglial vascular tis-
sue that extends radially from the cerebral white matter through the
cerebral cortex into the subarachnoid space (which is obliterated by
this tissue, resulting in hydrocephalus). Few, if any, normal sulci are
seen in the cortex. Characteristics of the cortex may be difficult to
appreciate in the hydrocephalic neonate, whose cortex is compressed
by the enlarged ventricular system (Fig. 5-48); therefore, careful obser-
vation is required to make the diagnosis before the ventricles have been
decompressed. Characteristic brainstem anomalies include pontine
hypoplasia, an enlarged quadrigeminal plate with fusion of the supe-
rior and inferior colliculi, and a distinctive “kink” in the dorsal pons;
a second “kink” may be present at the ventral cervicomedullary junc-
tion (Figs. 5-46 and 5-47). The cerebellum is small and dysmorphic
with abnormal foliation; the vermis is more severely affected than the
hemispheres (Figs. 5-46 to 5-48, often referred to—incorrectly—as
“cerebellar polymicrogyria”). Orbital imaging findings include ocular
asymmetry, secondary to congenital microphthalmos or congenital
5/6/2011 8:59:12 PM
 412 Pediatric Neuroimaging

FIG. 5-46. Walker-Warburg phenotype. A. Sagittal T1-weighted image shows ventriculomegaly with extremely stretched
corpus callosum. The brainstem is characterized by kinking at the pons (small white arrowhead) and cervicomedullary
junction (large white arrowhead), a huge quadrigeminal plate (white arrows) and a very small cerebellar vermis. B. Axial
T2-weighted image shows the very small cerebellar hemispheres (white arrows) and a midline pontine cleft (black arrow).
C and D. Axial T2-weighted images show the appearance of the cobblestone cortex. Image from this patient (C) shows a
smooth outer cortical surface with nodules of gray matter protruding radially inward. Images from a different patient (D)
beautifully show radially oriented bands of neurons (black arrows), separated by strands of gliotic white matter.

glaucoma, with vitreal and subretinal hemorrhages due to retinal dys-
plasia or sublenticular hemorrhage due to persistent hyperplastic pri-
mary vitreous (PHPV) (Fig. 5-49). See later section of this chapter for
a discussion and descriptions of ocular anomalies. Rarely, a coloboma
is identified. No correlation has been noted between the MR appear-
ance of the brain or orbits and the mutated gene (125).
The WWP can be detected by fetal MRI during the mid second
trimester (Fig. 5-50) by observation of the very small cerebellum, the
characteristic brainstem, the very large tectum, the ventriculomegaly,
and (if imaged between 20 and 24 weeks, when a distinctive pattern of
cerebral lamination is normally seen (see Chapter 2) (433), the absence
of the normal cerebral lamination. The ocular findings (microphthal-
mia, colobomas) are confirmatory, if detected.
Fukuyama Congenital Muscular Dystrophy Phenotype FMCD is
the most common congenital muscular dystrophy in Japan (396,397).
It is an autosomal recessive disorder, with the vast majority of Japa-
nese cases (with the classic phenotype) being caused by an ancient ret-
rotransposon insertion in the 3’ noncoding region of the FKTN gene at
chromosome 9q31–33 (434,435). However, other mutations of FKTN
can cause the very severe WWP (426,436) and the milder limb-girdle
muscular dystrophy phenotype (437); thus, as stated above, clinical
phenotype is dependent on the effect of the mutation on the function
of the protein in the linkage of RGCs to the pial limiting membrane and
the structural integrity of the membrane (409). Patients with FCMD
phenotype present with hypotonia and severe developmental delay;
seizures develop during the first year of life in about half of affected

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 Chapter 5 • Congenital Malformations of the Brain and Skull 413

FIG. 5-47. Walker-Warburg phenotype with occipital cephalocele. Sagittal T1-weighted image (A) shows hydrocephalus
with the pontine (small white arrowhead) and cervicomedullary junction (large white arrowhead) kinks, a very small vermis,
and a small cephalocele (white arrow) protruding through the occipital bone. Coronal T2-weighted image (B) nicely shows
the cobblestone cortex and an extremely small cerebellum.

individuals. Analysis of serum shows elevated creatine kinase level;
this elevation typically leads to a muscle biopsy, which shows changes
consistent with muscular dystrophy (396,397,438,439). Patients with
FCMD may have ocular abnormalities (in particular dysplasias of
the retina that lead to myopia, nystagmus, chorioretinal degeneration
[440]), but they are less clinically severe than those in MEB and WWP.
Hydrocephalus is less common than in patients with WWP. Anomalies
of the corpus callosum and cephaloceles are uncommon.
Neuroimaging with MR reflects the gross pathologic findings
(438,439,441–443). Within the cerebral cortex, three types of abnormal-
ity are seen pathologically (441). Of these, two are detected by imag-
ing: unlayered PMG, which is seen primarily in the frontal lobes, and
cobblestone cortex, which is largely temporo-occipital (439). The fron-
tal PMG is seen as irregularity of the cortical surface and cortical-white
matter junction (Fig. 5-51). The temporo-occipital cobblestone cortex
is thick with a smooth outer surface (Fig. 5-51) but a slightly irregular

FIG. 5-48. Walker-Warburg phenotype in a neonate. Sagittal T1-weighted image (A) shows massive hydrocephalus. Note that the pons is
very thin and the quadrigeminal plate is enlarged with fused colliculi. Axial T2-weighted image (B) shows massive ventriculomegaly. The
characteristic “cobblestone” cortex is seen, although it is more difficult to appreciate in the setting of severe hydrocephalus.

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 414 Pediatric Neuroimaging
FIG. 5-49. Ocular anomalies in Walker-Warburg phenotype include intravitreal hemorrhage (A), subretinal hemorrhage (B), and
persistent hyperplastic primary vitreous (C and D).
inner surface. As in many patients with WWP, partly contiguous nodules
of gray matter can be identified deep to the inner surface of the cortex
(Fig. 5-51). Most patients with FCMD have dysmorphic cerebellar cor-
tex, which is manifest on imaging studies as dysmorphic folia with sub-
cortical cysts. These cysts tend to be located in the dorsal midportion of
the cerebellar hemisphere, particularly in the superior semilunar lobule
(Fig. 5-51) (438). On histology, the cysts are found to have leptomenin-
geal tissue within them and a molecular layer of nearly normal cerebellar
tissue lining their walls, suggesting that they may have formed from sub-
arachnoid spaces that were engulfed by fusion of neurons and glia that
migrated beyond the cerebellar pial limiting membrane (438,443). The
other major finding on imaging studies of FCMD is delayed myelination.
The abnormal white matter is hypodense on CT and shows abnormal T1
hypointensity and T2 hyperintensity on MRI. Of interest, when myeli-
nation does occur, it begins in the subcortical white matter (Fig. 5-51)
and extends centrally (439) in a pattern completely opposite to that of
normal development (in which periventricular and deep white matter is
myelinated first and subcortical white matter last, see Chapter 2).
FMCD is difficult to detect by fetal MRI. In our experience, the
abnormality can be suspected in the early third trimester when a delay
in sulcation is associated with cerebellar cysts. If the cysts cannot be
detected, the delay in sulcation itself is nonspecific.
Muscle-Eye-Brain Phenotype The MEB phenotype was originally
thought to be a specific disorder (398,399), found predominantly
Barkovich_Chap05.indd 414
in Finland and caused by mutations of POMGnT1 (444), which
participates in O-mannosyl glycan synthesis. It turns out that MEB
can also be caused by mutations in a number of different genes, the
molecular products of which are involved in that pathway, includ-
ing POMGnT1 (445), POMT1 (408), LARGE (446), and FKRP (406).
Affected patients are hypotonic and have impaired vision (manifest as
impaired visual fixation) from birth; epilepsy is common and mental
retardation is usually severe (399). Spasticity typically begins to develop
after age 5 years (399).
On pathologic examination, the cerebral cortex of patients with
MEB shows abnormal convolutions with a granular (cobblestone) sur-
face to the cerebral cortex. A limited area of agyria may be seen over the
occipital convexity. Light microscopy shows resemblance to the cor-
tex in WWP and FCMD in that irregular bundles of myelinated axons
penetrate the cortex from the white matter and gliovascular strands
cut through the cortex from the pia, thereby separating the cortex into
irregular neuronal clusters (432). No horizontal lamination or verti-
cal columns of cortical neurons can be identified. Similar gliovascular
strands penetrate the cerebellar cortex, which is dysplastic and shows
cysts similar to those in Fukuyama CMD (432).
Neuroimaging of patients with MEB reveals diffusely abnormal
cerebral cortex, which resembles PMG; it is thickened with decreased
number and depth of sulci, with most severe involvement in the frontal
lobes (Figs. 5-52 and 5-53). Myelination is delayed (Fig. 5-52B and C)
and, as in FCMD, it begins in the subcortical, instead of deep, white
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 Chapter 5 • Congenital Malformations of the Brain and Skull 415

FIG. 5-50. Fetal MRI of Walker-Warburg phenotype. A and

B. Sagittal images at 22 (A) and 30 (B) weeks gestation show the
large tectum (black arrows), pontine kink (small black arrow-
head), and cervicomedullary kink (large black arrowhead). The
cerebellar vermis is very small at both stages. C. Axial image
shows marked ventriculomegaly with a thin cerebral mantle.

matter (Fig. 5-52C). Patches of T2 hyperintensity may remain within
the cerebral hemispheres (Figs. 5-52D and 5-53B) even after myelina-
tion is completed. The brainstem is characterized by a very hypoplas-
tic pons with a vertical anterior midline cleft (Fig. 5-53A) and a large,
abnormally rounded midbrain tectum (Fig. 5-52A). The ventricles are
typically large, the Sylvian fissures are wide, and the cerebellum is hyp-
oplastic with dysmorphic folial pattern and cortical/subcortical cysts
(Figs. 5-52C and 5-53A) (447). Hydrocephalus may be present and
require shunting, the septum pellucidum may be absent and the cor-
pus callosum may be dysmorphic or hypoplastic; it is not clear whether
the latter findings are developmental or due to hydrocephalus. Thus,
the imaging appearance can be considered intermediate between the
WWP and FCMD phenotype.
The diagnosis of MEB phenotype can be suggested on fetal MRI if
a fetus is found to have a large tectum and small pons with ventral cleft
in association with delayed or abnormal sulcation (Fig. 5-54). A finding
of ocular anomalies (colobomas, microphthalmia) or cerebellar cysts
confirms the diagnosis.
Bilateral Frontoparietal Polymicrogyria The syndrome called bilat-
eral frontoparietal polymicrogyria (BFPP) is an autosomal recessive
syndrome that is found primarily in families from central Asia and the
Middle East, although families have been found in the western hemi-
sphere, as well (128). It has been well described and the causative gene
(GPR56) has been identified at 16q12.2–21 (128,448). In the cerebrum,
the gene product appears to be important for attachment of the distal
end of RGCs to the pial limiting membrane; when the gene is knocked
out in animal models, gaps appear in the membrane, allowing over-
migration of neurons (405). In the cerebellum, expression of GPR56
appears to be important in the adhesion of migrating granule cells to
extracellular matrix molecules of the pial basement membrane in the
rostral cerebellum (449). These pathophysiologic mechanisms are very

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 416 Pediatric Neuroimaging

FIG. 5-51. Fukuyama congenital muscular dystrophy in an 11-month-old girl. A. Sagittal T1-weighted image shows hypoplas-
tic pons, hypoplastic vermis, and fused colliculi. B. Axial T2-weighted image shows multiple cerebellar cortical cysts. C. Axial
T1-weighted image shows lack of myelin in the cerebral white matter and absence of normal gyri, particularly in the temporal
and occipital lobes. D. Axial T2-weighted image at the same level as (C) shows irregularity of the cortical-white matter junction
(open black arrows) in the frontal lobes, suggestive of polymicrogyria, and temporal/parietal cobblestone lissencephaly. Note the
nodules of gray matter (solid black arrows) just central to the occipital cortex. E–G. Coronal T1-weighted images show myelina-
tion (arrows) beginning in the subcortical white matter with the deep and periventricular white matter still unmyelinated.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 417

FIG. 5-52. Myelinating MEB phenotype. Images (A–C) were acquired at age 18 months, image (D) was acquired at age 4 years.
A. Sagittal T1-weighted image shows hypoplastic pons, dysmorphic cerebellar vermis with cortical cysts, and fused midbrain colliculi.
B. Axial T2-weighted image shows abnormally shallow sulci in the frontal lobes and incomplete myelination. Note that the subcorti-
cal U fibers are affected in the frontal lobes, but spared in the parietal and occipital lobes. C. Coronal T1-weighted image shows that
the subcortical white matter is myelinating, but the deep white matter is not; this pattern is characteristic of congenital muscular
dystrophies. Note the cortical/subcortical cerebellar cysts (white arrows). D. Axial T2-weighted image shows progression of myelina-
tion. Note that several areas of abnormal patchy T2 hyperintensity (white arrows) remain.

similar to that described with other disorders described in this section;
thus, it is not surprising that a cobblestone-like malformation devel-
ops. The phenotype is similar to, but milder than, MEB. In view of the
cobblestone-like pathophysiology, some argue that it is not correct to
call this disorder PMG; however, BFPP is the term currently being used
in the literature and it will be used here. Affected patients show a charac-
teristic syndrome of developmental delay in both cognitive and motor
spheres, disconjugate gaze (typically esotropia), refractory seizures
(most commonly symptomatic generalized epilepsy), and ataxia (450).
MRI in BFPP shows thickened, irregular frontal cortex; the medial
aspects of the frontal lobes are often involved, which helps differentia-
tion from true PMG. Abnormal foci of T2 prolongation are commonly
seen in the white matter immediately subjacent to the cortex. The cor-
pus callosum is large and shows abnormal contour. The cerebellum is
small and dysmorphic, with an appearance similar to those of patients
with CMD, but only a few, small cysts are seen and those only occa-
sionally. The pons is typically small (128), but not as small as in MEB
(Fig. 5-55).

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 418 Pediatric Neuroimaging

FIG. 5-53. MEB phenotype. Axial T2-weighted

images show midline pontine cleft (white arrow-
heads in A), cerebellar cysts (white arrows in A),
abnormal frontal gyri (white arrows in B) and foci
of abnormal myelination (white arrowheads in B).

FIG. 5-54. Thirty-two-week fetus with MEB pheno-

type. A. Sagittal image shows ventriculomegaly with large
tectum (black arrow), small pons, and small cerebellum.
Pontine kink is similar to that in Walker-Warburg syn-
drome phenotype. B. Axial image shows small cerebel-
lar hemispheres and small pons with midline cleft (white
arrow). C. Axial image shows marked ventriculomegaly
and abnormal cortex with multiple small gyri.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
Other Congenital Muscular Dystrophy Syndromes Other congenital
muscular dystrophy syndromes have been described that do not fit well
into the Walker-Warburg, FCMD, MEB, or BFPP phenotypes. These
include CMD with occipital agyria (see Chapter 3 and Fig. 3–17) (422),
and those with cerebellar cysts and leukodystrophy without cortical
malformations or hydrocephalus (Fig. 5-56) (425,451,452). From the
point of view of the neuroimager, it is important to remember that
the findings of leukodystrophy, cobblestone cortex, cerebellar subcor-
tical cysts, small pons, and rounded quadrigeminal plate suggest the
diagnosis of cobblestone malformation due to abnormal pial basement
membrane formation. Additional clinical, genetic, and imaging char-
acteristics will contribute to the final diagnosis.
Lissencephaly (The Agyria-Pachygyria Complex) The term lis-
sencephaly means “smooth brain” and refers to a paucity of gyral and
sulcal development on the surface of the brain. Agyria is defined as an
absence of gyri on the surface of the brain in association with a thick
cortex and is synonymous with “complete lissencephaly,” whereas pachy-
gyria is defined as the presence of a few broad, flat gyri with thickened
cortex and is used interchangeably with the term “incomplete lissen-
cephaly.” These definitions adopt the concepts of Hennekam and Barth
that proper use of the terms agyria and pachygyria requires a thick cortex
and that these malformations result from an arrest of neuronal migra-
tion (199). A finding of broad gyri and shallow sulci in the absence of
thickened cortex should be considered a simplified gyral pattern, result-
ing from either deficient cell production or impaired white matter devel-
opment in utero (199). Of importance in distinguishing pachygyria from
PMG (see section “Malformations Secondary To Abnormal Late Migra-
tion and Cortical Organization”) is the observation that the sulci seen in
pachygyria (and in simplified gyral patterns) are normal, early forming
sulci that can be identified and named by those experienced in neuro-
anatomy; the sulci in PMG are abnormal and do not correspond to those
described in neuroanatomy texts. In addition, the cortex of pachygyria
has smooth inner and outer surfaces, whereas that of PMG will be seen
to have irregularities due to the microgyri and microsulci (453).
Both agyria and pachygyria are likely caused by abnormal regu-
lation of microtubule activities. Microtubules are involved in many
key intracellular processes, such as mitotic spindle orientation, vesicle
transport, and nuclear migration (454,455). Most genes known to cause
classic lissencephaly are known to participate in microtubule dynam-
ics and abnormalities of this function almost certainly causes, in some
way, an arrest of normal neuronal migration (454). Lissencephalies are,
Barkovich_Chap05.indd 419
419
FIG. 5-55. Bilateral frontoparietal
polymicrogyria due to GPR56 mutation.
Sagittal (A) and axial (B) T2-weighted
images show small pons, small dysmor-
phic cerebellum, and a cobblestone-like
cortex (white arrows in B), with abnor-
mal sulci and the cortex composed of
radially-oriented bundles of neurons.
therefore, distinct from MSG pattern, in which too few neurons are
produced or too many undergo apoptosis (programmed cell death),
and from cobblestone malformation due to abnormal pial basement
membrane formation, which are associated with overmigration of neu-
rons. Patients with LIS1 mutations seem to have defects in outgrowth
of neuronal processes (the “arms” that extend outward from the neu-
ronal cell body and act as leading processes) and in transporting the cell
nucleus into the neuronal processes; as a result, the postmitotic neuron
cannot navigate from the ventricular zone to the radial glial pathway
(456). Both GABAergic interneuron migration from the ganglionic
eminences and glutamatergic neuron migration from the dorsal hemi-
spheric germinal matrix seem to be affected in lissencephaly (457).
Classic Lissencephaly/Band Heterotopia Spectrum Classic
lissencephaly is the term that describes the appearance seen with the
first described and most common form of lissencephaly: a thick cortex
composed of (a) a thin molecular layer adjacent to the pia, (b) a thin
outer cortical layer, (c) a “cell-sparse zone” medial to the outer corti-
cal layer, and (d) the thickest part of the cortex located deep (medial)
to the cell-sparse zone (Fig. 5-57). Some patients with classic lissen-
cephaly have a defect of the LIS1 (also called PAFAH1B1) gene at locus
17p13.3 (124,458,459). A subset of the group with LIS1 mutations also
has mutation of the adjacent YWHAE gene, resulting in characteris-
tic facial anomalies (bitemporal hollowing, prominent forehead, short
nose with upturned nares, prominent upper lip, thin vermilion border
of the upper lip, small jaw); this group is classified as the Miller-Dieker
syndrome (460,461). Other patients with classic lissencephaly have
mutations of the DCX gene at chromosome Xq22.3-q23 (X-linked lis-
sencephaly [462]); these patients are typically hemizygous boys whose
mothers have band heterotopia (122,463,464) (affected female siblings
also have band heterotopia). A third gene, TUBA1A at chromosome
12q12, accounts for approximately 7% of classic lissencephaly with a
four-layer cortex and cell-sparse zone (465); the diagnosis can be sug-
gested if an anomalous corpus callosum (absent rostrum, abnormally
curved body, or vertical splenium), small cerebellum, rounded hip-
pocampi, or thin brainstem are identified (131,465,466).
It has been estimated that 40% to 75% of patients with classic lis-
sencephaly have mutations of either LIS1 (up to 60%) or DCX (∼12%)
(131,467–469), meaning that up to half of lissencephaly patients have
other mutations; this is not surprising in view of the many genes that
are involved in normal neuronal migration. Irrespective of the causative
gene, children with classic lissencephaly have similar neurological
5/6/2011 8:59:21 PM
 420 Pediatric Neuroimaging

FIG. 5-56. Congenital muscular dystrophy due to FKRP mutation

in a 13-month-old child. Sagittal T1-weighted image (A) shows small
pons and small, vertical callosal splenium. Coronal T1-weighted
image (B) shows hyperintensity from early myelination in subcortical
(black arrows) but not deep white matter; note cerebellar cysts (white
arrows). Axial T2-weighted image (C) shows irregular, microgyric-
like cortex (black arrows) in both frontal lobes.

FIG. 5-57. Schematic showing cortical archi-

tecture in classic lissencephaly. In complete
lissencephaly (agyria), a large cell-sparse zone
(open black arrow) separates the molecular layer
(layer I) and an outer cortical layer (layers III, V,
VI in figure) from a thick deeper layer of dis-
organized neurons. In incomplete lissencephaly
(pachygyria), the outer cortical layer is thicker,
the cell-sparse zone (black arrow) thinner, and
the inner cortical layer smaller.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
syndromes, although the age of onset and severity of the clinical
syndrome may vary depending upon the severity of the cortical mal-
formation (335,461,470,471). Those with complete classic lissenceph-
aly are typically hypotonic at birth, gradually developing appendicular
and oropharyngeal spasticity as their nervous system matures (470,472).
Children with incomplete lissencephaly have less severe motor abnor-
malities and hypotonia (470). Infantile spasms are common in severely
affected infants. The development of medically refractory epilepsy at a
very early age, with increasingly complex seizure disorders over time, is
characteristic. Systemic anomalies, particularly those of the ears, eyes,
heart, and kidney, are present in the more severely affected patients
(429,460,461,470,473).
Mothers of boys with lissencephaly due to DCX mutations have
the same mutation of the X chromosome as do their offspring but
have band heterotopia instead of lissencephaly (474), or may even have
mental retardation or epilepsy with completely normal MR studies
(475,476). These patients seem to have either mild mutations or inac-
tivation of a large percentage of the abnormal X chromosomes (475).
Many patients with band heterotopia have a significantly reduced num-
ber of sulci and gyri (477). As it has been shown that band heterotopia
can be caused by mild mutations of DCX or LIS1 (478,479) or other
genes (204), they are probably better classified as a form of incomplete
lissencephaly. They are therefore discussed in the “Lissencephaly (The
Agyria-Pachygyria Complex)” section rather than the “Heterotopia”
section in this edition.
Macroscopic examination of the brain shows that most patients in
this group have areas of both agyria and pachygyria, that is, incomplete
lissencephaly. The severity of the gyral pattern is related to the num-
Barkovich_Chap05.indd 421
421
ber of neurons that are mutated and to the severity of the mutation
(126,464,469,478,480–483). Fewer neurons with mutations, secondary
to mosaicism or heterozygosity, or mutations that have (presumably)
less severe effects on neuronal migration result in milder phenotypes
(less severe pachygyria or band heterotopia) (469,475). In patients with
LIS1 mutations, the areas of agyria are most frequently parietooccipital
in location while the pachygyric areas are more common in the fron-
tal and temporal regions (470,472,484); indeed, about two thirds of
patients with posterior predominant lissencephaly have mutations of
LIS1 (471). Some patients have more severe pachygyria or agyria in the
frontal lobes with less severe involvement of the occipital lobes; most of
these patients seem to have mutations of DCX (485). Microscopically,
the cerebral cortex in patients with LIS1 mutations is composed of a
normal molecular layer, a thin outer layer composed of neurons that
would normally be in cortical layers 5 and 6, a cell-sparse zone contain-
ing neurons that would normally be in layer 4, and a thick inner layer
composed of neurons that would normally be in cortical layers 2 and 3
(Fig. 5-57) (486). The inner layer of neurons is thought to represent
neurons that were prematurely stopped during their migration to the
cortex. No radial or horizontal organization is seen in the cortex of
patients with TUBA1A mutations; a cell-sparse zone may (466) or may
not (131,466) be identified, depending upon the location of the muta-
tion and, perhaps, other factors.
Imaging studies of patients with complete classic lissenceph-
aly (agyria) reveal a smooth brain surface with diminished white
matter and shallow, vertically oriented, Sylvian fissures (Fig. 5-58)
(461,470,472,487,488). In patients with LIS1 and DCX mutations, a
thin outer cortical layer is separated from a thick deeper cortical layer
FIG. 5-58. Agyria in a neonate. Sagittal T1-
weighted image (A) shows no medial hemispheric
sulci other than the parietooccipital sulcus. Axial
(B) and coronal (C) T2-weighted images show
a smooth cerebral surface and the typical corti-
cal pattern with thin (dark) outer cortical layer,
relatively thick (bright) cell-sparse zone, and thick
(dark) inner cortical layer (black arrows). Vol-
ume of white matter is diminished. Note relative
enlargement of the ventricular trigones.
5/6/2011 8:59:24 PM
 422 Pediatric Neuroimaging

by a zone of white matter (the cell-sparse zone, Fig. 5-58) that seems
to myelinate normally as the child matures. The cerebrum has been
described as having a figure-of-eight appearance on axial images as a
result of the shallow, vertical Sylvian fissures. In cases of severe lissen-
cephaly, sagittal images may show callosal hypogenesis with a charac-
teristic vertical splenium. The ventricular trigones and occipital horns
are enlarged, mostly because of underdevelopment of the calcarine
sulci (Fig. 5-58) (472). The brainstem often appears small, probably
because many of the corticospinal and corticobulbar tracts do not
form. Absence of the corpus callosum or severe pontine/cerebellar
hypoplasia should suggest a TUBA1A mutation (489,490). Agyria can
sometimes be detected by prenatal imaging (MRI or ultrasound) by
the absence of gyri, persistence of a cell-sparse zone after 25 gestational
weeks (Fig. 5-59) and the abnormal morphology of the sylvian fissures
(in the normal fetus, the base of the sylvian fissure, the insula, has a
“square” appearance with sharply angled margins, whereas the lissen-
cephalic patient has a shallow, rounded sylvian fissure [491]).
Incomplete lissencephaly, in which areas of pachygyria are present
together with areas of agyria (Figs. 5-60 and 5-61) or areas of normal
brain, is much more common than complete lissencephaly. Areas of
pachygyria also have a thickened cortex, but broad gyri and shallow
sulci (Figs. 5-60 and 5-61) are present. Pachygyria can be distinguished
from PMG when thin section, high resolution images are obtained
(453). In pachygyria, the cortical-white matter junction is smooth,
and, in some cases, a layer of normal white matter can be detected in
the cell-sparse zone (Figs. 5-60 and 5-61). In PMG, the cortical-white
matter junction is always irregular (453) (see Fig. 5-62 and the sub-
sequent section “Polymicrogyria” under “Malformations Secondary to
Abnormal Cortical Organization and Late Migration”). Pachygyria can
be focal or diffuse. When focal (Fig. 5-61), it is almost always bilateral
and typically posterior in patients with LIS1 mutations. When diffuse
(Fig. 5-60), it is often associated with regions of agyria and is typi-
cally more severe in the parietooccipital region of the brain (and least
severe in the frontal and temporal lobes) in LIS1 mutations (485). The
mid-frontal lobes are most severely affected in pachygyria secondary
to DCX mutations (Fig. 5-63) (485). When patients have classic lissen-
cephaly with more severe involvement in the anterior cerebrum than
in the posterior cerebrum, a good family history should be obtained.
Band heterotopia may be found in some female family members if
there is family history of seizures (Fig. 5-63D).

FIG. 5-59. Agyria in a 32-week fetus. Sagittal image (A)

shows a mature posterior fossa with large pons and cere-
bellar vermis. Axial (B) and coronal (C) image show that,
despite fetal maturity, the surface of the brain remains
smooth. A cell-sparse zone (white arrows) can be seen; nor-
mally, “layers” of the cerebral cortex are not seen after about
25 weeks. Also notice the persistent rounding of the sylvian
fissures (black arrowheads); the maturation of the insulae
normally cause “squaring” of the sylvian fissures by about
23 to 24 gestational weeks (see Chapter 2).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 423

FIG. 5-60. Diffuse pachygyria (chromosome 17-linked). A. Parasagittal T1-weighted

image shows thickened cortex with relatively few and large gyri and sulci. B. Axial
T1-weighted image shows that the pachygyria is more severe in the parietal and occipi-
tal lobes than in the frontal lobes. The sylvian fissures (curved black arrows) are abnor-
mally vertical. C. Axial T2-weighted image shows hyperintensity (small white arrows),
representing the cell-sparse zone, in the parietal lobe.

Lissencephaly with Cerebellar Hypoplasia. Some patients with
classic lissencephaly have anomalies of the corpus callosum or cerebel-
lar hypoplasia (Fig. 5-64) (131,485,492). Patients with DCX mutations
may have complete callosal agenesis or an abnormally shaped corpus
with a flat callosal body and vertical splenium (493). Patients with
LIS1, DCX, and TUBA1A mutations all can have cerebellar hypoplasia
(131,485,492,494), but it is usually only mildly hypoplastic in LIS1 and
DCX mutations, likely resulting from the fact that the same ligands and
processes that are involved in neuronal migration in the cerebrum are
also at work in the cerebellum. Of the well-characterized lissenceph-
alies, only TUBA1A lissencephalies consistently have anomalies of the
corpus callosum, cerebellum, and hippocampus (Fig. 5-64); TUBA1A
mutations comprise greater than 30% of lissencephalies with signifi-
cant cerebellar hypoplasia (465). Severe callosal hypoplasia/hypogen-
esis is nearly always associated, along with a very hypoplastic brainstem
(Fig. 5-64A). The cortex is pachygyric, but not as thick as in LIS1 or
DCX mutations (465). In my experience, undulation of the deep
cortical layer (Fig. 5-64B) is also most common with TUBA1A muta-
tions. Therefore, if both cerebellar and callosal anomalies are present
in a patient with the appearance of classic lissencephaly, particularly if
the deep cortical layer is undulating, testing for TUBA1A mutations is
warranted.
Band heterotopia. Band heterotopia (477,495), also called “double
cortex” (496,497), is the mildest form of classic lissencephaly. The layer
of arrested neurons is thinner, the cortex is thicker, and the cortex has
a more normal gyral pattern than in pachygyria. Affected patients are
almost exclusively female and may present at any age, although they
usually present in childhood with developmental delay of variable
severity and mixed seizure disorders (477,496–498). Several authors
have described patients who are normal except for relatively mild
seizure disorders (463,477,496). Rarely males can have band heterotopia

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 424 Pediatric Neuroimaging
FIG. 5-61. Posterior pachygyria. A. Parasagittal T1-weighted image shows
normal appearing frontal cortex with pachygyria (white arrows) in the
parietal and occipital lobes. B. Coronal T1-weighted image shows a smooth
cortical-white matter junction (open black arrows) and the cell-sparse zone
(solid black arrows).
secondary to somatic mosaicism of LIS1 or hemizygous mutations for
DCX (477–479,499–501). One case report has revealed band hetero-
topia associated with trisomy 9p; mutation analysis of LIS1 and DCX
was negative (204). Other reports of patients with 9p duplication have
been reported with epilepsy, mental retardation, and brain abnormali-
ties, suggesting that this is another cause of band heterotopia (498). In
addition, we have seen a region of band heterotopia in a patient with
Zellweger syndrome (see Chapter 3). Thus, the indications are that,
although most cases are due to DCX mutations, mutations of many
genes involved in neuronal migration can cause band heterotopia. His-
tologic analysis shows that the subcortical bands contain heterotopic
neurons that are of small pyramidal shape without clear radial orienta-
tion. The neurons may be arrayed into clusters, sheets, or wide bands.
The layer of heterotopic neurons is separated from the overlying cortex
and underlying lateral ventricles by normal white matter. Of interest,
the overlying cerebral cortex has normal cytoarchitecture (4,502).
On imaging, band heterotopia appear as homogeneous bands of
gray matter that are situated between the lateral ventricles and the cere-
bral cortex and separated from both by a layer of normal-appearing
white matter (the white matter may be incompletely myelinated in
infants, Figs. 5-65 and 5-66). The overlying cortex typically has normal
Barkovich_Chap05.indd 424
FIG. 5-62. Polymicrogyria. Note the irregular cortical-white matter junc-
tion (black arrows). Contrast with Figures 5-60 and 5-61.
thickness with shallow sulci; thickness of the outer cortex can be used
as a (rather arbitrary) marker to differentiate band heterotopia (thin in
lissencephaly, normal in band heterotopia). Band heterotopia may be
complete, surrounding the central white matter (Figs. 5-65 and 5-66),
or partial (463,503); when partial, the frontal lobes seem to be pref-
erentially involved in women (DCX mutations, Fig. 5-63D), whereas
the posterior brain regions are more commonly involved in men (LIS1
mutations) (463,498,503). Rarely, a second layer of heterotopia may
be identified in the temporal lobe (477). A more severe anomaly of
the cortex is associated with a worse clinical prognosis for epilepsy.
Foci of T2 prolongation may be seen in the cerebral white matter; the
presence of these foci is associated with a poor motor outcome (477).
When imaged in a neonate, the band may be mistaken for myelinating
white matter; identification of the cell-sparse zone between the band
and the cortex (Fig. 5-67), in addition to the shallow sulci, will help to
make this differentiation easier. When studied by PET using 18F-FDG,
band heterotopia are found to have a glucose uptake that is similar to
(504,505) or greater than (506) normal cortex. This finding contrasts
with the hypometabolism found in cortical dysplasias and in most epi-
leptogenic foci. Morell et al. (507) have found epileptiform discharges
emanating from the band, suggesting that it is the source of the seizure
activity in affected patients. Others have found increased blood flow to
the portion of the band that underlies the motor cortex using BOLD
imaging (508,509). This combination of findings suggests that the
band may have substantial communications with the rest of the brain
and may send out projection fibers to communicate with the body.
Variant Lissencephalies Variant lissencephaly is a term used to
describe brain anomalies with thick cortex (not as thick as in classic lis-
sencephaly) and reduced sulcation, but no cell-sparse zone (486). Four
different groups are currently in this category and it will likely grow.
X-linked Lissencephaly with Callosal Agenesis and Ambiguous
Genitalia. X-linked lissencephaly with callosal agenesis and ambiguous
genitalia appears to be a separate type of lissencephaly (510,511) that
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 Chapter 5 • Congenital Malformations of the Brain and Skull 425

FIG. 5-63. Members of family with X-linked lissencephaly. A and B. Sagittal T1-weighted (A) and axial T2-weighted (B) images show
pachygyria in the frontal lobes (white arrows), but more normal gyral pattern posteriorly. C. Axial T2-weighted image of a 7-month-old
boy, who is the nephew of the patient shown in (A) and (B). Note that the more normal gyri (white arrows) are in the posterior regions
of the brain and the more severe pachygyria/agyria is anterior. Note the cell-sparse zone (white arrowheads) in the agyric region. D. Axial
T2-weighted image of the mother of the boy in (C) and the sister of the man in (A) and (B) shows bilateral, right larger than left, anterior
band heterotopia (white arrows).

is caused by mutations of the ARX gene at Xp22.13 (512). The protein
product of ARX appears to function in the proliferation and develop-
ment of cortical neurons (both interneurons and projection neurons)
(513,514), as well as those of the thalamus, hippocampus, striatum, and
olfactory bulbs. Of interest, mutations of this gene cause a wide variety
of syndromes, from hydrocephalus with abnormal genitalia to mental
retardation with agenesis of the corpus callosum and abnormal genita-
lia, to infantile epileptic-dyskinetic encephalopathy, infantile spasms or
mental retardation with normal-appearing brains (514,515). All affected
patients with X-linked lissencephaly and ambiguous genitalia to date
have been genotypic males, and all have had intractable neonatal onset
epilepsy (typically myoclonic seizures), normal head size at birth with
severe microcephaly developing over the first few months of life, poor
temperature regulation, chronic diarrhea, and ambiguous or underde-
veloped genitalia (510,516,517). Related females may have mental retar-
dation and epilepsy and, often, agenesis of the corpus callosum (516).

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 426 Pediatric Neuroimaging

FIG. 5-64. Lissencephaly with callosal anomaly and cerebellar hypoplasia. Sagittal T1-weighted image (A) shows
severe pontocerebellar hypoplasia and absence of the corpus callosum. Axial T2-weighted image (B) shows a smooth
cortical surface with an undulating deep cortical layer (black arrows). The combination of callosal agenesis, pontocer-
ebellar hypoplasia, and undulating deep cortex should raise the possible diagnosis of TUBA1A mutation.

FIG. 5-65. Typical appearance of band

heterotopia. Parasagittal T1-weighted
image (A) shows the gray-matter-intensity
band (b) separated from the cortex by a
layer of partially myelinated white mat-
ter (m). Note that the cortex has nor-
mal thickness but shallow sulci. Axial
T2-weighted image (B) and coronal
T1-weighted image (C) show ventricu-
lomegaly and incomplete subcortical
myelination.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-66. More severe band heterotopia. Coronal T2-weighted image
shows a thicker layer of heterotopia (b) with fewer, shallower sulci. This is
difficult to separate from pachygyria, but we use the normal thickness of
the outer cortical layer as a marker of band heterotopia.
On pathologic examination, brains of affected patients show
absence of the corpus callosum without Probst bundles; a trilayered
cortex (composed of a cellular molecular layer, a thin middle layer
composed of mainly pyramidal neurons, and a thick inner layer com-
posed of multipolar neuronal types); small, disorganized basal ganglia;
hypoplastic or absent olfactory bulbs and optic nerves; spongy, gliotic
white matter containing numerous heterotopic neurons; and dysplastic
hypothalamus lacking most of its normal nuclei (486,516,518).
Imaging studies show anterior pachygyria, with only a few, shallow
sulci, and posterior agyria (Fig. 5-68); no cell-sparse zone is identified.
FIG. 5-67. Band heterotopia in an infant. The band (b) is separated from
the overlying cortex by an unmyelinated cell-sparse layer (c).
Barkovich_Chap05.indd 427
427
The cerebral cortex, usually measuring about 6 to 7 mm in thickness,
is thicker than normal but is thin compared to that in lissencephaly
secondary to LIS1 or DCX mutations (which are usually about 15 mm
thick) (512). The corpus callosum is always completely absent and the
basal ganglia are either small and dysplastic (often cystic, Fig. 5-68) or
completely absent. The brainstem and cerebellum appear normal.
Lissencephaly Secondary to Mutations in the Reelin (Reln) Signal-
ing Pathway. Lissencephaly secondary to mutations of the reelin sig-
naling pathway results in severely affected children, who are hypotonic
at birth and showed marked delay in motor and cognitive milestones;
they do not sit or stand unsupported, nor do they develop language
(494,519,520). Generalized epilepsy begins at an early age; some
affected patients have congenital lymphedema (519). Reelin, the protein
FIG. 5-68. Neonate with X-linked lissencephaly with agenesis of the
corpus callosum and ambiguous genitalia due to ARX mutation. Sagittal
T1-weighted image (A) shows absence of the corpus callosum and abnor-
mal sulcation of the medial cerebral hemisphere. Axial T1-weighted image
(B) shows areas of pachygyria and agyria with moderately thick cortex. Note
that the cortex is less thickened than in lissencephaly secondary to XLIS or
DCX mutations. No cell-sparse zone is identified. Basal ganglia are nearly
absent, with enlarged perivascular spaces (white arrows) in their place.
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 428 Pediatric Neuroimaging

FIG. 5-69. Variant lissencephaly secondary to reelin (RELN) mutation. A. Sagittal T1-weighted image shows abnormal gyral
pattern of the medial hemisphere, a very small and unsulcated cerebellum and a small pons. The callosal splenium is incompletely
formed. B. Coronal T1-weighted image shows decreased sulcation of the cerebrum, moderately thickened cortex. Note that no
cell-sparse zone is identified.

product of the RELN gene (which maps to 7q22), is an extracellular
matrix protein that is critical for the normal disengagement of migrat-
ing neurons from RGCs in mice and, likely, in humans. In its absence,
younger migrating neurons are unable to pass neurons generated ear-
lier and migrate to the outer layers of the cortex (181,521). As a result,
the cortex is disorganized, with layer 6 neurons closest to the molecu-
lar layer (layer1), followed by layer 5, layer 4, etc. (Normally, layer 5
migrates past layer 6, layer 4 migrates past layer 5, etc. See discussion
at the beginning of the section “Malformations of Cortical Develop-
ment.”) Mutations of other genes in the reelin signaling pathway, such
as the very low density lipoprotein receptor (VLDLR) gene, localized to
chromosome 9p24, and the apolipoprotein E receptor 2 gene (APOE2)
at chromosome 19q13.2, cause similar impairments of neuronal
migration and organization and result in similar malformations (522).
Mutation of VLDLR is seen in the disorder that has been called the
disequilibrium syndrome (520,523).
Imaging studies of children with RELN mutations shows a thick-
ened cortex (measuring up to 1 cm in thickness) with too few sulci
(Fig. 5-69); of interest, no cell-sparse zone is identified. Hippocampi are
incompletely rotated. The brainstem and cerebellum are extremely small.
The cerebellum is completely smooth, with no foliation (Fig. 5-69). The
appearance is extremely characteristic and is sometimes referred to as
the Norman-Roberts type of lissencephaly (494). Patients with VLDLR
mutations have the same finding, but less severe (Fig. 5-70) (522).

FIG. 5-70. Variant lissencephaly secondary to mutation of very low density lipoprotein receptor (VLDLR) gene.
Sagittal T1-weighted image (A) shows abnormally broad midline gyri with few midline sulci. The pons and cerebel-
lum are abnormally small and the cerebellum (white arrows) has insufficient foliation. Axial T2-weighted image
(B) shows insufficient sulcation but normal cortical thickness. (These images are courtesy of Dr. Robert Sevick,
Calgary.)

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 Chapter 5 • Congenital Malformations of the Brain and Skull
Lissencephaly with Central Predominance. In some patients with
lissencephaly, the most severe gyral anomalies are in the posterior
frontal region (524). This pattern has been described to occur in the
Baraitser-Winter syndrome (276), a disorder characterized by micro-
cephaly, ocular anomalies (iris and retinal colobomas, ptosis, hyper-
telorism, epicanthic folds), ptosis, mental retardation, dysmorphic
features, and short stature (525). We have also seen this pattern in a
family with DCX mutations. Imaging characteristically shows abnor-
mal sulcation with simplified gyral pattern (too few sulci) and frank
pachygyria (with cortical thickening) in the suprasylvian/paracentral
cortex. Thin subcortical band heterotopia have been reported poste-
riorly in a few cases (525). Pathology seems to be similar to that of
lissencephaly from DCX mutations (486).
Heterotopia Gray matter heterotopia are collections of nerve cells in
abnormal locations secondary to arrest of radial migration of neurons.
(Note that the word heterotopia is plural; the singular form of the noun
is heterotopion). Heterotopia can be isolated or can be seen in associa-
tion with other structural anomalies. While one might argue that all
anomalies secondary to abnormal neuronal migration are heterotopia
(in the sense that all are composed of normal nerve cells in abnormal
locations), the term heterotopia is reserved for cases in which the ecto-
pic neurons are in nodular or laminar form and are located in an area
other than the cortex.
Patients with heterotopic gray matter almost always come to
medical attention as a result of a seizure disorder (526–528). For
the purposes of clinical evaluation and prognostication, it is useful
to divide heterotopia into three groups: (a) periventricular (sub-
ependymal) heterotopia; (b) focal subcortical heterotopia; and (c)
leptomeningeal heterotopia (7). Leptomeningeal heterotopia is the
result of overmigration of neurons through gaps in the pial limiting
membrane; those with genetic causes were discussed in the previ-
ous section concerning malformations resulting from gaps in the pial
limiting membrane. When isolated or due to in utero injury to the
pial liming membrane, they cannot be detected by imaging at this
time. Another disorder, referred to as band heterotopia (or, some-
times, double cortex) was discussed in this section in previous edi-
tions of this book. However, band heterotopia are better classified
as a mild form of lissencephaly (7) and are discussed in the “Classic
Lissencephaly/Band Heterotopia Spectrum” section, earlier in this
Barkovich_Chap05.indd 429
429
section “Malformations Secondary to Abnormal Cortical Organiza-
tion and Late Migration.”
Periventricular (Subependymal) Nodular Heterotopia Patients
with PVNH can be separated into two large groups. Most patients have
heterotopia that are asymmetric, few in number, and largely confined
to the trigones and the temporal and occipital horns (Fig. 5-71); these
are rarely familial but may be associated with other brain anomalies
such as the Chiari II malformation, cerebellar hypoplasia, cephaloceles,
ectopic posterior pituitary gland, PMG, frontonasal dysplasia, Donnai-
Barrow syndrome, fragile X syndrome, and agenesis of the corpus cal-
losum (129,195,529–532). A smaller number of patients have a large
number of heterotopic nodules that completely or nearly completely
line the walls of the lateral ventricles (Fig. 5-72). PVNH may be famil-
ial, with both X-linked and autosomal recessive patterns of inheritance
(127,533,534). A number of causative genes have been identified (533),
including the filamin-A (FLNA) gene at chromosome Xq28 (535–537)
and the ARFGEF2 gene at chromosome 20q13 (associated with micro-
cephaly [127]). Other loci associated with PVNH include 1p36 (538),
5q14.3–15 (132), and 7q11.23 (539). It is currently thought that PVNH
are caused by loss of integrity of the neural ependymal at the ventricu-
lar wall, either due to physical trauma or disruption of intracellular
vesicle trafficking due to mutations (540). The loss of integrity of the
neural ependyma may disrupt the attachment of RGCs, thus disrupt-
ing migration.
Whether sporadic or familial, children with isolated heterotopia
(i.e., no other brain or visceral anomalies) usually manifest mild clini-
cal symptoms, with normal development, normal motor function, and
onset of seizures during the first or second decade of life. Seizures are
typically mixed partial complex and tonic-clonic (129,528,536,537,541).
Focal cortical dysplasia may be found in the overlying cortex, possibly
acquired due to proliferation of seizure activity via axons connecting
the epileptogenic heterotopia with the affected cortex (542). Girls with
X-linked PVNH often have a large cisterna magna and may have a
small cerebellar vermis (Fig. 5-72) (526,535,536). Boys with syndromic
subependymal heterotopia may have associated cortical malformations
(Fig. 5-73), syndactyly, ear abnormalities, and severe mental retarda-
tion (535). Both girls and boys with FLNA mutations are more likely to
have congenital cardiovascular defects such as patent ductus arteriosus
or cardiac valvular anomalies, and a propensity for premature stroke
FIG. 5-71. Periventricular nodular het-
erotopia confined to the walls of the tem-
poral horns, trigones, and occipital horns
of the lateral ventricles. Axial T1-weighted
image (A) and coronal T2-weighted image
(B) show nodules of heterotopic gray mat-
ter (white arrows) protruding into the
ventricular trigones. When confined to
temporal horns and trigones, PVNH can be
difficult to identify on axial images.
5/6/2011 8:59:32 PM
 430 Pediatric Neuroimaging
(129,543). Girls or boys with periventricular heterotopia and other
malformations (callosal agenesis, schizencephaly, PMG, subcortical
heterotopia, cephalocele, etc.) are more likely to suffer from significant
cognitive impairment; their seizures tend to develop earlier (during the
first decade) and are more difficult to control (541).
On imaging studies, PVNH are smooth, round or ovoid masses
(Figs. 5-71 to 5-73) that are isointense with gray matter on all imaging
sequences. When ovoid, the long axis is parallel to the adjacent ventric-
ular wall. They may appear exophytic, protruding into the adjacent lat-
eral ventricle (Fig. 5-71), and sometimes causing the ventricle to appear
compressed or they may extend into adjacent white matter (Fig. 5-72).
They are differentiated from the subependymal hamartomas of tuberous
sclerosis (see Chapter 6) by (a) their shape (hamartomas of tuberous
sclerosis are irregular and their long axis tends to be perpendicular to
the adjacent wall of the ventricle [544–546]), (b) their signal intensity
(subependymal hamartomas of tuberous sclerosis are usually isoin-
tense to hypointense compared to mature white matter [239,546], not
isointense with gray matter), and (c) the fact that they do not enhance
after intravenous infusion of paramagnetic contrast (239,544). PVNH
Barkovich_Chap05.indd 430
FIG. 5-72. Diffuse periventricular nodular
heterotopia associated with FLNA mutation. Sagittal
T1-weighted image (A) shows small cerebellar vermis
(white arrows) with enlarged pericerebellar cisterns.
Axial T2-weighted image (B) shows continuous het-
erotopia (white arrows) along the ventricular bodies,
while coronal T2-weighted image (C) shows hetero-
topia (white arrows) extending into white matter lat-
eral to ventricular bodies and temporal horns.
due to FLNA mutations vary in configuration depending on what
part of the FLNA protein the mutation affects and how severely pro-
tein function is impaired (533,543,547). Although most patients with
mutation of this gene show diffuse PVNH lining the walls of the bod-
ies of the lateral ventricles, some with local missense mutations may
show only a few bilateral peritrigonal PVNH (543). Familial heteroto-
pia also have an increased incidence of associated mega cisterna magna
(543,548,549).
PVNH can be identified by fetal MRI and fetal brain sonography
(550,551), appearing as nodules of gray matter intensity in the wall of
the lateral ventricle (Fig. 5-74). As in the postnatal diagnosis, they are
often associated with other anomalies such as mega cisterna magna,
cephalocele, or callosal anomalies. It may be difficult to differentiate
heterotopia from remaining areas of germinal matrix. In this regard,
it is important to remember that the germinal zone involutes early in
the posterior portions of the ventricles; therefore, residual nodules in
the walls of the trigones, a common location for PVNH (Fig. 5-74), are
likely to be heterotopia. If uncertain, a follow-up MR examination in
2 to 3 weeks may be useful.
5/6/2011 8:59:33 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 431

PVNH are sometimes associated with ventriculomegaly and, as a

result, affected fetuses may be detected as abnormal on routine fetal
sonography. More and more, these fetuses are referred for fetal MRI to
look for the cause of the ventricular enlargement (550). The walls of
the lateral ventricles should be closely scrutinized on all such studies
to look for nodules of gray matter intensity. The presence of associated
mega cisterna magna increases the likelihood of finding PVNH.
Rarely, periventricular heterotopia are smooth and linear, con-
forming to the contour of the wall of the lateral ventricle (Fig. 5-75).
The significance of these heterotopia and their relationship to PVNH
(or to band heterotopia) are unclear.

Focal Subcortical Heterotopia Focal subcortical heterotopia is the

FIG. 5-73. X-linked periventricular heterotopia in a male. Axial T2-
weighted image shows heterotopia (small black arrows) completely lining
the ventricles. Foci of dysmorphic cortex (large black arrows) are present.
name given to large, swirling, curvilinear masses of mixed gray mat-
ter and white matter, extending from cortex to ventricle, and often
containing blood vessels and CSF (possibly from subarachnoid space)
(528,552). Patients with focal subcortical heterotopia have variable
motor and intellectual disturbances, depending upon the volume and
the effect on the overlying cortex. Children with bilateral, large, thick
subcortical heterotopia present with moderate to severe developmental
delay and motor dysfunction. Those with large unilateral heterotopia
have hemiplegia and less severe (if any) mental retardation; children
with small or thin unilateral subcortical heterotopia may have normal
motor function and normal development (528,552). Almost all affected

FIG. 5-74. Fetal MRI of periventricular nodular hetero-

topia. Parasagittal (A), axial (B), and coronal (C) images
show the heterotopia (white arrows) as nodules of gray-
matter intensity protruding into the ventricular lumen.

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 432 Pediatric Neuroimaging

FIG. 5-75. Periventricular linear heterotopia. Coronal (A) and axial (B) images show a smooth, curvilinear layer of gray
matter (arrows) lining the walls of the lateral ventricles. The relationship of these linear heterotopia to nodular subependymal
heterotopia and to band heterotopia is unclear.

patients eventually develop epilepsy, usually during the first or second
decades (528,552). Some early reports suggested that surgical resection
may be useful in patients with subcortical heterotopia and medically
refractory epilepsy (553).
On neuroimaging, focal subcortical heterotopia appear as large,
somewhat heterogeneous masses that are isointense to cortical gray
matter on all sequences. They sometimes appear as multinodular gray
matter masses (Fig. 5-76) and other times appear to be composed of
swirling, curvilinear bands of gray matter (Fig. 5-77). The portion
of the hemisphere that is affected is almost always small compared
with the contralateral side, and the overlying cortex is thin with shal-
low sulci, often resembling PMG (Figs. 5-76 and 5-77). Subcortical
heterotopia may appear to exert mass effect on the adjacent ventricle
or the interhemispheric fissure (Fig. 5-77) and, thus, may be mistaken
for tumors. Further scrutiny of the images, however, will show that the
affected region of the hemisphere is small and that the apparent mass
effect is actually distortion of the hemisphere caused by the dysplasia.
Thus, heterotopia can be differentiated from tumors, which will enlarge
the affected hemisphere and, other than compression from mass effect,
has normal overlying cortex. Other important features in distinguishing
heterotopia from tumors are that heterotopia lack surrounding edema,
they remain isointense with gray matter on all imaging sequences and
with all imaging modalities, and they do not enhance after adminis-
tration of contrast agents (487,527,528). Associated brain anomalies

FIG. 5-76. Small area of subcortical heterotopia. Axial (A) and coronal (B) T1-weighted images show gray matter (black
arrows) extending from the wall of the trigone to areas of abnormal cortex (black arrowheads). The coronal image (B) shows
the multiple small nodules of gray matter that compose the lesion. Note that the affected portion of the hemisphere is small
and the overlying cortex has abnormal sulcation, both typical of subcortical heterotopia.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 433

FIG. 5-77. Large area of subcortical heterotopia. Axial (A) and coronal (B) T2-weighted images show large curvilinear,
swirling masses of gray matter (white arrows) extending from the ventricular surface to the cortex in the middle third
of the right cerebral hemisphere. The overlying cortex is thin and has areas of abnormally deep sulcation (white arrow-
heads). The affected hemisphere is small. (These images courtesy Dr. Gilbert Vezina, Washington, D.C.)

are common; callosal agenesis or hypogenesis is present in up to 70%, with an associated derangement of sulcation; in areas of PMG, no nor-
and the ipsilateral basal ganglia are dysmorphic in greater than 70% mal sulci are seen.
(552). Subcortical heterotopia will sometimes appear to contain ves- Patients with PMG may present with developmental delay, focal
sels or fluid, thereby mimicking tumors. Closer examination in these neurologic signs and symptoms, or epilepsy, depending upon the
cases will show that these are cerebrospinal fluid and vessels coursing portion(s) of brain involved (556). It may be associated with con-
inward from the cerebral cortex (528). The embryological mechanism genital infection (557,558) (also see Chapter 11), in utero ischemia
by which the CSF and vessels get into the center of the cerebral hemi- (559,560), or chromosomal mutations (many have been identified
sphere is unclear. [200,209,448,561–570]). No difference in neurologic manifestations
Occasionally, regions of heterotopia course radially through the has been detected in patients who have PMG due to different causes
cerebral mantle from the cortex to the ventricular surface (Fig. 5-78). (200,557,571,572). Affected patients may present at any age. The
These patients almost always come to medical attention because of severity of the clinical presentation depends upon the extent of corti-
epilepsy; occasionally, they have fixed neurological deficits as well, with cal involvement; bilateral involvement and involvement of more than
the type of deficit depending on the location of the lesion. These trans-
mantle heterotopia can be differentiated from closed lip schizencephaly
by the absence of a dimple at the ventricular surface, indicating the
absence of a cleft between two tightly apposed walls of a schizenceph-
alic cleft. The relationship of transmantle heterotopia to schizencephaly
and to transmantle dysplasias (FCD Type II) is being investigated.
No fetal diagnoses of subcortical heterotopia have been reported.
Marsh et al. (554) reported that proton spectroscopy of hetero-
topia shows elevated creatine and choline with normal NAA. Li et al.
(310) found that the NAA/Cr ratio is variable, ranging from normal to
low compared with age matched normal controls. In our limited expe-
rience, perfusion of heterotopia is similar to that of cerebral cortex.

Malformations Secondary to Abnormal Cortical Organization

and Late Migration
Polymicrogyria PMG is a malformation of cortical development in
which the process of normal cortical development is interrupted dur-
ing the late stages of neuronal migration and during the stages of corti-
cal organization. The result is the abnormal development of the deeper
layers of the cerebral cortex and the formation of multiple small gyri. FIG. 5-78. Transmantle heterotopia. Coronal 3D GRE image shows a linear
Thus, it is classified as a disorder of cortical organization (7). PMG has focus of gray matter (black arrows) extending from the cortex to the ventric-
a range of histologic appearances, all having in common a derange- ular surface. No dimple is seen at the ventricular surface to suggest the pres-
ment of the normal six-layered lamination of the cortex (190,336,555) ence of a cleft (which would be indicative of closed-lip schizencephaly).

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 434 Pediatric Neuroimaging
half of a single hemisphere are poor prognostic indicators, portending
moderate to severe developmental delay and significant motor dys-
function (572). The malformation may be focal, multifocal, or dif-
fuse; it may be unilateral, bilateral, and asymmetrical, or bilateral and
symmetrical. The Sylvian fissure is affected in 60% to 80% of cases
(556,573); however, any area, including the frontal, occipital, and
temporal lobes, can be involved (190,571–575). Associated brain mal-
formations are common and include corpus callosum agenesis and
hypogenesis, cerebellar hypoplasia (9), PVNH (531), and subcortical
heterotopia (576). Affected patients may be microcephalic, normo-
cephalic, or macrocephalic (200).
Imaging of Polymicrogyria PMG has a variable appearance on
MRI studies (577–579). The pattern depends partially upon the plane
of imaging, the thickness of the slices and the stage of myelination
of the brain at the time of the imaging study, but the variability also
reflects different morphologies of PMG (579). The most common
appearance is a slightly thick cortex with cortical surface an irregu-
larly bumpy outer and inner surface; high resolution images can some-
times resolve individual gyri in these cases (Fig. 5-79B). However, the
outer surface may be paradoxically smooth because the outer cortical
(molecular) layer fuses over the microsulci (Fig. 5-79A). The affected
cortex may appear thick and coarse (Fig. 5-79) or fine and delicate
(Figs. 5-80 and 5-81). When the microgyri are small, PMG may be
missed or misdiagnosed on routine spin-echo images. Images with
thin sections and optimal gray matter-white matter contrast (we use
volume 3DFT spoiled gradient acquisition [T1 weighted] and volume
3DFT fast spin-echo [T2-weighted] images, both with ≤1.5 mm parti-
tion size) are obtained. Evaluation in three planes is often necessary
to detect irregularities of the gray matter-white matter junction, which
are often the only evidence of dysmorphic brain (Fig. 5-81) (453). The
volume acquisitions can be displayed as 3D images and can be utilized
for stereotactic localization, aiding in surgical therapy, if appropriate.
The degree of myelination also has an effect on appearance. In unmy-
elinated regions, the polymicrogyric cortex looks thin (2–3 mm) and
bumpy, while in myelinated areas it looks thicker (5–8 mm) and rela-
tively smooth (577). The reason proposed for this is that a 4 to 5 mm
layer of gliotic white matter runs through the polymicrogyric cortex,
blending in with white matter in the unmyelinated brain and blend-
ing in with cortex after myelination (Fig. 5-82) (577). Whatever the
Barkovich_Chap05.indd 434
reason, it is important to realize that both of these cortical appearances
can be seen in patients with PMG.
Regions of PMG can be flat and congruent to the arc of normal
cortex (Fig. 5-79), or may extend centripetally, with the cortex appear-
ing as if it were buckled or folded inward (Figs. 5-82 and 5-83). The
infolding of cortex may be small or large; the character of the cortex
in these regions of infolding is similar to that in superficial PMG, with
bumpy, irregular inner and outer cortical surfaces. PMG may be unilat-
eral (∼40%) or bilateral (∼60%). As stated above, the cortex s urround-
ing the sylvian fissures is involved in up to 60% to 80% of cases, with
the frontal lobe being most commonly involved (∼70%), followed by
parietal (63%), temporal (38%), and occipital (7%) lobes (575). The
striate cortex, cingulate gyrus, hippocampus, and gyrus rectus are typi-
cally spared (575). Rarely, in less than 5% of affected patients, poly-
microgyric cortex will be calcified; this is likely dystrophic in nature,
related to prenatal injury or infection or, possibly, to repeated seizure
activity. Finally, it is important to realize that anomalous venous drain-
age is common in areas of dysplastic cortex (580), seen in up to 51%
(575). Large vessels are especially common in regions where there is a
large infolding of thickened cortex (Fig. 5-83). Such large vessels, when
seen in association with abnormal, thickened cortex, should not be
mistaken for vascular malformations. Angiography is not indicated.
On fetal MRI, PMG can be detected by the appearance of shal-
low sulci earlier than expected (Fig. 5-84, and see list of timing of nor-
mal sulcal development in Chapter 2) and in unexpected locations. In
our experience, this is the earliest finding of PMG; a previous injury
may have been detected at the site. Later in development, many small
gyri and sulci may be seen (Fig. 5-84). In bilateral PMG syndromes,
appearance of normal sulci is delayed and shallow abnormal sulci may
develop. The normal “squaring” of the sylvian fissure that normally
develops between about 21 and 24 gestational weeks (see Chapter 2)
does not occur if the sylvian region is affected by the PMG.
Syndromes Associated with Polymicrogyria
Bilateral Perisylvian Polymicrogyria. Several specific syndromes
are associated with cerebral PMG. Kuzniecky et al. first described the
syndrome of bilateral perisylvian PMG (also called congenital bilat-
eral perisylvian syndrome [581]), which is the most common PMG
syndrome. This syndrome may be sporadic or familial (564,582).
The inheritance patterns appear to be heterogeneous, suggesting that
FIG. 5-79. Coarse focal polymicrogyria. Axial
T2-weighted images show left posterior perisylvian
polymicrogyria extending from the insular cortex
posteriorly into the temporal operculum (white
arrows). Note how the high resolution images allow
resolution of some individual microgyri (white
arrowheads in B), but some microgyri are so closely
apposed that the cortex appears paradoxically
smooth (black arrowheads in A).
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 Chapter 5 • Congenital Malformations of the Brain and Skull 435

FIG. 5-80. Delicate focal polymicrogyria. A. Parasagittal

T1-weighted image shows thin, delicate PMG throughout the
lateral left frontal lobe. B and C. Axial T1-weighted (B) and
coronal T2-weighted (C) images show the delicate irregular-
ity of the individual gyri (white arrows) over the left frontal
convexity.

FIG. 5-81. Thin section axial T2-weighted image shows delicate polymicro-
gyria (arrows) localized to the right circular sulcus of an infant.

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 436 Pediatric Neuroimaging

FIG. 5-82. Evolution of MR appearance of polymicrogyria. A. Axial T2-weighted image at age 2 months. Polymicrogyria is seen in much of the right hemi-
sphere. In the right parietal infolding of cortex (white arrow), the undulation of the cortex can be seen. B. Axial T2-weighted image at age 10 months shows
increased myelination of the brain. The right parietal infolding (white arrow) of cortex now shows a linear hyperintensity near the cortical-white matter
junction. The undulation of the cortex is no longer apparent. C. Axial T2-weighted image at age 3 years shows the infolding (white arrow) to be composed
of apparently thickened cortex without obvious undulations.

FIG. 5-83. Infolding of polymicrogyria with anomalous venous

drainage. A. Parasagittal T1-weighted image shows infolding of
cortex (black arrows) in left posterior frontal lobe. B and C. Axial
precontrast and postcontrast T1-weighted images show large
venous structures (white arrows) draining from the abnormal
sulcus (black arrows).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 437

FIG. 5-84. Fetal MRI of polymicrogyria. Coronal image (A) at 23 gestational weeks shows small gyri (white arrows) in the right
frontal lobe; the anterior frontal lobe should be agyric at this age. Axial image (B) of another fetus at 31 weeks shows microgyri (white
arrows) over the left frontal convexity. Compare to normal gyri in the contralateral hemisphere.

mutations of several different genes can cause this malformation
(582); three locations (Xq21.33-q23 [SRPX2], 22q11.2, and Xq28) have
been identified (200,211,562,568). Sporadic cases with severe involve-
ment may present with a syndrome of developmental pseudobulbar
palsy (oropharyngeal dysfunction and dysarthria, 100%), epilepsy
(80%–90%), mental retardation (50%–80%), and, sometimes, congeni-
tal arthrogryposis (581,583–585). Less severely affected patients present
in infancy or early childhood with developmental delay (60%), poor pal-
atal function (40%), hypotonia (30%), arthrogryposis (30%), or motor
deficits (25%) (584,586); seizures (many clinical types) are present in
40% to 60% (584,586). Studies of familial cases of congenital bilateral
perisylvian PMG show a lower incidence of these clinical manifestations
(582,587), possibly because patients with minimal symptoms are more
readily identified and examined. Developmental reading disorder and
reading impairment without severe motor or cognitive handicap may
be the cause of seeking medical attention in this group (588).
MRI of bilateral perisylvian PMG typically has a coarse PMG
appearance, but the appearance of this malformation varies consider-
ably with severity. Bilateral perisylvian PMG can be graded according to
severity (with grade 1 the most severe and grade 4 the mildest) (587):
Grade 1, with perisylvian PMG extending to the frontal or occipital
pole (Fig. 5-85);
Grade 2, with PMG extending beyond the perisylvian region but not
to either pole (Fig. 5-86);
Grade 3, with PMG of the perisylvian region only (Fig. 5-87);
Grade 4, with PMG restricted to the posterior perisylvian regions.
Other Bilateral Polymicrogyria Syndromes. Other syndromes of
bilateral symmetrical PMG have been described (578). Several groups
have described bilateral symmetrical frontal polymicrogyria (Fig. 5-88)
(589). These patients typically present with spastic quadriparesis and

FIG. 5-85. Grade 1 bilateral perisyl-

vian polymicrogyria. Sagittal (A) and
axial (B) images show course poly-
microgyria centered in both sylvian
fissures and extending to the occipital
poles.

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 438 Pediatric Neuroimaging

FIG. 5-86. Grade 2 bilateral perisylvian polymicrogyria. Axial T2-weighted images (A and B) show extensive
coarse polymicrogyria centered in both sylvian fissures but sparing the frontal and occipital poles.

epilepsy. Guerrini et al. (574,590) have described patients with bilateral
medial parietaloccipital polymicrogyria (Fig. 5-89). The authors have
seen cases of bilateral lateral parietal PMG and many with combinations
of the above-mentioned patterns; thus, it appears that any region of cor-
tex may be involved by bilateral, symmetrical PMG (578). A syndrome
of congenital hemiplegia and epilepsy has been described in patients
with large areas of unilateral PMG (591). These patients typically pres-
ent in infancy with delayed motor development. A familial syndrome
of unilateral polymicrogyria has also been described (130). In contra-
distinction to the coarse pattern of PMG in bilateral perisylvian PMG,
bilateral frontal PMG and bilateral parasagittal parietooccipital PMG
have more delicate PMG patterns. A different imaging appearance is
seen in BFPP secondary to GPR56 mutations, which is better classified
as a malformation secondary to abnormal pial basement membrane
formation (405) and has been discussed in that section.
Epilepsy Syndromes Associated with Polymicrogyria. Epilepsy
syndromes can also be associated with PMG (571,572,574,583,592,593),
including Aicardi syndrome, which was discussed in section “Anom-
alies of the Cerebral Commissures” on callosal anomalies, oculo-
cerebral-cutaneous syndrome (Delleman syndrome [246,247], which
has frontal predominant PMG, PVNH, enlarged lateral ventricles or
hydrocephalus, agenesis of the corpus callosum sometimes associ-
ated with interhemispheric cysts, a large, dysplastic midbrain tectum,
absent cerebellar vermis, and small cerebellar hemisphere), DiGeorge
syndrome (also called the 22q11.2 deletion syndrome in which several

FIG. 5-87. Grade 3 bilateral perisylvian polymicrogyria. Axial T1-weighted images show the polymicrogyria
restricted to the sylvian fissures and immediate suprasylvian areas.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 439

FIG. 5-88. Bilateral frontal polymicrogyria.

Axial T1-weighted images show delicate poly-
microgyria (white arrows) extending through
the entirety of the frontal lobes.

genes are deleted resulting in cardiac, renal, and parathyroid anomalies
as well as right > left PMG [211]), and Warburg Micro syndrome
(microcephaly, microcornea, congenital cataract, mental retardation,
optic atrophy, and hypogenitalism with hypotonia, callosal hypo- or
agenesis, and frontoparietal PMG [268–270]). It is interesting to note
that the epileptogenic focus is typically not within the polymicrogyric
cortex itself, but in the cortex adjacent to the PMG, known as the para-
microgyral zone (594). Studies in laboratory animals show increases in
postsynaptic glutamate (excitatory) receptors and decreases in GABAA
(inhibitory) receptors in the paramicrogyric cortex (594), factors that
likely promote epileptogenesis. In addition, the polymicrogyric cortex
appears to have fewer axonal connections with the rest of the brain
(594). This lack of connections may be the reason why PMG cortex
does not function normally and why seizures emanate from the para-
microgyral zone instead of the dysplastic cortex itself.
Megalencephaly Syndromes with Polymicrogyria. A syndrome of
megalencephaly with polymicrogyria and hydrocephalus has been
described. Affected children present at birth or in early infancy with
macrocephaly and hypotonia, and show delayed motor and cogni-
tive development. Epilepsy, postaxial polydactyly, cutis marmorata,
midface capillary malformation, and coarse facial features are fre-
quently present (595–599). Imaging (Fig. 5-90) reveals ventriculo-
megaly (from progressive hydrocephalus) and PMG, which is most
severe in the perisylvian region (typically Grade 1 or 2). Progres-
sive tonsillar herniation often accompanies the progressive hydro-
cephalus (600); therefore, sequential MR studies may be indicated
(600). This disorder is now thought to include those previously
called megalencephaly-polymicrogyria-polydactyly-hydrocephalus
syndrome and macrocephaly capillary malformation syndromes
(597–599).

FIG. 5-89. Parasagittal parietooccipital polymicrogyria. Parasagittal (A) and axial (B) T1-weighted images show polymi-
crogyria (black arrows) coursing through the parasagittal parietal white matter.

Barkovich_Chap05.indd 439 5/6/2011 8:59:43 PM

 440 Pediatric Neuroimaging
FIG. 5-90. Megalencephaly with polymicrogyria and hydrocephalus in a 4-year-old with delayed development and
seizures. Sagittal T1-weighted image (A) shows enlarged third ventricle and pointed, herniating cerebellar tonsils. Axial
T2-weighted image (B) shows large lateral ventricles and perisylvian polymicrogyria (white arrows).
Megalencephaly, mega corpus callosum, and polymicrogyria
patients have large heads at birth and exhibit rapid head growth such
that they continue to increase relative to normals. In addition, they lack
motor and speech development and have a distinctive facies with frontal
bossing, a low nasal bridge, and large eyes (601). MRI shows bilateral,
symmetrical megalencephaly with a thick corpus callosum, increased
volume of white matter, wide sylvian fissures, and diffuse PMG.
Proton MR spectroscopy seems to be normal in regions of PMG
(310).
Schizencephaly Schizencephaly, sometimes called agenetic por-
encephaly, is the term used to describe gray-matter lined clefts that
extend through the entire cerebral mantle, from the ependymal lining
of the lateral ventricles to the pial covering of the cortex (602,603).
It is classified as a malformation due to abnormal cortical organiza-
tion (7) because it is known to be associated with vascular disrup-
tions and because an overwhelming number of cases seem to be
associated with PMG. Schizencephaly is a rare malformation, with
a population prevalence of approximately 1.5 per 100,000 popula-
tion (604). It is associated with young parental age (604). One third
of affected patients have a non-CNS abnormality, more than half of
which may be classified as secondary to vascular disruption, includ-
ing gastroschisis, bowel atresias, and amniotic band syndrome. Some
reported cases were associated with prenatal infection, while others
had chromosomal aneuploidy and still others were familial, suggest-
ing genetic causes, but no genetic locus was identified (605–608).
Although past reports suggested that the malformation may be asso-
ciated with mutations of the EMX2 homeobox gene, this association
was not verified and more recent studies have questioned it (609); no
genetic basis for familial schizencephaly has been found at the time
this chapter was written. Taken together, these observations suggest
that schizencephaly has heterogeneous causes, many of which include
vascular disruption (604).
Patients with schizencephaly typically present with seizures, hemi-
paresis, or variable developmental delay. The severity of the patients’
symptoms is related to the amount of involved brain (610–613). Those
patients with a single cleft with fused lips generally have epilepsy and,
perhaps, a mild hemiparesis but are otherwise developmentally normal.
Patients with unilateral clefts with separated lips usually present with
Barkovich_Chap05.indd 440
macrocephaly and hemiparesis, ultimately developing epilepsy (>80%)
and a mild to moderate developmental delay, depending upon the size
and location of the cleft within the brain (610,611,614). Patients with
bilateral clefts tend to be severely retarded with early onset of epilepsy,
severe motor anomalies, and, frequently, blindness (610–613). The
blindness probably results from optic nerve hypoplasia, which is seen
in up to one third of patients with schizencephaly (487,615–617). The
optic nerve hypoplasia, in conjunction with a high incidence of absence
of the septum pellucidum, results in the classification of many affected
patients in the category of septooptic dysplasia (later section of this
chapter) (616). Some authors have noted that epilepsy is less common
in bilateral than in unilateral schizencephaly (618). They speculate that
the bilateral clefts may impair spread of the epileptic discharges. How-
ever, most reports suggest that seizures begin earlier and have worse
outcome when clefts are bilateral (610,613).
For prognostic purposes, patients with schizencephaly are divided
into those with unilateral (∼60%) and bilateral clefts (∼40%). The
clefts are further divided into those with fused lips (15%–20%) and
those with separated (open) lips; those with separated lips are divided
into small clefts and large clefts (610,611,614,619). In the clefts with
fused lips, the walls appose one another directly, obliterating the CSF
space within the cleft at that point (Fig. 5-91). When the lips are sepa-
rated, CSF fills the cleft all the way from the lateral ventricle to the sub-
arachnoid spaces surrounding the hemispheres (Figs. 5-92 and 5-93)
(602,603,611,617).
On pathologic exam, the gray matter lining schizencephalic clefts
is dysmorphic and does not exhibit normal cortical lamination. The
clefts can be unilateral or bilateral and are most commonly located
near the precentral and postcentral gyri (4); in fact, the locations in
which they occur are nearly identical to those in which PMG occurs
(572,611).
Imaging studies of schizencephaly show a full thickness CSF-filled
cleft through the affected hemisphere; gray matter, typically charac-
terized by a bumpy outer surface and an irregular gray matter-white
matter junction (Fig. 5-92B), lines the cleft (487,488,611,613,617).
The appearance of schizencephaly on fetal MRI is identical to that on
postnatal MRI (Fig. 5-92A). Closed lip schizencephalies may look like
transmantle heterotopia if the walls of the cleft are fused through the
entire cortical mantle; indeed, transmantle heterotopia (Fig. 5-78) may
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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-91. Closed-lip schizencephaly. Coronal T1-weighted image shows
irregular gray matter extending from the cortex to the ventricular surface.
The lips of the cleft come in contact (white arrows) in only part of the
cleft.
Barkovich_Chap05.indd 441
441
be an extreme closed lip schizencephaly. Although any portion of the
brain can be involved, the frontal horns and the anterior aspects of
the temporal horns are relatively spared (619). When schizencephaly
is bilateral (40%–50%), clefts are nearly (but not exactly) symmetrical
in about 80% (Fig. 5-92), but the size may vary (Fig. 5-93); their loca-
tion is frontal or parietal in approximately 60% to 65% of cases, and
temporal or parietal in approximately 25% to 30%. The clefts are open
bilaterally in approximately 60%, closed bilaterally in approximately
20%, and closed on one side and open on the other in approximately
20% (610,611,619). When schizencephaly is unilateral (50%–60%), the
lips are open in about 65% and closed in about 35%; the location is
mid to posterior frontal or parietal in approximately 80%, temporal
in approximately 10%, and occipital in approximately 10% (610,611).
The gyral pattern of the cortex adjacent to the cleft is usually abnormal,
demonstrating sulci that radiate into the cleft. The gray matter lining
the cleft may extend into the ventricle and resemble PVNH (Fig. 5-92).
If the cleft has narrow open lips or closed lips, a dimple is usually seen
in the wall of the lateral ventricle where the cleft communicates (Fig.
5-91). The dimple is often a helpful sign of continuity of the cleft with
the ventricle when the lips of the cleft are fused and helps to differenti-
ate schizencephaly from transmantle heterotopia or deep infoldings of
PMG. Of note, clefts with fused lips might be missed if the imaging plane
FIG. 5-92. Bilateral open-lip schizencephaly with small
clefts. A. Coronal image of 22-week fetus shows bilateral
gray matter-lined clefts (arrows) and absence of the sep-
tum pellucidum. Note the CSF is continuous from the
subarachnoid space to the ventricle. B. Axial T2-weighted
postnatal image shows that the gray matter lining the
clefts is thick and irregular, suggesting polymicrogyria;
these can resemble periventricular nodular heteroto-
pia when they extend into the ventricle (black arrow-
head). The clefts (black arrows) are completely open.
Note expanded calvarium (e) overlying the large cleft.
C. Parasagittal T1-weighted image shows the superior-
to-inferior extend of the cleft (white arrows).
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 442 Pediatric Neuroimaging
FIG. 5-93. Coronal T2-weighted image shows bilateral schizencephaly
with large open clefts (white arrows). The black arrowhead points to a ven-
triculostomy catheter from a shunt.
is parallel to the plane of the cleft. For that reason, imaging should always
be performed in at least two planes (three planes is best) in patients
who present with seizures or developmental delay. Dysmorphic cere-
bral cortex, most likely PMG, may be present in a “mirror-image”
location in the hemisphere contralateral to a unilateral schizenceph-
aly, particularly when the schizencephaly is large and open-lipped
(Fig. 5-94) (572,611); thus, the contralateral hemisphere should always
be scrutinized. The septum pellucidum is absent in approximately 70%
of patients with schizencephaly and is almost always absent when the
clefts are bilateral and frontal; when unilateral, the septum is more
commonly absent when the cleft is open-lipped (Fig. 5-94) rather than
closed-lipped (620).
FIG. 5-94. Axial T2-weighted image shows a large open lip right hemi-
sphere schizencephaly (S) with expansion (black arrowheads) of the overly-
ing calvarium. Note an infolding of polymicrogyria (white arrows) in the
contralateral hemisphere.
Barkovich_Chap05.indd 442
The calvarium is often expanded over the opening of an open lip
schizencephaly (Figs. 5-92 and 5-94). The expansion may result from
longstanding CSF pulsations that emanate from the lateral ventricles
and propagate through the cleft. Another possible cause of calvarial
expansion relates to a thin membrane (the “roofing membrane”) that
overlies the cleft at the cerebral surface and separates the ventricular
CSF within the cleft from that in the overlying subarachnoid space
(619); this membrane may expand beyond the cortex, cause localized
pressure on the inner table of the calvarium and slowly expand the
calvarium. When plagiocephaly is severe, the insertion of a ventricu-
loperitoneal shunt may help to dampen the pulsations and partially
reverse the cranial asymmetry.
The appearance of schizencephaly on fetal MR is identical to that
on postnatal MR (Fig. 5-92A). Keep in mind that visualization of the
cerebrum in three planes is especially important when imaging the
small fetal brain.
Focal Cortical Dysplasia Without Dysmorphic Neurons (Minor
Malformations of Cortical Development, Focal Cortical Dyspla-
sia Types I, III) Focal cortical dysplasia without dysmorphic neurons
has been divided into three histological groups: mMCD, FCD Type
I, and FCD Type III (340,344,621). These groups have similar clini-
cal and imaging characteristics and can be considered together. Their
causes are unknown, but it is likely that many result from acquired
brain injuries (121), as Type I and mMCD are associated with a sig-
nificant incidence of prenatal and perinatal adverse events (suggesting
that they may be caused by such events [280]), whereas Type III are
associated with hippocampal sclerosis (FCD Type IIIa), epileptogenic
tumors (DNET and ganglioglioma, FCD Type IIIb), vascular malfor-
mations (FCD Type IIIc), or scarring from injury due to trauma, por-
encephaly, or encephalitis (FCD Type IIId) (for more information, see
[121,280,315,344,621] and references therein). These disorders tend
to present at older ages than FCD Type II (discussed in the section
“Malformations Secondary to Abnormal Stem Cell Proliferation or
Apoptosis” of this chapter), are more often found in adults, have lower
seizure frequencies, and are more commonly found in the temporal
lobe (315).
Type I FCDs can be considered a focal structural abnormality of
the cerebral cortex and, usually, the underlying white matter. Abnor-
mal neurons are not seen, although large pyramidal neurons may
be aberrantly positioned in upper cortical layers; neither balloon
cells nor dysplastic neurons are identified and abnormal cells do not
extend medially to the ventricular surface (338,340,344,353,622,623).
The structural abnormality may be predominantly radially oriented
(FCD Type Ia), horizontally oriented (FCD Type Ib), or both (FCD
Type Ic) (344). Patients with these types of FCD almost always
present with partial seizure disorders and normal neurologic exams
(315).
The MR appearance of Type I FCD is variable, suggesting that
this is a heterogeneous disorder. At least 50% of affected patients have
a normal initial MRI. When the MRI is abnormal, the most common
appearance is that of focal blurring of the cortical-white matter junc-
tion on T1- and T2-weighted images with FLAIR hyperintensity (Fig.
5-95) (280,340). Subcortical white matter may be isointense to cortex,
sometimes because the affected cortex is abnormally hypointense,
but other times (particularly in temporal lobe epilepsy) because the
white matter is abnormally hyperintense on FLAIR and T2-weighted
sequences. Some degree of volume loss (gray matter or white mat-
ter atrophy) is found in about half of affected patients (Fig. 5-96)
(280,315), possibly reflecting the previously mentioned history of
late prenatal or perinatal adverse events in some patients (FCD Type
IIId). As a result, the cortex may appear thin (Figs. 5-96 and 5-97);
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 Chapter 5 • Congenital Malformations of the Brain and Skull
indeed, thick cortex is unusual. The abnormality is typically subtle
and the MR scan may be initially interpreted as normal (280,315,624).
Careful evaluation with thin sections and optimal gray matter-white
matter contrast may be needed to show the focal cortical thinning or
blurring of the cortical-white matter junction (Figs. 5-96 and 5-97)
(354,625,626). FLAIR images with narrow windows may also be useful
to detect cortical or subcortical hyperintensity; if the brain is incom-
pletely myelinated, however, the abnormality is nearly impossible to
separate from immature white matter. Moreover, if dyslamination is
the only abnormality (this is technically an mMCD rather than FCD
Type I [342]), even high-resolution MRI may be completely normal
(624). The relative signal intensity of dysplastic cortex and underly-
ing white matter may change with age; therefore, serial MR studies
may be necessary to find the focus in young infants (627).
As mentioned above, FCD is often associated with other condi-
tions; these are now called FCD Type III (344). The best described of
these conditions are hippocampal sclerosis (FCD Type IIIa) (628,629),
neuronal-glial tumors (FCD Type IIIb, with dysembryoplastic neu-
roepithelial tumors [DNETs] [630,631] and gangliogliomas [632], see
Chapter 7), and glial scars (ischemic [633] or traumatic [634], FCD
Barkovich_Chap05.indd 443
443
FIG. 5-95. Type I focal cortical dysplasia. Coronal T1- (A)
and T2- (B) weighted images show a focal area of blur-
ring of the cortical-white matter junction (white arrows).
Coronal FLAIR image shows hyperintensity (white arrows)
at the cortical-white matter junction.
Type IIId) or vascular malformations (FCD Type IIIc) (344). Imaging
of FCD Type III may be seen as cortical thinning (FCD Type IIId, Fig.
5-96) or as T2/FLAIR hyperintensity of the white matter adjacent to
the hippocampal sclerosis (FCD Type IIIa, Fig. 5-98).
As mentioned in the opening paragraph of this section “Malforma-
tions of Cortical Development,” a number of papers have indicated that
functional imaging studies such as magnetic source imaging (MSI, which
is MEG coregistered to MRI), PET scanning, or SPECT scanning may be
useful in detecting small areas of FCD (284–289,293,295,304,313,624);
these studies are particularly useful for FCD Type I where the initial
MRI is often read as normal (315). As noted earlier, PET and SPECT are
nonspecific and correlative MRI is always needed. Our approach is to
use these other techniques in those patients who have some localization
to their seizure disorder or their EEG, but a normal initial MR scan. If
the PET study shows an area of hypometabolism or MSI shows local-
ized epileptic spikes, a high-resolution volumetric MR scan (see Chap-
ter 1 for technique) is performed to generate images in multiple planes
and is coregistered with the functional data for better anatomic local-
ization. The cortex in that area is then closely scrutinized on the MRI
for any abnormality of the cortical surface or gray-white junction.
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 444 Pediatric Neuroimaging

FIG. 5-96. Focal atrophy in Type I focal cortical dysplasia. Axial

T1-weighted image (A) shows thinning of the medial frontal cortex
(black arrows) and focal volume loss (note enlarged sulci). Coro-
nal T2-weighted image (B) better shows the volume loss and con-
firms cortical thinning (white arrows). Axial 18F-FDG PET image
(C) shows focally reduced uptake (white arrow) in the anterome-
dial frontal lobe and more generalized anterior frontal decreased
uptake (white arrowheads).

FIG. 5-97. Type I FCD can be extremely small and subtle, requiring thin section imaging in multiple planes. Axial T1 (A) and FLAIR (B) images
show focal blurring of the cortex-white matter junction at the fundus of the right superior frontal sulcus (arrows). Note that the cortex in the affected
area appears thin, with intensity similar to gray matter on the coronal T2-weighted image (C). This finding was missed on four previous MRI scans.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-98. FCD Type III is defined as focal cortical dysplasia adjacent to other epileptogenic pathology such as
hippocampal sclerosis, tumors, or vascular malformations. These coronal FLAIR images show abnormal hyper-
intensity of temporal white matter (white arrows in A and B) adjacent to a small, sclerotic hippocampus (white
arrowhead in B).
ANOMALIES OF VENTRAL
PROSENCEPHALON DEVELOPMENT
Holoprosencephaly
The holoprosencephalies are a group of disorders that are characterized
by a failure of differentiation and midline cleavage of the prosencepha-
lon. In the normal embryo, a single prosencephalic vesicle is established
at the rostral end of the neural tube between days 22 and 24 of gestation
by closure of the anterior neuropore. Fate maps of the early prosen-
cephalon show that regions that will become the future structures of
the prosencephalon (the deep gray nuclei, cerebral cortex, optic nerves,
olfactory regions, etc.) are already established before the neural tube
closes. Those structures that will normally form the most rostral medial
portions of the brain fail to form in holoprosencephaly (635). As a
result, the portions of the brain that are normally located more laterally
lie close to or within the midline and may remain unseparated across
the rostral midline of the brain. In these locations (most commonly
the anterior prosencephalon and the third ventricle), the interhemi-
spheric fissure fails to form and, as a result, the cerebrum fails to divide
into distinct cerebral hemispheres; in addition, the medial aspects of
the hemispheres have failed to form so the structures that are normally
positioned more laterally are in the midline, not separated from identi-
cal structures of the contralateral hemisphere. In mild cases, cells that
would normally be positioned slightly off of the midline are formed,
but lie closer to the midline than normal. In severe cases, all structures
normally destined to be anywhere close to the rostral midline remain
unformed and only a small ball of rostral telencephalic tissue forms. In
these very severe cases, the premaxillary segments of the face are not
induced to form, either, with the result being arrhinia, midline facial
clefts, and hypotelorism (with cyclopia in extreme cases).
Holoprosencephaly is caused by both teratogens and genetic fac-
tors (636). Holoprosencephaly can be seen in congenital anomaly syn-
dromes (Smith-Lemli-Opitz and Pallister-Hall syndromes are among
the best known); up to 45% of affected patients have clear cytogenetic
abnormalities such as Patau syndrome (trisomy 13), Edwards syn-
drome (trisomy 18, less common), and triploidy (637). Facial dys-
morphism, particularly hypotelorism and midline facial clefts, are
Barkovich_Chap05.indd 445
445
frequently seen in the more severe forms (638–641). The embryogenesis
of holoprosencephaly has not been clearly elucidated. Mutations of
at least ten different genetic loci have been implicated in the develop-
ment of familial holoprosencephaly: HPE1 on chromosome 21q22.3
(642); HPE2 (SIX3) on 2p21 (643); HPE3 (SHH) on 7q36 (644); HPE4
(TGIF) on 18p (636); and HPE5 (ZIC2) on 13q32 (645), HPE6 at 2q37
(646), HPE7 (PTCH1) at 9q22.3 (647), HPE8 at 14q13 (648), HPE9
(GLI12) at 2q14 (649). All of these genes seem to be involved in dorsal
or ventral induction of the prosencephalon. Additional chromosomal
regions (on chromosomes 1, 3, 5, 6, and 20) have been implicated, as
well (636), supporting the genetic heterogeneity of this disorder. Muta-
tions are found far less commonly in sporadic cases of HPE (636,650).
Familial cases of HPE are very heterogeneous; individuals carrying the
same mutation may range from very severe to clinically normal due to
the influence of environmental or teratogenic factors such as alcohol,
diabetes, cholesterol, retinoic acid, or modifier genes (651).
Mutations of human sonic hedgehog gene (SHH) at the HPE3 locus
(652), which cause an autosomal dominant form of holoprosencephaly
(653), have been studied most extensively (636,654). SHH is a protein
that has a role in maintenance of the notochord; as the notochord is
essential for the production of prechordal mesenchyme (the prechordal
plate) and induction of the ventral forebrain, this discovery supports
the concept that defects of dorso-ventral induction can cause holo-
prosencephaly. Also well-studied are mutations of dorsalizing factors
(chemicals that induce development of the dorsal midline, such as the
interhemispheric fissure and choroid plexuses) such as bone morpho-
genic proteins (BMPs) and the ZIC2 gene (645,655–657). Of note, both
overexpression of ventralizing factors and underexpression of dorsalizing
factors have been shown to impair dorsal induction (658). Indeed, vari-
ous mutations of ZIC2 are associated with all types of HPE: disturbances
of the BMP pathway and ZIC2 mutations that impair roof plate develop-
ment cause the MIH variant of HPE (67) (a disturbance of dorsal induc-
tion), while classic HPE is caused by different mutations of ZIC2 that
result in impaired formation of the prechordal plate (659) (a disturbance
of ventral induction). Thus, normal brain development results from a
balance of normal dorsalizing and ventralizing factors; HPE results from
disturbances of this balance in the developing prosencephalon.
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 446 Pediatric Neuroimaging
Clinical presentation depends upon the severity of the malforma-
tion. Severe cases are investigated at birth due to facial dysmorphism,
macrocephaly (from hydrocephalus), microcephaly, or neonatal
seizures. Less severe cases may be studied because of epilepsy, move-
ment disorder, or developmental delay.
DeMyer has divided holoprosencephaly into three subcategories in
which the most severe malformation affects the ventral prosencepha-
lon: alobar, semilobar, and lobar (640,641). These categories are useful
for classifying holoprosencephalies of different severities, (although
the divisions among these categories are far from distinct [635]).
MIH, also called syntelencephaly, is a variant in which the dorsal pros-
encephalon is more severely affected (66,660). The reader should be
aware, however, that the holoprosencephalies represent a continuum
of forebrain malformations, that no clear distinction among the dif-
ferent categories exists, and that other classification systems have been
suggested (66,616,635,638,640,641,660). Indeed, the authors have seen
a lack of cerebral hemispheric separation at nearly every location in the
telencephalon, as well as some that result in lack of separation of the
cerebellar hemispheres (rhombencephalosynapsis, section “Arrhinia/
Arrhinencephaly” of this chapter), as well.
Classic Holoprosencephaly
In classic holoprosencephaly, the most anterior, ventral aspects of the
prosencephalon (anterior frontal lobe, hypothalamus, caudate heads,
third ventricle) are most severely affected while the more posterior,
dorsal aspects (parietal and occipital lobes) are least affected.
Alobar Holoprosencephaly
Although alobar holoprosencephaly is the most common form of hol-
oprosencephaly diagnosed by prenatal ultrasound (661,662), affected
patients are rarely imaged postnatally by CT or MRI. This rarity prob-
ably stems from the fact that most affected infants are stillborn and
others have a very short life span (663). Alobar holoprosencephaly is
the most severe form of holoprosencephaly. Most affected children have
FIG. 5-99. Severe fetal alobar holoprosencephaly. Sagittal (A) and axial (B) fetal MRI at 22 weeks gestational age
show a small crescent of brain (white arrows) in the anterior calvarium, containing a large monoventricle (v) and
continuous with a large dorsal cyst (c).
Barkovich_Chap05.indd 446
severe neurologic disorders, manifesting seizures, abnormal neonatal
reflexes, and abnormalities of tone from the time of birth, in addition
to severe midline facial deformities and hypotelorism, resulting from
absence or hypoplasia of the premaxillary segment of the face. In the
extreme forms, the orbits and globes are fused, resulting in cyclopia
(664,665).
Imaging studies are severely abnormal, as well. In affected patients,
the ventral medial portions of the brain (the anterior, inferior parts of
the frontal lobes, caudates, hypothalami, and the basal ganglia) and
face (nasal bones, medial aspects of maxilla, ethmoids, and vomer)
never form. As a result, the hypothalami and basal ganglia are fused and
reduced in volume and the third ventricle is absent (Fig. 5-99) (635). No
interhemispheric fissure, falx cerebri, or corpus callosum can be identi-
fied. Most commonly, the cerebrum is composed of a pancake-like mass
of tissue in the rostral-most portion of the calvarium. No sylvian fis-
sures can be identified in most cases and, when present, these fissures
lie in the most anterior portion of the brain close to the midline (666).
A crescent shaped holoventricle (i.e., no septum pellucidum or third
ventricle) is continuous with a large dorsal cyst, which usually occupies
most of the volume of the calvarium (Fig. 5-99). Alobar HPE is easily
recognized on fetal MRI or sonography by the absence of the septum
pellucidum and absent interhemispheric fissure (Fig. 5-99A and B). The
vascular supply to the cerebrum consists of multiple small vessels aris-
ing directly from the internal carotid and basilar arteries. In less severe
cases, discrete anterior and middle cerebral arteries may be identified.
The anterior cerebral arteries in these cases are nearly always azygous,
with a single arterial trunk supplying branches to the midline sections
of the brain.
Semilobar Holoprosencephaly
In the semilobar form of holoprosencephaly, the brain is more devel-
oped than in the alobar form and the facial anomalies are mild or absent.
Affected children may be referred for microcephaly, macrocephaly
(usually associated with a dorsal cyst), or developmental delay. Motor
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 Chapter 5 • Congenital Malformations of the Brain and Skull 447

FIG. 5-99. (Continued) Sagittal (C), coronal (D), and axial (E) postnatal
images show similar findings, with the exception that some sulcation has
occurred in the cerebral cortex. Note the small, fused mass of deep gray
matter in the ventral midline of (D).

abnormalities typically consist of upper extremity choreoathetosis and
lower extremity spasticity (667,668).
Imaging studies reveal that the interhemispheric fissure and
falx cerebri are partially formed posteriorly; however, the anterior
(frontal) regions of the brain remain continuous across the midline
and underdeveloped (Figs. 5-100 to 5-102). Rudimentary temporal
horn formation is seen, although the hippocampus is incompletely
formed (Fig. 5-100). The septum pellucidum is absent in all forms of
holoprosencephaly. The frontal lobes are poorly developed and the
sylvian fissures are positioned abnormally anteriorly in the cerebrum
(Figs. 5-101 and 5-102) (666). The callosal splenium is present with-
out a callosal body or genu in many patients with semilobar holo-
prosencephaly (Figs. 5-102) (57,63,638). Holoprosencephaly is the
only brain anomaly described in which the posterior corpus callosum
forms in the absence of any anterior callosal formation. As the spec-
trum of holoprosencephaly is observed from the most poorly differ-
entiated alobar brain to the most differentiated lobar brain, we see a
gradient of development in which the separation of the hemispheres,
development of the falx cerebri, and development of the cerebral
hemispheres progress from the occipital pole to the frontal pole of
the cerebrum. The anterior extent of corpus callosum development
correlates with the anterior extent of interhemispheric fissure forma-
tion (65). Because the severity of classic holoprosencephaly is related
to how completely the ventral/anterior (hypothalamus and low fron-
tal) regions of the brain are developed, the anterior extent of callosal
formation, which reflects the anterior extent of cerebral develop-
ment, can be used as an approximate marker of brain development
in holoprosencephalic patients. In other words, the further anterior
the corpus forms, the better developed the brain. The deep cerebral
nuclei are typically partially separated, but the hypothalami, caudate
heads, and thalami remain partly unseparated, resulting in a small
third ventricle (Figs. 5-101 and 5-102). In the most severe cases, the
central gray matter may be significantly reduced in volume and fused
into a mass (Fig. 5-100) (635).

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 448 Pediatric Neuroimaging

FIG. 5-100. Severe semilobar holoprosencephaly with thalamic fusion and dorsal cyst.
Midline sagittal transfontanelle sonogram (A) shows an abnormal gyral pattern, presence
of a callosal splenium (small white arrows), and a moderate-sized dorsal cyst (large white
arrows). Note that p denotes posterior and a denotes anterior. Coronal transfontanelle image
(B) through the anterior cerebrum shows a large gray matter mass (white arrows) consisting
of fused thalami and basal ganglia. No interhemispheric fissure or ventricle is present at this
level. Coronal transfontanelle image more posteriorly (C) shows the central gray matter mass
separating the lateral ventricles. A rudimentary interhemispheric fissure (open white arrows)
is present. Axial noncontrast CT image (D) shows the central gray matter mass separating
rudimentary temporal horns. No interhemispheric fissure is seen. CT image at a higher level
(E) shows the relationship of the dorsal cyst (white arrows) to the lateral ventricles. Axial
T1-weighted images (F and G) after shunting of the cyst shows the brain with the appearance
of a ball.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
On fetal MRI, semilobar holoprosencephaly is identified better if
the fetus is more mature; 20 weeks is too early to see the absence of the
anterior portions of the corpus callosum and the lack of separation
of the anterior-ventral cerebral hemispheres, but these features and
the small frontal lobes may be detected by 23 weeks (Fig. 5-102A–C).
Absence of the septum pellucidum may not be identified unless the
ventricles are enlarged.
Dorsal cysts are sometimes seen in semilobar holoprosencephaly,
almost always when thalamic fusion is present (Figs. 5-100 and 5-101)
(669). In all likelihood, a combination of thalamic fusion and aqueduc-
tal dysgenesis prevents egress of CSF into the fourth ventricle in these
patients; the dorsal cyst thus represents a dilated pineal or suprapineal
recess of the fourth ventricle. After shunting of the cyst, the brain takes
on the appearance of a ball (Fig. 5-100) (638–641,670). Myelination is
typically delayed (671).
Lobar Holoprosencephaly
Patients with lobar holoprosencephaly have less severe clinical mani-
festations than do patients with alobar or semilobar holoprosen-
cephaly. Affected patients typically present with mild or moderate
developmental delay, hypothalamic-pituitary dysfunction, or visual
problems (667,668). Some patients are initially classified as having
“cerebral palsy.” The point at which a brain is identified as being lobar,
in contrast to semilobar, holoprosencephaly is poorly defined. The
frontal lobes are more fully developed than in semilobar holoprosen-
cephaly; as a result, frontal horns of the lateral ventricles are present
(although they may be dysmorphic) and the sylvian fissures may look
normal or nearly normal (666). The deep cerebral nuclei are nearly
completely formed (Fig. 5-103) (635). In these patients, the inter-
hemispheric fissure and falx cerebri extend into the frontal area of
the brain, although the anterior falx may be hypoplastic. The septum
pellucidum is absent, even in mild cases (Fig. 5-104). The hippocampi
are normal or nearly normal and the temporal horns and third ven-
tricles are better defined than in the semilobar brains (638–641,670).
Thus, as a general rule, if the third ventricle is fully formed, some frontal
Barkovich_Chap05.indd 449
449
FIG. 5-100. (Continued)
horn formation is present, and the posterior half of the callosal body is
formed (in addition to the splenium), holoprosencephaly can be classified
as lobar (Fig. 5-104).
As the abnormalities in lobar holoprosencephaly are rather subtle
and are confined to the ventral/anterior portions of the cerebrum, this
diagnosis is difficult on fetal MRI unless thin (3 mm), high quality
coronal images are obtained through the anterior portions of the cere-
brum to identify the abnormal configuration of the frontal horns of
the lateral ventricles, absence of the septum pellucidum and the lack of
separation of the ventral portions of the frontal lobes and hypothala-
mus (Fig. 5-103).
Syntelencephaly (Middle Interhemispheric Variant)
In some patients, the interhemispheric fissure is formed in the anterior
frontal and in the occipital lobes, but the hemispheres are fused in the
posterior frontal and parietal regions (66). This condition is called MIH
variant of HPE or syntelencephaly. This malformation also seems to
result from a defect in dorsal-ventral induction of the telencephalon, but
in MIH, the problem is reduced induction of the dorsal midline struc-
tures (67,660) (in contrast to classic HPE in which ventral induction is
reduced). Indeed, animal models suggest that failed induction of the roof
plate leads to MIH, possibly as a result of reduced ZIC2 function (ZIC2
is a zinc finger gene that is expressed in the dorsal and ventral midline
of the developing embryo) or focally increased BMP expression (BMP is
involved in dorso-ventral induction of the embryo) (67). Patients are less
severely affected clinically than in semilobar or alobar holoprosenceph-
aly, usually manifesting mild to moderate cognitive impairment, appen-
dicular spasticity, and mild visual impairment (66,672). Choreiform
movements and hypothalamic insufficiency, present in most patients
with classic holoprosencephaly, are conspicuously missing from patients
with MIH (668). Facial features include normal interocular distance, or
even hypertelorism, and a broad, flat nose rather than hypotelorism as
in classic HPE (655). Most patients are microcephalic.
Imaging in MIH shows normal appearing basal forebrain with
normal basal ganglia and olfactory sulci, and normal appearing
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 450 Pediatric Neuroimaging

FIG. 5-101. Moderately severe semilobar holoprosencephaly.

Sagittal T1-weighted image (A) shows large dorsal cyst with cerebel-
lum inferiorly displaced and compressed. Axial T2-weighted images
(B and C) show that the sylvian fissures (small white arrows) are
abnormally anterior and medially rotated and the frontal lobes are
small. No interhemispheric fissure is present anteriorly. The basal
ganglia and thalami are small and nonseparated in the midline,
resulting in a small third ventricle. At a higher level (C), a crescentic
monventricle has no septum pellucidum.

anterior interhemispheric fissure. The anterior falx cerebri may be

normal or slightly hypoplastic. In the posterior frontal or parietal
lobes however, the interhemispheric fissure and falx become dysplas-
tic and then disappear as the two hemispheres become continuous
across the midline (Fig. 5-105). Sometimes sulci (typically extensions
of the sylvian fissures) are continuous or nearly continuous across
the midline, as well (Fig. 5-105D). We have seen one case of MIH
associated with an occipital cephalocele. Fetal MRI of MIH shows
absence of the septum pellucidum, absence of the body of the corpus
callosum, and lack of separation of the cerebral hemispheres in the
posterior frontal and anterior parietal lobes (Fig. 5-106) (673). This
is one of the few conditions in which the callosal genu and splenium
are formed in the absence of the callosal body (see section “Anomalies
of the Cerebral Commissures” on Callosal Anomalies earlier in this
chapter and Fig. 5-105A).
Arrhinia/Arrhinencephaly
Absence of the olfactory lobe of the brain, a condition known as arrhi-
nencephaly, may be isolated or may be associated with anomalies of
the base of the brain and midline structures of the face (absence of the
nose itself is known as arrhinia) (4). The olfactory sulci and olfactory
bulbs are invariably absent or dysplastic in these cases. In the fetus,
olfactory sulci begin to develop at about the 16th gestational week.
The sulci are just lateral and parallel to the interhemispheric fissure.
They remain shallow until 28 to 30 weeks, when they begin to deepen
from posterior to anterior. They can currently be identified by fetal
MRI by about the 30th gestational week (Fig. 5-107A and B) (674). The
olfactory bulbs lie just above the cribriform plates, where they receive
olfactory nerves from the nasal cavities. They lead into the thinner
olfactory tracts, which conduct the axons of the secondary olfactory

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 Chapter 5 • Congenital Malformations of the Brain and Skull 451

FIG. 5-102. Relatively mild semilobar holoprosencephaly. A. Midline

sagittal image from fetal MRI shows the presence of a posterior inter-
hemispheric fissure and posterior corpus callosum (white arrows). No
CSF is seen in the anterior midline of the cerebrum. B and C. Axial (B)
and coronal (C) images from fetal MRI show only a very rudimentary
interhemispheric fissure (black arrows) in the anterior cerebrum. Syl-
vian fissures (white arrowheads in B) are rotated anteriorly. No discrete
basal ganglia are seen. D. Midline sagittal T1-weighted postnatal image
from a different patient shows small frontal lobes and the presence of
only a posterior corpus callosum (black arrows). E. Axial T2-weighted
image shows larger, better separated basal ganglia with a tiny remnant
of anterior third ventricle (white arrowhead). Sylvian fissures (white
arrows) are abnormally anterior and medially rotated.

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 452 Pediatric Neuroimaging

FIG. 5-103. Prenatal and postnatal MR images of a patient with severe

lobar holoprosencephaly. A. Coronal image of a 30-week fetus immediately
anterior the frontal horns of the lateral ventricles shows a rudimentary
interhemispheric fissure (black arrows, note also the absence of an anterior
falx cerebri) dorsally and lack of separation of the cerebral hemispheres
ventrally. B. Axial image shows dysmorphic frontal horns (arrows) and
shallow anterior interhemispheric fissure. C. Postnatal axial T2-weighted
image shows the dysmorphic frontal horns (white arrows), shallow anterior
interhemispheric fissure, and azygous anterior cerebral artery (black arrow).
Note the caudate heads (c) touching in the midline, a finding more common
in semilobar HPE. This illustrates the lack of clear differentiation among the
subtypes of holoprosencephaly.

FIG. 5-104. Mild lobar holoprosencephaly. Midline sagittal T1-weighted image (A) shows the anterior corpus callosum terminating at the superior genu
(black arrow), with absence of the inferior genu and rostrum. Axial T1-weighted image (B) shows continuity of the caudates across the midline (white
arrow). Note also mild hypotelorism. Coronal T1-weighted image (C) shows very narrow frontal horns of the lateral ventricle without septum pellucidum
and lack of separation of the walls of the hypothalamus (white arrows).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 453

FIG. 5-105. Middle interhemispheric variant of holoprosencephaly. Sagittal T1-weighted image (A) shows the presence of a
callosal splenium (white arrows) and genu (white arrowhead) without intervening callosal body. Coronal T2-weighted image
(B) shows continuity of the posterior frontal lobes across the midline without intervening interhemispheric fissure. Note char-
acteristic gray matter (white arrow) on the surface of the narrow, nonseparated lateral ventricles. Axial T2-weighted images
(C and D) show an anterior and posterior interhemispheric fissure with absent interhemispheric fissure in the posterior frontal
lobes. Sylvian fissures, which appear nearly normal in (C), continue upward to meet over the cerebral hemispheres (white
arrows in D).

neurons in the lateral, intermediate, and medial olfactory striae to their
specific terminations within the olfactory cortex. Although the olfac-
tory bulbs can be first identified by histology at Carnegie stage 18 (44th
day of development), they cannot be identified by fetal MRI until after
30 weeks because of their small size and the current limits of technol-
ogy (674). They are best identified postnatally by thin section (3 mm
or less) coronal T2-weighted images (Fig. 5-107C), where they are seen
to undergo a characteristic maturation pattern (675).
Arrhinencephaly is typically associated with multiple congeni-
tal anomalies, with cleft lip, cleft palate, hypoplasia/absence of the
nose and nasal cavity, and holoprosencephaly being the most com-
mon (676). Olfactory agenesis has been reported in 23% of patients
with CHARGE association (coloboma, heart disease, choanal atresia,
retarded growth and mental development, genital anomalies, and
ear malformation) in an autopsy series (677) and small olfactory
bulbs with shallow olfactory sulci were seen in all ten patients in
a series studied by MRI (678). Ocular anomalies (hypertelorism,
microphthalmia, and iris colobomas) (679) and other developmental
anomalies of the nose and paranasal sinuses (680) may be seen as
well. Arrhinencephaly is most likely the result of either a severe focal
injury in utero or mutation of a gene involved in early development
of the rostroventral prosencephalon. When multiple anomalies are
present, the condition is usually diagnosed in early infancy. In the
rare cases when the disorder of the olfactory apparatus is isolated,
the anomaly may remain cryptic until the child’s absence of olfactory
sensation is discovered.

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 454 Pediatric Neuroimaging
It is important to specifically look at the olfactory structures and
the midline structures of the brain in any patient with abnormalities
of olfaction or midline facial anomalies, particularly if the CHARGE
association is suspected, as this finding strongly supports the diagno-
sis. Indeed, neuroimaging studies are usually performed in patients
with facial anomalies primarily to assess associated anomalies of the
brain; therefore, MRI is the study of choice. On CT, arrhinia shows
variably severe absence of the nose and nasal cavity, with a high
arched hard palate and absence of the nasal bones (Fig. 5-108) (681).
In milder cases, congenital nasal pyriform aperture stenosis or choa-
nal atresia may be present, just as they may be present in holoprosen-
cephaly (682,683). MRI typically shows arrhinencephaly as absence of
the olfactory sulci, olfactory bulbs, and olfactory tracts (Fig. 5-108A)
(684). Anomalies of the hypothalamic-pituitary axis (HPA), corpus
callosum, and ventral forebrain are the most common associated find-
ings. When anosmia or hyposmia is associated with hypogonadotropic
hypogonadism, the diagnosis of Kallmann syndrome should be con-
sidered (see section “Anomalies of the Hypothalamic-Pituitary Axis”
later in this chapter).
Barkovich_Chap05.indd 454
FIG. 5-106. Middle interhemispheric variant of
holoprosencephaly, fetal MRI. Inferior axial image
(A) shows absence of the septum pellucidum and
presence of anterior and posterior interhemispheric
fissures. More superior image (B) shows continuity
of the hemispheres across the midline (white arrows).
Coronal image (C) confirms continuity of the hemi-
spheres across the posterior frontal midline.
Septooptic Dysplasia
Septooptic dysplasia, as described by de Morsier in 1956, consisted
of two major findings: hypoplasia of the optic nerves and hypoplasia
or absence of the septum pellucidum (685). It is currently considered
to be a heterogeneous disorder loosely defined by any combination
of optic nerve hypoplasia, pituitary gland hypoplasia, and midline
abnormalities of the ventral or rostral cerebrum (686). In all prob-
ability, the “syndrome” of septooptic dysplasia is the end result of
several different genetic abnormalities (primarily abnormal expres-
sion of genes in the ventral and rostral prosencephalon) and in utero
injuries (616,687–690). One family with septooptic dysplasia and
several individuals with a sporadic form of the syndrome have been
shown to have mutations in a gene called HESX1, which is produced
by tissue adjacent to the developing prosencephalon and is located at
chromosome 3p21.1–3p21.2 (686,691,692). This location suggests that
proper induction of the prosencephalic midline depends upon HESX1
expression, and supports the concept of an overlap of these patients
with those manifesting holoprosencephaly. HESX1 is also produced
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 Chapter 5 • Congenital Malformations of the Brain and Skull
(at a later stage of development) by Rathke pouch primordium, a fact
that possibly explains the observed hypopituitarism of many affected
patients (693). More recently, duplications of SOX3 and mutations of
SOX2 and SOX3, transcription factors involved in pituitary develop-
ment, have been implicated in the etiology of SOD (694).
Approximately, two thirds of patients with SOD have hypo-
thalamic-pituitary dysfunction (695–699); indeed, some authors
(particularly endocrinologists) consider it an essential part of the syn-
drome. The clinical presentation is variable, as expected from a het-
erogeneous disorder. Visual symptoms may include nystagmus and
diminished visual acuity; however, patients can have normal vision
(696). Occasionally, hypotelorism is present. When hypothalamic-
pituitary dysfunction is present, it is usually manifested as growth
retardation secondary to deficient secretion of growth hormone
and thyroid stimulating hormone (695,698,699). The diagnosis of
septooptic dysplasia is made by ophthalmological examination in
Barkovich_Chap05.indd 455
455
FIG. 5-107. Normal olfactory apparatus on MRI.
Axial (A) and coronal (B) scans of 30-week fetus show
the olfactory sulci (white arrows) between the gyrus
rectus and medial olfactory gyrus. Because they form
from posterior to anterior, they are seen earliest just
anterior to the suprasellar cistern (A). Olfactory bulbs
are not seen in the fetus. On postnatal scans (C), both
the olfactory bulbs (white arrows just above the cribri-
form plate) and olfactory sulci (white arrowheads) are
easily seen on coronal T2-weighted images.
conjunction with neuroimaging. When hypoplasia of the optic discs
is seen in association with partial or complete absence of the septum
pellucidum, the diagnosis is established.
Imaging studies show hypoplasia or complete absence of the
septum pellucidum, resulting in box-like frontal horns (Fig. 5-109)
(616,639,700,701). Patients with complete septal absence have a higher
incidence of hypothalamic-pituitary dysfunction and worse neurologi-
cal and developmental outcome than those with partial septal absence
(702). The absence of the septum can often be identified on the sagittal
image by the low position of the fornices (Fig. 5-109A). High qual-
ity, thin section coronal MR images allow confirmation of the absent
septum and facilitate the diagnosis of hypoplasia of the optic nerves
in severe cases (Fig. 5-109C). However, determining mild hypoplasia
of the optic nerves, chiasm and tracts by neuroimaging is extremely
difficult; in fact, optic nerve hypoplasia is recognized on neuroimag-
ing studies in only about 50% of affected patients (616). Severe optic
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 456 Pediatric Neuroimaging
nerve hypoplasia is best identified on sagittal and coronal, rather than
axial, MR images; bulbous dilatation of the anterior recess of the third
ventricle and a large suprasellar cistern may be associated. Of note,
patients with unilateral optic nerve hypoplasia uncommonly have
brain anomalies other than minor pituitary pathology (Fig. 5-109)
(702). Brodsky et al. (687) showed that patients with neuroradiologic
findings limited to isolated optic nerve hypoplasia or optic nerve hyp-
oplasia in conjunction with partial or complete absence of the sep-
tum seem to have a good developmental prognosis, whereas those
with hemispheric anomalies or posterior pituitary ectopia have more
guarded prognoses. Another study showed that 49% of patients with
optic nerve hypoplasia have an abnormal septum pellucidum, while
64% have a hypothalamic-pituitary abnormality (703). Patients with
Barkovich_Chap05.indd 456
FIG. 5-108. Arrhinia with arrhinen-
cephaly. Coronal T1-weighted image
(A) shows absence of the olfactory
sulcus and bulbs. Axial CT image
(B) shows that the nasal cavity is
absent. Oblique view of 3D reforma-
tion (C) shows absence of the nasal
bones. (This case courtesy Clark Car-
roll, MD.)
normal septum and HPA on MRI had normal endocrine function,
22% of those with abnormal septum and normal HPA had abnormal
endocrine function, 35% of those with normal septum and abnormal
HPA had abnormal endocrine function, and 56% of those with abnor-
mal septum and HPA had abnormal endocrine function. Therefore,
MR evaluation of the septum pellucidum and HPA may be useful to
predict the likely spectrum of endocrinopathy (703).
Several distinct MR subgroups have been identified in patients
with septooptic dysplasia (616,687). One group shows a high incidence
of malformations of cortical development (especially schizencephaly,
PMG, and gray matter heterotopia [616,687,702]) and partial absence
of the septum pellucidum (Fig. 5-110); these patients are often found
to have incomplete rotation of the hippocampi, as well (702). The
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 Chapter 5 • Congenital Malformations of the Brain and Skull
finding of hippocampal anomalies is strongly associated with callosal
anomalies and neurologic/developmental difficulties (702). Small optic
nerves in this group may be the result of transsynaptic degeneration of
the optic nerves secondary to prenatal destruction/hypogenesis of the
optic radiations. A second group has findings of complete absence of
the septum pellucidum and hypoplasia of the cerebral white matter,
often resulting in ventriculomegaly, but normal cerebral cortex. Some
patients in this second subset have hypoplasia of the anterior falx cere-
bri or the genu of the corpus callosum (Fig. 5-111), compatible with
impaired induction of the rostral end of the neural tube, in addition to
the ventral region where the hypothalamus is generated. Some patients
(perhaps a third subset) with septooptic dysplasia have posterior pitu-
itary ectopia (Fig. 5-109) (687,704) and a fourth subset likely includes
those in the family described by Dattani et al. (686,691), who have
hypogenesis of the corpus callosum.
Isolated Absence of the Septum Pellucidum
Isolated absence of the septum pellucidum is a relatively rare struc-
tural anomaly that may have no neurologic manifestations. However,
Barkovich_Chap05.indd 457
457
FIG. 5-109. Septooptic dysplasia with ectopic posterior pituitary
lobe. Sagittal T1-weighted image (A) shows the hyperintense pos-
terior pituitary lobe (white arrow) at the median eminence of
the hypothalamus instead of in the sella turcica. The fornices
(white arrowheads) are too low, suggesting absence of the septum
pellucidum. Coronal T1-weighted image (B) confirms absence of
the septum and the presence of an ectopic posterior pituitary (white
arrow). More anterior coronal STIR image (C) shows a hypoplastic
right optic nerve (white arrow).
neurologic deficits are present in the majority of patients with appar-
ently isolated absence of the septum (705). Because isolated septal
agenesis is rare, the brain should be carefully scrutinized for associated
anomalies when the septum is absent. Abnormalities associated with
septal absence include holoprosencephaly, callosal agenesis, septooptic
dysplasia, schizencephaly, bilateral PMG, malformations secondary to
abnormal pial basement membrane formation such as WWS and MEB,
chronic severe hydrocephalus, hypothalamic-pituitary anomalies, and
Chiari II malformations (260,575,701,705).
Anomalies of the Hypothalamic-Pituitary Axis
Abnormalities of the pituitary gland are often visible by MRI. The pitu-
itary gland may be too small or it may be enlarged by congenital cysts
(cysts are discussed in Chapter 7); the posterior pituitary gland (some-
times referred to as the pituitary “bright spot” for its hyperintense signal
on T1-weighted MR images) may be absent or ectopic (in the pituitary
stalk or in the hypothalamus proper at the median eminence); or, very
rarely, the pituitary gland and stalk may be duplicated or even tripli-
cated. Abnormalities of the hypothalamus are more difficult to detect
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 458 Pediatric Neuroimaging

FIG. 5-110. Septooptic dysplasia with schizencephaly. Coronal SPGR T1-weighted images show hypopla-
sia of the left intracranial optic nerve (black arrow in A) and, more posteriorly, bilateral schizencephalies
(white arrows in B).

by imaging, as it is difficult to differentiate the hypothalamus from
surrounding structures, even with very thin section coronal images, and
it is so small that subtle anomalies are difficult to appreciate. Nonethe-
less, developmental hypothalamic abnormalities, such as hamartomas
(discussed in Chapter 7) or lack of midline separation, may occasion-
ally be detected if the region is carefully scrutinized. A basic under-
standing of the embryology of the region facilitates an understanding
of hypothalamic and pituitary anomalies.
Embryology
Between 28 and 32 days of embryonic life, a shallow vesicle known
as Rathke pouch or Rathke cleft appears on the roof of the foregut,
immediately rostral to the notochord. Traditionally, Rathke pouch has
been considered to arise from the buccal cavity; however, recent evi-
dence supports origin from neuroectoderm, along the anterior neural
ridge (706). Whatever the origin, Rathke pouch contacts and comes to
lie anterior to a downward extension of the embryonic hypothalamus
known as the neurohypophysis, or posterior pituitary lobe (Fig. 5-112).
The connection of Rathke pouch with the buccal cavity then undergoes
obliteration, although portions of it may persist as the craniopharyn-
geal canal or as nests of ectopic pituitary tissue in the nasopharynx
or sphenoid sinus. After its connection to the buccal cavity is obliter-
ated between 42 and 44 days of gestational age, Rathke pouch becomes
known as the adenohypophysis, or anterior pituitary lobe (707,708).
The molecular biology of this transition has been elucidated and is
nicely reviewed in several publications (709,710).
Between 37 and 42 days gestational age, lateral lobes form in the
developing adenohypophysis. These lobes, known as the tuberal pro-
cesses, will differentiate into the pars tuberalis. Between 42 and 44 days,
the tuberal processes surround the infundibulum and developing

FIG. 5-111. Septooptic dysplasia with dysgenesis of the corpus callosum. Sagittal T1-weighted image (A) shows lack or formation of the
callosal genu despite a normal appearing body and splenium. Coronal T1-weighted image (B) shows absence of the septum pellucidum and
hypoplasia of the left optic nerve (black arrow).

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 Chapter 5 • Congenital Malformations of the Brain and Skull
neurohypophysis laterally and give some definition to the developing
hypophysis. Between 44 and 48 gestational days, the midline anterior-
lobe cells that are in close proximity to the posterior lobe differentiate
into the primordium of the pars intermedia. All of the components of
the mature HPA are now in place by day 49 and will slowly evolve into
the mature system (707,708).
Functional specialization of the pituitary gland involves the for-
mation of the portal circulatory system and differentiation of hor-
mone-secreting cells. It is postulated that this differentiation requires
directed contact of the gland with the hypothalamus (711). The genetic
basis of pituitary cell differentiation is being established and seems to
involve transient signaling gradients that induce nuclear genes to pro-
duce mediators that lead to cell specification (712). These mediators
include numerous transcription factors acting as repressors or activa-
tors, and associated coregulators that arise from the adenohypophysis
and neighboring structures (709,710,713). Details of these factors are
beyond the scope of this book. Suffice it to say that mutations of certain
genes that are important in pituitary development cause fairly specific
deficiencies in anterior and posterior pituitary development as well as
development of other brain and visceral structures (713).
The development of the hypothalamus is not as well understood.
It is clear that hypothalamic cells are generated in the floor plate of
the developing neural tube very early in the region of Henson node,
then move rostrally under the influence of the prechordal plate and its
secreted proteins such as SHH (714). Therefore, disorders that result
from abnormal induction of the ventral midline forebrain, such as hol-
oprosencephaly, nearly always result in abnormalities of the hypothal-
amus and abnormal hypothalamic function (715). In addition, some
hypothalamic cells migrate to the hypothalamus from other regions of
the developing embryo (716). Therefore disorders of cell migration can
also lead to hypothalamic dysfunction. From an imaging perspective,
the important point is to evaluate the hypothalamus, in addition to the
pituitary gland, with thin section, T1- and T2-weighted images in all
patients with hypothalamic-pituitary dysfunction.
Pituitary Absence, Hypoplasia, and Duplication
Absence or hypoplasia of the pituitary gland is a rare anomaly that
involves absence or hypoplasia of both the anterior and posterior lobes
and, in many cases, the pituitary stalk (717); this disorder is nearly always
fatal at birth. Commonly associated anomalies include hypoplasia
Barkovich_Chap05.indd 459
459
FIG. 5-112. Formation of the pituitary gland. A. Between 28
and 32 days of embryonic life Rathke pouch (RP) appears on
the roof of the foregut, immediately rostral to the notochord.
Rathke pouch contacts, and comes to lie anterior to a downward
extension of the embryonic hypothalamus known as the neuro-
hypophysis, or posterior pituitary lobe (nh). B. The connection
of Rathke pouch with the buccal cavity undergoes obliteration
between 42 and 44 days gestational age, at which time Rathke
pouch becomes known as the adenohypophysis, or anterior
pituitary lobe (ah). C. Between 44 and 48 gestational days, the
midline anterior lobe cells that are in close approximation to
the posterior lobe differentiate into the primordium of the pars
intermedia (pi). All of the components of the mature hypotha-
lamic-pituitary axis are now in place and will slowly evolve into
the mature system.
of the adrenal glands, thyroid, testes, ovaries, and penis. The sella is
small and flat, and sometimes is covered by a layer of dura. Pituitary
hypoplasia (Fig. 5-113) is much more common than aplasia; more
importantly, affected patients can survive with hormonal replacement
therapy (717,718). These patients may have short stature as a result of
deficiency of growth hormone and, therefore, fall into the category of
pituitary dwarfism (see next section). Mutations of a number of differ-
ent genes have been discovered to cause pituitary hypoplasia, with vari-
able types of inheritance and different specifics regarding the effects
upon production of specific hormones and development of the ante-
rior and posterior lobes of the pituitary (713,719).
Very rarely, the hypothalamus and pituitary gland may be dupli-
cated (Fig. 5-114), or even triplicated (720); other anomalies of the
face and brain are nearly always present (721–723). The most common
of these are facial dysmorphism (ranging from hypertelorism to facial
clefting), anomalies of the tongue, cleft palate, pharyngeal teratomas,
agenesis of the corpus callosum, anomalies of the circle of Willis (par-
ticularly partial fenestration of the basilar artery [724]), and anoma-
lies of the olfactory bulbs and tracts (722,723). Delayed or precocious
puberty may be found in affected patients (725).
Pituitary Dwarfism
Pituitary dwarfism is composed of a heterogeneous group of disorders,
all caused by growth hormone deficiency and characterized by short
stature, slow growth, defective dentition, and delayed skeletal matura-
tion. Males are affected two to three times as commonly as females.
The hormonal deficiency may be limited to growth hormone, or may
involve multiple adenohypophyseal and neurohypophyseal hormones.
This diagnosis is suspected if a patient is exceptionally short for age
according to standard growth charts, is growing poorly for age without
evidence of any other disorder, or has short stature and any signs or
symptoms of CNS abnormality (726,727). A number of familial and
genetic causes of isolated growth hormone deficiency and combined
pituitary hormone deficiencies (CPHD) have been described (713,728),
but these are rarely found in clinical practice (713,729).
Imaging studies show a range of features, including a small sella
turcica and anterior pituitary lobe (Fig. 5-113), hypoplasia or absence of
the pituitary stalk, and presence of the high signal intensity neurohypo-
physis (posterior lobe) in the infundibulum or at the median eminence
of the hypothalamus (“ectopic bright spot”) (Fig. 5-115) (730–733).
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 460 Pediatric Neuroimaging

FIG. 5-113. Severe anterior pituitary hypoplasia. Sagittal (A) and coronal (B) T1-weighted images show a tiny anterior pituitary
lobe (white arrow), which is smaller than the hyperintense posterior pituitary.

FIG. 5-114. Pituitary duplication. Sagittal T1-weighted image (A) shows an abnor-
mally thick floor (open white arrows) of the third ventricle. Coronal T1-weighted
images show a thick bar of gray matter at the floor of the third ventricle with two pitu-
itary stalks (small white arrows in B) exiting from it and two separate pituitary glands
(black arrows in C).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 461

FIG. 5-115. Anterior pituitary hypoplasia with ectopic posterior pituitary lobe. Sagittal and axial T1-weighted images show
a small infundibulum (not visible), small anterior pituitary lobe, and ectopic posterior pituitary lobe at the median eminence
of the hypothalamus (white arrow). Such patients commonly have other anomalies such as absent corpus callosum, and large
anterior commissure (white arrowhead).

Only about 40% of patients with pituitary dwarfism will have the full
spectrum of hypothalamic-pituitary imaging features; those patients
with the full spectrum are likely to have multiple hormone deficien-
cies (CPHD) and lower levels of growth hormone (727,731,732). Post
contrast thin section MRI will not visualize the pituitary stalk in such
patients and the ectopic posterior pituitary gland will be located in the
median eminence (Fig. 5-115) (733). Conversely, MR scans of patients
with isolated growth hormone deficiency are more likely to have a nor-
mal sized adenohypophysis and a visible infundibulum than those with
multiple hormonal deficiencies (733,734); the ectopic posterior pitu-
itary gland will typically be found along the pituitary stalk (Fig. 5-116).
This less severe anomaly is sometimes called “partial” pituitary ectopia
(733). When complete posterior pituitary ectopia (posterior pituitary
located within the median eminence of the hypothalamus) is pres-
ent, patients have a higher incidence of CPHD (49%), breech delivery
(32%) and associated brain and skull base anomalies (12%) (727,735),
including callosal anomalies (Fig. 5-115), optic nerve hypoplasia, and
PVNH (529,713,719).
Although most patients with CPHD present in the neonatal period
and have a very small pituitary gland, patients with homozygous or
compound heterozygous mutations of the PROP1 gene present with
profound growth retardation in childhood (736). PROP1 is a transcrip-
tion factor whose expression leads to normal development of pituitary
gonadotropes, somatotropes, lactotropes, and thyrotropes. Inactivating
mutations lead to deficiencies in luteinizing and follicle-stimulating
hormones, growth hormone, prolactin, and thyroid stimulating

FIG. 5-116. “Partial” posterior pituitary ectopia. Postcontrast sagittal (A) and noncontrast coronal (B) T1-weighted
images show a large posterior pituitary gland (white arrows) that is located along the intact pituitary stalk. The anterior
pituitary gland is normal in size for a young child. No other anomalies were identified.

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 462 Pediatric Neuroimaging

hormone. Mutations of PROP1 seem to account for about 40% of
cases of CPHD (737–739). In contrast to most types of CPHD, which
are characterized by a small gland and small sella turcica, imaging of
CPHD patients with PROP1 mutations is characterized by enlargement
of the pituitary gland, with intrinsic T1 hyperintensity and marked T2
hypointensity of the anterior pituitary lobe (740,741).
Kallmann Syndrome (Hypogonadotropic
Hypogonadism)
Kallmann syndrome (OMIM 308700) (742) is a genetically heteroge-
neous disorder of neuronal migration in which olfactory cells and cells
that normally express luteinizing hormone releasing hormone fail to
migrate from the olfactory placode into the forebrain. Normally, both
of these cell types originate in the olfactory placode (in the nasal fossa)
and migrate superiorly and anteriorly along olfactory axons toward the
developing cerebral hemispheres (716). The migration is facilitated by
the recognition of specific neural-cell adhesion molecules on the sur-
face of cells along the pathway of migration (743,744). In X-linked Kall-
mann syndrome (OMIM 147950), the KAL1 gene (at Xp22.3), which
encodes a small extracellular matrix protein that presumably acts as a
permissive substrate for outgrowth of olfactory axons (50), is deleted;
as a result, the cells generated in the olfactory placode remain in the
nasal cavity (745). In autosomal dominant Kallmann syndrome, the
cause is a loss of function mutation of the gene for fibroblast growth
factor receptor 1 (FGFR1 [also called KAL2], located at chromosome
8p11.2-p11.1 [746]). FGFR1 mutations appear to cause about 10% of
Kallmann syndrome cases by impairing formation of gonadotropin
releasing hormone (747). (Of interest, gain of function mutations of
FGFR1 cause craniosynostosis; see later section of this chapter.) Other
genes causing Kallmann syndrome include PROKR2 at chromosome
20p13 (KAL3, OMIM 244200 [748]), PROK2 at chromosome 3p21.1
(KAL4, OMIM 610628 [748]), CHD7 at chromosome 8q12.1 (KAL5,
OMIM 612370 [749]), and FGF8 at chromosome 10q24 (KAL6, OMIM
612702 [750]).
Patients with Kallmann syndrome typically present with anosmia
or hyposmia and, in older children, with hypogonadism. Occasionally,
renal anomalies, cleft palate, and dental agenesis may be associated
(751). Establishing the proper diagnosis is important, as hormonal
treatments can restore reproductive function and patients can lead
relatively normal lifestyles (752). MRI can be important in establish-
ing the diagnosis (684), as it allows assessment of the formation of the
olfactory sulcus and bulbs, which are hypoplastic or absent in Kall-
mann syndrome. Although axial images can suggest the absence of the
olfactory sulcus (684,753), coronal scans, particularly thin section T2
RARE (FSE/TSE) images, will show the anatomy more definitively (Fig.
5-117). These observations can be made on fetal MRI, as well, if high
quality coronal images are obtained. If the hypothalamic hypofunc-
tion is severe, sagittal images may show a small pituitary gland (Fig.
5-117A). One should also look for associated cleft palate, dental agen-
esis, or renal anomalies (728).
Hypothalamic Dysgenesis
As stated in the introduction of this section, hypothalamic anomalies
are difficult to detect by MRI because the hypothalamus is so small and
is difficult to differentiate from surrounding structures. When patients
have abnormalities of hypothalamic function (usually manifested as
diabetes insipidus) or abnormal levels of the hormones produced in
the hypothalamus (usually releasing factors for pituitary hormones),
we typically look for either atrophy (presumably secondary to prior
injury) of the hypothalamus (typically manifested as asymmetric
enlargement of the anterior third ventricle), tumor of the suprasellar/
third ventricle region (see Chapter 7), or lack of normal development
of the hypothalamic/suprasellar structures. In terms of malformations,
we particularly scrutinize the optic chiasm to see that it is normally
formed and separated from the hypothalamus, and the walls of the
anterior third ventricle to make sure they are completely separated
(Fig. 5-118). The neurohypophysis should be evaluated as well to
ensure that its migration to the sella turcica has not been arrested at
the median eminence or in the pituitary stalk (719).
Anomalies of the Eyes
Embryology of the Eye and Orbit
At about the 22nd postconceptional day, the lateral walls of the dien-
cephalic portion of the (still open) neural tube take the shape of two
broad and shallow concavities; these are the incipient optic vesicles

FIG. 5-117. Kallmann Syndrome. Sagittal T1-weighted image shows

pituitary hypoplasia (white arrowheads) and small corpus callosum.
Coronal T1-weighted (B) and T2-weighted (C) images show absence of
the normal olfactory sulci separating the gyri recti from the medial orbital
gyri. Coronal T2-weighted image (D) shows normal olfactory sulci (white
arrowheads) and bulbs (arrows) for comparison.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 463

FIG. 5-117. (Continued)

FIG. 5-118. Hypothalamic anomaly in a child with hypotha-

lamic dysfunction. Sagittal T1-weighted image (A) shows hypo-
genesis of the corpus callosum (white arrows) without a visible
third ventricle, anterior commissure, or posterior commissure.
The pituitary gland looks normal. A small region of ectopic pos-
terior pituitary gland (white arrowhead) is visible at the median
eminence. Coronal T1-weighted image (B) shows a thick, asym-
metric (to the right side) optic chiasm (white arrowheads).
Coronal T2-weighted image (C) shows lack or separation of the
hypothalami resulting in continuity of the hypothalamic gray
matter across the midline (black arrows) and obliteration of the
anterior third ventricle.

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 464 Pediatric Neuroimaging

FIG. 5-119. Development of the eye. A. During the early fourth fetal week, the optic vesicle (OV) evagi-
nates from the diencephalic forebrain wall (FW) toward the lens placode (LP), which is a focal thickening
of ectoderm. As the ectoderm thickens, the optic vesicle becomes indented. B. Later in the fourth week, the
optic vesicle becomes cup-shaped (OC) under the continued influence of the lens placode. At the same
time, a second invagination occurs, forming a groove (the optic fetal fissure, OFF) running from the devel-
oping cup posteriorly to the forebrain wall. C. By the end of the fourth week, the optic cup invaginates such
that the sector that was closest to the ectoderm, the incipient retina (neuroretinal layer, NRL), has doubled
back against the incipient pigment epithelium (pigment layer, PL). These are still separated by the optic
ventricle (V), which is in communication with the third ventricle through the optic stalk (OS). The lens
vesicle (LV) has almost completely budded off of the ectoderm at this time.

(Fig. 5-119). Under the influence of the optic vesicle, the overlying
ectoderm begins to thicken to form the lens plate. The lens plate also
influences the development of the optic vesicle, resulting in thickening of
the underlying neural tissue that is destined to become the neural retinal
layer. Late in the fourth gestational week, the optic vesicle invaginates
to form the optic cup and the lens plate extends into the hollow of the
cup. At the same time, a second invagination occurs to form a groove
running lengthwise along the ventral aspect of the optic cup; this is
the optic fetal fissure, also called the choroidal fissure (Fig. 5-119).
Mesenchyme will migrate through this fissure to form the primary vit-
reous and the hyaloid artery. The optic cup invaginates deeply such
that the sector of its wall that was closest to the surface ectoderm at
the vesicle stage (that portion destined to become the neural retinal
layer) becomes doubled back against the sector that will become the
pigment epithelium (Fig. 5-119C). The pigment epithelium will ulti-
mately differentiate into rods, cones, and ganglion cells. A cup-shaped,
CSF-containing slit develops between the incipient neural retinal and
pigment epithelium layers (Fig. 5-119C), remaining continuous with
the third ventricle. During the fifth and early sixth gestational week,
the apposed margins of the fetal optic fissure fuse so that the site at
which the initial retinal axons had passed from the vitreal surface into
the fetal fissure becomes enclosed within the retina as the optic nerve
head. The axon bundles from the developing neural retinal layer run
within the thinner, more posterior aspect of the fetal fissure known
as the optic stalk; these will develop into the optic nerve. In the sev-
enth gestational week, the margin of the optic cup grows forward and
encloses the anterior portion of the lens to form the ciliary body. Later,
the optic cup extends even farther forward to form the epithelium of
the iris. A mass of cells that bud off from the iris will differentiate into
the pupilloconstrictor and pupillodilator muscles (25,754–756). The
genetics of ocular development are complex but are slowly being elu-
cidated; currently, however, the mechanisms by which mutations cause
ocular anomalies are unclear (757–759).
Ocular Malformations
As the genetic basis of ocular malformations remains unclear at this
time, these malformations are most easily classified by differentiating
them into anophthalmia, microphthalmic malformations, and mac-
rophthalmic malformations. Ocular anomalies associated with specific
syndromes, such as Trisomy 13, septooptic dysplasia, WWS, MEB, and
the phakomatoses, are discussed in the sections and chapters on those
specific disorders.
Anophthalmia
The term anophthalmia refers to congenital absence of one or both
eyes. Some authors contend that true primary anophthalmia is incom-
patible with life and that the condition seen in live newborns is best
termed extreme microphthalmia or clinical anophthalmia (760,761).
We will use the term for any condition where no ocular globe or optic
nerve is identified. It can be divided into two major forms. Primary
anophthalmia, in which the ocular primordia never form, is very rare
and is probably the result of a mutation of genes that are important in
the development of the optic vesicle. The gene most strongly linked
to anophthalmia is SOX2 at chromosome 3q26.3-q27, mutations of
which have been shown to account for 10% to 20% of severe bilateral
anophthalmia/microphthalmia (762); affected infants commonly have

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-120. Anophthalmia. Axial T1-weighted image shows neither optic
nerves nor globes. Extraocular muscles are identified.
associated esophageal atresia, vertebral segmentation anomalies, facial
dysmorphisms, and anomalies of male genitalia (759,761). Mutations
of OTX2 on chromosome 14q22 and RAX on chromosome 18q21.3
have also been associated with primary anophthalmia (757,759). With
either cause, the brain (and in particular the “visual cortex”) appears
normal (763). Secondary anophthalmia is more common and is gen-
erally related to infection (such as rubella), trauma, vascular events,
toxic/metabolic events (hypervitaminosis or hypovitaminosis A), or
exposure to toxins occurring during the early part of the fourth ges-
tational week (764). In true anophthalmia (primary or secondary),
imaging shows that neither the optic nerves nor the globes are present
(Fig. 5-120). Extraocular muscles, the lachrymal apparatus, and blood
vessels may be identified.
Microphthalmic Malformations
Microphthalmia refers to a condition in which the eye is abnormally
small. It can be unilateral or bilateral and may result from a number of
different processes. Primary microphthalmia is a finding in many syn-
dromes (765); it can be the result of primary ocular hypoplasia, ocular
coloboma, PHPV, congenital infections (most commonly rubella, see
Chapter 11), chromosomal disorders (most commonly trisomy 13,
FIG. 5-121. Colobomas. Axial T2-weighted image (A) shows a small left coloboma (white arrows) with the posterior midline wall of the globe
being posteriorly displaced. Axial T1-weighted image (B) shows a large right retrobulbar cyst (large black arrows), extending posteriorly from a
small colobomatous globe (small black arrows). The contralateral (left) globe has been previously treated for retinal dysplasia.
Barkovich_Chap05.indd 465
465
but also mutations of SOX2, PAX6, CHD7, PAX2, SIX3, HESX1, SHH,
SIX6, RAX, and BCOR [757–759,765]), and inborn errors of metabo-
lism (most commonly Lowe syndrome, see Chapter 3). In children,
secondary microphthalmia is most commonly the result of retinopa-
thy of prematurity (ROP), ocular infection, or prenatal toxin exposure
(760,764,765); the imaging findings in secondary microphthalmia are
nonspecific, consisting of small ocular globe with small optic nerve.
Those conditions with specific imaging findings will be discussed in
some detail.
Colobomas Coloboma is the name give to a fissure or discontinuity
in any ocular structure; the most typical form is that resulting from
failure of the choroidal fissure to close properly (760); mutations of
many genes have been implicated in their formation, the two best char-
acterized being PAX6 at 11p13 (766) and GDF6 at 8q21.2-q22.1 (767).
Ocular colobomas are fairly common, often bilateral, and are usually
mild (the most common form is located in the inferior temporal aspect
of the iris and is cryptic to imaging); as a result, imaging studies of
most patients with colobomas are normal (768,769). They are asso-
ciated with many brain malformation syndromes, including Joubert
syndrome (JS), Aicardi syndrome, and WWS (769). Two variants of
colobomas have rather typical imaging findings. The morning glory
syndrome (named for the characteristic ophthalmoscopic appearance)
is a coloboma that affects the optic nerve at the optic disc; the syn-
drome is commonly associated with brain anomalies such as callosal
agenesis and basilar encephaloceles (770). Imaging studies have a char-
acteristic appearance in which a section of retina at the site of the optic
nerve head is displaced posteriorly (Fig. 5-121). The displaced por-
tion may be rectangular or cone-shaped. Contiguous retrobulbar cysts
may be present (Fig. 5-121B) (770). Coloboma with cyst (also called
microphthalmia with cyst) is a malformation caused by extensive pro-
liferation of the embryonic retina with consequent separation of the
inner and outer retinal layers (760,771). The walls of these cysts may
fuse with the wall of the globe to create a continuity of the cyst with
the vitreous cavity (Fig. 5-121B); large cysts, therefore, may be associ-
ated with extrusion of vitreous humor into the cyst and consequent
diminished size and displacement of the globe (Fig. 5-122). Indeed,
large cysts may be larger than the globe itself (Figs. 5-121B and 5-122)
and may cause proptosis (Fig. 5-122). The globe can be differentiated
from the cyst by the presence of a lens. Imaging studies will often dem-
onstrate continuity of the globe and the retrobulbar cyst, confirming
the diagnosis and aiding differentiation from other conditions (768).
Persistent Hyperplastic Primary Vitreous PHPV is a malformation
that is caused by a failure of regression of the fibrovascular tissue of the
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 466 Pediatric Neuroimaging
FIG. 5-122. Coloboma with cyst (microphthalmia with cyst). The large
cyst (large white arrows) is in continuity with the vitreous cavity (small
white arrows), which can be identified by the presence of the lens (white
arrowhead). The large size of the cyst has resulted in proptosis.
primary vitreous and of the hyaloid artery, which delivers blood to the
primary vitreous and the developing lens (760,772). The embryonic
intraocular vascular system is composed of two components: an ante-
rior system near the iris and a posterior retrolental system within the
vitreous. Persistence of these vessels often results in vascular prolifera-
tion, which can cause PHPV in the anterior or posterior segments of
Barkovich_Chap05.indd 466
the eye. In either case, patients typically present at birth or during the
first months after birth with microphthalmia, leukocoria (white pupil),
and congenital cataract (764,772). Indeed, PHPV is the second most
common cause of leukocoria (after retinoblastoma, see Chapter 7),
accounting for 20% to 25% of cases (773). Both autosomal domi-
nant (OMIM 611308) and recessive (OMIM 611311) forms have been
described. Most cases are unilateral, although bilateral PHPV is much
more common when associated with Norrie disease, WWS, and other
neurologic and systemic abnormalities (774).
Pathologically, patients with anterior PHPV have a shallow ante-
rior chamber, enlarged vessels in the iris, and a retrolental fibrovascular
membrane. Cataracts and intralenticular hemorrhage usually develop,
and the latter may lead to glaucoma. When posterior PHPV is present,
a fibrovascular stalk is seen traversing the globe from the optic nerve to
the posterior lens along a remnant of the hyaloid canal (Cloquet canal).
This is associated with elongation of the ciliary processes, dysplasia of
the optic disc, an indistinct macula and, sometimes, retinal folds. The
stalk may exert traction on the retina, resulting in retinal detachment
and subretinal hemorrhage. Malformations of the optic nerve and
retina are common (774,775).
The diagnosis can be made with any imaging modality. Ocular
ultrasound shows an echogenic mass of variable size posterior to the
lens; a hyperechoic band extends from the posterior surface of the
mass to the posterior pole of the globe. Doppler imaging will shows
flow within this band, representing persistence of the hyaloid artery
in Cloquet canal. Retinal detachment may be seen as a curvilinear,
echogenic structure within the anechoic vitreous (776). CT of PHPV
shows microphthalmia and portions or all of a vertical septum (the
hyaloid artery running through Cloquet canal) extending from the
head of the optic nerve to the site of the primary vitreous (immedi-
ately behind the lens) (Fig. 5-123) (772,777). A generalized increase in
attenuation of the vitreous is sometimes present. It is also important
FIG. 5-123. Persistent hyperplastic primary vitreous. Axial contrast-en-
hanced CT (A), contrast-enhanced, fat-suppressed T1-weighted MRI (B),
and axial fat-suppressed T2-weighted MRI (C) show a small left globe with
abnormal vitreal signal, an abnormally shaped lens, and abnormal struc-
ture located behind the lens (the persistent primary vitreous, black arrows)
and a tract (black arrowheads) extending from the lens to the optic nerve
head (seen best on MRI).
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 Chapter 5 • Congenital Malformations of the Brain and Skull
to confirm that no calcium is present within the globe; this confirms
that the leukocoria is not the result of a retinoblastoma (see Chapter
7). MRI better shows a variably enhancing mass located behind the
lens, Cloquet canal, the abnormal lens, elongated ciliary processes, and
associated retinal detachment with subretinal hemorrhage (Figs. 5-123
and 5-49) (776–778). Moreover, MRI does not result in exposure of
the developing eyes to ionizing radiation. At UCSF, MRI is typically
performed if ocular ultrasound strongly suggests either retinoblastoma
or PHPV; CT is still used for equivocal cases.
Retinopathy of Prematurity ROP is mentioned here primarily
because it is still occasionally seen in pediatric practices, and it should
not be mistaken for other disorders. ROP is caused by the vasocon-
strictive effect of high blood levels of oxygen (fortunately, the use of
antenatal steroids has markedly reduced the incidence of lung disease
associated with prematurity). The vasoconstriction results in chronic
retinal ischemia, which, in turn, causes neovascularization. The neo-
vascularization and its subsequent regression cause subretinal exuda-
tion, hemorrhage, and scarring; both the scarring and the subretinal
exudate may result in chronic retinal detachment and, eventually,
microphthalmia.
Imaging studies show changes that are nearly always bilateral but
often asymmetrical. Microphthalmia is always bilateral and, therefore,
may be difficult to appreciate; clinical history of prematurity should
always be sought when bilateral chronic retinal detachment is present.
Retinal detachment is more common in the temporal portions of the
globe. If retinal detachment is acute, subretinal fluid will be of high
attenuation on CT due to the presence of acute hemorrhage. Calci-
fication is rare and is seen only in long standing disease (779). MRI
will show high signal intensity on T1-weighted images and low signal
intensity on T2- and T2*-weighted images. More chronic detachment
will show low attenuation subretinal fluid on CT, intermediate to low
signal intensity on T1-weighted MR images and variable intensity on
T2 and gradient-echo images depending upon the amount of deoxyhe-
moglobin remaining (see [780] and Chapter 4). Scarring in the poste-
rior vitreous may be difficult to separate from retinoblastoma by MRI.
Ocular ultrasound is the study of choice to differentiate the noncalci-
fied scar of ROP from the calcified retinoblastoma (calcification causes
acoustic shadowing). Most important is a history of premature birth
with associated lung disease. If no history is available, look for bilat-
erality of the disease, microphthalmia, and the frequently associated
finding of brain injury secondary to prematurity (see Chapter 4); if
these findings are present, the abnormality will nearly always be ROP.
Macrophthalmia
Macrophthalmia refers to a condition in which the eye is abnormally
large. It is less common than microphthalmia and is usually the result of
congenital glaucoma (also called buphthalmos) secondary to increased
resistance to resorption of aqueous humor (781). The normal sagittal
diameter of the neonatal globe is 16 to 17 mm, increasing to 22.5 to 23
mm by age 3 years and then to 24 mm by age 13 years; it remains stable
in size thereafter (782). In congenital glaucoma, the flow of aqueous
humor from the anterior chamber is obstructed; as a result the anterior
chamber is enlarged from its normal depth of 3 mm (783). Congeni-
tal glaucoma may be an isolated finding (autosomal recessive primary
congenital glaucoma, OMIM 231300, is caused by mutation of CYP1B1
at chromosome 2p22-p21 [784]), or it may be seen in association with
systemic disorders such as Marfan syndrome and Smith-Lemli-Opitz
syndrome, some of the phakomatoses (particularly neurofibromato-
sis Type 1 and Sturge-Weber syndrome, see Chapter 6), some meta-
bolic disorders (particularly Lowe syndrome and homocystinuria, see
Chapter 3), and congenital infections (rubella, syphilis) (782,785). It is
Barkovich_Chap05.indd 467
467
FIG. 5-124. Congenital glaucoma (buphthalmos). Axial CT image
shows enlargement of the right globe in a patient with neurofibromatosis.
Enlargement is greater from front to back because much of the enlarge-
ment is in the anterior chamber and the orbital walls restrict medial-lateral
enlargement.
bilateral in up to 80% of affected patients (764). Imaging studies show
enlargement of the entire globe. Often the affected globe will appear
more elongated from front to back because (a) much of the enlarge-
ment is in the anterior chamber and (b) the medial and lateral orbital
walls restrict medial-lateral enlargement (Fig. 5-124).
Other Congenital Ocular Anomalies
Coats disease is a congenital, nonhereditary ocular anomaly caused by
a vascular disorder of the retina in which lipoproteinaceous exudate
accumulates in the subretinal space, leading to retinal detachment. In
addition, subretinal and posterior vitreous hemorrhages result from
rupture of small aneurysms within the retinal vascular malformation.
Males are most commonly affected (70%–80%), typically in the middle
years of the first decade of life, but the disorder may be detected at
nearly any age. The malformation is almost always unilateral (776,786).
Affected children typically present with diminished vision in the
affected eye and are found on examination to have leukocoria; there-
fore, differentiation from retinoblastoma (see Chapter 7) is essential.
Another important disease to exclude is infection by Toxocara canii
(also known as Toxocara endophthalmitis or larval granulomatosis,
and also discussed in Chapter 7). Ultrasound shows Coats disease as a
hyperechoic mass in the posterior vitreous without posterior acoustic
shadowing (776). Hemorrhage is common in the vitreous and subreti-
nal space. The CT features of Coats disease (Fig. 5-125A) are nonspe-
cific, showing a normal sized (sometimes slightly enlarged) eye with
retinal detachment, filling of the subretinal space with slightly dense
proteinaceous material, and variable obliteration of the vitreous space
(777,786). Of importance, calcification is absent in the vast majority of
cases of Coats disease (but present in most cases of retinoblastoma) and
the abnormal tissue is always intraocular (in contrast to retinoblastoma
where extraocular extension may occur). MRI may be useful in that
the proteinaceous exudate in Coats disease is of uniform signal inten-
sity, intermediate between brain tissue and vitreous, on T2-weighted
images and does not enhance on postcontrast images (Fig. 5-125B–D)
(777), whereas the tumor portion of an eye with retinoblastoma will be
of low intensity on T2-weighted images and enhances uniformly other
than in areas of necrosis (see Chapter 7) (787).
5/6/2011 9:00:13 PM
 468 Pediatric Neuroimaging

FIG. 5-125. Coats disease. A. Axial noncontrast CT image shows that the globes are of equal size. A hyperdense proteinaceous exu-
date (white arrowheads) lies in the back of the right globe. No calcification is seen, allowing differentiation from retinoblastoma. B.
Axial T2-weighted image shows that the exudate is homogeneous, other than some hypointensity at the interface with vitreous, and
of signal intensity intermediate between vitreous and brain tissue. C and D. Axial precontrast (C) and postcontrast (D) T1-weighted
images show the exudate to be nonenhancing, homogeneous, and of intensity similar to that of brain tissue.

other than the formation of the diencephalic-mesencephalic boundary

ANOMALIES OF MIDBRAIN-HINDBRAIN
DEVELOPMENT
Overview of Midbrain and Hindbrain
Development
Malformations of the midbrain and hindbrain (brainstem and cer-
ebellum) are being found more frequently in children with mental
retardation and congenital neurologic dysfunction (3,9,10). As with all
malformations, understanding of midbrain-hindbrain malformations
is greatly aided by an understanding of development of that region.
Therefore, a few paragraphs will be devoted to an overview of mid-
hindbrain development.
Patterning
After the neural tube is formed, it develops a series of vesicles at its
anterior (rostral) end: the prosencephalon (also called forebrain, which
will divide into the dorsal telencephalon and ventral diencephalon),
the mesencephalon (midbrain), and the rhombencephalon (hindbrain,
which will divide into the rostral metencephalon and caudal myel-
encephalon). This differentiation along the anteroposterior (AP) axis
(also called the rostral-caudal axis) is called patterning, a name given
to the early differentiation of the neural tube (788). The mechanisms
that result in early AP patterning are currently poorly understood and,
(DMB) and the midbrain-hindbrain boundary (MHB), are beyond the
scope of this book. In murine and chick models, the DMB appears to
form as the result of interactions among the Pax6, Pax2, and En1/2
molecular markers, Pax6 endowing diencephalic fate by repressing
Pax2 and En1, while En1 represses Pax6 expression in the mesencepha-
lon (789) (Fig. 5-126). Changes in the expression of these markers will
shift the DMB caudally (more Pax6) or rostrally (more Pax2/En1). The
location of the MHB is determined by the expression of Otx2 in the
caudal midbrain and Gbx2 in the rostral hindbrain; increases in the
expression of Otx2 or decrease in Gbx2 shifts the MHB caudally, while
decrease in Otx2 or increase in Gbx2 causes a rostral MHB shift (790).
The interaction of Otx2 and Gbx2 also specifies the location of the isth-
mus organizer (IsO, Fig. 5-126), a critical structure that organizes gene
expression and directs specification of cell type (791,792) and the nor-
mal development of the cerebellum (793).
At the same times that AP patterning is taking place, an analogous
process is occurring along the dorsoventral (DV) axis. DV patterning
depends on the relative amounts of dorsalizing factors (members of
the BMP family, which are produced by non-neural ectoderm) and
ventralizing factors (members of the SHH family, which emanate from
the notochord and floor plate) (714,792,794). Along the DV axis, the
mesencephalon is divided into the tegmentum (ventral region) and
tectum (dorsal region), while the metencephalon is divided into the

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 Chapter 5 • Congenital Malformations of the Brain and Skull 469

FIG. 5-126. Anteroposterior patterning and the Isthmus Organizer. Regionalization of the
brain starts with the formation of patterning centers that secrete signaling molecules such as
the FGFs. Fgf8 and Fgf17 are important signaling molecules at both the anterior forebrain and
the midbrain-hindbrain junction. In the forebrain, it helps to direct formation of the prefron-
tal cortex and other rostral structures by inducing cells to secrete the transcription factor Pax6.
At the midbrain-hindbrain junction, the patterning center known as the IsO is induced to
secrete Fgf8 and Fgf17 by the interaction of transcription factor Gbx2 from the rhombenceph-
alon and Otx2 from the caudal mesencephalon. The secretion of Fgf8 and Fgf17 then induces
further changes crucial to formation of the midbrain-hindbrain junction and the formation
of the cerebellum. The junction of the prosencephalon (pros) and mesencephalon is directed
by the interaction of Pax6 from the caudal prosencephalon (diencephalon) and En1/Pax2 from
the rostral mesencephalon. Changes in the concentration of Gbx2 or Otx2 alter the location of
the midbrain-hindbrain junction and can affect cerebellar formation, as the cerebellum forms
from the most rostral portion of the hindbrain. Similarly, alterations of Pax6 or En1/Pax2 will
alter the location of the diencephalic-mesencephalic junction.

pons (ventral region) and the cerebellum (dorsal region). The subtype
of the neurons in these regions is specified by expression of local HOX
genes (795), the influence of local organizers such as the IsO (Fig. 5-126
[796]), and on the presence of graded doses of signaling molecules,
such as SHH and BMP, from the floor plate and roof plate (792), all
influenced by local organizers, especially the IsO (796–798).
Cell Proliferation and Migration
On a macroscopic scale, the pontine flexure appears at about the fifth
gestational week, at which time the fourth ventricle has a thin roof
and laterally positioned dorsal (alar) plates (25,799). During the fifth
gestational week, cellular proliferation within the alar plates in con-
junction with formation of the pontine flexure forms the rhombic
lips, situated at the lateral walls of the fourth ventricle. The neuroepi-
thelial zones, in the roof of the fourth ventricle and the rhombic lips,
are the locations of the germinal matrices where the cells of the cer-
ebellum and many brainstem nuclei will form (Figs. 5-127 and 5-128)
(800,801). Between 9 and 13 postconceptional weeks, the Purkinje cells
of the cerebellar cortex and GABAergic neurons of the deep cerebellar
nuclei migrate radially outward from the ventricular zone (Fig. 5-127)
(802). In contrast, the neurons of the granular layer of the cerebel-
lar cortex and of the glutamatergic deep cerebellar nuclei originate
in the rostral rhombic lips and have more complex migration routes
that are guided by adhesion molecules, neurotrophins, and repulsive
molecules that may be on the surface of cells or in the interstitium
(Fig. 5-127) (793,803–807). Deep cerebellar nuclear neurons in mice
migrate rostrally in a subpial stream, express sequentially changing
transcription factors (Pax6, Tbr2, and Tbr1) as they migrate to a
nuclear transitory zone (NTZ). A subset of rhombic lip-derived cells
also express reelin, a key regulator of Purkinje cell migrations. In later
stages of development, the NTZ organizes into distinct deep cerebel-
lar nuclei (Fig. 5-127) (808). Other cells migrate tangentially from the
rhombic lips, over the cerebellar surface to form a transient EGL (see
Fig. 5-127), which acts as a secondary germinal matrix (800,809,810).
The EGL forms between the 10th and 11th postconceptional weeks
and persists until about 15 postnatal months. After migrating through
the EGL, the granule cell neuroblasts migrate inwards between clus-
ters of Purkinje cells with the presumed aid of glial (Bergman) fibers,

FIG. 5-127. Embryology of the cerebellar cortex. The cells that form the
cerebellum are generated in germinal zones lining the fourth ventricle. The
cerebellar ventricular zone in the rostral dorsal rhombencephalon gener-
ates neurons that will become GABAergic Purkinje cells and interneurons.
Some neurons migrate dorsally into the developing cerebellar hemispheres,
while others migrate to a transient nuclear transitory zone (not shown)
before migrating to form the deep cerebellar nuclei. Lateral to the cerebellar
ventricular zones are the rostral rhombic lips, where glutamatergic neurons
(granule neurons, projection neurons of the deep cerebellar nuclei, unipolar
brush cells) are generated. Some of these migrate to the nuclear transitory
zone and the deep cerebellar nuclei, while others migrate dorsally and later-
ally to form a transitory EGL. The developing granule cells migrate through
the EGL and undergo many mitoses there before terminating their migration
and then coursing inward, through the cerebellar molecular and Purkinje cell
layers before finally terminating their migration in the internal granular layer
of the cerebellar cortex. Cells formed in the more caudal rhombic lips form
the brainstem nuclei that connect to the cerebellum (see text).

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 470 Pediatric Neuroimaging
to form the internal granular layer (Fig. 5-127) (25,811,812). Also
formed at this time are the stellate and basket cells of the cerebel-
lar cortex (25,799,801,813,814). Several genes, the most important
being PAX6, ZIC1, and MATH1, support granule cell viability and
migration, while the Bergman glia are preserved by the expression of
PAX3 (815,816). Malexpression of these genes likely causes cerebellar
malformations.
The cerebellum contains five main classes of neurons, of which two
(Purkinje cells and inhibitory interneurons) produce GABA as a neu-
rotransmitter (these are called GABAergic neurons) and three (deep cer-
ebellar nuclear projection neurons, granule neurons, and unipolar brush
cells) use glutamate as a neurotransmitter (glutamatergic neurons).
Morphological and genetic approaches both suggest that all GABAer-
gic types are produced from the cerebellar ventricular zone (Fig. 5-127)
(808). Among glutamatergic types, deep cerebellar nuclear projection
neurons come from the rhombic lip (808). Granule cells are produced
from the EGL, which is a rhombic lip derivative (809,817). The origins
of unipolar brush cells have been difficult to discern (818), but new data
suggest that they are likewise produced from the rhombic lip (808).
Together, these findings suggest that most or all glutamatergic neurons
in the cerebellum originate from the rhombic lip (Fig. 5-127). Thus, cer-
ebellar neurogenesis seems divided according to the type of neurotrans-
mitters that the cells primarily synthesize and secrete, much as cerebral
neurogenesis is divided between the germinal zones in the more ventral
(subpallial) ganglionic eminences (which produce most, if not all, of
the GABAergic neurons) and the more dorsal (pallial) ventricular zones
(which produce most, if not all, of the glutamatergic neurons).
While cells produced in the rostral rhombic lips form the cer-
ebellum, those produced in the caudal rhombic lips form brainstem
nuclei that connect to the cerebellum: the precerebellar nuclei (inferior
olives, lateral reticular, and external cuneate nuclei). Thus, neurons of
brainstem nuclei also migrate to their final location (Fig. 5-128). Their
migration pathway consists of an initial tangential migration along the
periphery of the brainstem (some also migrate longitudinally along the
AP axis of the brainstem), followed by radial migration inward. Dur-
ing or at the end of the radial migration, axons are extended to con-
nect with the cerebellum or other CNS structures. With the exception
of the oculomotor (third nerve, deriving from the mesencephalon)
nuclei, cranial nerve nuclei are derived from rhombencephalic neu-
ronal precursors: fourth nerve from rhombomere 1, fifth nerve from
rhombomeres 2–3, sixth nerve from rhombomeres 5–6, and seventh
Barkovich_Chap05.indd 470
FIG. 5-128. Brainstem embryology. Many of the neu-
rons of brainstem nuclei that connect to the cerebellum
are formed in the caudal rhombic lips (RL). These cells
initially migrate tangentially to the surface of the brain-
stem (1) until they receive chemical signals directing
them to either cross the midline (2) or turn and migrate
radially inward for a variable distance (3) before stop-
ping at the site where a nucleus will form. These neurons
then sprout axons that migrate through the milieu of the
developing brainstem (4) to form synapses with specific
targets.
nerve from rhombomeres 4–5 (819). Due to their compartmental
identity, the neuronal progenitors display programmed migratory
behaviors and send axons along defined trajectories to their peripheral
targets. While the position of the neural cell progenitors along the AP
axis determines the identity of the nucleus, its sensory or motor func-
tion is determined by its position along the DV axis. Graded expres-
sion of specific chemicals (SHH, Pax6, and Nkx.2.2) along the DV axis
appears to generate domains conducive to either motor (ventral) or
sensory (dorsal) neuron development (819). Another chemical, the
paired-like homeodomain protein Phox2b, is required for the forma-
tion of all branchial and visceral, but not somatic, motor neurons in
the hindbrain (820).
Cell Connections (Neurite Formation, Axon Migration,
and Synapse Formation)
Although multiple connections exist among cerebellar neurons, there
are only two major afferent projections to the cerebellar cortex. Mossy
fibers, from the basis pontis and the spinal cord make contact and syn-
apse with granule cells, whereas climbing fibers from the contralateral
inferior olives make contact with Purkinje cell dendrites (801,814,821).
In addition, axons from locus coeruleus, raphe nuclei, and substantia
nigra synapse with Purkinje cells. The only efferent fibers from the cer-
ebellar cortex are from the Purkinje cells, which connect with many
brainstem nuclei, in addition to the cerebellar nuclei (822). The cere-
bellar nuclei, in turn, connect with pontine and other brainstem nuclei
through the middle cerebellar peduncles. Most of these connections
develop while the cells are still migrating to their final locations.
Interactions of Brain and Meninges
Two final important concepts concern the development of the cerebel-
lum, particularly as it relates to posterior fossa cysts. The first concept
is that the development of the leptomeninges overlying the cerebel-
lum affect cerebellar growth; mutations in or damage to the posterior
fossa leptomeninges impair cerebellar development (823,824). The
second concept concerns the complex development of the roof of the
fourth ventricle. Bonnevie and Brodal (825) have shown that the roof
of the fourth ventricle of the mouse is divided by a ridge of develop-
ing choroid plexus into the anterior and posterior membranous areas
on the 11th gestational day (Fig. 5-129). By the end of the 11th day,
the anterior membranous area (above the choroid ridge) is incorpo-
rated into the developing choroid plexus. The posterior membranous
5/6/2011 9:00:15 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 471

FIG. 5-129. Schematic showing normal and abnormal development of the fourth ventricle. Early in gestation,
the roof of the fourth ventricle is divided by a ridge of developing choroid plexus into anterior and posterior
membranous areas (A). Normally, the anterior membranous area is incorporated into the developing choroid
plexus (B). The posterior membranous area remains and eventually cavitates to form to the midline foramen of
Magendie (C). If the anterior membranous area is not incorporated into the developing choroid plexus (D) or if
there is delayed opening of the foramen of Magendie, the roof of the fourth ventricle can balloon posteriorly to
form a fourth ventricular-cisterna magna cyst (E), identical to what is seen in the Dandy-Walker malformation.

area (below the choroid ridge) remains; an area within it eventually
cavitates to form the midline foramen of Magendie. The lateral foram-
ina of Luschka open at some later, as yet unknown, time. Sometimes,
the anterior membranous area balloons outward during development,
forming a collection of ependymal lined CSF inferior to the vermis.
This structure is known as Blake pouch. Persistence of Blake pouch,
also called Blake pouch cyst, is one of the mimics of the Dandy-Walker
malformation (826–828).
Classification of Midbrain-Hindbrain
Malformations
Several classification systems have been proposed for cerebellar malfor-
mations (8,829,830). Most of these are morphological classifications.
Although morphology is useful for imaging diagnosis, it does not help
in understanding the pathogenesis of disorders, nor the relationship of
disorders of the hindbrain to those supratentorial malformations that
often accompany them. Moreover, classifications of cerebellar malfor-
mations have not taken into account that the cerebellum is embryo-
logically a part of the dorsal pons and is, therefore, an extension of the
brainstem. Recently, a classification of midbrain and hindbrain mal-
formations has been proposed that is based on embryology and genet-
ics, as well as morphology (Table 5-6) (10). As this classification seems
most useful for both understanding and diagnosis of the disorders, and
as it includes both midbrain and hindbrain, we will follow it in our
discussion of malformations.
Mid-Hindbrain Malformations Secondary to Early
Patterning Defects, or to Misspecification of Germinal
Zones
Antero-Posterior Patterning Defects
These uncommon malformations result from abnormal segmentation
of the midbrain and pons (resulting in long midbrain and short pons,
(Fig. 5-130) or short midbrain and long pons [831]) or of the pons and
medulla (resulting in a long pons and short medulla or, more com-
monly, a short pons and long medulla) (9,10); affected patients typically
have cranial neuropathies or long tract signs. Segmental shifts in the
brainstem are also seen in humans with Athabaskan brainstem dysgen-
esis syndrome (seen in Native American tribes) and Bosley-Salih-Alo-
rainy syndrome (observed in Saudi and Turkish families), both caused
by homozygosity for mutations of HOXA1 (832), resulting in horizon-
tal gaze abnormalities, hearing loss, facial weakness, hypoventilation,
mental retardation, and autism spectrum disorder (833). Anomalies of
the vascular system and the inner ear may be seen, as well (833).
Disconnection Syndromes Brainstem disconnection syndromes
(834–838) are disorders in which the superior portion of the brain-
stem is connected to the inferior portion only by a thin cord of tis-
sue (Fig. 5-131). Affected infants are profoundly affected from birth,
with mildly dysmorphic features (downward slanting eyes, low-set
ears, mild micrognathia, and widely spaced nipples) (834). Neurologic
examination reveals weak suck, diminished corneal, gag, and oculo-
cephalic reflexes, pronounced flexor tone, and hyperactive deep tendon
reflexes with minimal ocular motility, and disturbed respirations that
require mechanical ventilation (837,838). In three reported patients,
the disconnection was in the lower midbrain/upper pons and in four
it was in the lower pons/upper medulla. Neuropathological analysis of
two cases by Sarnat et al. (834) showed a thin midline cord passing
from the upper segment to the lower segment with hypoplasia of the
cerebellar vermis and hemispheres and an anomalous basilar artery.
Histological investigation revealed a poorly organized mixture of neu-
rons in the tegmentum, but no evidence of any reactive astrogliosis to
suggest hypoxia or ischemia; this was interpreted as providing evidence
in favor of a brainstem malformation, rather than a disruption. In con-
trast, Barth et al. (838) found central cavitation that they interpreted a
syrinx and postulated a vascular cause.
Diagnosis is established by MRI, which shows a relatively nor-
mal upper brainstem that abruptly tapers into a thin band of tissue

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 472 Pediatric Neuroimaging
TABLE 5-6 Classification Scheme for Midbrain-Hindbrain Malformations
I. Malformations secondary to early antero-posterior and
dorso-ventral patterning defects, or to misspecification of
mid-hindbrain germinal zones
A. Antero-posterior patterning defects
1. Gain, loss or transformation of the diencephalon and midbrain
a. Long or short midbrain
2. Gain, loss or transformation of the midbrain and
rhombomere-1
a. Midbrain-pontine brainstem disconnection
b. Large midbrain with small pons
c. Short midbrain with large pons and large anterior vermis
3. Gain, loss or transformation of lower hindbrain structures
a. Ponto-medullary brainstem disconnection
b. Short pons with long medulla
B. Dorso-ventral patterning defects
1. Defects of alar and basal ventricular zones (VZs) germinal
matrix
2. Defects of alar VZ only
a. Cerebellar agenesis (with or without pancreatic agenesis)
b. Profound cerebellar hypoplasia due to granule cell
hypoplasia
c. Rhombencephalosynapsis
3. Defects of basal VZ only
a. Duane syndrome
b. Möbius syndrome
II. Malformations associated with later generalized developmental
disorders that significantly affect the brainstem and cerebellum
(and have pathogenesis at least partly understood)
A. Developmental encephalopathies associated with mid-
hindbrain malformations
1. Cerebellar aplasia or hypoplasia
B. Mesenchymal-neuroepithelial signaling defects associated with
mid-hindbrain malformations
1. Dandy-Walker malformation
2. Mega cisterna magna
3. Retrocerebellar arachnoid cysts
4. Cerebellar vermian hypoplasia
C. Malformations of neuronal and glial proliferation that promi-
nently affect the brainstem and cerebellum
1. Cerebellar tubers (tuberous sclerosis)
2. Lhermitte-Duclos disease/Cowden syndrome
3. Microcephaly with disproportionate brainstem/cerebellar
hypoplasia
Adapted from Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 2009;132:3199–3230,
with permission.
(sometimes not visible on imaging) that connects to the lower segment
of normal appearing brainstem. The cerebellum is typically small
(Fig. 5-131). The vertebrobasilar vasculature is abnormal, with ves-
sels or the posterior circulation typically very narrow or even absent;
fetal posterior cerebral arteries are usually present. One reported case
showed absent cervical vertebral arteries with reconstitution via persis-
tent segmental arteries and PVNH (839).
Dorso-Ventral Patterning Defects
Defects in dorso-ventral patterning are postulated to result in abnor-
mal development or function of specific mid-hindbrain ventricular
Barkovich_Chap05.indd 472
D. Malformation of neuronal migration that prominently affect
the brainstem and cerebellum
1. Lissencephaly with cerebellar hypoplasia
2. Neuronal heterotopia with prominent brainstem and CBL
hypoplasia
3. Polymicrogyria with cerebellar hypoplasia
4. Malformations with basement membrane and neuronal
migration deficits (cobblestone malformations)
E. Diffuse molar tooth type dysplasias associated with defects in
ciliary proteins
1. Syndromes affecting the brain with low frequency involve-
ment of the retina and kidney
2. Syndromes affecting the brain, eyes, kidneys, liver and
variable other systems
III. Localized brain malformations that significantly affect the BS
and CBL (pathogenesis partly or largely understood, includes
local proliferation, cell specification, migration and axonal
guidance)
A. Multiple levels of mid-hindbrain
1. Horizontal gaze palsy with progressive scoliosis
2. Congenital fibrosis of extraocular muscles
3. Duane radial ray syndrome
4. Diffuse brainstem hypoplasia
B. Midbrain malformations
1. Dorsal midline cleft in Trisomy 14
C. Malformations of Rh1 including cerebellar malformations
1. Cerebellar nodular heterotopia with overlying dysgenesis
2. Cerebellar foliation anomalies
3. Duplication of cerebellar hemisphere
D. Pons malformations
1. Pontine tegmental cap dysplasia
2. Pontine dysgenesis with dorsal or ventral clefts
E. Medulla malformations
1. Medullary tegmental caps with callosal agenesis/hypogenesis
IV. Combined hypoplasia and atrophy in putative prenatal onset
degenerative disorders
A. Pontocerebellar hypoplasias
B. Mid-hindbrain malformations with CDG
C. Other metabolic disorders with cerebellar or brainstem
hypoplasia or disruption
D. Cerebellar hemisphere hypoplasia (rare, more commonly
acquired than genetic, often associated with clefts or cortical
malformation)
zones and structures derived from them, including abnormal forma-
tion of brainstem nuclei, cranial nerves, or any cerebellar structures.
Cerebellar Hypoplasia Cerebellar hypoplasia has many different
morphologic variations and many causes. For example, abnormal
development of the superior rhombic lip germinal zone may cause dif-
fuse granule cell hypoplasia (with consequent severe diffuse cerebellar
hypoplasia) while abnormal development of the cerebellar ventricu-
lar germinal zone due to mutation of the PTF1A gene causes cerebel-
lar (and pancreatic) agenesis (840,841); surprisingly, some affected
patients may have relatively mild neurologic deficits (842). Indeed, poor
5/6/2011 9:00:17 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-130. Antero-posterior patterning defect. Sagittal T1-weighted
image shows an abnormally long midbrain (white arrows) and short pons,
suggesting a defect in AP patterning.
correlation is found between the severity of the cerebellar deformity
and the severity of the clinical syndrome; for example, some patients
with isolated unilateral (843–845) and bilateral (842,845,846) cerebel-
lar hypoplasia have few or no cerebellar signs or symptoms and may
be intellectually normal (847). Associated CNS anomalies (heterotopia,
callosal anomalies, and PMG) are commonly associated, however; the
presence of associated anomalies markedly increases the incidence of
neurodevelopmental disability (842).
Many cerebellar hypoplasias are the result of inborn errors of
metabolism, congenital infections, or gross chromosomal anomalies
FIG. 5-131. Brainstem disconnection syndrome. Sagittal T1-weighted
image shows disconnection of the lower brainstem from the upper brain-
stem. The ventral pons (white arrowhead) and the cerebellum (c) are small.
No neural tissue is seen in the location where the middle portion of the
medulla would be expected (white arrows).
Barkovich_Chap05.indd 473
473
(14,15,557,842,848–850). Some of these, such as the congenital
disorders of glycosylation (CDG) Type 1 and pontocerebellar hyp-
oplasia seem to be the result of cerebellar atrophy that begins before
birth; these are discussed in Chapter 3. Others are due to lack of for-
mation or lack of migration of the cells that compose the cerebellum
(discussed below in the section “Malformations of Neuronal Migration
that Prominently Affect the Brainstem and Cerebellum”). Unilateral
hemisphere hypoplasia might be due to early fetal injury or to genetic
mutations with somatic mosaicism (845).
Imaging of cerebellar hypoplasia shows a spectrum of findings,
depending upon the severity of the hypoplasia and the presence or
absence of associated anomalies. When hypoplasia is severe, the cer-
ebellum may appear essentially absent (Fig. 5-132A and B). When the
hemisphere is slightly larger, small fissures can be seen between the
small folia, allowing the differentiation of hypoplasia (normal fissures,
Fig. 5-132C) and dysgenesis. When less severe, the diagnosis of cerebel-
lar hypoplasia can be subtle. Localized vermian hypoplasia can best be
detected by acquiring high-resolution volumetric images, reformatting
an image in the midline sagittal plane, and looking for all vermian lob-
ules. When lobulation is normal, look for the rostrocaudal size of the
vermis to run from the bottom of the inferior colliculus to the obex in
a neonate, and from the intercollicular sulcus (midway between the
superior colliculi and inferior colliculi of the quadrigeminal plate) to
the obex on the midline sagittal image; if smaller (Fig. 5-132D and E),
the vermis is hypoplastic. In the fetus, where vermian anatomy is more
difficult to assess, it is easiest to measure the size of the vermis and
compare it to established standards (see Chapter 2 and published mea-
surements [851]); however, moderate and severe hypoplasia can be
detected on midline sagittal images (Fig. 5-132G). The cerebellar hemi-
spheres are best assessed in the coronal plane, which best shows the
horizontally oriented fissures (Fig. 5-132F and H). Note that the pons
is often small in cerebellar hypoplasia (Fig. 5-132), probably because
many axons from the cerebellum normally course through the ven-
tral and central pons. When the cerebellum is small, the size of these
axonal pathways is diminished. Thus, the presence of a small pons in
the setting of a small cerebellum should not automatically result in a
diagnosis of pontocerebellar hypoplasia. Pontocerebellar hypoplasia is
the name given to a distinct group of disorders, as described in the pre-
vious paragraph and, more completely, in Chapter 3. A small pons in
the setting of a small cerebellum only means that the small cerebellum
is a result of prenatal events.
Brain-stem Effects of Dorsal-Ventral Patterning Defects Defects
of the basal ventricular zone result in defects of specific cranial nerve
nuclei such as the abducens and facial nerves (852,853). Patients with
these latter disorders are sometimes described as having Möbius syn-
drome, a syndrome defined by congenital palsy of the sixth and sev-
enth cranial nerves (854); imaging findings vary (therefore, this is not
a radiologic diagnosis) from normal to pontine calcifications on CT to
pontine malformation to absence of the facial colliculus (855–858). It
is likely that Möbius syndrome is a heterogeneous disorder caused by
many different developmental and disruptive disorders involving the
pons; there is no characteristic radiologic appearance.
Rhombencephalosynapsis Rhombencephalosynapsis, originally
described by Obersteiner in 1914 (859), is an anomaly character-
ized by lack of separation of the cerebellar hemispheres, with absence
or severe hypoplasia of the cerebellar vermis and midline continu-
ity (commonly called “fusion”) of the cerebellar hemispheres, deep
cerebellar nuclei, and superior cerebellar peduncles. All published
cases have been sporadic. Two patients with consanguineous parents
have been reported (860,861). The cause is unknown, but one of the
5/6/2011 9:00:17 PM
 474 Pediatric Neuroimaging

FIG. 5-132. Cerebellar hypoplasia, range of severity. Note the presence of pontine hypoplasia in all. A and
B. T1-weighted sagittal (A) and coronal (B) images show profound cerebellar hypoplasia, with only a tiny
amount of cerebellar tissue (white arrows). C. Sagittal T1-weighted image shows a very tiny vermis (white
arrow), but some normal vermian lobulation is visible. D. Sagittal T1-weighted image in a neonate shows mild
to moderate vermian hypoplasia. The normal neonatal vermis should extend from the inferior colliculi of the
midbrain tectum to the obex. E and F. Sagittal (E) and coronal (F) T1-weighted images show moderate verm-
ian hypoplasia. The cerebellar hemispheric hypoplasia is asymmetric, with the right hemisphere (white arrows
in F) smaller. Note cerebral periventricular nodular heterotopia (black arrows in F).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 475

FIG. 5-132. (Continued) G and H. Sagittal (G) and coronal (H) fetal MR images from different patients show moderate
vermian hypoplasia (G) and right cerebellar hemisphere hypoplasia (H).

authors has seen two cases associated with holoprosencephaly, sug-
gesting a defect in dorsal-ventral patterning. Rhombencephalosyn-
apsis is a part of the cerebello-trigeminal-dermal dysplasia syndrome
(OMIM 601853, also called Gomez-Lopez-Hernandez syndrome), in
which it is associated with trigeminal anesthesia and bilateral bands of
temporal alopecia, as well as short stature, mental retardation, mid-
face hypoplasia, oxycephaly due to bilateral lambdoid suture synos-
tosis, low set ears, and fifth finger clinodactyly (862–864). It has also
been described in conjunction with the VACTERL-H association
(vertebral anal, cardiac, tracheoesophageal, renal, and limb anomalies
with hydrocephalus) (865) and autosomal dominant polycystic kid-
ney disease Type 1 (866). Affected fetuses may sometimes be identi-
fied by ventriculomegaly with absent septum pellucidum; high quality
images may show midline continuity of the cerebellar hemispheres
(Fig. 5-133) (865,867,868). Clinical presentation after birth is variable
and ranges from severe congenital hydrocephalus to severe cerebral
palsy with epilepsy and mental retardation to mild truncal ataxia
and normal cognition; most patients have some degree of cognitive
dysfunction, often associated with attention deficit and hyperactivity
(869,870). Motor milestones are often delayed and physical exam will
typically show a cerebellar syndrome with dysmetria, dysdiadochoki-
nesis, and dysrhythmokinesis.
In addition to partial (20% of affected patients) or complete
absence (80%) of the cerebellar vermis, autopsy studies show the most
common brain anomalies to be midline continuity of the deep cerebel-
lar nuclei, superior cerebellar peduncles, and thalami; absence of the
septum pellucidum; olivary hypoplasia; anomalies of the limbic system;
callosal agenesis or hypogenesis; and hydrocephalus (717,865). How-
ever, many patients do not have all of these findings and a wide range
of other associated supratentorial, infratentorial, and non-neurologic
anomalies have been reported in association with the cerebellar defor-
mity (717,865,869,871).

FIG. 5-133. Prenatal and postnatal images of

rhombencephalosynapsis. A. Coronal fetal MRI
shows massive ventriculomegaly with absent
septum pellucidum. The cerebellum is dispro-
portionately small and appears continuous
across the midline. B. Axial fetal MRI confirms
continuity of cerebellar hemispheres across the
midline (white arrowheads) without intervening
vermis.

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 476 Pediatric Neuroimaging

FIG. 5-133. (Continued) C. Sagittal T1-weighted image 1 day after

birth shows massive hydrocephalus. D. Axial T2-weighted postnatal
image confirms absence of the septum pellucidum. E. Axial T2-weighted
image at the fourth ventricle confirms continuity of the cerebellar folia
and the deep cerebellar nuclei (white arrows) across the midline, con-
firming the diagnosis.

As affected patients may be initially detected due to a finding of fetal
ventriculomegaly (Fig. 5-133), an effort should be made to identify a
normal vermis in fetuses with severe ventriculomegaly and absent sep-
tum pellucidum; if the midline sagittal image shows abnormal vermian
foliation or coronal/axial images shows continuation of the cerebellar
hemispheres across the midline (Fig. 5-133), rhombencephalosynapsis
should be the diagnosis. In affected neonates, imaging studies often
show severe hydrocephalus with absent septum pellucidum and appar-
ent aqueductal stenosis (Fig. 5-133C). The cerebellum should be scru-
tinized in such cases for evidence of a show a characteristic appearance
of absence of the vermis with dorsal midline continuity of the cerebel-
lar hemispheres, cerebellar nuclei (Fig. 5-133E), and superior cerebellar
peduncles, in addition to the ventriculomegaly (Fig. 5-133D). The cer-
ebellar anomaly may be difficult to detect on CT, but may be suggested
if dorsal pointing of the fourth ventricle (Fig. 5-134D) is detected in
a patient with large lateral ventricles and absence of the septum pel-
lucidum (present in >50%). The diagnosis is most easily established
on MRI by the observation that the cerebellar folia appear continuous
across the midline without intervening vermis. This feature is most
easily seen on coronal images through the posterior cerebellum, but
it is also suggested by lack or the normal vermian folial pattern on the
midline sagittal image and the narrowing of the posterior aspect of the
fourth ventricle on axial images (Fig. 5-134). If possible, DTI may be
helpful, as the color fractional anisotropy maps show axons running
superior-inferior in the midline instead of the normal left-right axon
orientation of the vermis (872).
It is noteworthy that about 20% of affected patients may have a
small, dysplastic inferior vermis, referred to as incomplete rhomb-
encephalosynapsis (865); in such patients, the diagnosis can still be
made by observation of continuous folia across the midline superiorly.
Once the diagnosis is established, the cerebral cortex, ventricles, and
limbic system should be carefully evaluated. In addition to the previ-
ously discussed hydrocephalus and absent septum pellucidum, associ-
ated anomalies include cortical malformations and bilateral lambdoid
suture synostoses (869) (see section “Craniosynostosis Syndromes” of
this chapter).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 477

FIG. 5-134. Classic rhombencephalosynapsis. Sagittal T1-weighted image (A) shows abnormal foliation of the vermis.
Coronal T1-weighted image (B) and axial T2-weighted image (C) show the continuity of the cerebellar white matter (white
arrows) across the midline. Slightly more rostral T2-weighted image (D) shows posterior pointing (white arrow) of the fourth
ventricle.

Malformations Associated with Generalized
Developmental Disorders that Significantly Affect
the Brainstem and Cerebellum
Mesenchymal-Neuroepithelial Signaling Defects Associated
with Mid-Hindbrain Malformations—The Dandy-Walker
Complex
The Dandy-Walker malformation and related disorders (cerebellar
hypoplasia, mega cisterna magna, and retrocerebellar arachnoid cysts)
are a group of disorders that have generated considerable confusion
and controversy (827,873–875). The Dandy-Walker malformation
consists of an enlarged posterior fossa with a high position of the ten-
torium, hypoplasia or agenesis of the cerebellar vermis, and a dilated,
cystic-appearing fourth ventricle that fills nearly the entire posterior
fossa (Fig. 5-135) (874,876). However, there is a wide variation in the
severity of the vermian hypoplasia, the size of the fourth ventricle, and
the elevation of the tentorium. In addition, wide variation can be seen
in families with the same genetic mutation, ranging from mild vermian
hypoplasia to mega cisterna magna to varying severities of true Dandy-
Walker malformation (824,877). Of interest, one of the causative genes,
known as FOXC1 (at chromosome 6p25.3), is expressed only in the
mesenchyme (developing leptomeninges) overlying the cerebellum and
not in the cerebellum itself (824). This observation suggests (a) that
abnormal mesenchymal development in the posterior fossa results in
malformations of both the cerebellum and the overlying leptomenin-
ges, (b) that the mesenchyme interacts with the developing cerebellum
during embryogenesis, and (c) that mutations causing maldevelopment
of both the cerebellum and its overlying mesenchyme are likely neces-
sary for development of a true Dandy-Walker malformation. Thus,
retrocerebellar arachnoid cysts and enlargement of the cisterna magna
(called mega cisterna magna, an enlarged posterior fossa secondary to
an enlarged cisterna magna, but a normal cerebellar vermis and fourth

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 478 Pediatric Neuroimaging

ventricle, Fig. 5-136) are a part of the Dandy-Walker spectrum from
an embryogenesis perspective. However, in the absence of mass effect
(causing hydrocephalus) or associated cerebral/cerebellar dysgen-
esis, these findings seem to be of little, if any, clinical significance. If
a brain malformation or hydrocephalus is present, patients often have
developmental delay (874,876,878–880). The degree of developmental
delay seems to be related to the level of control of hydrocephalus, to
the extent of associated supratentorial anomalies (878,881,882), and
to the degree of cerebellar dysgenesis, manifested as lobulation of the
vermis; normal lobulation is associated with good intellectual outcome
whereas some have found that abnormal vermian lobulation is asso-
ciated with poor intellectual outcome (880,883). Seizures, hearing or
visual difficulties, systemic abnormalities, and other CNS abnormali-
ties are associated with poor intellectual development; the presence
of two of these four risk factors identifies patients with borderline or
lower intelligence 94% of the time (878).
On imaging studies, the classic Dandy-Walker malformation is
identified by hypoplasia or absence of the cerebellar vermis, hypopla-
sia of the cerebellar hemispheres, an enormous fluid-filled fourth ven-
tricle, and a large posterior fossa with high tentorium and elevation
of the torcular Herophili (Fig. 5-135) (884). The brainstem is typi-
cally compressed against the clivus. The cerebellum may be markedly
(Fig. 5-135), moderately (Fig. 5-137), or mildly (Fig. 5-138) hypoplas-
tic and the vermis markedly (Fig. 5-135), moderately (Fig. 5-137), or
mildly (Fig. 5-138) rotated. The mega cisterna magna may be differen-
tiated by the presence of a normal (in size, lobulation, and orientation)
vermis. Both of these should be differentiated from the Blake pouch
cyst, in which the inferior aspect of the fourth ventricle herniates

FIG. 5-135. Prenatal and postnatal images of a classic Dandy-Walker malformation. Sagittal (A) and axial (B) fetal MR
images show a high tentorium (white arrows), high torcular Herophili (white arrowhead), hypoplastic cerebellum (black
arrow), and large cisterna magna (C) that expands the posterior fossa. Sagittal (C) and axial (D) postnatal MR images show
that the posterior fossa and cisterna magna (C) have both enlarged, hydrocephalus has developed (note big third ventricle
and shunt catheter [small black arrows in C] and large temporal horns in D). The hypoplastic vermis (large black arrows) has
been pushed further upward. The heterogeneity in the lateral ventricles is a result of intraventricular hemorrhage.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 479

FIG. 5-136. Mega cisterna magna. Sagittal T1-weighted image shows a large posterior fossa (white arrows in A) with
enlargement, but no displacement, of leaves of the falx cerebelli (black arrows in B) and normally formed cerebellum,
indicating that this is not an arachnoid cyst or a Dandy-Walker malformation.

through the foramen of Magendie into the vallecula and retrovermian
cistern (826,827,875). However, no precise MRI characteristic allows
separation of the mega cisterna magna from a Blake pouch cyst or from
a mild Dandy-Walker malformation, as the walls of the cyst cannot
be adequately identified, even with thin section steady-state imaging
techniques. In view of the observation that all malformations in this
group are associated with abnormal development of the posterior fossa
mesenchyme and that abnormal neurodevelopment is more related to
parenchymal anomalies than to the cyst or hydrocephalus, this distinc-
tion may be academic.
Associated anomalies are common: hydrocephalus in 70% to 90%,
callosal anomalies in as many as 30%, PMG or gray matter heteroto-
pia in 5% to 10%, and occipital cephaloceles in up to 16% (878,879).
Syringohydromyelia may be present if the cyst obstructs CSF circula-
tion through the foramen magnum (885). With any of the anomalies in
this group, the cerebellar hemispheres may appose each other inferiorly
after the posterior fossa cyst has been shunted; midline sagittal images
may then simulate the appearance of an intact vermis (Fig. 5-139).
Axial or coronal images will show the cerebellar hemispheres in appo-
sition without an intervening vermis.
Malformations of Neuronal and Glial Proliferation
that Prominently Affect the Brainstem and Cerebellum
Cerebellar Tubers (Tuberous Sclerosis) Tuberous sclerosis is dis-
cussed in Chapter 6 (Phakomatoses).
Lhermitte-Duclos Disease/Cowden Syndrome (Dysplastic Cer-
ebellar Gangliocytoma) Also known as diffuse hypertrophy of the
cerebellar cortex, dysplastic cerebellar gangliocytoma was first reported
by Lhermitte and Duclos in 1920 (886). Depending upon the source, it

FIG. 5-137. Sagittal T1-weighted image shows a moderate Dandy-Walker FIG. 5-138. Sagittal T1-weighted image shows a malformation in the
malformation with only moderate vermian hypoplasia and moderate Dandy-Walker spectrum with mild vermian hypoplasia combined and
posterior fossa enlargement. severe cisternal enlargement.

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 480 Pediatric Neuroimaging
FIG. 5-139. Dandy-Walker malformation after shunting of the posterior fossa cyst. Sagittal T1-weighted image (A) shows the
corpus callosum is hypogenetic with only the genu present. The posterior fossa is enlarged as a result of a high tentorium. On first
glance, the vermis looks intact. However, the vermis is hypoplastic (arrows mark the lower limit) with cerebellar hemispheres in
the midline beneath it. The axial T2-weighted image (B) at the level of the inferior fourth ventricle shows the cerebellar hemi-
spheres in apposition (arrows) without an intervening vermis.
may be classified as a tumor, a malformation, or part of a phakomato-
sis syndrome. Patients may become symptomatic at any age as a result
of mass effect from the lesion with resultant intracranial hypertension
(887–889). Cerebellar signs are usually mild or absent (890). Alterna-
tively, the anomaly may be discovered incidentally at autopsy or during
imaging for an unrelated condition (887–889). Associated anomalies
may include megalencephaly, heterotopia, microgyria, polydactyly,
partial gigantism, macroglossia, and multiple visceral hamartomas and
neoplasms (890,891). The visceral lesions are nearly identical to those
seen in Cowden disease (a multiple hamartoma syndrome character-
ized by mucocutaneous manifestations of trichilemmomas, related fol-
licular malformations, and distinctive hyalinizing, mucinous fibromas
and oral papillomas [892]), suggesting an association between the two
disorders; this suggestion is supported by reports of families with evi-
dence of both syndromes (893,894). Cowden disease is an autosomal
dominant disorder, caused by mutation of the tumor suppressor gene
PTEN at chromosome 10q23.3 [895]), that is associated with increased
frequency of malignancies and other lesions of the breast, thyroid,
colon, and pelvic adnexa (896). Other CNS manifestations of Cowden
disease include macrocephaly, meningiomas and hearing loss. Not sur-
prisingly, in view of this association, familial cases of Lhermitte-Duclos
syndrome have been reported (891,896).
Pathologically, Lhermitte-Duclos disease consists of a sharply mar-
ginated region of enlarged cerebellar cortex. Typically, a portion of one
cerebellar hemisphere is involved; the process may extend into the ver-
mis or, rarely, the contralateral hemisphere (717). Microscopically, one
sees a thick layer of ganglion cells replacing the granular layer of the
cerebellar cortex, a thick hypermyelinated marginal layer, and a thin
Purkinje cell layer (717).
CT scans show the presence of a nonspecific hypodense cerebellar
mass (897). MRI shows a sharply marginated cerebellar mass with T1
and T2 prolongation; coursing through the mass are curvilinear struc-
tures of gray matter intensity that appear to be the cerebellar cortex (Fig.
5-140). In apparent contradiction of pathological findings, the cortical
ribbon appears of normal or slightly less than normal thickness (898).
Barkovich_Chap05.indd 480
Enhancement has been reported after intravenous administration
of paramagnetic contrast (899), but it appears to be uncommon
(Fig. 5-141). Mass effect from the lesion can cause cerebellar tonsillar
herniation, often described as a Chiari I malformation, and associated
syringomyelia (900). Diffusion-weighted imaging shows diffusivity sim-
ilar to cerebellar cortex (153,901,902), while perfusion imaging shows
increase in relative cerebral blood volume, relative cerebral blood flow,
and mean transit time (900). Proton MR spectroscopy with intermedi-
ate (135 milliseconds) echo time shows rather characteristic findings of
elevated lactate and slightly reduced NAA (by about 10%), myo-inositol
(by 30%–80%), and choline (by 20%–50%) (153,900,902,903). The
MRS, therefore, is a very useful technique to help distinguish this local-
ized dysplasia from neoplasm, in which choline is nearly always elevated
(see Chapter 7). FDG PET and Tl-201 SPECT show increased uptake of
tracer and, therefore, are not good tests to use for this distinction (902).
Microcephaly with Disproportionate Brainstem/Cerebellar
Hypoplasia
Cerebellar Hypoplasia due to CASK Mutations A familial disorder
consisting of microcephaly and mental retardation with abnormal cere-
bral cortical development and profound pontocerebellar hypoplasia has
recently been associated with heterozygous loss-of-function mutations
of a gene called CASK, located at chromosome Xp11.4 (904). The pro-
tein product, CASK, is thought to have several functions during devel-
opment, including enhancing transcriptional activity of TBR1, a protein
that regulates expression of the protein Reelin (an important substance
in neuronal migration and cortical lamination of the cerebrum and cer-
ebellum [148,905]). Indeed, neuropathologic analysis of a patient with a
hemizygous CASK mutation showed a severely hypoplastic cerebellum,
a small brainstem, and abnormalities of cortical layering in the cerebrum
and cerebellum. MRI shows profound cerebellar and brainstem hypopla-
sia (Fig. 5-142), often with blurring of the cerebral cortical-white matter
junction and abnormal cerebral sulcation (904). A distinctive feature is
the normal-to-large appearing corpus callosum (Fig. 5-142), which is an
unusual finding in microcephaly.
5/6/2011 9:00:25 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 481

FIG. 5-140. Lhermitte-Duclos syndrome. Sagittal T1-weighted image (A) shows hypointensity (black arrows) of the posterior
left cerebellar hemisphere. Axial T1-weighted (B) image shows the hypodense region has mass effect, displacing fourth ventricle
(open white arrow) and medulla (solid black arrows).

Malformations of Neuronal Migration that Prominently Affect
the Brainstem and Cerebellum
These disorders, including lissencephaly, malformations due to gaps in
the pial limiting membrane, heterotopia, and PMG, were discussed in
section “Malformations of Cortical Development” of this chapter. Not
unexpectedly (because the factors determining cell proliferation and
cell migration are similar supra- and infratentorially), cerebellar hyp-
oplasia is often present in such malformations; thus, the midbrain and
hindbrain should be carefully examined in all such patients.
Diffuse Molar Tooth Type Dysplasias Associated with Defects
in Ciliary Proteins (Joubert Syndrome and Related Disorders/
Syndromes with “Molar Tooth” Malformation)
The concept of molar tooth dysplasias has evolved from that of a
rare cerebellar malformation presenting in children with episodic
hyperpnea, abnormal eye movements, ataxia, and mental retardation
(906–909) to a much more complicated entity encompassing multi-
ple syndromes. Recent work has shown that this brainstem/cerebellar
malformation (called by some the “molar tooth midbrain-hindbrain

FIG. 5-141. Lhermitte-Duclos syndrome. Axial T2-weighted image (A) shows heterogeneous hyperintensity
in the cerebellum with mass effect (white arrows) upon the pons. Postcontrast T1-weighted image (B) shows
heterogeneous, pial enhancement of the malformation.

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 482 Pediatric Neuroimaging

FIG. 5-142. Cerebellar hypoplasia

secondary to mutation of CASK. Sagit-
tal T1-weighted image (A) and coronal
T2-weighted image (B) show moder-
ate cerebellar and pontine hypoplasia.
The cerebrum has mildly diminished
white matter and some blurring of
the cortical-white matter junction. A
small periventricular nodular hetero-
topion is present (white arrow) in the
left trigone.

malformation” because axial images through the midbrain have the

appearance of a tooth) is seen with many associated anomalies that
TABLE 5-7 Joubert Syndrome and
encompass many syndromes; these are called, as a group, Joubert
syndrome and related disorders (JSRD) (235,910–915). The genetic Related Disorders
basis of JSRD appears to be highly heterogeneous (234,914–917).
Most of the related syndromes seem to be the result of mutations to Primary criteria
genes encoding ciliary proteins (912–915,917), which are important Neurological signs Hypotonia/ataxia
in a wide range of functions, including ciliogenesis, body axis forma- Developmental delay
tion, renal function, brain development, and ocular development. Oculomotor apraxia
Therefore, mutations that affect these structures cause a wide range
of disorders (918). Radiologic hallmark Molar tooth sign
The classification of JSRD has recently been revised (235). Zaki Occasional features Mental retardation
et al. (235) divided these malformation syndromes into four separate (seen in all forms) Breathing abnormalities
disorders: JS, COACH (Cerebellar vermis hypoplasia, Oligophrenia, Postaxial polydactyly
Ataxia, Ocular Coloboma, Hepatic fibrosis) syndrome, CORS (Cere- Mild retinopathy
bro-Oculo-Renal Syndrome), and Oculo-Facial-Digital Syndrome
Secondary criteria
Type VI (OFD-VI syndrome). Patients with all JSRD syndromes have
hypotonia, ataxia, developmental delay (cognitive and motor), oculo- Joubert syndrome Mild retinopathy
motor apraxia, and the “molar tooth sign” on brain MRI; occasional Mild nephropathy
features (seen in all forms) include mental retardation, postaxial poly- COACH syndrome Hepatic fibrosis
dactyly, mild retinopathy, and PMG (235,919). Other defining charac- (at least one) Coloboma (choroidal or retinal)
teristics are listed in Table 5-7 (235).
Cerebello-oculo-renal Ocular signs (at least one)
The genetic bases of these various disorders are being elucidated,
syndrome (CORS) Retinopathy (Typically congenital
although they are complex. Nine genetic loci associated with JSRD have
blindness)
been identified at chromosomes 9q34.3 (JBTS1, gene is unknown),
Coloboma
11p11.2-q12.3 (JBTS2, gene is unknown), 6q23 (JBTS3, AHI1, encod-
Renal signs (at least one)
ing Jouberin), 2q13 (JBTS4, NPHP1), 12q21 (JBTS5, CEP290), 8q22
Cysts
(JBTS6, TMEM67), 16q12 (JBTS7, RPGRIP1L), 3q11.2 (JBTS8,
Nephronophthisis
ARL13B), and 4p15.3 (JBTS9, CC2D2A) (234,916–918,920,921). Of
Renal failure
interest, AHI1 is involved in normal axon outgrowth and decussation
(922), which probably relates to the lack of decussation of many white Oro-facial-digital Oro-facial signs (at least one)
matter tracts in molar tooth malformations (see below). The multiplic- syndrome Type VI Cleft lip/palate
ity of causative genes implies that the molar tooth midbrain-hindbrain Tongue tumors
malformation may be the result of several different processes; there- Notched upper lip
fore, identification of the molar tooth sign does not, in itself, allow a Digital signs (at least one)
diagnosis to be made. Mesaxial polydactyly
Few neuropathology studies of affected individuals have been Preaxial polydactyly
reported. Friede reported a small, dysplastic cerebellar vermis with Bifid digits
midline clefting, dysplasias and heterotopia of cerebellar nuclei, near
Adapted from Zaki MS, Abdel-Aleem A, Abdel-Salam GMH, et al. The molar
total absence of the pyramidal decussation, and anomalies in the struc-
tooth sign: a new Joubert syndrome and related cerebellar disorders classification
ture of the inferior olivary nuclei, descending trigeminal tract, solitary system tested in Egyptian families. Neurology 2008;70:556–565, with permission.
fascicle, and dorsal column nuclei (717). Yachnis and Rorke (923)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 483

reported absence of decussation of the superior cerebellar peduncles
and central pontine tracts, as well. Saito et al. found that “the midline
structures of the brainstem are disordered both structurally and func-
tionally” in JS (924).
The imaging features of the molar tooth malformation are char-
acteristic (908). Sagittal images show a small vermis that is situated
abnormally high such that the fastigium of the fourth ventricle is at
the upper pons or at the pontomesencephalic junction, rather than
its normal position at the middle or low-middle pons. Thin sagittal
images will often show that the midbrain-pons junction is abnormally
thin (Fig. 5-143). The vermian folial pattern is abnormal (Fig. 5-143).
Coronal images typically show a cleft (Fig. 5-143B) in the superior
vermian midline. The small size of the dysmorphic vermis results in a
triangular-shaped mid-fourth ventricle (Fig. 5-143C) and a “bat-wing”
shaped superior fourth ventricle on axial images. Inferiorly, below the
small vermis, the two cerebellar hemispheres come into apposition in
the midline (Fig. 5-143C). The superior cerebellar peduncles do not
cross in the dorsal midbrain; they are usually large, nearly horizontal
and can be clearly seen as they extend between the midbrain and cer-
ebellum, surrounded by CSF (Fig. 5-143). The midbrain is small in its
anterior-posterior diameter, particularly in the midline (Fig. 5-143A),
probably because of the absence of the decussation of the superior cer-
ebellar peduncles. The characteristic appearance of the midbrain on
axial images, with the enlarged superior cerebellar peduncles and the
absence of their decussation, gives the classic “molar tooth sign” on
axial images (Fig. 5-143D). Diffusion tensor tractography confirms the
absence of decussation of the superior cerebellar peduncles (872).
From the imaging perspective, it is important to remember two
facts: first, multiple syndromes have a molar tooth posterior fossa mal-
formation; and second, these groups of patients cannot be differen-
tiated by neuroimaging alone. Therefore, all patients with the molar
tooth malformation should be screened for supratentorial anomalies
(hypothalamic hamartoma, PMG or other malformations of cortical
development), ocular, hepatic, and renal disease (235). The ultimate
diagnosis will depend on whether other anomalies are found and,
ultimately perhaps, on the genetic analysis.
Patients with JSRD are frequently referred for fetal MRI after rou-
tine fetal sonography shows an enlarged retrovermian CSF space (a
“large cisterna magna”). These patients should be carefully scrutinized
for a small vermis (the midline cleft is difficult to see in the fetus), a
narrow midbrain-pons junction (Fig. 5-144A and B) and the pres-
ence of a molar tooth sign on axial images, and the presence of large,
horizontal superior cerebellar peduncles on coronal (Fig. 5-144C) or
parasagittal images (925). Detection of these imaging features should
strongly suggest the diagnosis of JSRD and should initiate a search for
associated findings such as renal cysts, microphthalmia (associated
with retinal dysplasia), ocular colobomas, polydactyly, hamartomas of
the tuber cinereum, or tumors of the tongue.
Localized Brain Malformations that Significantly Affect
the Brainstem and Cerebellum
Malformations Affected Multiple Levels of Mid-Hindbrain
Horizontal Gaze Palsy with Progressive Scoliosis In the early
1970s, Dretakis and Konodoyannis (926,927) and Crisfield (928)
reported a group of patients with congenital scoliosis associated with
horizontal gaze palsy. This disorder was subsequently found to be
autosomal recessive, caused by mutations of the ROBO3 gene, located
at chromosome 11q23-q25 (929,930). The ROBO3 protein has been
shown to be important for midline crossing of axons in the brainstem
and spinal cord (930). Affected patients have congenital horizontal
gaze palsy: no horizontal smooth pursuit, saccades, optokinetic nys-
tagmus, or vestibuloocular responses, but vertical motions are normal.
Convergence movements may be markedly reduced. Scoliosis devel-
ops during childhood and has variable severity (931). Diagnosis can be
made by MRI, which shows characteristic anomalies of the brainstem.
Midline sagittal images show a small pons, but the diagnosis is estab-
lished from axial images, which show a dorsal midline pontine cleft
and both dorsal and ventral midline clefts of the medulla (Fig. 5-145).

FIG. 5-143. Molar tooth malformation characteristic of Joubert syndrome and related disorders. Sagittal T1-weighted
image (A) shows the dysplastic, small cerebellar vermis (black arrows) that lies abnormally high. Note the abnormal folial
pattern. The isthmus (white arrow) is abnormally narrow. Coronal T1-weighted image shows the large superior cerebellar
peduncles (white arrows) and the vermian cleft (white arrow). Axial T1-weighted images (C and D) show the triangular
fourth ventricle (C), resulting from absence of the inferior vermis, and the “molar tooth” appearance of the midbrain (D)
secondary to the narrow isthmus (small white arrow) and the large superior cerebellar peduncles (larger white arrows).

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 484 Pediatric Neuroimaging

FIG. 5-143. (Continued)

FIG. 5-144. Fetal MR images of a molar tooth malformation

shows a small vermis (black arrows) and large cisterna magna
(C) on the sagittal image (A), narrow isthmus (black arrows)
on the axial image (B), and large horizontal superior cerebellar
peduncles (black arrows in C).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 485

FIG. 5-145. Horizontal gaze palsy with progressive scoliosis. Midline

sagittal T2-weighted image of the brain (A) shows a small brainstem, in
particular a small pons, with abnormal dorsal concavity (black arrows).
Axial T2-weighted images (B and C) show the midline brainstem cleft
(black arrows) resulting from a lack of axonal crossing of the midline.

The appearance of the medulla has been described as looking like a
butterfly (Fig. 5-145C) (932). The cerebellum and midbrain appear
normal, while spine images show progressive scoliosis with no under-
lying spinal cord lesion. Diffusion tensor tractography shows no
decussation of rostro-caudally directed axonal bundles (ventral or
dorsal) (933,934), which is concordant with neurophysiological stud-
ies (933,935). Images of the spine show progressive scoliosis.
Congenital Fibrosis of Extraocular Muscles Congenital fibrosis of
the extraocular muscles (CFOEM) is one of a group of congenital neu-
romuscular diseases that are currently called congenital cranial dysin-
nervation disorders. They include congenital, nonprogressive sporadic
or familial abnormalities of cranial musculature that result from devel-
opmental abnormalities of one or more cranial nerve with primary or
secondary muscle dysinnervation (936). Three phenotypes of CFOEM
have been described, all of which are the result of maldevelopment
of the oculomotor nerve (cranial nerve III) and its corresponding
motoneurons; the precise phenotype depends upon which of the five
subnuclei of CN III are affected (819,937). The best characterized of
these disorders is CFOEM2, an autosomal recessive disorder in which
affected individuals are born with bilateral exotropia and ptosis due to
mutations of the PHOX2A gene at chromosome 11q13 (938). Diagno-
sis is confirmed by MRI, which shows a normal appearing brainstem,
but very small or absent oculomotor nerves (939). Very thin sections
using steady-state imaging techniques (constructive interference in
steady state [CISS], fast imaging employing steady-state acquisition
[FIESTA]) to optimally identify the cranial nerves should be used in
these cases.
Midbrain Malformations
Tectal Enlargement Two groups of patients have been described in
which striking enlargement of the midbrain tectum was identified (9).
The most common of these is patients with the oculocerebrocutaneous
(also called OCCS and Delleman) syndrome, a disorder characterized
by a colobomatous ocular malformation, skin appendages (predomi-
nantly located near the orbit), and cerebral malformations consist-
ing of unilateral frontal PMG with PVNH, agenesis of the corpus
callosum (sometimes with interhemispheric cyst), large dysmorphic

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 486 Pediatric Neuroimaging

tectum, absent cerebellar vermis, and small cerebellar hemispheres
(246,247,940). Milder cases of OCCS may have normal orbits and cere-
bral hemispheres; they are identified by enlarged inferior colliculi and
absent cerebellar vermis (Fig. 5-146). Another group of patients with
tectal enlargement was characterized by an enormously enlarged quad-
rigeminal plate, but no other brain anomalies (9). The mechanism by
which these tectal anomalies develop is not known (9).
Midbrain Clefts Midbrain clefts are malformations of unknown cause
that result in oculomotor dysfunction, internuclear ophthalmoplegia,
and ptosis, probably due to involvement of the oculomotor nuclei
and median longitudinal fasciculus (941,942). In severe cases, ataxia,
dysarthria, and deafness may be present (942,943). It is likely that this
abnormality can be acquired due to intracranial hypotension, and this
is by far the most common cause (944). Therefore, all patients with this
appearance should be evaluated for intracranial hypotension. Some cases
may be developmental (941,942,945), as many patients are initially
discovered in childhood and have associated brain anomalies (10). In
either case, imaging shows a midline cleft in the mesencephalon, extend-
ing from the interpeduncular cistern posteriorly to the aqueduct that
seems nearly continuous with the third ventricle (941,942). Indeed, the
thalami seem to extend inferiorly into the cerebral peduncles, as if the
diencephalic-midbrain junction were inferiorly displaced and resulting
in a widened midbrain (10). The aqueduct may be elongated anteriorly,
as in an aqueductal “pouch” that appears to be an inferior extension
of the third ventricle into the midbrain. In our experience, cerebellar
hypoplasia is nearly always seen in congenital cases.
Midline Dorsal Clefts: Trisomy 14 The authors have seen a single
brain study of a patient with trisomy 14 in which a dorsal cleft was
present in the midbrain, giving the appearance on sagittal images of
a markedly widened aqueduct. Oculomotor dysfunction was present.
The embryogenesis of this malformation is unknown.
Malformations of Rh1 Including Cerebellar Malformations
Cerebellar Nodular Heterotopia with Overlying Dysgenesis
Although abnormal clusters of gray matter in the cerebellar white mat-
ter may be found incidentally, they usually coexist with other cerebellar

FIG. 5-146. Oculocerebrocutaneous (Delleman) syndrome, mild

case. Sagittal T1-weighted image (A) shows marked dorsal elongation
of the inferior colliculi (white arrow) and a dysmorphic-appearing
midline cerebellum. Axial T1-weighted images (B and C) show the
dysmorphic tectum (white arrows in B) and absence of the vermis
(C). In more severe cases, the corpus callosum is absent and polymi-
crogyria is present in a cerebral hemisphere. (These images courtesy
Dr. Junichi Takanashi, Chiba, Japan.)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 487

FIG. 5-147. Cerebellar heterotopia with

occipital dysplasia. Coronal T2- weighted
image (a) shows a large cluster of hetero-
topic neurons (white arrows) in the deep
right cerebellar hemisphere; the overlying
cortex has abnormal sulcation. Axial T2
weighted image through the lower cere-
brum (b) shows enlargement and abnormal
sulcation (white arrows) of the right occipi-
tal lobe. Note the hypoplastic left ocular
globe (white arrowheads).

malformations, most commonly abnormal foliation of the overlying
cerebellar cortex (717). Symptoms seem to arise from accompanying
malformations and not from the heterotopia themselves, but the source
of the symptoms is difficult to determine due to poor understanding
of the functions of the cerebellum (946–948). Imaging shows variably
sized nodules of gray matter intensity within the cerebellar white mat-
ter, usually associated with abnormal overlying foliation (Fig. 5-147).
In our experience, the occipital cortex is nearly always dysmorphic in
these patients (Fig. 5-147B).
Cerebellar Foliation Anomalies (Cerebellar Cortical Dysgene-
sis) Often referred to as cerebellar PMG or (in pathology literature) as
cerebellar heterotaxias, cerebellar cortical dysgenesis describes a group
of conditions in which the folial pattern of the cerebellar cortex is dis-
turbed, usually in association with diminished volume of the affected
portion of the cerebellum. In the absence of supratentorial anomalies,
affected patients are typically mildly affected (autistic features, speech
delay, ocular apraxia) or asymptomatic (845,949); the diagnosis may
be made incidentally when imaging is performed for unrelated rea-
sons. When focal, cerebellar foliation anomalies are typically isolated
anomalies. These anomalies are thought to result from disruption of
normal cerebellar cortical development by a genetic cause, such as a
mutation in a gene that alters the proliferation and migration of cer-
ebellar cortical neurons (particularly granule cells), or by a destructive
event in utero: fetal infection (especially with cytomegalovirus), prena-
tal hemorrhage, hypoxia-ischemia (which seems to particularly affect
the Purkinje cells), or exposure to toxins such as alcohol or radiation
(845,949,950).
Focal hemispheric dysgenesis is usually identified by abnormal
contour of the affected hemisphere or by lack of the normal arboriza-
tion of the cerebellar white matter (Figs. 5-148 and 5-149). (Normally,
the cerebellar fissures are radially oriented from the deep cerebellar

FIG. 5-148. Abnormal vermian foliation. Normal sagittal T1-weighted image (A) shows the primary fissure and prepyramidal
fissures separating the vermis into three sections of similar size. Sagittal T1-weighted image (B) shows abnormal foliation of the
vermis, diagnostic of vermian dysgenesis. Note that no normal primary fissure or prepyramidal fissure can be identified.

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 488 Pediatric Neuroimaging

FIG. 5-149. Two cases of focal cerebellar dysgenesis. Coronal T1-weighted images show (A) focal cortical thinning and
abnormal foliation in the right lateral posterior cerebellum (black arrows) and (B) focal left cerebellar hypoplasia with a
vertical cleft (white arrows).

nuclei on coronal images and the white matter bundles follow that
same orientation.) Abnormal fissure orientation (Fig. 5-149A) should
raise suspicion for focal dysgenesis; loss of volume or a frank cleft
may accompany the abnormal fissuration (Fig. 5-149B) (845). Focal
vermian dysgenesis is best identified on sagittal images by abnormal
contour or location of the fourth ventricle, or by abnormal foliation;
normally, the primary fissure and the prepyramidal fissure are easily
seen on midline sagittal images, roughly dividing the vermis into thirds
(Fig. 5-148A); an inability to identify them (Fig. 5-148B) should sug-
gest a malformation. Occasionally, diffuse (Fig. 5-150) malformations
of the cerebellar cortex are encountered without associated supraten-
torial dysplasias (951). Diffuse cerebellar cortical dysgenesis is usu-
ally associated with malformations of cerebral cortical development,
typically PMG or cobblestone cortex (see section “Malformations of
Cortical Development” in this chapter) (4,717). When the dysgenesis
is unilateral and the affected hemisphere is small, the anomaly is better
classified as cerebellar hemisphere hypoplasia (discussed later in this
section).
Duplication of Cerebellar Hemisphere
The authors are aware of only two cases of duplication of the cerebel-
lar hemisphere, one of which was associated with ipsilateral internal,
middle, and external ear duplication (952). In one patient, the affected
patient had no cerebellar signs or symptoms, while the second had a
calvarial protuberance in the occipital region, generalized hypotonia,
depressed deep tendon reflexes, and mild truncal ataxia. MRI in the

FIG. 5-150. Diffuse cerebellar cortical dysgenesis. Axial (A) and coronal (B) T1-weighted image show diffusely abnormal
foliation, with abnormally deep, nearly vertical fissures rather than normal fissures radiating outward from the deep cerebellar
white matter.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 489

sagittal and coronal planes makes the diagnosis if the supernumerary ventral and middle pons are absent. Jissendi-Tchofo et al. (954) propose
hemisphere and its peduncles can be identified. The embryologic cause three potential mechanisms, including abnormal axonal navigation,
of this malformation is not known. abnormal neuronal migration, and a combination of the two.

Pons Malformations
Pontine Tegmental Cap Dysplasia Patients with this pontine teg-
mental cap dysplasia present with cranial neuropathies; the eighth cra-
nial nerve is most commonly affected, followed by the seventh and fifth
cranial nerves. A swallowing disorder may be present, suggesting ninth
nerve involvement. Affected children may have gross deficits in motor
and cognitive function, suggesting supratentorial involvement, as well
(953,954). The diagnosis is made by MRI, which shows a small ventral
pons in association with a round or “beak-shaped” dorsal pontine protu-
berance (the tegmental cap, Fig. 5-151). The middle cerebellar peduncles
are small to nearly absent. Color fractional anisotropy maps show that
the tegmental cap is a white matter structure, composed of transversely-
oriented axons that seem to connect to the middle cerebellar peduncles
(Fig. 5-151F) and that the normal ventral transverse pontine fibers in the
Pontine Dysgenesis with Dorsal or Ventral Clefts Dorsal and ven-
tral longitudinal clefts are seen in the pons in a number of conditions;
they are rarely isolated malformations (9). Nearly all affected patients
have a combination of cranial neuropathies and long tract signs. The
clefts are believed to result from a defect in axonal navigation across
the pontine midline, particularly a defect in ventral pontine crossing of
axons from the middle cerebellar peduncles; as many of the molecular
signals that guide axons across the midline are similar in the cerebrum
and the brain stem, it is not surprising that many affected patients have
anomalies of the corpus callosum (Fig. 5-152) (9). Ventral pontine
clefts are also very common in patients with MEB and WWSs (see sec-
tion “Malformations of Cortical Development” earlier in this chapter)
(9) and are seen in horizontal gaze palsy with progressive scoliosis (see
above in this section) (932).

FIG. 5-151. Pontine tegmental cap dysplasia. Sagittal T1-weighted images

show ventral pontine hypoplasia and the appearance of a rounded (white
arrows in A) or beak-like (white arrows in B) “cap” over the dorsal pons. Axial
(C) and coronal (D) T1-weighted images show the “cap” (white arrows) forming
a rather flat anterior border to the fourth ventricle. Normal color FA map (E) of
the pons shows the red decussation of the middle cerebellar peduncles (white
arrows), blue corticospinal and corticopontine tracts (white arrowheads), red
transverse pontine fibers to pontine nuclei (black arrowheads), blue dorsal lon-
gitudinal tracts (black arrows) and green middle cerebellar peduncles (m). FA
map of pontine tegmental cap dysplasia (F) shows absence of the ventral decus-
sation of the middle cerebellar peduncles, a single ventral group of longitudinal
pontine fibers (blue fibers, white arrows), and the tegmental cap (red fibers, white
arrowheads), whose red color indicates transverse orientation of the fibers. The
middle cerebellar peduncles (green fibers, black arrows) are very small. Color
coding: red, transverse; blue, supero-inferior; green, anteroposterior.

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 490 Pediatric Neuroimaging

FIG. 5-151. (Continued)

FIG. 5-152. Brainstem cleft with callosal anomaly. Midline sagittal T1-weighted image (A) shows callosal hypogenesis
with only a small anterior corpus callosum (black arrows). The brainstem appears very thin. Axial T2-weighted image
(B) shows a large midline dorsal and ventral pontine cleft; on other images, the cleft continued into the medulla.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 491

FIG. 5-153. Dorsal medullary cap malformation. (A) Sagittal T2-weighted image shows nearly complete corpus
callosum agenesis and a dorsal gray matter intensity medullary mass (black arrow). (B) Axial T1-weighted image
shows the medullary cap remains of gray matter intensity, suggesting it is composed of ectopic neurons. Other images
showed hippocampal anomalies and abnormalities of the cerebellar nuclei in this patient. (These images courtesy
Dr. Susan Blaser, Toronto.)

Medulla Malformations
Medullary Tegmental Caps with Callosal Agenesis/Hypogen-
esis Rarely, dorsal medullary protuberances are identified on MRI in
infants being imaged for multiple anomalies of the musculoskeletal
(clinodactyly, rocker bottom feet), genitourinary, or gastrointestinal
systems. On sagittal images, a dorsal (tegmental) cap is seen at the level
of the medulla; absence or severe hypogenesis of the corpus callosum
is common in these patients (Fig. 5-153). The nature and cause of the
“cap” are not clear at present.
seen and others have reported patients with cerebellar hypoplasia after
incidentally noted intrauterine or early postnatal cerebellar hemor-
rhage (Fig. 5-154) (10,845). On MRI, the affected cerebellar hemi-
sphere ranges in size from nearly completely absent to slightly small.
The contour of the hemisphere may be smooth or irregular (with or
without clefts). Signal intensity of the affected hemisphere is usually
normal. Supratentorial findings range from normal to ventriculom-
egaly to schizencephaly and other cortical malformations.

Combined Hypoplasia and Atrophy in Putative Prenatal

Onset Degenerative Disorders
Pontocerebellar Hypoplasias
The pontocerebellar hypoplasias are discussed in Chapter 3, under the
heading of “Cerebellar Atrophy.”
Mid-Hindbrain Malformations with Congenital Disorders of
Glycosylation
The CDG are discussed in Chapter 3, under the heading of “Cerebellar
Atrophy.”
Other Metabolic Disorders with Cerebellar or Brainstem
Hypoplasia or Disruption
These disorders are discussed extensively in the last section of Chap-
ter 3.
Cerebellar Hemisphere Hypoplasia
Unilateral cerebellar hypoplasia is a rare anomaly. It is typically found
when imaging a patient with developmental delay or evaluation of a
syndrome such as Möbius or Goldenhar syndromes; occasionally, it is
found incidentally when imaging for unrelated events such as trauma
or headaches (843–845). Most authors believe that it is much more
commonly acquired than genetic, as it is often associated with cer-
ebellar clefts or cortical malformation (10,845,949). Indeed, we have
ANOMALIES OF THE CRANIOCERVICAL
JUNCTION (THE CHIARI MALFORMATIONS)
In 1891, Chiari (955) described three malformations of the hind-
brain, all of which were associated with hydrocephalus. These three
malformations will be discussed in the order in which they were
described.
Chiari I Malformations
The Chiari I malformation is defined as caudal cerebellar tonsillar ecto-
pia; that is, caudal extension of the cerebellar tonsils below the foramen
magnum. Affected children typically present clinically with occipital
or posterior cervical headaches (especially when straining or cough-
ing), lower cranial nerve palsies, otoneurologic disturbances (such as
disequilibrium, tinnitus, or vertigo), or dissociated anesthesia of the
extremities secondary to syringohydromyelia (956,957). Syringomy-
elia is present in about 10% at the time of diagnosis (958). Impaired
oropharyngeal function is reported to be common in children less than
3 years old (959). Several cases have been reported in which sleep apnea
was attributed to the Chiari I malformation (960–962). In infants and
nonverbal children, headaches may be manifested as irritability or
crying, often associated with arching (hyperextension) of the neck
(963). Older age at time of diagnosis is associated with increased risk
of headache and significant neurologic symptoms (958). Nystagmus,

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 492 Pediatric Neuroimaging
FIG. 5-154. Unilateral cerebellar hypoplasia secondary to prenatal cerebellar injury. Coronal fetal MR image
(A) shows heterogeneity (white arrows), likely hemorrhage, in the left cerebellar hemisphere. Postnatal coronal
T2-weighted image (B) confirms left cerebellar hypoplasia (black arrows) but shows no evidence of blood. (These
images courtesy Dr. Guido Gonzales, Santiago, Chile.)
particularly downbeat nystagmus, is reported to be strongly associated
with lesions of the foramen magnum, particularly with the Chiari I
malformation (964).
The Chiari I malformation is likely the result of several different
processes. The most common type of Chiari I malformation appears
to be the result of an abnormally small bony posterior fossa, as (a)
the clivus is often short or abnormally horizontal in affected patients
(Figs. 5-155 and 5-156) (965,966), (b) the straight sinus is more vertical
than normal (Fig. 5-157), (c) a strong correlation exists between poste-
rior fossa volume and degree of cerebellar ectopia (967), and (d) a high
incidence of craniovertebral anomalies has been noted (966,968,969)
in affected patients. Up to 90% of affected patients have median basi-
lar invagination (Figs. 5-156 and 5-158), with 20% showing additional
paramedian invagination. Many of the patients with basilar invagina-
tion and shortened clivus also have C-1 assimilation (969). There is
remodeling of the inferior surface of the foramen magnum that leads
to bony indentation between the assimilated C-1 and the superior fac-
ets of C-2. The foramen magnum is, thus, in an abnormal position that
results in an irreducible posterior odontoid invagination (Fig. 5-156)
(970). The odontoid invagination in combination with the abnormal
clivus, compounded by the tonsillar herniation and the abnormal posi-
tion of the inferior medulla, leads to progressive neural compromise
(Fig. 5-156) (969).
However, this theory of causation applies only to part of the group
that we identify by imaging as having the Chiari I malformation.
A number of other subgroups of patients can be identified with tonsil-
lar extension through the foramen magnum and resultant compression
of the neural structures and CSF spaces. One cause of such malforma-
tions may be effects ventriculoperitoneal shunts that are placed for
treatment of infantile hydrocephalus (956,971). It is likely that these
patients have premature closure of their cranial sutures because shunt-
ing of CSF reduces the volume of their brain; as a result, the forces
required to keep the sutures open disappear. When the brain subse-
quently grows enough to fill the cranial vault, the calvarium cannot
grow quickly enough to keep up with brain growth; as a result, the
brain grows downward with the tonsils ultimately protruding through
the foramen magnum. Similar tonsillar herniation can result from cal-
varial thickening in dysplasias of bone (972). Premature closure of mul-
tiple cranial and facial sutures due to genetic causes, such as Crouzon
Barkovich_Chap05.indd 492
syndrome and Pfeiffer syndrome, can develop Chiari I malformations
because the suture closure (particularly the lambdoid sutures) results in
a small posterior fossa and skull base, possibly exacerbated by increased
venous sinus pressure (973–975). Other syndromes that result in a
small skull base (primarily chondrodystrophies), can also result in ton-
sillar ectopia/Chiari I malformations (976,977).
Another group of patients with Chiari I malformation are those
with acquired deformities of the foramen magnum that lead to basilar
invagination (978). These patients, nearly always adults, also present
with headaches, cranial neuropathies, or syringohydromyelia. A fourth
subgroup, actually mislabeled as Chiari I malformations, is composed
of patients with myelomeningoceles and mild hindbrain anomalies
consisting primarily of tonsillar ectopia (2% of myelomeningocele
patients in Emery’s series of 100 autopsies of patients with myelom-
eningoceles had tonsillar ectopia as their only hindbrain anomaly
[979]). The patients in this subgroup have myelomeningoceles at birth,
often have supratentorial anomalies such as hypogenesis of the corpus
callosum, mild tectal beaking, and fenestrations of the falx, and prob-
ably should be classified as Chiari II malformations with mild hind-
brain manifestations.
Two other groups deserve mention. The first is patients with long
standing “compensated” hydrocephalus or pseudotumor cerebri who,
in fact, have chronic tonsillar herniation; indeed, up to 12% of patients
with longstanding pseudotumor cerebri may develop chronic tonsil-
lar herniation (980). The second is patients with intracranial hypoten-
sion secondary to chronic CSF leaks (the “sagging brain”) (981,982).
Both of these groups of patients can present with headaches that are made
worse by activity and, hence, may be considered as candidates for fora-
men magnum decompression, which is precisely the wrong therapy. The
group with chronic increased intracranial pressure can be identified by
looking for signs of hydrocephalus (large anterior recesses of the third
ventricle, commensurately enlarged temporal horns in the absence of
large Sylvian fissures, see Chapter 8) or pseudotumor cerebri (dilated
optic nerve sheaths, compressed venous structures, empty sella) on the
imaging studies. Those with intracranial hypotension can be identified
by the character of their headache (made worse by standing up, better
by lying down), associated clinical signs and symptoms (nausea, vom-
iting, cranial neuropathies, vertigo, hyperacusis, neck pain/stiffness)
(944,983,984) and certain specific imaging characteristics (Fig. 5-159):
5/6/2011 9:00:38 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 493

FIG. 5-155. Chiari I malformation with associated syringohydromyelia. A. The cer-

ebellar tonsil (white asterisk) is enlarged, compressed (pointed), and extends more
than 1.5 cm below the bottom of the foramen magnum. Notice that the upper cervi-
cal spinal cord is compressed (white arrow) between the odontoid and the cerebellar
tonsil. B. Sagittal T1-weighted image of cervical spine shows cervical hydromyelia
(white arrows). C. Axial T2-weighted image shows that the central canal of the cord
is dilated, confirming hydromyelia.

FIG. 5-157. Chiari I malformation. Sagittal T2-weighted image shows

FIG. 5-156. Chiari I malformation. Sagittal T1-weighted image shows compressed, low-lying cerebellar tonsils (white arrows). The clivus is nor-
platybasia and shortened clivus. Note the odontoid process pointing poste- mal, but the posterior fossa is small because of a steep tentorium cerebelli,
riorly and distorting the cervicomedullary junction. manifested by the nearly vertical straight sinus (large white arrows).

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 494 Pediatric Neuroimaging

FIG. 5-158. Chiari I malformation with horizontal clivus. Sagittal T1-weighted image (A) shows an abnormally
horizontal clivus (white arrows) and low, pointed cerebellar tonsils (black arrows) with little subarachnoid space
around the tonsils, medulla, and upper cervical spinal cord. Axial T2-weighted image (B) at the foramen magnum
level shows the medulla (m) being compressed (white arrows) by the low-lying tonsils (t).

FIG. 5-159. Tonsillar ectopia secondary to

intracranial hypotension. Sagittal T1-weighted
image (A) shows low-lying cerebellar tissue (white
arrowheads), flattening of the ventral pons (black
arrows) against the clivus, an enlarged pituitary
gland (white arrow), and sagging floor of the
third ventricle. Axial T2-weighted image (B)
shows some narrowing of the lateral ventricles
and excessive fluid (white arrows) in the subdural
space surrounding the cerebral hemispheres.
Coronal T1-weighted image (C) shows smooth,
uniform enhancement (white arrows) of all dural
surfaces.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 495

the brainstem and third ventricle “sag” inferiorly, the pituitary gland is
upwardly convex, the dura is thickened and shows marked enhance-
ment after administration of intravenous contrast, and the dural
venous sinuses are enlarged (944,981,982). In very severe, longstanding
cases, the midbrain may appear swollen and flattened (944). In these
patients, the site of the CSF leak (often a spinal arachnoidal diverticu-
lum) should be identified and the leak treated (983,984). The CSF leak
can be diagnosed by the finding of extrathecal CSF on spinal imag-
ing (MRI first with myelogram to follow if MRI is equivocal); initial
treatment of choice is epidural blood patch (983,984). As a result of
another, iatrogenic, cause of intracranial hypotension, Chiari I malfor-
mations can develop as a consequence of lumbar to peritoneal shunting
of cerebrospinal fluid (985,986); the tonsillar herniation in this situa-
tion, which is similar in pathophysiology to spontaneous intracranial
hypotension, may reverse after removal of the shunt.
In general, tonsillar ectopia should not be considered pathologic
unless the tonsils are compressed (pointed) and the CSF spaces at the
foramen magnum and C-1 are effaced. Mild cerebellar tonsillar ectopia
(<5 mm below a line from the basion to the opisthion on a sagittal
midline image in adults, and with no compression of the cervicomed-
ullary junction or the subarachnoid space at that level) appears to be
of no clinical significance in most patients (987–989). Indeed, Milhorat
et al. (966) found that the tonsils were at least 5 mm below the fora-
men magnum in 91% of patients with symptomatic Chiari I malfor-
mations. Thus, it appears that when the tonsils extend more than 5 mm
below the foramen magnum and the retrocerebellar cisterns and those
surrounding the craniocervical junction are obliterated on MRI, clini-
cal symptoms are more likely to develop (966). The extent of asymp-
tomatic tonsillar descent below the foramen magnum appears to be
age dependent. Children between the ages of 5 and 15 years old have
slightly greater tonsillar ectopia than adults or children younger than
5 years old. Asymptomatic tonsillar ectopia of 6 mm should not be
considered pathologic in children between the ages of 5 and 15 years
(988,990). The dens should also be evaluated on the sagittal images,
as abnormally increased posterior inclination of the dens is associated
with an increased incidence of syringohydromyelia (991).
Although routine MRI studies are often sufficient to make the
diagnosis of Chiari I malformation, CSF flow studies are sometimes
useful in patients in whom either the clinical history or imaging study
is atypical or borderline. Flow studies will show decreased CSF flow
at the level of the foramen magnum, decreased CSF flow through the
vallecula and increased motion of the brainstem and cerebellar ton-
sils in patients with symptomatic Chiari I malformations (Fig. 5-160)
(992–994). Of note, patients with normal CSF flow studies are rarely
symptomatic from their Chiari I malformation (995,996) and nearly
all patients with Chiari I malformations and syringohydromyelia (995)
or occipital headaches (996) have abnormal CSF flow studies. In addi-
tion to the qualitative findings, quantitative analysis of CSF motion
shows prolonged CSF systole in the prepontine cistern, reduced sys-
tolic velocities and duration of CSF systole in the cervical subarach-
noid space just below foramen magnum, increased CSF velocity at the
foramen magnum, and increased duration of CSF systole in the cervi-
cal subarachnoid space at the C-2 to C-3 level (most pronounced in
patients with syringes) (994). Some improvement of all of the above
flow characteristics is seen after successful foramen magnum decom-
pression (993–996).
In all patients with Chiari I malformations, the spine should be
imaged to look for concurrent syringohydromyelia (Fig. 5-160E) which
has an estimated incidence of 20% to 65% (966,989,997,998). Syringo-
hydromyelia is discussed in Chapter 9.

FIG. 5-160. Normal and abnormal CSF flow studies at the foramen magnum. A–D. Normal CSF flow. Images during CSF systole show
abundant downward flow (high signal intensity) through the anterior and posterior foramen magnum and the foramen of Magendie.
Note that there is little apparent brainstem or cerebellar motion. E. Sagittal T2-weighted image shows horizontal clivus (white arrows),
vertical straight sinus (white arrowheads), severe tonsillar herniation, and cervicothoracic syringohydromyelia (black arrows). F–I.
Reduced CSF flow and increased tonsillar motion in a patient with a Chiari I malformation. During CSF systole (F and G), the column of
CSF flow is compressed (black arrowheads) at the level of the posteriorly pointing odontoid. Increased downward motion (hyperintensity,
black arrowheads) of the brainstem and cerebellar tonsils is present. As CSF diastole begins (H), hypointensity of anterior CSF flow is
noted but is again reduced at the odontoid. Low signal intensity develops in the brainstem and cerebellum (black arrows in I), indicating
increased upward motion of those structures.

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 496 Pediatric Neuroimaging

FIG. 5-160. (Continued)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 497

Chiari II Malformations
The Chiari II malformation is part of a complex malformation
involving the hindbrain, spine, and mesoderm of the skull base and
spinal column (999). Virtually all patients with Chiari II malformations
have myelomeningoceles (some define the Chiari II malformation as
the hindbrain deformity seen in patients with myelomeningoceles and,
indeed, the initial descriptions were of patients with myelomeningo-
celes [955,1000]). Often, the myelomeningocele is discovered in utero
as a result of prenatal sonography or elevation of alpha-fetoprotein on
amniocentesis. After postnatal closure of the myelomeningocele (usu-
ally within the first 48 hours of life), more than 80% of affected patients
develop hydrocephalus (1001); it is in the evaluation of the hydroceph-
alus that the radiologist is most often exposed to these patients in the
postnatal period (although imaging is also performed prenatally by
fetal sonography and fetal MRI). Less commonly, the infant develops
swallowing difficulties, stridor, apneic spells, weak cry, or arm weak-
ness and is imaged to look for compression of the brainstem at the
foramen magnum or C-1 level (1002). Patients with brainstem dys-
function have a significantly greater mortality than those without, even
if decompressive surgery is performed (1003). Epilepsy occurs in 17%
of patients with myelomeningoceles, almost always a result of CNS
pathology beyond the manifestations of the Chiari II malformation:
encephalomalacia/stroke, PVNH, or calcifications (1004).
Neural tube closure is a complex process, requiring a number of
cell biological functions. Mutations of more than 200 genes have been
found to cause neural tube defects in mice; however, the pattern of
occurrence in humans suggests a multifactorial polygenic or oligogenic
etiology (1005), emphasizing the importance of gene-gene and gene-
environment interactions in the origins of these defects. Defects of the
cytoskeleton, cell cycle and molecular regulation of cell viability are
prominent among the mice with neural tube defects (1005). In addi-
tion, many transcriptional regulators and proteins that affect chroma-
tin structure are necessary for neural tube closure (1005), although
the downstream molecular pathways regulated by these proteins are
unknown. Some key signaling pathways involved in the formation of
myelomeningoceles have been identified, including over-activation of
SHH signaling and loss of function in the planar cell polarity path-
way, retinoid signaling, and inositol signaling (1005). These processes
involved in neural tube closure are critical to the development of focal
expansions of the central canal of the developing neural tube that will
eventually form the cerebral vesicles and ventricles (1006). If the pos-
terior neuropore fails to close, the cerebral ventricles will fail to expand
sufficiently for a normal sized posterior fossa to form and for the
thalami to separate normally; as a result, a pressure gradient develops
between the intracranial (higher pressure) and intraspinal (lower pres-
sure) spaces. The pressure gradient causes posterior fossa structures
to stretch and herniate downward. This theory, proposed by McLone
and Knepper (1006), is supported by results of fetal myelomeningo-
cele repair, which show improvement of the posterior fossa malfor-
mation, in addition to improvement of hydrocephalus (Fig. 5-161)
(1007,1008).
This same theory (1006) also explains the characteristics of the
hindbrain findings, which are best conceptualized as resulting from a
normal sized cerebellum developing in an abnormally small posterior
fossa with a low tentorial attachment in the setting of a rostral-to-caudal

FIG. 5-161. Chiari II malformation before (at 22 post conceptual weeks) fetal repair of myelomeningocele and after
birth. A and B. Fetal MR images. Sagittal image (A) shows ventriculomegaly associated with hypogenesis of the corpus
callosum (small white arrows point to hypogenetic corpus), small crowded posterior fossa with cerebellum (small black
arrows) herniating through foramen magnum, and lumbosacral spina bifida (large black arrows). Axial image (B) shows
marked ventriculomegaly.

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 498 Pediatric Neuroimaging

FIG. 5-161. (Continued) C–E. Postnatal images. Sagittal

T1-weighted image (C) shows the hypogenetic callosum (small
white arrows). The cerebellum has returned to almost normal
after in utero closure of the myelomeningocele. The quadrigemi-
nal plate (large white arrows) is slightly beaked inferiorly and
posteriorly. Axial T2-weighted image (D) shows that the ventricle
size has returned to nearly normal after the myelomeningocele
repair. Axial T1-weighted image shows an incidental nodule of
heterotopic gray matter (arrow) in the wall of the left ventricular
trigone. Our experience indicates that about 15% of patients with
myelomeningoceles have periventricular nodular heterotopia.

pressure gradient. The result is that the cerebellum is “squeezed” out
of the posterior fossa as it grows. The cerebellum is indented superi-
orly by the tentorium and inferiorly by the foramen magnum or, more
commonly, the posterior arch of C-1. The pons and fourth ventricle
are stretched inferiorly and narrowed in their anterior-posterior diam-
eters (Figs. 5-162 and 5-163). The medulla is also stretched inferiorly
and extends below the foramen magnum. The cervical spinal cord is
stretched inferiorly as well. The dentate ligaments, which attach to the
lateral aspects of the spinal cord and hold it in place, allow a variable
amount of caudal displacement of the cervical spinal cord; however,
the ligaments eventually restrict caudal displacement of the cord. If
the medulla is “sucked” down further than the dentate ligaments will
allow the spinal cord to move, a characteristic cervicomedullary kink
is formed (Figs. 5-162 and 5-163). This kink is seen in approximately
70% of patients with the Chiari II malformation (979,999). The cer-
ebellum sometimes extends anterolaterally into the cerebellopon-
tine and cerebellomedullary angles, wrapping around the brainstem
(Fig. 5-163). The fourth ventricle is low in position (typically below
the pons), vertically oriented, and narrowed in its anterior-posterior
diameter (Figs. 5-162 and 5-163). The cerebellar vermis is usually par-
tially herniated into the cervical spinal canal (Figs. 5-162 and 5-163).
The herniated cerebellum often degenerates; when this degeneration
is severe, virtually no cerebellum may be present (Fig. 5-164) (999).
Occasionally, the fourth ventricle can herniate posteriorly and infe-
riorly, behind the medulla and beneath the vermis; this condition is
known as “an encysted fourth ventricle” (999). The fourth ventricle
may also be isolated or “trapped” (see Chapter 8) as a result of a com-
bination of aqueductal narrowing (or scarring) and diminished CSF

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 Chapter 5 • Congenital Malformations of the Brain and Skull 499

FIG. 5-162. Severe Chiari II hindbrain malformation. Sagittal T1-weighted image (A) shows a severe hindbrain anomaly. The quadrigeminal plate (small
white arrows) is stretched posteriorly and inferiorly, the cerebellum is small and stretched inferiorly. The fourth ventricle (small white arrowhead) is at
the craniocervical junction. A tongue of cerebellar tissue (black arrows) extends inferiorly into the cervical subarachnoid space. The cervicomedullary
kink (large white arrowhead) lies just ventral and inferior to the cerebellar tissue. Note the abnormal posterior extension of the third ventricle (large white
arrow). Axial T2-weighted images (B and C) show periventricular nodular heterotopia (black arrows) and a large massa intermedia (white arrow), as well
as ventriculomegaly. Note that the temporal cortex seems to have too many gyri that are too small; this is stenogyria due to the shunted hydrocephalus.

flow through the fourth ventricular outflow foramina or the basilar
cisterns (Fig. 5-165).
The fourth ventricle may be very small in patients with Chiari II
malformations (Fig. 5-162); therefore, the isolated fourth ventricle may
not look enlarged on casual observation. Consequently, a “normal-
sized” fourth ventricle in a patient with a Chiari II malformation should
initiate a search for hydrocephalus. When affected patients have hydro-
cephalus or an isolated fourth ventricle, the spine should be examined
because of a high incidence of associated syringohydromyelia (Fig.
5-165). Conversely, when worsening syringohydromyelia develops in
patients who have had myelomeningocele repairs (almost all of whom
will have a Chiari II malformation), the head should be studied to look
for worsening hydrocephalus or a trapped fourth ventricle.
The mesencephalic tectum (quadrigeminal plate) is often distorted
in patients with the Chiari II malformation, probably secondary to
compression by the temporal lobes combined with the rostral-caudal
pressure gradient; the result is that the tectum is stretched posteri-
orly and inferiorly (“beaked” tectum, Figs. 5-162 and 5-164) (1009).
Another finding that may be present is a posterior concavity of the
petrous bones and, less commonly, clivus (Fig. 5-165), probably result-
ing from pressure effects of the cerebellum and brainstem in the small
posterior fossa (1010). This “scalloping” of the petrous bones may be
difficult to appreciate on MRI.
Supratentorial anomalies are commonly associated with Chiari
II malformations. Abnormalities of the corpus callosum are seen in
70% to 90% of affected patients, usually consisting of hypoplasia or

FIG. 5-163. Typical Chiari II malformation. Sagittal T1-weighted image (A) shows mild enlargement of the inferior colliculi (white arrow), narrowing
and inferior displacement of the fourth ventricle (white arrowhead), and the cerebellar tongue and cervicomedullary kink in the upper cervical spine.
The corpus callosum is thin and lacks an inferior genu. Axial T2-weighted images (B and C) show cerebellar tissue (white arrows) extending anteriorly
around the brainstem due to the small posterior fossa.

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 500 Pediatric Neuroimaging
FIG. 5-164. Chiari II malformation with near absence of the cerebellum. (A) Sagittal T1-weighted MR images show callosal hypo-
genesis, a very small posterior fossa, elongation of the tectum (small white arrows) and only a small remnant of the cerebellum (in the
cervical subarachnoid space, large white arrow). In (B), the occipital lobe (white arrowhead) can be seen extending down to the foramen
magnum.
hypogenesis (absence of the splenium and absence of the rostrum)
(Figs. 5-161 and 5-163) (57); callosal hypogenesis may, however, be
more severe (Fig. 5-165). PVNH are present in 10% to 15% of affected
children (Fig. 5-162). Enlargement of the caudate heads and massa
intermedia is common (1011). Another common anomaly, possibly
due to chronic hydrocephalus, is fenestration of the falx cerebri, with
interdigitation of gyri across the interhemispheric fissure at the sites
of fenestration; this is a nonspecific finding seen in all patients with
chronic hydrocephalus and in many with congenital mesenchymal
FIG. 5-165. Chiari II malformation with isolated fourth ventricle. Sagit-
tal T1-weighted image shows a large fourth ventricle (white arrows) with a
very narrow aqueduct and decompressed lateral ventricles. Note multiple
small gyri in the occipital lobe, compatible with stenogyria. The corpus cal-
losum is hypogenetic. The clivus is very thin, presumably due to pressure
erosion. Note the cervical syringohydromyelia (white arrowheads).
Barkovich_Chap05.indd 500
dysgenesis. Prominence of the occipital horns and of the posterior
third ventricle is common and can remain even after shunting (Fig.
5-162) (1011–1013), possibly related to the abnormal corpus callosum
and resulting from a deficiency of white matter tracts in the posterior
aspect of the cerebrum. Also after shunting, the medial walls of the
ventricular trigones often appear dysplastic and a large CSF-contain-
ing structure may appear between the atria and occipital horns of the
lateral ventricles. The gyral pattern is often abnormal in the temporal
and occipital lobes after shunting, having the appearance of multiple
small gyri (Figs. 5-162 and 5-165). This pattern is not PMG, because
the cortex is of normal thickness but may be secondary to decompres-
sion of the expanded (by hydrocephalus) cortex, abnormal interaction
of the developing cerebral cortex with the overlying leptomeninges, or,
much less likely, to cortical dysgenesis of the hemisphere medial to the
atria and occipital horns. This appearance has been called stenogyria
(717,1014).
Analysis with DTI and fiber tracking shows abnormalities of the
fornices and cingula, which were reported as discontinuous or dys-
plastic in 69% to 77% of patients (1015). (These abnormalities may
be associated with memory and learning deficits, although this result
needs to be confirmed.) The cause of these white matter anomalies
may be genetic or mechanical (secondary to hydrocephalus) (1015).
When very young patients with the Chiari II malformation are
imaged on CT, irregularity of the surfaces of the inner and outer table
of the skull is frequently seen. This lacunar skull or Luckenschädel
appearance is explained by McLone and Knepper as being the result of
incomplete expansion of the calvarium in utero, with resultant disorga-
nization of the collagenous outer meninges from which the membra-
nous calvarium forms (1006). It is of no diagnostic significance in the
era of CT and MRI, and it seems to normalize by age 6 months.
The multiple findings described above are present in a variable
proportion of patients (Table 5-8). It is unusual to see all of the cere-
bral and cerebellar manifestations of the Chiari II malformation in a
single patient. The hindbrain deformity can be extremely severe, with
near-total absence of the cerebellum or it can be relatively mild with
only cerebellar tonsillar ectopia. The patients with mild hindbrain
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 Chapter 5 • Congenital Malformations of the Brain and Skull 501

ANOMALIES OF THE MESENCHYME

TABLE 5-8 Frequency of Brain and (MENINGES AND SKULL)
Spine Anomalies in Patients
Cephaloceles and Other Calvarial and Skull Base
with Chiari II Malformations
Defects
Anomaly Frequency Definition, Causes, and Classification
Myelomeningocele Always Definition and Causes

Hydrocephalus Almost always The term cephalocele refers to a defect in the skull and dura with
extracranial extension of intracranial structures. Cephaloceles are
Dysplastic tentorium Almost always divided into four types (1018,1019). Meningoencephaloceles are her-
Small posterior fossa Almost always niations of CSF, brain tissue, and meninges through the skull defect.
Meningocele refers to herniation of the meninges and CSF only. Atretic
Luckenschädel Almost always
cephaloceles are forme fruste of cephaloceles consisting of dura, fibrous
Caudal displacement of brainstem Usually tissue, and degenerated brain tissue; they are most common in the pari-
Cervicomedullary kink Usually etooccipital area. Glioceles consist of a glial-lined cyst containing CSF.
In all of these conditions, the skull defect and herniation most com-
Upward cerebellar herniation Usually
monly occur in the midline. Occasionally, cephaloceles may develop in
Large massa intermedia Usually adults, due to gradual thinning of bone, most commonly in the walls of
Elongated cranial nerves Usually the sphenoid sinus or mastoid air cells. Ultimately, dura, leptomeninges,
and sometimes brain may herniate through the thinned bone causing
Tectal beak Usually an acquired cephalocele. These can become symptomatic (usually hear-
Callosal hypogenesis Usually ing loss or recurrent otitis and otorrhea) and require repair (1020).
The cause of congenital cephaloceles has not been fully deter-
Syringohydromyelia ∼50%
mined. Some argue that cephaloceles result from a failure of neuru-
Malformations of cortical development Occasionally lation (failure of primary neural tube closure) (1021–1024). These
Aqueductal stenosis Occasionally authors note that the most common sites of cephalocele and myelocele
formation correlate well with either failure of closure of the sites of
primary neural tube closure (1021), failure of the closure to propa-
gate from the site of primary closure (1022), or abnormal location of
deformities are often classified as having the Chiari I malformation; closure (1023). Others argue that the disorders of neurulation should
however, the presence of supratentorial anomalies and myelomenin- result in cerebral tissue with disorganized neuroepithelial patterning,
gocele suggests that these patients belong in the Chiari II classification. such as exencephaly, rather than the typically well-developed neural
It should be noted that the term “Arnold-Chiari malformation” is only structures seen in cephaloceles (4,1025). These authors believe that
properly applied to the Chiari II malformation. cephaloceles are the result of a postneurulation event in which brain
tissue herniates through a defect in the mesenchyme that will become
cranium and dura (1025,1026). In support of this theory, Gluckman
Chiari III Malformations et al. (1025) showed that in a chick model there is a critical time point
The Chiari III malformation was originally defined as a condition (at the end of the embryonic period) during postneurulation rapid
characterized by herniation of posterior fossa contents (the cerebel- brain growth when encephaloceles are prone to occur; neural tissue
lum and, sometimes, brainstem) through a posterior spina bifida at the herniates through a mesenchymal defect resulting in decompression
C-1 to C-2 level (955). A variable amount of cerebellar tissue remains of the primitive ventricle. This theory best explains the distorted,
in the posterior fossa. Rather than a variant of Chiari malformation, stretched appearance seen in the brain adjacent to the calvarial defect.
in the authors’ opinion, this condition should be considered a high However, it is most likely that cephaloceles can be the end result of
cervical myelocystocele (see Chapter 9 for a discussion of myelocys- several developmental disorders. Those extending through the skull
toceles). Using this definition, Chiari III is an extremely rare condi- base, which is formed of endochondral bone, may be caused by either
tion; the author has seen only three such cases. More recently, many failure of induction of the bone resulting from faulty closure of the
neurosurgeons have begun to classify all low occipital encephaloceles neural tube (1027,1028) or failure of the basilar ossification centers to
or those with an occipito-cervical encephalocele with a small poste- unite (1029). The calvarium and cranial dura are derived from mesen-
rior fossa and a caudally displaced brainstem (1016) or herniation of chyme that migrates from the neural crests and the paraxial mesoderm
posterior fossa contents through a low occipital and/or upper cervical (1030,1031). Cephaloceles through the calvarium may be secondary to
osseous defect (Fig. 5-166) (1017). Patients diagnosed by these more defective induction of the bone, focal dysgenesis of the dura, pressure
recent criteria are more common; therefore, the diagnosis of Chiari III erosion of the bone by an intracranial mass or cyst (1027,1032,1033),
malformation has become more common in the past 10 years. or failure of closure of the neural tube (1021,1022).
Affected patients usually present with difficulty in breathing and
swallowing as well as with long tract signs (that may be secondary to Classification of Cephaloceles
the disorganization of brainstem nuclei), seizures and developmental Cephaloceles are named for the location of the bone defects through
delay (1017). Definitive diagnosis is established by MRI, which shows which they course. The categories of cephaloceles include the (a)
the cerebellum, brainstem, or cervical spinal cord herniating through occipito-cervical (involving the occipital bone, foramen magnum, and
a high cervical spina bifida (Fig. 5-166). Treatment is surgical repair; posterior arches of upper cervical vertebrae, and often called Chiari
outcome is guarded (1017). III malformations as discussed in the previous section), (b) occipital,

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 502 Pediatric Neuroimaging
FIG. 5-166. Chiari III malformation. Sagittal T1-weighted image (A) and axial T2-weighted image (B) show
cerebellar and brainstem tissue (arrows) herniating through dorsal osseous defects in the lower occipital bone
and the upper cervical vertebrae.
(c) parietal, (d) frontal, (e) temporal (along the superior surface of the
petrous ridge), (f) frontoethmoidal (between nasal bones and ethmoid
bone), (g) sphenomaxillary (through orbital fissures into pterygo-
palatine fossa), (h) spheno-orbital (through defect in sphenoid bone
or optic canal/orbital fissure into orbit), (i) nasopharyngeal (through
ethmoid, sphenoid, or basiocciput into nasal cavity or pharynx), and
(j) lateral (along coronal or lambdoid sutures) (1034). A complete dis-
cussion of cephaloceles in all of these locations is beyond the scope of
this book. In this section, cephaloceles in the four most common and,
therefore, most clinically relevant locations will be discussed. Nasal
dermoids and nasal gliomas are included in the section on frontoeth-
moidal cephaloceles, as the clinical presentation can be very similar;
moreover, dermoids and cephaloceles may have a common etiology
(1029,1035). Finally, this section includes a discussion of calvarial der-
moids and other masses that present as calvarial masses in childhood,
as well as congenital calvarial defects, both of which can mimic cepha-
loceles.
Occipital Cephaloceles The occipital bone is the most common
location for cephaloceles in the white populations of Europe and North
America, accounting for approximately 80% of cephaloceles in that
group. With Western populations becoming more ethnically mixed,
however, frontal cephaloceles are being seen much more frequently
and are now, overall, as common as occipital ones (1036). As with all
cephaloceles, neurodevelopmental outcome is related to the size of
the cephalocele, the amount of tissue present in the sac, and the pres-
ence of associated anomalies (up to 50%) (1036,1037). Supratentorial
and infratentorial structures are involved with equal frequency. Not
uncommonly, supratentorial structures, infratentorial structures, and
the tentorium are all included within the cephalocele. The tentorium
cerebelli may be dysplastic (1038). The diagnosis is usually obvious
clinically, and imaging studies are ordered to answer two major ques-
tions: (a) are other severe brain anomalies present? and (b) do the dural
venous sinuses (superior sagittal sinus, straight sinus, and transverse
sinuses) course within the cephalocele? MRI is the modality of choice
Barkovich_Chap05.indd 502
to answer these questions (Figs. 5-167 to 5-169). CT better depicts the
bony changes (Fig. 5-169A), but routine MRI studies (Figs. 5-167 and
5-168) will show the amount of brain tissue versus fluid in the cepha-
locele in addition to demonstrating associated cerebellar cortical dys-
plasia, venous sinus anomalies, dorsal interhemispheric cysts, callosal
anomalies, gray matter heterotopia, tonsillar and brainstem ectopia, or
Dandy-Walker malformations, all of which have higher frequencies in
patients with cephaloceles (1018,1027,1033,1039). The integrity and
the course of the dural venous sinuses are best demonstrated by the use
of MR venography (1038,1040) acquired at the time of the MRI study
(Figs. 5-167 and 5-170). Noncontrast 2D time of flight (TOF) acquisi-
tion in the coronal plane is optimal for the venogram (1040).
Frontoethmoidal Cephaloceles, Nasal Dermoids, and Nasal
Gliomas
Embryology. Frontoethmoidal cephaloceles, nasal gliomas, and nasal
dermoids are included in the same section because all three can pres-
ent as congenital midline nasal masses (229). Moreover, all three are
believed to have a similar embryological derivation, resulting from a
lack of normal regression of a projection of dura that extends through
the embryologic foramen cecum, between the developing nasal cartilage
and nasal bone (Fig. 5-171) (229,1029). If the dural projection remains
adherent to the skin and pulls it inward, a small dimple will develop on
the surface of the nose. The dimple is the orifice of a dermal sinus tract
that can extend superiorly along the path of the dural projection for a
variable distance, sometimes all the way into the cranial vault through
the foramen cecum (Fig. 5-172). Dermal or epidermal cysts can develop
anywhere along the dermal sinus tract. Cephaloceles presumably
result from herniation of intracranial tissues into the dural projection
through the foramen cecum (Fig. 5-173) (1029). Nasal gliomas (nasal
cerebral heterotopia) are accumulations of dysplastic brain tissue in the
nasal cavity or subcutaneous tissue that are separate from intracranial
contents (Fig. 5-174). They are postulated to result from herniation of
brain tissue into the dural projection with subsequent regression of the
more superior portion of the projection (229,1029).
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 Chapter 5 • Congenital Malformations of the Brain and Skull 503

FIG. 5-167. Occipital cephalocele with gray matter heterotopia. A. Sagittal T1-weighted image shows a small pos-
terior fossa with brainstem and cerebellum stretched posteriorly toward an occipital bone defect. A mostly cystic
mass (white arrows) extends through the defect. B. Axial T2-weighted image shows the vermis stretched posteriorly
through the calvarial defect. A small amount of vermis extends through the calvarial defect. C. Axial T1-weighted
image shows multiple subependymal nodules (white arrowheads) of gray matter in the walls of the lateral ventricles.
D. Sagittal view of a 2D TOF venogram shows no venous anomalies.

Clinical and Imaging Aspects. The frontoethmoidal region is
the most common location of encephaloceles in southeastern Asia
(1018,1027,1041–1043) and, with the extensive migration of people
from southeastern Asia to North America, they have become roughly
as common as occipital cephaloceles in North America (1036). They
are subdivided by location into three subtypes. Nasoethmoidal cepha-
loceles are the most common of the frontoethmoidal region (1044),
extending through a defect between the nasal bones and the nasal carti-
lage. In the nasofrontal group, the defect is located between the frontal
and nasal bones. The defect in naso-orbital cephaloceles is bordered
anteriorly by the frontal process of the maxilla, and posteriorly by the
lacrimal bone and the lamina papyracea of the ethmoid bone (1043).
Many frontoethmoidal cephaloceles involve both the nasoethmoidal
and naso-orbital regions (1041). Clinical presentation of frontoeth-
moidal cephaloceles, nasal dermal cysts, and nasal gliomas is similar,
usually nasal stuffiness or a nasal mass (1028,1042). If examination
reveals a nasal dimple, the diagnosis of dermal sinus is established and
an imaging study is required to search for an associated (epi)dermal
cyst and intracranial communication of the sinus, which puts the child
at risk for intracranial infection (Fig. 5-175). If no dimple is seen, an

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 504 Pediatric Neuroimaging

FIG. 5-168. Occipital cephalocele.

A. Sagittal T1-weighted image shows
a large occipital cephalocele. Both
supratentorial and infratentorial
brain tissues are distorted as they
enter the sac along with CSF from
cisterns and the fourth ventricle. B.
Axial T2-weighted image shows the
supratentorial and infratentorial
structures stretching into the cepha-
locele sac.

FIG. 5-169. Small occipital infratentorial cephalocele.

(A) Surface rendering of the calvarium from a CT scan shows a
tiny opening (black arrow) in the midline just above the nuchal
muscular insertion line. On sagittal T2-weighted image (B), the
lesion (white arrow) appears to be filled with CSF but is obscured
by chemical-shift artifacts. The posterior fossa looks otherwise
normal. (C) A T1-image shows the cephalocele (white arrows) as
a CSF-intensity lesion coursing through subcutaneous fat.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 505

FIG. 5-170. Use of MR venography to demonstrate dural sinuses in cephalocele sac. Sagittal T1-weighted image (A) shows the occipital cephalocele. 2D
TOF venogram (B) shows dural venous sinuses (arrows) in the cephalocele sac. This is important information for the surgeon.

FIG. 5-171. Embryology of the frontoethmoidal

region. Nasal dermoids, frontoethmoidal cephaloce-
les, and nasal gliomas all are believed to have similar
embryologic derivations. Frontal cephaloceles presum-
ably result from lack of closure of the fonticulus fronta-
lis (A) with herniation of brain tissue or dura through
the calvarial opening. Normally, a projection of dura
extends through the embryologic foramen cecum (B),
between the developing nasal cartilage and nasal bone.
Normal regression leads to a normal skull base and
frontonasal region, as in (C). Lack of regression leads to
frontonasal pathology. (Reprinted from Barkovich AJ,
Vandermarck P, Edwards MB, Cogen PH. Congenital
nasal masses: CT and MR imaging features in 16 cases.
Am J Neuroradiol 1991;12:105–116, with permission.)

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 506 Pediatric Neuroimaging

FIG. 5-172. Formation of nasal dermal sinuses. If the dural projection (Fig. 5-171B)
remains adherent to the skin, a small dimple will develop on the surface of the nose. The
dimple is the orifice of a dermal sinus tract that can extend superiorly along the path of
the dural projection for any distance, including all the way into the cranial vault through
the foramen cecum. Dermoids or epidermoids may develop anywhere along the tract.
(Reprinted from Barkovich AJ, Vandermarck P, Edwards MB, Cogen PH. Congenital
nasal masses: CT and MR imaging features in 16 cases. Am J Neuroradiol 1991;12:105–
116, with permission.)

FIG. 5-173. Formation of frontoethmoi-

dal cephaloceles. Cephaloceles presumably
result from herniation of intracranial tissues
into the dural projection through the fon-
ticulus frontalis (A) or foramen cecum (B).
(Reprinted from Barkovich AJ, Vandermarck
P, Edwards MB, Cogen PH. Congenital nasal
masses: CT and MR imaging features in 16
cases. Am J Neuroradiol 1991;12:105–116,
with permission.)

FIG. 5-174. Formation of nasal gliomas (nasal cerebral heterotopia). These accumulations
of dysplastic brain tissue in the nasal cavity or subcutaneous tissue are postulated to result
from herniation of brain tissue into the dural projection (Fig. 5-171B) with subsequent
regression of the more superior portion of the projection. (Reprinted from Barkovich AJ,
Vandermarck P, Edwards MB, Cogen PH. Congenital nasal masses: CT and MR imaging
features in 16 cases. Am J Neuroradiol 1991;12:105–116, with permission.)

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 Chapter 5 • Congenital Malformations of the Brain and Skull 507

FIG. 5-175. Nasal dermal sinus with epidural dermoid cyst. Axial CT scan (A) shows an enlarged, unclosed foramen cecum (white
arrow). Midline sagittal reformation of CT scan (B) shows an anterior frontoethmoidalnasal bony canal (black arrows) corresponding
to the dermal sinus tract, with remodeling of surrounding bone. Midline sagittal T2 MR image (C) shows the encysted epidural por-
tion of the dermal tract (t), the naso-ethmoidal tract (white arrows) leading from the dimple (white arrowhead) and adjacent brain
edema and abscess (black arrows). Axial T1contrast-enhanced image (D) shows that the dermal tract, epidural cyst, and intracerebral
abscess all enhance. Surgery demonstrated that the dura was intact, but inflamed, with adjacent infection of the leptomeninges and
brain; pathology demonstrated presuppurative cerebritis.

imaging study is usually ordered to establish the presence or absence of
a connection of the mass with intracranial contents.
CT evaluation of the nasofrontal region is often difficult in the neo-
nate, as the anterior skull base is largely cartilaginous at birth. There-
fore, it is crucial to understand the evolution of the CT appearance of
this region in the normal neonate and infant. In the normal neonate,
no calcified bone is seen in the region of the crista galli and cribriform
plate; the absence of ossification should not be misinterpreted as a sign of
a cephalocele. Ossification begins in the lateral aspect of the roof of the
ethmoidal labyrinth and spreads toward the midline. By age 6 months,
50% of the anterior skull base has ossified; however, the anterior
midline of the anterior cranial fossa is still not ossified. Ossification of
the midline cribriform plate and crista galli begins around age 2 months
and shows a steady increase to age 14 months, after which little change
is seen. The percentage of ossified skull base steadily increases over the
first 2 years of life. By 24 months, 84% of the anterior skull base is com-
pletely ossified, except for a cartilaginous gap anteriorly in the region of
the foramen cecum. The knowledge of this development is important
when evaluating for the presence of cephalocele in an infant (1045). If
a cephalocele is suspected, an MRI should be obtained.
If thin section (preferably ≤2 mm), contiguous T1- and T2-weighted
images can be obtained, MRI is the modality of choice in the evaluation

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 508 Pediatric Neuroimaging

FIG. 5-176. Nasal dermal sinus with intracranial dermoid. Axial CT after intrathecal injection of iodinated contrast (A) shows a filling
defect (arrows) superior to the foramen cecum. Sagittal reformation (B) shows erosion of the adjacent inner table of the frontal bone
by the dermoid. (Reprinted from Barkovich AJ, Vandermarck P, Edwards MB, Cogen PH. Congenital nasal masses: CT and MR imaging
features in 16 cases. Am J Neuroradiol 1991;12:105–116, with permission.)

of nasal dermal sinuses (229). Although CT better shows the relationship
of the dermal sinus to specific bones as it courses through the nasal sep-
tum, MRI better shows associated intracranial (epi)dermal cysts (Figs.
5-175B, C and 5-177) and does not use ionizing radiation; moreover,
intrathecal contrast is not necessary for MR evaluation. If MRI is not
available or is contraindicated, CT should be performed using no more
than 1.0 mm slice thickness; subarachnoid infusion of iodinated contrast
helps to detect intracranial masses (Fig. 5-176). MRI should be obtained
using both T1 and T2 weighting and 1 to 2 mm image thickness in the
sagittal, coronal, and axial planes. Fast spin-echo/turbo spin-echo T2
images are preferable, as artifact from the different magnetic suscepti-
bilities of air, bone, and brain are minimized; thin section volumetric
fast spin-echo images are ideal, as there is no interslice gap and the data
can be reformatted in any plane. (Epi)dermal cysts will be isointense to
hyperintense compared to brain (Figs. 5-175 and 5-177) (1046). Care
should be taken not to mistake normal marrow in the crista galli or the
nasal process of the frontal bone (see Fig. 2–19B) for a dermoid tumor.
FLAIR images are more sensitive than T1-spin echo or FSE/TSE in the
detection of inclusion tumors but do not show the relationship to the
calvarium as well. 3DFT spoiled gradient-echo images (MP-RAGE,
SPGR, 3DFLASH, T1-FAST, TFE) can be used to obtain thinner slices but
may be degraded by susceptibility artifact from interfaces of intracranial
contents with bone and air. To avoid this artifact, the echo time should
be as short as possible. Finally, the administration of a gadolinium-
compound intravenously may demonstrate the enhancement associ-
ated with infection (Fig. 5-175D). Because the dermal tract is open at
the skin, infection is a common complication of dermal sinuses/cysts in
this location like in the spine and posterior fossa.

FIG. 5-177. Nasal dermoids with intracranial extension. A and B. Sagittal T1-weighted image with fat suppression shows a hypointense
mass (black arrow) expanding the foramen cecum and extending into the epidural space. Axial T2-weighted image (B) shows the intracra-
nial hyperintense mass (black arrows) just anterior to the crista galli. C. Sagittal T1-weighted image in a different patient shows a glabellar
mass (large arrows) and a (epi)dermal cyst (small arrows) extending from the glabellar region superiorly through the foramen cecum into
the intracranial cavity. D–F. Sagittal T1- (D) and T2- (E) weighted images from another patient show a glabellar mass (m) that extends
through an enlarged fonticulus frontalis into the extradural space; the foramen cecum (arrow) is normal. Axial T1-weighted image (F)
shows the heterogeneous mass extending posteriorly (white arrows) along the sinus tract.

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 Chapter 5 • Congenital Malformations of the Brain and Skull
FIG. 5-177. (Continued)
MRI is superior to CT in the evaluation of cephaloceles and nasal
gliomas because it directly shows the extension of brain tissue through
the bone defect (Figs. 5-177 to 5-179) in cephaloceles and the lack
thereof in nasal gliomas (Fig. 5-180) (1047). Imaging in the sagittal
plane is optimal for this determination. The signal intensity of nasal
gliomas is similar to that of both epidermoid tumors and brain tis-
sue (1047); therefore, anatomic factors are more important than signal
characteristics in making a distinction between these malformations.
In difficult cases, acquisition of CT images through the defect after
intrathecal contrast administration can be helpful to determine whether
the soft tissue mass is continuous with the subarachnoid space; sagittal
reformations of ≤1 mm images are optimal. MRI is also superior to
CT in showing the presence or absence of associated brain anomalies
(Fig. 5-179), the presence of which has profound prognostic implica-
tions. Anomalies of the corpus callosum, interhemispheric lipomas, and
malformations of cerebral cortical development frequently accompany
nasofrontal encephaloceles. Frontoethmoidal encephaloceles are not
uncommonly seen in association with craniofacial anomalies, callosal
dysgenesis, or lipomas, often in the form of midline craniofacial dysra-
phisms (also known as frontonasal dysplasia, see sections “Associated
Barkovich_Chap05.indd 509
509
Anomalies and Syndromes,” “Intracranial Lipomas” and Fig. 5-181)
(1018,1048,1049). Hypertelorism is common in all cephaloceles in this
group and in nasal gliomas because of separation of midline structures
by the herniating brain tissue.
Parietal Cephaloceles and Atretic Cephaloceles Parietal cepha-
loceles are uncommon, comprising approximately 10% of cephaloceles
(1018). They are usually associated with significant underlying brain
anomalies and, consequently, have poor prognoses. Among the most
commonly associated anomalies are the Dandy-Walker malformation,
callosal agenesis with interhemispheric cyst, WWS, and holoprosen-
cephaly (1032,1034,1039,1050). Because of the proximity of parietal
cephaloceles to the superior sagittal sinus, it is particularly important
to locate the position of the dural venous sinuses with respect to the
cephalocele in these patients (Fig. 5-182). Neurosurgical repair is much
more difficult when the sinus is located within the cephalocele.
A high percentage of parietal cephaloceles, and indeed of all cepha-
loceles, fall into the category of atretic cephaloceles (1032,1050), small
defects in the skin and calvarium that are postulated to be a result
of a persistence of midline neural crest cells that prevent the mutual
5/6/2011 9:00:58 PM
 510 Pediatric Neuroimaging

FIG. 5-178. Frontoethmoidal cephalocele. Off-midline sagittal T2-weighted image (A) shows a rounded, well demarcated high
signal mass (white arrows) just lateral to the foramen cecum, anterior to the olfactory bulb. Coronal T2-weighted image (B) shows
that the mass is contained within the right nasal cavity and communicates with the intracranial space through a narrow canal (white
arrowheads) in the ethmoid bone.

induction of ectoderm and mesoderm (1051,1052). Atretic parietal
cephaloceles usually present as small (5–15 mm), hairless midline
masses near the vertex (1032). A sharply marginated calvarial defect
is present below the skin lesion, through which the cephalocele com-
municates with the intracranial cavity via a strand of connective tissue
(Fig. 5-183). The calvarial defect may be too small to see on standard
spin-echo MR images; thin section (1–2 mm) spoiled gradient-echo
(T1-weighted with gradient spoiler or T2 steady-state images such as
CISS/FIESTA [1053]) or fast spin-echo MR images or thin CT images
may be necessary to establish the communication. Atretic parietal
cephaloceles have a very high incidence of associated anomalies (100%
in Yokota’s series [1032]), including porencephalies, interhemispheric
cysts, and callosal agenesis (1018). Venous anomalies, particularly fen-
estration of the superior sagittal sinus and persistence of an embry-
onic falcine sinus (sometimes associated with absence of the vein of
Galen and straight sinus) are seen in most affected patients (Fig. 5-183)
(1053–1055).
Atretic parietal-occipital or occipital cephaloceles (Fig. 5-184) usu-
ally present as nodular, small (<15 mm) masses just above the exter-
nal occipital protuberance (1032). They enter the calvarium through a

FIG. 5-179. Fronto-orbital cephalocele. A. CT soft tissue remodeling of the face shows a huge left lateronasal and infraorbital skin-covered mass.
B. CT, bone surface rendering of the floor of the anterior cranial fossa shows a wide defect (black arrows) anterior to the ethmoids in the location
where the foramen cecum should have been.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 511

FIG. 5-179. (Continued) C. MR venogram, seen from above, demonstrating displacement of

the facial veins (white arrows); note venous anomalies such as the prominent occipital sinus
(O) on the right. D. Off-midline sagittal reformation of CT scan, showing the wide frontoeth-
moidal canal. E. Midline sagittal T2 image with the brain herniating (white arrows) through an
enlarged foramen cecum. F. Off-midline sagittal T2-weighted image demonstrating the CSF-
filled cephalocele (C) inferior to the orbit; note the diffuse periventricular gray matter hetero-
topia (black arrows).

small calvarial defect and then penetrate the dura immediately below
the torcular Herophili, which is typically located higher than usual.
The tracts typically terminate in the falx cerebri or tentorium cerebelli.
Patients with atretic occipital cephaloceles appear to have a low inci-
dence of associated anomalies and a good prognosis for normal devel-
opment (1032).
Nasopharyngeal Cephaloceles Nasopharyngeal cephaloceles are
also very uncommon. They are important, however, as they are occult
cephaloceles; they are not obvious on clinical examination. In con-
trast to cephaloceles in other locations, which are obvious on physical
examination and thus diagnosed at birth, nasopharyngeal cephaloce-
les are often discovered toward the end of the first decade of life. The
usual clinical presentation may be persistent nasal stuffiness or exces-
sive “mouth-breathing” by the child secondary to obstruction of the
nasopharynx (1027,1028) or spontaneous CSF rhinorrhea (1056). Clin-
ical examination will reveal a nasal or pharyngeal mass that increases in
size with Valsalva maneuver. Associated intracranial and ocular anoma-
lies are common. Agenesis of the corpus callosum is seen in approxi-
mately 80% of affected patients (Fig. 5-185). Hypoplasia of the optic
discs is seen on ophthalmologic exam; retinal dysplasia and colobomas
may be apparent on imaging studies, as well (Fig. 5-185D), sometimes
associated with the “morning glory syndrome” (1057). Diminished
visual acuity and hypothalamic-pituitary dysfunction are common
because the inferior third ventricle, hypothalamus, and optic chiasm
are stretched as they extend into the sac (Fig. 5-185) (1027,1028).
The diagnosis of nasopharyngeal cephalocele can be made by plain
film or imaging studies. On a submental vertex plain film, a hole of
variable diameter with well-defined sclerotic margins is seen in the
sphenoid, ethmoid, or, rarely, basi-occipital bone. Imaging studies
demonstrate a large sac of CSF extending through this bone defect
into the nasopharynx. In large encephaloceles, erosive changes will be
seen in the hard palate. When the defect is in the ethmoid or sphenoid
bone, the third ventricle, hypothalamus, pituitary gland, optic nerves,
and optic chiasm may all be contained within the encephalocele sac
(Fig. 5-185) (1027,1028). Correct characterization of these lesions by
the radiologist is crucial. If the encephalocele is misdiagnosed as a soft
tissue mass, the ensuing biopsy may be devastating.
Fetal Imaging of Cephaloceles As in other malformations, the
diagnosis of cephaloceles in fetuses primarily depends on ultrasound,
with MRI being indicated to provide a better depiction of the lesion

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 512 Pediatric Neuroimaging

FIG. 5-180. Nasal glioma. T1 (A) and T2 (B) off-midline

images show a mass (m) in the nose that is of the same sig-
nal as the brain. Axial T1-weighted image (C) with contrast
again shows a similar appearance to the brain. No com-
munication is seen between the mass and the intracranial
cavity (in contrast to Fig. 5-178).

FIG. 5-181. Midline craniofacial dys-

raphism. Axial CT (A) shows lipoma
(open curved arrows) with peripheral
calcification (solid arrows) extend-
ing through a frontal calvarial defect.
Sagittal T1-weighted image (B) shows
the interhemispheric lipoma (arrows)
extending from the posterior frontal
region down through the crista galli
into the nasofrontal area. The corpus
callosum is absent.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 513

FIG. 5-182. Parietal cephalocele. Midsagittal T2-weighted

image (A) shows a cephalocele at the posterior margin of
the parietal lobes, containing mostly CSF with some tissue
(black arrow) at the level of the skull defect. The junction
of the falx cerebri, the tentorium and the falx cerebelli is
malformed, extending too far dorsally and the straight
sinus correspondingly elevated. The superior colliculi and
superior vermis appear “pulled” toward the defect. The
corpus callosum is abnormally thin and short. Sagittal
reformat of a CT venogram (B) demonstrates the presence
of venous structures (white arrows) within the cephalo-
cele. Sagittal view of an MR TOF venogram (C) demon-
strates the abnormal sino-venous pattern but fails to show
the venous content of the cephalocele.

FIG. 5-183. Atretic parietal cephalocele. Sagittal T2-weighted image (A) shows a small subcutaneous mass (white arrows)
in the parietal region. No continuity is seen of the brain tissue with the mass. Sagittal reformation from 2D TOF MR veno-
gram (B) shows abnormality of the dural venous sinuses, with a persistent falcine sinus (white arrows) and absence of the
normal straight sinus.

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 514 Pediatric Neuroimaging

FIG. 5-184. Atretic parietal cephalocele. Midsagittal T2 image (A) shows a midline bony defect; just external to the defect, some
fluid is present in the small cephalocele (white arrow). A CSF channel at the level of the parietooccipital sulci extends from the suprav-
ermian cistern to the defect. The straight sinus is elevated and corresponds in location to a falcine sinus. Anteroposterior view of an
MR venogram (B) shows fenestration of the superior sagittal sinus, which courses on either side of the atretic cephalocele.

and to identify any other CNS malformations. The features that are
looked for are the same in fetuses as in neonates (Figs. 5-186 to 5-188);
MRI is used in our practices because it demonstrates more details and
may allow diagnosis of a more specific disorder better than ultrasound
(Fig. 5-187). Also, as fetal MRI is used for prognostication, it should be
remembered that cephaloceles are not static disorders: they are sub-
mitted to the combined influence of brain growth and CSF forces, and
the neonatal abnormality may be more severe than the abnormality
assessed at midgestation (Fig. 5-188).
Fontanelle Dermoids and Other Calvarial Masses of Child-
hood A number of different types of lesions can present as masses on
the head in children and mimic cephaloceles on clinical exam (1058).
When the mass is located at the anterior fontanelle, the most common
diagnosis is dermoid. Dysembryoplastic dermoid tumors (commonly
referred to as dermoid “cysts” even though they are usually solid and
filled with keratin) comprise about 20% of all scalp lesions (1059).
Dysembryoplastic dermoids are simple benign teratomatous tumors;
they differ from the dermal sinuses, tracts and cysts that result from a
failure of the separation of the skin from the neural tube (in the spine
or posterior fossa) or from the dura (in the frontonasal area) and are
better described as inclusion cysts. Patients with calvarial dermoids
typically present in the first few months of life with a soft or firm mid-
line solitary mass over the calvarium. The most common location is
the anterior fontanelle, although they often occur along other cranial
or facial sutures or within the diploic space of the calvarium; they may

FIG. 5-185. Sphenoidal cephalocele. Axial CT image (A) shows large, sharply marginated hole (arrows) in the sphenoid bone. Sagittal CT refor-
mation (B) shows the large bony defect with CSF (arrows) herniating within it. Sagittal T1-weighted image (C) reveals the encephalocele extending
down through the sphenoid bone into the nasopharynx and impression upon the posterior hard palate (small arrows). The dorsum sella (curved
arrow) remains intact. The optic chiasm (open white arrow) runs through the encephalocele. The corpus callosum is absent. Axial T1-weighted
image (D) shows the cephalocele defect (white arrows) and a small left globe (black arrows) with retinal detachment.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 515

FIG. 5-185. (Continued)

occur practically anywhere. Size and imaging characteristics are variable.
In infants, ultrasound with a high resolution (7–10 MHz) transducer is
an excellent first study, showing a sharply defined mass with an echo-
genic capsule. Over the first year of life, the mass may diminish in size
and become increasingly echogenic (1060). CT shows a soft tissue mass
that is typically hypodense, well defined, round, and causes minimal
scalloping of adjacent bone. MRI shows a well-defined mass that is
typically isointense to immature brain but may be isointense to CSF
(Fig. 5-189) (1061); the same appearance is seen when identified in the
fetus (Fig. 5-190). Separation from the underlying intracranial space is
easily identified in both the coronal and sagittal planes.
Martinez-Lage et al. (1058) and Yoon and Park (1062) reported the
frequency of various pathologic entities that presented as masses on the
head in childhood and adolescence. They found that the incidence var-
ies depending upon the age of the patient at the time of presentation
(Table 5-9). They found that MRI was best single radiologic exam to
evaluate the patient prior to surgery. Malignant tumors were rare and
included mainly rhabdomyosarcomas and metastatic neuroblastoma
(see Chapter 7); rarely melanotic neuroectodermal tumors of infancy
(see Chapter 7) develop in the cranial vault in infants, typically in the
region of the anterior fontanel or other sutures (1063).
Solitary infantile myofibromatosis of the skull is a benign tumor
that is composed of fascicles, whorls, and nodules of spindle-shaped
cells with myofibroblastic features (1064). Radiologically, they appear
as solitary lytic lesions of calvarium that show increased uptake on
99m
Tc-methylene diphosphonate bone scan. On CT, these sharply defined
masses originate in the calvarium or dura, have soft tissue attenuation,
and show marked enhancement after administration of iodinated con-
trast. On MRI, they exhibit long T1 and T2 relaxation times compared
with gray matter and otherwise show similar features to those seen on
CT (1065,1066). Prognosis is excellent after excision (1067).
Sinus pericranii are dilated extracranial veins that communicate
with the dural sinuses by way of transcalvarial emissary veins. On
clinical examination, they appear as soft, bulging masses in the scalp
that are usually less than 1.5 cm in diameter and are most commonly
located close to the midline in the frontal region (1068). Rarely, they

FIG. 5-186. Occipital cephalocele associated with a Dandy-Walker cyst in a 21-week-old fetus. A. Sagittal midline
image shows the huge fourth ventricular cyst (4), a considerably elevated tentorium, expanded squamous occipital
bone and posterior herniation of the cephalocele (C). B. Axial image demonstrates the herniated CSF-filled cephalocele
(c) extending through the cranial defect.

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 516 Pediatric Neuroimaging

FIG. 5-187. Atretic occipital cephalocele in a 23-week-

old fetus. A. The sagittal midline image reveals the small
bone defect (black arrow); it also shows posterior dis-
placement of the upper brainstem. B. Axial image shows
the defect (white arrow) in the tentorial dura and in the
calvarium. C. A higher cut demonstrates a cerebral cleft
with irregular ependymal lining (black arrows), either gray
matter heterotopia or ependymal destruction.

FIG. 5-188. Evolution of an occipital cephalocele. Sagittal image (A) in a 20-week-old fetus shows the huge CSF-filled cephalocele (c) with
a relatively small solid component (black arrow) at the bony defect. Note also the reduced volume of CSF. Sagittal postcontrast T1 image of
the same child during the neonatal period (B) still shows a mostly CSF-filled cephalocele, but the solid component has become larger and
includes cerebellar as well as cerebral tissue. Note the prominent venous channels in the sac.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 517

FIG. 5-189. Dermoid of the anterior fontanelle. Sagittal T1-weighted image

shows a low intensity mass (arrows) overlying the anterior fontanel, sepa-
rated from intracranial contents by intact calvarium.

occur in lateral frontal and temporal locations (1069). Diagnosis is
made clinically (the lesions are soft and spontaneously reduce when
intracranial pressure is reduced) and patients usually require no treat-
ment (1068). Imaging studies will show a soft tissue mass that enhances
after contrast infusion and is accompanied by scalloping of the outer
table of the skull (1070); intracranial vascular anomalies, in particu-
lar developmental venous anomalies, are frequently present (1071).
The calvarial defect can sometimes be seen on a thin section CT or
MR image; sagittal images may show the relationship to the under-
lying dural venous sinus (Fig. 5-191A) (1058,1070). The best way to
confirm the diagnosis is with the use of Doppler sonography, which
will show flow within the lesion as well as communication with an
underlying venous sinus (Fig. 5-191B). Angiographic analysis is no
longer necessary. If performed, injection of the internal and external
carotid arteries will often show an underlying vascular anomaly, most
commonly a developmental venous anomaly but, occasionally, an arte-
riovenous fistula (1071).
Imaging Appearance of Surgically Repaired Cephaloceles A
tract of CSF is almost always seen extending into the deep portion of
the brain from the cephalocele sac (Fig. 5-192). This CSF tract per-
sists after surgical repair and is very helpful in identifying patients
who have had prior repairs of encephaloceles. Another helpful finding
on imaging studies is distortion of the brain resulting from stretch-
ing of the brain tissues toward the site of the encephalocele. This dis-
tortion probably results from in utero extrusion of non-myelinated
brain tissue through the calvarial defect. Unmyelinated brain tissue is
extremely soft and is easily deformed. The brain tissue tends to retain

FIG. 5-190. Dermoid of the scalp, 22-week-old fetus. A. Off-midline sagittal image showing a well demarcated, bright rounded
mass (black arrow) in the scalp at the level of the anterior fontanelle. B. Same case, coronal image, shows the mass (black arrow) just
to the side of the fontanelle. Note the similarity to Fig. 5-189.

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 518 Pediatric Neuroimaging

TABLE 5-9 Calvarial Masses in Childhood (by Age)

First year of life Epidermal cysts
Cephalohematomas (see Chapter 4) Malignant tumors
Dermoids and epidermoids (see Chapter 7) Leptomeningeal cysts (see Chapter 4)
Hemangiomas Angiomas
Tumors (see Chapter 7) Atretic cephaloceles
Metastatic neuroblastoma Sinus pericranii
Ewing sarcoma Ages 8–17 y
Leukemic masses Fibrous dysplasia
Infantile myofibromatosis Dermoids and epidermoids
Melanotic neuroectodermal tumor of infancy Osteomas
Sinus pericranii Langerhans cell histiocytosis
Atretic cephaloceles Sinus pericranii
Ages 1–7 y Angiomas
Dermoids and epidermoids Plexiform neurofibromas (see Chapter 6).
Langerhans cell histiocytosis (see Chapter 7)
From (1058) and (1062).

the configuration it held at the time of myelination, so the distorted
tail of tissue pointing toward the calvarial defect remains throughout
the patient’s life (979).
Other Congenital Calvarial Defects Other than those associated
with cephaloceles, congenital defects of the cranial vault are rare. The
most common are parietal foramina and defects associated with cutis
aplasia congenita.
Parietal Foramina. Parietal foramina are oval, usually paired defects
that are parasagittally located in the mid to posterior parietal bones
(1072). Parietal foramina may appear unilateral in early infancy, but
the bilaterality only becomes apparent with development of the ridge
of bone along the sagittal suture (Fig. 5-193A) (1073). The overlying
skin and hair are normal. Normal bone growth never occurs within
the defects (1072). Most parietal foramina are smaller than 1 mm in
diameter by the time the calvarium matures and serve as conduits for
small emissary veins. However, in a small number of patients (about
1 in 20,000), parietal foramina are enlarged, remaining up to 5 cm in
diameter; these are known as giant parietal foramina or foramina pari-
etalia permagna, and they are often associated with mutations of the
homeobox genes MSX2 (located at chromosome 5q34–35, known as
PFM1) or ALX4 (located at chromosome 11p11–12, known as PFM2)
(1074–1076). Both are inherited in an autosomal dominant manner.
They are more common in Asians than Europeans and represent the
most common type of congenital skull defect (1074). Affected children
are typically asymptomatic, although bulging of the scalp at the defect is
often noted during crying. A syndrome has been described that includes
craniofacial dysostosis and mental retardation, attributed to deletion
of the short arm of chromosome 11 (1077). Another report associates
craniosynostosis, delayed fontanelle closure, parietal foramina, imper-
forate anus, and skin eruption; it is known as CDAGS (1078).
In addition to these syndromes, giant parietal foramina are worthy
of note in this neuroimaging text because they may be mistaken for

FIG. 5-191. Sinus pericranii. Sagittal postcontrast T1-weighted image (A) in a child with a soft mass near the midline over the parietal convexity has an
enhancing lesion (white arrow) that seems to communicate with the superior sagittal sinus through a small calvarial defect. Doppler sonogram through
the lesion (B) shows that the mass communicates with the superior sagittal sinus (SS) through an emissary vein (e).

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 Chapter 5 • Congenital Malformations of the Brain and Skull 519

cephaloceles on fetal imaging and because they are associated with

rather characteristic intracranial anomalies. Fetal sonography and fetal
MRI may show focal bulging of cerebrospinal fluid beyond the margins
of the calvarium in the parasagittal parietal bone (1079). This should
not be mistaken for a cephalocele, as it will resolve over time. Recogni-
tion of the known associated anomalies may aid the correct diagnosis.
The tentorium has a high insertion with a consequent large posterior
fossa. As a result of the tentorial anomaly, one or more medial occipi-
tal gyri herniate inferiorly into the tentorial incisura, giving a charac-
teristic appearance on MR studies (Fig. 5-193B). Finally, the straight
sinus is underdeveloped, resulting often in the presence of persistent
embryonic venous structures such as falcine sinuses (Fig. 5-193B) and
persistent median prosencephalic veins (1075,1076). Coronal or sag-
ittal images may show the parietal cortex appearing to protrude into
the calvarium (Fig. 5-193C). Associated malformations may include
craniosynostosis, vertebral anomalies, digital anomalies, clavicular
hypoplasia, and absence of the acromion process.

FIG. 5-192. Postoperative occipital cephalocele. Sagittal T1-weighted Calvarial Defects associated with Cutis Aplasia. Cutis aplasia con-
image shows stretching of the cerebellum toward a tract (open arrows) of genita is the name given to the absence of a portion of skin at birth, in
CSF that leads to the site of prior cephalocele repair. a localized or widespread area (1080). It most commonly (60%–70%)

FIG. 5-193. Parietal foramina. Surface reformation

of CT scan (A) shows large defects (black arrows) in
the parietal bones of an infant. Sagittal T1-weighted
image (B) shows an anomalous connection (white
arrows) of the straight sinus and the superior sagit-
tal sinus. Venous anomalies are commonly present
and are likely related to the presence of the foramina.
Coronal T2-weighted MR scan (C) shows parietal
lobe and blood vessels (white arrows) herniating into
the calvarial defects.

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 520 Pediatric Neuroimaging
FIG. 5-194. Calvarial defect associated with cutis aplasia congenita. Axial
postcontrast CT image shows parietal calvarial defect (arrows) with abnor-
mal thinning of the overlying skin.
presents as a solitary defect on the scalp, but multiple lesions sometimes
occur. The majority of scalp lesions develop on the vertex just lateral
to the midline. Most are sporadic, but some familial cases have been
reported and some teratogens have been postulated to be responsible
(1080). The lesions are noninflammatory and well-demarcated; they
may be circular, oval, linear, or stellate, and range in size from 0.5 cm to
as large as 10 cm. If they form early in gestation, these lesions may heal
before delivery and appear as an atrophic, membranous, or parchment-
like scar with associated alopecia, whereas less mature defects present
at birth as ulcerations, occasionally involving the dura or meninges.
About 20% of cases involving the scalp have associated calvarial defects
(Fig. 5-194), probably due to the same forces that caused the cutaneous
lesion (1081). The skull lesions do not heal by spontaneous regenera-
tion (1082).
Isolated congenital defects of the calvarium with intact brain,
scalp, and meninges are rare (1082). These defects usually occur in the
midline and are of variable size (ranging from 1 to 10 cm [1073]). They
probably represent either a fusion defect or a congenital failure of ossi-
fication of a portion of a calvarial bone. As a result of their location,
these calvarial defects may expose the sagittal sinus as well as the dura
mater and, therefore, such defects increase the possibility of serious
complications such as meningeal infection and hemorrhage; mortality
rates of up to 12% have been reported (1074). Bone regeneration rarely
occurs without surgical intervention (1073,1082). Perlyn et al. (1074)
have classified these along with other congenital calvarial defects and
discuss potential therapies.
Persistence of the Anterior Fontanelle. The range of normal closure
of the anterior fontanelle is generally regarded to be 4 to 26 months
(1083); more than 95% are closed by the age of 19 months. Delayed
closure may be associated with increased intracranial pressure, bone
diseases (vitamin D rickets, hypophosphatasia, osteogenesis imper-
fecta, cleidocranial dysostosis), endocrine disorders (athyrotic hypo-
thyroidism), chromosomal abnormalities (trisomy 13, 18, or 21), and
Barkovich_Chap05.indd 520
drug or toxin exposure (fetal hydantoin syndrome) (1084). Rarely, no
cause is found (1085).
Intracranial Lipomas
Intracranial lipomas are most commonly found incidentally, when
imaging is performed for reasons unrelated to their discovery, although
they can rarely be associated with epilepsy, particularly when they are
located over the surface of the cerebral cortex (1086,1087). Lipomas are
malformations; they are believed to result from abnormal differentia-
tion of the meninx primitiva, the undifferentiated mesenchyme that
surrounds the developing brain (1088–1090). Normally, the meninx
primitiva differentiates into the leptomeninges and the subarachnoid
space. For some, as yet unknown, reason, some areas of meninx dif-
ferentiate into fat in some patients, forming intracranial lipomas. As
a result of their formation from the meninx, intracranial lipomas are
almost always located in the subarachnoid space. As they are mal-
formations, not neoplasms, lipoma cells do not multiply (they will
hypertrophy, like other normal fat cells, when patients gain weight or
receive steroid therapy) and almost never exert mass effect on adja-
cent structures. Moreover, because lipomas are, essentially, maldiffer-
entiated subarachnoid space, blood vessels and cranial nerves often
course through them. Therefore, surgical treatment is rarely indicated
and has high morbidity. The most common locations for intracranial
lipomas are the deep interhemispheric fissure (dorsal to the corpus
callosum, 40%–50%), the quadrigeminal plate/supravermian cisterns
(20%–30%), the suprasellar/interpeduncular cisterns (10%–20%),
the cerebellopontine angle cisterns (∼10%), and the Sylvian cisterns
(∼5%) (1087,1090). Occasionally, lipomas are found on the surface of
the cerebrum (1086). In such situations, blood vessels course through
the lipoma and the underlying cortex is dysgenetic with poorly defined
cortical lamination, fusion of the molecular layer, disrupted basal lam-
ina, prominent astrocytosis, and abnormal synaptic profiles (1086).
Interhemispheric lipomas (commonly called “callosal lipomas” or
“lipomas of the corpus callosum” because they are situated adjacent
to the corpus) are almost always associated with hypogenesis or agen-
esis of the corpus callosum. These malformations can be large and
lobulated in appearance (these most typically are seen in the anterior
callosal region) or thin and curvilinear (these are typically seen in
the posterior callosal region, curving around the most posterior part
of the corpus). Encephaloceles and cutaneous lipomas can be asso-
ciated, as well, usually in the frontal region. In fact, several midline
developmental disorders appear to have lipomas of the interhemi-
spheric fissure as a part of the syndrome. Many of these are associated
with midline facial clefts, basilar cephaloceles, and retinal dysplasia,
a condition known as midline craniofacial dysraphism or frontona-
sal dysplasia (see Fig. 5-181 in section of this chapter on frontona-
sal cephaloceles) (93). When interhemispheric lipomas and callosal
anomalies are associated with median cleft lip or palate and cuta-
neous polyps of the face, a diagnosis of Pai syndrome can be made
(1091,1092).
Skull radiographs of patients with intracranial lipomas may be
normal or, in large interhemispheric lipomas, may reveal punctate or
curvilinear midline calcifications with adjacent lucent (fat density)
regions (75). On CT, lipomas are sharply demarcated areas of marked
hypodensity in affected cisterns (Fig. 5-195). Lobulated interhemi-
spheric lipomas may extend inferiorly into the choroid plexus of the
ventricles, anteriorly in front of the callosal genu, posteriorly behind
the hypoplastic body or splenium, or dorsally into the interhemi-
spheric fissure. Calcification is often present in lobulated interhemi-
spheric lipomas, most commonly within a fibrous capsule surrounding
the lipoma (1093). The calcification may be curvilinear, located at the
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 Chapter 5 • Congenital Malformations of the Brain and Skull 521

FIG. 5-195. Large, lobular interhemispheric lipoma. Axial CT scan

(A) through the lipoma shows a lucent area (large white arrows) in the inter-
hemispheric fissure immediately superior to the corpus callosum. Small
peripheral calcifications (small white arrows) are seen within the wall of the
lipoma. Sagittal T1-weighted image shows a large bulky interhemispheric
lipoma (large white arrows). (B) Note that the corpus callosum (small white
arrows) is hypogenetic with no anterior genu, rostrum, or splenium. Coronal
T1-weighted image (C) shows the lipoma extending into the velum inter-
positum and then through the choroidal fissures into the lateral ventricles.

periphery of the lipoma (Fig. 5-195A) or, less commonly, nodular and
within the center of the lipoma. Calcification is less common in lipo-
mas located elsewhere. The full extent of the lipoma and associated
callosal hypogenesis can only be fully appreciated on MRI.
The MR appearance of a lipoma is that of a hyperintense mass on
T1-weighted sequences, becoming hypointense on conventional spin-
echo T2-weighted images as the TE increases (Figs. 5-195 and 5-196)
and when fat suppression is applied. On fetal MRI, lipomas are isointense
to slightly hypointense compared with surrounding brain (Fig. 5-196).
Smaller lipomas typically have no adjacent brain malformations, but dys-
plastic brain tissue often accompanies large ones; for example, the cer-
ebellar vermis is sometimes small and dysmorphic when adjacent to a
large supravermian/collicular lipoma (1087). When lipomas are large, it
is easy to see associated chemical shift artifact (areas of hypointensity and
hyperintensity on opposite sides of the lipoma in the frequency encod-
ing direction, seen best on conventional T2-weighted images acquired
with a short bandwidth), resulting from the different chemical shifts
of water and fat protons (Figs. 5-197 and 5-198). The presence of the
chemical shift artifact should alert the reader that the lesion is fat, and not
blood. Application of a fat suppression sequence will make the lipoma
hypointense to gray matter (Figs. 5-198 and 5-199), confirming the
diagnosis. Fat suppression is useful to differentiate small hypothalamic
lipomas from ectopic posterior pituitary glands (Fig. 5-199, also see
section on “Anomalies of the Hypothalamic-Pituitary Axis” of this
chapter). Lipomas in the suprasellar (Fig. 5-199) and quadrigeminal
plate/supravermian cisterns (Fig. 5-200) are typically small and may
not show obvious chemical shift artifact. In contrast, lipomas in the
interhemispheric fissure (Fig. 5-195), sylvian fissure (Fig. 5-198), and
cerebellopontine angle (Fig. 5-201) may be quite large. Chemical-shift
artifact may be difficult to differentiate from signal voids due to rapid
flow in arteries; this is a particularly important issue in sylvian fissure
lipomas (Fig. 5-198) and interhemispheric lipomas. Fat suppression is
particularly important to make this distinction and to identify cranial
nerves coursing through the lipomas (Fig. 5-201), as sylvian fissure
lipomas are sometimes associated with aneurysms of the middle cere-
bral vessels (1094).
Interhemispheric lipomas may appear large and lobulated or thin
and curvilinear. Lobulated interhemispheric lipomas tend to be located
more anteriorly (Figs. 5-195 and 5-196), may wrap around the ante-
rior and posterior ends of the corpus callosum, and sometimes extend
through the choroidal fissure and into the stroma of the choroid plex-
uses of the lateral ventricles (Fig. 5-195). Curvilinear lipomas are thin
and typically extend posteriorly behind the corpus (Fig. 5-197), some-
times wrapping around and coursing into the velum interpositum. The

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 522 Pediatric Neuroimaging

FIG. 5-196. Fetal and postnatal MRI of a lobulated

interhemispheric lipoma. Fetal sagittal (A) and axial
(B) images show an intermediate intensity mass
(white arrows) in the region of the corpus callosum.
The corpus callosum itself is poorly seen. Postnatal
sagittal T1-weighted image (C) shows the lipoma
(white arrows) immediately dorsal to the hypoge-
netic corpus callosum (white arrowheads).

FIG. 5-197. Small, linear interhemispheric lipoma with chemical-shift artifact. Sagittal T1-weighted image (A) shows a
linear hyperintense mass (large arrows) above a hypogenetic corpus callosum (note the small splenium). Axial T2-weighted
image (B) shows marked chemical-shift artifact manifested as hypointensity (black arrows) posterior to the hyperintense
lipoma. This is a result of mismapping of the fat protons due to their chemical shift being several parts per million different
than that of water protons.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 523

FIG. 5-198. Sylvian fissure lipoma mimicking an aneurysm. Axial T1-weighted image
(A) shows a hyperintense lesion (white arrows) in the sylvian fissure in the region of
the middle cerebral artery trifurcation. Axial T2-weighted image (B) shows heterogene-
ity (white arrow) in the lesion, with curvilinear hyperintensity in the anterior portion
of the lesion, representing mismapped fat protons, and hypointensity in the posterior
portion of the lesion, representing absence of signal due to mismapping of fat protons.
This suggests that the lesion is a lipoma, as the anteroposterior plane was the frequency
encoding plane. Coronal T1-weighted image with fat suppression (C) shows absence of
signal in the lesion (white arrows), confirming that it is a lipoma.

FIG. 5-199. Hypothalamic, interpeduncular cistern lipoma: value of fat suppression. Sagittal T1-weighted image (A) shows the
small lipoma (white arrow). Postcontrast sagittal T1-weighted image with fat suppression (B) shows hypointensity (white arrow)
at the site of the lipoma. Note that the fat in the calvarium and clivus have also become hypointense.

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 524 Pediatric Neuroimaging

FIG. 5-200. Quadrigeminal plate/supravermian lipomas. Sagittal T1-weighted images shows a small (white arrow in A) and a large
(white arrows in B) lipoma located between the inferior colliculus and the superior cerebellar vermis.

adjacent corpus callosum is essentially always hypogenetic, with lipoma
extending around the posterior portion of the corpus; no callosal fibers
are seen dorsal or posterior to the lipoma (Figs. 5-195 to 5-197) (1090).
When affected patients have associated facial dysmorphism, computed
tomography is extremely helpful for the evaluation of the bony cranio-
facial anomalies and the planning of surgical reconstruction.
Arachnoid Cysts
Pathologic Characteristics
Arachnoid cysts are congenital lesions of the arachnoid membrane
that expand by CSF secretion. Light and electron microscopic stud-
ies have conclusively demonstrated that congenital arachnoid cysts
(also called true arachnoid cysts) are intra-arachnoid in location; their
inner and outer walls consist of sheets of arachnoid cells that join
with normal arachnoid at the margins of the cyst (1095–1098). True
arachnoid cysts differ from cysts caused by trauma or inflammation
(sometimes called arachnoid loculations, acquired arachnoid cysts, or
secondary arachnoid cysts) in that the latter are merely loculations of
cerebrospinal fluid surrounded by arachnoidal scarring (1096,1098).
Ultrastructural studies have shown that the cells lining true arachnoid
cysts contain specialized membranes and enzymes for secretory activ-
ity (1099). When true arachnoid cysts expand, therefore, the mecha-
nism appears to be an accumulation of CSF secreted by cells in the cyst
wall rather than by osmotically induced filtration or a ball-valve mech-
anism. The precise differences between arachnoid cysts that expand
over time and those that remain stable in size have yet to be worked
out (1098,1100,1101).

FIG. 5-201. Cerebellopontine angle lipoma enveloping cranial nerve. Axial CT scan (A) shows a hypodense mass (white arrows) in the right cerebel-
lopontine angle. Postcontrast axial T1-weighted image (B) shows the lesion (white arrows) to be hyperintense. Fat-suppressed postcontrast T1-weighted
image (C) shows suppression of the high signal intensity (white arrow), confirming that it is a lipoma. Note the cranial nerve (white arrowhead) coursing
through the lipoma.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 525

Arachnoid cysts usually arise within and expand the margins of
CSF cisterns that are rich in arachnoid. The sylvian fissures are the most
common location for arachnoid cysts, accounting for up to 50% of
these lesions. The cerebellomedullary/cerebellopontine angle cisterns
are the next most common location (∼15%), followed by the cerebral
convexity (∼13%), suprasellar region (∼11%), retrocerebellar cisterns
(∼10%), interhemispheric fissure (∼5%), quadrigeminal plate cistern
(∼5%), and “other” locations (∼12%) (1101,1102).
Clinical Characteristics
Arachnoid cysts usually occur sporadically. They have a higher inci-
dence in individuals with autosomal dominant polycystic kidney dis-
ease, being reported in as many as 8.1% of patients with this disorder
(1103), and in Aicardi syndrome (87). Most cysts, if not associated
with other anomalies, remain clinically silent and are only detected
incidentally (1104). In the rare cases in which arachnoid cysts produce
symptoms, the physical and neurological signs and symptoms reflect
their anatomical distribution and, in particular, their effect on CSF
flow. Small cysts, up to several centimeters in size, are asymptomatic
and their discovery is almost always incidental. When middle cra-
nial fossa cysts are large, they are often discovered as a result of cra-
nial asymmetry (Fig. 5-202); occasionally middle cranial fossa cysts
may be associated with seizures, headaches, or, rarely, hemiparesis
(1096), but the actual relationship of these symptoms to the cyst is
questionable (1101). The incidence of hydrocephalus associated with
arachnoid cysts is low, and current estimates of less than 10% (1104)
are much higher than the authors’ experience would suggest. When
hydrocephalus develops, it is usually associated with large supraten-
torial cysts, suprasellar cysts, posterior fossa cysts, or quadrigeminal
cistern cysts. Resultant symptoms include intracranial hypertension,
macrocephaly, or visual loss (see Chapter 8). Suprasellar cysts may also
cause hypothalamic-pituitary dysfunction and the bobble-head doll

FIG. 5-202. Large middle cranial fossa arachnoid cyst in a neurologically asymptomatic child with plagiocephaly.
Coronal T1-weighted image (A) and axial T2-weighted image (B) show the cyst (C) to be isointense with CSF. The
left hemicalvarium is expanded (white arrows), the left cerebral hemisphere is compressed, and the midline (inter-
hemispheric fissure, septum pellucidum) is shifted from left to right. Axial FLAIR (C) and average diffusivity (D)
images confirm that the mass is composed of CSF.

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 526 Pediatric Neuroimaging
syndrome (1096,1097,1105). When hydrocephalus is present, it may
be communicating or non-communicating and may result from either
defective CSF resorption or mechanical obstruction to egress of CSF
from the ventricles (1106). After treatment of the cyst, cognitive and
neurological outcome are excellent (1107).
Imaging Characteristics
Arachnoid cysts appear on CT and MRI as sharply marginated, homo-
geneous, unilocular masses that have signal identical to CSF on both
CT and MRI. The use of FLAIR and diffusion sequences (Fig. 5-202)
can help to confirm the diagnosis of cyst. On transfontanelle sonog-
raphy, they are sharply marginated, sonolucent masses with a well-
defined posterior border and enhanced through transmission. Fetal
MRI shows the cyst as a CSF-intensity mass that displaces adjacent
parenchyma with a very sharp margin between the parenchyma and
the mass (Fig. 5-203).
Suprasellar arachnoid cysts can expand in all directions from the
suprasellar cistern. They may extend inferiorly into the sella turcica,
laterally into the middle cranial fossa, and posteriorly into the inter-
peduncular and prepontine cisterns. As the cyst expands superiorly, it
fills the space previously occupied by the third ventricle and pushes the
third ventricle superiorly (Fig. 5-204). In this process, it can disrupt
the pituitary stalk and compress the hypothalamus. In very large cysts,
the superior pole of the cyst can obstruct both foramen of Monro,
causing hydrocephalus; it may even bulge further superiorly between
the leaves of the septum pellucidum (Fig. 5-204). The posterior pole of
the cyst may displace the pineal gland inferiorly and cover the entrance
of the aqueduct. The cyst can stretch the optic nerves and chiasm, as
well. Extension into the middle cranial fossae may be seen. MRI usu-
ally easily makes diagnosis, with the midline sagittal image showing the
cyst displacing the floor of the third ventricle superiorly (Fig. 5-204).
The major differential diagnoses of suprasellar arachnoid cysts are
epidermoids and cystic astrocytomas. By standard MR and CT tech-
niques, epidermoids are usually less sharply marginated than arach-
noid cysts and are more heterogeneous; however, there are cases in
which differentiation by standard spin-echo MRI is impossible. As dis-
cussed in the section on “Epidermoids” in Chapter 7, differentiation
FIG. 5-203. Fetal MRI of a cerebellopontine angle arachnoid cyst. Parasagittal (A) and axial (B) images show the sharply margin-
ated, CSF-intensity cyst (white arrows) situated in the left cerebellopontine angle and displacing adjacent parenchyma. The fourth
ventricle (white arrowhead) is slightly compressed and displaced to the right.
Barkovich_Chap05.indd 526
is straightforward using diffusion imaging, FLAIR, or magnetization
transfer imaging. If these techniques are not available, cisternography,
using intrathecal water-soluble contrast (Iohexol 180 mg of iodine
per mL, 3 mL injected intrathecally via lumbar puncture) may be neces-
sary to differentiate epidermoids from arachnoid cysts. After intrathe-
cal injection of contrast, the patient is scanned after being placed prone
in the head-down position (30°) for 2 minutes. A sharp border between
the lesion and surrounding CSF is seen with arachnoid cysts whereas
irregular interdigitation into the interstices of the mass is noted with
epidermoids. Cystic astrocytomas are more easily differentiated. Intra-
venous administration of paramagnetic contrast will show an enhanc-
ing solid tumor component in cystic astrocytomas; arachnoid cysts do
not enhance and do not have mural nodules.
Cysts of the middle cranial fossa differ somewhat in appearance,
depending upon size. Approximately 20% are small, biconvex or semi-
circular lesions with little mass effect and no expansion of bone (1097).
These small cysts can be missed on CT because of bone artifact and
volume averaging; indeed, many CSF collections in the anterior middle
cranial fossa are not cysts at all, but focal enlargements of the sylvian
fissure. Neither small cysts nor enlargements of the fissures are gener-
ally considered to be of clinical significance.
Approximately 50% of middle cranial fossa cysts are of moder-
ate size (Fig. 5-205). They occupy the anterior and middle portions of
the temporal fossa and frequently displace the tip of the temporal lobe
posteriorly, superiorly, and medially. They cause a characteristic flat
medial border of the sylvian fissure and open the lips of the fissure lat-
erally. The temporal fossa is usually mildly expanded by these lesions.
Approximately 30% of middle cranial fossa cysts are large, occupy-
ing nearly the whole temporal fossa, sometimes extending to the fron-
tal fossa and convexity (Fig. 5-202). These large cysts cause substantial
mass effect with expansion of the hemicranium, compression of adja-
cent brain and midline shift (Fig. 5-202). In neonates, they cause mac-
rocephaly and plagiocephaly, which is often the reason the children are
imaged. When located anteriorly, they can extend into the orbit via the
optic canal. Subdural and intracystic hemorrhages, which may follow
trauma or occur spontaneously, sometimes complicate middle cranial
fossa arachnoid cysts. The bleeding is probably caused by the disruption
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 Chapter 5 • Congenital Malformations of the Brain and Skull 527

FIG. 5-204. Suprasellar arachnoid cyst. Sagittal T1-weighted image (A) shows the large suprasellar cyst extending upward to com-
press the third ventricle and downward into the prepontine cistern. The optic chiasm (curved white arrow) is displaced superiorly and
anteriorly. Note that the anterior wall of the cyst extends further anteriorly than the anterior cerebral arteries. The anterosuperior
surface of the pons (black arrows) is distorted. The inferior wall of the cyst (small white arrows) can be seen in the prepontine cistern.
The lateral ventricles have been decompressed by a ventriculoperitoneal shunt. Axial T1-weighted reformatted image (B) shows the
cyst (short black arrows) extending into the interpeduncular cistern, displacing the cerebral peduncles. T1-weighted images reformat-
ted in the coronal plane (C and D) show the cyst extending laterally into the right middle cranial fossa and displacing the uncus and
parahippocampal gyrus (small arrows in C) and extending upward to obstruct the foramina of Monro. Arrows in (D) point to the cyst
walls at the foramina.

of cortical veins, which frequently traverse the cyst near its periphery.
These veins bleed readily with slight manipulation at the time of sur-
gery (1108). Concurrent subdural or intracystic hemorrhage should
be carefully ruled out in any patient with signs of arachnoid cyst and
acute progression of symptoms. Specific attention should be paid to
the temporal fossa in any patient with clinical signs consistent with an
arachnoid cyst and radiographic evidence of a temporal fossa hem-
orrhage. Similarly, the possibility of concurrent subdural hematoma
should be considered whenever a sylvian fissure cyst appears to be
separated from the inner table of the calvarium (1097). Middle cranial
fossa arachnoid cysts may rupture into the subdural space spontane-
ously, or after trauma as a result of preexisting or traumatic communi-
cation (Fig. 5-206) (1109,1110); this results in formation of a subdural
hygroma. Rarely, spontaneous disappearance of arachnoid cysts has
been reported; this presumably results from spontaneous decom-
pression of the cyst into the subdural space, perhaps through a weak
portion of the cyst wall (1111).
Approximately 25% of arachnoid cysts occur in the posterior
fossa (Fig. 5-207). These lesions are usually large (>5 cm) at the time
of presentation (1097,1106,1112). Although the cysts can occur any-
where in the posterior fossa, the cerebellopontine angle and inferior
or dorsal midline (Fig. 5-207) are the most common locations. The
major importance of these lesions is in their differentiation from the
cysts of the Dandy-Walker complex. This distinction is made via a
combination of clinical and radiological features. Patients with retro-
cerebellar arachnoid cysts are most commonly asymptomatic. If they
rapidly enlarge, affected children may present with signs of cerebellar
dysfunction (ataxia, dysdiadochokinesis) secondary to compression of
the cerebellum by the cyst. In contrast patients with the Dandy-Walker
malformation usually present in infancy either with hydrocephalus or

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 528 Pediatric Neuroimaging
FIG. 5-205. Moderate sized middle cranial fossa arachnoid cyst. Parasagittal T1-weighted image (A) shows the hypointense cyst
(white arrows) displacing the anterior portions of the frontal and temporal lobes posteriorly. The T2-weighted axial image (B) shows
only moderate mass effect with minimal midline shift when compared to the large cyst in Fig. 5-202.
developmental delay (873). Radiologically, differentiation is made by
determining whether the cyst is an enlarged fourth ventricle (Dandy-
Walker malformation), is in communication with the fourth ventricle
(Dandy-Walker complex, but not the true Dandy-Walker malforma-
tion), or whether it is isolated from the surrounding subarachnoid space
(arachnoid cyst). Magnetic resonance cisternography with 3D steady-
state imaging such as CISS or FIESTA can depict thin membranes such
FIG. 5-206. Spontaneous rupture of a middle cranial fossa arachnoid cyst
into the subdural space. Noncontrast CT shows a large right middle cranial
fossa arachnoid cyst (C) with an enlarged frontal subdural space (SD). The
patient has hydrocephalus.
Barkovich_Chap05.indd 528
as the walls of cysts (1113). Analysis of CSF flow, using flow-sensitive
steady-state free procession imaging or phase-contrast studies, is
sometimes helpful in determining whether there is free communica-
tion between the cyst and the fourth ventricle; however, flow can be
complex and such studies may be misleading. The most reliable meth-
odologies, in particularly difficult cases, are CT cisternography and
ventriculography. These methods will always allow determination as to
whether the cyst communicates with the subarachnoid space (cyst fills
after lumbar injection of iso-osmolar nonionic contrast and tilting the
patient’s head down in the supine position), the ventricular system (the
cyst fills after injection of iso-osmolar nonionic contrast into the lat-
eral ventricle and tilting the head up), or is an isolated arachnoid cyst
or loculation (cyst doesn’t fill on either injection). Large retrocerebel-
lar cysts may be associated with anomalies of the dural venous sinuses
(Fig. 5-207).
Therapy
By far, most arachnoid cysts are asymptomatic and require no treat-
ment. Symptomatic arachnoid cysts can be treated either by fenestra-
tion or by cyst-peritoneal shunting. After shunting, the cyst appears
completely or nearly completely decompressed. After adequate treat-
ment of the cyst, the associated hydrocephalus usually resolves as well.
Craniosynostosis
Nonsyndromic Craniosynostosis
Diagnosis of Craniosynostosis
Craniosynostosis can be broadly grouped into two categories. Primary
craniosynostosis refers to premature fusion of one or more cranial
sutures as a developmental error. The cause is thought to be a develop-
mental anomaly of the skull base. Secondary synostosis refers to pre-
mature sutural closure resulting from other causes such as intrauterine
compression of the skull, the effect of teratogens, or lack of brain
growth. Craniosynostosis may be seen both in otherwise normal indi-
viduals and as a part of syndromes associated with other developmen-
tal anomalies (1114–1117). Overall, about 15% of cases are syndromic,
5/6/2011 9:01:19 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 529

FIG. 5-207. Retrocerebellar and infracerebellar arachnoid cysts. A–C. Retrocerebellar

cyst. Sagittal T1-weighted (A) and axial T2-weighted (B) images show a retrocerebellar
CSF collection (arrows) that is isointense with CSF and is causing scalloping of the inner
table of the occipital bones. Maximum intensity projection from a 2D TOF MR veno-
gram (C) shows an abnormally high bifurcation of the superior sagittal sinus. D and E.
Infracerebellar cyst. Axial SE T2-weighted (D) and coronal FLAIR (E) images show an
infravermian arachnoid cyst (white arrows), superiorly displacing the cerebellar vermis
and laterally displacing the inferomedial aspects of the cerebellar hemispheres.

Barkovich_Chap05.indd 529 5/6/2011 9:01:20 PM

 530 Pediatric Neuroimaging
that is, associated with other anomalies of the brain or body. Of the
remaining 85%, 75% to 80% are simple nonsyndromic, involving only
one suture, and 20% to 25% are multisuture nonsyndromic (1118).
The precise cause of premature sutural closure has not been fully
clarified. In the normal patient, sutures close when the growth of the
brain slows. It is known that early slowing or cessation of brain growth
results in early closure of the cranial sutures. An interesting theory,
called the microspicule hypothesis, has been proposed based on find-
ings in an animal model (1119). The microspicule hypothesis contends
that microspicules of bone are continually growing across open sutures
but are fractured by calvarial expansion due to the normal forces of
growth. If the normal forces causing expansion of the calvarium dis-
appear, due to either bone anomaly or lack of cranial growth, the
microspicules are not fractured and the sutures begin to close, result-
ing in premature synostosis (1119). More recent molecular biologic
studies suggest that interactions of fibroblast growth factors (FGFs)
and their receptors (FGFRs) influence the balance between the pro-
liferation of osteoprogenitor cells and the differentiation of new bone
in the membranous bones of the calvarium; these processes take place
at the sutures (1117). When the balance is shifted from proliferation
of progenitors to production of bone, the sutures appear to close. All
of the genes that have been found to be causative in craniosynostosis
syndromes (FGFR1, FGFR2, FGFR3, TWIST1, and MSX2) seem to par-
ticipate in the molecular pathways involved in this process (1117). Still
another study suggests that the formation of the membranous bone
of the calvarium is related to the BMP pathway, which is initiated in
the skin ectoderm in the dorsal midline. It appears that expression of
a BMP inhibitor (noggin) maintains the patency of the cranial sutures
until some event related to slowing of brain growth causes the expres-
sion of noggin to decrease (1120). As molecular biologic techniques
improve, the precise factors involved in the development and subse-
quent closure of the cranial sutures are slowly being elucidated.
When isolated to a single suture, craniosynostosis is usually spo-
radic and presents as an abnormally shaped head. Isolated sagittal
synostosis accounts for about 60% of simple nonsyndromic cranio-
synostosis (NSC) cases (1121) and causes a long, narrow head shape
(scaphocephaly or dolichocephaly, Fig. 5-208); this disorder is easy to
diagnose clinically and probably does not need radiologic evaluation
unless it is atypical (1122). Of note, affected patients may have speech
Barkovich_Chap05.indd 530
and language deficits (1123). Isolated metopic synostosis accounts
for 18% of simple NSC cases (1118) and causes a prominent, wedge-
shaped forehead (trigonocephaly, Fig. 5-209); underlying syndromes,
such as 11q23 deletion, 9p deletion, Opitz C syndrome, and various
aneuploidies, are seen in up to 30% of affected patients (1124). Isolated
unilateral coronal (20%–30% of NSC, with 60%–75% of those affected
being female, Fig. 5-210) or lambdoid (<5% of NSC, Fig. 5-211) synos-
tosis causes cranial asymmetry (plagiocephaly). Considering only
craniosynostosis in which a molecular diagnosis is made, the most
common form is Muenke syndrome, followed by Saethre-Chotzen syn-
drome (1117). Of note, the most common cause of plagiocephaly is not
synostosis, but “positional flattening” resulting from the neonate being
positioned almost exclusively in the supine position with the head usu-
ally tilted to the same side, only bottle-feeding with the bottle on the
same side, and slow motor development (1125).
Multiple suture involvement is seen in about 5% of patients with
NSC (1126). Clinically, they are divided into two groups; those with
premature fusion of two sutures and those with complex craniosynos-
tosis due to involvement of more than two sutures (1126). Patients
with two-suture fusion have similar courses to those with monosu-
tural fusion (normal development, normal intelligence, and normal
intracranial pressure) other than a higher rate of reoperation (25% vs.
5%) (1118,1121,1127). In contrast, those with complex craniosynos-
tosis have a high incidence of increased intracranial pressure, Chiari I
malformation, and developmental delay, while the rate of reoperation
is 37% (1118). Indeed, it seems likely that mutations and diagnosis
of specific syndromes are significantly higher among complex cran-
iosynostosis than among simple ones (1128). Of NSC patients with
multiple suture involvement, 40% to 50% have oxycephaly secondary
to bilateral coronal and lambdoid synostosis, 30% to 40% have brachy-
cephaly secondary to bilateral coronal synostosis, and about 20% are
“unclassified” secondary to multiple assorted sutural synostoses. It is
important to remember that some cases of single or dual suture synos-
tosis may be genetic. This is particularly true for coronal synostoses;
the recurrence risk for bilateral coronal synostosis is 5% to 7% (1129).
Bilateral lambdoid synostosis should raise suspicion for rhomb-
encephalosynapsis (see earlier section in this chapter on cerebellar
malformations). Craniosynostosis syndromes are discussed in the fol-
lowing section.
FIG. 5-208. Scaphocephaly secondary to sagittal suture
synostosis. Axial CT image (A) shows an elongated, narrow
head secondary to sagittal synostosis. Note the ridge of bone
(white arrow) along the prematurely closed suture. Superior
view (B) of 3D reformation shows the closed sagittal suture
with ridge (large black arrows) and the open metopic (white
arrows), coronal (large black arrowheads), and lambdoid
(small black arrowhead) sutures.
5/6/2011 9:01:22 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 531

FIG. 5-209. Trigonocephaly. Axial

CT shows (A) a pointed frontal region
(arrows) secondary to premature clo-
sure of the metopic suture. 3D sur-
face reformation of the calvarium (B)
shows a ridge of bone (black arrows)
along the prematurely closed suture.

Radiology of Synostosis request 3D reconstructions of the calvarium (derived from CT scans,

Isolated sagittal, metopic, or unilateral coronal synostosis is diagnosed
clinically and confirmed by plain films of the skull; cross-sectional
imaging studies are not indicated to assess the sutures. The characteris-
tic findings on skull films are available in any standard text on pediatric
radiology. Briefly, premature sagittal synostosis causes scaphocephaly
and ridging along the sagittal suture (Fig. 5-208), premature metopic
synostosis causes trigonocephaly and ridging along the metopic suture
(Fig. 5-209), and premature coronal synostosis shows plagiocephaly
and an uplifting of the lateral orbital roof (Fig. 5-210), giving the
“Harlequin eye” appearance.
Although experienced surgeons may treat single suture synos-
tosis without the assistance of imaging studies, many surgeons now
see Figs. 5-208 to 5-211) in order to plan their surgery. Neuroimaging
is also performed to look for underlying brain anomalies; therefore,
both soft tissue CT images (or MRI) to look at the brain and bone
algorithm CT images to look at the calvarium should be photographed
or archived. Infants with trigonocephaly may have anterior midline
anomalies (Opitz C syndrome, Jacobsen syndrome, holoprosencephaly,
or many others [1126,1128]). Those with unilateral posterior plagio-
cephaly (unilateral occipital flattening) may have an underlying brain
anomaly or brain damage (either anatomic or secondary to metabolic
disease). Both brain anomalies and brain damage can cause reduced
infant mobility and result in extended periods of lying on their backs,
primarily on one side. This secondary flattening, resulting from lack of

FIG. 5-210. Plagiocephaly secondary to unilateral coronal suture synostosis. Bone window image from axial CT scan (A)
shows plagiocephaly; the right hemicalvarium is smaller than the left. The left coronal suture (white arrow) is open, but no
right coronal suture can be seen. The sagittal suture (white arrowhead) is displaced to the right. Anterior view of 3D reforma-
tion of the calvarium (B) shows the open left coronal suture (small black arrows) and fusion of the right (black arrowheads).
Note the elevation of the right orbital roof (large black arrows), the so-called Harlequin eye sign of coronal synostosis.

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 532 Pediatric Neuroimaging
FIG. 5-211. Plagiocephaly secondary to unilateral lambdoid suture synostosis. Bone window from axial CT scan
(A) shows flattening of the right occipital region (white arrowheads) and bulging on the left (white arrow) secondary
to closure of the left lambdoid suture. The ear is in normal position or slightly posterior. Postero-inferior view of 3D
reformation of calvarium (B) shows better the bulging of the left occiput (white arrow) ipsilateral to the synostosis.
The right lambdoid suture (black arrows) is open.
infant movement, is usually not associated with synostosis. Sawin et al.
(1130) have noted that occipital flattening (occipital plagiocephaly) is
commonly associated with benign enlargement of the subarachnoid
spaces (typically frontal, sylvian, and basal cisterns), usually without
ventriculomegaly (see Chapter 8 for a discussion of benign enlarge-
ment of the subarachnoid spaces); they postulated that increased
compliance of the skull in the presence of large subarachnoid spaces
predisposes the patients to positional flattening. Other predisposing
factors for posterior plagiocephaly include supine positioning during
early infancy (overwhelmingly most common), torticollis, prematurity,
and developmental delay (1131). It is important to emphasize that this
positional flattening of the skull is usually not associated with any neuro-
logic abnormality, but is merely a result of laying supine for long periods of
time, which is common because supine positioning of infants seems to
reduce the incidence of sudden infant death syndrome (1132). Features
that are useful in helping to identify nonsynostotic occipital plagio-
cephaly are forward displacement of the ipsilateral ear (with lambdoid
synostosis the ipsilateral ear is posteriorly displaced) and ipsilateral
frontal bossing (1133). In the absence of underlying neurologic abnor-
mality, the vast majority of cases of occipital plagiocephaly are non-
synostotic and improve once the children no longer lay on the same
side of their head all the time (1131,1133–1135). If necessary, the child
may wear a helmet during sleep (1134–1136).
The radiologic evaluation of children with unilateral occipital pla-
giocephaly is evolving. In most cases, when the children are develop-
ing normally, no radiologic studies are necessary. A follow-up clinical
exam after instructing parents to change head positions in the crib or,
in older infants, using molding helmets, will usually yield a confident
diagnosis (1134). Plain skull films are not helpful in either ruling out
underlying brain abnormality or in diagnosing lambdoid synostosis.
If the children have any neurologic abnormalities, an MRI should
probably be obtained, as MRI is the most sensitive method for detect-
ing brain abnormalities. MRI can also provide information regarding
Barkovich_Chap05.indd 532
the position of the ipsilateral ear (as above, with lambdoid synostosis,
the ipsilateral ear is posteriorly positioned—pulled back by sutural
fusion—whereas the ear is anteriorly positioned—pushed forward—
in infants with positional flattening of the occiput) (1137). CT should
be obtained if surgery is contemplated, as it more accurately depicts the
cranial sutures; in particular, 3D reformations should be constructed
from the CT data (Figs. 5-208, 5-210, and 5-211). 3D reformations of
CT images of the calvarium are the definitive method of making the
radiologic diagnosis of suture synostosis, but they should be acquired
with as low a dose of radiation as possible while performing a technically
adequate study (see Chapter 1).
It is important to recognize that sutures may appear falsely closed
when the plane of imaging is parallel to the suture. When the reforma-
tions are constructed from axial images, the upper part of the lamb-
doid suture is the most common area to falsely appear closed. Certain
compensatory changes in calvarial shape are seen with occipital plagio-
cephaly of any etiology. The anterior portion of the ipsilateral middle
cranial fossa is enlarged. The orbit is elevated and there is increased lat-
eral convexity of the squamous portion of the ipsilateral temporal bone.
Addition abnormalities found in isolated coronal synostosis include
expansion of the ipsilateral inferior occiput (below the suture), narrow-
ing of the sphenopetrosal angle, decreased size of the ipsilateral frontal
fossa, flattening and posterior displacement of the ipsilateral frontal cal-
varium, compression of the ipsilateral anterior cranial hemifossa, and
medial, posterior, and superior displacement of the orbital roof (1138).
Anomalies of venous drainage can occur with multisutural synos-
tosis of both syndromic and nonsyndromic causes (1139,1140). If sur-
gical intervention is being contemplated, it is essential to evaluate the
intracranial venous sinuses with venography (MR venography is the
study of choice because of the absence of ionizing radiation) (1141).
Abnormal venous pressure may be associated with increased intrac-
ranial pressure (or frank hydrocephalus) and consequences of this
elevated pressure should be contemplated and addressed in advance
5/6/2011 9:01:23 PM
 Chapter 5 • Congenital Malformations of the Brain and Skull 533

(974,1139). Moreover, in the setting of increased intracranial venous
pressure, transcalvarial emissary veins may enlarge around the cranial
sutures (974); surgeons should be alerted to this possibility.
Abnormal Fontanelle Closure
The anterior fontanelle is almost always seen on axial CT scans of
neonates and infants. In general, the fontanelle should not close until
the age of about 12 months, and should be closed by about 18 months.
Premature closure of the fontanelle is sometimes a sign in impaired
brain growth; in such cases, it is associated with microcephaly and
with premature suture fusion. Delayed closure of the anterior fon-
tanelle is usually associated with syndromic craniosynostosis, in
which the inability of the calvarium to grow at the sutures is partially
compensated by the persistent patency of the fontanelle, allowing
the brain to grow upward (turricephaly). Other conditions in which
the fontanelle closure is delayed include athyrotic hypothyroidism,
bone dysplasias (achondrogenesis Type II, campomelic dysplasia,
cleidocranial dysostosis, hypophosphatasia, osteogenesis imperfecta,
pycnodysostosis, thanatophoric dysplasia, rickets), and chromosomal
anomalies (Down syndrome, Trisomy 13p, Aase syndrome, progeria,
Russell-Silver syndrome, Triploidy syndrome, Trisomy 9p, Trisomy 18,
and Zellweger syndrome).
Syndromic Craniosynostosis
Background
Syndromic craniosynostosis includes those disorders in which the
face and the skull develop abnormally, typically in conjunction with
anomalies of other bones, usually the hands and, particularly, fingers.
Approximately 15% of all craniosynostosis cases present with associ-
ated anomalies involving mainly the face and limbs and are consid-
ered to be syndromic (1118,1128). More than 180 syndromes manifest
craniosynostosis and at least half of them seem to follow Mendelian
patterns of inheritance (London Dysmorphology Database, http://
www.lmdatabases.com/about_lmd.html). From an embryological per-
spective, genetic studies show that some calvarial cells are increased in
number in children with FGFR2 mutations and that these cells have
an increased maturation rate, leading to increased subperiosteal bone
matrix formation and premature ossification of the calvarium during
fetal development (1142).
Although several different syndromes are defined on the basis of
clinical features, a precise classification of affected patients is difficult
because of considerable overlap (1128). In addition, patients with
mutations of the same gene can have different phenotypic manifes-
tations and vice versa (1143–1146). Identical FGFR2 mutations have
been found in patients carrying the diagnosis of Crouzon, Pfeiffer,
and Jackson-Weiss craniosynostosis syndromes, suggesting that these
entities may represent a clinical spectrum of the same disorder, with
the differences resulting from the effect of genetic modifiers (1126).
In addition, an identical FGFR2 mutation has been found in unrelated
patients with Pfeiffer and Apert syndromes (1147). Moreover, the same
phenotype can be caused by mutations in different genes, as in cases of
Pfeiffer syndrome due to FGFR1 and FGFR2 mutations (1145). Thus,
as in many genetic disorders, the precise phenotype of the affected
patient is mostly likely related to the effects of both epigenetic factors
and gene mutation upon the function of the protein product; many

TABLE 5-10 Inherited forms of craniosynostosis

Syndromes/OMIM
(McKusick) Number Site of Mutation Classification Essential Features Inheritance
Apert, Apert- Chromosome Acrocephalosyndactyly I, II Craniosynostosis, severe syndactyly of Autosomal
Crouzon/101200 10q26 (FGFR2) hands and feet, down-turned mouth, dominant
hypertelorism
Nonsegmentations of C-spine
Venous anomalies
Chiari I malformations
Callosal, septal ageneses
Limbic anomalies
Saethre- Chromosome Acrocephalosyndactyly III Craniosynostosis, facial asymmetry, low Autosomal
Chotzen/101400 7p21.2 hair line, ptosis, deviated nasal septum, dominant
(TWIST) syndactyly of second, third fingers
Normal cognition
Muenke/602849 Chromosome Nonsyndromic coronal Craniosynostosis, thimble-like middle Autosomal
4p16.3 (FGFR3) craniosynostosis phalanges, coned epiphyses, carpal dominant,
and tarsal fusions usually
Commonest syndromic cause of paternal
craniosynostosis, usually unilateral or
bilateral coronal
Pfeiffer, Chromosome Acrocephalopolysyndactyly Craniosynostosis, malformed enlarged Autosomal
Noack/101600 10q26 (FGFR2) I, V thumb and great toe, soft tissue syndac- dominant
Chromosome tyly of second, third digits, polydactyly,
8p11 (FGFR1) stenosis/atresia of external auditory
Others (?) canal, normal intelligence

(Continued)

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 534 Pediatric Neuroimaging

TABLE 5-10 Inherited forms of craniosynostosis (Continued)

Syndromes/OMIM
(McKusick) Number Site of Mutation Classification Essential Features Inheritance
Carpenter, Summitt, unknown Acrocephalopolysyndactyly Craniosynostosis, preaxial polydactyly, Autosomal
Goodman, Sakati- II, III, IV soft tissue syndactyly, malformed ears, recessive
Nyhan/201000 obesity, hypogenitalism, variable mental
retardation
Crouzon, craniofacial Chromosome Craniosynostosis with other Craniosynostosis, maxillary hypoplasia, Autosomal
dysostosis/123500 10q26 (FGFR2) somatic abnormalities shallow orbits with proptosis, bifid dominant
uvula or cleft palate
Crouzon with Chromosome Chiari I malformations
acanthosis nigrans 4p16.3 (FGFR3) Venous anomalies
Jugular venous stenosis
Craniosynostosis, Unknown Craniosynostosis with other Craniosynostosis and fibular aplasia Autosomal
fibular aplasia, somatic abnormalities recessive
Lowry/218550
Craniosynostosis, Chromosome Craniosynostosis with other Craniosynostosis, varus deformity of Autosomal
midface hypopla- 10q26 (FGFR2) somatic abnormalities great toes and tarsal fusion dominant
sia, foot defects, Chromosome
Jackson- 8p11 (FGFR1)
Weiss/123150
Craniosynostosis, Unknown Craniosynostosis with other Craniosynostosis, cleft lip and palate, Autosomal
mental retardation somatic abnormalities choroidal coloboma, mental retardation recessive
clefting/218650
Craniosynos- Chromosome Craniosynostosis with other Synostosis of one or more sutures, Autosomal
tosis, radial 8q24.3 somatic abnormalities bilateral radial aplasia recessive
aplasia, Baller- (RECQL4)
Gerold/218600
Craniosynostosis, Chromosome Craniosynostosis with other Synostosis of multiple sutures, mandibu- Autosomal
arachnodactyly 15q21.1 (FBN1) somatic abnormalities lar and maxillary hypoplasia, multiple dominant
hernia, Shprintzen- abdominal hernias, exophthalmos,
Goldberg/182212 mental retardation
Craniosynostosis Chromosome Craniosynostosis (variable) Synostosis ranges from metopic ridging to Autosomal
Type 2 (Boston 5q34–5q35 with digital abnormali- cloverleaf skull dominant
Type Craniosynos- (MSX2) ties (short metatarsals)
tosis)/604757
X-linked hypo- Chromosome Sagittal synostosis with Sagittal synostosis, dolichocephaly. Occa- Autosomal
phosphatemic Xp22.2–22.1 growth retardation, sionally multiple sutures recessive
rickets/307800 (PHEX) rachitic/osteomalacic
bone disease, hypophos-
phatemia, and renal
defects in phosphate
resorption

craniosynostosis syndromes are allelic and have overlapping features.
Nonetheless, it is useful to have some method to classify these disor-
ders, and Table 5-10 is included for this purpose.
Of the many types of suture synostosis patterns, bilateral coronal
synostosis (Fig. 5-212) is the most common combination, but com-
bined bilateral coronal and lambdoid synostosis or a combination
of bilateral coronal synostosis and sagittal synostosis can be seen,
among others. When the sagittal suture is synostotic in conjunction
with both coronal sutures (and, sometimes, both lambdoid sutures),
the membranous bone of the calvarium expands between the sutures
but not at them, resulting in a characteristic lobulated skull con-
figuration known as cloverleaf skull or Kleeblattshädel (Fig. 5-213).
Multiple synostosis syndromes may be isolated or associated with
syndactyly, polydactyly, fusion of cervical vertebrae, anomalies of
the middle ear, or other somatic anomalies (Table 5-10) (1114–
1116,1128,1148,1149).

Barkovich_Chap05.indd 534 5/6/2011 9:01:24 PM

 Chapter 5 • Congenital Malformations of the Brain and Skull 535

FIG. 5-212. Turricephaly secondary to bilateral coronal synostosis.

Sagittal T1-weighted image (A) shows the “tower head” appearance
with the frontal lobe extending upward (white arrows) through the
late-closing anterior fontanelle and the anterior corpus callosum
(black arrows) being pulled up, as well. Axial T2-weighted images
show lateral expansion of the temporal lobes (white arrows in B) and
shortening of the frontal lobes (white arrows in C) secondary to the
shortened anterior cranium. Lateral view of 3D reformation of cal-
varium (D) shows complete closure of coronal suture, while superior
view (E) shows the persistently open fontanelle (black arrows).

Barkovich_Chap05.indd 535 5/6/2011 9:01:24 PM

 536 Pediatric Neuroimaging

FIG. 5-213. Kleeblattschädel with venous anomaly and hemorrhage in a neonate with no identified genetic disorder. Sagittal
T1-weighted image (A) shows an extremely small posterior fossa, leading to compression and inferior displacement of posterior
fossa structures. The head is towering and the ventricles are enlarged secondary to hydrocephalus. Posterior fossa is small and
posterior fossa structures are crowded, resulting in severe herniation of posterior fossa structures through the foramen mag-
num. Axial noncontrast CT scan (B) shows hypertelorism, lateral bulging of the middle cranial fossae, and an area of mixed
hypodensity (solid arrows) and slight hyperdensity (open arrows), indicating a hemorrhage, in the right temporal lobe. Coronal
T1-weighted image (C) shows the right temporal lobe hemorrhage (white arrows), the markedly enlarged ventricles, and the
bulging of the middle cranial fossa. The configuration of the calvarium is that of a cloverleaf skull. Maximum intensity projection
from an MR venogram (D) shows nearly complete absence of the transverse and sigmoid sinuses, suggesting that the temporal
lobe hemorrhage was the result of venous hypertension or infarction.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 537

enlargement of the frontal horns. This combination of forces results

TABLE 5-11 Key Imaging Findings in in an appearance of turricephaly (tower head, Figs. 5-212 to 5-214).
In addition, because of the premature sutural fusion, the skull base
Craniofacial Anomalies and posterior fossa are abnormally small. This characteristic skull
shape can be detected prenatally with fetal MRI (Fig. 5-215) (1150)
Common and should allow prenatal diagnosis of the multiple suture synostosis
Multiple sutural synostosis syndrome, although the details to diagnose the precise syndrome may
not be visible.
Enlarged anterior fontanelle Anomalies of the underlying brain are present in a significant
Small skull base number of affected patients (1114,1151,1152) and their identification
is the primary reason for obtaining MR studies. Although PMG is not
Ventriculomegaly/hydrocephalus
described in these disorders, we have seen several cases (Fig. 5-216).
Anomalies of venous drainage This finding is not altogether unexpected in view of the known inter-
Dysplastic calvarial bone action of the cerebral cortex and overlying meninges (often abnormal
in craniosynostosis syndromes) during development (414,1153). Ven-
Anomalies of the external and middle ear
triculomegaly (Figs. 5-213 and 5-214) is very common, probably as a
Less common result of the small skull base (resulting in mechanical resistance to CSF
Tonsillar herniation/Chiari I malformation outflow) and small jugular foramina (resulting in increased resistance
to venous outflow); this situation results in increased venous pressure,
Agenesis/hypogenesis of the corpus callosum venous engorgement, cephalocranial disproportion, and increased
Agenesis/hypogenesis of the septum pellucidum CSF pressure (973,1151,1154–1157) (Figs. 5-213 and 5-214). Frank
Dysmorphic hippocampi hydrocephalus is present in approximately 12% of affected patients
(Fig. 5-213) (1158) and is most common in Crouzon and Pfeiffer syn-
Dysmorphic cerebral cortex dromes (as high as 60% in some series [1156]). If nearly all sutures are
closed, the ventricles may remain small in spite of increased intrac-
ranial pressure, enlarging only after craniofacial surgery has opened
the calvarium (1158) (see discussion in Chapter 8). The differentia-
Imaging of Craniosynostosis Syndromes tion of benign ventriculomegaly from hydrocephalus can be difficult,
As stated above, considerable overlap exists among the craniofacial as discussed in Chapter 8, and is dependent upon assessment of subtle
manifestations of the different syndromes; therefore, a general descrip- features such as the degree of enlargement of the anterior recesses of
tion of the imaging findings will be given (for a summary, see Table the third ventricle. Of note, enlargement of the temporal horns is not
5-11). The shape of the head, as viewed on sagittal MR images, is a good sign of hydrocephalus in this group of patients, as the temporal
quite characteristic in most patients with multiple sutural synostosis horn enlargement is merely a consequence of the middle cranial fossa
syndromes. Because the coronal, sagittal, and lambdoid sutures close being disproportionately enlarged (Fig. 5-217).
early, the brain grows upward and anteriorly through a very enlarged Venous anomalies are common and may be the result of diver-
anterior fontanelle (Figs. 5-212 to 5-214), resulting in disproportionate sion of venous outflow through enlarged emissary veins (1140,1158).

FIG. 5-214. Apert syndrome with calvarial anomaly, venous anomalies, and cephalocele. A. Sagittal T1-weighted image
shows turricephaly with enlarged ventricles. The cerebrum towers anteriorly via an enlarged anterior fontanelle. The
skull base is small and the posterior fossa structures are crowded. B. Axial T1-weighted image shows disproportionate
enlargement of the frontal horns secondary to upward extension of the cerebrum through the anterior fontanelle.

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 538 Pediatric Neuroimaging

FIG. 5-214. (Continued) C and D. Axial T2-weighted images show the dysplastic bone of the calvarium, with irregular spicules
extending inward; the meninges are always dysplastic, as well. Note the hypertelorism and the extension of the left occipital lobe
(encephalocele, white arrows) through the calvarium in (D). E and F. Axial CT images in a different patient show the herniation of
brain tissue (white arrows) through a defect in the occipital bone and the spicules of bone extending inward from the calvarium.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 539

FIG. 5-214. (Continued) G. MR venogram shows hypoplasia of

the left transverse sinus and abrupt termination (black arrow) the
right transverse sinus. H. Lateral view of 3D reformation of CT
scan shows the turricephaly and small skull base characteristic
of Apert syndrome. I. Anterosuperior view of 3D reformation of
CT scan shows bilateral coronal suture closure and the marked
enlargement of the anterior fontanelle (black arrows) that results
from the head growth in the setting of bilateral coronal suture
synostosis.

Increased intracranial pressure typically appears during the second
year of life, as the cranial sutures begin to close (1157), but may nor-
malize as the emissary veins enlarge (emissary veins carry the venous
blood from intracranial to extracranial veins through enlarged emis-
sary foramina in the calvarium) (1159). Small jugular foramina are
present in the majority of patients with venous anomalies and are the
probable cause of venous hypertension (1141,1160). As described in
the previous section on nonsyndromic craniosynostosis, preoperative
identification of venous anomalies is important for surgical planning;
therefore, venography should be a part of the preoperative evalua-
tion of these patients (Figs. 5-212 and 5-214) (1139,1141,1161). MRV,
catheter venography, or CTV will work, but CTV gives the most detail
regarding the small venous channels and their transcalvarial course,
even if low dose techniques are used (see Chapter 1).
The small skull base, in conjunction with high intracranial pres-
sure, is the probable cause of the high incidence of cerebellar herniation
through the foramen magnum, usually called Chiari I malformations
(Figs. 5-212 and 5-217), in these syndromes (973,1158,1162). This phe-
nomenon seems to be particularly common in Crouzon syndrome, in
which lambdoid sutures close particularly early and tentorial attach-
ment to the calvarium is particularly low (973), in Pfeiffer syndrome
(Fig. 5-217), and in the Kleeblattschädel deformity (Fig. 5-213) (974).
Other common brain anomalies in craniosynostosis syndromes include
cortical dysplasias, callosal agenesis or hypogenesis, agenesis or hypo-
genesis of the septum pellucidum, distortions or malformations of the
hippocampus, and cephaloceles (Fig. 5-217) (1114,1140,1151,1152,
1154,1163); all these seem to be most common in Apert syndrome.
CT with bone windows or the first echo T2 sequence on MRI often
shows a dysmorphic-appearing calvarium with thin, irregular bone
(Figs. 5-214 and 5-217) that is difficult to separate from the underlying
dura at the time of surgery. Cephaloceles may result from brain, CSF,
or dura herniating through the abnormal skull (Figs. 5-214 and 5-217)

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 540 Pediatric Neuroimaging

FIG. 5-215. Fetal MR images of craniosynostosis syndromes. A and B. Apert syndrome at 23-week gestational age. Sagittal image
(A) shows no evidence of turricephaly; however, coronal image (B) shows some expansion of the middle cranial fossae (white
arrows) already at this age. C and D. Apert syndrome at 31-week gestational age. Sagittal image (C) shows superior expansion of the
frontal calvarium (white arrows), compatible with turricephaly. Coronal image (D) shows more marked expansion of the middle
cranial fossae (arrows) and some ventriculomegaly.

(1140). Patients with multiple synostoses have hypertelorism and shal-
low orbits with marked proptosis (Figs. 5-213, 5-214, and 5-217). In
addition, anomalies of the external and middle ear, again resulting
from the abnormal formation of the skull base, will often be found if
1 mm sections are acquired with bone algorithm through the petrous
pyramids (1114,1163).
CHROMOSOMAL ANOMALIES
Chromosomal anomalies have only recently been systematically
catalogued and characterized with respect to their pathologic and
neuroradiologic findings (1164). An amazing website, called OMIM,
has been created and has an enormous amount of information on
most diseases that have been described (http://www.ncbi.nlm.nih.gov/
omim/). Readers are highly recommended to visit this site when ques-
tions arise concerning specific disorders. I have tried to include the
chromosomal mutations associated with malformations in the appro-
priate sections of this and other chapters (especially Chapters 3 and 6).
The field is rapidly evolving as the genetic bases of many anomalies are
elucidated. It is interesting to note that many sets of siblings have iden-
tical dysmorphic features and brain anomalies that still fit no known
genetic syndrome. As genetic evaluations become more common and

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 Chapter 5 • Congenital Malformations of the Brain and Skull
more precise, the chromosomal abnormalities that cause these disor-
ders will most likely be discovered.
A few well-known genetic syndromes that affect the brain and
their associated brain anomalies are discussed in this section. More
complete lists can be found in genetics and pediatric textbooks and
on OMIM. Ideally, as essentially all of the major types of brain anoma-
lies that are seen in genetic disorders are described in this chapter, this
imaging information, combined with the lists of chromosomal disor-
ders and their intracranial anomalies, will allow diagnoses to be more
easily established. In this section, I will concentrate on the well-defined
syndromes of trisomy 21 (Down syndrome), trisomy 18 (Edwards
syndrome), trisomy 13 (Patau syndrome), the Fragile X syndrome,
inversion duplication of the short arm of chromosome 8, and the Wolf-
Hirschhorn syndrome.
Trisomy 21
Down syndrome, caused by trisomy of chromosome 21, is the most
common chromosomal disorder with an incidence of about 1 in 1,000
Barkovich_Chap05.indd 541
541
FIG. 5-216. Apert syndrome with polymicrogyria.
Sagittal T1-weighted image (A) shows marked turri-
cephaly (white arrows) and an enlarged proximal aque-
duct (white arrowheads). Posterior fossa structures are
crowded. Axial T2-weighted images (B and C) show
areas of dysplastic bone/meninges (white arrows) and
several areas of abnormal-appearing cortex (black
arrows), consistent with polymicrogyria.
live births (1165). The disorder is a leading cause of mental retarda-
tion with 80% of affected patients being severely retarded (IQ < 50).
Although examination of the brain at autopsy shows many abnormali-
ties, including senile plaques and neurofibrillary tangles at an early age,
reduced brain weight, a narrow superior temporal gyrus, and hypoplas-
tic inferior frontal gyrus, imaging studies are not dramatic. Patients are
brachycephalic with a short, round brain, reduced AP diameter of the
frontal lobes, a narrow superior temporal gyrus, small cerebellum and
pons, and forward kinking of the brainstem (1166). Premature cerebral
atrophy and senile calcifications of the globus pallidus may be seen.
Cervical spine abnormalities are common in Down syndrome.
The most common anomaly is atlantoaxial subluxation, presum-
ably as a result of ligamentous laxity, which has a prevalence of 10%
to 22% (1167,1168). Ligamentous laxity may also contribute to
the increased incidence of atlanto-occipital subluxation in affected
patients (1169,1170). Superimposed upon the ligamentous laxity,
a high incidence of bony anomalies of the upper cervical spine puts
the affected child in even greater jeopardy of spinal cord injury with
relatively minor trauma. Odontoid anomalies, such as hypoplasia and
5/6/2011 9:01:31 PM
 542 Pediatric Neuroimaging

FIG. 5-217. Infant with severe craniofacial anomaly from Pfeiffer syndrome. A. Sagittal T1-weighted image shows marked turricephaly with a very small
posterior fossa. The cerebellum is herniated (black arrows) through the foramen magnum. An occipital cephalocele (white arrows) herniates through a
calvarial defect. Anomalies of venous drainage were present. B. Coronal T1-weighted image shows enlarged middle cranial fossae and resultant temporal
horn enlargement. C. Axial T2-weighted image shows bilateral proptosis, enlarged temporal horns, and markedly compressed posterior fossa structures. The
cerebellum (black arrowheads) wraps around the brainstem. D. Axial T1-weighted image shows marked brachycephaly, expanded middle cranial fossae, and
cerebellar tissue herniated though the midline occipital calvarial defect (black arrows) to form an encephalocele. E and F. Anterior (E) and posterior (F) views
of 3D reformation of the skull show the enormous anterior fontanelle (black arrows in E), the posterior calvarial defect of the cephalocele (black arrowheads
in F), and the “Swiss cheese” appearance of the posterior calvarium resulting from the many areas of thinning of dysplastic calvarial bone.

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 Chapter 5 • Congenital Malformations of the Brain and Skull 543

FIG. 5-218. Trisomy 18. Sagittal T1-weighted image (A) shows callosal agenesis, a simplified cerebral cortical gyral pattern, pontine hyp-
oplasia and cerebellar hypoplasia with a large posterior fossa (Dandy-Walker complex). Axial T1-weighted image (B) shows shallow sulci
and a simplified cortical gyral pattern.

dysplasia of the odontoid and os odontoideum, have been described Trisomy 13

(1171,1172). Patients may also have hypoplasia of the posterior arch
of C-1 (1167) and they can develop progressive basilar invagination
(1171). The craniocervical junction should always be closely scruti-
nized in patients with Down syndrome, and, as stated in Chapter 4,
these patients should be observed regularly for neurologic dysfunction
and neck pain and should be carefully examined after even minor neck
trauma. Plain film radiographs of the cervical spine with flexion and
extension views are adequate for patients without neurological deficits.
However, patients with neurologic signs or symptoms, or with a history
of signs or symptoms referable to craniocervical junction anomalies,
should undergo MRI with sagittal flexion and extension T1-weighted
images. T2-weighted images should also be obtained to look for areas
of high signal within the cord, indicative of prior injury.
Trisomy 18
Trisomy 18, also known as Edwards syndrome, is the second most
common trisomy encountered in newborns, occurring in about 1 in
5,000 live births. Patients are dolichocephalic with malformed low set
ears, micrognathia, short upper lip, short palpebral fissures, epicanthal
folds, midline facial clefts, ptosis, corneal opacities, and microphthal-
mos. Characteristic hand and foot anomalies, where the fingers flex
and override (most commonly, the index finger overlaps the long fin-
ger and the small finger overlaps the ring finger) and the great toe is
dorsiflexed, are common. Anomalies of the cardiac, gastrointestinal,
and urogenital systems are common (717,1165,1173).
The most consistently identified neuropathologic findings are
anomalies of the cerebral gyral pattern, hypoplasia of the cerebel-
lum and basis pontis, hypogenesis or agenesis of the corpus callo-
sum, and dysplasia of the hippocampus, lateral geniculate body, and
inferior olivary nucleus (717). CT may show dolichocephaly and cer-
ebellar hypoplasia but is not as useful as MRI in demonstrating the
gyral anomalies, callosal hypogenesis, and hippocampal dysplasia
(Fig. 5-218) (1165,1166).
Trisomy 13, also known as Patau syndrome, occurs in about 1 in 6,000
live births. The clinical features include microcephaly, severe mental
retardation, absent eyebrow, shallow supraorbital ridges, anophthalmia,
microphthalmia with coloboma, micrognathia, cleft palate, malformed
ears, and cardiac anomalies. Holoprosencephaly occurs in 80% of affected
infants. In those patients without holoprosencephaly, reported anoma-
lies include callosal agenesis, olfactory hypoplasia, cerebellar cortical dys-
plasias, and inferior vermian hypoplasia (Fig. 5-219) (1165,1173).
Fragile X Syndrome
The fragile X syndrome (also known as the Martin-Bell syndrome) is
the most common genetic cause of mental retardation, being present
in 1/1,500 live-born boys (1174). The disorder is caused by an unstable
sequence of DNA in the FMR1 gene located at chromosome Xq27.3;
the sequence codes for a trinucleotide repeat that is greatly amplified
in affected individuals (1175,1176). Affected males have a prominent
forehead and mandible, narrow midface, large ears, and macroorchid-
ism; they may show autistic behavior, perseverative speech, and tac-
tile defensiveness (1177). Pathologic findings include subependymal
and subpial heterotopia, siderosis of the globus pallidus with myelin
loss, and hypoplasia of the cerebellar vermis (4). The most commonly
described neuropathologic abnormality is abnormal dendritic spine
morphology, leading to abnormal synapses. Most patients with Fragile
X syndrome have normal imaging studies, although early atrophy has
been reported. Preliminary studies indicate that fractional anisotropy
is reduced in the frontal lobes of affected patients (1178).
Inversion Duplication of Short Arm of
Chromosome 8
Inversion duplication of the short arm of chromosome 8 (ID8p) is a
rare unbalanced chromosome aberration with an estimated incidence

Barkovich_Chap05.indd 543 5/6/2011 9:01:33 PM

 544 Pediatric Neuroimaging
FIG. 5-219. Trisomy 13. Sagittal T1-weighted image (A) shows mild callosal hypogenesis with mild vermian hypoplasia.
Oblique coronal T1-weighted image (B) shows bilateral hippocampal hypoplasia.
of 1 in 10,000 to 30,000 newborns (1179). The clinical features vary, but
affected children are generally characterized by minor facial dysmor-
phisms, severe developmental delay, infantile hypotonia (which pro-
gresses to spasticity), feeding difficulties, and scoliosis (1180). Epilepsy
develops in about 30% (1180). The diagnosis can be made by routine
chromosomal analysis. Imaging typically shows callosal agenesis or
severe hypoplasia, hypoplasia of the inferior cerebellar vermis (often
with enlarged retrocerebellar CSF spaces), delayed white-matter myeli-
nation, and foci of T2 and FLAIR hyperintensity in the periventricular
white matter. The white matter abnormalities vary from a few small
spots to multifocal, confluent areas involving most of the brain (1180).
Wolf-Hirschhorn Syndrome
The Wolf-Hirschhorn syndrome, caused by partial deletion of the
short arm of chromosome 4, is characterized by severe growth retar-
dation and mental defect, microcephaly, “Greek helmet” facies, and
closure defects (cleft lip or palate, coloboma of the eye, and cardiac
septal defects). Most patients are never able to walk without support
(1181,1182). Diagnosis is made by characteristic facies and the associ-
ated anomalies. Little neuropathology information is available. MRI of
the brain is characterized by marked reduction of white matter, callosal
hypoplasia, and, in some cases, characteristic cysts in the periventricu-
lar white matter adjacent to the tips of the frontal horns.
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5/6/2011 9:01:37 PM
 CHAPTER

The Phakomatoses
6 GILBERT VEZINA AND A. JAMES BARKOVICH

Neurofibromatosis type 1 Neurocutaneous melanosis

Clinical manifestations Clinical manifestations
Cranial and intracranial manifestations Pathological manifestations
Spinal manifestations Neuroimaging manifestations
Neurofibromatosis type 2 Incontinentia pigmenti
Clinical manifestations Clinical manifestations
Imaging of intracranial manifestations Pathological and neuroimaging manifestations
Imaging of spinal manifestations Hypomelanosis of Ito
Other forms of neurofibromatosis Clinical manifestations
Tuberous sclerosis complex Neurological manifestations
Clinical manifestations Neuropathological and neuroimaging manifestations
Cutaneous manifestations Basal cell nevus syndrome
Ocular manifestations Clinical manifestations
Intracranial manifestations Neuroimaging manifestations
Non-CNS manifestations PHACE (posterior fossa malformations, facial
Sturge-Weber disease hemangiomas, arterial anomalies, cardiac anomalies
Clinical manifestations and aortic coarctation, eye anomalies) syndrome
Intracranial pathology Clinical manifestations
Neuroimaging manifestations Neuroimaging manifestations
Extra-CNS manifestations Diffuse neonatal hemangiomatosis
von Hippel-Lindau disease Chédiak-Higashi syndrome
Clinical manifestations Progressive facial hemiatrophy (Parry-Romberg syndrome)
Ocular manifestations Epidermal nevus syndrome
Brain and spinal cord manifestations Clinical manifestations
Papillary cystadenomas of the endolymphatic sac Ocular and brain manifestations
Visceral manifestations Encephalocraniocutaneous lipomatosis
Ataxia-telangiectasia Clinical manifestations
Clinical manifestations Neuroimaging manifestations
Pathological and neuroimaging manifestations Other overgrowth syndromes
Nijmegen breakage syndrome

he phakomatoses are disorders characterized by multiple
T hamartomas and other congenital malformations affecting
mainly structures of ectodermal origin, that is, the nervous
system, the skin, the retina, and the globe and its contents; visceral
organs are also involved, but in general to a lesser extent. Classically,
four diseases were included in this group: von Recklinghausen neuro-
fibromatosis, tuberous sclerosis (Bourneville disease), retinocerebellar
angiomatosis (von Hippel-Lindau disease), and encephalotrigeminal
angiomatosis (Sturge-Weber disease). However, many other heredi-
tary diseases have subsequently been classified under the heading of
phakomatoses. Patients with several phakomatoses (and other inherited
cancer predisposition syndromes) have increased genetic susceptibil-
ity to multiple primary malignancies, which is enhanced by sensitivity
to ionizing radiation (1). In these disorders, listed in Table 6-1, care
should be used to minimize exposure to radiation during diagnosis,
treatment, and follow-up; MRI should be the favored imaging modal-
ity. A discussion of all of the neurocutaneous disorders that have been
described is beyond the scope of this book. Instead, we describe those
that are most commonly seen in practice and likely to be seen in mod-
erate to large-sized outpatient and inpatient practices.

569

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 570 Pediatric Neuroimaging
TABLE 6-1 Inherited Cancer Predisposition
Syndromes in Which Exposure
to Ionizing Radiation Should
be Minimized
Nijmegen breakage syndrome
Ataxia-telangiectasia
Nevoid basal cell nevus syndrome
Li-Fraumeni syndrome
Hereditary retinoblastoma
Neurofibromatosis type 1
(Modified from Reference 471)
NEUROFIBROMATOSIS TYPE 1
Neurofibromatosis type 1 (NF1) is one of the most common autosomal
dominant central nervous system (CNS) disorders. It has a world-
wide incidence of approximately 1 per 2,500 to 3,000 individuals,
without preference for race or sex (2–5). NF1 is the disorder initially
described by von Recklinghausen in 1882 (5). The genetic locus has
been mapped to chromosome 17q11.2 (4). The NF1 gene produces
a cytoplasmic protein called neurofibromin, which is enormous and
appears to have many functions. In the CNS, it is expressed primarily in
neurons, Schwann cells, oligodendrocytes, and astrocytes (2,3). Under-
standing of the molecular pathogenesis of NF1 and the functions of
the NF1 gene helps explain the extensive clinical and imaging features
of this syndrome. Understanding the functions of NF1 also allows for
the development of targeted therapies to improve the management of
clinical problems associated with NF1 (6,7). The functions of neurofi-
bromin include the following:
1. It appears to act as a tumor suppressor gene that functions in part
as a negative regulator of the RAS protooncogene (8).
2. It acts as a regulator of neural stem-cell proliferation, survival, and
astroglial differentiation, and is a regulator of neuroglial progeni-
tor function (9,10). Neurofibromin is required for intracellular
cyclic AMP (cAMP) generation in both neurons and astrocytes;
abnormal levels of cAMP appear to be, at least in part, responsible
for the abnormalities in glial and neuronal development evident in
NF1 patients.
3. It regulates ERK signaling in GABA release, an important pathway
involved in learning (and therefore in learning disabilities) (11).
4. It is involved in the maintenance of the vascular wall. Neurofibro-
min is expressed in the vascular endothelium; loss of neurofibro-
min likely causes smooth muscle proliferation, possibly in response
to nonspecific injury to the vascular wall (10), which can lead to
vasculopathy.
5. It is involved in bone formation and remodeling. Neurofibromin
is expressed in osteoblasts; it inhibits collagen synthesis, promotes
mineralization, and regulates osteoclastogenesis (103).
6. It seems to be required for normal myelination by Schwann cells
(12). In addition, the gene for oligodendrocyte myelin glycopro-
tein, a major myelin protein, is embedded within intron 27b of the
NF1 gene (13). Therefore, it is not surprising that abnormalities of
myelin/white matter are seen in patients with NF1.
Barkovich_Chap06.indd 570
Phenotypic expression of the disease is extremely variable, both clini-
cally and radiologically; this variation has resulted in attempts to cor-
relate phenotypes with underlying genetic factors (14). Overall, no
genotype-phenotype relationships have been identified by mutational
analyses of NF1 patients (15). Genetic modifiers, and possibly environ-
mental modifiers (at the level of the cellular milieu), unlinked to the
NF1 locus, likely contribute to the variable expressivity of the disease
(16). Diagnostic criteria are listed in Table 6-2.
Clinical Manifestations (Tables 6-2 and 6-3)
Cafe au lait spots are the first manifestation of NF1 to develop; they
are sometimes present at birth and usually develop at the age of 2 years
(7). Freckling within the axilla will develop later in about two thirds
of patients (17–19). Cutaneous neurofibromas begin to appear around
the onset of puberty and increase in number throughout life. Lisch
nodules, which are best seen by slit lamp examination, begin to appear
in childhood and are present in almost all affected adults (17–19).
A number of other features are characteristic of this disease, the most
important from the neuroimaging standpoint being gliomas of the
optic pathway (and other intracranial astrocytomas, which may have
a higher incidence in patients with optic pathway tumors [20,21]),
kyphoscoliosis, sphenoid wing dysplasia, vascular dysplasias, nerve
sheath tumors, and macrocephaly. NF1 is associated with an increased
incidence of tumors, with the frequency of brain tumors (other than
optic glioma) being 1.5% to 2.0% and that of extra-CNS tumors (most
commonly sarcomas, pheochromocytomas, and leukemia) being 3%
to 5% (22). Megalencephaly is common; the cerebral enlargement is
primarily attributable to an increase in cerebral white matter volume,
with a smaller contribution from the gray matter (23). About 4% to 7%
of patients have epilepsy, primarily related to intracranial masses and
cytoarchitectural abnormalities (24).
Cognitive impairment is found in 30% to 65% of children with NF1
and consists of a wide range of learning disabilities (most frequently
problems with attention, perception, executive functioning, and aca-
demic achievement) (17,18,25–27). The most common neuropsy-
chological manifestation of NF1 in childhood is a specific learning
disability, defined as a major discrepancy between ability (intellect or
TABLE 6-2 Criteria for Diagnosis of
Type 1 Neurofibromatosis
The diagnosis of NF1 requires two or more of the following:
(1) Six or more cafe au lait spots over 5 mm in greatest diameter
(over 15 mm in postpubertal individuals)
(2) Two or more neurofibromas of any type or one or more plexi-
form neurofibroma
(3) Freckling in the axillary or inguinal areas
(4) Optic glioma
(5) Two or more Lisch nodules (pigmented hamartomas of the iris)
(6) A distinctive osseous lesion such as sphenoid dysplasia or
thinning of long bone cortex
(7) A first-degree relative (parent, sibling, or offspring) with NF1
(Adapted from Reference 473)
5/6/2011 9:03:45 PM
 Chapter 6 • The Phakomatoses 571

populations of NF1 patients, those with and those without a degree of

TABLE 6-3 Incidence of Clinical cognitive impairment. Multiple studies have attempted (with variable
success) to establish a correlation between the presence of the char-
Features of NF1 acteristic T2 bright foci seen in NF1 children and the cognitive defi-
cits evident in psychometric testing (26,28–31). The methodologies of
Feature Incidence these studies are complicated by the peculiar temporal evolution of the
Cutaneous Lesions T2 bright foci: they are absent at birth; they appear in early childhood
and reach peak numbers around age 7 to 12 years; and they essentially
>6 Café au lait spots >95% disappear by the end of the second decade of life. One of the most con-
Axillary freckling 65%–85% sistent markers of cognitive deficits between age 8 and 18 years appears
to be the presence of T2 bright foci in the thalami (26,28–32).
Cutaneous neurofibromas
Although learning disabilities are common in NF1, intellectual dis-
Age 0–9 y 15% ability affects a much smaller proportion of patients. Some mentally
Age 10–19 y 45% disabled NF1 patients have been found to have deletions of the entire
NF1 gene, leading to a distinctive phenotype that includes the devel-
Age 20–29 y 85%
opment of a large number of neurofibromas and a distinctive facial
Over age of 30 y 95% appearance (33,34). Affected patients also appear to have a greater
Lisch nodules number of structural anomalies detected in their brains by MR studies.
It is unclear whether this phenotype is the result of haploinsufficiency
Age 0–4 y 20% for the NF1 gene or whether a deletion of portions of contiguous genes
Age 5–9 y 40% contributes to the clinical picture (33,34).
Age 10–19 y 80% It is important to remember that few features of NF1 are likely
to be present in any particular patient. For example, one patient may
Over age of 20 y 95% have a normal vascular system and a normal intellect but have severe
Neurologic Lesions kyphoscoliosis, while another may have a normal spine and normal
cognition but have severe hypertension from renal artery stenosis.
Plexiform neurofibromas 30%
Because this chapter is about neuroradiology, we concentrate on the
Head and neck only 2%–4% CNS manifestations of NF1, which have an incidence of about 15%
Malignant peripheral nerve tumors 2%–3% (18,19). Because of this high incidence, with many lesions occurring at
an early age when signs and symptoms may be difficult to elicit, some
Lifetime risk 10%
centers advocate MR screening of asymptomatic children with NF1
Cognitive deficits (at least once between age 2 and 6 years); the value of such screening
Mental retardation 5% exams has not been determined in a large prospective cohort.
Learning disabilities 50%
Scoliosis 10%–26% Cranial and Intracranial Manifestations
Optic pathway gliomas 15% Optic Pathway Gliomas
Symptomatic 5% The most important primary brain abnormality in NF1 is the optic
Short stature 20%–30% pathway glioma (OPG) (18,35,36). OPG is seen in 15% to 20% of indi-
viduals with NF1, and 30% to 50% of these tumors will cause clini-
Macrocephaly 50%
cal symptoms, including vision loss and precocious puberty (32,33);
Epilepsy 5% therefore, the incidence of symptomatic optic pathway tumors is about
Other Systems 5% to 7%. Almost all OPGs present before age of 7 years; the tumor
can be isolated to a single optic nerve or can involve both optic nerves,
Pseudarthrosis of long bones 3%
the chiasm and the optic tracts (Figs. 6-1 to 6-4). Primary involvement
Sphenoid wing dysplasia 1% of the optic nerve is more common in the NF1 population, while spo-
Renal artery stenosis 1% radic OPG (patients without NF1) more commonly involves the chi-
asm and optic radiations (37). The prognosis is poorer for tumors that
Osteoporosis up to 50% involve the optic chiasm or tracts as compared to those involving only
Adapted from 3,7,19,103. the optic nerves (36,38). Irrespective of the distribution, the clinical
course of NF1-associated OPG is more indolent than in the sporadic
OPG (37,39).
Optic pathway tumors are most commonly of low histological
grade. Although those involving only the optic nerves are sometimes
aptitude) and achievement (performance) in patients with IQ scores classified as hamartomas rather than neoplasms, most OPG are pilo-
in the normal range. Specific learning disability has been estimated to cytic astrocytomas; in addition, some optic pathway tumors sponta-
occur in 30% to 45% of children with NF1, which is more than three neously involute over time in patients with NF1 (40–42). Therefore,
times the prevalence in the general population (26,27). The occurrence aggressive therapy is usually not indicated unless symptoms progress
of cognitive deficits does not seem to be associated with the clinical or radiologic evidence of progression is noted. Uncommonly, optic
severity of the disease (26). In fact, a bimodal distribution of full scale pathway tumors can be highly malignant, demanding a very aggressive
IQ scores is seen in children with NF1, suggesting that there are two treatment approach (38).

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 572 Pediatric Neuroimaging

FIG. 6-1. Optic pathway glioma in NF1. A. Sagittal T1-weighted image

shows a large mass (white arrows) replacing the chiasm and extending
posteriorly to the mammillary body and superiorly (black arrow) into the
fornices and septum pellucidum. B. Postcontrast axial T1-weighted image
shows enhancing tumor (white arrows) in the optic tracts, with extension
toward the mesial temporal lobes. C. Axial T2-weighted image at a higher
level reveals tumor infiltration in the optic tracts to the level of the lateral
geniculate body/posterior thalamus (white arrows). Tumor infiltration of
the fornices is also evident (black arrows).

Tumors of the optic nerve diffusely expand the nerve, producing
a fusiform mass. Two architectural forms can be distinguished. The
first is a diffuse expansion of the optic nerve itself without significant
subarachnoid tumor (Fig. 6-2C). The second is tumor infiltration of
the subarachnoid space, creating a rim of tumor around a relatively
unaffected nerve (Fig. 6-3) (43,44). Postcontrast MRI using fat sup-
pression will distinguish the two architectural forms of optic nerve
gliomas. When the nerve is diffusely infiltrated, enhancing tumor fills
the optic nerve sheath, whereas infiltration of the subarachnoid spaces
shows a rim of enhancing tumor around a minimally enhancing optic
nerve. Optic nerve tortuosity is commonly observed in NF1, even in
the absence of optic nerve glioma.
As discussed in Chapter 7, CT is adequate for evaluating tumors
of the intraorbital optic nerves. The orbital fat provides intrinsic con-
trast against which to visualize these lesions. Enlargement of the optic
nerve is usually fusiform, although occasionally the enlargement can
be rather eccentric; therefore, axial images should be obtained every
1 to 2 mm, preferably with helical scanning, and then reformatted
for optimal depiction of the nerves. Enlargement of the optic canals
will usually be seen if bone windows are used. CT cannot distinguish
the two architectural forms of optic gliomas and is less sensitive in
assessing intracranial involvement, such as involvement of the optic
chiasm. Unless the chiasm is very enlarged by gross tumor involve-
ment, it is necessary to inject intrathecal water-soluble contrast to see

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 Chapter 6 • The Phakomatoses 573

FIG. 6-2. Optic pathway glioma with extensive infiltration. A. Sagittal

T1-weighted image shows a mass extending from the chiasm and hypothalamus
(arrows) extending toward the mamillary bodies and the fornices. The pons is
slightly enlarged and shows abnormal low T1 signal. B. Axial T2-weighted image
shows that T2 hyperintense tumor has infiltrated into the medial basal gan-
glia/internal capsules (white arrows) and the fornices (black arrow). The tumor
has extended posteriorly to the level of the lateral geniculate bodies. C. Axial
T2-weighted image at a lower level reveals diffuse tumor infiltration, manifested
as hyperintensity of the pons and middle cerebellar peduncles (long white arrows).
Both optic nerves (short white arrows) are enlarged with homogeneous low T2
signal.

the chiasm well. In children, approximately 3 mL of nonionic contrast
(concentration 150 mg of iodine per mL) is injected via lumbar punc-
ture. The patient is tilted 45° head down (Trendelenburg) in the prone
position for approximately 2 minutes and then transported to the CT
scanner and imaged.
MRI is the preferred imaging modality for evaluating the entire
CNS in NF1, and this includes the optic nerves; moreover, the use of
MRI eliminates exposure of the child to ionizing radiation. Assess-
ment of the precise diameter of the intraorbital optic nerves may be
hampered by chemical shift artifact resulting from the location of the
nerve adjacent to orbital fat. The use of a fat suppression pulse, how-
ever, will eliminate the chemical shift artifact and allow the nerve to be
evaluated well. The intracranial optic nerves, optic chiasm, optic tract,
and optic radiations are all beautifully demonstrated with MRI. T1 and
fat-suppressed T2-weighted axial and coronal sequences, using ≤3 mm
slice thickness, should be obtained through the globes, optic nerves,
and optic chiasm, and followed by fat-suppressed contrast-enhanced
T1 axial and coronal images. A routine brain scan should follow to
look for involvement of the optic tracts and other areas of brain. Fluid
attenuated inversion recovery (FLAIR) and T2-weighted images show
involvement of the optic tracts as high signal intensity extending pos-
teriorly, often to the level of the lateral geniculate bodies (Figs. 6-1
and 6-2). Extension beyond the optic pathway can be identified when
present: superiorly into the hypothalamus, fornices, and septum pel-
lucidum; laterally into the temporal lobes; posteriorly into the optic
radiations; and inferiorly into the cerebral peduncles and the brain-
stem (Fig. 6-2). Rarely tumor can extend into the lateral ventricles.
Care should be taken not to mistake enlarged subarachnoid spaces
within the optic nerve sheaths (the result of ectasia of the dura sur-
rounding the optic nerves) for optic nerve tumors. The enlarged

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 574 Pediatric Neuroimaging

FIG. 6-3. Optic nerve tumor

with infiltration of the optic
nerve sheath. A. Postcontrast axial
T1-weighted image with fat sup-
pression shows enlarged, enhanc-
ing the left optic nerve (long white
arrow) and tumor infiltration into
the dilated perineural spaces (low
T1 signal bordered by a thin rim of
enhancement (short white arrows).
The right optic nerve (black
arrows) shows a smaller tumor.
B. Oblique sagittal T2-weighted
image of the left optic nerve with
fat suppression reveals thickening
and elongation of the nerve. The
sheath around the nerve shows
marked dilatation and hyperin-
tense signal (white arrows).

FIG. 6-4. Multivoxel spectroscopy of optic pathway tumor

in NF1. A. Axial FLAIR image shows tumor infiltration in the
chiasm/hypothalamus (long white arrow) and into the optic
tracts (short white arrows). B. Color map of the choline-to-
creatine ratio (Ch:Cr) from a long echo (TE = 270) multivoxel
spectroscopy reveals the highest ratio of choline to creatine
(red color) at the level of the chiasm/hypothalamus. Signifi-
cant Ch:Cr elevation is also evident in the thalami bilaterally
(yellow color). C. MR spectra from four different ROIs (num-
bered in image B). Highest (Ch:Cr) is evident in box 1, at the
level of the chiasm/hypothalamus. Ch:Cr levels are elevated
in the thalamus (boxes 3, 4) compared to the putamen (box 2);
this suggests the presence of microscopic tumor infiltration
in the thalamus, despite the normal FLAIR signal.

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 Chapter 6 • The Phakomatoses 575

perioptic spaces have signal intensity identical to cerebrospinal fluid,
do not enhance after administration of contrast, and are nonprogres-
sive (45). Care should also be taken not to confuse extension of OPG
into the optic tracts (and beyond) with the characteristic T2 bright foci
encountered in pediatric patients with NF1 (see next section). Differ-
entiation of the two pathologies can be very difficult; features of OPG
infiltration include contiguity, mass effect, low T1 signal on precon-
trast images, enhancement after contrast administration, and signifi-
cant elevations of choline (at MR spectroscopy) (Fig. 6-4) (46).
Other Gliomas and Tumor-Like Conditions
Astrocytomas are more common in NF1 than in the general population
(18,35,47,48); they can arise anywhere in the CNS. Juvenile pilocytic
astrocytomas (Fig. 6-5) are most common, but other low-grade (49)
and higher-grade tumors (47,50) also occur. Almost any part of the
CNS can be affected, but the suprasellar area (see above) is the most
common site; the brainstem (Figs. 6-6 and 6-7) is another common
site for tumors in NF1 (51). It is of interest to note that the brainstem
tumors occurring in NF1 seem to differ biologically from brainstem
tumors in other patients; most do not require therapeutic intervention
(51). In contrast to the predominance of pontine tumors in the general
population, the medulla is the most common site of brainstem tumor
origin in NF1, followed by the mesencephalon (particularly the peri-
aqueductal region/tectum) and the pons. This difference in location
may partly explain the indolent course and vastly better long-term out-
come of most brainstem tumors in NF1 (51–54). However, an indolent

FIG. 6-5. Development of a juvenile pilocytic astrocytoma in an area of extensive myelin vacuolation. A. Axial T2-weighted image of a 2-year-old child
reveals multifocal hyperintensity (white arrows) consistent with vacuolation around the fourth ventricle. This is a very typical location. B. Axial T2-weighted
image 1 year later reveals some overall increase in the load of hyperintense abnormalities. A more distinct, focal lesion (white arrow) has enlarged in the
right middle cerebellar peduncle. C and D. Axial T2-weighted (C) and postcontrast axial T1-weighted (D) images obtained at age 6 years show interval
incomplete resolution of the presumed vacuolation. A partially enhancing, tumor (white arrow) is clearly evident in the right middle cerebellar peduncle.
Pathology revealed a pilocytic astrocytoma.

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 576 Pediatric Neuroimaging

FIG. 6-6. Medullary tumor-like lesion in NF1, with resolution. A. Axial T2 image shows focal enlargement and increased T2 signal in the left posterior
medulla (short arrows), consistent with a small tumor. A neurofibroma is evident beyond the left hypoglossal canal (long arrow). B. Axial T2-weighted image
5 years later shows nearly complete resolution of the medullary lesion, with only slight residual thickening. The neurofibroma (arrow) at the skull base persists.

FIG. 6-7. Midbrain juvenile pilocytic astrocy-

toma (biopsy proven) in a 14-year-old adolescent
with NF1. A. Postcontrast T1-weighted image
shows a sharply marginated, intensely enhancing
mass (white arrow) in the dorsal inferior midbrain.
B. Axial FLAIR image demonstrates the well-cir-
cumscribed hyperintense mass (white arrow) to
have minimal surrounding edema. C. Single voxel
long echo (TE = 270) spectroscopy of the tumor
reveals a very high Ch:Cr (3.49; normal < 1.5) and
presence of lactate (double arrows). These MRS
findings, worrisome for a malignant tumor, are
commonly observed in pilocytic astrocytomas.
N-acetylaspartate–to-creatine ratio (NAA: Cr)
is decreased (1.68; normal > 2). The NAA:Cr is
higher than expected for a glial neoplasm, likely
secondary to contamination of the voxel by sur-
rounding (normal) brain tissue as the voxel (2 × 2
× 2 cms size) is slightly larger than the tumor.

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 Chapter 6 • The Phakomatoses 577

FIG. 6-8. Probable hamartomatous enlargement of the brainstem. A. Sagittal T1-weighted image reveals diffuse enlargement of the pons and, especially,
medulla (white arrows); the signal intensity is normal. B. Axial T2-weighted image shows enlargement and heterogeneously increased signal in the dorsal
right pons and middle cerebellar peduncle, with slight mass-effect on the fourth ventricle (arrow).

course is common in NF1 patients with diffuse pontine tumors, a
tumor type that typically has a very poor prognosis (see Chapter 7)
(54). Moreover, tumors of the mesencephalic tectum in patients with
NF1 are usually biologically benign and may regress spontaneously
(55). Thus, management of brainstem tumors in children with NF1
is generally not aggressive unless clinical progression is seen––isolated
radiologic progression is considered less serious.
Mild enlargement of the pons, medulla, and middle cerebel-
lar peduncles is occasionally observed in children with NF1 in asso-
ciation with, and likely the result of, extensive myelin vacuolation
(Fig. 6-8). This hamartomatous enlargement should not be misdiag-
nosed as a brainstem glioma; differentiating features from infiltrat-
ing gliomas include normal or nearly normal signal in T1-weighted
images, only modest (and usually heterogeneous) signal increase on
T2 images, absence of contrast enhancement, and lack of progression
on follow-up scans. The T2 signal abnormalities partly regress during
adolescence, though the brainstem remains enlarged. For more discus-
sion of brainstem tumors, see Chapter 7.
Other common locations for astrocytomas (other than the optic
system and tectum) in children with NF1 are the cerebellum (Fig. 6-5),
the corpus callosum, and the cerebral hemispheres (Fig. 6-9) (35,48,56).
Astrocytomas are discussed extensively in Chapter 7. Hamartomatous
enlargement of the hypothalamus is occasionally seen in children with
NF1 (Fig. 6-10), though usually without association with precocious
puberty or gelastic seizures. They project within the walls of the hypo-
thalamus in the lower third ventricle (intrathalamic/sessile configura-
tion). Like hypothalamic hamartomas in children without NF1, they
are nearly isointense to gray matter on T1- and T2-weighted images
and do not enhance (57); they should not be confused for a chiasmatic
or hypothalamic glioma.

FIG. 6-9. Grade 2 (fibrillary)

glioma in the left temporal
lobe of a 10-year-old child with
NF1. A. Axial T2-weighted
image shows a tiny, hyperin-
tense lesion (white arrow) in
the white matter of the poste-
rior left temporal lobe. B. Axial
T2-weighted image a year later
shows an ovoid, well-defined
T2 bright focus in the same
location (arrow), representing
the enlarged tumor.

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 578 Pediatric Neuroimaging
FIG. 6-10. Hypothalamic hamartoma in a 15-year-old boy with NF1. A. Sagittal T1-weighted image shows a gray matter intensity mass (short white arrows)
in the floor the third ventricle, posterior to the chiasm (long white arrow) and anterior to the mammillary bodies (black arrow). B. Coronal T2-weighted
image reveals bilateral gray matter intensity mass (black arrows) in the floor and left lateral wall of the hypothalamus.
In a small but significant number of patients with NF1,
hydrocephalus is present (58–60). The site of obstruction of CSF flow
is usually the aqueduct of Sylvius, resulting from benign aqueductal
stenosis, from extensive vacuolation of the tissues surrounding the
aqueduct (see next section), or from tumors (astrocytomas or hama-
rtomas) of the adjacent tectum or tegmentum of the mesencepha-
lon. The differentiation of these causes of aqueductal obstruction is
extremely difficult with CT (59). The tectal lesions usually do not show
significant contrast enhancement when they are small and, therefore,
subtle calcifications or distortions of the posterior third ventricle and
proximal aqueduct must be identified. The diagnosis of a tectal glioma
is relatively simple using MRI. In contrast to benign aqueductal steno-
sis (in which the proximal aqueduct is dilated and the tectum displaced
superiorly and thinned, see Chapter 8), gliomas enlarge the tectum and
may completely obliterate the aqueduct. Occasionally, the tectum may
appear short and thick in aqueductal stenosis because of mass effect
on the rostral aspect of the tectum by a dilated suprapineal recess (see
Chapter 8). In these cases, the patient should be reevaluated after ven-
tricular decompression.
Characteristic Hyperintense T2 Lesions and
White Matter Abnormalities
MRI has disclosed the presence of characteristic hyperintense T2/
FLAIR lesions in pediatric patients with NF1, located in the brain-
stem, cerebellar white matter, basal ganglia (especially the globus pal-
lidus), thalamus, internal capsule, corpus callosum, and occasionally
the corona radiata (Figs. 6-6 to 6-9) (29,61,62); the subcortical white
matter and centrum semiovale are not involved. These lesions are
characteristically multiple; they have little or no mass effect (unless
extensive confluence is evident, in which case mild mass effect may
be detected, Fig. 6-8); they do not elicit vasogenic edema, their signal
appears normal on T1-weighted images, and they do not enhance
after intravenous administration of paramagnetic contrast. Diffu-
sion studies show increased diffusivity; anisotropy is normal but
transverse eigenvalues are increased (63). Intermediate echo (TE =
144 msec) proton MR spectroscopy shows nearly normal NAA/Cr
and moderately increased Cho/Cr (46). Though there is wide indi-
vidual variability, these lesions are typically absent in the first year or
Barkovich_Chap06.indd 578
two years of life. New lesions appear from late infancy to about age
of 12 years (Fig. 6-11) (61); new lesions almost never develop after
age of 15 years. The lesions start to regress, starting late in the first
decade of life (62,64), so that they are almost never seen in patients
over the age of 20 years (Figs. 6-11 and 6-12). In the peak age group
(6–12 years), they are seen in up to 90% of NF1 children (32,65,66).
A pathologic analysis has shown that these are regions of myelin
vacuolation, where the layers of myelin become separated as they spi-
ral around the axon (67). As might be expected, water diffusivity is
increased in these areas of T2 hyperintensity to a greater degree than
in other areas of the brain (68).
The discovery that the oligodendrocyte myelin glycoprotein gene
is imbedded within the NF1 gene (13) and that neurofibromin is
required for Schwann cell myelination (12) further supports dysgen-
esis of myelin as the cause of the white matter abnormalities in NF1.
The vacuolization may develop, therefore, in regions where the myelin
is inherently abnormal; presumably the return of normal T2/FLAIR
signal on subsequent exams reflects myelin repair or remyelination
(69). The increased diffusivity of white matter (even normal appearing
white matter) in NF1 (70,71) further supports the concept of abnormal
myelin as an underlying cause.
In view of the frequency with which these T2/FLAIR hyperintense
foci are encountered in children with NF1, close imaging follow-up
or biopsy is not indicated as long as they occur in the characteristic
locations; are not hypointense on T1-weighted images; and lack associ-
ated mass effect, edema, and enhancement. However, a growing astro-
cytoma of the basal ganglia, pons, or cerebellum, when small, may
be indistinguishable from one of these lesions on noncontrast MRI
(Fig. 6-5)––especially in cases when there are numerous, confluent T2
hyperintense foci in some of the other expected locations. In this situ-
ation, it is recommended that the patients have a follow-up contrast-
enhanced MR scan, including diffusion-weighted imaging, perfusion
imaging, or proton MR spectroscopy, 6 months to a year after the first
study. A tumor will typically enhance or show progressive enlargement
or mass effect on adjacent structures (Fig. 6-5); it may also have locally
reduced diffusion in its solid portion (68), have increased blood vol-
ume (72), and show elevated choline with decreased creatine and NAA
on proton spectroscopy (46,73–76).
5/6/2011 9:03:54 PM
 Chapter 6 • The Phakomatoses 579

FIG. 6-11. Evolution of character-

istic focal T2 bright signal abnor-
malities in pediatric NF1. A and B.
Axial FLAIR images through the
posterior fossa (A) and the basal
ganglia (B) in a 4-year-old child.
Multiple small hyperintense foci
are seen within the deep cerebellar
hemisphere (arrows, A). Two small
lesions are evident in the right glo-
bus pallidus (short white arrows, B),
along with ill-defined hyperinten-
sity in the left globus pallidus (long
white arrow) and the left side of the
splenium (black arrow). C and D.
Corresponding axial T2-weighted
FLAIR images in the same patient
at age 12 years. The previous signal
abnormalities in the deep cerebel-
lum have mostly resolved, with a
few new white matter foci evident
(white arrows, C). New T2 bright
foci have developed in the right
globus pallidus (long white arrow,
D) and the bilateral posterior thal-
ami (short white arrows, D); the left
globus pallidus lesion is no longer
visible.

FIG. 6-12. Partial resolution of

basal ganglia signal abnormalities in
NF1. A. Axial T2-weighted image at
age 7 years shows multiple bilateral
hyperintense abnormalities (white
arrows) in the globi pallidi and inter-
nal capsules. B. Axial T2-weighted
image 4 years later shows significant
regression of the abnormalities.

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 580 Pediatric Neuroimaging

FIG. 6-13. T1 prolongation in the basal ganglia in NF1. A and B. Axial T2- and T1-weighted images show typical hyperintensity on both T1- and
T2-weighted images in the bilateral globi pallidi. The T2 hyperintensity in the posteromedial thalami (white arrows) is also typical.

The characteristic T2 hyperintense foci seen in the globi pallidi of lesions described above (66). NF1-related hippocampal T2 changes
patients with NF1 have a somewhat different radiologic appearance should not be confused with hippocampal sclerosis (in which case the
than the cerebellar foci in that they are sometimes slightly hyperintense hippocampal volume is decreased) or with neoplastic infiltration.
on T1-weighted images (Fig. 6-13) (62,69,77,78). (Calculation of T1 In addition to these focal lesions, many patients with NF1 have both
values shows that the frontal white matter, caudate nuclei, putamina, an increased volume of cerebral white matter and a larger midsagittal
and thalami also have some T1 shortening [78], but it is not appar- corpus callosum area than age-matched controls (Fig. 6-15) (81,82);
ent to visual inspection in these other areas). The hyperintensity on not surprisingly, these findings are more pronounced in patients with
T1-weighted images develops after the T2 prolongation appears and
persists after T2 prolongation disappears, a time course that suggests
that the T1 shortening represents delayed or reactive formation of
myelin (69). This view is supported by the finding of increased cho-
line and decreased NAA in the thalami of patients with the charac-
teristic T2 prolongation of the globus pallidus, a finding that may
reflect remyelination and neuropil injury in regions of dysmyelination
(79). The characteristic lack of enhancement, location, bilaterality,
and T1 hyperintensity help differentiate these presumed hamartomas
from astrocytomas. However, as with all small, nonenhancing foci of
T2 prolongation in the brain, the biological behavior of white matter
lesions in NF1 cannot be predicted with complete accuracy by imaging
alone. Benign-appearing lesions can degenerate into neoplasms (80),
and neoplastic-looking lesions can shrink or disappear (40–42). Also
remember that focal lesions developing in the cerebral cortex or in the
subcortical or adjacent white matter do not represent characteristic T2
bright lesions of pediatric NF1 (Fig. 6-9) (66); if present, these should
be followed by sequential imaging, as they may potentially represent
low-grade neoplasms.
Occasionally, the hippocampi of pediatric patients with NF1
can show diffusely increased signal on T2/FLAIR images, often with
increased volume (Fig. 6-14); this finding can be unilateral or bilateral,
is not progressive, and persists throughout childhood and adolescence FIG. 6-14. High-resolution coronal FSE T2-weighted image reveals
(66). The nature of the hippocampal abnormality is not known; how- hyperintense T2 signal of both hippocampal formations (white arrows)
ever, is not likely to represent myelin vacuolation as these hippocampi (compare signal to that of adjacent temporal cortex). The right hippocam-
have a different temporal evolution than the NF1 dysmyelinating pus is brighter and larger than the left.

Barkovich_Chap06.indd 580 5/6/2011 9:03:57 PM

 Chapter 6 • The Phakomatoses 581

macrocephaly (∼40% of those with NF1 [78]). In a recent study, a

larger corpus callosum was associated with significantly lower IQ (83).
It is postulated that the abnormal increase in callosal volume results
from increased myelination of callosal axons or redundancy of fibers
connecting the cerebral hemispheres (due to reduced apoptosis) (83).

FIG. 6-15. Sagittal T1-weighted image shows an abnormally thick corpus
callosum (white arrows). The ventral pons (black arrows) is prominent.
Vascular Dysplasia
Dysplasia of the cerebral vasculature is increasingly recognized in chil-
dren with NF1; it develops at a young age, with prevalence of up to 6%
(84–86). The known significant incidence of vascular abnormalities in
the cerebral vasculature and in other parts of the body makes vascular
dysplasia a distinct clinical entity. Any child with NF1 who has seizures,
mental retardation, paralysis, or severe headaches may have a vascular
dysplasia, particularly in the absence of a brain tumor or hydrocepha-
lus. However, clinically, a majority of NF1 patients with vascular dys-
plasia do not have focal deficits as a result of their cerebral arteriopathy
by the time the dysplasia is diagnosed with MRI. Intracranial vascular
dysplasias can also complicate irradiation for optic nerve or optic chi-
asm gliomas (presumably a radiation arteritis; see discussion in Chap-
ter 3). NF1-related vascular dysplasia can progress overtime (Fig. 6-16)
and may require revascularization surgery (84,86).

FIG. 6-16. Progressive NF1-related

vasculopathy. A. Axial T2-weighted
image at age 18 months shows nor-
mal appearing signal voids in the
basilar and proximal anterior and
middle cerebral arteries––note the
normal right MCA (arrow). B. Axial
T2-weighted image 2 years later
shows diminished size of the right
MCA signal void (white arrow).
C. Coronal reconstructed MIP
image from a 3D TOF MRA reveals
a lack of flow-related enhancement
in the right MCA (arrows), con-
sistent with an acquired complete
occlusion (or very severe stenosis).

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 582 Pediatric Neuroimaging
FIG. 6-17. Vascular dysplasia in NF1. A. Axial T2-weighted image shows absence of the left cavernous carotid artery. B. Arteriogram of the aortic arch
shows absence of the left common carotid artery origin and significant stenosis (arrow) of the proximal left subclavian artery.
Most commonly the dysplasia consists of intimal and smooth
muscle proliferation, with resultant stenosis or occlusion, in the carotid
(common or internal), proximal middle cerebral, or proximal anterior
cerebral arteries (Figs. 6-16 and 6-17). Moyamoya phenomenon with
marked enlargement of the lenticulostriate arteries (which function as
collateral vessels) is seen in many such patients (87). (Moyamoya is
discussed further in Chapter 12.) Fusiform arterial dilation, cerebral
aneurysms, and arteriovenous fistulas are also described, although less
commonly (84,87,88). The dysplasias can be difficult to detect on stan-
dard CT or MR images; with MR, close inspection of the arterial signal
voids (Fig. 6-16), especially the distal carotid arteries and the circle of
Willis (to detect narrowing of the cavernous or supraclinoid carotids
and proximal middle and anterior cerebral arteries), is essential in
patients with NF1 to avoid delays in clinical detection of these lesions;
note that the intracranial vessels are poorly seen on FLAIR images, so
acquisition of T2-weighted spin-echo images should be strongly consid-
ered when imaging children with NF1, particularly those with declining
function. If vascular dysplasia is suspected, MR (or CT) angiography
should be performed; conventional, catheter angiography is usu-
ally reserved for a presurgical workup. Angiography generally shows
either severe stenosis or occlusion of the proximal cerebral vessels
(Fig. 6-17). Most modern MR scanners allow excellent angiography
of the large and medium-sized intracranial vessels, and CT angiogra-
phy is also excellent if helical scanners are used; therefore, these should
be the modalities of choice if angiography is to be performed. MRI
is preferred over CT in order to avoid exposure to ionizing radiation
(see Chapter 1 for technical details).
Cranial Nerve Tumors
Cranial nerve tumors are uncommon in NF1, which mainly causes
glial tumors and neurofibromas of peripheral nerves. Schwannomas
are much more common in NF2 (see next section). The only cranial
nerve that is frequently involved in NF1 is the optic nerve, which has
been discussed above and is, in fact, a diencephalic white matter tract
that has been misnamed as a cranial nerve. The other cranial nerves are
rarely, if ever, involved. When schwannomas occur in patients with NF1,
Barkovich_Chap06.indd 582
the possibility of “overlap” syndromes (syndromes with characteristics
of both NF1 and NF2) is often raised (89,90). Although patients with
features of both NF1 and NF2 clearly exist, the true implications of the
overlap in affected patients are not known (91).
Calvarial and Orbital Abnormalities
Other cranial/intracranial manifestations of NF1 include deficiency of
the sphenoid wing and of the occipital bone along the lambdoid suture.
Only sphenoid dysplasia is of any clinical importance, as it allows her-
niation of the temporal lobes into the orbit (Fig. 6-18). The pulsations
of the temporal lobe may be transmitted through the globe, thus being
visible externally as pulsatile exophthalmos (or enophthalmos sec-
ondary to atrophy of orbital contents). The globe may be dysplastic,
enlarged (buphthalmos), or hypoplastic. Sphenoid wing deficiency is
nearly always associated with plexiform neurofibromas (PNs) in the
orbit or periorbital regions (Fig. 6-18). Recent work indicates that the
abnormalities of the bony orbit may progress over time, suggesting
that these are not simple dysplasias of bone, as previously postulated,
but may in part result from erosions by the adjacent neurofibromas
(Fig. 6-18) or optic nerve tumors (92,93).
Neurofibromas and Plexiform Neurofibromas
Another cause of intracranial complications in NF1 is excessive growth
of craniofacial PNs. PNs are locally aggressive congenital lesions com-
posed of tortuous cords of Schwann cells, neurons, and collagen in a
disorganized intercellular matrix (48). They tend to progress along the
nerve of origin (usually small, unidentified nerves) into the intrac-
ranial space, causing distortion and compression of the brain. Most
commonly, PNs develop in the orbit where they act as masses, causing
impaired ocular movements and exophthalmos (Fig. 6-19). The neck
is another common location for neurofibromas, with an estimated
occurrence of 25% to 30% in patients with NF1 (Fig. 6-20) (94). Neck
masses, their appearance, and their differential diagnoses are discussed
in Chapter 7. The growth rate of PNs is unpredictable; they grow more
quickly in young children and during adolescence (7,95,96). Soli-
tary neurofibromas have slightly greater signal intensity than skeletal
5/6/2011 9:04:00 PM
 Chapter 6 • The Phakomatoses 583

FIG. 6-18. Dysplasia of the

sphenoid wing with associated
plexiform neurofibroma. A. Axial
T2-weighted image shows an
extensive neurofibroma (white
arrows) infiltrating the supe-
rior orbit and the left temporal
fossa (the V1 distribution). The
greater wing of the sphenoid
bone is dysmorphic, result-
ing in anterior extension of the
contents of the left middle cra-
nial fossa. B. Axial T2-weighted
image at a slightly lower level
shows the inferiorly displaced,
proptotic left globe. Neurofi-
broma is also evident within an
enlarged pterygopalatine fossa
(V2 distribution, white arrows).

muscle on T1-weighted sequences. On T2-weighted sequences, the
lesions have variable signal intensity. Most commonly, the periphery
of the lesions tends to be of high T2 signal intensity with respect to
muscle, whereas the center of the lesions is often of low signal inten-
sity (97–99); this has been referred to as the “target sign” (Fig. 6-20)
(100). The central area of decreased T2 intensity is probably related to
the known dense central core of collagen within these lesions (98,99).
Collagen has a low mobile proton density and therefore is of low signal
intensity on T2-weighted images.
On both MRI and CT, PNs appear as masses that most commonly
arise in the region of the orbital apex or superior orbital fissure (in the
distribution of the first division of the trigeminal nerve, Fig. 6-19) but
can occur anywhere in the body. They tend to be of low attenuation
on CT and generally show little enhancement after administration of
intravenous contrast. On MRI, the masses are heterogeneous, display-
ing mostly low signal intensity as compared with brain on T1-weighted
images and high signal intensity on T2-weighted images (Fig. 6-19)
(101). Enhancement after administration of paramagnetic contrast

FIG. 6-19. Plexiform neurofibroma and multiple solitary neurofibromas. A. Axial T2-weighted image shows innumerable small subcutaneous neuro-
fibromas (small open arrows). Note the “target sign” appearance of the large left infratemporal lesion (curved white arrow). In addition, PNs (large solid
white arrows) are present in the inferior orbits bilaterally and extend (large open white arrows) posteriorly into the cavernous sinuses, left greater than right.
B. Postcontrast axial T1-weighted image with fat suppression shows inconsistent enhancement of the neurofibromas. Note that enhancing tumor extends
posteriorly from the left cavernous sinus along the cisternal segment (arrow) of the fifth cranial nerve. C. Postcontrast axial T1-weighted image with fat
suppression at a level below (B) shows multiple enhancing tumors throughout the face and infratemporal fossae.

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 584 Pediatric Neuroimaging
FIG. 6-20. Malignant nerve sheath tumor developing within a plexiform neurofibroma in a 15-year-old adolescent who recently experienced lower neck
pain. A and B. Axial (A) and coronal (B) T2-weighted images with fat suppression reveal a mass in the right brachial plexus. Central target signs (black
arrows) are evident in the more superficial aspects of the lesion, characteristic of plexiform neurofibroma. In the deeper portion of the mass, a larger conflu-
ent area (white arrows) without target sign is evident. Malignant nerve sheath tumor was confirmed by needle biopsy of this area.
is variable, although at least a portion of the tumor usually enhances
(usually the central aspect, corresponding to central the T2 hypoin-
tense [“target”] components [Fig. 6-20]). Careful evaluation of the
images often reveals extension of orbital tumors into the cavernous
sinus, nasopharynx, or pterygomaxillary fissure (Fig. 6-19).
Spinal Manifestations
Scoliosis and Intramedullary Tumors
Abnormal curvature of the spinal column (scoliosis, kyphosis) is the
most common skeletal abnormality reported in patients with NF1. In
Holt’s series, it was present in 32% of affected children; the incidence
increases with age (102). The abnormal curvature is usually mini-
mal or mild in degree, and can resemble idiopathic adolescent sco-
liosis. It can be severe, in which case dystrophic curves are commonly
encountered, with potential for rapid progression (Fig. 6-21) (103).
Dystrophic curves are associated with a high incidence of paraspi-
nal or other internal neurofibroma next to the vertebra. Dysplasia
of the vertebral bodies is common, as are hypoplasia of the pedicles,
transverse processes, and spinous processes; scalloping of the poste-
rior aspects of the vertebral bodies; and hyperplastic bone changes
(94,104). It is not certain whether these bony anomalies result from
a primary mesodermal dysplasia or are secondary to the effects of
nerve sheath tumors. Plain film radiography is essential to demon-
strate the scoliosis optimally. CT is the optimal modality for demon-
strating the changes of the individual vertebrae, as it shows superior
bone detail. However, most of the bony changes are well visualized
with high quality MR studies.
When abnormal spinal curvature is present, the question often
arises as to whether it results from the dysplastic bone of neurofibro-
matosis or from an intrinsic spinal cord lesion such as a tethered cord,
syringomyelia, or intrinsic spinal cord tumor. If an intrinsic spinal cord
tumor is present in a patient with NF1, it is likely to be an astrocytoma
Barkovich_Chap06.indd 584
(105). The appearance of intramedullary astrocytomas in children with
NF1 is no different from that of other intramedullary astrocytomas
(see Chapter 10). In the absence of any neurologic signs or symp-
toms, the incidence of an underlying spinal cord disorder is very low
in children with dextroscoliosis (convexity of the curvature to the
right). However, children with levoscoliosis, especially if it is rap-
idly progressive, associated with pain, or associated with neurologic
deficits, have a significantly higher incidence of underlying spinal
cord abnormalities (106). Imaging of scoliosis is discussed further
in Chapter 9.
Dural Dysplasia and Meningoceles
Dural ectasia is identified in 75% of patients with posterior vertebral
scalloping, and in 25% of those with lateral scalloping. Lateral menin-
goceles are diverticula of the thecal sac (most commonly at the tho-
racic level) that extend laterally through widened neural foramina.
Most authorities feel that the meningoceles result from a primary
mesodermal dysplasia (104,107); the primary abnormality in affected
patients may also be hypoplasia of the pedicles (which makes it pos-
sible for the dural sac to herniate laterally in response to spinal fluid
pressure). Weakness in the meninges allows the thecal sac to be focally
stretched in response to CSF pulsations. The protrusions from the the-
cal sac slowly erode the bony elements of the neural foramina, allowing
the meningoceles to form. The thoracic region is thought to be pri-
marily affected because of the lesser development of the paravertebral
muscles and the relatively high pressure difference between the nega-
tive pressure of the thorax and the spinal CSF (108). The CT appear-
ance of a lateral meningocele is that of a wide neural foramen with
a CSF-attenuation dumbbell-shaped mass extending through it. The
corresponding vertebral body is usually markedly scalloped (109). The
MR appearance of these lesions is similar in that the neural foramen is
markedly widened and the spinal canal is enlarged as a result of scal-
loping of the posterior vertebral body at the level of the meningocele
5/6/2011 9:04:03 PM
 Chapter 6 • The Phakomatoses 585

FIG. 6-21. Rapid progression of cervical kyphosis (without surgical

intervention) in NF1. A. Sagittal T1-weighted image at age 10 years
shows a focal kyphotic deformity in the midcervical spine (black
arrows) secondary to dysplasia and erosions of the adjacent cervical
vertebrae. B. Postcontrast axial T1-weighted image with fat suppression
through the midportion of the kyphosis reveals enhancing, infiltrat-
ing plexiform neurofibroma in the prevertebral space (short arrows),
extending laterally into the right vertebral foramen (long arrow). The
anterior aspect of the vertebral body is eroded (white arrowheads). The
subarachnoid spaces (black arrowheads) along the posterior/right lat-
eral aspect of the cord are enlarged secondary to the dural ectasia and
kyphotic deformity. C. Sagittal T1-weighted image 6 years later reveals
marked progression in kyphotic angulation.

(Fig. 6-22). The meningocele is isointense with CSF on all imaging
sequences. Differentiation from neurofibromas can be made by not-
ing the absence of the central low intensity focus on the T2-weighted
images (98). Neurofibromas are of higher signal intensity than CSF on
T1-weighted images (compare Fig. 6-22 with Fig. 6-23).
Nerve Sheath and Other Soft Tissue Tumors
Another major abnormality affecting the spine in NF1 is intraspinous
or paraspinous neurofibromas (48). Spinal neurofibromas develop in a
large number of patients with NF1, in all segments of the spine (110).
In some families, neurofibromas are nearly entirely limited to the spine
(111). Spinal neurofibromas are far less common in children with NF1
than in adults (110). In addition, spinal nerve sheath tumors are less
commonly symptomatic in NF1 (only 1%–2% are symptomatic [110])
than in NF2 (30%–40% symptomatic [112]). Scoliosis appears to be
more common in NF1 patients with spinal neurofibromas than in
those without (113). About 90% of these tumors are extradural, with
more than half being intraforaminal (110). In contrast, most nerve
sheath tumors in NF2 are intradural (114).
There has been debate in the pathology literature as to whether
the paraspinous tumors in NF1 are schwannomas or neurofibro-
mas; most nerve sheath tumors in NF1 appear to be neurofibromas

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 586 Pediatric Neuroimaging
(97). Schwannomas are uncommon in NF1; conversely, neurofibro-
mas are fairly distinctive features of von Recklinghausen disease and
rarely occur in any other setting. It is probably not possible to dif-
ferentiate these tumor types by imaging; moreover, there are argu-
ments as to the exact pathology and pathogenesis of these tumors
(35,48,115,116). Neurofibromas are tumors of the nerve sheaths that
also involve the nerves themselves; they have a higher content of col-
lagen and elastin than schwannomas (115). The cell of origin of these
tumors is thought to be the fibroblast (35). Although isolated spinal
Barkovich_Chap06.indd 586
FIG. 6-22. Scoliosis, dural ectasia, and lateral meningoceles
in NF1. A. Coronal T2 weighted image shows a focal cur-
vature in the upper thoracic spine, and two moderate
sized lateral meningoceles (white arrows) extending out
of the spinal canal through widened upper thoracic neu-
ral foramen. B. Sagittal T2-weighted image shows scallop-
ing of the posterior vertebral bodies (white arrowheads).
C. Axial T2-weighted image through the level of the lower
meningocele shows displacement of the spinal cord to the
left (white arrows).
neurofibromas can be seen in patients unaffected by NF1, patients
with von Recklinghausen disease can have neurofibromas of vary-
ing sizes at many levels throughout the spinal canal (35,98). Patients
with NF1 typically have only a few (5 or 6) nerve sheath tumors. In
contradistinction, patients with NF2 typically have many (more than
10) spinal nerve schwannomas (see Section “Imaging of Spinal Mani-
festations” on NF2 below).
The MR appearance of neurofibromas is that of ovoid lesions that
may be entirely within the spinal canal, causing canal enlargement, or
5/6/2011 9:04:05 PM
 Chapter 6 • The Phakomatoses 587

FIG. 6-23. Extensive plexiform and spinal neurofibromas with cord compres-
sion in NF1. A. Coronal T2-weighted image of the lumbar spine and upper
pelvis shows extensive plexiform neurofibroma (subcutaneous and muscular
spaces). Intraspinal involvement is evident at the level of the kidneys (black
arrows). B and C. Axial FSE T2-weighted image (B) and postcontrast axial SE
T1-weighted image (C) through the upper lumbar spine show large bilateral
neurofibromas (n) expanding the spinal canal and neural foramina; the intra-
dural component of the right-sided neurofibroma displaces the thecal sac to
the left (white arrows). Extensive PNs infiltrate the retroperitoneum.

may extend outward from the spinal canal through widened neural
foramina (Fig. 6-23) (97,98). When small, intradural neurofibromas
appear as nodules of soft tissue along the nerves roots, most commonly
identified along the cauda equina (Fig. 6-24). Extension through the
neural foramen is accompanied by enlargement of the neural foramina
by pressure erosion of the bone. Neurofibromas shows a slightly greater
signal intensity than skeletal muscle on T1-weighted sequences and
high intensity periphery with variable intensity center on T2-weighted
sequences (97–99), sometimes resulting in the aforementioned “tar-
get sign” (Fig. 6-23) (100). On CT, the paraspinal neurofibromas have
low attenuation when compared to muscle. Intraspinal neurofibromas
(which can be intrathecal or extrathecal) may displace the spinal cord
or nerve roots of the cauda equina to the contralateral side of the canal
(Fig. 6-23). When bilateral neurofibromas are present at a single level,
the cord can be compressed into a narrow, central band of tissue that is
elongated in the anterior-posterior direction (Fig. 6-25). Under these
circumstances, the risk of damaging the cord during an attempted sur-
gical decompression is very high.
It is well established that malignant peripheral nerve sheath tumor
(MPNST, (neurofibrosarcomas) occurs in NF1; most arise within preex-
isting PNs (35,48,117). Patients with NF1 harbor a 10% lifetime risk of
developing a MPNST (7,48,117). The risk of malignancy increases with
age. Neurofibrosarcomas usually present with localized motor deficits
or pain and dysesthesias with or without evidence of a rapidly enlarg-
ing mass. Currently, 18F-fluorodeoxyglucose (FDG) positron emission
tomography (PET) imaging seems to be the best way to differentiate
benign from malignant nerve sheath tumors, with malignant tumors
showing significantly higher uptake of FDG than benign tumors (118).
The MR features of benign and malignant nerve sheath tumors are not
always sufficiently different to distinguish them. Both can be large and

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 588 Pediatric Neuroimaging
relatively well circumscribed, and neither commonly invades adjacent
structures. MR findings indicative of a MPNST (Fig. 6-20) includes
irregular tumor shape, unclear margins, intratumoral lobulation, pres-
ence of high signal intensity foci on T1-weighted images, lack of target
sign, heterogeneous enhancement, and a lower rate of enhanced area
(98,100,119). Of note, marked heterogeneity can be seen in benign
tumors as well (101), so this is not a specific imaging sign.
FIG. 6-25. Bilateral C-1 to C-2 spinal neurofibromas with spinal cord
compression in NF1. Axial T2-weighted image shows neurofibromas (white
arrows) that compress the thecal sac and spinal cord (small white arrow-
heads). An intradural neurofibroma component is evident on the right
(large white arrowhead) (asterisk denotes odontoid process of C-2).
Barkovich_Chap06.indd 588
FIG. 6-24. Multiple small intraspinal
neurofibromas. A. Sagittal T2-weighted
image shows multiple small nodular soft
tissue intensity foci (white arrows) in the
subarachnoid space. B. Axial postcontrast
T1-weighted image shows that the lesion
(arrow) at the sacral level enhances.
NEUROFIBROMATOSIS TYPE 2
Clinical Manifestations
Neurofibromatosis type 2 (NF2) has also been called neurofibroma-
tosis with bilateral acoustic schwannomas. NF2 is a separate disease
altogether from NF1. NF2 is associated with an abnormality of chro-
mosome 22 (critical region in about 6 megabases within 22q12 [120]),
verifying that it is a separate entity from von Recklinghausen disease
(NF1), which has a locus on chromosome 17 (4,121,122). The prod-
uct of the NF2 gene is called merlin (moesin-ezrin-raxidin-like pro-
tein, also called schwannomin); it is a tumor suppressor gene that is
believed to control interactions between affected cells and surround-
ing structures (both cells and molecules) in the extracellular matrix.
Mutated merlin inhibits cell adhesion, which is important for regu-
lating cell growth, and is more soluble than normal protein, making
its interaction with the cytoskeleton unstable (123,124). A correlation
has been identified between the type of mutation of the NF2 gene
and the phenotype of the affected patients in that nonsense and frame
shift mutations cause more severe disease (younger age at onset and
diagnosis, more tumors), than missense mutations or mild deletions
(125,126).
NF2 is also autosomal dominant, but it is much less frequent than
NF1, with an estimated incidence of 1 in 50,000 (127). About 50% of
cases represent new mutations, and as many as one third are mosaic
for the underlying disease causing mutation (127). The major feature
of NF2 is the presence in nearly all affected individuals of bilateral
vestibular schwannomas (Figs. 6-26 and 6-27). Other tumors of the
CNS, particularly meningiomas and other schwannomas (Fig. 6-28),
may be present as well. (Most children with meningiomas do not
have NF2; however 72% of pediatric meningiomas harbor deletions
of the NF2 gene [128]). In contrast to the situation in adults, hearing
loss is an uncommon presentation in childhood; seizures (caused by
meningiomas) and facial nerve palsy are much more common pre-
senting symptoms, as are neurologic symptoms related to brainstem
and/or spinal cord tumors (127,129,130). Tumor load tends to be
extensive in pediatric patients; cranial meningiomas are seen in 60%
5/6/2011 9:04:07 PM
 Chapter 6 • The Phakomatoses 589

FIG. 6-26. Small bilateral acoustic schwannomas in NF2. A. Postcontrast axial T1-weighted image shows bilateral enhancing masses (arrows) filling the
internal auditory canals. On the right, the mass extends into the vestibule (arrowhead). B. Axial steady-state acquisition T2-weighted image (FIESTA) shows
replacement of hyperintense CSF signal in the internal auditory canals by the hypointense schwannomas (arrows), and a filling defect in the right vestibule
(arrowhead) from intralabyrinthine tumor extension.

of cases, cranial schwannomas (other then vestibular) in 36%, and
spinal schwannomas and meningiomas each in 80% (130). Cutane-
ous manifestations are much less frequent than in NF1. Only about
25% of affected patients will have café au lait spots and, when pres-
ent, the spots are pale and few in number (< 5) (112,131). Cutane-
ous nerve sheath tumors (predominantly schwannomas) are seen
in about 65% of affected patients, but are minimal in size and few
in number (112). When present, however, cutaneous schwannomas
tend to develop during the first decade of life, before the cranial nerve
schwannomas, which typically do not develop until the age of 10 to
15 years (131–133). Subcapsular cataracts are present in more than
half of patients, and may be present during childhood (112,134).
Therefore, skin tumors and cataracts are valuable clues in the early detec-
tion of children with NF2 (131–133). The established diagnostic criteria

FIG. 6-27. Bilateral acoustic schwannomas in an adolescent

with NF2. Postcontrast axial SE T1-weighted image with fat
suppression shows bilateral nerve VIII schwannomas (white
arrows) expanding the internal auditory canals, extending
into the cerebellopontine angle cisterns, and compressing the
middle cerebellar peduncles, especially on the left.

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 590 Pediatric Neuroimaging

FIG. 6-28. NF2 with multiple schwannomas. A. Postcontrast axial T1-weighted image of NF2 patient reveals bilateral trigeminal schwannomas. The left-
sided schwannoma is limited to the cisternal portion of the nerve (white arrow), while the right-sided one involves the cisternal portion (small black 5) and
the trigeminal ganglion (large black 5). B. Postcontrast axial T1-weighted image shows bilateral eighth nerve schwannomas (white arrows), schwannoma of
the left temporal branch of the third division of the fifth cranial nerve (white arrowhead), and the large schwannoma involving the right trigeminal ganglion
(black 5). C. Postcontrast axial T1-weighted image at a slightly more inferior level shows, in addition to the fifth nerve tumors described in (B), a ninth nerve
schwannoma (white arrow) in the cerebellomedullary cistern. D. Postcontrast coronal T1-weighted image shows the large right-sided fifth nerve schwan-
noma (white arrows) extending through and expanding the right foramen ovale.

for NF2 are listed in Table 6-4. It should be noted that these criteria
do not work well in children or in patients with no family history of
NF2 (as many as 50% of affected patients [127,135]), and need revi-
sion. Indeed, less than 20% of patients with NF2 are diagnosed during
childhood (133). However, early diagnosis has important implications,
as age at diagnosis is the strongest single predictor of relative risk of
mortality and is a useful index for patient counseling and clinical man-
agement (136).
Some authors have noted that NF2 can be subdivided into two large
groups (137). Type 1, also called Gardner’s form of NF2, is the mildest
form of the disease with late onset. Patients have slowly growing eighth
cranial nerve schwannomas and not more than one other tumor (men-
ingioma or schwannoma). Type 2, also called Wishart’s form of NF2
or the Wishart-Lee-Abbott form, is a more severe form characterized
by early onset and the presence of multiple tumors, including schwan-
nomas, meningiomas, ependymomas, and sometimes astrocytomas.
Patients with Type 2 NF2 have a higher incidence of cataracts and skin
tumors, as well as CNS tumors, than those with Type 1 NF2 (112).
These subgroups have proved useful for prognostic purposes; however,
the reader should remember that, as with nearly all such groupings,
many patients with NF2 have intermediate severity of the disease and
may not fall neatly into either form.

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 Chapter 6 • The Phakomatoses 591

The imaging characteristics of schwannomas and meningiomas are

TABLE 6-4 Criteria for Diagnosis of described in Chapter 7. If bilateral acoustic tumors are present or a
diagnosis of NF2 is suspected for other reasons, the imaging procedure
Neurofibromatosis Type 2 of choice should be contrast-enhanced MRI of the entire brain and
spine, with thin (≤3 mm) sections through the posterior fossa. Schwan-
Main Criteria: nomas and meningiomas both enhance brightly after the infusion of
(1) Bilateral tumors of the 8 cranial nerves demonstrated by intravenous contrast. Multiple very small meningiomas and schwan-
contrast-enhanced MRI. nomas that were not apparent on the precontrast scan are frequently
(2) A parent, first-degree relative, or offspring with NF2 and a identified on the postcontrast study (62,112).
unilateral eighth nerve tumor at less than age of 30 years or 2 An important point is that schwannomas and meningiomas are
of the following: unusual tumors in children and young adults (under age 30 years).
If a meningioma or schwannoma is seen in a young patient, a contrast-
• Neurofibroma enhanced MR scan should be obtained through the brain to look for other
• Meningioma asymptomatic schwannomas or meningiomas that may aid in establish-
ing the diagnosis of NF2. Regularly repeated contrast-enhanced MR
• Glioma
scans are recommended for patients in whom the disease is estab-
• Schwannoma lished, as new tumors continue to develop throughout life and surgical
• Juvenile lens opacity (posterior subcapsular cataract of or gamma knife therapy is necessary when they grow large enough to
cortical cataract) cause hydrocephalus or symptoms.
Additional Criteria:
(1) A unilateral vestibular schwannoma diagnosed before the age
Imaging of Spinal Manifestations
of 30, plus any two of the following: The characteristic spinal manifestations of NF2 are multiple paraspi-
• Meningioma nal nerve sheath tumors (mostly schwannomas with some neurofi-
bromas), intraspinal meningiomas, and intramedullary spinal cord
• Glioma tumors (112,125,130). Spinal tumors affect close to 75% of patients
• Schwannoma (112,129,130). Intraspinal and paraspinal nerve sheath tumors are
• Juvenile cortical cataract very common in patients with NF2 (97,112) and can nearly always be
detected with proper imaging technique in patients beyond the age of
• Juvenile lens opacity (posterior subcapsular cataract of 15 years. Because they have more extramedullary spinal tumors, patients
cortical cataract), or with NF2 more frequently develop symptoms of cord compression from
(2) Multiple meningiomas (2 or more) and a unilateral vestibular the multiple extramedullary tumors than do patients with NF1. Coro-
schwannoma nal imaging optimally shows the nerve root tumors and their relation to
the spinal cord. Nerve sheath tumors may be intramedullary, extramed-
(3) Multiple meningiomas (2 or more) and any 2 of the following:
ullary intraspinal, extraspinal, or may involve both the intraspinal and
• Glioma extraspinal compartments in addition to the intervening neural fora-
• Neurofibroma men. The tumors are isointense to neural tissue on T1-weighted images,
hyperintense (usually) on T2-weighted images, and enhance uniformly
• Schwannoma
after intravenous administration of paramagnetic contrast (Fig. 6-29E).
• Cataract As with NF1, axial images are helpful in evaluating any deformity of the
cord and the relationship of the tumors to the cord.
Manchester criteria (Modified NIH criteria). Adapted from References 127
Intrinsic spinal cord tumors and syringohydromyelia occur with
and 135.
an increased incidence in NF2 (105,117). The most common intrinsic
cord tumors are ependymomas, although astrocytomas and intramed-
ullary schwannomas are seen (125). These can be solitary (most often
involving the conus medullaris and filum terminale), or multiple,
The mainstay of management of NF2 is surgical removal of symp- occurring at all levels of the neural axis. Contrast-enhanced MR is the
tomatic cranial and spinal tumors. However, there are recent reports imaging modality of choice. Without the administration of contrast,
of shrinkage of vestibular schwannomas and improvement of hearing ependymomas of the spinal cord may be difficult to differentiate from
with therapies targeted to the intracellular signaling pathways involved multiloculated syringohydromyelia. Ependymomas and astrocytomas
in tumorogenesis (138). of the spinal cord are sometimes difficult to distinguish by CT and
MRI. However, the presence of a centrally located, contrast-enhancing
tumor with sharply marginated borders suggests the diagnosis of
Imaging of Intracranial Manifestations
ependymoma. Further characteristics of intramedullary neoplasms are
As a result of the absence of cutaneous and ocular manifestations, described in Chapter 10.
patients with NF2 may not develop any clinical manifestations of the Meningiomas are common in the intraspinal as well as intracranial
disease until the second, third, or even fourth decade of life (112,132). compartment in NF2 (117). As in patients without neurofibromatosis
Moreover, it may fall upon the radiologist to make the diagnosis of NF2 (see Chapter 10), spinal meningiomas are most common in the tho-
in affected patients. The characteristic intracranial abnormalities are racic region. They are intradural, extramedullary masses that displace
schwannomas of the vestibular (Figs. 6-26 and 6-27) and other cranial the spinal cord as they grow. These dural-based masses will sometimes
nerves (most commonly the oculomotor and the trigeminal nerves) cause pressure erosion of the adjacent bone. They can be identified
(Fig. 6-28) and meningiomas (often multiple, Figs. 6-28 and 6-29). as extramedullary, intradural masses on CT with intrathecal or IV

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 592 Pediatric Neuroimaging

FIG. 6-29. NF2 with bilateral acoustic schwannomas and multiple meningiomas. A. Axial postcontrast T1-weighted image through the posterior fossa shows
enlarged, enhancing seventh and eighth nerve complex on the left (solid white arrow). Enhancement is also seen in the genu of the left facial nerve (open white
arrow) and at the right porus acousticus (black arrow). B–D. Axial and coronal postcontrast images show multiple meningiomas, including bilateral intraven-
tricular meningiomas (arrows in B). E. Postcontrast sagittal T1-weighted image shows innumerable schwannomas arising from the cauda equina.

contrast. MRI is the preferred diagnostic modality; sagittal and coronal
images are essential to visualize the extent of the tumor and its rela-
tionship to the spinal cord and neural foramina. These lesions are usu-
ally isointense with cord on both T1- and T2-weighted images. They
uniformly enhance after contrast infusion (139–141).
Syringohydromyelia has been described in association with neu-
rofibromatosis. The syrinx is almost always a secondary phenomenon,
resulting from either a primary tumor of the spinal cord or an intra-
dural, extramedullary mass, such as a meningioma or neurofibroma,
that alters the CSF dynamics of the surrounding spinal subarachnoid
space (see Chapter 9) (142,143). The syrinx will often disappear after
removal of the tumor (143,144). The cause of the syrinx cavity result-
ing from primary spinal cord lesions is less clear. The syrinx most likely
results from altered CSF dynamics; however, in some patients, the syr-
inx may be caused by fluid secreted into the spinal cord and central
canal by the tumor (145). If syringohydromyelia is seen in neurofibro-
matosis (either NF1 or NF2) and no extramedullary mass can be seen,
a thin section, contrast-enhanced MRI of the spinal cord should be
performed to rule out an intramedullary lesion. Syringohydromyelia is
discussed in more detail in Chapter 9.

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 Chapter 6 • The Phakomatoses 593

of affected patients have normal intelligence, only 75% have epilepsy,

OTHER FORMS OF and almost any organ of the body can be affected (169). As a result,
NEUROFIBROMATOSIS more sophisticated criteria for clinical diagnosis of the disorder have
Although the previous sections have made the distinction of NF1 from been established and are listed in Table 6-5 (170). Adenoma sebaceum
NF2 seem clear, the reality is that some patients have a syndrome that is the term used to describe a nodular rash of brownish red color that
appears to be an overlap between the two forms (89,90). For this rea- is disseminated over the face; the rash typically originates in the naso-
son, a third type, NF3, has been described that combines some of the labial folds and eventually spreads to cover the nose and the middle
features of types 1 and 2 (146,147). The genetics of this group is not
clear. Moreover, Riccardi has described several other, additional, forms
of neurofibromatosis (147). It now seems clear that the other forms of
the disease are merely variations of NF1, with different types or sites of TABLE 6-5 Diagnostic Criteria for
mutations or with limited expression due to somatic mosaicism. Tuberous Sclerosis Complex
(Revised 1998)
TUBEROUS SCLEROSIS COMPLEX
Major Features
Clinical Manifestations
Facial angiofibromas or forehead plaque
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic
Nontraumatic ungual or periungual fibromas
disease that is characterized by the presence of tumor-like lesions
(hamartomas) in multiple organ systems. Two separate genes have Hypomelanotic macules (more than three)
been identified that are mutated or deleted in patients with tuberous Shagreen patch (connective tissue nevus)
sclerosis. The TSC1 gene is localized to chromosome 9q34 (148,149)
Multiple retinal nodular hamartomas
and codes for a protein called hamartin, while the TSC2 gene has
been localized to chromosome 16p13.3 (150,151) and codes for a Cortical tubera
protein called tuberin; mutations can be identified in 75% to 85% Subependymal nodule
of TSC patients (15,152–155). Hamartin and tuberin interact physi-
cally in vivo, a fact that clarifies how mutations in two different genes Subependymal giant cell astrocytoma
result in the common phenotype (156,157). These proteins form a Cardiac rhabdomyoma, single or multiple
heterodimer that functions as a tumor suppressor by inhibiting the Lymphangioleiomyomatosisb
mTOR kinase cascade. Increased activation of mTOR results in disor-
ganized cellular overgrowth and abnormal differentiation (155,158– Renal angiomyolipomab
161); mutation of either protein seems to lead to both increased Minor features
protein translation and cell size enlargement (162). TSC2 mutations
Multiple randomly distributed enamel pits in dental enamel
are about five times more common than mutations of TSC1 (155).
TSC1 mutations are slightly less common in sporadic TSC cases Hamartomatous rectal polypsc
(those with no family history, about two thirds of all patients) and Bone cystsd
are somewhat more common (15%–50%) in familial cases (15). It
Affected first-degree relative
is of interest that the TSC2 gene is located only in 48 base pairs of
DNA from the gene for adult-onset polycystic kidney disease (PKD1). Cerebral white matter radial migration linesa,d
When patients have a continuous deletion of both TSC2 and PKD1, Gingival fibromas
they have a particularly severe phenotype with very early onset of
PKD1 and early renal failure (163). Nonrenal hamartomac
Few differences in the clinical phenotype have yet been noted in Retinal achromic patch
patients with one mutation as compared with the other (164), although “Confetti” skin lesions
it appears that individuals with mutations of TSC1 seem to have less
risk of intellectual impairment, a lower frequency of seizures, fewer Multiple renal cystsc
subependymal nodules and cortical tubers, fewer retinal hamartomas, Definite TSC Either two major features, or one major plus two
milder renal disease, and less severe facial angiofibromas (154,165), minor features
whereas those with TSC2 mutations probably have a higher risk of
Probable TSC One major plus one minor feature
renal cysts (166). However, some TSC2 mutations have relatively mild
phenotypes, probably because the effect of the particular mutation on Possible TSC Either one major feature or two or more minor features
tuberin function is the ultimate factor in determining the severity of a
When cerebral cortical dysplasia and cerebral white matter migration tracts
the phenotype (161). Overall, about 75% of TSC mutations are spon- occur together, they should be counted as one rather than two features of
taneous (155); however, before concluding that an affected child is a new tuberous sclerosis.
mutation, it is necessary to examine both parents thoroughly, including b
When both lymphangioleiomyomatosis and renal angiomyolipomas are
Wood light examination, neuroimaging and, if possible, chromosomal present, other features of tuberous sclerosis should be present before a definite
analysis from multiple tissues including germ cells (167). A 2% to 3% diagnosis is assigned.
c
risk of recurrence in future pregnancies remains even if both parents Histological confirmation is suggested.
d
seem unaffected (167). Radiologic confirmation is sufficient.
Classically, TSC has been characterized by the clinical triad of TSC, tuberous sclerosis complex.
mental retardation, epilepsy, and characteristic skin lesions known From (170).
as adenoma sebaceum (168). Recent experience has shown that half

Barkovich_Chap06.indd 593 5/6/2011 9:04:13 PM

 594 Pediatric Neuroimaging
of the cheeks in the infraorbital region. Increasing awareness of the
condition has resulted in a revision of the estimated incidence from
approximately 1 in 100,000 patients (168,171,172) to 1 in 6,000 live
births (164,173). No racial or sexual predilection has been detected.
The intracranial abnormalities of tuberous sclerosis are postulated to
result from an abnormal expression of genes within the cells of the ger-
minal matrices of the developing brain (174,175). As a consequence,
these stem cells do not differentiate, develop, or migrate properly (176).
The result is the presence of dysplastic, disorganized cells in the sub-
ependymal region, the cortex, and along curvilinear pathways between
them (13,174,177).
Seizures are evident in about 90% of affected individuals. Infantile
spasms or myoclonic seizures that begin in infancy or early childhood
are the presenting symptom of tuberous sclerosis in approximately
80% of patients; indeed, a significant number (10%) of infants present-
ing with infantile spasms have tuberous sclerosis (178). The infantile
spasms evolve into other seizure types, most commonly symptomatic
generalized epilepsy (∼60%), partial epilepsy (∼20%), or a mixture
of partial and generalized epilepsy (∼20%) (179). The seizures often
decrease in frequency with increasing age (180), particularly when the
epilepsy is partial (181). Patients with TSC can have nearly any type of
seizure; therefore, the diagnosis of tuberous sclerosis should be con-
sidered in any child with epilepsy. The incidence of cognitive impair-
ment is about 50% (182). Among the impaired patients, approximately
two thirds will be moderately to severely retarded, and one third only
mildly to moderately affected. Cognitive impairment in TSC is a mul-
tifactorial condition; a link exists between cognitive disabilities and
lesion load (based on the proportion of brain volume occupied by
tubers), age at seizure onset, and history of infantile spasms (183);
however, these factors explain only part of the intelligence quotient
variability (155).
Neuroimaging often plays an important role in making the diag-
nosis of TSC (184,185); characteristic abnormalities are present on
neuroimaging studies in more than 95% of affected patients (185).
These CNS abnormalities are present from before the time of birth
(Fig. 6-30), whereas the cutaneous malformations, such as adenomata
sebaceum, may not develop until much later in childhood. All children
who have infantile spasms without a known cause should have a
Barkovich_Chap06.indd 594
FIG. 6-30. In utero MRI of a
fetus with tuberous sclerosis. A.
Coronal single shot half-Fourier
RARE image through the fetal
brain shows a cortical tuber (black
arrowheads) extending from the
right frontal cortex through the
cerebral mantle to the supero-
lateral surface of the right lateral
ventricle. A subependymal hama-
rtoma (black arrowhead) is also
present. B. Coronal image through
the parietal lobe and chest shows a
large cardiac rhabdomyoma (R) in
addition to a parietal tuber (black
arrow).
neuroimaging study, as making the diagnosis of tuberous sclerosis is
important and influences treatment (164). Current recommendations
are for cranial imaging every 1 to 3 years in children (and every 3–6
months if a giant cell tumor is present) and renal ultrasound every
1–3 years at all ages (because renal angiomyolipomas may enlarge at a
concerning rate) (186,187).
Cutaneous Manifestations
Although not radiologically apparent, cutaneous adenomata sebaceum
is a characteristic component of tuberous sclerosis and the imager
should have a general knowledge of its clinical characteristics, which
were described in the previous section. These lesions, which are histo-
logically classified as angiofibromas, usually develop between age of 1
and 5 years. Angiofibromas also occur in other areas of the body, most
commonly the trunk, gingiva, and periungual regions; in these regions
they develop later (typically after age 5) and may continue to develop
throughout life (188). Depigmented nevi in the form of oval areas with
irregular margins (ash-leaf spots) occur on the trunk and extremi-
ties and are as common as angiofibromas. Depigmented nevi appear
sooner than the adenoma sebaceum; indeed, they are often present at
birth and are frequently the cutaneous lesions that lead to a diagnosis
of tuberous sclerosis in children with seizures (189). In light-skinned
children, the depigmented nevi may be demonstrable only under an
ultraviolet light. Café au lait spots are occasionally seen in patients with
tuberous sclerosis, but their incidence is similar to that in the general
population; their presence in isolation should not suggest a diagnosis
of neurofibromatosis (190). Rarely, patients may develop lesions of the
scalp that induce hyperostosis of the underlying calvarium; histologi-
cally, these seem to be epidermal inclusion cysts. The other common
cutaneous lesions of tuberous sclerosis, shagreen patches and subun-
gual fibromas, do not usually appear until after puberty and are not
discussed here.
Ocular Manifestations
Ocular findings are common in tuberous sclerosis. The most common
of these is the retinal hamartoma, an astrocytic proliferation that is
5/6/2011 9:04:13 PM

seen on or near the optic disc in 15% of affected patients (168,171).
Retinal hamartomas are usually present in both eyes and are often
multiple (180). They may not be present at birth, developing over
the first few months to years of life (191,192); the affected globe may
be microphthalmic (191) and leukocoria may be present, leading to
presumptive diagnoses of persistent hyperplastic primary vitreous
(see Chapter 5) or retinoblastoma (see Chapter 7). They originate as
fairly flat, semitransparent, whitish lesions. Eventually, when they turn
whitish gray or yellow and become nodular, they are said to resemble
a clump of mulberries (193). Retinal hamartomas are seen on CT as
nodular masses originating from the retina (Fig. 6-31); when hama-
rtomas calcify, they can be seen as small, calcified retinal masses that
may be difficult to differentiate from a retinoblastoma (191,194). The
presence of calcified subependymal nodules in the brain will help make
the differentiation. On MRI, retinal hamartomas appear as solid retinal
nodules that show moderate uniform enhancement after administra-
tion of paramagnetic contrast (Fig. 6-31). A subretinal exudate may be
present, leading the ophthalmologist toward a presumptive diagnosis
of Coats disease (see Chapter 5) (195); again, the observation of sub-
ependymal nodules in the brain will lead to the proper diagnosis. The
reader should be aware that, although they are most common in tuber-
ous sclerosis (they are seen in over half of the cases), retinal hamar-
tomas are seen occasionally in the other phakomatoses as well (194).
Intracranial Manifestations
Subependymal Hamartomas (Nodules)
Several characteristic lesions occur in the brain in TSC. The most
common of these are subependymal hamartomas (or nodules), which
Barkovich_Chap06.indd 595
Chapter 6 • The Phakomatoses 595
FIG. 6-31. Retinal hamartoma. A. Axial noncontrast CT image shows
a subretinal exudate with a focal nodule (arrow). B. Axial T1-weighted
image shows a nodule (arrow) in the right globe that is isointense to the
subretinal exudate. C. Postcontrast axial T1-weighted image shows that
the nodule enhances moderately.
differ histologically from the cortical hamartomas (tubers) and there-
fore behave differently on imaging studies. The subependymal nodules
tend to be located along the ventricular surface of the caudate nucleus,
most often on the lamina of the thalamostriate sulcus immediately
posterior to the foramen of Monro (171). Less commonly, the nodules
may be detected along the frontal and temporal horns and the lateral
ventricular bodies, the third ventricle or the fourth ventricle.
In neonates, subependymal hamartomas can be detected by trans-
fontanelle sonography, on which they appear as echogenic subependy-
mal masses (Fig. 6-32A). They cannot be differentiated from germinal
matrix hemorrhages or gray matter heterotopia by cranial sonography
alone. The imaging appearance of subependymal hamartomas on CT
and MR changes with the age of the patient. They are rarely calcified
in the first year of life; the number of calcifications typically increases
with the age of the patient (184). Thus, they may be difficult to detect
on CT scans of infants (Fig. 6-33C), but become progressively easier
to identify as they calcify (Fig. 6-34, also 6-37B). On MR scans, sub-
ependymal hamartomas appear as irregular subependymal nodules
that protrude into the adjacent ventricle. Their appearance changes
as the signal of the surrounding white matter changes (177,196). In
fetuses and infants, who have unmyelinated white matter, the hamar-
tomas are relatively hyperintense on T1-weighted images and hypoin-
tense on T2-weighted images (Figs. 6-32 and 6-33) (197); in fetuses
and premature infants, these may be mistaken for subependymal
hemorrhages unless other lesions of tuberous sclerosis are identified.
As the brain myelinates, the subependymal nodules gradually become
isointense with the white matter. They are most easily visualized on
T1-weighted images where they contrast with low signal intensity of
the CSF. Small nodules may not be apparent on T2-weighted images.
5/6/2011 9:04:14 PM
 596 Pediatric Neuroimaging

FIG. 6-32. Tuberous sclerosis in a young infant. A. Coronal

transfontanelle sonogram shows hyperechogenic subependy-
mal hamartoma (small white arrow) and hyperechogenic
cortical tubers (large white arrows). B–D. Axial T1-weighted
images show hyperintense subependymal nodules (small solid
arrows), hyperintense cortical lesions (large open arrows), and
linear transmantle hyperintensities (small open arrows) that
extend from the ventricular surface to the cortex. The trans-
mantle hyperintensities will become invisible as the white
matter myelinates. E. Axial T2-weighted image shows the large
calcified left posterior frontal tuber (arrows). The linear trans-
mantle dysplasias are more difficult to identify on T2-weighted
images.

Barkovich_Chap06.indd 596 5/6/2011 9:04:15 PM

 Chapter 6 • The Phakomatoses 597

FIG. 6-33. Evolution of tuberous sclerosis in an infant.

A. Axial T1-weighted image shows a hyperintense subependymal
nodule (arrowhead) along the body of the right lateral ventricle.
Multiple hyperintense lesions (arrows), many linear in configu-
ration, are evident in the deep cortical and subcortical regions.
B. Axial T2-weighted image at 13 days of age shows the right sub-
ependymal nodule (white arrowhead). Only a few of the cortical
and subcortical abnormalities evident in the T1-weighted image
(A) are appreciated; these are denoted by white arrows. C. Non-
contrast axial CT scan at 4 months of age shows multiple sub-
ependymal nodules (arrows), which are slightly hyperdense (but
not yet calcified) compared to cortex. D and E. Axial T2-weighted
image (D) and T1-weighted image with magnetization transfer
(E) at 18 months of age. The cortical tubers are T2 hyperintense;
many are associated with broadening/clubbing of the overlying
cortex (arrowheads, D). The MT image (E) demonstrates the
tubers and multiple hyperintense linear white matter lesions
(white arrows in E). Increased T2 signal in the periatrial white
matter (small arrows, D) is not secondary to dysplasia but sec-
ondary to poor myelination in this region, as these areas are
isointense to surrounding white matter on the corresponding
MT image (E). Magnetization transfer suppresses signal from
water molecules partially bound to myelin (see Chapter 2).

Barkovich_Chap06.indd 597 5/6/2011 9:04:17 PM

 598 Pediatric Neuroimaging
FIG. 6-34. Axial noncontrast CT scan shows multiple calcified subependy-
mal hamartomas (white arrows) along the walls of the lateral ventricles.
A hypodense right frontal tuber can also be identified (black arrow).
Larger subependymal nodules manifest variably low signal intensity
on the T2-weighted images, depending upon the extent of calcification
(177,198,199). T2*-weighted gradient-echo or susceptibility-weighted
images are optimal for showing the calcification because of the mag-
netic susceptibility differences of calcium and brain. After intravenous
administration of paramagnetic contrast, subependymal nodules show
variable enhancement; some will enhance markedly, some mildly, and
some not at all (177,200,201). The presence or absence of enhancement
has no clinical significance. Subependymal nodules have increased dif-
fusivity and reduced fractional anisotropy compared to surrounding
white matter (202).
FIG. 6-35. Progressive enlargement of SEGA. A. Postcontrast coronal T1-weighted image in a 4-year-old child with TSC shows an enhancing SEGA (white
arrow) in the region of the left foramen of Monro. The lateral and third ventricles are mildly enlarged, unrelated to the intraventricular mass. B. Coronal
contrast-enhanced T1-weighted image 3 years later reveals significant interval growth of the mass. The ventricles are not significantly changed.
Barkovich_Chap06.indd 598
Subependymal Giant Cell Astrocytomas
Subependymal giant cell astrocytoma (SEGA) is a term given to an
enlarging subependymal nodule that is usually situated near the fora-
men of Monro. Anatomically, these tumors differ from the subependy-
mal hamartomas by their size and their tendency to enlarge; their
characteristic location and tendency toward enlargement usually result
in a clinical presentation of hydrocephalus (fatigue, decreased appe-
tite, morning headache, visual field deficit, or behavioral problems)
(177,187,203). Their incidence in TSC is approximately 5% to 10%
(171,177,184,187). Histologically, subependymal lesions in patients
with tuberous sclerosis appear to span a continuum between sub-
ependymal hamartomas and giant cell tumors; although some lesions
are clearly in one category or the other, many lesions have histologic
characteristics of both (168).
On imaging studies, SEGAs are identified by the demonstration
of tumor growth on serial studies (Fig. 6-35) or by the development
of hydrocephalus associated with tumors near the foramen of Monro.
Although most are identified near the foramen of Monro (Figs. 6-35
and 6-36), SEGAs can occur anywhere along the ependymal surface.
Neither signal intensity nor the presence or absence of enhancement
is useful in making the distinction between benign hamartomas and
giant cell tumors (177); although it is clear that essentially all SEGAs
enhance, many hamartomas enhance, as well, so enhancement is not a
useful criterion. The size criteria by which subependymal lesions should
be diagnosed as tumors rather than nodules are still being debated
(187). Braffman et al. (177) have proposed a size criterion, suggest-
ing that subependymal lesions greater than 12 mm diameter should be
classified as giant cell tumors. However a measurement alone may not
truly indicate the presence of a SEGA; for example, two adjoining sub-
ependymal nodules of 6 mm size can be mistaken for a 12-mm SEGA.
Therefore, it seems that demonstration of growth on serial imaging
(Fig. 6-35) is a more reliable criterion than absolute size.
SEGAs tend to grow into the ventricle and uncommonly invade
brain parenchyma. Rarely, they degenerate into higher-grade, or infil-
trating, neoplasms (203,204). Such degeneration should be suspected
radiologically if the tumor is seen to invade the brain parenchyma
5/6/2011 9:04:19 PM

FIG. 6-36. Large SEGA in a patient with TSC. A. Coronal contrast-enhanced T1-weighted image shows a large, uniformly enhancing mass (long white arrow)
in the left frontal horn. A 6-mm enhancing subependymal nodule (short white arrow) is evident in the lower right frontal horn. B. Coronal T2-weighted
image demonstrates slight heterogeneity in the appearance of the left sided SEGA; despite benign histology, a mild amount of edema surrounds the anterior
commissure (long white arrow). The right-sided subependymal nodule (short white arrow) is slightly irregular in appearance.
(interstitial edema will typically be seen in the adjacent parenchyma)
or if rapid enlargement is seen. The treatment of benign giant cell
tumors is controversial. There is a trend toward neurosurgical resec-
tion of SEGAs prior to the development of symptomatic hydrocepha-
lus (and to prevent possible degeneration into a higher-grade tumor),
as patients who present with acute obstructive hydrocephalus have a
poorer surgical outcome (187). Few surgeons believe that shunting of
the obstructed lateral ventricle is sufficient treatment. Rarely, giant cell
tumors occur in patients with no other evidence of TSC (117); these
tumors have a worse prognosis for disease-free survival than the giant
cell tumors of TSC (205). It has not been determined whether these
neoplasms represent a forme fruste of TSC or a spontaneous tumor
unrelated to the genetic abnormality that causes TSC.
Cerebral Tubers (Hamartomas)
The cerebral tubers are the most characteristic lesions of tuberous scle-
rosis pathologically. Macroscopically, these hamartomas are smooth,
whitish, slightly raised nodules that appear as enlarged, atypically
shaped gyri; they may be either round or polygonal. Histologically, they
consist of bizarre giant cells, dense fibrillary gliosis, and diminished,
disordered myelin sheaths (35,171); balloon cells may be seen, making
these lesions histologically indistinguishable from focal cortical dyspla-
sia type IIb (see Chapter 5) (206). Any single patient may have as few as
one to two or have dozens (18). They are most commonly supratento-
rial, although 15% of affected patients have cerebellar tubers (207). The
proportion that calcifies has not been reliably determined. The num-
ber of calcified cortical lesions seen on CT increases with age; by age
10 years, calcified cortical tubers are present in up to 50% of patients
with tuberous sclerosis (184). The cortical calcifications may be gyri-
form, simulating the appearance of Sturge-Weber disease on CT (208).
In infants, cortical tubers can be seen on transfontanelle ultra-
sound where they appear as foci of hyperechogenicity (Fig. 6-32A).
Neonatal and infantile cortical hamartomas appear on CT as lucen-
cies within broadened cortical gyri. The lucency diminishes with age,
making the noncalcified cortical tubers difficult to identify in older
children and adults. In adults, this difficulty is exacerbated by beam
Barkovich_Chap06.indd 599
Chapter 6 • The Phakomatoses 599
hardening by the overlying calvarium, making identification of cor-
tical tubers quite difficult unless they are calcified (Fig. 6-37) (168),
even with helical scanners. The MR appearance of cortical tubers also
changes with age. In fetuses and neonates, they appear as gyri that
are hyperintense compared to the surrounding unmyelinated white
matter on T1-weighted images and hypointense to white matter on
T2-weighted images (Figs. 6-30, 6-32 and 6-33); about 20% of affected
gyri are enlarged (177,209,210). The T1 hyperintensity/T2 hypointen-
sity may extend through the cerebral mantle to the ventricle from the
tuber (see next section) (197,209,210). The appearance changes as the
white matter myelinates and becomes isointense to the lesion. In older
infants, tubers have a low intensity center on T1-weighted images and
high signal intensity on T2-weighted and FLAIR images (Fig. 6-38).
Those tubers with inherent T1 shortening that are hidden as myelina-
tion ensues may be detected in older children and adults by the use
of magnetization transfer techniques: after suppression of the high
intensity of myelination by application of a magnetization transfer
pulse, parenchymal lesions may be more apparent than on standard
T1-weighted images (Fig. 6-38C) (211,212).
T1 images with magnetization transfer and FLAIR images are
the most sensitive sequences in detection of parenchymal lesions in
children and adults with TSC (213,214). The efficacy of FLAIR in the
imaging of unmyelinated neonates and infants has not been dem-
onstrated. Although it is not clear that any advantage is gained by
identifying every parenchymal lesion instead of most of them, FLAIR
imaging makes cerebral parenchymal lesions of tuberous sclerosis
more conspicuous in myelinated brains and, therefore, makes more
cortical lesions visible (213). However, unless 3D volumetric FLAIR is
acquired, artifacts around the foramina of Monro, secondary to CSF
flow, make subependymal nodules in that region difficult to identify.
Whatever sequence is used, the tubers themselves seem predomi-
nantly subcortical, separate from the overlying cortex (Figs. 6-33 and
6-38A). The inner (medial) margins of the tubers are poorly defined
on all imaging sequences. Although cortical tubers may become
isointense with normal white matter on T1-weighted images, they
become hyperintense on the T2-weighted images in the mature brain
5/6/2011 9:04:20 PM
 600 Pediatric Neuroimaging

FIG. 6-37. Cortical tuber in TSC. A. Axial T2-weighted image of a 4-month-old baby with TSC shows focal cortical hypointensity and thickening
(short white arrows) along the left superior frontal sulcus. A faint line (long white arrow) extends toward the left frontal horn, typical of the transmantle
nature of tubers. B. CT scan in the same patient at age 13 years. The left frontal tuber is hyperdense, with a focal calcification (short white arrow) at the deep-
est part of the sulcus. A small calcification (long white arrow), probably a small subependymal hamartoma, is noted in the right temporal horn.

(Fig. 6-38A) (177,198–200). The signal characteristics probably result
from the diminished myelin and dense astrogliosis within them. It is
important to realize that the high signal intensity on the T2-weighted
images does not imply malignant degeneration. In fact, neoplastic
degeneration of cortical tubers is extremely rare. Cyst-like cortical
tubers (based on low signal appearance on FLAIR images [Fig. 6-38B])
are seen more commonly in younger patients than in older children
and adults (214); patients with cyst-like tubers appear to have a more
aggressive seizure phenotype (215). When cortical tubers calcify they
may appear bright on T1-weighted images, presumably because of
T1 shortening caused by the crystals of calcium (216). Degenerated,
calcified cortical tubers will sometimes enhance after contrast admin-
istration and display low T2 signal. On diffusion weighted studies,
cortical tubers have increased diffusivity and decreased anisotropy
compared to normal white matter (202). On MR perfusion imaging,
most (>90%) cortical tubers are hypoperfused relative to mean gray
matter (Fig. 6-39A–C); presence of hyperperfused tubers is associated
with increased seizure frequency (217).

FIG. 6-38. Cortical tubers in TSC. A. Axial FSE T2-weighted image shows multiple hyperintense cortical tubers (arrows). B. Axial FLAIR T2-weighted
image at the same level reveals lower signal in the mid left convexity tuber (arrow), consistent with a cystic (microcystic) change. C. Axial SE T1-weighted
image with magnetization transfer shows cortical tubers as regions of mixed hypointensity and hyperintensity. Suppressing the hyperintensity of the white
matter allows multiple white matter lesions (arrows) to be seen, some extending from the tubers to the lateral ventricular surface.

Barkovich_Chap06.indd 600 5/6/2011 9:04:21 PM

 Chapter 6 • The Phakomatoses 601

FIG. 6-39. Perfusion, diffusion,

and susceptibility imaging in TSC.
A–C. Dynamic susceptibility-
weighted perfusion imaging of a
cortical tuber. Axial FLAIR image
(A) shows a cortical tuber (white
arrows) in the left superior fron-
tal gyrus. Ovals 1 and 2 in (B)
show the locations of the voxels
that were sampled during the
dynamic perfusion study. Graph
of signal intensity versus time
(C) from voxels 1 and 2 shows
normal blood volume (area
under the curve) of the normal
left superior frontal gyrus (2)
but reduced blood volume of the
tuber (1).

Barkovich_Chap06.indd 601 5/6/2011 9:04:22 PM

 602 Pediatric Neuroimaging
When cortical tubers are solitary and no other visceral or CNS
manifestations of TSC are identified, the question will arise as to
whether the lesion is hamartomatous or neoplastic. In such cases, pro-
ton MR spectroscopy or perfusion MRI may be useful. Proton spec-
tra of tubers show normal to slightly elevated choline and slightly
diminished NAA (218,219). The myo-inositol peak is increased on
short TE (20–30 msec) spectra. In contrast, most childhood neoplasms
have marked elevation of choline and marked diminution of NAA
(see Chapter 7) (76,220). However, some low-grade neoplasms may
have spectra very similar to tubers. In these cases, perfusion imaging
may be helpful. Low-grade neoplasms have blood volume very simi-
lar to that of normal white matter, but tubers are quite hypovascular
(Fig. 6-39) (217).
Barkovich_Chap06.indd 602
FIG. 6-39. (Continued) D–G. Arterial
spin labeling, diffusion, and SWI of TSC.
Axial T2-weighted image (D) shows sub-
ependymal hamartomas (white arrows)
at the right foramen of Monro and left
trigone and a large cortical tuber (t) in
the left parietal lobe. Image from arte-
rial spin labeling perfusion (E) shows
reduced blood volume (hypointensity,
black arrow) within the left parietal
tuber. Average diffusivity map (F) shows
increased diffusivity (hyperintensity,
white arrow) in the same tuber. Sus-
ceptibility-weighted image (G) shows
markedly increased susceptibility (white
arrows) of the subependymal hamar-
tomas and reduced susceptibility (prob-
ably due to reduced blood supply, black
arrow) in the left parietal tuber. (Figures
D–G courtesy Dr. Erin Schwartz, Phila-
delphia.)
When children with TSC have medically refractory seizures, some
epileptologists now recommend surgical removal, as studies have sug-
gested a marked reduction in seizure frequency if most seizures can
be localized to a single lesion (221,222). In such cases, it is critical to
correlate the epileptiform activity of the brain with a single structural
lesion if the surgery is to be successful. PET scanning, using alpha
11-C-methyl-L-tryptophan, has proven helpful in the identification of
epileptic foci in TSC (223). In addition, epileptic tubers are associated
with the largest volume of hypometabolism relative to tuber size (based
on FDG-PET coregistered to MRI) and the highest ADC values in the
underlying white matter (224). BOLD imaging (221), magnetic source
imaging (225), and videotelemetry (222) may be useful to establish
this correlation. Of note, the medial temporal lobe should be carefully
5/6/2011 9:04:23 PM

evaluated with MR imaging as mesial temporal sclerosis may occur in
patients with TSC (226).
White Matter Lesions
Islets consisting of a grouping of neurons and glial cells are invariably
present in the white matter of patients with TSC (35,171). Microscopi-
cally, they contain bizarre cells including giant neurons and balloon
cells; the latter are dysplastic cells that may have characteristics of both
neurons and glia. These white matter foci also contain areas of hypo-
myelination similar to those seen in the cortical tubers (35,171). Many
of these clusters of heterotopic cells are microscopic and, therefore,
do not appear on imaging studies; however, they are manifested as an
increase in the diffusivity and reduced anisotropy of normal-appear-
ing white matter in affected patients (227). Others will present as fine
lines extending radially across the cerebral white matter. CT fails to
demonstrate these abnormalities. On MR, these white matter lesions
have the same signal characteristics as cortical tubers (Figs. 6-32,
6-33, 6-37, 6-38, and 6-40) and, if the proper imaging plane is used,
are seen to course through the entire cerebral mantle from the cor-
tex to the ventricular surface. They can be identified on T1-weighted
images in infants as subtle hyperintense regions (Fig. 6-32A); once the
white matter becomes well myelinated, they may be difficult to see on
T1-weighted sequences. On T1-weighted images with magnetization
transfer pulses (to suppress the hyperintensity of normal white matter),
FLAIR images, and T2-weighted images, they appear as well-defined
linear or curvilinear areas of high signal intensity (177,198–200,211);
indeed, T1-weighted images with magnetization transfer are the most
sensitive for detecting white matter lesions and show the most lesions in
the myelinated brain (Figs. 6-33E and 6-40) (213). In addition, magne-
tization transfer studies show diminished myelination in TSC, even in
“normal-appearing” white matter (228). This observation is supported
by the discovery of increased mean diffusivity and reduced fractional
anisotropy in normal-appearing white matter of patients with tuber-
ous sclerosis (229,230).
Larger white matter lesions have a variable appearance that
depends upon the amount of calcification within them. These lesions
have histologic and imaging characteristic identical to cortical tubers
and to focal cortical dysplasia type IIb (206) (see Chapter 5). On CT,
Barkovich_Chap06.indd 603
Chapter 6 • The Phakomatoses 603
FIG. 6-40. Value of magneti-
zation transfer imaging in TSC.
A. Axial FLAIR image reveals
one definite hyperintense lesion
(arrow) in the left parietal lobe. B.
Corresponding axial T1-weighted
image with magnetization trans-
fer shows multiple cortical hype-
rintense lesions (arrows) through
outthecortexandsubcorticalwhite
matter, highly suggestive of TSC.
these regions appear as low attenuation, well-defined regions within
the cerebral white matter that do not enhance after intravenous con-
trast infusion. When calcification occurs, it can involve all or part of the
lesion. Partially calcified nodules will have a mixed attenuation, with
one portion being of lower attenuation than the surrounding white
matter and the other portion of extremely high attenuation because
of the calcification (168,184). If the lesion is calcified, the calcification
may appear as low or high signal intensity on T1-weighted images,
depending upon the characteristics of the calcium crystals (216). Also,
as with cortical tubers, these white matter lesions have short T1 and
T2 relaxation times in fetuses, neonates and young infants (Figs. 6-32
and 6-33) (197,209,210). As with cortical tubers, enhancement is only
seen if the lesion has degenerated; under these conditions, calcification
is usually present.
Parenchymal Cysts
An unknown percentage of patients with TSC have cyst-like structures
in the cerebral hemispheric white matter (231); some reports suggest
an incidence of about 10% to 15% (213,232). The histology of these
lesions is not known, but their appearance is benign. The cysts are most
commonly periventricular, but may occur nearly anywhere (Fig. 6-41).
Their clinical significance is uncertain (231). They may grow slowly,
but none are known to exhibit malignant degeneration or to show
enough mass effect to necessitate intervention.
Cerebellar Lesions
Cerebellar lesions have been described in TSC but they are less com-
mon than cerebral pathology, occurring in about 15% of patients
(177,184,233). An incidence of 25% has been reported in a recent study
(234); in that study, patients with cerebellar lesions had overall higher
autistic symptomatology than patients without cerebellar lesions. The
posterior fossa lesions are histologically similar to those of the cere-
bral hemispheres, consisting of cortical tubers, heterotopic clusters
in the white matter and, occasionally, subependymal hamartomas
(35,171,177). The cerebellar hemispheric lesions are difficult to see by
CT unless they are calcified because of the beam-hardening artifact that
occurs in the posterior fossa. The CT and MR appearance of these cere-
bellar lesions is otherwise quite similar to the appearance of those in the
5/6/2011 9:04:25 PM
 604 Pediatric Neuroimaging
cerebral hemispheres (Fig. 6-42), appearing mainly subcortical, mani-
festing T2 hyperintensity, and undergoing degeneration/calcification
over time (177,184). They are differentiated from neoplasia by the fact
that they do not enhance; and they undergo degeneration, causing ex
vacuo enlargement of adjacent CSF spaces (Fig. 6-42).
Vascular Lesions
Vascular lesions are rare in TSC, although angiographic studies have
demonstrated aneurysms in the kidney, liver, aorta, iliac arteries, and
FIG. 6-42. Cerebellar tubers. Axial T2-weighted image shows multiple
hyperintense lesions (large white arrows) in the subcortical regions of the
lateral cerebellar hemispheres. The more superficial cortex is hypointense
(small white arrows), likely from mineralization. The overlying subarachnoid
spaces (arrowheads) are enlarged secondary to degeneration of the tubers.
Barkovich_Chap06.indd 604
FIG. 6-41. Subcortical
cysts in tuberous sclero-
sis. A. Axial postcontrast
T1-weighted image shows
enhancing subependymal
nodules and hypointense
cortical tubers, diagnostic
of TSC. B. More cephalad
image in the same sequence
shows parenchymal cysts
(arrows).
distal extremities in affected patients (235–237). The pathogenesis is
poorly understood, but defects in the media due to deficiency and
fragmentation of elastic fibers have been postulated (237). Involve-
ment of the cerebral vasculature is very rare, but aneurysms have been
reported and seem to involve children disproportionately (238,239).
More than half of the aneurysms have been discovered in the internal
carotid arteries or in the anterior cerebral artery distribution, loca-
tions that are uncommon in children (see Chapter 12). Therefore,
it has been suggested that the cerebral aneurysms that have been
reported in TSC are in some way related to the disease, rather than
being incidental (238,239). Certainly, an aneurysm should be consid-
ered a likely possibility and a cerebral angiogram performed if a child
with tuberous sclerosis presents with subarachnoid or intraparenchy-
mal hemorrhage.
Non-CNS Manifestations
Although brain, ocular, and cutaneous lesions are the hallmarks of
TSC, lesions also occur in the heart, kidneys, liver, lung, and spleen
(168). Renal hamartomas occur in 40% to 80% of patients with tuber-
ous sclerosis (171,240). Histologically, these lesions are angiomyolipo-
mas; they often arise in young adulthood and enlarge slowly. They are
usually asymptomatic, although hematuria, flank pain, or a palpable
abdominal mass may develop. Malignant degeneration is rare. On
ultrasound, angiomyolipomas are well-defined and highly echogenic.
The CT and MR appearances are remarkable for the presence of fat.
Benign rhabdomyomas of the heart (Fig. 6-30) are less common than
the renal hamartomas but are important because they can present as
a congenital cardiomyopathy (171). These tumors are always suben-
docardial and may be either circumscribed or diffuse. Because of their
serious consequences, some authors feel that all patients with TSC
should have screening echocardiography.
Pulmonary involvement is the next most common type of visceral
abnormality in patients with tuberous sclerosis (168). The characteristic
pulmonary lesion is called lymphangioleiomyomatosis. In this condi-
tion, the lung parenchyma undergoes cystic changes with a myoma-
tous proliferation of tissue and chronic fibrosis occurring in the septa
5/6/2011 9:04:25 PM

between the cysts. Other types of visceral lesions include adenomas
and lipomyomas of the liver, adenomas of the pancreas, and tumors of
the spleen (168). Bone lesions consist of multiple dense lesions in the
cranium and cystic changes in the metacarpals and phalanges of the
hands (35,168,171).
STURGE-WEBER DISEASE
Clinical Manifestations
Sturge-Weber disease, also known as encephalotrigeminal angioma-
tosis or meningofacial angiomatosis, is an almost entirely sporadic
developmental disorder that is marked by angiomatosis involving
the face, the choroid of the eye, and the leptomeninges. The facial
nevus flammeus, formerly referred to as an angioma or port-wine
stain, can involve part or all of the face. Ocular and facial involve-
ment without cerebral involvement (241) and ocular and cerebral
involvement without facial involvement (242) have been described
and are considered part of the syndrome. Other clinical compo-
nents of the syndrome are seizures, hemiparesis, hemianopsia, and
mental retardation. Although familial cases are reported, no clear
evidence of heredity has been discovered. Both sexes are equally
affected (243).
The facial nevus is composed of a plethora of thin-walled vessels
that most closely resemble capillaries. It is present at birth, usually uni-
lateral although occasionally bilateral, and involves the middle portion
of the face with no predilection for either side. The nevus does not
change with advancing years. More and more cases are being reported
of Sturge-Weber syndrome involving the brain without a facial nevus
(244–246).
Patients with the Sturge-Weber syndrome generally develop nor-
mally until they begin to have focal or generalized seizures. Infantile
spasms develop in approximately 90% of affected patients during the
first year of life, followed by development of tonic, atonic, or myoclonic
seizures (243,247). With time, the seizures become progressively refrac-
tory to medication. They are accompanied by an increasing hemipa-
resis in about 30% of patients, often accompanied by homonymous
hemianopsia. The majority of affected patients are mentally retarded
(243,247). Prognosis is poor when both cerebral hemispheres or the
majority of a single hemisphere is affected (247).
Barkovich_Chap06.indd 605
Chapter 6 • The Phakomatoses 605
Intracranial Pathology
The major pathological abnormality in Sturge-Weber disease is a
meningeal tangle of vessels, commonly referred to as an angioma,
which is ordinarily confined to the pia mater. This pathologic process
consists of multiple capillaries and small venous channels that are mat-
ted together on the surface of the brain. The arteries are involved to
a lesser extent and tend to undergo fibrosis. The combination of the
facial and pial angiomas has been postulated to result from persistence
of the architectonic features of the primordial sinusoidal vascular
channels that are present between the fourth and eighth week of gesta-
tion (248,249). At that time the ectoderm that will form the skin of the
upper part of the face overlies that part of the neural tube destined to
form the parietooccipital parts of the cerebrum. Normally, the superfi-
cial and deep portions of the vascular system become widely separated
during the extensive subsequent growth of the cerebral hemispheres
(248). According to Alexander, the persistence of primordial vessels
may explain why facial nevi in the area of the ophthalmic division
of the fifth nerve are associated with leptomeningeal angioma in the
occipital region, nevi in the region of the maxillary division are asso-
ciated with angiomas in the parietal convexity, and nevi involving all
three divisions are associated with angiomatosis of the entire convexity
of the hemisphere, including the frontal lobe (243). The weakness in
this theory lies in the inconsistent correlation between the location of
the facial nevus and the pial angioma. For example, frontal angiomas
can be present in association with maxillary nevi. Another possibility
is that the superficial venous drainage of the brain never fully devel-
ops and that the dilated capillaries and small venous channels (and
the nevus flammeus) are dilated in an attempt to compensate. Chronic
venous hypertension might then cause the parenchymal injury.
Cortical calcifications are another pathological finding in Sturge-
Weber syndrome (Fig. 6-43E). The calcifications occur exclusively in
areas of the brain subjacent to the angioma. They begin in the sub-
cortical white matter and later develop in the cortex, predominantly
in cortical layers two and three (243). They are found most frequently
in the temporoparietooccipital region of the brain but can be located
anywhere in the cerebrum (35,243,250). Cortical calcifications can be
bilateral in up to 20% of patients (250). Although their cause is not
confidently established, they are most likely caused by the chronic isch-
emia that results from impaired venous drainage (101).
FIG. 6-43. Child with Sturge-
Weber syndrome. A. Postcontrast
axial T1-weighted image at age 1
year shows diffuse leptomeningeal
enhancement and an enlarged right
choroid plexus (black arrowhead) on
the right; minimal leptomeningeal
enhancement (white arrows) is pres-
ent in the left frontal and occipital
poles. B. Axial T2-weighted image at
age 1 year shows mild enlargement of
ventricles and subarachnoid spaces.
Myelination of the right hemisphere
and left occipital pole (where the
most leptomeningeal enhancement
was seen) is accelerated. A large sep-
tal vein (white arrow) is present on
the left.
5/6/2011 9:04:27 PM
 606 Pediatric Neuroimaging
FIG. 6-43. (Continued) C. Postcontrast axial T1 image at age 7 years shows interval progression of the bilateral leptomeningeal angiomas. Multiple abnor-
mal prominent subependymal/intraventricular veins are seen as foci of signal void (white arrows). D. Axial T2-weighted image at age 7 years shows mild
asymmetric volume loss on the right and prominent subependymal veins (white arrows). E. Axial contrast-enhanced CT at age 15 years shows extensive
cortical calcification (black arrowheads) with posterior predominance. Prominent enhancing deep medullary and subependymal veins are faintly seen
(white arrows).
Neuroimaging Manifestations
Brain
Contrast-enhanced MR studies are the most accurate single imaging
studies for showing the extent of the pial angioma (251,252); contrast-
enhanced T2-weighted FLAIR images improve detection of leptom-
eningeal disease compared to postcontrast T1-weighted images (253).
Enhancement can sometimes be seen on CT if the patient is imaged
in infancy, prior to the appearance of cortical calcifications (250).
However, calcifications mask the enhancement as determined by CT;
moreover, MRI is more sensitive to the extent of enhancement than
CT (254). After intravenous administration of contrast, the angioma
appears on MRI as an area of enhancement that seems to fill the suba-
rachnoid space, covering the surfaces of the gyri and filling the corti-
cal sulci (Figs. 6-43 and 6-44). Dilated deep medullary veins, through
which venous blood is shunted from the superficial to the deep venous
system, can be seen in the white matter under the angioma (Fig. 6-44E)
(255,256). As demonstration of the extent of the angioma is critical in
determining the patient’s prognosis and the necessary extent of cortical
resection, contrast-enhanced MRI should be performed in all patients
for whom surgery for seizure control is planned (252). It is important
to note, however, that “burned-out” cases of Sturge-Weber syndrome,
in which the affected hemisphere is markedly shrunken and heavily
calcified, may not show enhancement (257). The reason for this lack of
enhancement is not clear, but it may relate to thrombosis of the vessels
comprising the angioma.
The effects of the pial “angioma” (and the associated restricted cor-
tical venous drainage) upon the underlying brain can also be assessed
by imaging. As mentioned earlier, calcifications occur in the cerebral
cortex underlying the pial angioma; they are the most frequent CT
finding of Sturge-Weber disease (Fig. 6-43E) (250,258). Calcifications
most commonly occur unilaterally over the posterior portion of the
hemisphere, although any portion of cerebral cortex may be involved.
The calcification is sometimes difficult to see on T1-weighted MRI
studies. It is more readily identified on T2-weighted images and, espe-
cially, on susceptibility-weighted imaging (SWI) or on T2*-weighted
Barkovich_Chap06.indd 606
gradient-echo images, which are more sensitive to the difference in
magnetic susceptibility between normal brain and calcium (Fig. 6-45)
(256). With the more sensitive techniques, a thin ribbon of low signal
intensity will be seen in or subjacent to the cerebral cortex in the affected
areas (256); these areas seem to correlate with reduced FDG uptake on
PET studies (256). Contrast-enhanced T1-weighted sequences demon-
strate leptomeningeal abnormalities to a greater extent than SWI; SWI
appears superior to contrast-enhanced T1 sequences in identifying the
enlarged transmedullary veins, the abnormal periventricular veins, the
cortical gyriform abnormalities, and the gray/white matter junction
abnormalities (Fig. 6-45) (259).
Dynamic MR perfusion studies reveal that the brain underlying
the enhancing pial angioma is hypoperfused. Cerebral hypoperfusion
is predominantly due to impaired venous drainage: in most cases, per-
fusion imaging reveals increased mean transit time with normal bolus
arrival; in the most severely affected regions reduced regional blood
flow can be observed (260,261). Proton MR spectroscopy of affected
brain regions shows elevated choline (possibly related to accelerated
myelination), reduced NAA (probably due to cortical/white matter
ischemic injury), and slightly elevated lactate (probably resulting from
ongoing ischemia). However, MRS abnormalities (NAA reductions,
elevation of choline) can be observed even in normal-appearing white
matter, distant from the leptomeningeal angiomatosis (262); similarly,
increased diffusivity has been documented in normal-appearing white
matter with diffusion-weighted imaging (263).
The choroid plexus is frequently enlarged in patients with Sturge-
Weber disease (264). In young children, the degree of plexal enlarge-
ment shows a positive correlation with the extent of the leptomeningeal
angioma; that is, the more extensive the parenchymal involvement, the
larger the choroid plexus (265). The enlarged choroid plexus is best
demonstrated on contrast-enhanced T1-weighted images as abnor-
mally prominent enhancement of the choroid may be seen ipsilateral to
the angioma (Figs. 6-43 and 6-44) (264). On T2-weighted and FLAIR
images, the affected choroid plexuses are enlarged and are hyperintense
to brain parenchyma (264). This phenomenon is most commonly a
result of hyperplasia of the choroid plexus, possibly related to increased
5/6/2011 9:04:28 PM
 Chapter 6 • The Phakomatoses 607

FIG. 6-44. Infant with Sturge-Weber syndrome. A. Post-

contrast axial SE T1 image at age 5 weeks shows enlarged
left choroid plexus (white arrowhead), but only minimal
pial enhancement in the left occipital pole (white arrows).
B. Axial T2-weighted image at age 5 weeks shows minimal
hypointensity of the left parietal white matter. C–E. Same
patient at 2 years of age; interval development of cortical
atrophy and loss of underlying white matter. Postcon-
trast axial SE T1 image (C) shows increased conspicuity
of the left parietal-occipital leptomeningeal angioma;
the left choroid plexus (white arrowhead) is enlarged.
Axial T2-weighted images (D and E) show atrophy and
hypointense subcortical white matter signal in the left
posterior frontal, parietal, and occipital lobes; abnormal
dilated medullary (white arrows) and subependymal
(black arrowhead) veins are seen.

Barkovich_Chap06.indd 607 5/6/2011 9:04:29 PM

 608 Pediatric Neuroimaging
FIG. 6-45. Child with Sturge-Weber syndrome and right hemispheric
atrophy. Axial SWI shows the diffuse, hypointense cortical and subcorti-
cal calcifications posteriorly throughout the atrophic right hemisphere.
Dilated, hypointense medullary and subependymal veins (white arrows) are
evident adjacent to the ventricle. (This figure courtesy Dr. Erin Schwartz,
Philadelphia.)
venous flow from the affected cerebral hemisphere through the deep
venous system and the plexus. These are sometimes referred to as
“angiomatous malformations of the choroid” (249).
In the infant with Sturge-Weber syndrome, the white matter
underlying the angioma typically shows accentuated T2 shortening
compared to the remainder of the brain (Fig. 6-44D and E) (266). This
is most likely secondary to abnormal hypermyelination; increased FA
and decreased diffusivity have been demonstrated in the involved white
matter using diffusion tensor imaging (267). The increased myelina-
tion may result from abnormal venous congestion or from repeated
seizures (268). Another possible contribution to the T2 shortening is
the presence of increased deoxyhemoglobin in capillaries and veins,
the result of restricted superficial venous drainage, with consequent
shunting of deoxygenated blood through the dilated deep medullary
veins into the deep venous system (269).
The ipsilateral cerebral hemisphere ultimately becomes atrophic
in most, but not all, patients with Sturge-Weber disease (Figs. 6-43
to 6-45); atrophy is uncommon at the time of seizure onset, however
(Fig. 6-44). As might be expected, atrophy is bilateral in those patients
with bilateral angiomas (270). The white matter subjacent to the
affected cerebral cortex appears as low density on CT scans and shows
T1 hypointensity and T2/FLAIR hyperintensity on MR (271). Diffu-
sion tensor imaging shows increased diffusivity and reduced fractional
anisotropy in the affected white matter (255). These imaging charac-
teristics most likely represent atrophy and astrogliosis in the ischemic
underlying brain.
Infratentorial involvement (presenting as leptomeningeal enhance-
ment, atrophy, and developmental venous anomaly) may be more fre-
quent than previously thought and has been reported in 10% to 40%
of cases (272).
Barkovich_Chap06.indd 608
Cranial asymmetry often results from cerebral hemiatrophy. The
ipsilateral calvarium is thickened and the ipsilateral paranasal sinuses
and mastoid air cells are enlarged because of the lack of brain growth
on the affected side. The thickened calvarium is seen on MRI as a wid-
ening of the fat-filled high-intensity diploic space. Midline structures
are often apparently displaced toward the side of the leptomeningeal
angioma. Occasionally, an enlarged hemicranium may be seen on the
side of the angioma. This paradoxical enlargement may be a result of
subdural hematomas accumulating in the affected hemicranium sec-
ondary to the cerebral atrophy (273).
Enlarged vessels are commonly seen on CT and MR studies in the
subependymal and periventricular region of the brain (Figs. 6-43D,
6-44E, and 6-45). Although venous malformations, arteriovenous
malformations, and dural arteriovenous fistulae may be seen in asso-
ciation with Sturge-Weber syndrome (274), the more likely cause for
these enlarged deep hemispheric vessels in most patients is enlarge-
ment of the vessels of the deep venous system of the brain (269,275).
When such enlargement occurs, it is a result of marked slowing of
blood flow in, or possibly thrombosis of, the maldeveloped superfi-
cial venous system of the brain. The pial angioma is associated with
the maldevelopment of, and diminished outflow through, the super-
ficial venous system. Therefore, venous blood is shunted through the
aforementioned deep medullary veins and into the deep venous system
of the brain (269,275). This redirected venous drainage should not be
mistaken for arteriovenous malformations in which enlarged feeding
arteries, as well as large veins, are present. The absence of superficial
venous drainage in the region of the pial angioma was an important
criterion in the diagnosis of Sturge-Weber disease prior to the advent
of CT (269,275).
PET using 18F-FDG has been used to study cerebral metabolism
in children with Sturge-Weber syndrome. In the early stages of the
disease, the affected area is typically hypermetabolic. However, hypo-
metabolism soon ensues (276). The authors have suggested that PET
is useful in surgical planning when cortical resection is contemplated
for treatment of intractable seizures and failure to attain develop-
mental milestones (276). Fusion of PET with MRI is more useful still
(255). The value of PET, as compared to contrast-enhanced MR, to
determine the extent of resection in affected patients has not been
established.
Eye Anomalies
Abnormalities of the globe are seen in about 30% of patients with
Sturge-Weber disease (243,277). Pathologically, affected patients have
angiomas of the choroid and sclera. They present with ocular pain or
retro-orbital pain from glaucoma or with acute visual deterioration
from retinal detachment. If the glaucoma begins in utero, the globe can
enlarge as a result of the increased intraocular pressure, a condition
known as buphthalmos. Buphthalmos is seen on CT and MR scans as
an enlarged, somewhat elongated globe. The choroidal angioma can
also be detected by MRI as thickening of the posterior wall of the globe
on noncontrast T1-weighted images, by crescentic high intensity in the
posterior globe on the first echo of T2-weighted images, and as crescen-
tic enhancement in the posterior globe on contrast-enhanced MRI of
the orbit using a fat-suppression pulse (Fig. 6-46) (278). The presence
of choroidal angioma correlates with the presence of bilateral disease
and with the extent of facial involvement; it does not correlate with the
size of the intracranial pial angioma (278). Care must be taken not to
misinterpret chemical shift artifact (seen as crescentic high intensity
along the posterior margin of the globe on T2-weighted images using
a short bandwidth) as a choroidal angioma; because of this potential
pitfall, use of a fat-suppressed, contrast-enhanced sequence is most
reliable.
5/6/2011 9:04:30 PM

FIG. 6-46. Angioma of the choroid, infant with Sturge-Weber syndrome.
Postcontrast axial T1 image shows marked enhancement (white arrows) of
the choroid of the right ocular globe, indicating the presence of a choroidal
angioma.
Extra-CNS Manifestations
Patients with Sturge-Weber syndrome do not typically have abnormal-
ities of the thoracic or abdominal viscera. However, some patients will
have angiomas of the viscera and extremities in conjunction with typi-
cal findings of Sturge-Weber syndrome (243,279,280). The angiomas
can be localized or diffuse; they can be located in the intestine, kidneys,
spleen, ovaries, thyroid gland, pancreas, or lungs (243). This combina-
tion of Sturge-Weber syndrome with involvement of the viscera and
extremities is called Klippel-Trenaunay-Weber syndrome by some
authors (281), while others consider the entire complex to be a part
of the Sturge-Weber syndrome (279), and still others consider it an
overlap syndrome (282).
VON HIPPEL-LINDAU DISEASE
Clinical Manifestations
Also known as CNS angiomatosis, von Hippel-Lindau disease is an auto-
somal dominant disorder with incomplete penetrance characterized by
retinal angiomas; cerebellar and spinal cord hemangioblastomas; renal
cell carcinomas; endolymphatic sac tumors; pheochromocytomas; pap-
illary cystadenoma of the epididymis; angiomas of the liver and kidney;
and cysts of the pancreas, kidney, liver and epididymis (283–285). von
Hippel-Lindau disease affects approximately 1 in 40,000 individuals;
both sexes are affected equally (286–288). The diagnosis is established
if patients have more than one hemangioblastoma of the CNS, one
hemangioblastoma with a visceral manifestation of the disease, or one
manifestation of the disease and a known family history (286). The
disease is caused by a defective tumor suppressor gene, called VHL, at
chromosome 3p25-p26 (287); its gene product, pVHL, is involved in
cell cycle regulation and angiogenesis. Inactivation of pVHL results in
overexpression of hypoxia inducible mRNAs, including VGEF (vascu-
lar endothelial growth factor) (288). von Hippel-Lindau can be diag-
nosed by molecular biologic techniques, with potential for diagnosis
in utero.
The diagnosis of von Hippel-Lindau disease is usually established
after identification of either the cerebellar or retinal tumors. Symptoms
typically begin during the third or fourth decade of life; it is unusual
for patients to present before the second half of the second decade
(283,286,289). Symptoms from the retinal angiomas typically antedate
Barkovich_Chap06.indd 609
Chapter 6 • The Phakomatoses 609
cerebellar complaints, but this order of events is by no means constant;
moreover, the ocular findings are nonspecific and often do not estab-
lish a definite diagnosis. The usual sequence of events is reactive reti-
nal inflammation with exudate and hemorrhage, followed by retinal
detachment, glaucoma, cataract, and uveitis. By the time the patient
is seen because of decreasing visual acuity or eye pain, the secondary
changes of retinal detachment may mask the underlying lesion. Head-
ache, vertigo, and vomiting result from the cerebellar tumor and asso-
ciated increased intracranial pressure, when present. Other cerebellar
findings such as dysdiadochokinesis, dysmetria, and Romberg sign are
common (289). Uncommonly, patients may have complaints of spinal
cord dysfunction such as loss of sensation or impaired proprioception.
It is rare, however, for patients to come for medical attention because
of symptoms of spinal cord or visceral lesions in this disease (286).
Rarely, patients present with hearing loss resulting from tumors of the
endolymphatic sac (290).
Ocular Manifestations
Angiomas of the retina are observed in over half of affected patients;
symptoms from these lesions are usually the earliest manifestation of
the disease (286). Retinal angiomas are best demonstrated clinically,
using indirect ophthalmoscopy and fluorescein angiography. The
angiomas are multiple in up to two thirds of patients and bilateral in
up to 50% (286,289,291). Although CT and MR can detect the sec-
ondary retinal detachment, the retinal angiomas themselves are usually
quite small and are rarely detected by imaging studies.
Brain and Spinal Cord Manifestations
Cerebellar hemangioblastomas are present in more than half of patients
with von Hippel-Lindau disease (286,291). They are the second most
frequent source of initial symptoms and frequently recur after surgical
resection. Hemangioblastomas may develop in childhood before the
age of 10 years, in the teen years, or in early adulthood (291). The most
common locations are the spinal cord (50%), cerebellum (38%), brain-
stem (10%), and cerebrum (2%) (Figs. 6-47 to 6-49) (292). Between
20% and 40% of the tumors are solid (35). If untreated, many solid
tumors will develop cysts and enlarge, but many tumors will remain
stable in size or grow slowly unless cysts develop (293). When grow-
ing, tumors exhibit a stuttering growth pattern and frequently remain
asymptomatic; thus, surgery based on radiologic progression alone is
often not indicated (294). Tumors associated with symptoms tend to
be larger and are more likely to be associated with peritumoral edema
or peritumoral cysts than asymptomatic tumors (295).
When the nodules of hemangioblastoma are large enough, they
will show contrast enhancement on CT; however, when the nodules
are small, the tumor may be indistinguishable from a benign posterior
fossa cyst or, in the absence of a cyst, they may not be detected at all
(250,296). The MR appearance of the cystic lesions is that of sharply
marginated, peripheral cerebellar masses showing T1 hypointensity
and T2/FLAIR hyperintensity (Figs. 6-47 and 6-48) (297,298). Precon-
trast and postcontrast T1-weighted sequences are the most useful for
detection of hemangioblastomas (299). If a solid nodule can be seen
within the wall of the cyst, it will often have small curvilinear areas of
signal void within it, representing enlarged feeding and draining vessels
(300). Solid hemangioblastomas appear as ill-defined, solid masses that
can be difficult to identify without administering paramagnetic con-
trast (Fig. 6-50) (297,298). In general, they show T1 hypointensity and
T2/FLAIR hyperintensity, although hemorrhage is occasionally present,
resulting in high signal intensity on noncontrast T1-weighted images.
The use of MR contrast agents increases sensitivity for detection of
5/6/2011 9:04:31 PM
 610 Pediatric Neuroimaging

FIG. 6-47. Solid and cystic cerebellar hemangioblastomas in von Hippel-Lindau disease. Postcontrast sagittal (A) and coronal (B) T1 images show a large
cerebellar cyst with an enhancing mural nodule in the superior-most vermis (long black arrows). A second small nodule (short black arrows) is seen in the
left cerebellar tonsil.

small lesions; solid portions of tumor enhance intensely (Figs. 6-47
to 6-50) (297,299). Angiography may still be performed in order to
show the location and size of the arteries supplying the tumor. The
angiographic appearance of the hemangioblastoma is highly charac-
teristic, showing tangles of tightly packed, wide vessels that become
opacified in the early arterial phase. A nonvascular (cystic) portion of
the mass is often seen (301). These angiographic findings can also add
diagnostic specificity to a lesion that is detected on CT or MRI.
In the past, hemangioblastomas of the spinal cord were thought
to be uncommon because of the rare clinical manifestations of spinal
cord pathology in patients with von Hippel-Lindau disease. However,
autopsy data suggests that these lesions may be more common than was
previously suspected (35,286,289). Indeed, MRI demonstrates a con-
siderably larger number and higher incidence of spinal cord hemangio-
blastomas than were previously believed to exist (Figs. 6-48 and 6-49)
(298); the spinal cord is the most common location for hemangioblas-
tomas in this disease (292). Syringomyelia is present in the majority
of patients with spinal cord hemangioblastomas; symptoms are most
often due to the cyst and not the solid portion of the tumor. Differen-
tiation of syringomyelia from tumor cysts and from cord edema can be
difficult, but T2-weighted images can often help differentiate cyst from
edema, as the cysts are typically of higher signal intensity and have

FIG. 6-48. Cerebellar and spinal cord hemangioblastomas in von Hippel-Lindau syndrome. A. Axial T1-weighted image shows a right cerebellar cyst (large
black arrows) with a mural nodule (small solid black arrows) containing a curvilinear signal void (small open white arrow). A second nodule (small solid white
arrows) with curvilinear signal voids is seen in the anterior left cerebellar hemisphere. B. Postcontrast image shows enhancement of the solid portions of
both hemangioblastomas. C. Sagittal T2-weighted image shows multiple curvilinear flow voids in the subarachnoid spaces and a mass (white arrows) at L-4.
Multiple other hemangioblastomas are difficult to see. D. Sagittal postcontrast T1-weighted image of the spine shows the large L-4 mass (white arrows) with
some internal flow voids (black arrowheads) and innumerable other enhancing hemangioblastomas (white arrowheads).

Barkovich_Chap06.indd 610 5/6/2011 9:04:31 PM

 Chapter 6 • The Phakomatoses 611

FIG. 6-49. Medullary, cervicomedullary, and spinal cord hemangioblastomas in von Hippel-Lindau syndrome. A. Sagittal T1-weighted image through
the upper spinal cord after IV contrast infusion. An enhancing mass (black arrow) with surrounding cyst/edema (white arrowheads) is seen at the cervical-
medullary junction with exophytic extension into the cisterna magna. A second lesion (white arrow) is present at the T2 level dorsally. Both lesions were
hemangioblastomas. The more caudal lesion was not clinically suspected. B. Sagittal T2-weighted image shows the cervicomedullary mass (large white
arrows) as hypointense, a flow void (black arrowhead) adjacent to the mass, a tumor cyst (white arrowheads), and edema of the adjacent spinal cord (small
white arrows). C. Axial postcontrast T1-weighted image at the upper medullary level shows an enhancing hemangioblastoma (white arrows) in the left
inferior cerebellar peduncle.

sharp margins, whereas edema is less hyperintense and has indistinct
margins (Fig. 6-49). It is difficult to differentiate idiopathic syringomy-
elia from syringomyelia secondary to hemangioblastomas without the
use of an MR contrast agent. Following intravenous administration of
paramagnetic contrast, the tumor enhances markedly, facilitating the
diagnosis (297,302). Another specific MR characteristic of spinal cord
hemangioblastomas is the enlarged feeding and draining vessels that
are manifest as serpiginous areas of signal void within and adjacent to
the tumor (297,300).
Hemangioblastomas may also occur within the brainstem
(Fig. 6-49) or the cerebral hemispheres (250). The radiologic appear-
ance of these lesions is identical to that of the cerebellar or spinal cord

FIG. 6-50. Recurrent hemangioblastomas

in von Hippel-Lindau syndrome. A. Axial
noncontrast T1-weighted image shows
hypointensity (arrows) from prior surgery,
but no evidence of recurrent tumor. B. Post-
contrast scan shows multiple enhancing cer-
ebellar tumors.

Barkovich_Chap06.indd 611 5/6/2011 9:04:33 PM

 612 Pediatric Neuroimaging
hemangioblastomas. They may be cystic with a solid nodule or entirely
solid; the solid portion contains curvilinear signal voids and shows
marked contrast enhancement. The diagnosis is obviously facilitated
by knowledge of the diagnosis of von Hippel-Lindau syndrome or the
presence of other hemangioblastomas.
Papillary Cystadenomas of the
Endolymphatic Sac
Another tumor that has a high incidence in von Hippel-Lindau dis-
ease is the papillary cystadenoma of the endolymphatic sac (303,304).
Although most papillary endolymphatic sac tumors appear to occur
sporadically, patients with von Hippel-Lindau disease are at greater risk
for developing these tumors than the general population; the incidence
of papillary cystadenomas of the endolymphatic sac in von Hippel-
Lindau disease is about 7% to 15% (290,305). Patients with endolym-
phatic sac tumors typically present with hearing loss; therefore, the
finding of hearing loss in a patient with known von Hippel-Lindau
Barkovich_Chap06.indd 612
disease should prompt neuroimaging directed at the endolymphatic
sac. Conversely, the discovery of an endolymphatic sac tumor in a
patient under the age of 30 years should incite a search for the presence
of ocular, cerebral, cerebellar, or renal masses. Patients who develop
bilateral papillary angiomatous tumors of the endolymphatic sac may
be presumed to have von Hippel-Lindau disease (304).
The imaging findings of papillary cystadenomas of the endolym-
phatic sac are rather characteristic. The tumors originate from the
endolymphatic epithelium within the vestibular aqueduct, along the
posteromedial margin of the petrous pyramid (305). CT shows bone
destruction with scattered calcifications centered at the level of the
vestibular aqueduct (Fig. 6-51A). T1-weighted MR images show a het-
erogeneous mass that is predominantly isointense to brain with areas
of high signal intensity. T2-weighted images show a predominantly
hyperintense mass with areas of low signal intensity (Fig. 6-51B and C).
Larger tumors show vascular signal voids. The tumors enhance homo-
geneously or heterogeneously after administration of paramagnetic
contrast (Fig. 6-51D and E) (290,306). Angiography shows vascular
FIG. 6-51. Papillary cystadenoma of the endolymphatic
sac in von Hippel-Lindau syndrome. A. Axial noncontrast
CT scan shows bone destruction (white arrows) of the
inner ear and mastoid air cells. B. Axial 3D T2-weighted
image shows a hyperintense mass (white arrows) near the
vestibular aqueduct orifice and growing into the mastoid
air cells. C. Axial T1-weighted image shows the hetero-
geneous mass (white arrows), demonstrating peripheral
hyperintensity and central hypointensity. D and E. Axial
and coronal postcontrast T1-weighted images show that
the mass (white arrows) becomes relatively homogeneous
after administration of contrast due to enhancement of the
relatively hypointense center.
5/6/2011 9:04:35 PM

tumors with supply primarily from external carotid branches, although
some supply from internal carotid and vertebrobasilar branches may
be found in larger tumors (290,306).
Visceral Manifestations
The major visceral manifestation of von Hippel-Lindau disease is renal
cell carcinoma, which occurs in up to 40% of patients. These tumors
are frequently multicentric or bilateral (289). They occur later in life
than most of the neurologic manifestations, with the average presenta-
tion during the fifth decade of life (286). Pheochromocytomas may be
present in 10% to 15% of patients. Cysts occur in virtually all visceral
organs, including the liver, omentum, mesentery, spleen, adrenal gland,
and epididymis. Adenomas can occur in the liver and epididymis
(286,296). Thus, affected patients must be evaluated with abdominal
and pelvic imaging studies as well as neural axis imaging.
ATAXIA-TELANGIECTASIA
Clinical Manifestations
Ataxia-telangiectasia is an autosomal recessive disorder characterized
by a complex set of clinical features that include cerebellar degenera-
tion, dilation of blood vessels, severe immune deficiencies, premature
aging, predisposition to cancer, and acute radiation sensitivity (307–
311). The incidence is approximately 1 per 40,000 live births (307).
The gene (called ATM for ataxia-telangiectasia, mutated) has been
identified and is located on chromosome 11q22–23 (312). The gene
encodes a nuclear protein kinase that is needed for detecting DNA
damage or for blocking cell growth until the damage is repaired; cells
in affected patients have frequent chromosomal aberrations including
chromosomal breaks, rearrangements, and aneuploidy (311). Affected
patients usually present with cerebellar ataxia, which manifests itself
when the child starts to walk. The ataxia is followed by a progressive
neurological deterioration. Eventually, the children are confined to a
wheelchair and exhibit oculomotor abnormalities, dysarthric speech,
choreoathetosis, endocrine abnormalities, and myoclonic jerks
(307,308,313).
FIG. 6-52. Ataxia telangiectasia in a 7-year-old child. A. Sagittal T1-weighted image shows mild to moderate atrophy of the cerebellar vermis, more severe
superiorly. B. Coronal FLAIR image reveals mild atrophy of the superior and lateral cerebellar hemispheres.
Barkovich_Chap06.indd 613
Chapter 6 • The Phakomatoses 613
Characteristic skin changes (mucocutaneous telangiectasias) begin
to appear between 3 and 6 years of age. They appear first on the bulbar
conjunctiva and subsequently on the ears, face, neck, palate, dorsum
of the hands, and antecubital and popliteal fossae. Other associated
dermatologic changes can be seen as well (308,309). Recurrent bacte-
rial and viral sinopulmonary infections occur in most patients, lead-
ing to bronchiectasis and pulmonary failure, the most common causes
of death. Malignancies develop in 10% to 15% of affected patients
(314). Lymphomas and leukemia predominate in younger patients,
whereas epithelial malignancies occur much more frequently in adults
(314,315).
Pathological and Neuroimaging
Manifestations
The major neuropathological finding in ataxia-telangiectasia is degen-
eration of the cerebellar cortex. Purkinje cell and granule cell degrada-
tion can be found in the vermis, the hemispheres, or both. The cause
of this neuronal degeneration and atrophy has not been fully discov-
ered; however, some authors have found ATM-mediated damage in the
nuclei of the Purkinje and granule cells, suggesting that DNA damage
resulting from the abnormalities in this protein are the cause (316).
Additional CNS findings include atrophy of the cerebellar nuclei, ante-
rior horn cell atrophy and demyelination of the gracile fascicule in the
spinal cord, and the existence of nucleocytomegalic cells in the anterior
pituitary gland (317). In addition, spongy degeneration of the cerebral
cortex has been described surrounding degenerated cortical blood ves-
sels in adults with this disorder (317).
The major abnormalities seen on CT and MRI are cerebellar corti-
cal atrophy, manifested as diminished cerebellar size, dilation of the
fourth ventricle, and increased cerebellar folial prominence (318).
Initially, the atrophy involves the vermis and the lateral aspect of the
cerebellar hemispheres, with more severe and extensive atrophy (and
more severe ataxia) developing with longer duration of the disease
(Fig. 6-52) (319). Hemorrhage may occur as a result of rupture of
parenchymal telangiectasias. Cerebral infarcts may result from emboli
that are shunted through vascular malformations within the lungs.
5/6/2011 9:04:36 PM
 614 Pediatric Neuroimaging
Older patients may have multiple foci of hypointensity in the cerebral
white matter on T2*-weighted images, presumably secondary to multi-
ple small hemorrhages from the abnormal blood vessels (313,320,321).
Proton MR spectroscopy acquired in the cerebellum with TE = 144
msec shows reduction of all metabolites with reduced NAA/Cho and
increased Ch/Cr ratios (vermis > hemispheres) compared with age-
matched controls (321,322).
When cerebellar atrophy is an isolated finding in a young child
with cerebellar ataxia and progressive neurologic deterioration, the
possible diagnosis of ataxia-telangiectasia should be raised. For a dis-
cussion of other causes of cerebellar atrophy in childhood, see the last
portion of Chapter 3.
Nijmegen Breakage Syndrome
The Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive
genetic syndrome that is classified as an ataxia-telangiectasia–related
disorder; thus it is included in this section. However, NBS appears to be
a distinct disorder, both clinically and genetically (323), resulting from
mutations of the NBS1 gene at chromosome 8q21 (324). The protein
product of the gene, called nibrin, is involved in repair of DNA (325,326).
The disease appears to be prevalent in the central European population,
in whom the presence of a common founder mutation in NBS1 has been
found (326). Affected children present with microcephaly (OFC below
third percentile at birth, with progressively declining percentile), distinct
facies (sloping forehead, receding mandible, prominent midface and
nose, upward slanting of the palpebral fissures), and early growth retar-
dation (327,328). Intelligence is initially normal to borderline low, but
most progress to moderate intellectual disability by adolescence (329).
Immunodeficiency is present, leading to recurrent infections and a pre-
disposition to cancer, predominantly lymphoma, at a young age (329).
Because of the DNA repair defects, these children are particularly sensi-
tive to ionizing radiation; exposure to x-rays should be avoided.
Imaging findings seem to be composed of hypogenesis of the cor-
pus callosum (seen in ∼50%) and consequent diminished white matter
around the trigones and occipital horns of the lateral ventricles (329).
Sinus disease is reportedly common and sphenoid sinus pneumatiza-
tion delayed (329). Searches should be made for opportunistic infec-
tions and tumors, particularly lymphoma and leukemia.
NEUROCUTANEOUS MELANOSIS
Clinical Manifestations
Neurocutaneous melanosis (NCM) was first described by Rokitan-
sky, who reported about a 14-year-old girl with a giant congenital
melanocytic nevus and mental retardation who developed late-onset
hydrocephalus (330). Since that initial report, over 100 cases have been
reported (331). Most cases are sporadic. Giant congenital nevi are
themselves a relatively rare birthmark, occurring in approximately 1
in 20,000 to 50,000 live births (332). When these birthmarks are asso-
ciated with melanosis of the leptomeninges or brain, a diagnosis of
NCM can be made. A deregulation of hepatocyte growth factor/scatter
factor (HGF/SF) signaling has been implicated in the pathogenesis of
NCM. HGF/SF is a cytokine that stimulates the proliferation, migra-
tion, and morphogenesis of different types of cultured epithelial cells
(333). It plays an important role in the normal distribution and pro-
liferation of melanocytes, as transgenic mice overexpressing HGF/SF
have been found to develop multiple pigmented nevi in both the skin
and leptomeninges (333). Moreover, abnormal expression of an HGF/
SF receptor called Met has been immunohistochemically detected in
the cutaneous nevus of an infant with NCM (333).
Barkovich_Chap06.indd 614
With few exceptions, individuals with NCM have congenital
pigmented nevi on the head and neck or dorsal spine area, commonly
with presence of multiple satellite nevi (334). Two thirds of affected
patients have a giant congenital melanocytic nevus, usually of the lum-
bosacral region, while one third have numerous small melanocytic nevi
without a single large lesion (335). Symptomatic CNS disease typically
develops at less than 2 years of age, while a smaller, second peak of onset
of symptoms occurs at puberty or during adult life. The most common
neurological complications include seizures, cranial nerve dysfunction,
and signs and symptoms of increased intracranial pressure. Hydro-
cephalus is seen in two thirds of cases and is thought to result from
extensive leptomeningeal infiltration with melanosis or with develop-
ment of intracranial melanoma (331,336). Spinal involvement occurs in
approximately 20% of cases, and may result in myelopathy, radiculopa-
thy, and bowel or bladder dysfunction (335). The prognosis of symp-
tomatic NCM is poor; the majority of patients die within 3 years of their
initial neurologic symptoms, either from CNS malignant melanoma or
from progressive growth of “benign” melanocytic cells (332).
An asymptomatic form of NCM was originally suggested by the
finding of leptomeningeal melanocytosis on postmortem examination
of two patients. Frieden et al. (337,338) recently documented a surpris-
ingly high incidence of MR abnormalities in asymptomatic children
with giant cutaneous melanocytic nevi. Of 43 children with giant cuta-
neous melanotic nevi over their head and neck or spine, 23% (10/43)
had focal areas of T1 shortening strongly suggestive of melanotic
deposits in one or multiple areas of the brain, particularly the temporal
lobes (amygdala), cerebellum, pons, and/or medulla (337). Additional
findings included intracranial mesenchymal abnormalities (including
arachnoid cyst), cerebellar hypoplasia, spinal lipomas, tethered spinal
cord, and Chiari type I malformation. Despite the frequent finding of
melanotic deposits, no patient went on to develop CNS melanoma,
with an average duration of 5 years follow-up (338). This is in striking
contrast to the usual outcome of symptomatic NCM, where death usu-
ally occurs within 2 to 3 years. This result suggests that the brain MR
findings in asymptomatic individuals may be more analogous to those
in the skin. If so, affected patients would have a somewhat increased
risk of both cutaneous and primary CNS melanoma over their lifetime,
but not necessarily an immediate dismal prognosis or even certainty of
neurologic symptoms (338).
In 1972, Fox proposed the following criteria for diagnosing NCM:
(a) unduly large or unusually numerous pigmented nevi in association
with melanosis or melanoma of the pia-arachnoid, (b) no evidence of
malignant change in any of the cutaneous lesions, and (c) no evidence
of malignant melanoma in any organ apart from the meninges (332).
A revision of Fox’s criteria has been proposed in order to more accu-
rately define the population at risk (335,339): (a) large or multiple (3
or more) congenital nevi in association with meningeal melanosis or
CNS melanoma, where large is defined as a diameter equal to or greater
than 20 cm in an adult, 9 cm on the scalp of an infant, or 6 cm on
the body of an infant; (b) no evidence of cutaneous melanoma, except
in patients in whom the examined areas of the meningeal lesions are
histologically benign; and (c) no evidence of meningeal melanoma,
except in patients in whom examined areas of the skin are histologi-
cally benign. Those cases with histologic confirmation are considered
definite; all others are considered provisional diagnoses.
Pathological Manifestations
Pathologists may find a substantial number of benign melanotic cells
within the basilar meninges of normal patients at autopsy, as both mel-
anocytes and the basilar pia-arachnoid derive from neural crest (340–
342). Patients with NCM, however, have orders of magnitude of more
5/6/2011 9:04:37 PM

melanotic cells, which may be distributed diffusely or demonstrate
nodularity within the meninges (332,339). A number of potential
explanations for the abnormal accumulation of melanotic cells in the
meninges have been proposed, including abnormal migration of mel-
anocyte precursors (343), abnormal expression of melanin-producing
genes within the leptomeningeal cells (344), or rapid proliferation of
“normal” melanin-producing leptomeningeal cells. The abnormal mel-
anin-producing cells are often present in the perivascular spaces along
vessels that penetrate the brain from the basilar cisterns and result in
parenchymal melanin deposits (339,345).
The anterior temporal lobes and cerebellum appear to be the
most common locations for accumulation of melanotic cells in NCM
(339,346–351). In the anterior temporal lobe, the amygdala seems par-
ticularly commonly affected (339,346,350–352). Other common loca-
tions include the thalami, pons, cerebellum, and the base of the frontal
lobe (335,339,346,352). It is likely that the preferential spread to these
locations is a result of their close proximity to the basilar meninges.
Neuroimaging Manifestations
CT scans in children with NCM may show the associated hypoplasia
of the cerebellum or pons, but the foci of melanin-containing cells
Barkovich_Chap06.indd 615
Chapter 6 • The Phakomatoses 615
show only subtle hyperdensity and are difficult to see unless they have
converted into a melanoma. Leptomeningeal involvement is difficult to
appreciate unless malignant degeneration has occurred, in which case
contrast-enhanced images may show leptomeningeal enhancement.
MRI shows foci of T1 hyperintensity, and sometimes T2 hypointen-
sity, in the brain parenchyma or meninges (Figs. 6-53 and 6-54), sig-
nal characteristics that are compatible with the T1 and T2 shortening
effects of melanin. These deposits of melanin are more easily detected
in the unmyelinated brain, as the T1 and T2 shortening caused by
white matter myelination makes the melanin less conspicuous (338).
Thus, MR screening for melanotic deposits is best performed early in
infancy. FLAIR images show both parenchymal and leptomeningeal
melanosis as hyperintense compared to normal parenchyma (353). The
intraparenchymal foci of abnormal signal are typically 3 cm or less in
diameter; they are most commonly seen in the anterior temporal lobe,
cerebellum, and brainstem (Figs. 6-53 and 6-54) (352,354). The T1 and
T2 shortening is presumably the result of the presence of paramagnetic
stable free radicals in melanin (identified by electron spin resonance
studies) (355,356). The unpaired electrons in free radicals interact with
water protons via dipole-dipole interactions with subsequent shortening
of both T1 and T2 relaxation times (357,358). When extensive melano-
sis is present, affected children typically have hydrocephalus (Fig. 6-55).
FIG. 6-53. Neurocutaneous melanosis. A. Sagittal
T1-weighted image in a 3-month-old infant shows
hyperintensity in the basis pontis (black arrows)
and along the surface of the vermis (white arrows).
The pons and vermis are slightly small. B. Axial
T1-weighted image shows hyperintense melanin
deposits in the basis pontis (white arrows), right
amygdala (large black arrow), and cerebellar folia
(small black arrows). C. Sagittal T1-weighted image
of the same child at age 5 years shows hypoplasia of
the pons and cerebellum (arrows), but no evidence
of leptomeningeal melanosis. Melanosis becomes
more difficult to detect as the brain matures. It is
not certain whether this reflects changes in the lep-
tomeningeal melanosis or changes of the relative
signal intensities of the melanotic deposits and the
brain parenchyma.
5/6/2011 9:04:37 PM
 616 Pediatric Neuroimaging

FIG. 6-54. Neurocutaneous melanosis

with extensive cerebellar involvement.
A. Axial T1-weighted image shows foci of
hyperintense melanin (white arrows) ante-
rior to the temporal horns of the lateral
ventricles. B. Coronal T1-weighted image
shows extensive hyperintensity within the
cerebellar hemispheres. Both hemispheres
are hypoplastic, the left more so than the
right.

FIG. 6-55. NCM with hydrocephalus. A. Sagittal

T1-weighted image shows severe hydrocephalus. The cer-
ebellum appears slightly small and the cisterna magna is
enlarged. B. Axial T1-weighted image shows multiple hyper-
intense deposits of melanin in the cerebellar hemispheres. C.
Axial T1-weighted image at the level of the midbrain shows
bilateral melanin deposits (white arrows) anterior to the tem-
poral horns of the lateral ventricles.

Barkovich_Chap06.indd 616 5/6/2011 9:04:38 PM


Degeneration of the melanocytic accumulation into melanoma can
only be determined by the identification of progressive growth of the
lesion, by the presence of surrounding edema or mass effect, or by the
presence of central necrosis (352). Some authors have identified abnor-
mal meningeal enhancement on MR studies of patients with NCM
(359,360); when seen in patients with increased intracranial pressure,
this finding likely represents diffuse leptomeningeal spread of tumor
(360). However, enhancement is almost never seen until the melanotic
deposits have undergone malignant degeneration and spread through-
out the subarachnoid spaces (360).
Cerebellar (primarily vermian) and brainstem hypoplasias
(Fig. 6-53) are typically seen when melanosis is present around the
cerebellum and pons, respectively (352,354). Over time, the melanotic
deposits in the leptomeninges may become cryptic to imaging detec-
tion (Fig. 6-53C); when imaged at this stage, patients may be mistak-
enly diagnosed as having idiopathic pontocerebellar hypoplasia, unless
this history of large cutaneous melanotic nevi in infancy is obtained. In
up to 10% of patients with NCM and cerebellar hypoplasia, the fourth
ventricle enlarges and a diagnosis of the Dandy-Walker malformation
can be made (335,361–363). Other findings that have been reported
include tethered spinal cord (338), spinal lipomas (usually subpial),
and arachnoid cysts (both intracranial and intraspinal) (337).
INCONTINENTIA PIGMENTI
Clinical Manifestations
Incontinentia pigmenti, or Bloch-Sulzberger syndrome, is a rare disor-
der characterized by congenital skin lesions, dental and skeletal dyspla-
sia, ocular abnormalities, and nonprogressive CNS involvement (364).
The name is derived from an apparent dislocation of melanin from
the basal cell layer of the epidermis to the upper dermis (365). The
disorder is almost exclusively seen in females, with mutations localized
to the IKK-gamma gene (also called NEMO) at chromosome Xq28.
FIG. 6-56. Incontinentia pigmenti in a 3-week-old baby. A. Axial noncontrast CT scan shows edema (arrows) in the left hemisphere, the posterior right
hemisphere, and in the left thalamus. B. Axial T2-weighted image shows multifocal hyperintense lesions corresponding to the regions of abnormal low
attenuation seen on the CT image (A).
Barkovich_Chap06.indd 617
Chapter 6 • The Phakomatoses 617
The mutation appears to be lethal in males; in the few reported male
cases, postzygotic mosaicism for the NEMO gene is evident (366).
The characteristic cutaneous lesions are linear vesicular or bullous
eruptions that begin in the first 6 months of life (367). Four stages of
cutaneous lesions are described: stage 1 is characterized by erythema,
vesicles, and pustules; stage 2 by papules, verrucous lesions, and hyper-
keratosis; stage 3 by hyperpigmentation; and stage 4 by pallor, atrophy,
and scarring (368). Ocular abnormalities are primarily retinal vascular
anomalies with consequent retinal fibrosis (369); microphthalmia may
be seen in conjunction with persistent hyperplastic primary vitreous.
The CNS is affected in 30% to 50% of affected patients, with resultant
epilepsy (about 25%), intellectual deficit (<10%), spastic or flaccid
quadriplegia, and ataxia (370,371). Symptoms may begin any time in
childhood, sometimes as early as the first week of life; neonatal enceph-
alopathy has been described (372,373). Affected patients become pro-
gressively microcephalic.
Pathological and Neuroimaging Manifestations
Few reports on the neuropathology of incontinentia pigmenti have
been published (374,375). The reports suggest the presence of zones
of neuronal loss accompanied by regions of minor cortical dysplasia
(374,375). Some authors suggest an inflammatory process, while oth-
ers have found no evidence of inflammation and suggest vasculopathy
as the cause (372,373).
Findings on neuroimaging studies are variable. Patients who are
neurologically normal usually have normal imaging studies (376,377).
Those with neurologic signs and symptoms have regions of hypoden-
sity (on CT) or T2 hyperintensity (on MRI) (Fig. 6-56) involving the
cerebral cortex and subjacent white matter, either bilaterally or in the
hemisphere contralateral to the clinical symptoms (364,376). T1 hyper-
intensity may be present in the affected cortex of young infants (Fig.
6-56) (372,378). Cerebellar lesions, when present, also involve the cortex
5/6/2011 9:04:40 PM
 618 Pediatric Neuroimaging
FIG. 6-56. (Continued) C. Axial noncontrast T1-weighted image shows multiple foci of hypointensity and hyperintensity, likely representing encepha-
lomalacia with gliosis, calcification, or subacute blood. D. Coronal gradient-echo T2-weighted image confirms the presence of multiple small hemorrhagic
foci revealed as foci of hypointense T2* signal (arrows).
and underlying white matter and have similar signal characteristics to
the cerebral lesions (364). The regions that are involved can correspond
to intervascular boundary zones (“watershed zones,” see Chapter 4),
suggesting a possible vascular cause for the lesions; other lesions are
not vascular in distribution, suggesting an inflammatory origin (376).
Affected neonates and young infants may also have foci of T1 hyperin-
tensity and T2 hypointensity in the periventricular white matter (Fig.
6-56), likely representing either hemorrhage or reactive astrogliosis;
focal regions of T2 hyperintensity are seen in the cortex. Sequential
scans in affected infants show progressive cortical and, more promi-
nently, white matter cavitation/atrophy, with an end result of asym-
metric ventricular enlargement and an appearance of diffuse white
matter atrophy (similar to end-stage white matter injury of prematu-
rity, Chapter 4) (372,378). Patients with abnormalities detected in the
cerebral hemispheres also have thinning of the corpus callosum (365),
presumably from damage to cortical neurons and the transcallosal
axons emanating from them. The ocular globes may show subretinal
hemorrhage, or abnormally high signal of the vitreous on T2-weighted
images (364). Later in infancy or childhood, microphthalmia may be
seen, resulting from retinal vascular abnormalities (372), possibly via a
similar mechanism that causes the brain injury.
HYPOMELANOSIS OF ITO
Clinical Manifestations
Hypomelanosis of Ito (formerly referred to as incontinentia pigmenti
achromians [379]) is a common, but poorly known, neurocutaneous
disorder. The pathogenesis of the disorder is unknown and is likely mul-
tifactorial. Autosomal dominant inheritance has been seen in some (but
not all) cases; frequency is equal among males and females (380). Karyo-
type analysis reveals a variety of chromosomal rearrangements, gener-
ally associated with mosaicisms. Therefore, most experts now believe that
hypomelanosis of Ito is not a distinct entity but is rather a symptom of
Barkovich_Chap06.indd 618
many different genetic disorders, and that the chromosomal abnormalities
disrupt expression or function of pigmentary genes (381,382).
The most characteristic clinical feature of hypomelanosis of Ito is
the presence of cutaneous hypopigmented zones with irregular borders,
streaks, whorls, and patches (383,384). Other skin alterations are seen
in up to 40% of affected patients and include café au lait spots, angiom-
atous nevi, nevus marmorata, nevus of Ota, Mongolian blue spot,
heterochromia of the iris or hair, diffuse alopecia, grayish-white trichor-
rhexia, and mottled hair (385). Musculoskeletal abnormalities include
hemihypertrophy, kyphosis, scoliosis, hyperlordosis, rudimentary ribs,
genu recurvatum, pes valgus, and pes cavus (384). Genital and cardiac
anomalies are found in 10% or less of affected patients (384,385).
Neurological Manifestations
Most clinical interest in hypomelanosis of Ito derives from the fre-
quency and importance of the neurological complications. These con-
sist primarily of seizures and intellectual disability, both of which are
present in more than half of affected patients (384,385). Seizures usu-
ally develop during the first year of life and consist of infantile spasms,
major motor seizures, partial motor seizures, and other forms of myo-
clonic epilepsy (384,385). While some patients suffer from generalized
seizures that are well controlled with anticonvulsant therapy, many
have severe, pharmacoresistant focal seizures (386). Developmental
delay is reported in 75% of affected patients and moderate to severe
cognitive deficits (IQ < 70) in 57%; only 20% of patients have an IQ
above 85 (385). Other reported neurologic manifestations include
macrocephaly, microcephaly, and hypotonia (385).
Neuropathological and Neuroimaging
Manifestations
Pathologic studies of hypomelanosis of Ito have shown malforma-
tions of cortical development, such as heterotopia and cerebral and
5/6/2011 9:04:41 PM

FIG. 6-57. Odontogenic keratocysts in BCNS. A. Coronal noncontrast CT scan in a 10-year-old child shows a large mass (arrowheads) arising from the left
maxillary alveolar ridge. An unerupted tooth (arrow) is evident superiorly. B. Coronal fast spin-echo T2-weighted image in a 7-year-old child shows a small,
heterogeneous mass (white arrows) in the anterior left maxillary ridge. The unerupted tooth (arrowhead) is evident superiorly.
cerebellar polymicrogyria (387,388). Imaging studies have shown evi-
dence of atrophy and hemiatrophy (384,389), white matter alterations
(prolonged T1 and T2 relaxation times) (384), hemimegalencephaly
(390) and more focal cortical malformations (384), lissencephaly (389),
callosal hypogenesis (389), and polymicrogyria with heterotopia (389)
(imaging characteristics of these malformations are discussed and
illustrated in Chapter 5). Focal/unilateral anomalies causing intrac-
table seizures are amenable to surgical resection (391). In addition, a
number of patients have normal neuroimaging studies or show only
enlarged perivascular spaces. Given the range of genetic, clinical, and
neuroradiological features, it seems best to think of hypomelanosis of
Ito not as a specific entity but as a clinical syndrome encompassing
multiple cutaneous and CNS disorders.
BASAL CELL NEVUS SYNDROME
Clinical Manifestations
The basal cell nevus syndrome (BCNS), also known as nevoid basal cell
carcinoma syndrome and as Gorlin syndrome, is an autosomal domi-
nant disorder characterized by five major components: numerous basal
cell cancers and epidermal cysts of the skin, odontogenic keratocysts
of the mandible and maxilla, palmar and plantar pits, calcification of
the falx cerebri, and skeletal anomalies (392,393). Macrocephaly, often
pronounced, is evident in 50% of cases (394). The cause is believed to
be a mutation of the PTCH gene that is located at chromosome 9q22.3
(395). Patients most commonly are initially seen due to development of
basal cell carcinomas, which may appear as early as age of 2 years (396).
Basal cell carcinomas more commonly proliferate during puberty, with
the nape of the neck being the most common location. An enormous
number of neoplasms and anomalies have been described in this syn-
drome (393,397). As this is a neuroradiology text, only manifestations
in the face, spine, and CNS are covered.
Neuroimaging Manifestations
The most common manifestations seen on neuroimaging are
odontogenic keratocysts and calcifications of the intracranial dura
Barkovich_Chap06.indd 619
Chapter 6 • The Phakomatoses 619
(Figs. 6-57 and 6-58). The keratocysts are typically multiple (average,
3–6; range, 1–30) and involve both the mandible and maxilla (398–
400). They appear after the seventh year of life, and are present in 80%
of affected patients over the age of 20 years (398). About half of patients
with BCNS present with swelling, 25% with mild pain, and 15% with
an unusual taste following keratocyst rupture, while 30% are asymp-
tomatic (398). The cysts tend to recur after surgery. Rarely, ameloblas-
toma or squamous cell carcinoma may arise from the keratocyst (393).
The radiologic appearance is that of a sharply marginated lesion that
seems to originate from the root of a tooth (Fig. 6-57). The cyst has the
signal of water (low attenuation on CT, hypointense on T1-weighted
MR images, and hyperintense on T2-weighted MR images). The over-
lying cortical bone is expanded and thinned.
Early calcification of the dura mater is a common radiologic
manifestation of the BCNS (393). The falx cerebri is the dural struc-
ture most commonly affected (in 65%–90%), with the diaphragma
sella (60%–80%), tentorium (20%–40%), and petroclinoid ligaments
(20%) all commonly involved in this process. This calcification can be
appreciated as increased attenuation and irregular thickening of these
structures on CT (Fig. 6-58B and C) and as hypointensity with irregu-
lar thickening on MRI. MRI demonstrates dysgenesis or agenesis of the
corpus callosum in approximately 10% of cases (399).
Developmental anomalies of the spinal column are common, with
kyphoscoliosis (25%–40%), cervical or thoracic spinal bifida occulta
(50%–60%), and a lack of segmentation of cervical or upper thoracic
vertebral bodies (30%–40%) being the most common manifestations
(393). Anomalies of the spinal cord have not been reported.
Patients with BCNS have an increased incidence of medullo-
blastoma (Fig. 6-59); the frequency of medulloblastoma in patients
with the syndrome is 4% to 20%, whereas the frequency of BCNS
among patients with medulloblastoma is 1% to 2% (401,402). Indeed,
medulloblastoma may be the cause of initial presentation of the BCNS.
BCNS patients with medulloblastoma characteristically present dur-
ing the first 2 years of life (397), in contrast to the usual presentation
between age of 5 and 9 years in the general population. Therefore, chil-
dren who are diagnosed with medulloblastoma before the age of 4 years
should be carefully examined for other signs of the BCNS; in this situation,
5/6/2011 9:04:42 PM
 620 Pediatric Neuroimaging

FIG. 6-58. BCNS and multiple radiation-induced tumors

in a teenager previously treated for a childhood medullo-
blastoma. A and B. Axial noncontrast CT scans at age 16
years show extensive calcification (black arrows) of the ten-
torium cerebelli and falx cerebri. An isodense meningioma
is evident (white arrows, B). Enlarged right sylvian fissure
(white arrow, A) results from volume loss secondary to ear-
lier resection of a meningioma. C–E. MRI study at age 19
years. Axial T2-weighted image (C) and contrast-enhanced
fat-suppressed T1-weighted image (D) show a new men-
ingioma (black arrows) arising from the left petrous apex,
with surrounding edema. A surgical defect is evident in the
right temporal lobe from prior meningioma resection. A
low T2 signal lesion (white arrows, C) is evident in the pos-
terior ethmoidal region, surrounded by T2 bright sinona-
sal secretions. Coronal fat-suppressed T2-weighted image
(E) through the nasal cavity demonstrates the mass (white
arrows), which fills the left nasal cavity and most of the eth-
moid air cells; it erodes the floor of the anterior cranial fossa
(white arrowhead). Biopsy revealed a rhabdomyosarcoma.

Barkovich_Chap06.indd 620 5/6/2011 9:04:42 PM


the presence of dural-based calcification, even small ones (Fig. 6-59B), is
highly indicative of the BCNS (403,404). At pathology, there is a prepon-
derance of two histological variants: medulloblastoma with extensive
nodularity, and desmoplastic medulloblastoma (405). The radiologic
appearance of medulloblastoma in this group of patients does not dif-
fer in any way from that of nonsyndromic patients (discussed in Chap-
ter 7). It should be noted that because of the abnormality of a tumor
suppressor gene, it is best to avoid radiation therapy for medulloblas-
toma treatment, as it can result in the subsequent appearance (over
a 10-year period) of a large number of tumors in the radiation field
(Fig. 6-58) (403,404,406). Basal cell carcinomas, which are the most
common secondary tumors, may be quite invasive and have a predilec-
tion for perineural spread. Therefore, contrast-enhanced MR scans should
be obtained and the cranial nerves should be particularly scrutinized in
a search for enhancement. Postradiation meningiomas, schwannomas,
sarcomas, and osteochondromas have also been reported (406).
Other tumors of the CNS are much less common. Meningiomas
(Fig. 6-58) appear to have an increased incidence (397), and astro-
cytomas, craniopharyngiomas, and oligodendrogliomas have been
reported in patients with the syndrome (393). These tumors all appear
to have a similar radiologic appearance and clinical behavior to those
occurring in the general population (see Chapter 7).
PHACE (POSTERIOR FOSSA
MALFORMATIONS, FACIAL
HEMANGIOMAS, ARTERIAL ANOMALIES,
CARDIAC ANOMALIES AND AORTIC
COARCTATION, EYE ANOMALIES)
SYNDROME
Clinical Manifestations
Both Pascual-Castroviejo and his colleagues and Frieden et al. have
reported that a high percentage of patients with cutaneous vascular
malformations of the head and neck have associated anomalies of
the intracranial structures, particularly blood vessels (407,408,409).
Both groups have proposed that this association of cutaneous and
intracranial pathology constitutes a phakomatosis. Although Pascual-
Castroviejo et al. (408) have proposed that it be called the cutaneous
hemangioma-vascular complex syndrome, Frieden et al. (409) have
suggested the term PHACES syndrome (Posterior fossa malformations,
Barkovich_Chap06.indd 621
Chapter 6 • The Phakomatoses 621
FIG. 6-59. Early diagnosis of BCNS in
a 3-year-old child. A. Axial T2-weighted
image shows a heterogeneous, low signal
intensity mass (white arrows) within the
posterior portion of the right cerebellar
hemisphere. B. Axial noncontrast CT
scan obtained preoperatively revealed
multiple small dural-based calcifications
such as this one (white arrow) in the falx
cerebri.
facial Hemangiomas, Arterial anomalies, Cardiac anomalies and aortic
coarctation, Eye anomalies, and Sternal clefting and/or Supraumbili-
cal raphe), and the latter name has become standard. Affected patients
typically present as a result of their cutaneous anomaly, typically
hemangiomas involving the face, neck, or scalp. As many as 20% of
patients with segmental hemangiomas (in distinction from localized
hemangiomas) meet diagnostic criteria for PHACE (OMIM 606519)
(410). Hemangiomas of the upper half of the face seem to correlate
with structural brain, cerebrovascular, and ocular anomalies, while
hemangiomas in a mandibular distribution are associated with ventral
developmental defects, such as sternal abnormalities and supraumbili-
cal raphe (410). The segmental relationships of these vascular abnor-
malities suggest a common metameric origin of cells originating in
the neural crest (411,412). Most affected patients are neurologically
normal but have some degree of intellectual disability (408). However,
among those patients with structural brain anomalies, neurodevelop-
mental abnormalities are found in 90% (413).
Many authors make the point that patients with this syndrome are
easily differentiated from those with the Sturge-Weber syndrome by
both differences in the cutaneous lesions and in the intracranial vascu-
lar anomalies. To summarize, patients with Sturge-Weber have a large
segmental facial hemangioma, most commonly involving the lateral
forehead (S2) or the maxillary region (S3) (414); about 20% of these
patients have anomalies of brain parenchyma or the blood vessels that
feed the brain (410). Intracranially, patients with Sturge-Weber have a
capillary/venous malformation that results in impaired cortical venous
drainage and progressive brain injury, whereas patients with the cuta-
neous hemangioma-vascular complex syndrome have persistence of
primitive arteries or absence/dysgenesis of normal major intracranial
arteries (408). As a result of these vascular anomalies, patients with the
PHACE syndrome are at a high risk for the development of cerebral
aneurysms.
The most common extracutaneous anomalies of these patients
involve the CNS, where structural abnormalities are present in 50% of
patients (414). Cerebellar anomalies appear to be the most common
structural brain anomaly seen in PHACE syndrome, most commonly
cerebellar hemispheric or vermian hypoplasias (410); true Dandy-
Walker malformations are much less common (414). Polymicrogyria
(415), cerebral hemispheric hypoplasia, periventricular nodular het-
erotopia, anomalies of the corpus callosum, anomalies of the septum
pellucidum, and intracranial hemangiomas are also described (416);
these are often ipsilateral to the facial hemangioma (414). When
5/6/2011 9:04:44 PM
 622 Pediatric Neuroimaging

present, the intracranial hemangioma is most commonly located in the
internal auditory meatus ipsilateral to the facial hemangioma; ipsilat-
eral cerebellar hemisphere hypoplasia may be present (416).
Cerebrovascular anomalies associated with PHACE are encoun-
tered in about 80% of cases and comprise a spectrum of congenital
and progressive large artery lesions. They can be classified into five
major groups: (a) hypoplasia or agenesis of major cerebral vessels,
(b) persistence of embryonic vessels, (c) progressive vascular stenosis
or occlusion, (d) segmental dolichoectasia of cerebral vessels, and (e)
anomalous vasculature (417,418). The most common arterial anoma-
lies (seen in up to 60% of affected patients) are saccular aneurysms,
aberrant origins or courses of the internal carotid and major intracere-
bral arteries, arterial dysplasias, and persistence of fetal anastomoses.
Agenesis of cerebral vessels, segmental stenoses, and occlusions of the
major intracranial vessels may also be detected (418–422). Hypoplasia
of the A1 segment of the anterior cerebral artery is common in the nor-
mal population (13%) but seems to be much higher in patients with
PHACE (414). Progressive occlusive vasculopathy, with a moyamoya-
like pattern, is also described (423). Several authors have suggested that
affected children have an increased incidence of cerebral infarction
(422). Cardiac or aortic anomalies are seen in about 35% of patients,
with aortic coarctation, patient ductus arteriosus, and ventricular sep-
tal defects being the most common (424). Ophthalmologic anomalies
are seen in about 20%, most commonly microphthalmos (ipsilateral
to the facial hemangioma), optic nerve hypoplasia/atrophy, iris vessel
hypertrophy, iris hypoplasia, and congenital cataracts. Reported ventral
defects include sternal clefting and supraumbilical raphe (410,413).
Otolaryngic abnormalities are also common, and include middle ear
atelactasis, tympanic membrane, and airway hemangiomas (425).
An association between combined venous lymphatic vascular mal-
formations (CVLVMs, formerly called lymphangiomas) of the orbit
and intracranial venous malformations has been reported (426). Katz
et al. (426) found that 28% (7/25) of patients with orbital CVLVMs
had venous malformations of the brain, most commonly involving the
cerebellum, brainstem, and deep cerebral nuclei. The authors found
that those patients with associated intracranial venous malformations
had diffuse orbital lesions with bony expansion of the orbit, extension
of the orbital malformation through the superior orbital fissure, both
superficial and deep components of orbital involvement, and, in the
majority of cases, both intraconal and extraconal involvement. These
venous malformations are not a part of the PHACES syndrome.
Neuroimaging Manifestations
The most common anomalies are vascular and include anomalous
course or origin of the anterior cerebral arteries; persistence of the
embryonic carotid-vertebrobasilar arterial connections (persistent
trigeminal artery is most common, Fig. 6-60); absence or hypoplasia

FIG. 6-60. PHACES syndrome in a 10-year-old girl. A. Axial

T2-weighted image shows a small right cerebellar hemisphere
(black arrowheads) and an anomalous vessel (black arrow) in the
prepontine cistern. B. Maximum intensity projection image from
a 3D time of flight angiogram shows that the anomalous vessel is a
persistent right trigeminal artery (arrowheads). C. Collapsed view
from a 3D time of flight MR angiogram shows a dysplastic right
middle cerebral artery (arrows) as well as the persistent trigeminal
artery.

Barkovich_Chap06.indd 622 5/6/2011 9:04:45 PM

 Chapter 6 • The Phakomatoses 623

FIG. 6-61. PHACES syndrome. A and B. Axial contrast-enhanced fat-suppressed T1-weighted image (A) and axial T2-weighted image (B) show a large
hemangioma (arrows) infiltrating the anterolateral aspect of the right orbit and the right middle cranial fossa. The signal void of the right carotid artery is
absent. The right trigeminal cistern (black arrowheads) is enlarged. An enhancing lesion is seen in the right cerebellopontine angle cistern (white arrowhead
in A), consistent with an intracranial hemangioma (not seen in B due to isointensity with the cistern). The right cerebellar hemisphere is small. The inter-
hemispheric fissure of the cerebellum (white arrowheads in B) is too prominent, indicating hypoplasia of the vermis.

of the internal carotid artery (Fig. 6-61); absence of the external
carotid artery and absence of hypoplasia of the vertebral, posterior
cerebral, and posterior inferior cerebellar arteries (418). Large, dys-
morphic vessels (dysgenesis) may also be seen (Fig. 6-60C) (418), as
can occlusive vasculopathies that may result in the moyamoya syn-
drome (423). These vascular anomalies are typically associated with
hemangiomas of the S1 (frontotemporal) and/or S3 (mandibular)
facial segments. The most common parenchymal malformations of
the PHACES syndrome are diffuse cerebellar hypoplasia (including
the Dandy-Walker malformation, see Chapter 5), vermian hypoplasia
(Fig. 6-61B), and unilateral cerebellar hemispheric hypoplasia (Figs.
6-60 and 6-61) (408). Several patients have been reported to have
polymicrogyria, periventricular nodular heterotopia, and intracranial
hemangiomas (427). Anomalies of the aortic arch and cardiac mal-
formations are also reported (408). The major importance of recog-
nizing the existence of this syndrome is to recognize that all patients
with hemangiomas of the face should have an intracranial study that
includes both an imaging study of the brain (with particular attention
to the posterior fossa) and a vascular imaging study that visualizes the
aortic arch and the cervical and intracranial portions of the carotid and
vertebral arteries all the way to, and including, the major branches of the
circle of Willis (418,428).
DIFFUSE NEONATAL HEMANGIOMATOSIS
Diffuse neonatal hemangiomatosis is a rare condition characterized
by the presence of numerous progressive, rapidly growing cutane-
ous hemangiomas associated with widespread visceral hemangiomas
of the liver, lungs, gastrointestinal tract, brain, and meninges that
become manifest at birth or during the neonatal period (429). The
cutaneous lesions vary from 5 to 15 mm in diameter; they range in
number from 50 to more than 100 (430). Other commonly involved
organ systems include the liver, CNS, intestine, and lungs; nearly
any organ can be involved (431). If untreated, up to 60% of affected
patients die in the first few months of life as a result of high out-
put cardiac failure (431). Treatment options include steroid therapy,
radiation, laser therapy, cyclophosphamide, and angiogenesis inhibi-
tors (430,432).
Neuroimaging studies of affected patients show multiple heman-
giomas and hemorrhages in the brain and spinal cord (429,433,434).
Hemorrhage is common because the hemangiomas are composed
of dilated, thin-walled channels lined by a single layer of endothelial
cells. When multiple cerebral hemorrhages are seen in a neonate with
multiple cutaneous hemangiomas and congestive heart failure, the
diagnosis of diffuse neonatal hemangiomatosis should be strongly
considered.
CHÉDIAK-HIGASHI SYNDROME
The Chédiak-Higashi syndrome is a rare, autosomal recessive syn-
drome characterized by hypopigmentation (partial oculocutaneous
albinism), photophobia, decreased lacrimation, nystagmus, recurrent
pyogenic infections, and intermittent febrile episodes. The diagnosis is
established by examination of the blood, which demonstrates the pres-
ence of characteristic large peroxidase-positive panleukocytic granules,
and by identification of mutations of the CHS1 gene. Affected patients
may come to attention because of recurrent infection, bleeding dis-
orders, or neurologic signs and symptoms (435). Alternatively, they

Barkovich_Chap06.indd 623 5/6/2011 9:04:46 PM

 624 Pediatric Neuroimaging
may present with the onset of an accelerated phase of the syndrome, in
which a lymphohistiocytic infiltration occurs; they may subsequently
develop erythrophagocytosis, hepatosplenomegaly, and lymphade-
nopathy (437). The neurologic signs and symptoms generally reflect
brainstem and cerebellar involvement and include motor incoordina-
tion, horizontal nystagmus, intention tremor, and dysmetria. Seizures,
peripheral neuropathies, and mental retardation may also be present
(435,436). Neuropathology shows perivascular cellular infiltrations
with scattered microscopic gliomas in the cerebellum, brainstem, spi-
nal cord, and peripheral nerves (438). Treatment is bone marrow trans-
plantation, which is effective in treating the hematologic and immune
deficits (439).
Reports of neuroimaging studies in Chédiak-Higashi syndrome
are few (440). In our case, the patient had delayed myelination, promi-
nent CSF spaces (probable cerebral atrophy), and nonenhancing focal
regions of T2 prolongation in the cerebellum and brainstem. Ballard et
al. (440) reported similar findings in the cerebral white matter that did
not significantly change over a 1 month follow-up period.
PROGRESSIVE FACIAL HEMIATROPHY
(PARRY-ROMBERG SYNDROME)
The Parry-Romberg syndrome is a rare, acquired disorder character-
ized by progressive and self-limited atrophy of the skin, subcutaneous
tissues, and sometimes the underlying bone. It may start and stop at any
time during the first 2 to 3 decades of life, resulting in variable degrees
of deformity (441). Neurologic symptoms are evident in about 15%
of cases (442). Affected patients often develop partial epilepsy during
the course of their disease (443); as this epilepsy is often refractory to
medication, neuroimaging studies are frequently requested.
Few reports of neuroimaging in Parry-Romberg syndrome are
available (443–446). Cortical calcifications may be seen on CT studies
(444,445). Most reports describe low density in the cerebral white mat-
ter and enlargement of the lateral ventricle ipsilateral to the facial atro-
phy (445). In addition, T1 hypointensity and T2/FLAIR hyperintensity
are present in the ipsilateral greater than contralateral cerebral white
matter, and small cysts may be seen in the deep gray matter and cor-
pus callosum (443,444,447). DTI fiber tractography has demonstrated
asymmetric involvement of white matter tracts (446). Interestingly, the
sulci of the overlying cerebral cortex are small (effaced), rather than
large, and the MR spectra in the affected hemisphere can be normal
(447), suggesting that this is not a purely atrophic process. Indeed, the
few pathologic studies suggest a perivascular infiltrate in the affected
regions (suggestive of Rasmussen encephalitis) and anti-DNA antibod-
ies are found in some patients, suggesting that this is an autoimmune
inflammatory disorder (442,449).
EPIDERMAL NEVUS SYNDROME
Clinical Manifestations
The term epidermal nevus syndrome (ENS) refers to sporadic over-
growth neurocutaneous disorders of unknown etiology characterized
by the combination of an epidermal nevus and a significant abnor-
mality of the CNS, eye, or skeleton (449). The recent literature utilizes
the term “epidermal nevus” to refer to slightly raised ovoid or linear
plaques that are usually skin-colored in infancy but become more ver-
rucous and darker as time passes; these hamartomatous lesions are
encountered in approximately 1 in 1,000 newborns (450). The term
encompasses a number of different histologic types of cutaneous
lesions (450,451). Other authors include the Proteus syndrome, Feuer-
stein-Mims syndrome, nevus comedonicus syndrome, pigmented hairy
Barkovich_Chap06.indd 624
ENS, linear sebaceous nevus syndrome, and congenital hemidysplasia
with ichthyosiform erythroderma and limb defects (CHILD syndrome)
within the large category of ENS, while others split them into separate
groups (453).
The true incidence of ENS is unknown, but it is estimated that
8% to 18% of patients with epidermal nevi have systemic disorders
(451). It is not clear whether the location of the nevus correlates with
development of the associated neurologic syndrome; some authors
have noted a high incidence of nevi on the head and neck in patients
with neurologic and ocular symptoms (454), but others dispute this
correlation (455,456).
Ocular and Brain Manifestations
Ocular involvement is present in 45% to 68% of affected patients
(455,456,457). Many different ocular anomalies have been described,
including optic disc colobomas, optic nerve dysplasia, retinal dyspla-
sia, choroidal osteomas, anterior segment dysgenesis, and peripapillary
staphyloma (457).
CNS manifestations are evident in a majority of patients
(Table 6-6); unilateral hemimegalencephaly is the most striking,
typically developing ipsilateral to the skin lesions. Baker et al. (458)
found a 7% incidence of hemiatrophy, a 7% incidence of hemimega-
lencephaly, a 3% incidence of isolated gyral malformations, and no
posterior fossa malformations. Gurecki et al. (456) found CNS lesions
by imaging in 20/23 (87%) who had biopsy-proven epidermal nevi.
Seizures were reported in 52%, intellectual impairment in 53%, and
motor impairment in 91%. Imaging findings included heterotopia,
callosal hypogenesis, cerebellar vermian hypogenesis, and focal corti-
cal malformations. Pavone et al. (454) gathered data on 63 patients
with ENS. They found a high incidence (27%) of hemimegalenceph-
aly in these patients. They also noted the presence of infarcts, atrophy,
porencephaly, and calcifications in 5 of 17 patients with hemimegal-
encephaly, suggesting that underlying vascular dysplasia predisposes
to these acquired lesions (454). Vascular dysplasias (ICA hypoplasia/
occlusion, cerebral and spinal arteriovenous malformations) and vas-
cular lesions (cerebral infarction, porencephaly) have frequently been
reported; these observations support the theory that a vascular dyspla-
sia is present in at least some patients with this disorder (456,459,460).
TABLE 6-6 Neuroimaging Findings
in ENS
Primary
Malformations of cortical development (hemimegalencephaly,
polymicrogyria)
Gliomatosis
Hemiatrophy with and without parenchymal cysts
Vascular malformations
Intracranial/intraspinal lipomas
Secondary
Porencephaly
Infarctions
Atrophy
5/6/2011 9:04:47 PM

FIG. 6-62. Hemimegalencephaly in the ENS. Axial T2-weighted image
of a 5-month-old baby shows relative enlargement of the right cerebral
hemisphere with thick cortex, anomalous sulcation (large arrowheads),
and abnormal hypointensity of periventricular and deep white matter
(arrows).
MR imaging of patients with ENS reveals developmental malforma-
tions (Fig. 6-62). Neonatal white matter injury (with normal appearing
cortex) has also been documented in ENS (Fig. 6-63), supporting the
theory of a vascular etiology of destructive lesions in some affected
patients. Intracranial and intraspinal lipomas have been reported, as
FIG. 6-63. Periventricular white matter injury in ENS. Axial T1-weighted
image shows multiple foci of T1 hyperintensity (open black arrows) in the
periventricular white matter.
Barkovich_Chap06.indd 625
Chapter 6 • The Phakomatoses 625
have abnormally enhancing and enlarged nerve roots in the spinal
canal (461,462).
ENCEPHALOCRANIOCUTANEOUS
LIPOMATOSIS
Clinical Manifestations
Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic over-
growth neurocutaneous syndrome characterized by the presence of
skin lesions and ocular and CNS anomalies; the etiology of the dis-
order is unknown. The two most common clinical markers of the
disorder are ocular choristomas (including epibulbar and limbal der-
moids) and the nevus psiloliporus (a smooth, hairless fatty tissue of
the scalp) (463). Other skin lesions encountered include nonscarring
alopecia, subcutaneous fatty masses, and aplastic scalp defects. Jaw
tumors, bone cysts, and aortic coarctation are rarely seen. About two
thirds of patients develop normally or have mild mental retardation;
about one third has severe mental retardation. Seizures are present in
about half of patients. ECCL has been considered a localized form of
Proteus syndrome. However, Proteus syndrome is a progressive disor-
der; signs and symptoms of ECCL in general are present at birth and
are nonprogressive, with the possible exception of skeletal cysts and
jaw tumors (463).
Neuroimaging Manifestations
Intracranial lipomas are encountered in the majority of the patients;
the cerebellopontine angle is commonly affected (464,465). Spinal
lipomas are found in most patients and can extend over long seg-
ments; spinal MRI is recommended when ECCL is suspected. Con-
genital abnormalities of the meninges are also commonly seen, in
particular arachnoid cysts (Fig. 6-64). Vascular dysplasias (leptom-
eningeal angiomatosis [Fig. 6-64] and abnormal or excessive vessels)
and ischemic lesions (atrophy, porencephaly, hemispheric calcifica-
tions) can also be seen (464,465). Therefore, the clinical and radio-
logic manifestations of ECCL and ENS overlap significantly; a main
differential criterion is the skin lesion, which is complex in the ENS
and includes different forms of epidermal nevi, which change over
time (463).
OTHER OVERGROWTH SYNDROMES
Proteus syndrome is a complex hamartomatous disorder named after
the Greek god Proteus, who could change his form at will. It has mul-
tiple, diverse somatic manifestations that evolve over time and involve
the skeletal system, soft tissues, skin, and vascular systems (466). Partial
gigantism of the hands and/or feet, asymmetry of limbs, macrodac-
tyly, bony exostoses, soft tissue tumors (hemangioma, lymphangioma,
lipoma), and long bone overgrowth are common. Hemimegalenceph-
aly, polymicrogyria, and heterotopia are the most commonly reported
congenital anomalies of the CNS; others include abnormalities of the
corpus callosum, Dandy-Walker malformation, and periventricular
calcifications (467,468).
Cowden syndrome is an autosomal dominant multisystem disor-
der involving hamartomatous overgrowth of tissues of all three embry-
onic origins––including the CNS––and an increased predisposition to
cancers of the breast, thyroid, and endometrium. Approximately 80%
of patients have an identifiable germline mutation of the PTEN gene
on chromosome 10 (288,469). Within the CNS, the pathognomonic
feature is the presence of Lhermitte-Duclos disease (dysplastic ganglio-
cytoma of the cerebellum, see Chapter 5), although other associations
5/6/2011 9:04:47 PM
 626 Pediatric Neuroimaging
include macrocephaly, gray matter heterotopia, seizures, vascular
abnormalities, and mental retardation (470,471).
Bannayan-Riley-Ruvalcaba (BRR) syndrome also results from
mutations in the PTEN gene. This autosomal dominant syndrome is
associated with extreme macrocephaly and subtle cutaneous features
(including lipomas and hemangiomata); motor delays are common.
BRR and Cowden syndrome likely represent age-related manifestations
of the same condition (472).
Barkovich_Chap06.indd 626
FIG. 6-64. ECCL in a 3-month-old baby. A. Coronal non-
contrast T1-weighted image shows mild thickening of the
right-sided subcutaneous fat (arrows). The ipsilateral cerebral
hemisphere is atrophic, with enlargement of the lateral ventricle
and subarachnoid spaces. B. Axial post contrast T1-weighted
image with fat suppression demonstrates abnormal thicken-
ing and enhancement of the meninges (white arrows) over the
right lateral convexity. C. Axial T2-weighted image at a lower
level reveals a cyst in the right middle cranial fossa, distorting
the right temporal pole (arrows).
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 CHAPTER
Intracranial, Orbital, and Neck
7 Masses of Childhood
CHARLES RAYBAUD AND A. JAMES BARKOVICH
Introduction
Incidence and severity of brain tumors in Children
Changing concepts of the biology of brain tumors
Clinical features of brain tumors
Techniques of imaging pediatric brain tumors
Imaging characteristics used to identify brain tumors
Posterior fossa tumors
Intraparenchymal tumors
Extraparenchymal tumors
Supratentorial tumors
Tumors of the cerebral hemispheres
Sellar and suprasellar tumors
INTRODUCTION
Incidence and Severity of Brain
Tumors in Children
Brain CNS tumors represent the second most common type of cancer
(17% of all childhood cancer) and are the second most common cause
of cancer deaths (25%) in children, being exceeded only by leukemia
(1–3). There are approximately 20,500 primary brain tumors diagnosed
in the United States each year, and of these, 3,750 (or 18.3%) occur in
patients less than 19 years of age (4). This corresponds to an incidence
rate of 4.5/100,000 per year in persons aged 18 years or younger. A similar
incidence of 4.2/100,000 per year was reported in Sweden (1984–2005)
before the age of 15 years (5). In most large series, supratentorial tumors
(including the third ventricular tumors) and infratentorial tumors
occur in nearly equal frequency (6–9). However, supratentorial tumors
are more common in the first 2 or 3 years of life, whereas infratento-
rial tumors predominate from age 4 to 10 years (7–16). Both locations
develop tumors with nearly equal frequency in children older than 10
years. Whereas metastases, glioblastoma multiforme (GBM), and men-
ingiomas represent most of the tumor types encountered in adults,
these are uncommon in children. On the contrary, embryonal/primitive
neuroectodermal/medulloblastoma and pilocytic astrocytomas are the
most common tumors before age 9 years, and gliomas grade I to III
between 10 and 19 years. In addition, a multiplicity of diverse, uncom-
mon tumor types occur in 36.5% (17) (Table 7-1) to 47% (18); this
diversity sometimes makes a precise diagnosis uncertain.
Overall survival (OS) of brain tumors in children is 70% at 10 years,
but this obviously includes benign tumors for which complete resec-
tion is possible (5). In fact, OS is very low for the diffuse intrinsic pon-
tine glioma (<10%–15% survival at 5 years, mean survival 11 months)
(19,20), higher in patient with medulloblastoma (53% at 10 years) (5),
and about 85% to 90% in children with low-grade gliomas, including
Barkovich_Chap07.indd 637
Pineal region masses
Extraparenchymal tumors
Brain tumors in the first year of life
Radiation-induced tumors of the central nervous system
Tumors of the head and neck in childhood
Ocular tumors
Extraocular orbital masses
Masses of the face and neck
those in which the tumor could not be resected. Of note, the OS rate
continues to decrease in children (but not in infants) beyond 5 and
even 10 years (5). In one report, the risk of untimely death is increased
13-fold in adult survivors of childhood CNS malignancies; among chil-
dren surviving more than 5 years, more than 25% will die within 30
years of their diagnosis (by definition, before reaching the age of 49
years) (21). The most common cause of death is recurrence or progres-
sion of the disease (61%); others include subsequent neoplasms (9%),
cardiac disease (3%), and pulmonary disease (3%) (21). The risk of
early death is highest in survivors of medulloblastoma/PNET. In addi-
tion, neurological, neurocognitive, and endocrinological functions are
commonly altered in childhood CNS tumor survivors who have been
subjected to surgery, heavy radiotherapy, and chemotherapy (21–25).
Changing Concepts of the Biology
of Brain Tumors
Traditionally, tumors have been considered to result from “de-
differentiation” of mature cells. In 1997, it was recognized in leukemia
that all tumoral cells formed a hierarchy apparently derived from a
primitive hematopoietic cell (26). In a similar way, it was recognized
that brain tumors reproduce a hierarchy of deviant neuroepithelial
cells that are unable to proliferate, while the tumor growth results
from the activity of a small component of stem cell–like tumoral
cells that have been called Brain Tumor Stem Cells (BTSC) (1,27).
During brain development, normal stem cells (NSC) proliferate in
the early neural tube, each one producing two daughter cells (sym-
metric division) and, thus, increasing the cellularity of the develop-
ing brain. During the development of the cerebral cortex (from week
7), each NSC produces one progenitor cell and one daughter NSC
that remains within the proliferative pool (asymmetric division). The
progenitor cells give rise to the radial glial cells (future astrocytes),
637
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 638 Pediatric Neuroimaging

neurons, oligodendrocytes, and ependymocytes. Neuronal produc-

TABLE 7-1 Percentages of Histological tion mostly stops about mid-gestation, and glial mass production
decreases after the first years of life. However, quiescent NSC (called
Types of Tumors involving type B cells) persist in the subventricular zone (SVZ, see the section
the CNS at Hospital for on “Malformations of Cortical Development” in Chapter 5 for fur-
Sick Children ther discussion of the ventricular zone and SVZ) in the region of the
lateral ventricle and are able to periodically generate multipotent
progenitor cells (called type C cells). C cells give rise to more mature
Astrocytoma 39.4
transient progenitor cells (called type A cells), which, in turn, pro-
Low grade (WHO I-II) 32.3 duce neurons that renew the granule cells of the dentate gyrus and
High grade (WHO III-IV) 7.1 the interneurons of the olfactory bulbs indefinitely (27). These per-
sisting NSC are also able to replace damaged glial cells (astrocytes,
Embryonal 15.4
oligodendrocytes) in the setting of diseases such as ischemic necrosis
Medulloblastoma 10.6 and demyelination.
PNET 3.9 Rather than a mass of dedifferentiated mature neural cells, a
brain tumor now is perceived as a deviant reproduction of the normal
ATRT 0.9
development (1,27,28). As mentioned above, it has been recognized
Ependymoma 7.0 that only a few stem cell–like tumoral cells (called BTSC, brain cancer
Classic (WHO II) 4.9 stem cells [CSC], or brain cancer propagating cells [CPC]) have the
growth and the invasiveness characteristics of a tumor. These BTSC
Anaplastic (WHO III) 1.7 have many characteristics of NSC: proliferation, self-renewal, and
Myxopapillary (WHO I) 0.3 multipotency. In the same way as transplanted NSC reproduce nor-
Oligodendroglioma (WHO II) 1.7 mal brain cellularity, transplanted BTSC reproduce a tumor with the
same characteristics as the original tumor. Just as the NSC give rise
Craniopharyngioma 6.8 to progenitors that migrate away from the SVZ, the BTSC give rise
Neuronal, neuronal-glial 6.8 to tumors cells that may proliferate at a distance from the site where
Ganglioglioma 4.7 they originate. BTSC have the same molecular markers as the NSC
(CD133+ mainly) and respond to the same signaling proteins (nota-
DNET 1.9 bly EGFR, Notch, BMP, Shh, Wnt) (1,27–29). The cell type that devel-
Neurocytoma 0.2 ops into BTSC has not been identified. It is likely to be a precursor cell
Choroid plexus tumors 2.3 from the ventricular or SVZ. As it is estimated that it requires 4 to 7
mutations before a normal somatic cell acquires a cancerous pheno-
Papilloma (WHO I) 1.3 type, the life of the transient dividing progenitors before they divide
Carcinoma (WHO III) 1.0 might be too short (12 hours) to be affected by these mutations; in
Pineal 0.5 contrast, the life of a NSC is long (28 days), which might make it a
more likely candidate (27). Other factors that might be important in
Germ cell tumors 3.1 brain tumor development include presence of multiple genetic muta-
Pituitary 1.0 tions (in neurofibromatosis type 1 [NF1], the combined mutation of
Mesodermal 9.7 the Nf1 gene on one hand, and the mutation of the p53 gene or the
loss of the CDKN2A locus on the other hand, increase the forma-
Non meningothelial 5.0 tion of astrocytomas [27]) or modification of its environment. The
Meningioma 1.7 local stromal microenvironment, especially the vascularity, may play
Langerhans cell histiocytosis 3.0 a significant role in the development of tumors (the “seed and soil”
concept [30]). Perhaps more important is the realization that NSC are
Radiculo-neural 3.1 genetically programmed to respond to the environment within spe-
Schwannoma 1.8 cific segments of the neural tube. The CSC that derive from those seg-
ments are also genetically programmed to remain there. This suggests
Neurofibroma 1.3
that tumors such as ependymomas or pilocytic astrocytomas located
Miscellaneous in different CNS segments (e.g., hindbrain and forebrain) may have
Subependymoma a fully identical histology while being, molecularly, entirely different
tumors, with different natural history, clinical response to treatment,
Ganglioneuroma
and prognosis (31–33). Clearly, a better understanding of these fac-
Hemangiopericytoma tors will have an enormous impact of diagnosis and treatment of
Hemangioblastoma tumors in the future.
Primary CNS lymphoma
Primary CNS melanoma Clinical Features of Brain Tumors
Nearly all pediatric brain neoplasms form masses, which infiltrate
ATRT, atypical teratoid-rhabdoid tumor; DNET, dysplastic neuroectodermal
tumor; PNET, primitive neuroectodermal tumor; WHO, World Health or compress the adjacent parenchyma and result in local functional
Organization tumor grade. impairment. By occupying space in the cranial cavity and eliciting
From (17). edema, the tumor causes increased intracranial pressure, which may be
exacerbated by hydrocephalus if the tumor develops close to the mid-

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 639

TABLE 7-2 Indications for Neuroimaging in Pediatric Headache

1. Persistent headaches of <6 mo duration that do not respond to medical treatment
2. Headache associated with abnormal neurologic findings
3. Persistent headaches without family history of migraine
4. Persistent headache associated with substantial episodes of confusion, disorientation, or emesis
5. Headaches that awaken a child repeatedly from sleep or occur immediately on awakening
6. Family or medical history of disorders that may predispose the child to central nervous system lesions and clinical or laboratory findings
suggestive of CNS involvement
From (34).

line and restricts CSF circulation. All these factors combine to stretch
axonal pathways, distort and herniate segments of brain, compress the
vascular bed, and produce neurological impairment. Therefore, the
cardinal clinical features of brain tumors are increased intracranial
pressure (with or without hydrocephalus or macrocrania), seizures,
neurological and/or endocrinological deficits, and cognitive impair-
ment. These may evolve over a long or a short period of time, depending
on the location and aggressivity of the tumor. As always in intracranial
hypertension, acute decompensation may occur at any time, even in
the case of a benign tumor.
The symptoms of children with CNS tumors depend upon the
age at the time of presentation. Infants present with increasing head
circumference, nausea, vomiting, and lethargy (8). Children often
have the same presenting symptoms and signs; in addition, they may
complain of headache or decreased visual acuity and develop partial
onset seizures or focal neurological signs such as cranial nerve palsies,
truncal and limb ataxia, and hemiparesis. Deterioration in school per-
formance is often noticed in older children. Tumors developing in the
region of the hypothalamus frequently produce endocrine dysfunc-
tion such as diabetes insipidus, growth arrest, hyperphagia or preco-
cious puberty. A rapid deterioration points to aggressive, typically
malignant tumor, while a slow progression may go unnoticed until
a major deficit becomes apparent. For example, in benign tumors
such as craniopharyngiomas, rapid loss of vision may lead to diagno-
sis after years of diminished growth were not noticed. Headaches in
themselves are not an indication for neuroimaging (34). Indications
for neuroimaging in pediatric patients with headaches have been pub-
lished (Table 7-2).
TECHNIQUES OF IMAGING PEDIATRIC
BRAIN TUMORS
Imaging is critical to the diagnosis of brain tumor, as no other diag-
nostic test demonstrates the lesion with as much reliability. Although
CT may be the imaging method most commonly used for the ini-
tial diagnosis of intracranial neoplasms, MRI is the study of choice
because of its sensitivity and because the multiplanar imaging capa-
bility is extremely useful in determining the exact extent of the tumor
and its relationship to surrounding normal structures. MRI can be
used in conjunction with computerized navigation techniques that
greatly facilitate tumor resection. MRI has a particular advantage in
the analysis of tumors of the posterior fossa, in which artifacts from
the surrounding bone hinder CT analysis. Moreover, MRI is more
sensitive than CT for the detection of tumor spread via the suba-
rachnoid spaces, which is particularly common in pediatric tumors
(35–37).
For MR evaluation, T1, T2, and FLAIR imaging are the basic
sequences, acquired in three planes, for example T1 sagittal, T2 coro-
nal, and FLAIR axial. Sagittal T1 should preferably be obtained using
3D-GE sequences (MPRAGE/TFE/SPGR) because of their high spatial
definition and excellent gray-white contrast, in addition to the ability
to reformat the data in any plane. FSE T2 and FLAIR also should use
3D volumetric acquisition or, if 2D acquisition is preferred, thin slices
(3–4 mm or less if possible) with minimal gap to better demonstrate
the relationship of the tumor to surrounding structures. Generally,
midline (suprasellar, third ventricular—including pineal—and fourth
ventricular) masses are best imaged in the sagittal, coronal, and axial
planes; for suprasellar masses, thin sections should be obtained to help
determine the precise relationship of the mass to the optic chiasm, optic
nerves, and hypothalamus. Brainstem tumors are best seen in sagittal
and axial planes. Cerebral and cerebellar hemispheric masses are best
imaged in the axial and coronal planes. High-definition submillimetric
T2 imaging (constructive interference in steady state [CISS], FIESTA)
is useful for studies of the cerebral aqueduct and extracerebral masses
such as schwannomas. Diffusion-weighted imaging (DWI) is now
used routinely and has proved to be extremely useful in distinguishing
hypercellular from hypocellular tumors. Susceptibility-weighted imag-
ing (SWI) is sensitive to the presence of blood and calcification. MR
proton spectroscopy is useful to evaluate the impairment of the neu-
ronal function (NAA, 2.0 ppm), membrane construction and destruc-
tion (Cho, 3.2 ppm), energy metabolism (Cr, 3.0 ppm), and the degree
of necrosis (Lac, 1.33 ppm; Lip, broad peak at 0.9 ppm).
Gadolinium compounds (paramagnetic contrast) are always used
to appreciate the degree of permeability of the blood–tumor barrier
and to improve the detection of CSF spread of tumor (“drop metas-
tases”). It is administered in a dose of 0.1 mg/kg body weight, given as
an intravenous bolus immediately prior to the postcontrast sequences.
It is best to always administer the contrast agent at the same time rela-
tive to scanning, as delays allow the contrast to diffuse farther in the
extracellular space, resulting in larger regions of enhancement and may
result in a false interpretation of change in tumor size based on extent
of enhancement. Either flow compensation techniques (peripheral or
cardiac gating, or gradient moment nulling) or very short echo times
(<10 milliseconds) should be used when the tumor is in the posterior
fossa, to reduce obscuration of vital areas by spatial misregistration of
the contrast-enhanced flowing blood in the transverse and sigmoid

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 640 Pediatric Neuroimaging

sinuses. When a tumor prone to disseminate in the CSF spaces is sus-
pected, postcontrast T1 imaging of the entire spinal cord and cauda
equina should be performed in the sagittal plane, complemented with
localized axial images when drop metastases are suspected. Fat sup-
pression techniques are valuable in differentiating enhancing tumor
from epidural fat on T1-weighted images (37). Finally, presurgical
sequences may include axial millimetric 3D-GE sequences compatible
with the neuronavigation tools, functional MR imaging (fMRI) to
locate the main regions for motor and cognitive functions, especially
the language areas; sensorimotor white matter fascicles can also be
determined by diffusion tensor imaging (DTI).
When a CT scan is performed, the most important images are pre-
contrast images. These allow a reliable assessment of tumor cellularity:
high attenuation indicating high cellularity and low attenuation indi-
cating low cellularity. It also shows presence of blood and calcification.
Multiplanar reformats are useful, but, even though modern CT scans
have a much better resolution and fewer artifacts than older ones, the
anatomical quality is still inferior to that of MRI. Iodinated contrast
media are usually administered, but this is not really crucial if MRI is to
be performed shortly afterwards. The recommended contrast dose in
these patients is 3 mg/kg of contrast (concentration 300 mg I2/mL) up
to a maximum dose of 120 mL, usually given in a single bolus imme-
diately prior to the scan.
IMAGING CHARACTERISTICS USED
TO IDENTIFY BRAIN TUMORS
Imaging analysis must proceed by steps. In successive order, one must
find the lesion and recognize that it is a mass, locate it precisely (as
location, together with appearance, helps in recognizing the tumor
type and is basic to the therapeutic strategy), describe its character-
istic features (including vascularity, vascular permeability, and meta-
bolic spectrum), identify it as a tumor, assess the margins to determine
how much it infiltrates the surrounding tissue, evaluate the mass effect
locally and globally, and prepare the surgical approach. Subsequent
imaging will be used to assess the effects of therapy.
Detecting a mass lesion is usually not a problem with modern
imaging, especially with MRI. Masses are typically recognized on CT
or MRI on the basis of either density or signal intensity differences
from normal brain, mass effect causing distortion of normal brain
structures, or the presence of abnormal enhancement after the intra-
venous administration of contrast. (In the normal central nervous sys-
tem [CNS], contrast enhancement is only seen in the pituitary gland,
pituitary stalk, tuber cinereum of the hypothalamus, pineal gland,
blood vessels, and the choroid plexuses.) Almost all brain tumors
are either hypodense or hyperdense compared to normal brain on
noncontrast CT images, hypointense to myelinated white matter on
T1-weighted MR images, and hyperintense to myelinated white mat-
ter on T2-weighted MR images. Hemorrhage, necrosis, calcifications,
and patterns and intensity of contrast enhancement may vary among
tumors of similar histologic class, and even more so among tumors
of different cell type, but they may also overlap; these characteristics
are discussed more thoroughly later in this chapter. All tumors exhibit
mass effect. In the case of relatively slowly growing, peripherally
located tumors, the mass effect results in expansion or erosion of the
cranial vault. In more rapidly growing, more centrally located tumors,
the effect is a displacement of structures. Displacement may result in
herniation of brain tissue through or around rigid structures, such as
the falx cerebri, tentorium cerebelli, or foramen magnum. Supratento-
rial masses typically cause herniation medially under the falx cerebri
or downward through the tentorial incisura, whereas infratentorial
masses cause upward transtentorial herniation and downward her-
niation through the foramen magnum. Transtentorial herniation clas-
sically results in pressure on the midbrain with secondary effects on
eye movement and pupillary constriction (the “blown pupil”). Tran-
stentorial herniation may also result in stretching and compression
of the posterior cerebral arteries against the tentorium, and conse-
quent unilateral or bilateral infarction of the posterior cerebral artery

FIG. 7-1. Extraparenchymal tumor characteristics. A. Axial noncontrast T1-weighted image shows a sharply defined mass (meningioma, black arrows) in
the posterior fossa on the left. The ipsilateral cerebellopontine angle cistern (white arrows) is enlarged compared to the contralateral cerebellopontine angle
cistern (white arrowheads). The dilated right temporal horn indicates the presence of hydrocephalus due to compression/distortion of the fourth ventricle
and aqueduct. B. Perfusion curve (line 4, relaxivity in the vertical axis, time in the horizontal axis) shows characteristics typical of an extraparenchymal
tumor. The signal intensity decreases as the contrast bolus enters the tumor vessels but does not recover because contrast leaks into the interstitium of the
tumor in the absence of a blood–brain barrier. Line 5 shows the perfusion curve of normal cerebellar parenchyma.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 641

FIG. 7-2. Intraparenchymal tumor characteristics. A. Axial postcontrast T1-weighted image shows a poorly defined mass (arrows) in the left frontal lobe.
Surrounding sulci are compressed. B. Perfusion curve (line 5) shows characteristics of a typical intraparenchymal glial tumor. Signal intensity decreases as the
bolus of contrast courses through the tumor vessels, and then recovers nearly to baseline as the contrast leaves the tumor. The area over the perfusion curve of
the tumor (line 5) is greater than that of normal white matter (line 4), indicating increased blood volume in the tumor and, probably, high tumor grade.

distribution. Herniation of the cerebellar tonsils through the foramen
magnum can occur both with supratentorial and infratentorial masses;
tonsillar herniation, which is easily detected by MRI, can lead to respi-
ratory compromise.
If a mass is identified, it must be determined whether the lesion
arises from brain parenchyma or from extraparenchymal struc-
tures, such as meninges or the subarachnoid space. Extraparenchymal
lesions typically displace, rather than invade, normal brain structures
(Fig. 7-1); the cortex is displaced medially (away from bone) by the mass,
and this may result in an enlarged cistern. Intraparenchymal masses
tend to compress cisterns and sulci. A well-defined margin separates
the extraparenchymal mass from the brain; usually, little or no edema
surrounds the mass. Intraparenchymal masses often merge impercepti-
bly into the normal tissue surrounding brain (Fig. 7-2) and may generate
considerable edema. Other characteristics that are suggestive of an extra-
parenchymal origin are a relative paucity of mass effect for the size of the
lesion, extension of the mass across the midline without involving a cere-
bral commissure, involvement of bone, and relatively mild presenting
symptoms. The reader should be aware, however, that the differentiation
of intraparenchymal and extraparenchymal masses is not always easy.
Intraparenchymal masses may be exophytic, thereby enlarging the adja-
cent cistern, whereas extraparenchymal masses may invade the brain
and elicit edema. Intraparenchymal masses may grow slowly and gener-
ate relatively little mass effect. However, the general rules outlined above
will allow determination of the location of tumor origin in most cases.
A useful adjunct for differentiating intraparenchymal from extraparen-
chymal tumors is dynamic susceptibility-weighted contrast-enhanced
perfusion imaging. The perfusion characteristics of intraparenchymal
and extraparenchymal tumors are different because of the absence of
the blood–brain barrier in extraparenchymal tumors. This can be best
appreciated by looking at the DR2* curve, which will show a return of
relaxivity toward baseline level after the passage of the bolus in an intra-
parenchymal tumor (Fig. 7-2B), but persistence of abnormal relaxivity
(due to rapid extravasation of contrast into the interstitial spaces of the
tumor) in an extraparenchymal tumor (Fig. 7-1B).
A good anatomical analysis is central to the diagnosis of brain
tumor for three main reasons: it defines the resectability (e.g., cerebel-
lar versus hypothalamic pilocytic astrocytoma), it allows the neuro-
surgeon to choose the better approach, it can be a major indicator of
the nature of a tumor (e.g., ventral diffuse intrinsic pontine glioma
versus dorsal tegmental pontine or medullary pilocytic astrocytoma).
T1, especially high-definition 3D-GE T1 imaging, thin (3.0 mm)
T2 and FLAIR in different planes, submillimetric T2 CISS-FIESTA if
needed, all combine in providing the optimal information regarding
the precise location of the tumor (Table 7-3).
The structural characteristics of the tumor include the cellularity;
the presence of cysts, necrosis, blood or calcification; and the vascular-
ity and vascular permeability (blood–tumor barrier). (Obviously, any
abnormality of signal, diffusivity, of MR spectrum, etc., should be analyzed
only after consideration of the age and degree of maturation of the child;
serious mistakes can otherwise be made.) These characteristics alone often
permit the identification of the tumor type; even if they don’t, they ori-
ent toward its benign or malignant nature. Although CT cannot replace
MRI in this regard, it may be helpful. Low attenuation indicates high
water content/low cellularity (e.g., low grade glioma, tumor edema,
or necrosis); high attenuation close to that of gray matter suggests
high cellularity (e.g., medulloblastoma/PNET, germinoma); and avid
enhancement suggests high vascular permeability. Cystic components,
hemorrhage, and calcification are easily recognized and can help to
specify a diagnosis in some locations. However, MRI is more specific.
Reduced water diffusivity on diffusion imaging studies indicates the
high cellularity and high nuclear-cytoplasmic ratio (“little blue cells”)
found in embryonal tumors (medulloblastoma, PNET, pineoblastoma,
ependymoblastoma, retinoblastoma, and often atypical teratoid/rhab-
doid tumors [ATRT]) and germinomas rather than a less cellular (typi-
cally more benign) tumor type. Uncommonly, reduced diffusion may
result from recent tissue infarction (38). Other times, an area of reduced
diffusivity (38) or increased fractional anisotropy (FA) (39) in a low-
grade (high-diffusivity) tumor, such as a WHO grade II astrocytoma,
results from a focus of malignant transformation. Tumoral cysts always

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 642 Pediatric Neuroimaging

TABLE 7-3 Main Tumor Types per Location

Compartment Segment Nature Development Specificities
Posterior fossa
Brainstem Cervicomedullary PA Intrinsic/exophytic Cystic/solid
Ventral pons DIPG BA encased ↑ myo-inositol
Dorsal pons PA Dorsal/exophytic Often cystic
Middle peduncle PA Well demarcated Often cystic
Midbrain PA Intrinsic ↓ Aqueduct
4th ventricle Roof, vermian MB Ventral/ventricular Reduced diffusion
Floor, medullary Ependymoma Exophytic cisternal CM or CPA
Cerebellum Any PA Intrinsic Cystic/solid
3rd ventricle
Anterior Optic pathways PA NF1, intrinsic Solid mostly
Hypothalamus PA Infiltrative Solid mostly
Hypothalamus Cranio Postchiasmatic Solid/cystic/Ca++
Sellar/suprasellar Cranio Prechiamatic Solid/cystic/Ca++
Sella/hypothalamus GCT Regional Reduced diffusion
Sellar/suprasellar Adenoma Prechiasmatic Solid
Posterior Pineal PB Cisternal Reduced diffusion
Posterior V3 GCT Ventricular Reduced diffusion
Pineal PA Cisternal Solid/cystic
Lateral ventricles Tela choroidea CPP Choroid plexus ↑ myo-inositol
Monro CPC Invasive ++ ↑ Cho, ↓ Cr/PCr
SEGA TSC Solid, Ca++
Hemispheres
Central gray Any Gliomas BG + thalamus Any grade
White matter Any Gliomas Transcerebral Any grade
Any Ependymoma Not ventricular Solid/cystic/Ca++
Cortex Temporal GGG GM and WM Solid/cystic
Any DNET GM and WM Segment-like
Any PXA Brain and meninges Solid/cystic

BG, basal ganglia; Cranio, craniopharyngioma; CM, cisterna magna; CPA, cerebello-pontine angle; CPC, choroid plexus carcinoma; CPP, choroid plexus papil-
loma; DIPG, diffuse infiltrating pontine glioma; DNET, dysembryoplastic neuroepithelial tumor; GCT, germ cell tumors; GGG, ganglioglioma; GM, gray matter;
MB, medulloblastoma;. PA, pilocytic astrocytoma; PB, pineoblastoma; PXA, pleomorphic xanthoastrocytoma; SEGA, subependymal giant cell astrocytoma; TSC,
tuberous sclerosis complex; WM, white matter.

differ in signal intensity from CSF of arachnoid cysts or loculations;
contrast layering may be observed after intravenous contrast admin-
istration. Necrosis appears as rather heterogeneous loculations, typi-
cally showing nonenhancing, low T1, bright T2/FLAIR signal; it usually
reflects malignancy although it may be observed in large nonmalignant
tumors or in radiation injury (see Chapter 3). Vasogenic edema is well
depicted in the surrounding white matter but difficult to differentiate
from infiltrative tumors using T2, FLAIR, or even DWI (38). Recent
blood or blood residue are easily recognized with SWI. Invasion and
destruction of the white matter tracts is best differentiated from dis-
placement by use of FA maps or DTI tractography (38) but, in the set-
ting of severe vasogenic edema, anisotropy of the water diffusion can be
reduced and the tracts may not be identified.
The administration of contrast media allows assessment of the
integrity of the blood–brain barrier and, if perfusion imaging is used,
can determine blood flow, mean transit time (TT), blood volume,
and permeability of the tumoral blood vessels. Enhancement of the
lesion characteristically results from a combination of high vascularity
and of egress of contrast across the walls of abnormal vessels into the
interstitium of the tumor. This enhancement may be diffuse, patchy,
or ring-like; it may be intense or weak. A tumor with a same histology
may enhance differently in different patients, and in the same patient
on different studies. It is important to remember that, unlike in adults,
enhancement of a brain tumor in children is not evidence of malignancy;
indeed, some of the most benign tumors (such as pilocytic astrocy-
tomas) enhance the most. Although not commonly used in a clini-
cal setting, perfusion studies, especially dynamic contrast-enhanced
MRI can provide a relative quantification of the perfusion parame-
ters (cerebral blood volume [CBV], TT, cerebral blood flow [CBF]),
and from these inform about the tumor type and grade (Figs. 7-1 to
7-4) (38,40); it may also help in ruling out nonneoplastic tumor-like
lesions (38). Given the role of angiogenesis in tumor development,

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 643

TABLE 7-4 Main MRS Markers of Brain Tumors

Compound Location (ppm) Metabolic Marker of… Change in Tumors
NAA 2.0 Neuronal activity mostly ↓ (all)
Cr/PCr 3.0 Energy cascade =/↓ (PA)
Cho 3.2 Cellular membranes, density, turnover ↑ (all)
Lac 1.33 Necrosis, malignancy ↑ (PA, malignant)
Lip (short TE) 0.9/1.3 Necrosis ↑ (malignant)
mI (short TE) 3.6 Cellularity, astrocytes ↑↑ (CPP)
Tau (short TE) 3.36 Cerebellar development ↑ (MB)
Cho, choline; CPP, choroid plexus papilloma; Cr/PCr, creatine/phosphocreatine; Lac, lactate; Lip, lipid; MB,
medulloblastoma/PNET; mI, myo-inositol; NAA, N-acetylaspartate; PA, pilocytic astrocytoma; Tau, taurine.

and the fact that new therapeutic agents target the vascular prolifera-
tion, it may also provide an indicator of treatment efficacy (41,42).
Most reported studies, however, concern gliomas only (41), and adult
rather than pediatric brain tumors (38,43). Indeed, the pilocytic
astrocytomas, very common in children, are highly vascularized and
yet very benign. Permeability measures of the capillary bed may help
to reveal the most malignant part of a tumor and direct the surgeon
or the irradiation, but those studies are complex and still at a develop-
mental stage (38,43).
Proton MR spectroscopy has proved to be a useful marker of
the tumor types and of their aggressiveness in children (Table 7-4).
Several studies have demonstrated that most tumors have decreased
NAA (neuronal/oligodendrocytic marker), stable creatine except in
energy failure (tumor necrosis), and increased choline (membrane
turnover, cellularity) is increased. Choline, lactate, and lipid are com-
monly increased in malignant tumors (44–48). In addition, specific
tumors may have specific patterns on MR spectroscopy, such as high
taurine and creatine in medulloblastomas, high lactate in pilocytic
astrocytomas, and high myo-inositol in choroid plexus papillomas
(46). Malignant degeneration is signaled by increasing choline, while
effective therapy usually results in decrease of all peaks except lactate
(which increases). Recurrent tumor is signified by increasing choline
(Figs. 7-3 and 7-4) (46).
The differential diagnosis of a brain mass is broad, as any lesion
with abnormal signal or attenuation and some mass effect may be a
tumor. Dysplastic masses, such as gray matter heterotopia or focal
cortical dysplasia, are not a problem anymore with modern imag-
ing (reviewed in Chapter 5); they have characteristic locations, lit-
tle mass effect, low blood volume, do not elicit edema, and do not
enhance. Although not truly neoplastic, dysembryoplastic lesions
such as a dermoid or epidermoid cyst are included among tumors
and are described in this chapter, as well as other developmental cysts
such as the sellar/suprasellar Rathke cleft cyst or the posterior fossa
dermal cyst. High-definition MRI demonstrates that many cases of
aqueductal stenosis actually are due to benign tumors of the mid-
brain tegmentum or tectum; their diagnosis are discussed later in this
chapter.
Some lesions, however, are difficult to differentiate from tumor.
Abscesses typically develop in a context of infection (see dedicated
section in Chapter 11). Although they may appear morphologically
similar to malignant necrotic tumors, the enhancing rim typically is
thin and regular, and the central cavity demonstrates strongly restricted
diffusion (49) (Fig. 7-5). In contrast, the cystic/necrotic components
of most tumors generally (but not always!) show increased diffusion
due to cellular necrosis and increasing size of the intercellular space
(49). The reduction of water motion may be less apparent with small
abscesses, possibly secondary to averaging of diffusion information
from normal surrounding brain tissue (50). Proton MR spectroscopy
can also be a useful adjunct in differentiating tumor from abscess,
as the elevated choline peak that is characteristic of most tumors is
not present in abscess. Aliphatic peaks of amino acid peaks (alanine
[at 1.5 ppm], acetate [at 1.9 ppm], succinate [at 2.4 ppm], and leu-
cine, isoleucine, and valine [at 0.9 ppm] [51,52]) are seen instead (see
Chapter 11). A lactate peak is also seen in most pyogenic abscesses (53),
but lactate is commonly seen in tumors as well and therefore is not
helpful in making this differentiation. The peaks of alanine, lactate,
leucine, isoleucine, and valine can be confirmed by the fact that they
are inverted on point-resolved spectroscopy sequences using an echo
time of 135 to 144 milliseconds (51). Other types of infections, such as
cerebritis, are more difficult to differentiate from tumor, as they have
variable anatomic, metabolic, diffusion, and perfusion characteristics
that reflect the type and acuity of the infection (44,54). Infections are
further discussed in Chapter 11.
Large mass-like, isolated inflammatory lesions may be seen in acute
episodes of demyelination such as acute disseminated encephalomy-
elitis or multiple sclerosis (both discussed in Chapter 3). The clinical
context, a careful search for other associated lesions in the brain and
spinal cord, MR spectroscopy or advanced imaging such as DTI may
help. If not, the evolution and the response to anti-inflammatory treat-
ment give the final answer. Demyelinating plaques are hypodense on
CT images, hypointense on T1, and hyperintense on T2/FLAIR images.
They are often large and, in the subacute phase, manifest peripheral
enhancement. They are most easily differentiated from tumors by
their relative lack of mass effect, their incomplete rim of enhancement
(see Fig. 3-42 and discussion in Chapter 3), and by the presence of
deep medullary veins running radially through them, undistorted
(Fig. 7-6); typically, they will contact the superolateral wall of the lat-
eral ventricle but displace it minimally or not at all. Long echo MR
spectroscopy is not useful in this differentiation, as some demyeli-
nating plaques masses may have a large choline peak (Fig. 7-6), and
increased lactate and lipid due to the inflammatory infiltrates that
accompany them in the acute phase (55,56). Short echo proton spec-

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 644 Pediatric Neuroimaging

FIG. 7-3. Low grade intraparenchymal glial tumor. A. Axial postcontrast

T1-weighted image shows a homogeneous, sharply marginated, nonenhanc-
ing mass (T) deep in the left cerebral hemisphere. B. Proton MR spectra (TE
= 288 milliseconds) in a two dimensional array show that the spectra within
the mass have low NAA and creatine but only slightly elevated choline com-
pared to surrounding voxels containing normal brain. C. Perfusion curves
(relaxivity in the vertical axis, time in the horizontal axis) show similar blood
volume (which is proportional to the loss of signal intensity and decrease in
MR units) in the tumor (T, line 5) and normal brain tissue (N, line 6) in a
similarly located voxel in the contralateral hemisphere. This is characteristic
of most low-grade glial tumors (other than pilocytic astrocytomas).

troscopy may show increased glutamate and glutamine in demyelinat-
ing plaques (57). Dynamic susceptibility-weighted imaging may allow
differentiation of these lesions, as demyelinating lesions have low CBV
and are characterized by radially oriented linear streaks of increased
blood volume coursing through the lesion, representing blood in and
around the deep medullary veins (58). It has been reported that DTI
might help in this differentiation, as corticospinal axons in patients
with tumefactive plaque are few and truncated but in normal posi-
tion, while those in patients with tumors show dislocation and/or
dispersion (59).
Infarctions are most easily distinguished from tumors by clini-
cal presentation; neurologic deficits are characterized in infarcts by
an abrupt onset and in tumors by a slowly progressive or stuttering
course. In young infants, however, and in older children with infarcts
that occur in regions that do not cause obvious clinical deficits, the
history is less useful. On imaging, infarcts are distinguished by their
location (in a vascular distribution) and involvement of both gray
and white matter; tumors and infections typically originate in white
matter or at the gray-white junction. However, some tumors are pri-
marily cortical and may have an imaging appearance that is suggestive

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 645

FIG. 7-4. Comparison of high-grade intraparenchymal glial tumor (A–C) and pilocytic astrocytoma (D–F). A. Axial postcontrast T1-weighted image
shows a right parietal mass with a central enhancing component (T). B. Proton MR spectrum (TE = 288 milliseconds) shows low NAA, low creatine, but
very high choline in the tumor compared to surrounding normal voxels. Note that the abnormal spectra extend far beyond the enhancing portion of the
mass. C. Perfusion curves (relaxivity in the vertical axis, time in the horizontal axis) show markedly increased blood volume (resulting in decreased signal
and decreased MR units) in the tumor (T, line 2) compared to normal brain tissue (N, line 1) in a similarly located voxel in the contralateral hemisphere.
This is characteristic of high-grade glial neoplasms. D. Axial postcontrast T1-weighted image shows a markedly enhancing mass (white arrows) deep within
the right cerebral hemisphere.

Barkovich_Chap07.indd 645 5/6/2011 9:15:32 PM

 646 Pediatric Neuroimaging

FIG. 7-4. (Continued) E. Single voxel proton MR spectrum (TE = 288 milliseconds) from the center of a different pilocytic astrocytoma shows low NAA
and creatine (Cr), but very high choline (Ch) peak. In addition, lactate (L) is present at 1.33 ppm. These MRS finding are identical to those seen in high-
grade gliomas and emphasize the importance of correlating MRS findings with imaging characteristics that, in pediatric tumors, appear to be more specific.
F. Perfusion curves show substantially increased blood volume in the tumor (T, line 3) compared to contralateral normal brain tissue (N, line 2). Thus,
low-grade pilocytic astrocytomas have blood volume characteristics similar to those of high-grade tumors. Such studies should never be interpreted without
imaging correlation.

of acute infarction. DWI is the most useful technique if the infarct
is recent (<8–10 days) by showing significantly reduced diffusion in
an arterial territory, an unusual appearance for tumors, even those
characterized by low diffusivity (medulloblastoma, PNET, pineoblas-
toma, retinoblastoma, ependymoblastoma or germinoma). If differ-
entiation is difficult, a follow-up study should be obtained before a
biopsy. In an infarction, diffusivity will increase after 8 to 10 days
(less in infants, see Chapter 4), and enhancement will appear; mass
effect will progressively diminish afterward. Susceptibility-weighted
perfusion imaging can also be of use in differentiating tumor from
infarct, as tumors are typically hypervascular, while acute infarcts
are hypovascular (54). On MRS, lactate is high in infarcts during the
acute/subacute phase, and the choline peak, characteristic of most
tumors, is absent.
Vascular malformations such as a cavernoma are usually not a diag-
nostic problem due to the characteristic “blooming” appearance on SWI
(refer to Chapter 12). However, the diagnosis of the cause of an appar-
ently isolated spontaneous hemorrhage in a child may be difficult. If no

FIG. 7-5. Use of DWI to separate tumor from abscess. A. Axial FLAIR image demonstrates right frontal heterogeneous cortical-subcortical hyperintensity
(arrows) in a child presenting with seizures. Tumor is a strong possibility. B. Trace image from DWI demonstrates a sharply marginated focus of very high
signal (white arrows) in the medial aspect of the lesion, suggestive of a pus collection; the surrounding white matter shows low signal suggestive of interstitial
edema. C. T1-weighted image postcontrast shows ring enhancement of the nodule; the enhancement extends anteriorly along the falx (arrows) to the vicin-
ity of the foramen cecum. Findings suspicious for nasal dermal tract were also observed; surgery confirmed both the dermal fistula and the abscess.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 647

FIG. 7-6. Imaging characteristics that help to differentiate demyelinating plaques from neoplasia. A. Axial T2-weighted image shows linear venous
structures coursing undistorted through the mass. The presence of undistorted veins running through a mass strongly suggests demyelination, which
occurs in a perivenular location. B. Postcontrast axial T1-weighted image shows enhancement only in the anterior wall (white arrows) of the mass.
Enhancing veins (black arrowheads) are seen coursing through the lesion. C. Gradient echo, echo planar perfusion image shows susceptibility effects
from increased blood volume (hypointensity, arrowheads) in linear bands running through the lesion that correspond to the veins seen in A and B. This
finding is characteristic of demyelinating plaques. D. Proton MR spectrum (TE = 144 milliseconds) shows a large choline peak (Ch) and a lactate peak
(Lac, inverted at TE = 144 milliseconds), but no visible creatine or NAA peak. This spectrum is identical to that of a high-grade tumor and is not a useful
test for differentiation.

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 648 Pediatric Neuroimaging

arteriovenous malformation is demonstrated, and if the characteristic
appearance of a cavernoma is obscured by the abundance of fresh
blood, a hemorrhagic tumor, typically a highly malignant one cannot
be easily proved or disproved. Perfusion and spectroscopy are rendered
useless by the presence of blood. Careful examination of the adjacent
parenchyma and even a faint enhancement may reveal the tumoral ori-
gin of the hemorrhage. If not, follow-up imaging after resolution of the
blood may be necessary.
Finally, although uncommon, radionecrosis may be a real chal-
lenge in the follow-up of brain tumors; perfusion imaging may help
in demonstrating that the blood volume is reduced in the radiation
necrosis, while it is typically normal or increased in a tumor (see the
more detailed discussion in Chapter 3).
Pretherapeutic assessment is the next step, and it is the role of imag-
ing to provide all the elements of the therapeutic discussion. Therapeu-
tic options are surgical removal (as complete as possible), radiotherapy
(except in the first 3 years of life), chemotherapy, or a combination.
Typically, children with brain tumors are part of a therapeutic protocol
that has specific imaging requirements prior to treatment, during and
after completion of treatment. The first feature to look for is whether
the tumor is well demarcated from the surrounding structures. This
is the main condition of complete resectability: a poorly demarcated
tumor may be infiltrative or invasive and will not be completely resect-
able. Infiltration does not necessarily relate to the tumor grade. For
example, anterior optic pathway gliomas, although classified as grade I,
may infiltrate the hypothalamus or the basal ganglia, whereas a dorsal
medullary anaplastic ependymoma may not infiltrate any surround-
ing structure other than its site of origin at the obex. Infiltration is not
always apparent by morphologic imaging alone; additional techniques
such as perfusion imaging, MR spectroscopy, or DTI may be needed
to differentiate peritumoral edema from infiltration. In addition, the
new understanding of the biology of the brain tumors suggests that the
original BTSC, which is responsible for the growth of the tumor, may
be located in the SVZ, while the bulk of the tumor is composed only
of daughter cells that have migrated from their site of origin and are
unable to proliferate (see discussion on the brain tumor biology above).
Therefore, infiltration may be considered a mode of tumor expansion
that is independent from grade. In contrast, invasion is a property of
malignant cells; it is the ability of cancer cells to break through normal
anatomic barriers. For example, a pilocytic astrocytoma of the pineal
gland will compress but not invade the adjacent callosal splenium, but
a pineoblastoma will invade it easily. Any invasive tumor is biologically
malignant. The invasion may be local, in the surrounding structures, or
distant; brain tumor cells can migrate along axons or blood vessels and
travel to distant parts of the brain where reproduction and invasion or
infiltration can begin again. In addition, if brain tumors gain access to
the CSF pathways (medulloblastoma or germinomas mostly, but also
pilomyxoid astrocytomas [PMAs], ependymomas, and many other
histologies), they can disseminate throughout the neuroaxis. Assess-
ment for CSF spread of tumor should be a part of every pretherapeutic
assessment.
If the decision is made to remove the tumor, presurgical assess-
ment typically entails the acquisition of sequences that are compat-
ible with neuronavigation surgical tools (typically axial, enhanced
3D-GE volumetric T1 sequence such as MPRAGE/SPGR/TFE). The
so-called eloquent cortices, such as the sensory-motor area, and major
neurocognitive functions such as the language or the memory, may
be located using DTI, fMRI, and the appropriate paradigm (Fig. 7-7A
and B) (60). Along the same line, “eloquent” white matter tracts such
as the corticospinal tract or the optic radiations (especially the Meyer
loop along the medial temporal lobe) may be identified with DTI (Fig.
7-7A and C) (61). DTI may also show whether the fibers are simply
dislocated by the tumor, or infiltrated and even disrupted (Fig. 7-7C)
(62–65).
In general, arteriography is not used for the evaluation of neo-
plasms unless a highly vascular lesion is suspected based on vascular
flow voids seen on MRI or in the unlikely situation that a vascular mal-
formation cannot be ruled out by noninvasive studies. For example,

FIG. 7-7. Presurgical functional assessment A. Anatomic imaging (FLAIR) shows large solid and cystic left frontal lobe tumor (arrows) in a child with
refractory epilepsy. The appearance of the tumor is consistent with a pilocytic astrocytoma or a ganglioglioma, of which both can be surgically removed.
However, the proximity to the tumor of the language area (Broca) in this left hemisphere makes the procedure perilous. B. Using a specific paradigm (verb
generation and letter fluency), fMRI showed a strong activation of the ipsilateral Broca area (large black arrow), as well as on the contralateral operculum.
The visual cortex (small black arrows) and surrounding association areas also were activated. C. DTI with color-coded (by convention: red transverse, blue
craniocaudal, green ventrodorsal) FA map shows that the main fiber tracts adjacent to the tumor are displaced rather than infiltrated.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
in suspected hemangioblastomas, arteriograms are often obtained to
identify the location of the vascular pedicle supplying the mass, thus
potentially reducing blood loss at the time of surgery. Arteriography
may also be useful if noninvasive studies cannot clearly differentiate a
dural-based lesion from a parenchymal lesion, a situation that usually
arises in very large tumors. However, because large tumors sometimes
parasitize blood flow, arteriography can be misleading, demonstrating
dural vessels supplying intra-axial lesions or intracerebral vessels feed-
ing extra-axial tumors.
Follow-up neuroimaging is essential to evaluate the efficacy of
the treatment. Typically, an MRI is requested shortly after surgery to
appreciate the extent or the resection, the volume of residual tumor,
and any brain injury that might enhance and resemble recurrent
tumor on the subsequent follow-up study (66). It also detects eventual
postsurgical complications such as a significant ischemia or hemor-
rhage in the surgical field, and the ventricular size. Later studies are
usually scheduled according to therapeutic protocols that take into
account tumor histology as well as the chemotherapeutic and radia-
tion protocols. The MR assessment typically uses conventional imag-
ing. It should be noted that enhancement of the meninges and surgical
cavity is almost always seen on contrast-enhanced postoperative MR
studies. Enhancement along the surgical cavity reflects damage to the
blood–brain barrier and typically slowly resolves over 3 to 4 months; it
often correlates well with regions of reduced diffusion detected on the
immediate postoperative MRI (66). Dural enhancement can be thin or
thick but is usually smooth. It is present over the cerebral convexities
and along the tentorium and may persist for 20 years or more (67,68).
Nodular meningeal enhancement is more ominous and enhancement
of the pia or arachnoid should raise suspicion for subarachnoid tumor
spread. Besides the diagnosis of persistence, recurrence, or dissemina-
tion, MR imaging and spectroscopy can also detect unwanted effects
of the therapy such as a radiation necrosis (54,69,70), atrophy, and
the development of vascular malformations such as telangiectasias
and cavernomas, of vasculitis, and of late secondary induced tumors
(25,71).
POSTERIOR FOSSA TUMORS
By far, the most common posterior fossa tumors of childhood are
medulloblastomas, astrocytomas (of the cerebellum and brainstem),
ATRT, and ependymomas (Table 7-5). Although medulloblastomas,
ependymomas, and ATRT may appear to be intraventricular tumors,
they originate from the parenchyma and grow into the fourth ventri-
cle. They are, therefore, classified as intraparenchymal tumors. Note
that tumors originating from the brainstem are divided into several
different groups. This division results from the fact that tumors
originating from different sites within the brainstem have vastly dif-
ferent prognoses. Therefore, the diagnosis of “brainstem tumor” is
no longer sufficient and a more specific diagnosis should always be
rendered.
Intraparenchymal Tumors
Medulloblastoma
Medulloblastomas are highly malignant tumors composed of very
primitive, undifferentiated small, round cells. These undifferentiated
cells were given the name “medulloblast” by Bailey and Cushing in the
early 1900s, hence the name medulloblastoma (72). Together with the
primitive neuroectodermal tumors (PNETs) and the ATRT, they form
the group that the World Health Organization calls embryonal tumors
(73); all are highly malignant (WHO grade IV). As was mentioned
Barkovich_Chap07.indd 649
649
earlier in this chapter, in the section on tumor biology, it appears likely
that medulloblastoma derives from BTSC, mutated precursor cells
that compose the small but actively proliferating component of the
tumor. Given the complex development of the cerebellum with two
different proliferative zones (in the ventricular zone and the external
granular layer), different variants of medulloblastoma likely emerge
from distinct cell lineages, each with different cytogenetic abnor-
malities and a different prognosis (see Gilbertson and Ellison [74] for
review).
In children, medulloblastoma is the second most common brain
tumor (after astrocytoma) and the most common malignant brain
tumor (15%–20% of intracranial neoplasms in children); it is the most
common posterior fossa tumor in most series (30%–40% of posterior
fossa neoplasms), being slightly more common than the cerebellar
astrocytoma (8,75,76). They are the most common tumor in the 6 to
11 year age group, comprising about 25% of brain tumors affecting
children in that age range (77). Males are affected two to four times
as frequently as females. Medulloblastomas may also occur in adults,
accounting for 0.4% to 1.0% of adult brain tumors; overall, 14% to
30% of medulloblastomas occur in adults (78–80). Medulloblastomas
are seen with increased frequency in patients with basal cell nevus
(Gorlin) syndrome (see Chapter 6).
The duration of symptoms for patients with medulloblastoma
is usually short; approximately half will have symptoms for less than
1 month prior to diagnosis. The most common symptoms are head-
aches, vomiting, and nausea. The high incidence of vomiting may be
related to growth of the tumor in proximity to the area postrema, the
emetic center of the brain, which is located near the inferior aspect
of the fourth ventricle. In children less than 1 year of age, increasing
head size and lethargy are frequent presenting symptoms. In older
children and adults, ataxia is the symptom that usually initiates medi-
cal attention. Rarely, paraparesis or symptoms referable to the cauda
equina will result from tumor dissemination and necessitate medical
evaluation (8,81,82). Spinal metastases are present at initial diagnosis
in approximately 30% of patients and are a very poor prognostic sign
(83,84). Indeed, extent of disease at diagnosis is the feature most pre-
dictive of prognosis in affected children (85).
Pathology
Approximately two thirds of medulloblastomas in children are located
in the vermis, in contrast to adolescents and adults, in whom medullo-
blastomas are most often found in the cerebellar hemispheres. The
tumor usually forms a well-defined vermian mass widening the space
between the cerebellar tonsils. Anteriorly, it impinges upon the roof
of the fourth ventricle and causes partial or complete obstruction
to CSF flow. Posteriorly, it may project into the cisterna magna and
rarely extend downward to the level of the upper cervical spinal cord
(8,75). Occasionally, the tumor will extend laterally through the lat-
eral recesses into the cerebellopontine angle cisterns. Invasion of the
brainstem is seen in approximately one third of patients, usually result-
ing from direct extension across the fourth ventricle (86). Invasion of
the leptomeninges via dissemination along CSF pathways is frequent,
the literature reporting incidences of up to 100% (87–90). Intracra-
nially subarachnoid tumor spread is seen more prominently within
the Sylvian fissure and cisterns of the posterior fossa. Pathologically,
subarachnoid tumor appears as small grayish patches of tumor or as a
continuous “frosting” of tumor on the pia. Retrograde spread through
the aqueduct into the lateral and third ventricles can occur, as well.
From any of these sites, tumor may reinvade the brain parenchyma.
Drop metastases to the spinal subarachnoid space and cauda equina
are seen in approximately 40% of patients, most commonly at the tho-
5/6/2011 9:15:39 PM
 650 Pediatric Neuroimaging

TABLE 7-5 Posterior Fossa Tumors in Children

Intraparenchymal Tumors
Medulloblastoma Usually in 4th ventricle
T2 intensity of GM, restricted diffusion
Astrocytoma Usually hemispheric
T2 hyperintense
Ependymoma Exophytic toward cisterns
Atypical teratoid/rhabdoid tumor Large heterogeneous mass with necrosis, cysts
Solid areas have T2 intensity of GM
Brainstem tumors Ventral: diffuse infiltrating pontine glioma
Medulla, midbrain, peduncles: pilocytic
Teratoma Most common in young infants, heterogeneous, contains fat
Hemangioblastoma (uncommon) Cyst with intensely vascular mural nodule
Extraparenchymal tumors (uncommon)
Dermal cyst Usually enhances (infection)
Dermal tract to skin possible
Dermoid Short T1, saturates with FatSat
Epidermoid Isointense with CSF on T1/T2, not FLAIR
Internal heterogeneity
Restricted diffusion
Enterogenous (enteric) cysts Cyst of variable intensity
Ventral to brainstem
Teratoma Heterogeneous, contains fat
Schwannoma Along cranial nerves, consider NF2
Meningioma Dural based; consider NF2
Skull base tumors Bone involvement

racic and lumbosacral levels (87–90). Rarely, intramedullary metasta-
ses have been reported, presumably as a result of tumor dissemination
into the central canal of the spinal cord. Systemic metastases are rare
and most commonly develop after tumor recurrence. The skeleton is
the most common site of involvement followed by lymph nodes and
lung (87).
The latest WHO classification of the tumors of the CNS describes
several subtypes, all grade IV (73,91): the classic medulloblastoma
(65%–75%), desmoplastic medulloblastoma (7%), medulloblastoma
with extensive nodularity (3%), anaplastic medulloblastoma (10%–
22%), and large cell medulloblastoma (2%–4%) (73,74,91). Histologi-
cally, more than half of the medulloblastomas are of the classic type,
composed entirely of completely undifferentiated cells, and typically
located in the inferior vermis. Desmoplastic medulloblastomas are
detected more commonly in the second decade, are more commonly
located in the cerebellar hemispheres; they exhibit a striking nodu-
larity with meningeal hyperplasia, and have a more benign course
than the classic type. Medulloblastomas with extensive nodularity
are also located in the cerebellar hemispheres of infants younger than
3 years; their prognosis appears favorable (92,93). Anaplastic and large
cell medulloblastomas have the poorest prognosis (94–96). Any variant
of medulloblastomas may develop myogenic or melanotic histological
features (73,74,91); neuronal differentiation may occur in 7% of the
cases, while glial differentiation is rare, and ependymal differentiation
is so exceptional that it raises suspicion regarding the diagnosis (74).
Imaging Studies
On CT, a typical medulloblastoma classically appears as a well-defined,
hyperdense tumor of the cerebellar vermis (Fig. 7-8) or vermis and
hemisphere. Isolated involvement of the hemisphere is much less com-
mon and is suggestive of the desmoplastic variant in adolescents (78–
80,97) and the extensive nodularity variant in infants (92,93); these
laterally situated tumors may be exophytic and mimic tumors of the
cerebellopontine angle (98). As a result of their composition of small,
round cells with a high nuclear to cytoplasmic ratio, medulloblastomas
are almost always hyperdense or isodense compared to surrounding
white matter prior to the administration of intravenous contrast. The
lesion usually appears well demarcated from the surrounding paren-
chyma. Mild to moderate edema surrounds the tumor in approxi-
mately 90% of patients. Hydrocephalus is present in approximately
95% of patients at the time of presentation. Because the tumor usually
develops in the inferior portion of the vermis, it is often capped by the
deformed lumen of the upper part of the fourth ventricle; the aqueduct
may be dilated. Enhancement is seen in greater than 90% of medullo-
blastomas, most commonly diffuse, but sometimes irregular or even
absent (10,99).

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 651

FIG. 7-8. Typical medulloblastoma. A. Noncontrast CT image shows a well demarcated, rather homo-
geneous rounded mass (arrows) in the center of the posterior fossa, with increased attenuation compared
with cerebellar gray matter. This appearance and location are characteristic of classic medulloblastoma.
A few small necrotic cysts are common; punctate calcification may be seen as well. B. Sagittal T1 image
demonstrates the tumor (white arrows) filling the fourth ventricle. Its inferior margins (black arrow) are
somewhat blurred. Signal intensity of the tumor is approximately that of the supratentorial gray matter.
C. Coronal T2 image shows the signal of the tumor (T) to be close to that of the gray matter. Ventricular
CSF surrounds most of the tumor. Note the tonsillar herniation, and the tilt of the head (torticollis).
D. Axial FLAIR image best shows the hypointense small foci of necrosis (black arrows). E. Diffusion-
weighted image shows tumor hyperintensity, indicating reduced free water movement. This, like the
high attenuation on CT, reflects the high cellularity typical of medulloblastoma. F. Hypointensity of
the tumor (white arrows) on the calculated Dav map confirms the reduced diffusivity. The small areas of
hyperintensity within the tumor are necrotic or cystic foci. G. Postcontrast sagittal T1WI image shows
incomplete, irregular enhancement of the tumor.

Cysts or calcifications are found in 60% of CT studies in medullo-
blastomas, including calcification in up to 20% and cystic or necrotic,
nonenhancing regions in close to 50% (99,100). The presence of
intratumoral hemorrhage is very uncommon. Although the presence
of cystic, nonenhancing regions within the tumor may sway the neu-
roradiologist toward the diagnosis of pilocytic astrocytoma, the solid
portions of pilocytic astrocytomas are usually hypodense prior to the
administration of IV contrast, whereas medulloblastomas are mostly
isodense to hyperdense on precontrast studies (Fig. 7-8A) (10). In the
authors’ experience, the density of the tumor on the precontrast CT
scan is a very reliable means of differentiating these tumors. It is impor-
tant to look for falcine calcification if CT is performed. If calcification
of the falx cerebri is seen prior to shunting or the initiation of radiation
therapy, the possibility of medulloblastoma occurring in the setting of
basal cell nevus syndrome or Gorlin syndrome, described in Chapter 6,
should be considered and other manifestations of the syndrome should

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 652 Pediatric Neuroimaging
FIG. 7-9. Patchy enhancement in medulloblastomas. Postcontrast axial T1-weighted images (A and B) show varying degrees of enhancement. The arrow
in (B) points to a small tumor cyst.
be sought (101). As patients with basal cell nevus syndrome have a pro-
pensity to develop basal cell carcinomas in irradiated fields, the pres-
ence of the syndrome may lead to changes in therapy.
On MRI, the appearance of medulloblastomas is variable. Tumor
location and patient age are the most important factors in prospec-
tively making the correct diagnosis. The tumors are most commonly
situated within the inferior vermis (Fig. 7-8B) and can sometimes be
seen originating from the inferior medullary velum: a midline infe-
rior vermian tumor bulging ventrally in the fourth ventricle in a child
from 5 to 10 year old is likely to be a medulloblastoma. The most
common appearance is that of a round, slightly lobulated mass, isoin-
tense to normal gray matter on T1-weighted images. T2-weighted
sequences typically reveal a heterogeneous mass in which the solid
portions are hypointense or isointense compared to gray matter (Fig.
7-8C). The small round cells also result in the solid regions of the
tumor being hyperintense compared with normal cerebellar tissue on
DWI and hypointense on diffusivity maps (average diffusivity [Dav] of
solid portions of medulloblastoma is between 0.5 and 0.9 × 10−3 mm2/s
[102]) (Figs. 7-8E, F, and 7-9 D, E) (103–105). The signal intensities
presumably relate to reduced amount of free water within the tumor.
Less free water results in a shortened T2 relaxation time and reduced
diffusivity and, hence, lower signal intensity on T2-weighted and Dav
images. Heterogeneity probably results from the aforementioned
cysts and calcification (106). The enhancement pattern of the tumors
after intravenous infusion of paramagnetic contrast is variable;
enhancement may be patchy or uniform (Figs. 7-8 to 7-10). Signal
and enhancement characteristics of hemispheric medulloblastomas,
seen in adolescents and adults, are similar to those of fourth ventricu-
lar medulloblastomas seen in children. The cerebellar hemispheric
tumors often arise in the periphery of the hemisphere. Desmoplastic
tumors may incite desmoplastic reaction in the overlying meninges,
resulting in leptomeningeal enhancement that mimics a meningioma
(96) (Fig 7-10). It is important to be cautious in interpreting tumors
with this appearance in older children (second decade) and young
adults.
Proton spectroscopy, discussed in the introduction to this chapter,
typically shows high choline, low creatine, low NAA, and high lactate
Barkovich_Chap07.indd 652
values in medulloblastoma, reflecting its malignant nature (45,47,107–
109). In addition spectra with short TE show a significant taurine peak,
which is characteristic of medulloblastomas (45,110).
CSF spread of tumor is very poorly evaluated by noncontrast MRI.
Therefore, paramagnetic contrast should be used in the evaluation of
these patients both prior to and after resection of the tumor. The most
common locations for intracranial metastases are the vermian and
basilar cisterns, subependymal region of the lateral ventricles, and the
subfrontal region (Figs. 7-11 and 7-12). Intraventricular (subependy-
mal) metastases frequently show limited enhancement (Fig. 7-12D);
this should not cause confusion in the proper clinical setting, as
periventricular nodular heterotopia (see Chapter 5) are rarely seen as
incidental findings. MRI is the primary imaging method to evaluate for
the presence of drop metastases to the spinal cord or the cauda equina
and has, properly, replaced plain-film and CT myelography (35,36).
MR techniques for imaging the spine are discussed in Chapter 1. MRI
also seems to be more sensitive than CSF cytology in the detection of
subarachnoid spread of tumor in primary brain tumors, whereas CSF
cytology is more sensitive in the detection of hematologic tumors such
as leukemia and lymphoma (111). On contrast-enhanced MRI, drop
metastases may appear as a smooth enhancing coating of the spinal
cord or as brightly enhancing foci in the extramedullary, intradural
and, occasionally, intramedullary space (Figs. 7-12, 10–11 and see dis-
cussion in Chapter 10). The most common location is along the poste-
rior surface of the spinal cord in the thoracolumbar regions (along the
arachnoid septum that attaches the dorsal cord to the posterior dura,
known as the septum posticum) (Fig. 7-12F); the caudalmost aspect
of the thecal sac is also frequently involved. In the first few weeks after
posterior fossa craniectomy, however, artifacts (presumably from
dependent subarachnoid blood along the septum posticum, spinal
subdural collections, or even from “leakage” of contrast into the suba-
rachnoid and subdural space) are common (112,113). These artifacts
can be impossible to differentiate from CSF spread of tumor. These prob-
lems are best avoided by staging the tumor preoperatively with precontrast
and postcontrast scans of the brain and spine. Alternatively, tumor spread
to the spine can be assessed after waiting for two weeks after surgery before
imaging (114).
5/6/2011 9:15:40 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 653

FIG. 7-10. Desmoplastic medulloblastoma in a 15-year-old adolescent. A. Sagittal T1-weighted image shows a large rounded, well demarcated tumor
(arrows) in the superior aspect of the cerebellar hemisphere. B. Axial T2-weighted image demonstrates the tumor (arrows) to be slightly hyperintense
compared with cortex. Note the anterolateral superficial, almost exophytic location of the tumor in the left hemisphere; the pons and fourth ventricle are
displaced to the right. C. FLAIR image best depicts the associated hyperintense vasogenic edema. D. Diffusion-weighted image shows tumor hyperintensity,
indicating reduced free water movement. E. Hypointensity of the tumor (arrows) on a calculated diffusivity map confirms the reduced diffusion, which is
highly suggestive of medulloblastoma. F. Postcontrast image shows dense, homogeneous enhancement of the mass.

Medulloblastomas rarely disseminate hematogeneously since sys-
temic chemotherapy has been added to the therapeutic regimen (115).
When extra-CNS spread occurs, it may be seen years after initial treat-
ment, with a median interval of 12 to 32 months (116). As bone is
the most common site for extraneural metastases, neuroimaging
follow-up studies will usually show metastases in the diploic space of
the calvarium or in the marrow cavities of the vertebrae (114). These
skeletal metastases are typically very radiodense on plain films and CT;
they are hypointense on T1-weighted images and show enhancement
after administration of paramagnetic contrast (114). Signal intensity is
variable on T2-weighted images. Lymph nodes are another common
site of extraneural metastases in children, and may be detected on stud-
ies of the spine (96).
Atypical Teratoid/Rhabdoid Tumor of Infancy
and Childhood
Over the past 10 to 15 years, it has become apparent that some tumors
diagnosed as medulloblastomas by classical pathologic and radiologic
techniques have dramatically different biological features (117,118).
Children with these tumors, called “atypical teratoid/rhabdoid
tumors of infancy and childhood,” present at a younger age than true
medulloblastomas, with the median age at diagnosis being 2 to 4 years
(118–121) (median age for diagnosis of medulloblastoma is about
6 years). They belong to the same group of WHO grade IV embryonal
CNS tumors as the medulloblastoma (73). The importance of distin-
guishing ATRT from medulloblastoma lies in the lack of response of
ATRT to standard therapy for medulloblastomas. As a result of this
lack of responsiveness, the majority of patients with ATRT succumb
within 1 year of diagnosis, in contrast to those with medulloblastoma,
who frequently respond to chemotherapy (118,119,121,122). ATRT
can be distinguished from medulloblastomas by routine and special
microscopic techniques (118). However, many are nonetheless ini-
tially diagnosed as medulloblastomas or PNETs because rhabdoid
cells, the histologic hallmarks of ATRT, compose only a minority of
the neoplastic cells; thus, the specimens examined by the patholo-
gist may be indistinguishable from PNETs. From the reports avail-

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 654 Pediatric Neuroimaging

FIG. 7-11. Typical medulloblastoma with subarachnoid tumor spread. A. Sagittal T1-weighted image shows hydrocephalus and a hypointense mass
(arrows) obstructing the fourth ventricle. B. Axial T2-weighted image shows that the mass is nearly isointense to gray matter. C and D. Axial postcontrast
images show the main tumor enhancing homogeneously. Multiple foci of tumor (arrows) that has spread through the subarachnoid pathways are seen both
infratentorially and supratentorially.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 655

FIG. 7-12. Metastatic medulloblastoma. A. Postcontrast T1-weighted image shows enhancement around the periphery of the pons (small arrowheads), in
the cerebellar fissures (small arrows), and coating the cisternal portion of the right fifth cranial nerve (large arrow). B. Postcontrast T1-weighted image shows
a large tumor mass (arrows) in the region of the optic chiasm and a smaller deposit (arrowhead) in the right sylvian fissure. The chiasmal region is a com-
mon location for metastatic deposits because radiation ports try to miss the optic nerves and chiasm. C. Postcontrast T1-weighted image shows metastatic
deposits (arrows) in both sylvian fissures. D. Postcontrast T1-weighted image shows multiple intraventricular metastatic deposits (arrows) and a region of
subarachnoid tumor (arrowhead) in the cingulate gyrus. Intraventricular metastases frequently do not enhance.

Barkovich_Chap07.indd 655 5/6/2011 9:15:44 PM

 656 Pediatric Neuroimaging
FIG. 7-12. (Continued) E and F. Postcontrast sagittal T1-weighted images show enhancing tumor coating the spinal cord. A focal lesion (arrows) at the C-3
level appears to be invading the spinal cord. Note the hyperintensity of the vertebral bodies secondary to prior radiation therapy.
able (120,121,123–125), it would appear that these tumors are about
equally distributed between the supratentorial space (44%) and the
posterior fossa (44%) including the cerebellum (especially the vermis),
midbrain, and cerebellopontine angle cisterns. Both supratentorial and
infratentorial structures are involved in approximately 10%. The sep-
tum pellucidum, pineal gland, and spinal cord (2%) may be involved
as well. However, infratentorial ATRT occur mostly in patients less
than 3 years old, and supratentorial sites are most common in chil-
dren older than 3 years (118,120–122,125–127). As with medulloblas-
tomas, the tumor may spread through the subarachnoid space when
it arises in the ventricles or cisterns (119,128); indeed, Meyers et al.
(121) reported subarachnoid spread in 24% of their series at the time
of diagnosis.
Neuroimaging characteristics (Fig. 7-13) can be similar to
those of medulloblastomas in the posterior fossa and to germ-cell
tumors and PNETs when arising in the supratentorial compart-
ment (129). On noncontrast CT, the solid portions of the tumor
demonstrate attenuation similar to slightly higher than that of gray
matter, with calcification (130), hemorrhage, cysts, and necrosis
(120,121,124,125). On MRI, solid portions of the tumor are isoin-
tense to gray matter on T1-weighted images and isointense to slightly
hyperintense compared to gray matter on T2-weighted MR images
(120,125,126,130). DWI shows reduced diffusivity in the solid por-
tions of the tumor (121,125) with Dav values that overlap with those
of medulloblastoma (102). As on CT, necrosis, cysts, and hemorrhage
are identified in up to 50% (120,121,130,131), giving an appearance
of striking heterogeneity (132); medulloblastomas are generally less
Barkovich_Chap07.indd 656
heterogeneous. Proton spectroscopy shows elevated choline and
reduced NAA, although quantification of these changes has not yet
been reported (121); no data are available yet regarding the pres-
ence or size of taurine peaks. In contrast to medulloblastomas and
ependymomas, ATRT seem to originate as commonly from the cer-
ebellar hemispheres as from the midline/walls of the fourth ventricle
(Fig. 7-13) (130). The diagnosis of atypical teratoid/rhabdoid tumor
should be included in the differential diagnosis of tumors with the
neuroimaging appearance of small, round-cell tumors in both the
supratentorial and infratentorial compartments, particularly when
the tumor is very heterogeneous and the child is below the age of
4 years.
Cerebellar Astrocytomas
Astrocytomas are the most common brain tumor in children, account-
ing for 40% to 50% of primary pediatric intracranial neoplasms
(8,10,11,75). Approximately 60% of astrocytomas are located in the
posterior fossa with 40% in the cerebellum and 20% in the brainstem.
Depending on their histology and grading, various types of astrocy-
tomas are identified in the WHO classification (Table 7-6). Most cere-
bellar astrocytomas in children are of a specific histological type, called
juvenile pilocytic astrocytoma (JPA), which is considered a unique
tumor and is classified as grade I by the World Health Organization.
JPAs are the most benign astroglial tumors of the CNS (76). Malignant
astrocytomas of the cerebellum, even glioblastomas (grade IV astroglial
neoplasms), can and do occur in children, however (133), and have a
very poor prognosis (134).
5/6/2011 9:15:46 PM

TABLE 7-6 WHO Grades I is Benign,
Grades II to IV Reflect
Increasing Degrees of
Malignancy
Pilocytic astrocytoma
Pilomyxoid astrocytoma
Pleomorphic xanthoastrocytoma
Diffuse astrocytoma (any type)
Anaplastic astrocytoma
Glioblastoma (any type)
After Louis et al. (73).
Barkovich_Chap07.indd 657
Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 657
FIG. 7-13. Atypical teratoid/rhabdoid
tumor of infancy. A. Axial CT shows
a heterogeneous, partly necrotic high
attenuation mass (arrows) in the supe-
rior vermis. B. Sagittal T2-weighted
image demonstrates a huge mass in
the superior vermis, fourth ventricle,
and supravermian/quadrigeminal cis-
tern. The solid portions of the mass
are slightly hyperintense to gray mat-
ter; it has large necrotic portions (n)
and infiltrates the tectal plate. C. DWI
shows hyperintensity (reduced diffusiv-
ity) in the solid portions of the tumor.
D. Postcontrast sagittal T1-weighted
image shows partial enhancement
(arrows) of the mass.
JPAs are found with equal frequency in males and females and,
overall, compose about 70% of pediatric cerebellar astrocytomas (135).
The peak incidence of these tumors is from birth to 9 years of age (136),
but they remain common until about age 15 (77). Anaplastic astro-
cytomas (∼ 5%–15% of pediatric cerebellar astrocytomas) are more
common in older children, usually in the second decade (76,77,136).
Glioblastomas of the cerebellum are very uncommon and can present
WHO grade I at any age (18,133). In general, patients with cerebellar astrocytomas,
regardless of the histologic characteristics, present with early morning
WHO grade II
headache and vomiting, waxing and waning over a period of months
WHO grade II and finally becoming persistent and acute (8). Cerebellar signs, such as
WHO grade II truncal ataxia or dysdiadochokinesia, are frequently present. Prognosis
is related to extent of resection (137); therefore, best prognosis is asso-
WHO grade III ciated with single hemispheric location, small size, and cystic tumors
WHO grade IV with posterior mural nodules (137). Patients with cystic JPAs have an
excellent prognosis, with the 25-year survival rate being close to 90%
(11). The 25% of patients with the solid cerebellar astrocytoma have a
more guarded prognosis, with a 25-year survival rate of approximately
5/6/2011 9:15:46 PM
 658 Pediatric Neuroimaging

40% (11). With either variety, malignant transformation of benign cer-
ebellar astrocytomas is exceedingly rare, but does occur (138). Gross
total resection of pilocytic astrocytomas by surgery is usually curative.
Extension into the brainstem, seen in up to 25% of cerebellar astrocy-
tomas, renders complete resection difficult and reduces long-term sur-
vival (139). Tumors that are not surgically accessible may be treatable
by stereotactic radiosurgery (140).
Pathology
Cerebellar astrocytomas of childhood may originate in the midline or
in the cerebellar hemispheres; the frequency of these locations has been
debated (75,76,138,139,141). The tumor is usually large at the time of
presentation, with an average diameter of greater than 5 cm (75,76).
Cerebellar astrocytomas can be cystic, solid, or solid with a necrotic
center (8,75,142). Most frequently, the cystic lesions have a tumor nod-
ule (“mural” nodule) found within the cyst wall; the remainder of the
cyst wall consists of nonneoplastic, compressed cerebellar tissue. Cystic
astrocytomas with mural nodules account for approximately half of all
pediatric cerebellar astrocytomas (8,10,75,142). Another 40% to 45%
of cerebellar astrocytomas are composed of a rim of solid tumor with
a cyst-like, necrotic center. Necrosis of the tumor center is sometimes
incomplete and, on occasion, results in a polycystic appearance (142).
Non-necrotic solid tumors are seen in less than 10%. Some authors
describe a fourth type, with a mural nodule and an enhancing cyst wall
(139). The gross appearance does not correlate with histologic type
(136).
Histologic exam of pilocytic astrocytomas is characterized by a
combination of piloid tissue (dense sheets of elongated bipolar cells
and an abundance of Rosenthal fibers) and loose glial tissue (com-
posed of multipolar protoplasmic astrocytes and eosinophilic granular
bodies) (143). Calcification is seen on histologic examination in 20% of
cerebellar astrocytomas, most commonly in the solid variety. Tumoral
hemorrhage is very rare and probably more so in the cerebellum than in
other locations (144), but it may occur and be massive (145). Pilocytic
astrocytomas differ from most low-grade astrocytomas histologically
in that they are very vascular (143) and the endothelial cells within the
tumor have open tight junctions and fenestrations (146). The imaging
implication of these “holes” in the vascular walls is a very profound
enhancement of the tumors (see below).
A pilomyxoid variant (PMA) with monomorphous features, lack
of Rosenthal fibers, and myxoid background has been recently reported
(143); it is classified as a WHO grade II astrocytoma (73), less benign
that the JPA. PMA are predominantly located in the forebrain, espe-
cially in the suprasellar region (57%) and only rarely in the cerebellum
(10%) or the fourth ventricle (5%) (147).
Imaging Studies
The typical appearance of cerebellar astrocytoma is that of a large
vermian or hemispheric tumor that is predominantly cystic. The solid
portion of the tumor is usually isodense to hypodense to normal
white matter on noncontrast CT, with pilocytic tumors nearly always
hypodense; high-grade tumors may be hyperdense. Contrast enhance-
ment is usually irregular, half of the lesions showing mixed attenua-
tion (10). In addition to the heterogeneities caused by cysts and tumor
necrosis, heterogeneous enhancement is seen in the solid portion of
the tumor; some degree of contrast enhancement is virtually always
present (10). Tumors of pilocytic cytology show intense enhancement
of their solid portions (148).
When the tumor is cystic with a mural nodule, the cyst is round
or oval, whereas the mural nodule may be round, oval, or plaque-like.
After infusion of IV contrast, the nodule shows an intense, homoge-
neous tumor blush (Fig. 7-14). The wall of the cyst may appear slightly
hyperdense on CT because of the compressed cerebellar tissue; if
it does not enhance, pathology of the cyst wall almost never reveals
tumor (11). If the wall of the cyst enhances, tumor is usually found.
When the cyst results from necrosis of a solid astrocytoma, it may be

FIG. 7-14. CT of JPA of the cerebellum. A. Images from a noncontrast CT through the cerebellum. There is a cystic lesion involving the left cerebellar
hemisphere (open arrows). A solid nodule of tumor, which is of lower attenuation than surrounding cerebellum, is located within the medial aspect of the
cyst (closed arrow). B. After infusion of iodinated contrast, the nodule in the medial wall of the cyst is seen to uniformly enhance (closed arrows). The cyst
wall does not enhance. The slight increased intensity seen in the ventral wall of the cyst (open arrows) results from compression of adjacent brain tissue.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 659

unilocular or multilocular. A well-defined mural nodule is not seen;
instead, tumor enhancement surrounds the cyst and extends into the
cerebellum (10,11,149). Solid tumors are usually round to oval, lobu-
lated, and fairly well-defined masses that are isointense to hypointense
precontrast and show heterogeneous to homogeneous enhancement.
Rarely, no enhancement is discernible; nonenhancing tumors are
essentially never of pilocytic histology.
The MR appearance of cerebellar astrocytomas is variable,
depending upon the gross pathological appearance. Tumors vary in
size from small (Fig. 7-15) to very large (Fig. 7-16). Solid and cystic
components are identified, just as on CT. In general, solid portions
appear as low-signal intensity masses (although not as low as CSF)
on T1-weighted sequences and as high-intensity masses (although
not as high as CSF) on T2-weighted and FLAIR sequences (Figs. 7-15
to 7-17). Higher grade tumors may manifest lower signal intensity
on T2-weighted images, thereby mimicking medulloblastoma (133).
Note that the signal intensity of pilocytic tumors is not as dramatically
high on FLAIR images (Fig. 7-17) and therefore FLAIR images are less

FIG. 7-15. Small hemispheric astrocytoma; pathology revealed JPA. A. Sagittal postcontrast T1-weighted image shows a small hemispheric tumor (arrows)
with a small amount of central enhancement. B. Axial T2-weighted image shows the tumor (arrows) sitting in the cerebellar white matter abutting the fourth
ventricle. The central hyperintensity represents different histology of tumor but, because that region enhances, was not felt to represent necrosis. C. Axial
FLAIR image also reveals several areas of different signal intensity in the center of the tumor. D. Axial postcontrast T1-weighted image shows that the areas
of hyperintensity on the T2 and FLAIR images are the areas that enhance. These were felt to be areas of pilocytic tumor.

Barkovich_Chap07.indd 659 5/6/2011 9:15:48 PM

 660 Pediatric Neuroimaging
useful than conventional T2-weighted images for differentiating pilo-
cytic astrocytomas from higher grade tumors. Solid portions of tumor
will enhance with paramagnetic contrast (Fig. 7-16) in an identical
fashion to their enhancement with iodinated contrast on CT. As with
CT, it is possible to distinguish predominantly solid tumors with cen-
tral necrosis (Fig. 7-17) from cystic tumors (Fig. 7-16) as necrosis tends
to have irregular (Fig. 7-17), rather than smooth (Fig. 7-16), margins.
Also as with CT, enhancement of the cyst wall indicates the presence
of tumor. It is sometimes difficult to differentiate a solid from a cys-
tic mass with noncontrast MRI when the solid portion of the tumor is
homogeneous. A tumor should not be assumed cystic merely because it
demonstrates homogeneous low-signal intensity on T1-weighted and
homogeneous high-signal intensity on T2-weighted images, even if it
does not enhance. Further evidence, such as diffusivity equal to CSF,
wave forms from fluid pulsations or fluid-fluid levels should be sought
in order to reliably make this differentiation. Although the T2 charac-
teristics will usually allow differentiation of pilocytic astrocytomas from
Barkovich_Chap07.indd 660
FIG. 7-16. Large cystic JPA. A. Sagittal T1-weighted image
shows a large cystic mass involving the cerebellar hemisphere.
The more anterior, homogeneous hypointense component
(white arrowheads) was cystic while the posterior heteroge-
neous component (white arrows) was solid. B. Postcontrast
T2-weighted image through the posterior fossa shows the large
heterogeneous mass with cystic (c) and solid (s) components.
Note that the solid component of this pilocytic astrocytoma is
very hyperintense compared with brain parenchyma. This is typ-
ical of pilocytic astrocytomas. C. Postcontrast axial T1-weighted
image shows that the solid component (s) brightly enhances.
The walls of the cysts (c) do not enhance, indicating the absence
of tumor in the cyst walls.
medulloblastomas and ependymomas, the inexperienced physician may
wish to use calculated average diffusivity (Dav or ADC) values to help
in this differentiation. The solid components of pilocytic astrocytomas
will usually have higher Dav values (typically 1.25–1.95 × 10−3 mm2/s)
than the more cellular ependymomas and especially medulloblastomas
(102). However, there may be more overlap with other types of gliomas
and other less typical tumor pathologies so, as always, it is important to
take into account all imaging characteristics as well as patient age.
As discussed in the introduction to this chapter, the proton MR
spectra of cerebellar astrocytomas vary considerably depending upon
the histologic characteristics of the tumor (45,47,107–109). Interest-
ingly, however, significant differences have been reported in the spectral
composition between the cerebellar and the suprasellar pilocytic astrocy-
tomas, with significantly higher myo-inositol and glutamate/glutamine
peaks in the suprasellar tumors, and a trend toward lower creatine in the
cerebellar tumors (107,150). Such differences could be related to the fact
that, although JPAs are characterized by a similar histological appear-
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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
ance regardless of their location, the proliferating tumor stem cells that
produce the bulk of the tumor are location-specific and, therefore, are
cytogenetically different in different regions (see section on “Changing
Concepts of Brain Tumor Biology” earlier in this chapter) (32).
Ependymomas
Ependymomas constitute 8% to 12% of primary CNS neoplasms in chil-
dren and 10% to 20% of posterior fossa tumors in children; their rela-
tive frequency diminishes as children grow older, but affected children
can present at any age (9,77). In childhood, intracranial ependymomas
are more commonly infratentorial (70%) than supratentorial (30%)
and more commonly intracranial than intraspinal (see Chapter 10)
(9,151). There is a slightly increased preponderance in males (152–
154). Ependymomas of the posterior fossa have two age peaks, the first
occurring between the ages of 1 and 5 years and the second in the middle
Barkovich_Chap07.indd 661
661
FIG. 7-17. Solid JPA with central necrosis. A. Sagittal
T2-weighted image shows large hyperintense cerebellar mass
with a hyperintense solid periphery (s) and necrotic central foci
of hyperintensity (n). Obstructive hydrocephalus is present,
causing stretching of the corpus callosum around the dilated
lateral ventricles and ballooning of the anterior recesses of the
third ventricle. B. Coronal FLAIR image shows that the solid
periphery of the mass is hyperintense compared to gray matter
but not as hyperintense as is seen on T2-weighted images such
as A. The necrotic center (n) is relatively hypointense. C. Post-
contrast axial T1-weighted image shows that the solid periph-
eral portion of the tumor (white arrows) enhances uniformly, as
characteristic of pilocytic astrocytomas. The central nonenhanc-
ing region (black arrowheads) is necrotic tumor.
of the fourth decade. Patients with ependymomas of the posterior fossa
frequently present with a long clinical history. The delay in diagno-
sis probably results from the insidious onset of symptoms. Nearly all
affected children have nausea and vomiting resulting from the hydro-
cephalus and increased intracranial pressure (from tumor obstructing
the fourth ventricle) develops in 90% of patients (8,81). Other signs and
symptoms include torticollis and ataxia (when the tumor arises near
the obex) and lower cranial neuropathies (when the tumor arises in the
lateral recesses and grows into the cerebellopontine angle) (151).
Pathology
Ependymomas were at one time assumed to derive from differenti-
ated ependymal cells that line the floor and roof of the fourth ventricle
or from ependymal cell rests found posterior to the occipital horns,
and along the tela choroidea (76). However, new evidence indicates
5/6/2011 9:15:50 PM
 662 Pediatric Neuroimaging
that, like other CNS tumors, ependymomas result from mutated stem
cells, and those that produce ependymomas have been shown to be
the radial glia cells (33). In the cerebral hemispheres, radial glia can be
found throughout the thickness of the brain mantle, explaining why
supratentorial ependymomas are characteristically extraventricular
and may even be strictly intracortical (155).
Most ependymomas are solid in nature, with calcification seen
in up to 50% of posterior fossa ependymomas and cysts in approxi-
mately 20% (152). Approximately 20% of ependymomas are very soft
and deformable. Therefore, in contradistinction to most brain tumors
(which grow as steadily enlarging masses), ependymomas can insinu-
ate themselves through the subarachnoid spaces and around blood ves-
sels and nerves, often surrounding and engulfing structures. As a result
of their adherence to surrounding brain and their invasive growth pat-
tern, ependymomas are quite difficult to cure; removal of the entire
tumor is uncommon and the recurrence rate is high (8,81).
Posterior fossa ependymomas originate from the sides of the
medullary portion of the fourth ventricle. They are classified as WHO
grade II (cellular type with its variants) or III (anaplastic) (156), but
whether this correlates with outcome is not clear (157). (The term
ependymoblastoma does not describe a variety of ependymoma, but a
PNET [an embryonal tumor classified as WHO grade IV] with a “dif-
ferentiation potential solely along ependymal lines” [156]). Posterior
fossa ependymomas do not invade the medulla, instead form exophytic
masses that grow out of the ventricle into the surrounding cisterns.
Occasionally, ependymomas arise in the lateral recess without evi-
dence of tumor in the fourth ventricle (8,75,76,158). These laterally
occurring posterior fossa ependymomas have a worse prognosis than
those in the midline (158–160), probably because complete resection is
nearly impossible. For this reason, microanatomical localization of the
posterior fossa ependymomas correlates with the postoperative sur-
vival (159). Those in the lower midfloor (Fig. 7-18) originate from the
caudal end of the ventricle near the obex, extend dorsally into the ven-
tricle, toward the cisterna magna and into upper cervical canal, with
only minimal lateral extension toward nerves and arteries; they can be
resected almost completely and the reported mean survival time is 170
months. Those originating from the lateral recesses/vestibular areas
(Fig. 7-19) extend laterally toward the cerebellomedullary and cer-
ebellopontine angle cisterns, displace and encase the crossing cranial
nerves and arteries, and often involve the inferior cerebellar peduncle;
resection is always incomplete and the reported mean survival time is
40 months. A few ependymomas originate from the ventricular roof
(inferior vermis, Fig. 7-20), extend caudally into and through the fora-
men of Magendie, and can be totally resected; these have a reported
mean survival time of 116 months (159). Thus, imaging should strive
not only to identify the tumor but also to categorize it according to
these criteria (158).
Subarachnoid metastatic spread of benign ependymomas via cere-
brospinal fluid is uncommon (∼ 10%–12%) and the propensity for
subarachnoid spread correlates with histology (higher grade tumors
more commonly disseminate [161,162]) and with age of the patient
(younger patients have a higher incidence of dissemination [161]).
Therefore, when subarachnoid seeding is found at presentation, the
presence of an anaplastic ependymoma should be suspected, especially
in an older child or adult. In contrast to medulloblastomas, ependymo-
mas rarely have CSF dissemination at presentation; mean time from
diagnosis to dissemination is 6.8 years (161).
Imaging Studies
The most characteristic appearance of a posterior fossa ependymoma
on CT is that of an iso- to hyperdense (compared to gray matter)
Barkovich_Chap07.indd 662
posterior fossa mass (Figs. 7-18 to 7-20), with punctate calcifications
small cysts, and moderate, heterogeneous enhancement after intrave-
nous contrast administration (10,11). Extension of the tumor from the
lateral recess into the cerebellopontine angle or through the foramen
magnum into the cervical spinal canal further supports the diagnosis
of ependymoma. Small lucencies are seen within the tumor in approxi-
mately 15% of cases and nearly 50% will exhibit multifocal, small
calcifications (Fig. 7-18); large, clump-like calcifications are occasion-
ally seen. Intratumoral hemorrhage is found in approximately 10% of
patients (Fig. 7-20) (10,154).
On MRI, ependymomas may be homogeneous or heterogeneous.
T1-weighted images commonly reveal a slightly hypointense mass with
respect to brain parenchyma, sometimes with foci of marked hypoin-
tensity. T2-weighted images reveal a mass that is usually isointense
with gray matter (Fig. 7-19); foci of high intensity (necrotic areas or
cysts) and low intensity (calcifications or hemorrhage) may be present
within the tumor mass (Fig. 7-20). Fluid-fluid levels can sometimes
be seen within the cysts. Because of the marked variation in appear-
ance of the solid portion of the tumor, the diagnosis of ependymoma
is difficult to make on the basis of signal characteristics alone. The
most important imaging finding to identify ependymomas is extension
of the tumor through the fourth ventricular outflow foramina. Exten-
sion of tumor to the cisterna magna and through the foramen mag-
num into the dorsal cervical subarachnoid space, behind the cervical
spinal cord (Fig. 7-18), is quite characteristic and very nearly specific
for ependymoma. Similarly, extension of tumor from the lateral recess
(Fig. 7-19) into the cerebellopontine angle cistern with insinuation
around blood vessels and cranial nerves supports the diagnosis of
ependymoma. Midfloor-type ependymomas extend posteriorly; the
brainstem therefore is displaced ventrally, not laterally, and can be
seen wholly on a midline sagittal plane (Fig. 7-18B). Also, because the
tumor originates about the obex, the lowest part of the fourth ven-
tricle appears blurred on the midline sagittal plane, and cannot be
recognized on axial cuts (Fig. 7-18B and C). Axial cuts at this level
show that the tumor is essentially dorsal to the brain, quite symmetri-
cal, and usually without significant extension lateral to the medulla
(Fig. 7-18C); in these cases, cranial nerves and arteries are usually not
invaded, resection may be fairly complete and prognosis is quite good.
Lateral-type ependymomas originate in one of the lateral recesses and
extend toward the CP angle cistern; the brainstem is displaced con-
tralaterally and is only partially seen in the midline sagittal plane (Fig.
7-19B). On thin-section axial T2 images, the inferior extremity of
the fourth ventricle is free of tumor (Fig. 7-19C); tumor growth into
the CP angle cistern and prepontine cistern may be recognized (Fig.
7-19C), raising suspicion for involvement of cranial nerves, and local
arterial encasement (Fig. 7-19B). In such cases, satisfactory resection
is impossible. These lateral ependymomas may be completely extra-
ventricular (Fig. 7-19). Roof-type ependymomas originate from the
inferior vermis and extend into the ventricular lumen, through the
midline foramen of Magendie and into the cisterna magna and dorsal
to the upper cord (Fig. 7-20); they do not come in contact with cranial
nerves and do not encase arteries.
Although medulloblastomas can extend into the fourth ventricular
outflow foramina, they do not send narrow tongues of tissue through
the foramina in the same way as ependymomas. Astrocytomas involv-
ing the medulla frequently extend into the cervical spinal canal, but
are intramedullary (i.e., within the cord, not dorsal to it). Dorsally
exophytic medullary astrocytomas may extend through the foramen
magnum and lie posterior to the cervical spinal cord; however, upon
close examination, medullary tumors are seen to originate inferior to
the fourth ventricle and to push it upward.
5/6/2011 9:15:51 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 663

FIG. 7-18. Midfloor-type ependymoma (from the caudal ven-

tricular floor, close to the obex). A. Noncontrast CT discloses
a rounded high attenuation mass in the low posterior midline
of the posterior fossa (arrows). Note that the typical medullo-
blastoma is located more centrally (see Fig. 7-8A). B. Sagittal
T1-weighted image shows that the tumor (T) is attached to the
dorsal medulla, but is separate from the vermis. It extends dor-
sally into the cisterna magna and inferiorly toward the upper
C-spine. The brainstem is pushed ventrally but is in the mid-
line. C. On this axial FLAIR image, the mass (T) fills the cisterna
magna. Although it originates from the floor of the lower fourth
ventricle it does not invade the brain stem but rather extends
dorsally, displacing the vermis. There is no or only little exten-
sion toward the lateral medullary cisterns. Ependymomas in
this location typically don’t invade the more laterally-located
cranial nerves and vessels; complete resection therefore is pos-
sible and their prognosis is better than it is for the lateral-type
ependymomas. D. Axial DWI shows reduced diffusion of the
tumor compared with cerebellum. E. Postcontrast T1-weighted
image shows diffuse, homogeneous enhancement.

Barkovich_Chap07.indd 663 5/6/2011 9:15:52 PM

 664 Pediatric Neuroimaging

FIG. 7-19. Lateral-type ependymoma (origin in the lateral recess). A. Unenhanced CT shows a mass (T) located in the right side of the posterior fossa,
of similar attenuation to that of the gray matter. Note the fourth ventricle (arrow) displaced left of midline by the mass. B. Sagittal T2-weighted image
demonstrates a huge mass (T) that is nearly isointense to gray matter. The brainstem is displaced out of the plane of the image, suggesting that the mass is
pushing it from the side. Note the artery (arrow) encased within the tumor. C. Axial T2-weighted image demonstrates that the mass (T) is clearly mostly
extraparenchymal, and the laterally displaced fourth ventricle (arrow) is essentially tumor-free. Tumor location in the CP angle cistern commonly results in
the invasion of the cranial nerves and the encasement of the arteries, making complete resection nearly impossible; recurrences are common and prognosis
is worse than for the midfloor-type or roof-type ependymomas. D. Postcontrast T1-weighted image show no enhancement of the tumor (T); enhancement
is very variable in ependymomas.

DWI shows the solid portion of an ependymoma to be isoin-
tense to slightly hypointense compared with cerebellar white matter
(Dav values are intermediate between medulloblastoma and JPA, typi-
cally between 1.0 and 1.3 × 10−3 mm2/s [102]) (Figs. 7-18 and 7-20);
thus, they may be useful for differentiation from medulloblastoma or
an ATRT, which have considerably lower Dav. Proton MR spectra show
considerable heterogeneity (45). In general, ependymomas have low
NAA and moderately elevated choline and creatine. Short echo spectra
(TE = 30 milliseconds) show low to very high myo-inositol, although
never as high as in choroid plexus papillomas (45,107).
Proton MR Spectroscopy of Medulloblastomas,
Cerebellar Astrocytomas, and Ependymomas
This subject has already been discussed briefly in the introductory
section of this chapter. Data have been published looking at metabo-
lite ratios of proton spectra of posterior fossa pediatric brain tumors

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 665

FIG. 7-20. Roof-type ependymoma (from inferior vermis/

medullary velum). A. Axial noncontrast CT demonstrates a
dense posterior midline tumor (arrows) protruding into the
fourth ventricle, with a few punctate calcifications (arrowheads)
and a likely hemorrhage on its left anterior portion. B. Sagittal
T2-weighted image demonstrates the tumor (T) originating in
the inferior fourth ventricle and extending through the foramen
of Magendie into the dorsal cervical subarachnoid space. Note
the hemorrhagic/necrotic region (h) in the superior aspect of
the mass. This tumor originated from the caudal vermis; note
blurring of the tumor-vermis junction. The thin layer of CSF
separating tumor from the floor of the fourth ventricle shows it
is not a midfloor-type ependymoma. The dorsal, inferior exten-
sion of the tumor makes invasion of nerves and arteries less
likely; a total resection therefore is possible, which is the best
single factor of a good prognosis. C. Axial FLAIR image shows
blurring of the tumor-cerebellum junction dorsally (arrow) but
a sharp margin with the brainstem ventrally. D. DWI demon-
strates slight hyperintensity, suggesting moderate tumor cellu-
larity. E. Postcontrast T1-weighted image shows mild, patchy
enhancement of the tumor (T), again illustrating the variable
enhancement of ependymomas.

Barkovich_Chap07.indd 665 5/6/2011 9:15:55 PM

 666 Pediatric Neuroimaging
(45,107,109,163). In general, proton spectra of brain tumors yield
high choline (Cho) peaks and diminished peaks of creatine (Cr) and
N-acetyl aspartate (NAA), but different types of tumors have differ-
ent levels of Cho elevation and NAA and Cr diminution (45). Proton
spectra of normal cerebellum in the pediatric patient (at 1.5 T using
echo time of 135 milliseconds) yield NAA/Cho ratio of 1.49 ± 0.36 and
Cr/Cho ratio of 1.13 ± 0.23, whereas medulloblastomas yield NAA/
Cho ratio of 0.17 ± 0.09, and Cr/Cho ratio of 0.32 ± 0.19 (163) and
have elevated taurine when studied with short echo time (45). Low
grade astrocytomas and ependymomas typically have NAA/Cho and
Cr/Cho values between those of medulloblastomas and those of nor-
mal cerebellum on using echo times of 135 milliseconds 1.5 T (163);
both have elevated myo-inositol at 1.5 T with TE = 35 milliseconds,
which may help to differentiate them from medulloblastomas (45). It
has been suggested, therefore, that proton MRS may be useful in pro-
spectively differentiating medulloblastomas from astrocytomas and
ependymomas (163). Harris et al. suggest that ependymomas have
higher creatine than astrocytomas or medulloblastomas and that the
presence of high myo-inositol levels strongly suggests a diagnosis of
ependymoma when short echo time (30 milliseconds) is used at 1.5 T
(107). As these contradictory results indicate, the proton MRS findings
in tumors cannot be compared at different echo times; spectroscopy
parameters for tumor assessment need to be standardized. They also
suggest that the spectra of tumors with the same histologic type can
vary. Indeed, the metabolite values for all tumors seem to vary with the
type of histologic subtype and the degree of histological malignancy
(47,109); thus there is considerable overlap among the different tumor
types in individual cases. Moreover, pilocytic astrocytomas, considered
the most benign of glial brain tumors, have high choline, high lactate,
and low NAA (NAA/Cho ratio of 0.29, Cr/Cho ratio of 0.29 at TE =
20 milliseconds [164]), features that are usually associated with high
grade tumors. Finally, inflammatory lesions can have spectra that are
identical to those of malignant tumors (165). Therefore, even though
careful analyses of spectroscopy may, eventually, help to preopera-
tively differentiate among different histologies of brain tumors (45), it
still seems (even after 20 years of research on the subject) that proton
spectroscopy is more useful for differentiating recurrent tumor from
granulation tissue and radiation injury than for differentiating among
different tumor histologies.
Brainstem Tumors
General Concepts
Brainstem gliomas constitute approximately 15% of all pediatric CNS
tumors and account for 20% to 30% of infratentorial brain tumors.
Males and females are affected with equal frequency. The peak inci-
dence of these tumors is between 3 and 10 years of age, although they
can be seen at any age from neonates to adults (8,75,166,167). MRI
has simplified the diagnosis of brainstem tumors; it has also given new
information that has allowed the identification of subgroups with dif-
ferent therapeutic options and prognoses (166,168). In fact, brainstem
tumors should not be considered as a single entity but should be sepa-
rated into at least four separate major categories: medullary tumors,
pontine tumors, mesencephalic tumors, and tumors associated with
NF1. Within each of these broad categories, further separations can be
made, primarily into focal and diffuse tumors (see Table 7-3). Although
tumors of many different histologies (astrocytomas, gangliogliomas,
hemangioblastomas, PNETs, Langerhans cell histiocytosis [LCH], ger-
minomas, lymphomas, and glioblastomas, among others [169–175])
can develop in the brainstem, the vast majority are astrocytic tumors
(76,176). In general, dorsally exophytic tumors and other localized,
markedly enhancing tumors are pilocytic astrocytomas (176); as
Barkovich_Chap07.indd 666
these are often at least partially surgically resectable, they should be
specifically identified. However, most astrocytic tumors of the pons
(the most common location of brainstem tumors) have fibrillary
histology (177); these have a typical neuroimaging appearance (T2
hyperintensity, slightly blurry margins, minimal or no enhancement)
and, at many institutions, such tumors are treated without biopsy. It is
important to remember, however, that atypical features of a brainstem
mass, particularly marked enhancement prior to therapy, the presence of
subarachnoid tumor spread at presentation, isointensity to gray matter
on T2-weighted images (suggests a PNET), the presence of chronic blood
products (well marginated T1 shortening from methemoglobin or circular
areas of T2 shortening from hemosiderin), or the presence of extensive
acute hemorrhage, may signal the presence of a nonglial mass, such as cav-
ernoma, abscess, or nonastrocytic tumor. Such features should be brought
to the attention of the treating oncologist before therapy is initiated.
MRI is the study of choice when imaging neoplasms of the brain-
stem, because of the multiplanar capacity and the lack of artifact from
the bony structures of the skull base (178). When using MR to image
tumors of the brainstem, sagittal T2-weighted or FLAIR images should
always be obtained to help determine the full extent of the tumor and
thereby plan proper therapy. T2-weighted and FLAIR images are also
the most helpful for separating tumors into diffuse and focal groups
(179,180). Diffuse neoplasms comprise 60% to 75% of all brainstem
tumors and usually correspond to histology of grade III or grade IV
fibrillary astrocytoma (177). In the great majority of cases, they affect
the ventral pons and are labeled diffuse infiltrating pontine glioma
(DIPG). They tend to smoothly enlarge the affected area (see Figs. 7-22,
7-24, and 7-26) without focal areas of exophytic tumor, although they
can bulge anteriorly and surround the basilar artery (Fig. 7-24A-C).
They are generally poorly marginated and involve more than 50%
(usually more than 75%) of the brainstem in the axial plane at the level
of maximal involvement. Moreover, they tend to cross boundaries to
extend into adjacent segments or structures (e.g., pontine tumors into
medulla or midbrain); this extension into an adjacent structure, cau-
dally or (especially) cranially, is a poor prognostic sign (181). Minimal
or no contrast enhancement is seen on scans at presentation, although
enhancement is common after therapy. Focal neoplasms are generally
well marginated and involve less than 75% of the brainstem in the axial
plane (Figs. 7-23, 7-25, 7-27, and 7-28). Focal tumors often enhance,
but do not cross segmental boundaries to extend into adjacent seg-
ments or structures; as a result, when they enlarge they tend to become
focally exophytic. Histologically, most correspond to pilocytic astro-
cytomas (WHO grade I), but gangliogliomas, though less common,
are not unusual. Anaplastic or even PNETs may occasionally have this
appearance (177). Overall, focal neoplasms of the brainstem have a
much better prognosis than diffuse neoplasms (179,180,182–185), due
to their very slow evolution and in spite of the fact that complete resec-
tion is usually impossible.
Medullary Tumors
The medulla is the least common site of origin for tumors of the brain-
stem. Medullary tumors typically present in young children with signs
and symptoms of increased intracranial pressure (182,186). Dysfunc-
tion of lower cranial nerves may be found, resulting in difficulty in
swallowing and nasal speech (185). Eventually, affected patients may
develop hemiparesis or quadriparesis (185).
On neuroimaging, medullary tumors can be differentiated into two
major categories, focal dorsally exophytic tumors and diffuse tumors.
A third group of small, focal, intrinsic medullary tumors is usually seen
in the setting of NF1 (see Chapter 6).
Focal dorsally exophytic medullary tumors are generally sharply
marginated masses that originate in the dorsal aspect of the medulla
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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 667

FIG. 7-21. Dorsally exophytic medullary glioma extending into the cervical spinal cord. A. Sagittal T1-weighted image shows a large tumor originating
in the medulla and extending posteriorly between the cerebellar hemispheres. The cerebellum is pushed posteriorly and upward by the tumor mass (white
arrows). Caudal extension widens the cervical spinal cord (closed white arrowheads). B. Postcontrast sagittal T1-weighted image shows heterogeneous
enhancement of the mass.

and grow exophytically into the vallecula and cisterna magna, often
causing upward and posterior displacement of the inferior cerebel-
lar vermis (Fig. 7-21). The dorsal extension is a result of the inability
of the low-grade tumor to infiltrate caudally below the decussations
of the corticospinal tracts and medial lemnisci at the craniocervical
junction (177); uncommonly, they may extend into the tegmentum
pontis as well. Therefore, dorsally exophytic tumors should be con-
sidered as focal (177). The dorsal extension makes it difficult to dif-
ferentiate an exophytic medullary glioma from a cerebellar vermian
astrocytoma using axial images (10,11); therefore, acquisition of sag-
ittal images is essential. The exophytic component may extend infe-
riorly through the foramen magnum, dorsal to the cervicomedullary
junction, superficially mimicking an ependymoma (Fig. 7-21). Histo-
logically, these tumors are typically pilocytic astrocytomas (186) and,
therefore, they are of low attenuation on CT and are very bright on
T2-weighted MR images. Thus, they can be differentiated from mid-
floor type of ependymomas, which are isodense to gray matter on CT
and T2-weighted MR images. Medullary pilocytic astrocytomas tend
to invade the medulla in depth in addition to being exophytic, while
midfloor ependymomas tend to be almost exclusively exophytic from
their site of attachment on the fourth ventricle. In addition, dorsally
exophytic medullary tumors can be seen to push the fourth ventricle
upward, in contrast to ependymomas, which originate within the wall
of the fourth ventricle, grow into the ventricle, and expand it. Dorsally
exophytic medullary tumors inconsistently enhance after administra-
tion of contrast; when enhancement is present, it may be homogeneous
or heterogeneous (179).
Diffuse medullary tumors (Fig. 7-22) are more infiltrative neo-
plasms that typically extend rostrally into the pons or caudally into the
cervical spinal cord, but do not have a large exophytic component. Dif-
fuse medullary tumors have a significantly worse prognosis than their
dorsally exophytic counterparts (179), possibly because they are more
difficult for the neurosurgeon to adequately resect. On CT, diffuse med-
ullary tumors may be difficult to detect because of the extensive arti-
fact that may be present around the skull base and in the spinal canal;
the typical CT appearance is that of a mildly to moderately enlarged,
hypodense medulla. The full extent of these tumors is demonstrated
best by using sagittal T2-weighted or FLAIR MR sequences (Fig. 7-22).
Their typical MR appearance is that of a diffusely enlarged medulla,
exhibiting T1 hypointensity and T2/FLAIR hyperintensity, that infil-
trates into the caudal pons and rostral cervical spinal cord. Enhance-
ment is inconsistent and is usually focal or multifocal (179).
Focal medullary tumors (Fig. 7-23) are most commonly seen in the
setting of NF1. They are not usually identified on CT images. On MRI,
they appear as focal expansions of the dorsal medulla that exhibit T1
hypointensity and T2/FLAIR hyperintensity. Enhancement is uncom-
mon. These tumors seem to exhibit very slow growth, showing little
change on sequential imaging studies.

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 668 Pediatric Neuroimaging

FIG. 7-22. Diffuse medullary glioma. A. Sagittal T2-weighted image shows T2 prolongation (white arrows) associated with the tumor extending superiorly
(large white arrowheads) into the pons as well as inferiorly (small white arrowhead) into the spinal cord. B. Sagittal T1-weighted image shows expansion of
the medulla with poorly defined hypointensity (white arrows) centered in the medulla and extending inferiorly into the cervical spinal cord. The extension
into adjacent segments is not seen on this image. C. Axial T2-weighted image shows that the hyperintense tumor (arrows) involves more than 50% of the
transverse diameter of the medulla. D. Postcontrast T1-weighted image shows lack of enhancement of the mass (arrows), characteristic of diffuse tumors
of the brainstem.

Cervicomedullary tumors have much in common with cervical
spinal cord tumors and, indeed, usually originate in the cervical spinal
cord and push up the decussations of the corticospinal tracts and medial
lemnisci at the craniocervical junction, thereby appearing to invade the
medulla. These tumors are discussed in Chapter 10. It will suffice to say
in this section that most of these tumors are of low histologic grade,
with no or minimal infiltrative capacity (177). If the sagittal MR image
shows the tumor infiltrating into the spinal cord from the medulla or
vice versa, a high-grade tumor should be suspected.
Pontine Tumors
The pons is the most common location of tumors originating in the
brainstem. The classic presentation of a pontine tumor is cranial nerve
palsies, usually multiple, with pyramidal tract signs and cerebellar

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
dysfunction (ataxia and nystagmus) (8,166). Smaller, more focal
tumors may present with isolated cranial neuropathies (184). Hydro-
cephalus and signs of increased intracranial pressure are uncommon.
The prognosis for most patients is poor with an overall 5 year sur-
vival rate of approximately 10% despite optimal therapy (166,179,180).
Prognosis depends upon the location and aggressiveness of the tumor.
DIPGs, which are poorly circumscribed, large, and often extend into
the medulla and midbrain, are usually high grade fibrillary gliomas and
have extremely poor prognoses, with a two year survival rate of only
7% (176,187). However, more focal, smaller tumors, particularly those
that originate in the dorsal pons and are exophytic into the fourth ven-
tricle, have much better prognoses, with 5-year survival rates as high as
73% (176,179,180,182–184,188).
DIPGs (Fig. 7-24) are infiltrative masses that are hypodense on
CT, hypointense on T1-weighted MR images, and hyperintense on
Barkovich_Chap07.indd 669
669
FIG. 7-23. Focal medullary glioma in patient with NF1.
A. Sagittal T1-weighted image shows focal dorsal con-
tour abnormality (black arrows) in the dorsal medulla.
A hypothalamic mass (m) is also present. B and C. Axial
T1-weighted and T2-weighted images show the focal
mass (black arrows), expanding the left dorsal medulla.
T2-weighted and FLAIR MR images. Expansion by the tumor will
result in an increased sagittal dimension of the pons and posterior dis-
placement of the fourth ventricle. In addition, the floor of the fourth
ventricle may become flattened. When the tumor extends into the
cerebellar peduncles, the lateral aspects of the fourth ventricle can be
flattened, causing an apparent rotation of the ventricle. The pontine
surface is irregular, and contains exophytic nodules that can grow into
the cerebellopontine angle or prepontine cistern or can grow peripher-
ally along the cranial nerves. Anterior growth frequently engulfs the
basilar artery (particularly in fibrillary astrocytomas [176]), which
eventually lies within a deep groove bounded by tumor anteriorly and
laterally (Fig. 7-24B). Histologically, the tumor cells infiltrate widely
along the fiber tracts of the brainstem rather than destroying them so
that one sees tumor cells intermingling intimately with neurons and
nerve fibers (8,189). As a result of this characteristic, the appearance
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 670 Pediatric Neuroimaging

FIG. 7-24. Diffuse pontine glioma. A. Sagittal T1-weighted image shows an expanded pons with T1 prolongation involving more than 50% of the transverse
diameter of the pons. The fourth ventricle is compressed by the enlarged pons. Tumor mass is seen to extend anterior to the basilar artery (arrows). Hydro-
cephalus is not present. B. Axial FLAIR image shows the large pontine mass (white arrows) expanding the pons and engulfing the basilar artery (black arrow).
C. Postcontrast axial T1-weighted image shows the basilar artery (white arrow) engulfed by the mass. D. Proton MR spectrum (TE = 288 milliseconds)
shows very large choline peaks and small NAA peaks in the tumor mass. E. Perfusion curves (relaxivity in the vertical axis, time in the horizontal axis) show
markedly increased blood volume (resulting in decreased signal and decreased MR units) in the tumor (T) compared to normal brain tissue (N) in a simi-
larly located voxel in the cerebellum. This is characteristic of high-grade glial neoplasms.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
of the pons can return to normal after treatment of these tumors.
However, significant tumor recurrence is usually seen within 18 to
24 months following therapy (166,190). In spite of the marked enlarge-
ment of the brainstem and its frequent bulging into the fourth ventri-
cle, hydrocephalus is uncommon in pontine gliomas. Diffuse pontine
tumors rarely enhance after administration of contrast (179).
Focal pontine tumors (Fig. 7-25) are very uncommon, compris-
ing only about 10% of pontine tumors and, therefore, less than 5% of
Barkovich_Chap07.indd 671
671
FIG. 7-25. Focal pontine glioma. A. Sagittal T1-weighted image shows a
small hypointense mass (black arrows) in the dorsal pons. B. Axial FLAIR
image shows the hyperintense mass (white arrows) slightly protruding into
the fourth ventricle. C. Proton MR spectra (TE = 288 milliseconds) shows
that the choline peaks are not much elevated compared with unaffected
pontine and cerebellar voxels. NAA is decreased. These findings are more
characteristic of a lower grade neoplasm. D. Perfusion curves (relaxivity
in the vertical axis, time in the horizontal axis) show similar blood volume
(resulting in decreased signal and decreased MR units) in the tumor (T)
compared to normal brain tissue (N) in a similarly located voxel in the
cerebellum. This is characteristic of low-grade glial neoplasms.
brainstem tumors. By definition, these tumors occupy less than 50%
of the transverse area of the pons at the involved levels. They may be
located anywhere within the pons and may be poorly or sharply mar-
ginated. When they originate in the periphery of the pons, they may
grow exophytically into the fourth ventricle or cerebellopontine angle.
After administration of contrast, the solid portions of these tumors
typically enhance heterogeneously (179,182,184,188). They are usually
low-grade tumors, often pilocytic astrocytomas.
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 672 Pediatric Neuroimaging

FIG. 7-26. Diffuse midbrain glioma.

A. Axial T1-weighted image shows a
poorly marginated mass with foci of
hyperintensity (arrows), likely rep-
resenting blood, originating in the
midbrain and extending inferiorly
into the pons and superiorly into the
thalamus. B. Axial FLAIR image shows
the hyperintense mass extending from
the right cerebral peduncle anteriorly
into the temporal lobe (arrows). The
heterogeneity within the mass likely
represents necrosis. C. Postcontrast
T1-weighted image shows heteroge-
neous enhancement in the cerebral
peduncle and extending into the
temporal lobe (arrows). D. Postcon-
trast T1-weighted image shows het-
erogeneous enhancement in the pons
(arrows). The thalamus was similarly
involved (not shown). This rostral and
caudal extension is strongly suggestive
of a high grade tumor.

Proton MR spectroscopy and perfusion imaging may be useful in
differentiating low grade (Fig. 7-25), which have lower choline peaks
and smaller blood volumes, from high-grade tumors (Fig. 7-24). As
discussed with cerebellar tumors, however, pilocytic astrocytomas
(WHO grade I) have relatively high choline peaks and lactate peaks and
relatively high blood volumes, thus mimicking high-grade tumors.
Midbrain Tumors
The midbrain is the second most common site of tumors originating in
the brainstem. As with pontine and medullary tumors, midbrain tumors
should be separated by imaging into focal and diffuse tumors. In addi-
tion, many authors consider tectal tumors as a distinct third group of
midbrain tumors (191–193). In contrast to the predominance of dif-
fuse tumors in the pons, focal tumors are much more common in the
midbrain. The manner of patient presentation varies with the type of
tumor. Diffuse midbrain gliomas typically cause blurred vision or dou-
ble vision, often of acute onset and, sometimes, accompanied by motor
weakness. In contrast, patients with focal tumors typically present with
headache, vomiting, diplopia, and hemiparesis, with the exact symptoms
being dependent upon the location of the mass (188,192,194); upward
gaze paresis (Parinaud sign) may be present (192). Tectal tumors cause
signs and symptoms of hydrocephalus (see Chapter 8); upward gaze
paresis is conspicuously absent (188,191,192,195).
Precise diagnosis of the different midbrain tumors by neuroimag-
ing is very important in patient management; focal midbrain tumors
are treated surgically, whereas diffuse tumors are treated with chemo-
therapy/radiation, and tectal tumors are typically treated only by CSF
diversion unless tumor growth is documented on sequential imaging
studies (growth of tectal tumors is unusual [191,195]).
Diffuse midbrain tumors (Fig. 7-26) are uncommon tumors that
are centered in the midbrain, but extend rostrally into the cerebral
hemispheres and caudally into the pons and, sometimes, medulla.
These tumors have relatively little local mass effect and show mini-
mal enhancement (Fig. 7-26) after administration of paramagnetic
contrast.
Focal midbrain tumors (Fig. 7-27) are typically sharply circum-
scribed masses that focally enlarge the affected area. The tumor may be
midline or eccentric within the cerebral peduncle. They are typically of

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
low attenuation on CT, of low intensity on T1-weighted MR images, and
of high intensity on T2-weighted images. Hemorrhage or cysts are pres-
ent in approximately 25% of focal midbrain tumors (76,189,192). The
tumors occasionally extend superiorly into the thalamus and, less com-
monly, inferiorly into the pons (179,196). Administration of contrast
may show ring enhancement when the tumor is small; larger tumors
show homogeneous (Fig. 7-27) or heterogeneous enhancement (179).
Tumors of the quadrigeminal plate (Fig. 7-28), also called tectal
gliomas, are discussed in the section on “Pineal Region Masses.” These
tumors are, in general, extremely benign and are initially treated only
by CSF diversion of the resultant hydrocephalus. Sequential neuroim-
aging studies (preferably MR) are obtained to look for growth of the
Barkovich_Chap07.indd 673
673
FIG. 7-27. Focal midbrain glioma. A. Sagittal T1-weighted
image shows a sharply marginated hypointense mass (arrows)
within the tegmentum of the midbrain. B. Sagittal T2-weighted
image shows that the hyperintense mass (arrows) involves the
right cerebral peduncle and midbrain tegmentum. No surround-
ing edema is identified. C. Axial postcontrast T1-weighted image
shows nearly homogeneous enhancement of the solid portion
of the tumor. A small cyst (white arrowheads) is present at the
posterior tumor margin.
mass. Most will show no growth and can be followed without treat-
ment (188,191,193,195,197).
Brainstem Tumors Associated with Neurofibromatosis Type 1
Patients with NF1 have a high incidence of brain tumors, with the
brainstem being a common site of involvement (see Chapter 6). In one
series, brainstem tumors were detected in 9% of patients with NF1 who
were studied by MR (198). The relative frequency of sites of tumor
origin differs, with the medulla (Fig. 7-23) being the most common site
(68%–82%) in NF1, in contrast to the marked pontine predominance
in patients without NF1 (198–202). Although brainstem tumors of NF1
may have an identical imaging appearance to those that occur outside
5/6/2011 9:16:04 PM
 674 Pediatric Neuroimaging
the spectrum of NF1, their clinical behavior is often strikingly differ-
ent (198,200–202). Many of the patients with NF1 are asymptomatic
from their tumors, which are detected incidentally (198,201). The most
striking difference is that of tumor growth. In follow-up periods aver-
aging 3.75 to 4.3 years, only 32% to 42% of patients with NF1 showed
radiologic progression and only 14% to 18% showed clinical progres-
sion of these tumors (198,199,201). Even patients with tumors that
have imaging appearances identical to diffuse pontine tumors often
have relatively indolent clinical courses (198). Spontaneous remissions
have been reported (199). Therefore, the recommendation at present
is that only those tumors that exhibit rapid or unrelenting growth on
serial images or that produce significant clinical deterioration should
have intervention (198,201).
It is possible that localized proton MRS may help in the differ-
entiation of benign pontine enlargement (low grade tumor?) of NF1
Barkovich_Chap07.indd 674
FIG. 7-28. Glioma of the quadrigeminal plate. A. Sagittal TWI
shows an isointense to hypointense mass (m) expanding the tec-
tal plate with effacement of the intercollicular sulcus. The lateral
and third ventricles are markedly expanded due to hydrocepha-
lus. B. Sagittal T2 also demonstrates the enlarged tectal plate and
shows diffusely increased signal that extends around the aque-
duct and over the cap of the midbrain. C. Axial FLAIR image
shows the abnormal morphology and thickening of the tectal
plate (arrows) and the heterogeneous hyperintensity.
from pontine gliomas with more guarded prognoses. Broniscer et al.
have reported that patients with NF1 who have pontine enlargement
with benign clinical courses have significantly higher NAA and choline
levels, as detected by proton MRS, than patients with more clinically
aggressive pontine gliomas (203). Unfortunately, because metabolite
levels, as detected by MRS, vary from scanner to scanner, this is a rela-
tive measurement and no absolute values are available to differentiate
between these two entities.
Differential Diagnosis of Brainstem Tumors
The major differential diagnoses of brainstem tumors are encephali-
tis (viral, autoimmune, or protozoan [204,205]), abscess (see Chapter
11), demyelination (see Chapter 3) (206), dysmyelination secondary to
NF1 (see Chapter 6), LCH (175), hamartomas (206), resolving hema-
toma, cavernous malformation (see Chapter 12), and tuberculoma
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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 675

(207). Because of its exquisite demonstration of blood and blood
breakdown products, MR can differentiate brainstem astrocytomas
from cavernous malformations and subacute hemorrhage very easily.
Abscesses are now differentiated by the use of DWI (reduced diffusion
in abscesses, increased diffusion in cystic/necrotic tumors) and proton
spectroscopy (amino acid peaks are seen in abscesses but not tumors)
(49–52,208,209). Demyelination, Langerhans cell histiocytosis, and
dysmyelination due to NF1 can typically be differentiated by the pres-
ence of other lesions, a past medical history, or history of current dis-
ease. Tuberculoma can typically be identified by the short T2 relaxation
time of the caseated central portion (see Chapter 11). However, at this
time, it is still not possible to definitively differentiate acute encephali-
tis from a brainstem tumor on a single imaging study. History, labora-
tory studies, and, sometimes, sequential imaging studies are crucial to
making the correct diagnosis.
Hemangioblastoma
Hemangioblastomas are relatively rare benign tumors of vascular ori-
gin, with an incidence ranging from 1% to 2.5% of intracranial neo-
plasms. Less than 20% of hemangioblastomas occur in children, with
most being seen in young and middle-age adults. The incidence in
males exceeds that in females (8,75,76). Approximately 10% of heman-
gioblastomas occur in association with retinal angiomas, a condition
known as von Hippel-Lindau disease (see Chapter 6). Patients with von
Hippel-Lindau disease tend to have multiple hemangioblastomas of
the CNS, multiple cysts, or tumors involving the pancreas, liver, kidney,
and lung. Patients with hemangioblastomas may present with eryth-
rocythemia, thought to result from erythropoietin production by the
tumor (8,75,76).
Pathology
Hemangioblastomas occur most commonly in the cerebellar hemi-
sphere, especially the paramedian hemispheric area. Tumor origin
within the spinal cord is common and is often accompanied by syrin-
gomyelia. Rarely, hemangioblastomas may be located in the brainstem
or the cerebral hemispheres. As they originate from the surface of the
brain, a portion of the tumor is always connected to a pial surface. The
hemangioblastoma is classically described as a well-circumscribed,
soft, cystic tumor with a mural nodule. However, 30% to 40% of symp-
tomatic hemangioblastomas are solid; small, asymptomatic tumors are
much more commonly solid (210). On gross inspection, the solid por-
tion of the tumor may be intensely hemorrhagic. Calcification is not
found in these lesions.
Imaging Studies
The CT appearance of hemangioblastomas is usually that of a cystic or
solid posterior fossa mass. When large enough, the solid portion of the
tumor always enhances homogeneously and intensely after infusion of
intravenous contrast. However, when the solid portion of the tumor
is extremely small, it will not be seen on CT, particularly if it is in the
lower cerebellum or brainstem where artifact is most severe. Angiogra-
phy will confirm the vascular component of the tumor and will detect
small hemangioblastomas not seen on contrast CT. These very small
lesions can be reliably detected on contrast-enhanced MRI.
The most common MR appearance is that of a cystic mass with
a vascular mural nodule (Fig. 7-29) (211). The cyst may be hyperin-
tense on T1-weighted images if hemorrhage has recently occurred.
More commonly, cysts are hypointense on T1-weighted images and
hyperintense on T2-weighted images (211,212) (Fig. 7-29). Moreover,
on T2-weighted and FLAIR images, a peripheral rim of hyperinten-
sity may be seen as the result of surrounding edema. Solid portions of
tumor enhance dramatically after intravenous infusion of paramagnetic
contrast (213) (Fig. 7-29E and F). Other examples of MR images of
hemangioblastomas are provided in Chapter 6, in the section on “von
Hippel-Lindau Disease.” When the mural nodule is small, it may be
difficult to differentiate a hemangioblastoma from an arachnoid or
neuroepithelial cyst. In such cases, contrast-enhanced MRI should be
obtained in at least two planes, as volume averaging may obscure a
small region of enhancement in a single plane. When performed in at
least two planes, contrast-enhanced MRI allows identification of very
small tumor nodules, because they enhance intensely. Because of the
very dense vascularity of the tumor, MR angiography often shows the

FIG. 7-29. Hemangioblastoma of the dorsal medulla. A. Sagittal T2-weighted image shows a large loculated, heterogeneous mass (m) located in the dorsal
medulla, protruding into the inferior fourth ventricular. Signal is higher than that of the cerebellum, and multiple vascular signal voids (arrowheads) suggest
a rich vascularity. Although mostly solid, the tumor also contains two cysts (c) in its inferior aspect. There is massive associated edema in the medulla and
the upper spinal cord. B. Axial FLAIR imaging demonstrates hyperintensity of the tumor (m), multiple vascular signal voids and edema of the medulla.

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 676 Pediatric Neuroimaging

FIG. 7-29. (Continued) C. DWI shows low signal of the mass (m) with respect to the cerebellar hemispheres, reflecting intratumoral edema, and relatively
low cellularity. D. Maximum intensity projection from time-of-flight MR angiography shows the rich arterial network feeding the mass. E. Postcontrast
T1-weighted image reveals intense homogeneous enhancement of the solid part of the tumor (m), but not of the walls of the associated cysts (c). F. Conven-
tional angiogram, late arterial phase. This intense angiographic blush (b) is characteristic of hemangioblastomas.

main arterial feeder, and even some branching (Fig. 7-29D). In addi-
tion, conventional arteriography may be indicated sometimes to visual-
ize the hypervascular nidus (Fig. 7-29F), and many neurosurgeons will
order preoperative angiography on all suspected hemangioblastomas
to determine the location of the vascular pedicle prospectively. Pre-
operative embolization may serve to reduce blood loss and operative
morbidity. In all patients with suspected or known von Hippel-Lindau
disease, the spine should also be imaged, as affected patients have a
surprisingly high incidence of spinal hemangioblastomas (210).
Extraparenchymal Tumors
Schwannomas
Schwannomas are tumors derived from Schwann cells, which form the
myelin sheaths around the axons of nerves in the peripheral nervous
system. Schwannomas account for about 8% of primary tumors in
the intracranial cavity; however, they are more frequent in adults and
compose only 2% of posterior fossa tumors in children (8,75,214).
When schwannomas are diagnosed in childhood, the possibility of
type 2 neurofibromatosis (NF2) should be considered (see Chapter
6). An evaluation for other schwannomas and meningiomas should
be carried out (214). Schwannomas tend to occur at the sites of gan-
glia, i.e., at the transition from oligodendroglial cells to Schwann cells
(215). For example, vestibular schwannomas tend to occur at Scarpa
ganglion, which lies within the internal acoustic canal or in the cer-
ebellopontine angle. The location of the tumor often determines the
symptoms with which the patient presents. Because schwannomas are
tumors of the nerve sheath and not of the nerves themselves, patients
present with neuropathy only if the schwannoma occurs within a bony
canal. In such cases, outward growth of the tumor is restricted by bone;

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 677

FIG. 7-30. Schwannoma of the ninth cranial nerve. A. Axial T1-weighted

image shows a large mass (arrows) filling the cerebellomedullary angle
cistern, displacing the medulla (arrowheads) to the left, and entering the
jugular foramen anteriorly. B. Axial T2-weighted image shows the tumor
(arrows) to be heterogeneous, with areas of probably necrosis. C. Postcon-
trast T1-weighted image shows nearly homogeneous enhancement of the
mass.

the neoplasm therefore grows centripetally into the nerve causing com-
pression of the nerve and, hence, a neuropathy (216). However, if the
schwannoma occurs within the cranial cavity, symptoms will not occur
until growth of the tumor compresses adjacent neural structures; the
presenting signs and symptoms are those of brainstem compression or
hydrocephalus from compression of the aqueduct or fourth ventricle.
The most common nerve to be involved by a schwannoma is the eighth
cranial nerve, followed by the fifth, ninth, and tenth cranial nerves.
Other intracranial schwannomas are extremely rare, other than in the
setting of NF2 (215).
Imaging Studies
On noncontrast CT, schwannomas appear as hypodense to isodense
masses that occasionally calcify. Central necrosis can occur in large
lesions. After the infusion of intravenous contrast, the solid portion
of the tumor typically shows homogeneous enhancement (215). When
they occur within bony canals, schwannomas almost always enlarge
the canals by pressure erosion. For example, acoustic schwannomas
normally enlarge the internal auditory canal and facial schwannomas
frequently enlarge the facial canal within the petrous bone.
On MRI, schwannomas have prolonged T1 and T2 relaxation times
(217–219). Large schwannomas often show heterogeneity with areas of
high and low signal intensity on T2-weighted sequences (Fig. 7-30); the
areas of T2 hypointensity are most likely caused by the by-products of
intratumoral hemorrhage, whereas the areas of T2 hyperintensity are
usually regions of cystic necrosis. Presentation with acute intratumoral
hemorrhage is extremely rare. The enlarged cranial nerves coursing
through enlarged neural foramina (i.e., the foramen ovale and fora-
men rotundum in trigeminal schwannomas and the internal auditory
canal in acoustic schwannomas) and enlargement of adjacent CSF cis-
terns are easily demonstrated by MRI. Administration of paramagnetic
contrast results in enhancement of solid portions of the tumor (Figs.
7-30 and 7-31) (219). An example of schwannomas in the setting of
NF2 is illustrated in Figure 7-31 and several examples are in Chapter 6.
Small schwannomas may also be detected on high definition T2 imag-
ing (CISS/FIESTA) as focal enlargements of the nerve.
Dysembryoplastic Tumors (Epidermoids, Dermoids,
and Enteric Cysts)
Dermoids and Epidermoids: Presentation and Pathology
Dermoid and epidermoid tumors will be discussed in this section
because they occur somewhat more frequently in the posterior fossa
than in the supratentorial space or spine. Epidermoids develop from
the ectoderm-derived epidermis, whereas dermoids arise not only
from the epidermis but also from the subjacent dense connective tis-
sue, the mesoderm-derived dermis. Both of these tumors are believed
to arise from congenital rests of tissue that remain in the intracranial
cavity as a result of incomplete separation of the neuroectoderm from

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 678 Pediatric Neuroimaging
FIG. 7-31. Multiple schwannomas in a patient with neurofibromatosis
type 2. Postcontrast T1-weighted image shows bilateral enhancing acoustic
schwannomas (closed arrows) and an enhancing facial nerve schwannoma
(open arrow).
the cutaneous ectoderm at the time of closure of the neural tube.
Epidermoids are more common than dermoids (8,75,76).
The location of epidermoids shows a much greater variation than
that of dermoids, as well as a greater tendency to deviate from the
midline. The most frequent site is the cerebellopontine angle, fol-
lowed by the pineal region, the suprasellar region, and the middle
cranial fossa. Although epidermoids may present at any age, most
Barkovich_Chap07.indd 678
are diagnosed in middle age with a peak incidence during the fifth
decade. Epidermoids in the cerebellopontine angle tend to present
with cranial neuropathies. In contrast, suprasellar and pineal region
epidermoids present with hydrocephalus, while middle cranial fossa
epidermoids most frequently present with chemical meningitis sec-
ondary to leakage of tumor contents into the subarachnoid space
(8,75,76,220).
Dermoids are less common in the intracranial cavity than epider-
moids, but are more common in the spinal canal. In the intracranial
cavity they are most frequently located in the posterior fossa, either
within the vermis or in the fourth ventricle. In the spinal canal, most
dermoids occur in the lumbosacral region, either in an extramedul-
lary or an intramedullary location. Approximately 20% of dermoids
are associated with dermal sinuses; those dermoids associated with
dermal sinus tracts are most common in the spine, cerebellar vermis,
and subfrontal regions. Symptoms from intraspinal dermoids usually
arise in the first two decades of life, whereas those from intracranial
dermoids are more typically manifested in the third decade. Symp-
toms may be the result of obstruction of the CSF pathways, chemical
meningitis from leakage of the contents of the cyst into the CSF, or
(when associated with dermal sinus tracts) from infection and abscess
formation within the tract or the dermoid itself (8,75,76,221,222).
Extracranial dermoids, which typically present as masses on the head,
are discussed in Chapter 5. Spinal dermoids developing in associa-
tion with dermal sinuses are discussed in Chapter 9, whereas those
developing in the spine in the absence of dermal sinuses are discussed
in Chapter 10.
Imaging Studies
Epidermoids CT scans show epidermoids as low density, lobulated
masses that occur in characteristic locations (Fig. 7-32). The attenuation
is often identical to that of CSF, making identification of these extra-
axial lesions difficult. If necessary, the introduction of water-soluble
contrast into the subarachnoid space will demonstrate insinuation of
the contrast into the interstices of the epidermoid, revealing its charac-
teristic lobulated appearance (Fig. 7-32B). However, particularly with
FIG. 7-32. Epidermoid tumor: use of CT
cisternography. A. Contrast-enhanced CT
scan shows a low attenuation, nonenhanc-
ing suprasellar mass (arrows). Note that
the margins of the mass are somewhat
irregular and lobulated. B. After introduc-
tion of intrathecal contrast, the contrast
material can be seen to diffuse into the
interstices of the mass, showing a char-
acteristic lobulated appearance (arrows).
This lobulated appearance is very charac-
teristic of epidermoid tumors.
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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 679

FIG. 7-33. Infravermian epidermoid tumor. A. Sagittal T1-weighted image shows a hypointense, slightly heterogeneous, lobulated mass (arrows) with
lobular indentations on the dorsal medulla (arrowheads). Epidermoids are characteristically isointense with CSF. B. Axial T2-weighted image shows a lobu-
lated mass displacing the cerebellar hemispheres and medulla. C. Postcontrast axial T1-weighted image shows that the tumor does not enhance, instead
remaining isointense with CSF. D. Diffusion-weighted image (b = 1000 s/mm2) shows that the mass is heterogeneously hyperintense, indicated reduced
diffusion compared with CSF and differentiating it definitively from an arachnoid cyst, which would remain hypointense (see Fig. 7-34). The heterogeneity
is likely due to fibrous tissue and perhaps fluid in the interstices of the tumor.

FLAIR and diffusion-weighted sequences, the diagnosis of epidermoid
by MRI is so accurate that CT should only be used if MRI is not available.
On MRI, epidermoids appear as somewhat heterogeneous, mildly
lobulated extra-axial masses with prolonged T1 and T2 relaxation
times; enhancement is not seen after infusion of intravenous contrast
(Fig. 7-33). Thus, as with CT, most epidermoids have a signal inten-
sity that is similar to CSF on standard T1- and T2-weighted images.
Difficulty may arise in identifying small lesions and, once identified,
in differentiating an epidermoid from an arachnoid cyst (Fig. 7-34).
Cisternal epidermoids are identified by enlargement of the occu-
pied cisterns and the characteristic lobulated appearance of the mass
(Fig. 7-33) (223). Differentiation from a smooth-walled arachnoid
cyst is not difficult when the mass is large; a lobulated appearance and
the presence of linear heterogeneities (Fig. 7-33) within the mass sug-
gest that it is an epidermoid. Diagnosis is confirmed by DWI, which
shows diffusivity of a solid mass (signal intensity similar to or higher
than brain tissue, Fig. 7-33D), whereas cysts have characteristics of
fluid (similar to CSF, Fig. 7-34D) (224,225). FLAIR (Fig. 7-35) and
CISS sequences improve the conspicuity of epidermoids (225,226)
and also are useful in differentiating them from cysts. Alternatively,

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 680 Pediatric Neuroimaging

FIG. 7-34. Infravermian arachnoid cyst for contrast with epidermoid. A. Sagittal T1-weighted image shows a hypointense infravermian mass. The margins
of the displaced brain are completely smooth other than the fastigium of the fourth ventricle (arrow). No lobulations are seen, in contrast to the contour
around the epidermoid tumor in Figure 7-33. B. Axial T2-weighted image shows the homogeneous cyst displacing the medulla and cerebellar hemispheres.
No lobulations are seen. C. Postcontrast T1-weighted image shows absence of enhancement of the homogeneously hypointense mass. D. Diffusion-weighted
image (b = 1000 s/mm2) shows the cyst to be homogeneously hypointense, identical to CSF, indicating water diffusion equal to that of CSF. Contrast this
with the heterogeneous hyperintensity in the epidermoid tumor illustrated in Figure 7-33.

magnetization transfer techniques may be useful, as epidermoids will
show significant transfer of magnetization from the solid matrix of
the tumor to adjacent free water whereas cysts show no magnetiza-
tion transfer (227). Occasionally, epidermoids show T1 hyperintensity
(228); in this circumstance, they are more difficult to differentiate from
dermoids or lipomas. Differentiation can be made by application of fat
suppression; the high signal from dermoids or lipomas will be satu-
rated (disappear), but the high signal from epidermoids will remain
unaffected.
Dermoids The CT appearance of a dermoid is that of a fat-attenua-
tion, extra-axial mass that is usually located in the midline. As with epi-
dermoids, enhancement is not seen after infusion of IV contrast unless
the tumor is or has been infected (223). Whenever a midline dermoid
or epidermoid tumor is encountered, the occipital and naso-frontal
regions of the skull (when intracranial) or the posterior elements of the
vertebra (when intraspinal) should be examined for defects that might
indicate the presence of a dermal sinus tract. CT is more sensitive than
MRI for detection of the calvarial defect, although MRI is more sensi-
tive in detecting the tumor (229). Dermal sinuses result from a focal
nondisjunction of neural ectoderm from cutaneous ectoderm and
may be lined by fat (see Chapter 9). If infected, dermoid cysts have the
typical appearance of an abscess with a low diffusivity and a uniform,
contrast-enhancing rim surrounding them.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 681

FIG. 7-35. Utility of FLAIR and diffusion imaging in epidermoid tumors. A. Postcontrast axial T1-weighted image shows a hypointense mass (arrows) in
the left cerebellomedullary angle. B. Axial T2-weighted image shows the hyperintense mass (arrows) to have slightly lobulated margins. C. Axial diffusion-
weighted image (b = 1000 s/mm2) shows the mass (arrows) to be hyperintense, indicated reduced diffusion compared with cerebral parenchyma. D. Axial
FLAIR image shows the mass (arrows) is hyperintense compared with CSF, differentiating it from an arachnoid cyst.

On MRI, dermoids have hyperintense T1 and hypointense T2 signal
with associated chemical shift artifact, similar to lipomas (Fig. 7-36) (for
discussion of intracranial lipomas, see Chapter 5). The high signal inten-
sity will disappear after fat suppression is applied (Fig. 7-37). However,
dermoids are typically less lobulated than lipomas and will displace blood
vessels and nerves; lipomas engulf vessels and nerves (see Chapter 5).
Because affected patients often present with headaches from chemical
meningitis, inspection of the subarachnoid spaces and cerebral ventri-
cles for fatty droplets should be performed. Occasionally, the dermoid
contains a solid or cystic component (which will have T1 hypointensity
and T2 hyperintensity compared with normal brain) or calcification
(which has a variable signal on MRI [230]). Rarely, dermoid contain
hair and other components that lack mobile protons; in such cases, the
dermoid tumor will appear completely black on MR images.
Enteric (enterogenous) Cysts
Enteric cysts (also known as enterogenous, neurenteric, foregut, epi-
thelial, bronchogenic, endodermal, and respiratory cysts) are a part of
the split notochord syndrome. They are most commonly found in the
spine and are discussed more completely in Chapter 9. Briefly, they are
thought to result from a persistent endodermal-ectodermal adhesion.
Affected children typically present with headaches, gait disturbance,
cranial neuropathies, sensorimotor deficits, or recurrent aseptic men-
ingitis (231–233); however, they may be found incidentally (234).
Imaging studies show an extraparenchymal posterior fossa mass.
The most common locations are the cerebellopontine angle and the
prepontine cistern (231,232); however, they may be found in the fourth
ventricle or in the supratentorial subarachnoid spaces (233). Rarely, as
in the spine, intraparenchymal extension may be seen in intracranial
enteric cysts. The cysts have variable imaging characteristics, depending
upon the protein concentration. CT most commonly reveals sharply
demarcated, hypodense masses; occasionally, they may be isodense
or hyperdense to brain parenchyma (235) or show ring enhancement
(233). On MRI, T1-weighted images typically show the cysts to be
hyperintense with respect to CSF and hypointense or isointense with
respect to brain parenchyma (Fig. 7-38); they may be heterogeneous

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 682 Pediatric Neuroimaging

FIG. 7-36. Dermoid. A. Coronal T1-

weighted image shows a small mass of
diminished T1 relaxation time within the
right temporal lobe extending into the
temporal horn of the right lateral ven-
tricle (arrows). Note the dilatation of the
left temporal horn (arrow heads) and the
frontal horns (open arrows), indicative
of hydrocephalus. B. Axial T2-weighted
image shows fat floating within the fron-
tal horns of lateral ventricles (arrows) as a
result of rupture of the dermoid into the
ventricular system. Note the chemical-shift
artifact manifested as the low signal inten-
sity along the dorsal aspect of the dermoid
in the left frontal horn.

FIG. 7-37. Use of fat suppression in a

dermoid. A and B. Axial noncontrast CT
images show a fat-density mass (arrows)
expanding the left ambient cistern. C. Cor-
onal T1-weighted image shows a lobulated
heterogeneous hyperintense mass (large
open black arrows) in left ambient cistern,
curved around the free edge of the tento-
rium cerebelli. Note droplets of fat (small
black arrows) in the interhemispheric fis-
sure and sulci secondary to rupture of the
tumor into the subarachnoid space. D.
After application of fat suppression, the
hyperintensity of the fat (open black arrows)
is suppressed and the subarachnoid foci of
dermoid tumor appear hypointense.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 683

FIG. 7-38. Enteric (enterogenous) cyst. A. Sagittal T1-weighted image shows a slightly lobulated mass with diminished T1 relaxation time situated within
the premedullary space and extending through the foramen magnum into the ventral spinal subarachnoid space (arrowheads). B. Axial T1-weighted image
at the C1 level shows the mass sitting ventral within the spinal canal, slightly compressing the spinal cord (arrowheads).

(234). T2-weighted images typically show hyperintensity compared to
both CSF and brainstem, although when protein concentration is high,
they may be uniformly hypointense. Mild peripheral enhancement
may be seen possibly due to an inflammatory reaction (233). Rarely,
a fluid-fluid layer, or even air, may be identified (231,236). Associ-
ated anomalies of adjacent bone are rare (233). Differential diagno-
ses include arachnoid cyst, which has an identical appearance when
the enteric cyst contains clear fluid, and epidermoid tumor, which can
usually be differentiated by the use of diffusion imaging (epidermoids
have diffusion characteristics intermediate between brain parenchyma
and CSF, while enteric cysts have diffusion characteristics very similar
to CSF).
Teratomas
Intracranial teratomas are rare, and account for only 0.5% of primary
intracranial neoplasms. However, in children younger than 15 years
old, they account for 2% of intracranial tumors. Moreover, teratomas
represent a significant fraction of brain tumors that are diagnosed in
infancy (see section on “Tumors in First Year of Life” later in this chap-
ter). Intracranial teratomas are more common in males than females,
as a result of the preponderance of pineal teratomas in males. The clini-
cal presentation depends upon the location of the tumor. Hydrocepha-
lus is common, as it is in other midline tumors (8,76).
Pathology
Teratomas are most commonly found in the pineal and parapineal
regions, followed by the third ventricular region (especially its floor),
and the posterior fossa. Other than sacrococcygeal teratomas (see
Chapter 9), teratomas are less common in the spine than intracrani-
ally; they may occur at any spinal level and are associated with spina
bifida occulta. Most teratomas are well circumscribed and benign, but
some contain primitive elements and are highly malignant neoplasms
that carry a poor prognosis. Some secrete biochemical markers, such
as a-fetoprotein and b-human chorionic gonadotropin, which can
be measured in the CSF and serum. Grossly, teratomas are lobulated
and variegated in appearance. The tumors tend to have both solid and
cystic components and frequently contain calcification or bone. More
malignant areas of tumor show less differentiation (8,76).
Imaging Studies
On both CT and MRI, teratomas generally appear as sharply
marginated, heterogeneous lesions that are located in the midline. On
CT, they can be reliably diagnosed if both fat and calcium are noted
within the mass; when fat and calcium are seen in a midline lesion
with soft tissue intensity, the diagnosis of teratoma should be sug-
gested (Fig. 7-39A). On MRI, the presence of fat and soft tissue inten-
sity together with punctate foci of low signal intensity (suggestive of
calcium) in a midline mass should raise the suspicion of teratoma (Fig.
7-39B and C). The author has seen several patients, however, in whom
teratomas were of homogeneous soft tissue intensity on both CT and
MRI. Teratomas with a homogeneous imaging appearance are com-
monly malignant and are indistinguishable from many other types
of intrinsic brain tumors by imaging methods. Malignant teratomas
more often elicit vasogenic edema and also have more irregular shapes,
less sharply defined margins, fewer cysts, and smaller areas of calcifi-
cation than benign teratomas (237). The degree of contrast enhance-
ment is variable. A lack of contrast enhancement suggests a low-grade
tumor; however, the presence of enhancement does not assure that the
tumor is malignant. Further examples of teratomas will be shown in
the section on “Germ Cell Tumors” and in the section on “Tumors in
the First Year of Life.”
Miscellaneous Tumors of the Posterior Fossa
and Skull Base
Other tumors that occur in the posterior fossa in children are
extremely rare.

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 684 Pediatric Neuroimaging

FIG. 7-39. Teratoma. A. Noncontrast axial CT shows a dorsal posterior fossa

midline mass, which has a heterogeneous appearance (arrowheads). A large focus
of calcification is seen within the mass (arrow). Hydrocephalus is present, as
manifested by the enlarged temporal horns. B. Sagittal T1-weighted image shows
the teratoma to be of mixed signal intensity. Fatty components are of very high
signal intensity (arrow heads), soft tissue components are of soft tissue intensity
(solid arrows) and the calcification is of very low intensity (open arrow). C. Axial
T2-weighted image shows that the solid portion of the tumor is now of high signal
intensity whereas the fatty and calcified portions are now of low signal intensity.

Meningiomas histiocytoma, histiocytic lymphoma, and xanthoma disseminatum

Although meningiomas do occur in children, they are unusual and are
most frequently found in the supratentorial space (particularly arising
from the choroid plexus in the lateral ventricular trigone) in associa-
tion with Type 2 neurofibromatosis (see Chapter 6 and the section later
in this chapter).
(238–240). The most common histiocytic disorder to involve the CNS
is LCH, a clonal proliferative disorder of cells of the mononuclear
phagocytic and dendritic cell system of unknown pathophysiology
(241,242). LCH can involve the bone, the meninges, the choroid plexus,
or brain parenchyma.

Langerhans Cell Histiocytosis Bone Involvement in the Face and Head When an osteolytic mass
A number of histiocytic disorders may involve the CNS, including involves the skull base, orbit, or facial bones in a child, the diagnosis
Rosai-Dorfman disease, Erdheim-Chester disease, malignant fibrous of LCH should always be considered and a CT or MR scan should be

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 685

FIG. 7-40. Langerhans cell histiocytosis of the skull base. A. Axial CT image photographed with bone windows shows sharply demarcated defects (arrows)
in the squamous portion of the right temporal bone and in the midline of the occiput. B. Coronal contrast-enhanced CT scan shows enhancement (arrows)
of both lesions.

obtained to characterize the lesion and look for other signs of LCH.
Patients may present with tender, palpable skull masses, with proptosis,
or with evidence of cerebral or cerebellar dysfunction (175,220,241–
243). The most common imaging finding is that of a firm mass
involving the calvarium, orbit, or skull base. CT shows a sharply cir-
cumscribed skull lesion, most commonly involving the temporal bone
that enhances uniformly after administration of contrast (Figs. 7-40
and 7-41). Lesions may be single or multiple; thus, other lesions, in the
calvarium and extracranial bones, should be sought by skeletal sur-
vey. MRI shows the bone lesions as sharply defined soft tissue masses
that have signal intensity comparable to skeletal muscle and enhance
markedly after IV administration of paramagnetic contrast (Figs. 7-41

FIG. 7-41. Langerhans cell histiocytosis of the temporal bones. A. Axial CT with bone windows shows large, sharply marginated lytic defects (arrows) in the
mastoid and squamous portions of both temporal bones. B. Postcontrast axial T1-weighted image shows uniform enhancement (arrows) of the lesions.

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 686 Pediatric Neuroimaging

FIG. 7-42. MRI of Langerhans cell histiocytosis of the skull base.

A. Axial T1-weighted image shows a mass (open arrows) eroding
through the anterolateral wall of the right middle cranial fossa
(closed arrow). B. Axial T2-weighted image better defines the mass
(arrows), which has a hypointense rim. C. After administration of
contrast, the mass (arrows) uniformly enhances.

and 7-42) (241,244). Involvement of the mastoid is common and can
mimic mastoiditis (241).
Involvement of the Brain The most common signs and symptoms
of LCH involving the CNS are those of diabetes insipidus from involve-
ment of the pituitary stalk. An enhancing mass is typically seen in the
tuber cinereum or infundibulum (see section on “Sellar and Supra-
sellar Masses”). Rarely, Langerhans cell histiocytosis can affect regions
of the brain other than the hypothalamus (175,245,246). Patients may
present with acute neurologic deficit or with progressive neurologic
deficits of insidious onset. Early cerebellar and long-tract signs and
symptoms may progress to profound neurological dysfunction with or
without intellectual deficits (175,243,244,247). Findings in the brain
on imaging studies are variable. Affected patients may show diffuse
or focal regions of T1 hypointensity and T2/FLAIR hyperintensity
in the brainstem and corpus medullare of the cerebellum (Fig. 7-43)
(175,246,248). These findings reflect the histologic changes of demy-
elination, reactive astrogliosis, microglia activation, and loss of cells in
the Purkinje and granular cell layers of the cerebellar cortex (249,250);
however, the MR findings do not correlate with clinical deterioration

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 687

FIG. 7-43. Langerhans cell histiocytosis involving the pons and cerebel-
lar white matter. Axial T2-weighted image shows T2-prolongation in the
central pons (open arrows) and in the white matter of the cerebellar hemi-
spheres (closed arrows). These are the most common sites of parenchymal
involvement.

(251). Calcification may be seen in the cerebellar dentate nuclei on

CT. Diffuse atrophy and dilated perivascular spaces may be present
(246). Proton MR spectroscopy shows increased choline and reduced
NAA in the affected cerebellum, while 18-FDG PET shows reduced
uptake of glucose (252). Some patients have punctate lesions scattered
throughout the cerebrum, brainstem, and cerebellum. These punc-
tate lesions are granulomas, composed of Langerhans cells, microglial
cells, fibrillary astrocytes, CD1a+ histiocytes, CD68+ macrophages
and T and B cells (250); they show prolonged T1 and T2 relaxation
times compared with myelinated white matter and they enhance
markedly after intravenous infusion of contrast (175,243,244,247).
Typically, patients with cerebral parenchymal involvement also have
multiple lesions of the bone and most commonly have multisystemic
disease (249).

Chordoma
Chordomas are benign, slowly growing, locally infiltrative tumors that
arise from notochordal remnants. They are exceedingly rare in children
and only a few dozen cases are described in the literature. In contrast
to chordomas in adults, which are most common in the sacral region,
childhood chordomas are most common in the skull base and upper
cervical vertebrae; the most common location is at the sphenoid-
occipital synchondrosis (253,254). The behavior of these tumors in
children is similar to that in adults (255). Clivus chordomas usually
produce marked destruction of the sphenoid bone; they commonly
extend into the sphenoid sinuses, nasopharynx, and occasionally the
FIG. 7-44. Clivus chordoma. A. Sagittal T1-weighted image shows a large
ethmoid region. Patients with chordomas most frequently present with
mass (large arrows) pushing the pons posteriorly and pushing the pituitary
cranial neuropathies (diplopia, palatal or tongue weakness) resulting gland (small arrows) anteriorly. The displacement of the pituitary implies an
from extension of tumor into the cranial neural foramina. Headache, origin within the clivus. B. Postcontrast T1-weighted image shows a nearly
pyramidal signs, and symptoms of increased intracranial pressure may complete lack of enhancement of the tumor (arrows). C. Axial T2-weighted
also be present (254). On imaging studies, destruction of the clivus by image shows lateral displacement of both temporal lobes (arrows) and pos-
the tumor mass is readily apparent (256) (Figs. 7-44 and 7-45). When terolateral displacement of the pons by the hyperintense mass.

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 688 Pediatric Neuroimaging

FIG. 7-45. Clivus chordoma. A. Postcontrast sagittal T1-weighted image shows a large, mostly hypointense mass that has arisen from and destroyed most
of the basiocciput (white arrows). The lack of enhancement is common in pediatric chordomas. The pons (p) is pushed upward and the medulla (m) is
pushed dorsally and compressed by the mass. The fourth ventricle (arrowhead) is pushed posteriorly and compressed. BT. Axial T2-weighted image shows
prolonged T2 relaxation time within the tumor. The fourth ventricle (white arrows) is makedly pushed back. C. Axial T1-weighted image shows the bulky
hypointense mass distorting the brainstem and cerebellum and invading the clivus (white arrows). D. Axial FLAIR image shows the tumor (arrows) to be
somewhat heterogeneous.

tumor extends into the nasopharynx, it is often difficult to differentiate
from a primary nasopharyngeal tumor extending into the clivus. The
presence of spicules of bone within a minimally enhancing tumor on
CT should suggest the diagnosis of chordoma. The MR appearance of
chordoma is that of a large intraosseous mass extending into the pre-
pontine cistern, sphenoid sinuses, middle cranial fossa, or nasopharynx.
Considerable posterior displacement of the brainstem may be present
when the tumor is large (Figs. 7-44 and 7-45). Typical chordomas have
prolonged T1 and T2 relaxation values whereas chondroid chordomas
(a histological variant that have a significantly better prognosis [257])
have less T2 prolongation. FLAIR images often show more heterogene-
ity (Fig. 7-45D) than T2-weighted images (Fig. 7-45B). Enhancement
is variable, ranging from minimal to marked; in the author’s experi-
ence, chordomas of childhood (Figs. 7-44 and 7-45) rarely enhance. No
known correlation exists between degree of enhancement and tumor
grade or prognosis.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 689

FIG. 7-46. Chondrosarcoma of the skull base in a child. A. Axial

T1-weighted image shows a mass (white arrows) arising from the
petroclival synchondrosis and extending medially into the clivus and
laterally into the petrous apex. B. Fat-suppressed T2-weighted image
shows that the tumor (arrows) has prolonged T2 relaxation time. C.
Fat-suppressed T1-weighted image shows uniform enhancement of
the mass (arrows).

Chondrosarcomas
Very rarely, chondrosarcomas arise from the skull base in children.
Chondrosarcomas are malignant cartilaginous tumors that may arise
de novo or from sarcomatous changes in benign cartilaginous tumors,
such as chondromas or chondroblastomas. Only about 10% of chon-
drosarcomas present in the pediatric age group (258,259); the mean
age of presentation is in the third decade (220,260). A disproportion-
ate percentage (43%) of chondrosarcomas in children are high-grade
neoplasms with “unconventional” histology, most commonly the mes-
enchymal type (258,259). Patients typically present with headache,
sinus symptoms, proptosis, or cranial neuropathies. The most com-
mon locations are the petrooccipital, sphenooccipital, and sphenoeth-
moidal synchondroses, presumably arising from cartilaginous rests.
Extension into the cavernous sinus, sella turcica, sphenoid sinus, or
parapharyngeal space is common (261). On imaging studies, chon-
drosarcomas are heterogeneous (59% on MR, 44% on CT) second-
ary to mineralization and prominent fibrocartilagenous elements.
The nonosseous elements have long T1 and T2 relaxation times and
enhance heterogeneously after intravenous contrast administration.
As the tumors often lie adjacent to fat in the marrow, infratempo-
ral fossa, and deep facial regions, the use of fat saturation pulses is
helpful on postcontrast studies. These tumors are nearly impossible to
confidently differentiate from chordomas on imaging studies, as the
appearance is essentially identical (Fig. 7-46). However, paramedian
origin from the petroclival synchondrosis and uniform enhancement
favor the diagnosis of chondrosarcoma.

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 690 Pediatric Neuroimaging
FIG. 7-47. Metastatic neuroblastoma to skull base. A. Sagittal T1-weighted image shows elevation of the pituitary gland (arrows) by a mass that is isointense
to the basisphenoid bone. B. Postcontrast coronal T1-weighted image shows elevation of the periosteum (arrows) from the sphenoid bone by the tumor.
Neuroblastoma
When neuroblastoma presents with signs or symptoms referable to
the skull and brain, it is most commonly with proptosis or a scalp
mass secondary to metastasis to the orbital wall or calvarium (dis-
cussed later in this chapter). The involvement of brain parenchyma
by neuroblastoma is very rare, occurring in only 1% of cases (262).
Sometimes, neuroblastoma can originate in the upper cervical or skull
base portions of the sympathetic chain. These primary neuroblasto-
mas present as homogeneous, uniformly enhancing extraparenchy-
mal masses in the cerebellomedullary or cerebellopontine angles. An
extracranial, as well as intracranial, component will often be present,
giving a clue to the correct diagnosis. Neuroblastoma primary to other
parts of the body (abdomen, pelvis, or chest) may present with cra-
nial neuropathy as a result of metastasis to the skull base (Fig. 7-47).
The tumor appears as an enhancing, infiltrative mass that elevates the
periosteum from the bone. Identification of a mass or of periosteal
elevation is important in making the diagnosis of metastatic tumor to
the skull base, as the normal infant’s skull base contains hematopoi-
etic marrow that enhances (263). As a result, enhancement of marrow
in an infant or young child with neuroblastoma is not sufficient to
establish a diagnosis of metastatic disease. Ewing sarcoma (both pri-
mary and metastatic [264]) and leukemia, which can also involve the
skull base, all have identical neuroimaging appearances. Metastatic
neuroblastoma to the skull base, therefore, cannot be differentiated
from them.
Aneurysmal Bone Cyst
Only 2% to 6% of aneurysmal bone cysts involve the calvarium
(265,266). When they do, the orbital and occipital bones are most
commonly involved. Affected patients may present with proptosis, a
tender, enlarging mass on the head, or with signs of increased intrac-
ranial pressure, the latter sometimes associated with cerebellar dys-
function or cranial neuropathies (265,267). It is important to identify
that these lesions originate in the calvarium and to suggest the diag-
nosis of aneurysmal bone cyst, as preoperative embolization may be
Barkovich_Chap07.indd 690
useful to reduce intraoperative blood loss. Radiographic examination
shows an expansile calvarial lesion with classic “soap bubble” rim of
calcium around the lesion. CT shows a multilobular mass confined
by a smooth, fine peripheral layer of bone; a fluid-fluid layer may be
seen within the soap bubble calcification. Direct coronal CT images
may be useful to establish that the lesion is intraosseous. MRI shows
an expansile calvarial mass with a low intensity rim and smooth
margins. T1-weighted MR images show intrinsic heterogeneity with
intensity similar to that of gray matter. T2-weighted MR images show
heterogeneity and, often, fluid-fluid layers; the lower (dependent)
layer is very hypointense and the upper (nondependent) layer vari-
ably hyperintense (265,268). Other features include round to ovoid
regions of very high signal intensity, probably representing areas of
blood or areas of serum with a high protein concentration (269). This
appearance is no different than that seen in adults. Sagittal and coro-
nal images are often useful to determine that the mass originates from
the bone.
Ewing Sarcoma
Very rarely, Ewing sarcoma can arise primarily from the skull. The most
common location of origin is the temporal bone, followed by fron-
tal, parietal, and occipital bones. Patients typically present with signs
and symptoms of an intracranial mass: headache, vomiting, blurred
vision, ataxia, or cranial neuropathy. Imaging shows an extraparenchy-
mal mass that has typical characteristics of a small round cell tumor;
the mass is isodense to slightly hyperdense on noncontrast CT and
nearly isointense to cortical gray matter on noncontrast MRI. Diffuse
enhancement may be seen after intravenous administration of contrast
material (270,271). Sometimes the periosteum may be lifted off of the
inner table of the calvarium, resulting in an “onion skin” appearance
or coarse calcification on CT. Cystic regions can sometimes be found
within the mass. A key finding is the involvement of the overlying cal-
varial bone, giving evidence that it is a primary tumor of bone. This
appears as permeative destruction on CT and as alteration of the nor-
mal absence of bone signal on MRI (271).
5/6/2011 9:16:23 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 691

SUPRATENTORIAL TUMORS Hemispheric Astrocytomas

As previously stated, supratentorial tumors are more common than
infratentorial tumors in children less than 2 years and older than
10 years of age.
Tumors of the Cerebral Hemispheres
Astrocytomas are clearly the most common type of cerebral hemi-
spheric tumor of childhood. However, other diagnoses should be
strongly considered when hemispheric tumors are found in neonates
and infants (Table 7-7). In neonates, teratoma should always be con-
sidered, especially if the tumor is heterogeneous or has calcium or fat
within it. In infants, atypical teratoid/rhabdoid tumor, ependymoma,
desmoplastic infantile ganglioglioma, and primitive neuroectodermal
tumor should be considered in the diagnosis if the solid portions of the
tumor have a high attenuation on CT or if reduced diffusion and signal
intensities similar to gray matter are found on MRI. Finally, if a child
with a predominantly cortical tumor presents with a longstanding
seizure history, the diagnoses of ganglioglioma and dysembryoplastic
neuroepithelial tumor should be considered.
Pilocytic Astrocytomas, Astrocytomas, Anaplastic
Astrocytomas, Glioblastomas
Astrocytomas of the cerebral hemispheres constitute approximately
30% of supratentorial brain tumors in children. Most series show
a slight male predominance. All pediatric age groups are affected,
although there is a slight peak at 7 to 8 years of age. The presenting
signs and symptoms depend upon tumor location. Seizures, focal
neurological deficits, and symptoms of increased intracranial pres-
sure (headache, vomiting, and altered sensorium) are the most com-
mon presenting symptoms, but ocular/ophthalmological signs and
abnormal cognition may be present (8,76,272–275). Seizures are likely
to be the presenting symptom when the tumor is located in the frontal
or temporal cortex (276).
Pathology Grossly, hemispheric astrocytomas are similar to cerebellar
astrocytomas; they can be solid, solid with a necrotic center, or cystic
with a mural nodule. Most pediatric hemispheric astrocytomas have a
low histologic grade, although GBM does occur in childhood and has a
better prognosis than in adults (277,278). JPAs are less common in the

TABLE 7-7 Cerebral Hemispheric Tumors in Children

Tumor Key Findings
Astrocytoma Most common tumor
MR appearance varies with grade/histology
Giant cell tumor Develop from ventricular wall
Usually near foramen of Monro
Ependymoma Peritrigonal, heterogeneous
Primitive neuroectodermal tumor Young children, heterogeneous
Solid part: gray matter intensity
Astroblastoma Children and teens. Peripheral hemisphere.
Lobulated. Solid/cystic. Little edema.
Solid part: gray matter intensity on T2
Mixed neuronal-glial tumors Cortical location
Calcification, cysts common
Desmoplastic neuroepithelial tumors Young infants. Large cysts, solid part invades dura
Dysembryoplastic neuroepithelial tumor Cortical location,
Marked T2 hyperintensity
Atypical teratoid/rhabdoid tumor Young infants. Often large at presentation.
Cortical intensity on T2, cysts
Medulloepithelioma No enhancement
Plasma cell granuloma Hypointense on T2 images
Meningioangiomatosis Hypointense with hyperintense
periphery on T2 images
Germinoma Basal ganglia
Heterogeneous with solid and cystic areas; solid portions
isointense to gray matter on T2 and uniformly enhancing
Postransplant lymphoproliferative Multiple foci of gray matter intensity on T2 images, slightly
disorder Immunosuppressed children hyperintense to gray matter on FLAIR
Marked vasogenic edema
Markedly enhance

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 692 Pediatric Neuroimaging
cerebral hemispheres than in the cerebellum and, therefore, the over-
all prognosis of supratentorial astrocytomas is somewhat worse. The
tumors have no characteristic location, although they tend to occur
deep within the hemispheres, more frequently involve the basal gan-
glia or thalamus than do adult tumors, and may involve more than
one lobe of the brain (8,76,272,274,279). They are often very large at
the time of presentation. Pediatric astrocytomas, even those of low his-
tologic grade, may be multicentric at the time of presentation; this is
most likely the result of subarachnoid or intraventricular tumor spread
(280,281). Multicentricity is most common when the primary tumor
site is the hypothalamus (hypothalamic tumors are discussed in a later
section of this chapter).
Imaging Studies CT of the brain reveals considerable variation in
tumor appearance. The solid portion of the tumor tends to be isodense
to hypodense prior to intravenous contrast administration. After infu-
sion of contrast, the solid portion may enhance completely, partially,
Barkovich_Chap07.indd 692
FIG. 7-48. Cystic astrocytomas. A. Axial postcon-
trast CT shows a large cyst (open arrows) with an
enhancing mural nodule (closed arrow). When cysts
are this large, it is difficult to determine whether
they are intraparenchymal or extraparenchymal.
Therefore, contrast should be administered to all
patients with intracranial “cysts” to rule out the
presence of an enhancing mural nodule. B. Non-
contrast coronal T1-weighted image shows a small
cyst (arrows) in the temporal lobe. C. Postcontrast
T1-weighted image shows enhancement of a mural
nodule (arrows) within the cyst.
or not at all. The tumor can be completely solid, solid with a central
area of necrosis, or partially cystic with an enhancing solid component.
When cysts are large, it is often difficult to determine whether they
are intraparenchymal or extraparenchymal. Therefore, it is impor-
tant to administer contrast when cysts are detected. The presence of
an enhancing mural nodule (Fig. 7-48) makes the diagnosis of cystic
astrocytoma likely. It is not possible to differentiate benign from malig-
nant astrocytomas of the cerebrum by CT criteria alone. In general,
malignant tumors tend to be larger, their solid components have higher
attenuation, and they occur in younger children but these differences
are not significant enough to help determine pathology in individual
cases (282). Occasionally, hemorrhage is seen in high-grade supraten-
torial astrocytomas (10).
On MRI, astrocytomas typically appear as large, medially located
hemispheric masses that have prolonged T1 and T2 relaxation values
when compared with normal brain (Figs. 7-49 and 7-50). Although typ-
ically found deep within the hemisphere, they can occur in the cerebral
5/6/2011 9:16:24 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 693

FIG. 7-49. Pilocytic astrocytoma. A. Sagittal T1-weighted image shows a mass that is isointense with gray matter located in the left thalamic region
(arrows). Note that the anterior portion (arrowheads) is more hypointense, suggesting that it might be a cyst. B and C. Axial FLAIR (B) and T2-weighted
(C) images show the mass to have varying components with variable degrees of hyperintensity. D. After infusion of paramagnetic contrast, the varying
components of tumor are seen to include a tumor cyst (nonenhancing and the most hypointense, c), a proteinaceous cyst (mildly enhancing and slightly
hyperintense, p), a solid component (brightly enhancing, s), and a microcystic enhancing component (black arrows).

white matter or in the cortex. In general, pilocytic astrocytomas are
very hyperintense on T2-weighted and FLAIR images, elicit little or
no vasogenic edema in the surrounding white matter, have areas that
enhance quite markedly after administration of paramagnetic contrast,
and are associated with cysts of all sizes (Figs. 7-49 and 7-50). Cysts can
be separated from homogeneous, solid portions of tumor by FLAIR and
DWI: cysts have similar appearance to CSF. Low grade astrocytomas of
other histologies than pilocytic are homogeneous, free of hemorrhage,
well circumscribed, nonenhancing masses associated with mild or
no surrounding edema (Fig. 7-51). In contrast, higher grade tumors

Barkovich_Chap07.indd 693 5/6/2011 9:16:25 PM

 694 Pediatric Neuroimaging

FIG. 7-50. Pilocytic astrocytoma. A. Sagittal T1-weighted

image shows an ovoid thalamic mass with an anterior
(solid) component that is slightly hypointense compared
to surrounding brain and a more hypointense (cystic)
posterior component. B and C. Axial first and second
echo T2-weighted images show that the anterior solid
portion of the tumor is very hyperintense on both echoes.
D and E. Postcontrast T1-weighted images show uniform
enhancement in the anterior solid portion of the tumor.

FIG. 7-51. Grade II astrocytoma. T2-weighted (A), FLAIR (B), and postcontrast T1-weighted (C) images show that the tumor (arrows) is homogeneous
(no hemorrhage or necrosis), sharply marginated, elicits no vasogenic edema, and does not enhance.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 695

FIG. 7-52. Glioblastoma multiforme. A. Axial T2-weighted image shows a heterogeneous, partially cystic or necrotic mass in the right temporo-occipital
region with moderate peritumoral edema and significant mass effect upon adjacent structures. B. Postcontrast axial T1-weighted image shows moderate
rim enhancement and focal hypointensity in the right anterior portion (arrow) probably representing flow voids from feeding vessels.

show heterogeneity, resulting from areas of necrosis or hemorrhage,
and generate more extensive vasogenic edema (283) (Fig. 7-52). These
characteristics are not absolute; however, low-grade tumors can have
some high grade characteristics and vice versa. Enhancement patterns
after paramagnetic contrast infusion are similar to those seen on CT
after infusion of iodinated contrast (Figs. 7-49 and 7-50).
DWI is of some use in that solid areas of lower grade tumors
tend to have less tightly packed cells solid than areas of higher grade
tumors and, therefore, have higher diffusivity (284–287). Unfortu-
nately, higher-grade tumors more commonly undergo necrosis, which
increases diffusivity and diminishes the value of this technique.
As stated and illustrated in the first section of this chapter, some evi-
dence suggests that lower NAA/Cho ratio on proton MR spectroscopy
of glial tumors correlates with higher tumor grade (45,109); however,
pilocytic astrocytomas also have low NAA/Cho ratios (164), making
this ratio rather meaningless if used in isolation. In addition, inflam-
matory and dysplastic lesions may have spectroscopic characteristics
identical to that of malignant neoplasms (165). Other evidence sug-
gests that increased blood volume within the tumor as demonstrated
by perfusion imaging (54,109) correlates with higher tumor grade and
worsened survival (288). All of these characteristics, when combined
with imaging, can help to characterize a mass as a neoplasm. However,
determination of the histology of the neoplasm still requires biopsy
or resection. At the time of the writing of this book, no characteristic
features have been described that allow one to confidently differentiate
pediatric astrocytomas from ependymomas or oligodendrogliomas on
the basis of any MR characteristics.
SEGAs of tuberous sclerosis is better than that for patients with giant
cell components of ordinary astrocytomas (290), even though both are
considered grade I astrocytomas by the World Health Organization.
Indeed, there is some question whether the tumors associated with
tuberous sclerosis may have a different histology and should be clas-
sified separately from other astrocytomas with giant cell components
(291). Males and females are equally affected. The tumor may be diag-
nosed at any age, but peak occurrence is between ages 5 and 10 years.
When the affected child does not have tuberous sclerosis, the clinical
presentation is almost always that of hydrocephalus. Rarely, the tumors
can undergo malignant degeneration and invade surrounding brain
(8,76,289,292).
Pathology SEGAs usually arise from the wall of the lateral ventricle
near the foramina of Monro and produce hydrocephalus because of
obstruction at the foramen. They are believed to arise from the sub-
ependymal hamartomas that are part of the tuberous sclerosis complex
(see Chapter 6); in fact, the tumors bear histological similarity to the
subependymal hamartomas. Giant cell astrocytomas tend to be sharply
defined and homogeneous on pathological examination. They usually
are mostly intraventricular, but they may also develop deep in the brain
tissue. Focal calcification is common. Although usually histologically
benign, some show evidence of anaplasia (76,289). They may need to
be removed when they result in hydrocephalus. Recently, the use of
rapamycin or rapamycin-analogs has been shown to reduce the volume
of the tumor; however, the tumor expands again when the treatment is
discontinued (293).

Subependymal Giant Cell Astrocytoma
Subependymal giant cell astrocytoma (SGCA or SEGA) is the name
given to a mass that is characteristically associated with tuberous scle-
rosis. As these tumors occur in 5% to 15% of patients with tuberous
sclerosis (289), discovery of a giant-cell tumor should motivate a search
for other manifestations of this condition (see Chapter 6). SEGAs may
occasionally be found in other settings. The prognosis for patients with
Imaging Studies The CT and MR findings of tuberous sclerosis are
described in Chapter 6. The characteristic CT appearance of the sub-
ependymal giant cell astrocytoma is that of a hypodense to isodense,
well demarcated, rounded lesion originating from the ventricular wall,
most commonly in the region of the foramen of Monro, and usually
producing hydrocephalus (Fig. 7-53). Other subependymal masses,
both calcified and noncalcified, are usually present in the setting of

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 696 Pediatric Neuroimaging
FIG. 7-53. Giant cell astrocytoma. A. Noncontrast CT scan through the level of the foramen of Monro shows a mass originating from the foramen of
Monro (arrows) that is essentially isodense with brain. There is moderate vasogenic edema surrounding the mass. B. After infusion of iodinated contrast,
the mass uniformly enhances (arrows).
tuberous sclerosis. After the infusion of IV contrast, giant cell tumors
always uniformly enhance (10,294). Examination with MR also reveals
a well circumscribed, ovoid or rounded mass, most commonly in the
region of the foramen of Monro, and often extending into the adja-
cent lateral ventricle. Typically, the mass is hypointense to isointense
with brain tissue on T1-weighted sequences (Fig. 7-54) and hyperin-
tense on T2-weighted sequences (292,295–297). Multiple smaller sub-
ependymal nodules are almost always present if the child has tuberous
sclerosis. Moreover, on MRI, one typically sees multiple cortical
hamartomas that are identified by enlargement of the involved gyrus,
variable signal intensity on T1-weighted sequences and high signal
intensity on T2-weighted sequences (see Chapter 6 and Fig. 7-54).
Infusion of paramagnetic contrast results in uniform enhancement of
the giant cell tumor (Fig. 7-54B) (292,296). As stated in Chapter 6,
giant cell astrocytomas are characterized by slow, progressive growth.
If rapid growth or invasion of cerebral parenchyma is seen in a lesion
originating in the region of the foramen of Monro, it should raise sus-
picion of anaplasia.
Pleomorphic Xanthoastrocytoma
Pleomorphic xanthoastrocytomas (PXAs) are in some ways very simi-
lar to desmoplastic infantile gangliogliomas (DIG) and desmoplastic
astrocytomas of infancy (DACI) (see section on “Neuronal and Mixed
Neuronal-Glial Tumors” below). All are tumors that are dispropor-
tionately common in young patients, typically arise peripherally in the
cerebral hemispheres and involve the meninges, and have good prog-
noses despite histologic features that suggest high-grade malignancy.
However, unlike the desmoplastic tumors, PXAs are rarely diagnosed
in infants, being discovered most commonly in adolescents and young
adults (298–300). In addition, affected patients most commonly pres-
ent with seizures, probably because the cortex is nearly always involved.
Barkovich_Chap07.indd 696
The temporal lobe is the most common site (∼50%). Involvement of
the parietal lobe (15%–20%), frontal lobe (10%) and occipital lobe
(5%–10%) is less common (300). Rarely, other gray matter structures
such as the basal ganglia, cerebellum, or spinal cord may be the site of
origin (299).
Pathology Pathologically, PXAs arise in the periphery of the cere-
brum and often extend into and involve the leptomeninges, although
invasion of the dura is rare. Cystic components are seen in about half
of cases; the cysts may be quite large. Calcification is rare. Histologic
examination shows pleomorphic spindle cells containing deposits of
intracytoplasmic lipid within a dense fibrotic reticulin network. Mono-
nucleated and multinucleated giant cells and eosinophilic granular
bodies are present within the fibrosis (298–300).
Imaging The classic appearance of a PXA is that of a well-cir-
cumscribed peripheral temporal lobe mass. Solid components are
isodense to gray matter on CT and isointense to gray matter on
T1- and T2-weighted MR images (Fig. 7-55A and B), but in the
authors’ experience, diffusivity is not reduced, differentiating PXAs
from small round cell tumors such as PNET. They are hyperintense
to gray matter on FLAIR images (Fig. 7-55C). The isointensity or
near-isointensity to gray matter helps to differentiate these from
low grade astrocytomas, which typically have higher water content
and are more hypodense on CT, more hypointense on T1-weighted
images, and more hyperintense on T2-weighted images. Intratumoral
hemorrhage has been reported (Fig. 7-55A and B). The solid portion
enhances homogeneously (Fig. 7-55D) or heterogeneously, depend-
ing on whether microcystic change is present. Surrounding vasogenic
edema is usually minimal or absent. Invasion of the leptomeninges is
common, seen in more than two thirds of studies (Fig. 7-55D). As with
5/6/2011 9:16:29 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
all slow growing, peripherally located cerebral tumors, erosion of the
inner table of the calvarium is occasionally seen. Large or small cysts
(Fig. 7-55) are present in about half of cases; enhancement of the cyst
wall is variable (301,302). If angiography is performed, the solid por-
tion of the tumor is found to be avascular; if seen, a vascular blush
indicates focal necrosis (303).
Differential diagnosis depends on the age of the patient. In infants,
DIG and PNETs can have similar appearances. Pilocytic astrocytomas
can be differentiated by the high water content of solid portion of
the tumor and ependymomas can be differentiated by their relatively
deep location in the cerebral hemisphere, in contrast to the superfi-
cial location of the pleomorphic xanthoastrocytoma. In older children
and adolescents, the main differential diagnoses would be high-grade
astrocytomas, oligodendroglioma, and ganglioglioma.
Barkovich_Chap07.indd 697
697
FIG. 7-54. Giant cell astrocytoma. A. Coro-
nal T1-weighted image shows a mass in the
region of the left foramen of Monro (arrows)
and extending into the frontal horn of the
left lateral ventricle. B. After infusion of
paramagnetic contrast, the mass is seen
to uniformly enhance (arrows). C and D.
Axial T2-weighted image images near the
vertex show multiple subcortical areas of
prolonged T2 relaxation, compatible with
the cortical tubers that are characteristic of
tuberous sclerosis.
Neuronal and Mixed Neuronal-Glial Tumors
Gangliogliomas and Gangliocytomas
Gangliogliomas and gangliocytomas are tumors in which nerve cells and
glial cells, usually astrocytes, participate in the neoplastic process; in this
sense, they differ from most primary CNS neoplasms in which only the
glial cells show neoplasia. Gangliogliomas and gangliocytomas (also called
ganglioneuromas) are uncommon tumors, constituting approximately
3% of brain tumors in children and approximately 6% of supratentorial
pediatric brain tumors; they are found in older children and young adults
more frequently than younger children or infants (77). Males are affected
slightly more commonly than females (304,305). Although presentation
occurs most often during the late first decade or early second decade of
life (304), it is not uncommon for patients with these slowly growing
5/6/2011 9:16:30 PM
 698 Pediatric Neuroimaging

FIG. 7-55. Pleomorphic xanthoastrocytoma. A. Sagittal T1-weighted image shows an extensive transcerebral mass that involves the cortex. The deep
solid component is isointense to the cortex, and contains hemorrhagic (hyperintense) areas. The peripheral cystic component also is isointense, probably
due to the presence of blood. B. Axial T2-weighted image shows the deep portion of tumor (arrows) to be isointense to the parenchyma, the presence of
hypointense recent blood (arrowheads) and the bright signal of the cystic areas. C. Axial FLAIR image shows that the solid component (arrows) is slightly
hyperintense, while the cysts (c) are strongly hyperintense. No peritumoral edema is found. D. Postcontrast T1-weighted image shows that the solid portion
of the tumor enhances significantly. Note that the enhancement extends into the sulci and involves the falcine dura (arrows).

neoplasms to present for evaluation in adulthood. The clinical history
of affected patients is usually one of a protracted history of focal find-
ings. When the neocortex is affected, the history tends to be one of long
standing focal epilepsy; half of affected patients present with seizures,
most commonly partial complex epilepsy (304). Indeed, complete tumor
removal is generally curative whatever the presentation (306, 307). When
the region of the third ventricle and hypothalamus is affected, symptoms
(obesity, diabetes insipidus, or bulimia) tend to reflect hypothalamic dys-
function. These tumors should not be confused with dysplastic cerebellar
gangliocytomas (Lhermitte-Duclos syndrome), a congenital malforma-
tion described in Chapter 5 (8,308–311).
Pathology Mixed neuronal-glial tumors occur mainly in the cerebral
hemispheres; the temporal lobes are most commonly affected, fol-
lowed by the parietal lobe, frontal lobe, occipital lobe, third ventricle
(including pineal region), and hypothalamus (304,305). The cerebel-
lum, brainstem, and spinal cord can also be affected (172,304). The
tumors tend to be small, firm, and well-defined; foci of calcification
and cysts are frequent. The differentiation between ganglioglioma and
gangliocytoma is histological. Dysplastic neurons are a consistent find-
ing in these tumors; if neoplastic glial elements are present, the lesion
is called a ganglioglioma and when dysplastic neuronal elements are
found in the absence of neoplastic glia, the term gangliocytoma (or

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 699

FIG. 7-56. Gangliogliomas.

A. Axial contrast-enhanced CT
scan shows a lesion of mixed sig-
nal intensity in the left occipital
lobe near the visual cortex. Both
calcifications (open arrows) and a
low-intensity area (closed arrows)
are present. Areas of low attenu-
ation in gangliogliomas are not
necessarily cystic. B. Coronal
postcontrast T1-weighted image
shows a right frontal mass that
causes pressure erosion of the
inner table of the calvarium.
Although the mass was entirely
solid at surgery, part of it
enhanced (solid black arrow) and
most (open black arrows) did not.

ganglioneuroma) is used (312). Temporal lobe gangliogliomas can be
seen in association with mesial temporal sclerosis (313).
Imaging Studies Imaging findings of gangliogliomas and ganglio-
cytomas are identical. The CT appearance is that of a low density,
well circumscribed lesion with little mass effect or edema, typically
located within the cerebral cortex (Fig. 7-56). Solid portions of the
tumor can be isodense, mixed, or hypodense; when hypodense, care
should be taken not to assume that the hypodense area is a cyst. Cal-
cification is seen in approximately 35% of gangliogliomas on CT.
Contrast enhancement is variable; part or all of the solid portion of
the tumor may enhance or contrast enhancement may be completely
absent. Occasionally, the tumor can elicit surrounding edema (low
attenuation). When the tumor is peripherally located within the cere-
brum, erosion of the adjacent inner table of the calvarium may occur
(11,311,314).
On MRI, the ganglioglioma may have sharply or poorly defined
margins. The tumor may be solid (Fig. 7-56B), cystic (Fig. 7-57), cys-
tic with a mural nodule, or have the appearance of many small cysts
(Fig. 7-58). Signal intensity on T1-weighted sequences is variable
(and often mixed); T2-weighted sequences generally reveal high sig-
nal intensity. Regions of slight T1 hyperintensity, probably repre-
senting calcification, may be helpful in identifying these neoplasms
(Fig. 7-58). Solid portions of the tumor enhance variably (Fig. 7-56B).

FIG. 7-57. Ganglioglioma.

A. Axial T2-weighted image
shows a largely cystic, lobulated
mass (arrows) in the anterior
right temporal lobe. B. Axial
postcontrast T1 weighted image
shows that the lesion does not
enhance (arrows).

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 700 Pediatric Neuroimaging
As on CT, the peripheral location within the hemispheres and the ero-
sion of the adjacent calvarium can be helpful in making the diagnosis of
ganglioglioma (315). When located in the hypothalamic area, ganglio-
gliomas are difficult to differentiate from hypothalamic astrocytomas
(316). When located in cortex or subcortical white matter, differen-
tiation from astrocytomas, oligodendrogliomas, and dysembryoplastic
neuroepithelial tumors (DNETs) is difficult.
Desmoplastic Neuroepithelial Tumors (Desmoplastic Infantile
Ganglioglioma/Desmoplastic Astrocytoma of Infancy)
The DIG and the DACI are very similar tumors seen primarily in
infants and young children (317–322). Both are characterized by the
presence of both astrocytic and ganglionic cells with a prominent
desmoplastic stroma (predominantly fibroblasts). Despite areas that
appear to have a high number of mitoses mimicking high-grade ana-
plasia, the tumors demonstrate a surprisingly benign clinical course
(319,320,322,323). In view of their histologic and clinical similarities,
some authors have suggested that these tumors have a common ori-
gin with different histological differentiation (324). As a result, several
authors have suggested grouping these tumors together as desmoplas-
tic neuroepithelial tumors (321,324,325). That grouping will be fol-
lowed in this book.
Patients with DIGs and DACIs typically present in infancy with
macrocephaly or partial complex seizures, the median reported age
of presentation being about 5 months of age (318–321,326); rarely,
affected patients may present later in childhood (327). Evaluation
with neuroimaging reveals a large tumor arising in the cerebral hemi-
sphere; typically the cysts are quite large and dominate the image, but
occasionally the cysts may be relatively small at the time of the initial
imaging study (321). Involvement of multiple lobes is common with a
predilection for the frontal and parietal lobes. A cortical solid compo-
nent can always be identified; this solid component often involves the
leptomeninges (318,319,322) and, therefore, may appear extraparen-
chymal. The solid portion is iso- to hyperdense compared with gray
matter on CT and is isointense to cortex on T1- and T2-weighted MR
sequences. The solid portion enhances markedly after the administra-
tion of contrast (Fig. 7-59). Enhancement is not seen in the walls of
the cysts (326,328). Complete resection of the tumor may be curative,
obviating the need for chemotherapy or radiation (329).
Barkovich_Chap07.indd 700
FIG. 7-58. Ganglioglioma. A. Coronal
T1-weighted image shows a small cyst (small
straight arrow) in the right temporal cortex
with hyperintensity (curved arrows) in the
adjacent temporal white matter. B. Axial
T2-weighted image shows the hyperintense
tumor (arrows) in the right temporal cortex.
The suggestion of DIG or DACI as the possible diagnosis in infants
with large, cystic, cerebral tumors containing peripheral, plaque-like
solid components is important to clinical management because the his-
tologic characteristics may be confusing. In addition to the characteris-
tic desmoplasia with astroglial and neuronal tumor cells, these tumors
often have a component of small, mitotically active cells that can be
misinterpreted as malignant. Indeed, a number of reported patients
were initially treated aggressively with chemotherapy for high-grade
malignancies before the correct diagnosis was made (323,329). DIG
are differentiated from cystic astrocytomas by the peripheral location
and the relatively high density (CT) and T2 hypointensity (MRI) of the
solid tumor component as compared to the low density and long T2,
respectively, of astrocytomas. Other differential considerations, based
on the neuroimaging appearance, include high-grade astrocytoma,
pleomorphic xanthoastrocytoma, PNET, and ependymoma. If the lep-
tomeningeal component of tumor is large, meningioma and meningeal
sarcoma are differential considerations.
Dysembryoplastic Neuroepithelial Tumor
DNETs are benign masses of the cerebral cortex that nearly always pres-
ent as partial complex seizure disorders in children or young adults;
other neurologic signs or symptoms are rarely present (330–332).
These are common and important tumors; recent series indicate that
DNETs are the cause of as many as 20% of cases of medically refractory
epilepsy in children and young adults (333). The diagnostic criteria for
these tumors have evolved since the initial description of this tumor.
At present, the best criteria are as follows: (a) partial seizure disorder
beginning before age 20 years; (b) no neurologic deficit or a stable con-
genital deficit; (c) cortical tumor location (334). Rarely, the tumors
may develop in the deep parts of the cerebral hemisphere, particularly
in area of the caudate nucleus (335).
Pathology Pathologically, greater than 60% of DNETs are found
in the temporal lobe, approximately 30% in the frontal lobe, and
the remainder scattered through the parietal and occipital lobes, the
deep cerebral nuclei, brainstem, and cerebellum (330–332,334–336).
The tumors are solid but most have cystic or microcystic compo-
nents with “floating” neurons (331). Many are adjacent to regions of
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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 701

FIG. 7-59. Desmoplastic infantile ganglioglioma. A and B. Axial T2-weighted images show multiple large parenchymal cysts (white arrows) in the left
cerebral hemisphere, displacing midline structures to the right. Low intensity solid material (black arrows) is seen in the lateral aspect of the cysts. C and D.
Postcontrast coronal T1-weighted images show that the lateral solid component (open white arrows) enhances uniformly.

cortical dysplasia (FCD Type IIIb), but it is not clear whether both are
developmental or whether seizures resulting from the tumor cause the
FCD. Many tumors that, in the past, were histologically classified as
gangliogliomas or mixed oligo-astrocytomas would probably be char-
acterized as DNETs if reviewed today.
Imaging Studies Imaging studies show a very variable appearance,
which probably reflects significant biologic heterogeneity in those
lesions classified as DNETs. Despite this heterogeneity, almost all DNETs
are well-demarcated, lobulated cortical masses that are hypodense com-
pared to white matter on noncontrast CT. They are hypointense on T1
images and hyperintense on T2 images on MRI (Figs. 7-60 and 7-61)
(334,336–338). Cystic or microcystic components are present in about
30–40%; they appear as sharply defined areas of very hypointense T1
and hyperintense T2 signal and often give the tumor a characteristic
lobulated or multilobulated appearance (Fig. 7-61) (332,338–340).
These areas have variable signal on FLAIR images, ranging from
hypointense (appearing cyst-like) to hyperintense (332). Diffusivity
of the tumor is elevated compared with normal gray and white mat-
ter, probably because of its multicystic nature (340). Tumoral calcifica-
tion may be present in about one third of affected patients (330,336);
hemorrhage is rare (332). Because the lesions are primarily cortical and
therefore superficial, convexity DNETs may erode the inner table of
the calvarium (337) (Fig. 7-60). Subcortical extension is seen in about
30% (334,337,338); in such cases, the greatest diameter is at the cortical
level, leading to development of a triangular shape when viewed in the
coronal plane (339). Intracortical lesions tend to be round or oval. Con-
trast enhancement is seen in 20% to 40% and is typically patchy (339)
but may be diffuse (334,337,338); enhancement patterns may vary of
sequential studies (332).

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 702 Pediatric Neuroimaging

FIG. 7-60. Dysem-

bryoplastic neuroepi-
thelial tumor. A. Sagittal
T2-weighted image shows
a multilobular hyper-
intense homogeneous
mass in the base of the
left frontal lobe. Note the
scalloping of the orbital
roof (arrows), indicating a
slow growing, superficial
mass. B. Axial T1-weighted
image shows the tumor as
a sharply marginated, non-
enhancing, homogeneous
mass (arrows) in the left
frontal lobe.

FIG. 7-61. Dysembryoplas-

tic neuroepithelial tumor.
A. Parasagittal T1-weighted
image shows a cortical/sub-
cortical hypointense mass
(arrows) involving the pos-
terior frontal lobe. B and C.
Axial T2-weighted and post-
contrast T1-weighted images
show the multiple microcys-
tic components (arrows) that
compose the nonenhancing,
lobulated mass. D. Coro-
nal FLAIR image shows the
microcystic components and
the subcortical extension of
the tumor (arrows), seen in
about 30% of DNETs.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
Proton MR spectroscopy of DNETs shows no significant difference
of metabolite ratios from normal cortex other than myo-inositol/
creatine ratio, which is elevated (340). Dynamic susceptibility-weighted
perfusion imaging shows lower CBV than normal cortex (340).
Metabolically, these are inactive tumors with no significant glu-
cose uptake on 18F-fluorodeoxyglucose PET or on 11C-methionine PET
(341). Because of the marked variability in imaging appearance, the
diagnosis of DNET should be suggested any time a primarily corti-
cal tumor with high water content is seen in a patient with (a) a long
standing history of partial epilepsy and (b) a normal neurologic exam
or a stable, long standing neurologic deficit (334).
Supratentorial Ependymomas
Supratentorial ependymomas comprise between 20% and 40% of
childhood ependymomas (151). They occur in males more commonly
than females with a peak incidence between ages 1 and 5 years. The
presenting symptoms depend upon the location of the tumor. Signs of
increased intracranial pressure (headache, vomiting and altered sen-
sorium), ataxia, and focal seizures are the most common reasons for
presentation (8,151,154,274).
Pathology
Supratentorial ependymomas are identical histologically to their
infratentorial counterpart. Small foci of calcification are seen in about
one-half of cases; cystic areas are common, especially in the larger
lesions. Although pathology texts state that they are most commonly
located in the frontal lobe, where they usually abut the wall of the fron-
tal horn, our experience at UCSF and the radiology literature suggests
that they develop most commonly in the parietal and temporoparietal
regions. In contrast to infratentorial ependymomas, the supratentorial
tumors are uncommonly intraventricular; metastatic spread of tumor
through the CSF is, therefore, uncommon (8,75,76). As was mentioned
before about the posterior fossa ependymomas, the radial glia give
rise to the tumor stem cells of ependymomas. Therefore, supratento-
rial ependymomas often are located away from the ventricles; some
are strictly intracortical (31,33,155,342,343). Moreover, in contrast
to astrocytomas, ependymomas have fairly well defined margins at
their periphery; as a result, complete tumor resection is more likely
at surgery (344).
Barkovich_Chap07.indd 703
703
FIG. 7-62. Supratentorial
ependymoma. A. Axial non-
contrast CT scan shows a
hemispheric mass (arrows)
that is isodense with gray
matter. A small focus of cal-
cification (open arrow) is
seen within the tumor mass.
There is mild surrounding
vasogenic edema. B. After
infusion of iodinated con-
trast, there is heterogeneous
contrast enhancement.
Imaging Studies
As with the infratentorial ependymomas, those located supratentorially
have an extremely variable appearance on both CT and MRI. They
tend to be sharply demarcated tumors that are isodense to hyperdense
compared with normal brain on noncontrast CT scans; foci of calcifi-
cation and cystic areas are identified in about half of affected patients
(Fig. 7-62). The solid portion of the tumor enhances variably after
contrast administration. The diagnosis of ependymoma should be
entertained when an isodense frontal or parietal juxtaventricular mass,
with foci of calcification and cysts, shows heterogeneous enhancement
(11,154,345).
MRI generally shows large, heterogeneous tumors in a peritrigo-
nal location; however, the tumors may be intraventricular or subcor-
tical. The heterogeneity results from the combination of solid tumor
(isointense to gray matter on T1-weighted, T2-weighted, and FLAIR
images, diffusivity similar to normal brain tissue), intratumoral calci-
fication, cysts, and, occasionally, hemorrhage, which combine to give
a mixture of signal intensities with all imaging parameters (Figs. 7-63
and 7-64) (152,346). However, supratentorial ependymomas can
appear homogeneous on MRI (and thus be indistinguishable from
low-grade astrocytomas) or ring enhancing with extensive edema
(indistinguishable from a high-grade astrocytoma or a primitive neu-
roectodermal tumor). CSF spread of tumor is rare, as most tumors are
completely intraparenchymal in location (346).
Differential Diagnosis
When composing a differential diagnosis for a supratentorial brain
tumor in a child, one should remember that ependymomas are most
often seen in young children. Therefore, when a heterogeneous mid-
line tumor is seen on MRI in a child in the first year of life (especially
in the first 6 months), the first diagnosis considered should be tera-
toma. When heterogeneity is seen in a supratentorial tumor that is off
the midline and extraventricular, ependymomas, PNETs, and ATRT
should be considered as diagnoses, especially if the child is between
the ages of 1 and 5 years; both PNET and ATRT tend to have reduced
diffusivity when compared to normal cerebral parenchyma. When a
markedly heterogeneous intraventricular tumor with periventricular
extension is seen, the diagnosis of a choroid plexus carcinoma should
5/6/2011 9:16:38 PM
 704 Pediatric Neuroimaging
be suggested, although ependymomas may uncommonly have this
appearance.
Tumors with Neuroblastic or Glioblastic Elements
Primitive Neuroectodermal Tumor
PNETs were first conceptualized by Hart and Earle (347) who defined
them as highly cellular tumors composed of greater than 90% to 95%
undifferentiated cells. Although foci of differentiation along glial or
neuronal lines may be present within the tumor mass, the high percent-
age of undifferentiated cells theoretically sets these tumors apart from
other tumors. PNETs are histologically similar to medulloblastomas,
pineoblastomas, ATRT, and peripheral neuroblastomas. Many
neoplasms that were previously classified as primary cerebral neu-
roblastomas, primary cerebral medulloblastomas, ependymoblasto-
mas, and undifferentiated small cell neoplasms of the brain are now
considered by many to be PNETs, although some controversy exists
regarding the classification of these neoplasms (76,348). In the last
WHO Classification of Brain Tumors, CNS neuroblastoma, CNS
Barkovich_Chap07.indd 704
FIG. 7-63. Supratentorial ependymoma with small
cysts and necrosis. A. Axial FLAIR image shows a
heterogeneous mass adjacent to the left trigone. The
hypointense regions (white arrowheads) are tumor cysts,
the hyperintense regions (black arrowheads) are areas of
necrosis. The solid portion of the tumor has signal char-
acteristics similar to gray matter. B. Axial T2-weighted
image does not distinguish between cysts and necrosis.
C. Postcontrast axial T1-weighted image shows that the
necrotic areas of the tumor (white arrows) enhance but
the cysts (black arrows) do not.
ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma
are classified as subtypes of the PNETs (73). PNETs are uncommon
tumors, probably comprising less than 5% of supratentorial neo-
plasms in children, although their reported incidence varies widely,
probably because of variable willingness of pathologists to make
this diagnosis and a changing understanding of the tumor type (77).
Although they have been described in patients up to the age of 24
years, they are more commonly seen in children under the age of 5
years. Seizures, focal neurological deficits, and symptoms of increased
intracranial pressure (headache, vomiting and altered sensorium) are
the most common presenting symptoms. No male or female predomi-
nance has emerged. Patients most frequently present with macroceph-
aly (if diagnosed in infancy) or signs of increased intracranial pressure
or seizures (349–351).
Pathology Cerebral PNETs most frequently occur in the deep cere-
bral white matter and are usually quite large at the time of presentation.
Grossly, they have sharp margins, even though histological examination
5/6/2011 9:16:39 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 705

FIG. 7-64. Supratentorial ependymoma

with large cysts. A. Axial T2-weighted
image shows a heterogeneous cystic and
solid mass in the left temporal lobe. B.
Postcontrast axial T1-weighted image
shows the solid portion of the tumor
to enhance heterogeneously. The cysts
(arrows) are hyperintense compared to
ventricles and are therefore tumor cysts.

shows spread of the tumor cells peripherally beyond the apparent
tumor edge. Necrotic areas and foci of calcification are seen in about
one-half of tumors. Seeding of tumor through the CSF pathways and
metastases to the spinal cord, lungs, liver, and bone marrow has been
reported (8,76,351).
Imaging Studies On noncontrast CT, the solid portions of the PNET
tend to be hyperdense when compared to white matter, presumably
due to the high nuclear to cytoplasmic ratio and the subsequent high
electron density of the tumors (Fig. 7-65). Cystic areas and punctate
calcifications are common, and hemorrhage is seen in approximately
10%. After intravenous infusion of iodinated contrast, some enhance-
ment is always seen; it may be solid and homogeneous, heterogeneous,
or ring-like, depending upon the size and number of associated cysts
and necrotic (350,352,353).
The most typical MR appearance of a PNET is that of a large,
apparently sharply marginated mass that can be located either in the
cerebral hemisphere or the lateral ventricle (Figs. 7-65 to 7-67). As with
ependymomas, the tumors are remarkable for their marked variability;
appearance ranges from solid (Fig. 7-66) to cystic (Fig. 7-67) and from
homogeneous to markedly heterogeneous to a rim of solid tumor sur-
rounding central necrosis (Fig. 7-65). Solid portions are typically isoin-
tense to gray matter on T2-weighted and FLAIR images (354). Punctate
calcifications may be inapparent or appear as foci of low signal inten-
sity. Solid portions of the tumor show reduced diffusion on DWI (354)
and increased blood volume on susceptibility-weighted perfusion
studies (355) compared to normal surrounding brain. Cystic areas have
low intensity on T1-weighted sequences, have very high intensity on
T2-weighted sequences, and show increased diffusion. FLAIR images
help to differentiate necrosis (hyperintense) from cysts (hypointense)

FIG. 7-65. Primitive neuroectodermal tumor. A. Axial noncontrast CT scan shows a large heterogeneous mass principally in the left frontal lobe with low
attenuation cystic/necrotic areas (c) and higher attenuation (similar to cortex) solid areas (s). B. Axial FLAIR image shows necrotic areas (n) that are mark-
edly hyperintense compared to both the solid and cystic components. Hyperintensity is seen in the corpus callosum (arrows), indicating probably tumor
spread into the right hemisphere. C. Axial postcontrast T1-weighted image shows moderate enhancement (arrows) of the solid portion of the tumor.

Barkovich_Chap07.indd 705 5/6/2011 9:16:40 PM

 706 Pediatric Neuroimaging
(Fig. 7-65B). When hemorrhage is present (Fig. 7-66), it is of high sig-
nal intensity on the T1-weighted and FLAIR sequences and of variable
intensity on the T2-weighted sequences depending upon the chemical
state of the iron. Infusion of paramagnetic contrast results in variable
enhancement, similar to that seen on CT (356). When a large, sharply
marginated mass is seen in a young child, the diagnosis of PNET should
be suggested, particularly when the mass is markedly heterogeneous.
Differential diagnosis includes high grade glioma, ependymoma, and
ATRT.
Medulloepithelioma
Medulloepithelioma, a subtype of PNET in the last WHO classification
of tumors of the CNS (73) is the name given to a very rare tumor that
typically presents in the first 5 years of life with headache, nausea, and
Barkovich_Chap07.indd 706
FIG. 7-66. Nearly homogeneous primitive neuroec-
todermal tumor. A. Axial T2-weighted image shows a
left parietal mass (arrows) that is largely isointense to
gray matter. The mass appears well demarcated and
elicits little vasogenic edema. Some central hypoin-
tensity may represent calcium or blood. B. Axial
T1-weighted image shows the central area as hyper-
intense (arrows), again suggesting the presence of
calcium or blood. C. Postcontrast axial T1-weighted
image shows enhancement of only the central portion
(arrows) of the tumor. The enhancement suggests that
this area was undergoing necrosis and that the abnor-
mal signal on the noncontrast exams was blood due
to the necrosis.
vomiting secondary to increased intracranial pressure (76,357). These
tumors most commonly develop in the periventricular region of the
cerebral hemispheres, but may develop in the suprasellar region (358),
cerebellum, or brainstem. When the tumors develop in the posterior
fossa, presenting signs and symptoms may include cranial neuropathy,
hemiparesis, or even coma (357).
Pathology Medulloepitheliomas are characterized histologically by
the papillary, tubular, or trabecular arrangement of cells with an exter-
nal and internal limiting membrane that mimics the structure of the
primitive neural tube (76,357). These are highly malignant tumors
with a high incidence of intratumoral hemorrhage histologically and a
high incidence of recurrence after resection. The prognosis is very poor
(76,357).
5/6/2011 9:16:41 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
Imaging Studies Neuroimaging characteristics are similar to other
cerebral brain tumors, except that enhancement is uncommon after
administration of intravenous contrast material. Medulloepitheliomas
are typically well-circumscribed, homogeneous masses that are isodense
to slightly hypodense on noncontrast CT (10,357). MRI shows sharply
marginated masses that are hypointense on T1-weighted images and
hyperintense on T2-weighted images; slight internal heterogeneity may
be seen, particularly in large tumors. The lack of enhancement should
raise the possibility of a medulloepithelioma (357).
Atypical Teratoid/Rhabdoid Tumor
of Infancy and Childhood
ATRT are neoplasms of unknown histogenesis that were originally
described in the kidney and were named because their light micro-
scopic appearance resembles that of rhabdomyosarcoma. They are
Barkovich_Chap07.indd 707
707
FIG. 7-67. Intraventricular primi-
tive neuroectodermal tumor. A. Axial
T2-weighted image shows the tumor
(arrows) in the enlarged left occipital
horn. The tumor is isointense to gray
matter peripherally with a hyper-
intense center. B. Postcontrast axial
T1-weighted image shows heteroge-
neous enhancement of the mass. C.
Postcontrast coronal T1-weighted
image shows the marked enlargement
of the occipital horn more clearly. In
addition, spread of the tumor to the
superior wall of the ventricle (arrow)
is appreciated.
included in the group of embryonal tumors of the CNS in the last
WHO classification, together with medulloblastomas and PNETs
(73). ATRTs of the brain are rare, accounting for 1.3% of primary
CNS tumors in children and 6.7% of CNS tumors in children diag-
nosed before the age of 2 years (77,118,129,359). Most reported cases
of cerebral ATRT have presented in the first decade of life (usually
before the age of 4 years) with lethargy, vomiting, and visual distur-
bances. Prognosis continues to be dismal, with survival of less than
18 months in most cases (118–122,129,359). Some authors suggest
that gross total resection improves prognosis, but the tumors are typi-
cally so large at the time of presentation and the locations so challeng-
ing that total removal is not possible (121). These tumors have been
discussed in the section on “Tumors of the Posterior Fossa”; however,
approximately half of ATRT of the CNS arise in the supratentorial
compartment.
5/6/2011 9:16:42 PM
 708 Pediatric Neuroimaging

FIG. 7-68. Atypical teratoid/

rhabdoid tumor. A. Axial non-
contrast CT image shows a
large heterogeneous mixed
hyperdense and hypodense
mass (arrows) in the left pos-
terior parietal lobe, with ante-
rior vasogenic edema. B. Axial
T1-weighted image shows the
heterogeneous mass (arrows)
appears grossly well margin-
ated. C. Axial T2-weighted
image shows that the solid por-
tions of the heterogeneous mass
are isointense to gray matter.
Hyperintense portions probably
represent necrosis and hypoin-
tense portions likely represent
hemorrhage. D. Postcontrast
T1-weighted image shows het-
erogeneous enhancement. The
imaging appearance of these
tumors is identical to those of
PNETs and ependymomas.

Pathology are typically solid with areas of necrosis, hemorrhage, or calcification;

Pathologically, ATRT are solid with regions of necrosis, hemorrhage,
and cysts; margins are poorly defined. The characteristic histologic
feature is the rhabdoid cell, a round to ovoid cell with eccentric nuclei
and prominent nucleoli, abundant eosinophilic cytoplasm, and cyto-
plasmic hyaline inclusions. Rhabdoid cells are not abundant and can
be overlooked unless sought. Other characteristic histologic features
include abundant mitoses, malignant mesenchymal spindle-shaped
cells, cells with epithelial differentiation, and small round blue
(PNET) cells. The presence of these varying cell types is responsible
for the naming of the tumor as “teratoid/rhabdoid” (360).
Imaging Studies
On imaging studies, ATRTs are usually large (averaging 5 cm in diame-
ter) at the time of patient presentation (Figs. 7-68 and 7-69). The masses
the solid regions are isodense to hyperdense to gray matter on CT
(Fig. 7-68) and isointense to gray matter on MRI (120,121,130,361).
Areas described as cysts, but having the appearance of necrosis (irregu-
lar walls, see Figs. 7-68 and 7-69), are present in nearly all at the time
of presentation. Solid portions enhance heterogeneously after infusion
of intravenous contrast (121,129,359). Leptomeningeal tumor dissemi-
nation is present in about 20% of patients at the time of presentation.
DWI reveals reduced diffusivity compared with surrounding white mat-
ter (121). Proton MR spectroscopy shows elevated choline and reduced
NAA, but these changes have not been quantified (121). The tumors can-
not be differentiated from ependymomas or PNETs on the basis of their
imaging characteristics; as stated in the prior section, all three diagnoses
should be included in the differential. ATRTs and ependymomas appear
to be relatively more common in infants (below the age of 2 years).

Barkovich_Chap07.indd 708 5/6/2011 9:16:44 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
Astroblastoma
Although the term astroblastoma dates back to the time of Bailey and
Cushing, the current concept of this tumor derives from the work of
Bonnin and Rubenstein, who described a tumor of children and young
adults that is generally solid or solid and cystic, well circumscribed,
and defined histologically by the presence of astroblastic pseudoro-
settes and prominent perivascular hyalinization (362). It is classified
as “other neuroepithelial tumor” in the last WHO classification (73).
Recognition of astroblastoma as a distinct entity is supported by the
work of Brat et al. (363), who found chromosomal alterations that are
not typical of other hemispheric tumors of children and young adults.
Clinically, astroblastomas are tumors of children and young adults
(mean age of 14 years, range 3–46 years); a female predominance has
been noted in some studies (363). Presenting symptoms are typical of
Barkovich_Chap07.indd 709
709
FIG. 7-69. Atypical teratoid/rhabdoid tumor. A. Axial
T2-weighted image shows an enormous bilobed right
frontal mass, eliciting vasogenic edema and subfalcine
herniation. The solid portion of the mass (arrows) is
isointense to gray matter, but shows some heterogene-
ity, probably due to necrosis. B. Axial T1-weighted image
reveals more heterogeneity in the anterior portion of the
solid tumor (arrows) suggesting more necrosis in that
region. C. Postcontrast axial T1-weighted image shows
enhancement of the solid portion of the tumor. Note that
the anterior part of the solid tumor (white arrows), which
has more necrosis, enhances more than the posterior por-
tion (black arrows).
large cerebral tumors, most commonly headaches, vomiting, and sei-
zures. Histological grade varies greatly; prognosis is strongly correlated
with degree of malignancy (364,365).
Imaging studies reveal large, well-circumscribed lobulated masses
that are located in the periphery of the cerebral hemisphere. Typically,
both solid and cystic components are seen. The solid component is
typically hypointense on T1-weighted images, and heterogeneous on
T2-weighted images, largely of gray matter intensity and contain-
ing small, cystic-appearing heterogeneities. Relatively little vasogenic
edema surrounds the mass, which appears sharply marginated by
imaging (but is not sharply marginated pathologically). Solid por-
tions of the tumor enhance heterogeneously; ring enhancement is seen
around tumor cysts (364–366). Imaging features cannot differenti-
ate benign astroblastomas from malignant ones. No data concerning
5/6/2011 9:16:45 PM
 710 Pediatric Neuroimaging
proton spectroscopy or perfusion imaging have been reported. Our
experience with a single malignant astroblastoma revealed markedly
increased blood volume.
Oligodendroglioma
Although they constitute 5% to 7% of brain tumors in the general
population, oligodendrogliomas are rare in children. They appear to
constitute approximately 1% of pediatric brain tumors; males are more
commonly affected, with male: female ratios up to 2:1 (367). Affected
children most commonly present with seizures; other common symp-
toms include headache, visual field defects and weakness (367). In gen-
eral, oligodendrogliomas are slow-growing hemispheric lesions that
most commonly occur in the frontal and temporal lobes and are fre-
quently calcified (75,76). Prognosis is related to the histological grade
of the tumor (367) and, particularly, to the tumor genotype; tumors
with deletions of chromosomes 1p36 and 19q13 have more favorable
outcomes and better response to antiangiogenic agents (368,369).
Barkovich_Chap07.indd 710
FIG. 7-70. Oligodendroglioma. A. Axial
noncontrast CT shows a heavily calci-
fied mass in the left temporal lobe with
a medial hypodense component (arrow).
B. Axial T1-weighted image shows the
mass to be heterogeneous, with a hypoin-
tense central component (large black
arrows) and a more hyperintense periph-
eral component (small black arrows) that
may be from the calcification. Artifact
is misregistration from ocular motion.
C. Axial postcontrast T1-weighted image
shows marked enhancement of part of
the tumor (small arrow). Less marked
enhancement is seen anteriorly (large
arrows) in the calcified tissue that, at
surgery, was also found to be tumor.
D. Coronal T2-weighted image shows
the tumor to be heterogeneous. (This
case courtesy of Dr. Ennio Del Giudice,
Napoli).
Imaging Studies
The CT appearance of oligodendrogliomas in children is that of round
to oval, sharply marginated masses that originate at the cortical-white
matter junction and are hypo- to isodense compared with gray mat-
ter prior to contrast infusion. Contrast enhancement is variable,
but usually subtle. Calcification and cysts (Fig. 7-70) are present in
approximately 25% to 50% (370). Because the lesions grow slowly, the
inner table of the calvarium may be eroded when they are located in
the periphery of the brain (10). The MR appearance of oligodendro-
gliomas is completely nonspecific; they are most commonly sharply
defined and mildly heterogeneous, with T1 hypointensity and T2/
FLAIR hyperintensity (370). Regions of calcification may be hyperin-
tense (Fig. 7-70) or, if the calcification is dense enough, hypointense
on T1-weighted images. Solid portions of the tumor typically enhance
moderately after administration of paramagnetic contrast (Fig. 7-70),
but enhancement may be minimal or completely absent. The pres-
ence of calcium and the absence of enhancement are associated with
5/6/2011 9:16:46 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
improved survival (370,371). A diagnosis of oligodendroglioma may
be raised when a tumor develops in the frontal lobe, and is associated
with calcification, cysts, and limited or absent contrast enhancement;
these features separate the tumor from most astrocytomas. When
located in the temporal lobe, they are indistinguishable from ganglio-
gliomas. Anaplastic oligodendrogliomas show rim enhancement and
central necrosis, an appearance indistinguishable from high-grade
astrocytomas, ependymomas, and PNETs.
When evaluating posttreatment oligodendrogliomas for recur-
rence, it is important to remember that low-grade oligodendrogliomas
have significantly elevated rCBV compared with low-grade astrocy-
tomas and that both low-grade and high-grade oligodendrogliomas
have similar blood volumes (372,373), consistent with the increased
microvessel density seen in both low- and high-grade oligodendroglial
tumors (374). However, choline is significantly higher in high-grade
than in low-grade oligodendrogliomas and the presence of lactate or
lipid correlates with high tumor grade (374). Therefore, when evalu-
ating oligodendroglial tumor recurrence, proton MRS is superior to
dynamic susceptibility-weighted perfusion imaging.
Neuroglial Hamartomas (Glioneuronal Heterotopia)
Cerebral hamartomas are defined as lesions composed of disorganized
but mature cells, usually a combination of neurons (ganglion cells),
glia, and blood vessels. They are referred to by many names, includ-
ing neuroglial hamartomas (375), glioneuronal heterotopia (376,377),
and heterotopic cerebellum (378). Affected patients typically present
for medical evaluation because of seizures; neurological examination is
typically normal (379). They may be discovered in newborns as a result
of associated anomalies (378,380) or progressive head enlargement
(377), and in fetuses as an incidental finding on sonography (377). In
pathology series, about 3% of patients who undergo epilepsy surgery
are discovered to have glioneuronal hamartomas; associated cortical
dysplasia is often found (381–384).
Pathology of these lesions shows a mixture of mature and imma-
ture neuronal and glial cells with variable representation from the cere-
bellum, choroid plexus, and ependyma (375,376,380). The lesions may
be intracerebral or extracerebral, and sometimes extend outside of the
cranium, typically through skull base foramina (375,376). They do not
invade adjacent brain.
Imaging studies show lesions that are typically homogeneous or
slightly heterogeneous. The signal intensity is isointense to gray matter
on T1-weighted images, and isointense to slightly hyperintense to gray
matter on T2-weighted images, and variably hyperintense compared
to gray matter on FLAIR images. The lesions are usually nonenhanc-
ing, but minimal enhancement may be seen (377–379). Most com-
mon locations are the thalamus, mesial temporal lobe (Fig. 7-71A–C),
hypothalamus (Fig. 7-71D and E and see next section on “Suprasellar
Tumors”), and frontal lobe. In these locations, the major differential
diagnosis is ganglioglioma in older patients and teratoma in neonates.
Occasionally, glioneuronal heterotopia are seen in the interhemispheric
fissure, separating the two normal cerebral hemispheres.
Plasma Cell Granulomas (Inflammatory Pseudotumors)
Plasma cell granulomas (also called inflammatory pseudotumors or
myofibroblastic inflammatory tumors) are unusual tumors that can
present in nearly any organ at nearly any age. The lung is the most
frequent site of presentation, followed by the CNS, and the liver. Other
organs, involved less frequently, are the skin, adrenals, thyroid, orbit,
breast, spine, meninges, skull base, and skeletal muscle (385–389).
Plasma cell granulomas of the CNS can present at any age, with equal
distribution before and after the age of 20 years; thus, just under half
of the cases involving the CNS present in children (390). There is no
Barkovich_Chap07.indd 711
711
sex or racial predilection. The most common presenting symptoms are
headache, seizure, weakness, and cranial neuropathy; the precise pre-
sentation is dependent upon the location of the granuloma (388–392).
Pathology
Histologically, plasma cell granulomas are composed of myofibroblasts
and chronic inflammatory cells (lymphocytes, eosinophils, histiocytes)
with a predominance of plasma cells. When involving the CNS, they
may most commonly arise in the dura, but may be located anywhere,
including the cerebrum, cerebellum, hypothalamic-pituitary axis, and
choroid plexuses (390–393). When intraparenchymal, they tend to be
peripherally located; however, no lobar predilection has been reported.
Imaging Studies
On CT, plasma cell granulomas are hyperdense masses that are round
to ovoid and well-circumscribed. On MRI, they are sharply defined
masses that are hypointense on both T1- and T2-weighted images. They
show homogeneous enhancement after administration of intravenous
contrast (390,393). Dural-based plasma cell granulomas may cause
hyperostosis or erosion of the overlying bone; thus, they may mimic
meningiomas (388–390). When originating in the choroid plexus,
these signal characteristics may raise the possibility of a papilloma or,
in an older child or adult, a meningioma or xanthogranuloma (393).
Diffusion/perfusion characteristics are not reported. The possibility of
this diagnosis may be raised when a peripherally located parenchymal,
cavernous sinus, or choroid plexus mass exhibits low signal intensity
on T2-weighted images and homogeneous contrast enhancement.
Lymphoproliferative Disorders
Lymphoproliferative disorders, including CNS lymphoma, can develop
in children (or adults) who have immunodeficiency syndromes, such
as Wiskott-Aldrich syndrome, AIDS, and X-linked lymphoproliferative
disease (394), as well as in those who have undergone solid organ or
stem cell transplantation and are immunosuppressed to prevent rejec-
tion. As a result of the immunocompromise, lymphoid growth pro-
ceeds uncontrolled. Infection by Epstein-Barr virus is thought to play
a role, as Epstein-Barr seronegativity at the time of transplantation is a
strong risk factor; other risk factors include concomitant cytomegalo-
virus infection, the specific immunosuppressive regimen, the allograft
type, and young (pediatric) age (395–397). Lung, liver, and heart trans-
plant recipients generally have higher risks than do recipients of renal
transplants, possibly because of the different immunosuppressive regi-
mens (398). Involvement of the CNS is less common than involvement
of the thorax, abdomen, or head and neck (399). However, when the
CNS is involved, it is usually involved in isolation; therefore, a high
index of suspicion is essential when CNS disease develops in the post
transplant setting. Affected patients may present with focal neurologic
signs/symptoms, seizures, or signs of increased intracranial pressure
(headaches, nausea, vomiting) (395–398).
Imaging typically shows multiple lesions surrounded by extensive
interstitial edema (398,399). As is typical with collections of lympho-
cytes, the lesions are isointense to slightly hyperintense compared to
gray matter on T2-weighted images and slightly hyperintense to gray
matter on FLAIR images. Ring-like enhancement is typically seen after
administration of intravenous contrast (398). Diffusion is typically
reduced compared with surrounding brain tissue. Differentiation of
benign lymphocytic proliferation from frank lymphoma or infection
is usually not possible by imaging alone, so biopsy is typically per-
formed. However, if reduced immunosuppression, antiviral therapies
(to control Epstein-Barr virus replication), or cytokines (which boost
the immune system and control viral load) result in diminution of the
lesion load, biopsy may occasionally be avoided. The typical proton
5/6/2011 9:16:47 PM
 712 Pediatric Neuroimaging

FIG. 7-71. Glioneuronal hamartomas A–C. Temporal lobe hamar-

toma. Coronal T1-weighted image (A) shows a gray matter attenuation
mass (arrows) in the region of the left amygdala. Coronal FLAIR (B) and
T2-weighted (C) images show that the mass remains isointense to gray
matter. In addition, the mass did not change during 3 years of follow-up
studies (arrows). D and E. Suprasellar hamartoma. Sagittal T1- (D) and
axial T2-weighted (E) images show a heterogeneous mass with signal of
both gray and (unmyelinated) white matter involving midbrain, both thal-
ami and hypothalamus. The mass was stable for more than 4 years.

spectroscopic characteristics of benign lymphoproliferation have not
been described.
Germ Cell Tumors
Although most germ cell tumors are found in the suprasellar and
pineal regions (and will be discussed in those sections of this chapter),
a significant number, estimated at 4% to 14%, arise in the basal ganglia
and thalami, particularly in boys during the second decade of life (400–
405). Common symptoms and signs of germinomas in these regions
are progressive hemiparesis, fever of unknown origin, and visual dis-
turbances; some patients also have dementia, psychiatric signs, convul-
sions, precocious puberty, or diabetes insipidus.

Barkovich_Chap07.indd 712 5/6/2011 9:16:47 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
Pathology
Germ cell tumors include both germinomatous and nongerminomatous
types; the latter include teratoma (mature teratoma, immature tera-
toma, teratoma with malignant transformation), choriocarcinoma,
embryonal carcinoma, yolk sac tumors, and mixtures of these entities
(406). The histologic features of germinomas are characteristic, with
two distinct cell populations. Areas of large polygonal or spheroidal
cells with a frequently vacuolated cytoplasm and large round nuclei
with prominent nucleoli are separated by vascular trabeculae along
which are clustered small round cells resembling lymphocytes (76).
Some tumor cells may have an abnormal karyotype (407).
Imaging Studies
The CT appearance of a germinoma is that of an isodense to hyperdense,
well-marginated mass. When the tumors are large, low-attenuation,
cystic-appearing regions of necrosis will often be present. Uniform
enhancement of the solid portions of the tumor is seen after intra-
venous infusion of contrast. Germinomas of the basal ganglia can be
Barkovich_Chap07.indd 713
713
differentiated from astrocytomas by their high signal intensity relative
to white matter prior to contrast infusion (10,401,408–410).
On MRI, germinomas usually appear as heterogeneous, poorly-
marginated tumors, either round or lobulated, with relatively little
mass effect (411). The tumors are usually isointense to hyperintense
compared to cortical gray matter on T1-weighted, T2-weighted, and
FLAIR images. They typically, but not always, demonstrate reduced
diffusion diffusivity (ADC) maps (412). As a result of the iron depo-
sition that occurs in the globi pallidi during adolescence and early
adulthood, small tumors may appear hyperintense compared to the
basal ganglia on T2-weighted images. Indeed, the findings of small
basal ganglia germinomas are subtle on MRI, showing only subtle T1
shortening or T2 prolongation without significant enhancement (405).
Larger tumors demonstrate prolonged T1 relaxation times and isoin-
tensity to hyperintensity compared with gray matter on T2-weighted
images. Heterogeneity is common in larger germinomas of the basal
ganglia and thalami (Fig. 7-72); some degree of necrosis is present in
80% (50% are slightly necrotic, 30% are mostly necrotic) at the time of
FIG. 7-72. Germinoma of the basal gan-
glia. A. Axial T1-weighted image shows
multiple cysts (arrows) in the right basal
ganglia. B. Axial T2-weighted image at a
slightly higher level shows a solid com-
ponent (arrows) that is isointense to gray
matter, suggesting the diagnosis of small
cell tumor. C. Axial FLAIR image shows
the solid portion (arrows) remaining
isointense to gray matter. D. Postcon-
trast axial T1-weighted image shows that
the solid portion of the tumor (arrows)
enhances nearly uniformly.
5/6/2011 9:16:49 PM
 714 Pediatric Neuroimaging
initial imaging (403,404,410,413). The heterogeneity is most apparent
on T2-weighted and contrast-enhanced images (Fig. 7-72). Germino-
mas of the deep gray matter tend to be large at the time of original
imaging (403,404,413). The solid portions of germinomas strongly
enhance after infusion of paramagnetic contrast (Fig. 7-72), as do
CSF-borne metastases to the brain and spine. At the time of presenta-
tion, hemiatrophy is often present in the ipsilateral hemisphere and
brainstem (410,414). When a relatively shortened T2 relaxation time is
present in a basal ganglia mass, particularly in association with cysts or
ipsilateral hemiatrophy, germinoma should be considered, along with
lymphoma and PNET.
Meningioangiomatosis
Meningioangiomatosis is a disorder that involves the cerebral cortex
and, often, the overlying leptomeninges (75). The association of this
rare, benign, hamartomatous lesions may be seen in association with
Type II neurofibromatosis (415) is controversial. It is usually sporadic
(416). Patients typically present as children or young adults with sei-
zures, headaches, or dizziness (417), but the majority of cases are found
incidentally (418). Meningioangiomatosis found in neurofibromatosis
is usually an incidental finding, does not typically cause seizures, and is
often multifocal (416). Neurologic exam is typically normal (416). The
cause is unknown.
Pathology
The characteristic findings are cortical meningovascular fibroblastic
proliferation and leptomeningeal calcification (418). Histologically,
the disorder is characterized by transcortical fascicles of vascular fibro-
meninges that contain central capillaries. Adjacent cortex may contain
neurofibrillary tangles or hyalinization (418).
Imaging Studies
On CT, meningioangiomatosis appears as a peripheral mass that
is hyperdense prior to contrast administration and elicits mild to
moderate edema or hypomyelination in the adjacent white matter
(Fig. 7-73A) (417,419). Calcifications and cysts (perhaps locula-
Barkovich_Chap07.indd 714
tions of CSF) may be present. No significant mass effect is noted. MR
scans show heterogeneous masses that are isointense to hypointense
compared with gray matter on T1-weighted images and hypointense
with a hyperintense periphery on T2-weighted images (Fig. 7-73B)
(417,419–421). Eight of nine reported cases of postcontrast MR scans
showed heterogeneous enhancement (416,419,421). One case pre-
sented with extensive cerebral and intraventricular hemorrhage (421).
Sellar and Suprasellar Tumors
A Systematic Approach to Tumors of the
Hypothalamus and Pituitary
Suprasellar masses in children can be separated with some degree of
certainty based upon their imaging characteristics (Table 7-8). How-
ever, pediatric suprasellar masses can be differentiated to some degree
before even looking at the neuroimaging study. It is important to rec-
ognize that some clinical signs and symptoms indicate hypothalamic
involvement, whereas others indicate pituitary involvement. Knowl-
edge of the characteristic modes of clinical presentation is important
if the region is to be optimally imaged. Moreover, many tumor types
present with specific clinical signs and symptoms. The most common
presenting syndromes of hypothalamic and pituitary lesions and the
lesions that most commonly cause them are listed in Table 7-9. The
optimal imaging sequence for these tumors is thin section (3 mm or
less) precontrast T1-weighted and T2-weighted images in the sagit-
tal and coronal planes, followed by postcontrast T1-weighted sagit-
tal and coronal images. Postcontrast axial images through the entire
brain should be obtained for suprasellar masses, which often spread
through the CSF pathways. We have not found FLAIR sequences useful
for tumors in this region.
Normal Size of the Infundibulum (Pituitary Stalk)
When patients have central diabetes insipidus, imaging of the hypo-
thalamic/pituitary region is often ordered to exclude the presence
of a mass in the hypothalamus or the infundibulum. It can often be
FIG. 7-73. Meningioangiomatosis.
A. Axial noncontrast CT scan shows a
region of hypodensity (arrows) in the
left temporoparietal region. B. Axial SE
2000/80 image shows a heterogeneous
mass with central hypointensity and
surrounding hyperintensity.
5/6/2011 9:16:50 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 715

primary site of origin cannot be determined in many cases, tumors aris-

TABLE 7-8 Suprasellar Tumors in ing from these two locations are often discussed together. Astrocytomas
of the optic chiasm and hypothalamus make up 10% to 15% of
Children supratentorial tumors in children. Males and females are approxi-
mately equally affected. The usual age at presentation is 2 to 4 years; in
Tumor Key Characteristics contrast, patients with gliomas that involve only the optic nerve typi-
Craniopharyngioma Heterogeneous solid portion cally present slightly later (6 years) (425,426). Tumors restricted to the
Rim-enhancing cysts of variable optic nerve in children also have a different prognosis and are treated
intensities differently; therefore, they should probably be considered an entity dis-
tinct from the hypothalamic/chiasmal tumors (425,426). Nonetheless,
Astrocytoma T2 hyperintensity of solid portions considering the recent studies (427–430) demonstrating spontaneous
Germ cell tumors T2 isointensity to gray matter regression of tumors of the optic nerve and chiasm, both large and
Diabetes insipidus small, both in and out of the setting of NF1, childhood tumors of the
optic nerves and chiasm should, perhaps, be treated conservatively
Langerhans cell histiocytosis Enlarged, enhancing stalk
(428,430). Optic nerve tumors are discussed more completely in Chap-
Look for osseous lesions
ter 6, within the discussion of NF1, because about 15% of children with
Hypothalamic hamartoma Isointense to gray matter on T1, T2 NF1 develop optic system gliomas (431); a brief discussion is included
No enhancement. Sometimes cysts. in this section for convenience.
Arachnoid cyst Isointense to CSF The most common symptom of hypothalamic/optic pathway
No enhancement gliomas is diminished visual acuity, which is noted in almost 50% of
Suprasellar pituitary Intrapituitary mass
adenoma Expansion of sella turcica
Rathke cleft cyst Intrasellar, smooth walled TABLE 7-9 Common Clinical
Variable intensity. No enhancement. Presentations of Hypothalamic
Lymphocytic hypophysitis Identical to germ cell tumor or and Pituitary Lesions
(rare) Langerhans cell histiocytosis
Granuloma (sarcoidosis/TB) Involved infundibulum Hypopituitarism
Hypointense on T2 images Craniopharyngioma
Kallmann syndrome (see Chapter 5)
Septo-optic dysplasia (see Chapter 5)
Pituitary hypoplasia (see Chapter 5)
Idiopathic
difficult to determine the presence of a mass, as the findings at the time
of initial presentation may be absent or very subtle. A few facts can Diabetes insipidus
help in making the proper diagnosis. Most important is to remember Langerhans cell histiocytosis (histiocytosis X)
that diabetes insipidus occurs due to dysfunction of supraoptic or Germ cell tumors
paraventricular nuclei of the hypothalamus. Infiltration of these nuclei Craniopharyngiomas
can occur at a time when the infundibulum is still normal in size. As Lymphocytic hypophysitis
the infundibulum lacks a blood–brain barrier and, therefore, normally Tuberculosis (see Chapter 11)
enhances after intravenous administration of paramagnetic contrast, Sarcoidosis
one might find no imaging abnormality at the time of the initial MR Hypothalamic/pituitary malformations
study. However, a normal scan does not necessarily imply absence of Precocious puberty (boys before age 9 y, girls before age 8 y)
tumor (422)! It is very important to reimage the patient at regular (3–6 Hamartoma of the tuber cinereum
month intervals) so that the cause of the hypothalamic abnormality, Hypothalamic glioma
be it tumor, granuloma, or lymphocytic infiltration, can be detected Choriocarcinoma
and treated soon. It is also very helpful to know that the infundibu- Teratoma
lum should be no more than 2.7 mm at the pituitary insertion and Increased intracranial pressure
no more than 3.8 mm at the level of the optic chiasm on coronal and Hydrocephalus
sagittal MR images (423); greater thickness is highly suspicious for Head trauma
pathologic infiltration (423,424). Finally, the infundibulum should Hypoxic-ischemic brain injury
taper smoothly from it largest portion at the median eminence of the
tuber cinereum to its smallest portion as the insertion into the neuro- Delayed puberty (boys after age 14 y, girls after age 13 y)
hypophysis. Any abrupt changes in size should raise suspicion for an Hypothalamic astrocytoma
infundibular mass. Langerhans cell histiocytosis
Kallmann syndrome (see Chapter 5)
Chiasmatic/Hypothalamic Astrocytomas Pituitary adenoma
and Optic Nerve Tumors Amenorrhea
Gliomas originating in the optic chiasm often enlarge and involve the Pituitary adenoma
hypothalamus; similarly, astrocytomas arising in the hypothalamus Rathke cleft cyst
often grow anteriorly or inferiorly to involve the chiasm. Because the

Barkovich_Chap07.indd 715 5/6/2011 9:16:51 PM

 716 Pediatric Neuroimaging
patients, and is associated most strongly with involvement of post-
chiasmal portions of the optic pathways (432). The most common
sign is optic atrophy. Endocrine dysfunction, most commonly short
stature secondary to reduced growth hormone, is found in about
20% (433). Large tumors produce hydrocephalus secondary to exten-
sion into the anterior third ventricle and obstruction at the level of
the foramina of Monro. These large tumors are seen primarily in
infants who may present initially with macrocephaly. A combination
of emaciation, pallor, alertness, and hyperactivity (the diencephalic
syndrome) is found up to 20% of affected patients less than 3 years
of age (8,76,434).
Pathology
Depending upon the series, 20% to 50% of patients with astrocy-
tomas of the optic chiasm/hypothalamus have clinical evidence or
a positive family history of NF1. NF1 patients may develop tumors
primarily involving the optic nerves or the optic chiasm/hypothala-
mus. When the optic nerve is primarily involved, the affected nerve
expands in a fusiform fashion. A large majority of tumors originating
within the optic nerve grow extremely slowly and are histologically
classified as JPAs, histologically identical to pilocytic astrocytomas
that occur in other regions of the brain; malignant change is
extremely rare in these tumors (425,426,435). Indeed, optic pathway
tumors may involute spontaneously, both within (429) and outside
the setting of NF1 (428,436,437). This regression may relate to the
finding that the growth potential of pilocytic astrocytomas decreases
progressively with patient age (438). However, tumors originating
from the optic chiasm and the hypothalamus may have a higher his-
tologic grade and be frankly invasive (8,425,426,439). Astrocytomas
originating in the optic chiasm and hypothalamus may also spread
throughout the subarachnoid spaces via the CSF, even if the tumor
is of low histologic grade (280,281). Prognosis may be worse if the
tumor is multicentric at presentation (280,281). These more aggres-
sive tumors (WHO grade II) have a slightly different histological
appearance, tend to affect younger children and to occur more com-
monly in the hypothalamic/chiasmatic region; they are designated
pilomyxoid astrocytoma (PMA) (briefly described in the section on
“Cerebellar Astrocytomas” earlier in this chapter) (440).
Barkovich_Chap07.indd 716
FIG. 7-74. Optic nerve glioma. Axial CT using bone algorithm
shows the large left optic nerve tumor (open black arrows) and an
expanded left optic canal (closed black arrows).
Imaging Studies
The ready availability of fat suppression techniques on modern MR
scanners (441) has made MRI the procedure of choice for evaluating
tumors of the optic nerves and chiasm. CT displays the intraorbital
portion of the nerve, contrasted by orbital fat, very nicely; however, the
intracranial portions of the optic nerves and the chiasm are not as well
seen by CT as by MRI unless subarachnoid contrast is administered.
When fat suppression techniques are used, MRI shows all portions of
the optic nerves, the optic chiasm, the optic tracts, the hypothalamus,
and the third ventricle. In addition, MRI allows the structures to be
viewed in any plane; the coronal and sagittal planes are especially use-
ful for evaluating tumors in the sellar and suprasellar regions. Finally,
because of the possibility of radiation effects on the growing orbits and
brain (see discussion in Chapter 1) CT of the orbits should not be the
first imaging method chosen if others are available.
If MRI is not available or cannot be used, CT remains adequate
for evaluation of the intraorbital portions of the optic nerves. The
enlargement of the optic nerve by tumor can be smooth and fusiform
but is more commonly lobulated. The use of bone windows often
reveals enlargement of the optic canals (Fig. 7-74) as a result of pres-
sure erosion from the enlarged nerves. When the mass involves the
intracranial optic nerves, optic chiasm, optic tracts, or hypothalamus,
it almost always appears as a low density, lobulated suprasellar mass
prior to the administration of IV contrast. The tumors that grow
along the optic nerves in patients with NF1 have a unique appear-
ance in that the nerves have a characteristic downward kinking a few
millimeters behind the globe, possibly as a result of nerve elonga-
tion (442). Hemorrhage, calcification, and cyst formation are very
unusual in tumors of the optic nerves prior to radiation therapy.
After intravenous contrast administration, the mass enhances het-
erogeneously and to a variable degree. When the tumor is very large,
the enhancement can sometimes be seen extending posteriorly from
the mass along the optic tracts to the region of the lateral geniculate
bodies (443,444).
MRI is optimal for showing the relationship of the mass to the
chiasm, hypothalamus, and infundibulum. Moreover, when fat sup-
pression and paramagnetic contrast agents are used, the intraorbital
and intracanalicular portions of the nerve are demonstrated well
5/6/2011 9:16:51 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
(Figs. 7-75 and 7-76). MRI also helps to differentiate tumors in which
the optic nerve itself is infiltrated by tumor from those in which the
tumor predominantly infiltrates the subarachnoid space, leaving
the nerve itself relatively unaffected (435). When changes are largely
restricted to tubular enlargement of the optic nerves and chiasm, the
tumor typically appears homogeneous precontrast and enhancement
is variable after intravenous administration of paramagnetic contrast
(Fig. 7-76).
Astrocytomas of the optic chiasm and hypothalamus are almost
always hypointense on T1-weighted sequences and hyperintense on
T2-weighted and FLAIR sequences (Figs. 7-77 to 7-79). When large
and bulky, tumors of the chiasm and hypothalamus are typically het-
erogeneous, with large cystic and solid components; the solid portions
typically enhance markedly after contrast administration (Fig. 7-79)
(445). Although sagittal images best demonstrate the enlarged optic
chiasm and hypothalamus, the coronal plane is optimal for visualiz-
ing tumor invasion of the cerebral hemispheres and identification of
tumor in the optic canals, intracranial optic nerves, optic chiasm, and
Barkovich_Chap07.indd 717
717
FIG. 7-75. Optic nerve glioma restricted to orbit. A. Coronal
T1-weighted image shows the markedly enlarged right optic nerve
(arrows). B. Postcontrast fat-suppressed coronal T1-weighted image
shows marked enhancement of the mass. Fat saturation is essential
in performance of contrast-enhanced studies of the orbits or head
and neck. C. Sagittal T1-weighted image shows rope-like enlarge-
ment (arrows) of the intraorbital optic nerve.
optic tracts (Fig. 7-77C). The anterior cerebral artery, stretched over
the top of the mass, often creates a small indentation in the superior
surface of the tumor mass (Figs. 7-78 and 7-79). High signal inten-
sity extending from the optic chiasm to the lateral geniculate bodies
on T2-weighted images may represent extension of tumor or edema
within the optic tracts (442,446). PMAs are very similar on imaging to
pilocytic ones. It appears that they are more often hemorrhagic (25%)
and more commonly disseminate via the CSF (15%) (147,440,447).
Some studies have shown some differences in optic pathway gliomas
in patients with NF1 as compared to patients without NF1. In patients
with NF1, the orbital portion of the optic nerve is the most commonly
involved site, followed by the chiasm; extension beyond the optic path-
way is rare (2%). In contrast, optic pathway gliomas in patients without
NF1 affect the chiasm (91%) much more commonly than the orbital
nerve (32%); more than 2/3 extend beyond the optic pathway into
brain parenchyma. Cystic components are uncommon in NF1 (<10%)
but common (66%) in patients without NF1. Progressive enlargement
is much less common in NF1 (50% vs. 95% outside of NF1) (448).
5/6/2011 9:16:51 PM
 718 Pediatric Neuroimaging

FIG. 7-76. Bilateral optic gliomas with intracranial extension to optic chiasm. A–D. Postcontrast axial T1-weighted images show bilateral enlarged intraor-
bital optic nerves (small black arrows) extending through the optic canals (closed white arrows) and to the chiasm (open white arrows). Minimal enhancement
of the nerves and chiasm is present.

Barkovich_Chap07.indd 718 5/6/2011 9:16:53 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 719

FIG. 7-77. Pilocytic astrocytoma involv-

ing most of optic pathways and extending
into basal ganglia. A. Sagittal T1-weighted
image shows a large mass (arrows) origi-
nating in the region of the optic chiasm/
hypothalamus. The mass erodes the planum
sphenoidale (arrowheads). B. Postcontrast
axial T1-weighted image shows the mass
extending anteriorly towards the optic nerves
(arrowheads) and posteriorly towards the
optic tracts (arrows). C. Postcontrast fat-sup-
pressed coronal T1-weighted image shows
uniform enhancement of the enlarged optic
nerves (arrows). D. Axial T2-weighted image
shows the hyperintense tumor (arrows)
extending from the optic radiations into the
temporal lobes.

FIG. 7-78. Homogeneous chiasmatic/hypothalamic glioma. A. Sagittal T1-weighted image shows a lobulated suprasellar mass that erodes the posterior
planum sphenoidale and tuberculum sella (open arrows). Indentation of the superior surface of the mass (closed arrow) by the anterior cerebral artery is
characteristic. B. After administration of paramagnetic contrast, the tumor enhances uniformly.

Barkovich_Chap07.indd 719 5/6/2011 9:16:54 PM

 720 Pediatric Neuroimaging

FIG. 7-78. (Continued) C. Axial T2-weighted image shows the tumor to be hyperintense.

FIG. 7-79. Heterogeneous large chias-

matic/hypothalamic PMA. A. Sagittal
T1-weighted image shows a large mass
involving the suprasellar region, the
anterior two thirds of the third ventricle,
anteroinferior interhemispheric fissure
(closed arrow) and the prepontine cistern
(open arrow). Significant hydrocephalus
results from obstruction of the foram-
ina of Monro. The optic chiasm cannot
be discerned as a separate structure. B.
After infusion of paramagnetic contrast,
heterogeneous enhancement is observed.
The superior portion of the tumor
(arrows) is a large cyst. C. Axial postcon-
trast T1-weighted image shows hetero-
geneous enhancement of the mass. The
dilated anterior interhemispheric fissure
(arrows) was the result of a cyst with non-
enhancing walls extending anteriorly from
the tumor. D. Axial T2-weighted image
shows the tumor extending into the inter-
peduncular cistern (arrows) and splaying
the cerebral peduncles. The tumor has a
prolonged T2-relaxation time.

Barkovich_Chap07.indd 720 5/6/2011 9:16:56 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
Proton MR spectroscopy of suprasellar astrocytomas shows
increased choline and diminished N-acetyl aspartate. This finding may
be useful in the differentiation of astrocytomas from craniopharyn-
giomas, which show no normal metabolites (only a lipid peak at 1–2
ppm), and from pituitary adenomas, which show only a choline peak
or no metabolites at all (449).
Differential Diagnosis
The differential diagnosis of chiasmal/hypothalamic astrocytomas
includes craniopharyngiomas, germ cell tumors, hypothalamic gan-
gliogliomas (316), and granulomatous diseases such as tuberculosis
and sarcoidosis. Presentation before age 5 years favors the diagnosis of
astrocytoma, as does association with cutaneous or radiologic stigmata
of NF1. In addition, clinical history can be helpful. Diabetes insipidus
is usually present at the time of presentation of germ cell tumors and
granulomatous diseases; moreover, these masses typically show isoin-
tensity to gray matter on T2-weighted images and reduced diffusiv-
ity compared with normal brain, in contrast to the hyperintensity and
relatively high diffusivity seen in astrocytomas. Pediatric craniophar-
yngiomas can be differentiated from astrocytomas by their primarily
cystic appearance, by the higher signal intensity of the cysts, and by
the more granular, heterogeneous appearance of their solid component
(see the following section).
Craniopharyngioma
Craniopharyngiomas are tumors that are postulated to arise from rem-
nants of the craniopharyngeal duct (450,451). They may arise anywhere
along the pituitary stalk from the floor of the third ventricle to the
pituitary gland; rarely, they arise below the sella in the sphenoid sinus,
presumably along the path of the craniopharyngeal canal (451,452).
Craniopharyngiomas account for 3% of all intracranial tumors, 15%
of supratentorial tumors, and 50% of suprasellar tumors in children.
Although the incidence of craniopharyngiomas peaks between 10 and
14 years of age, a second peak occurs in the fourth to the sixth decade
of life. Males are more commonly affected than females. Symptoms vary
with the location of the tumor, size of the tumor, and the age of the
patient. Symptoms typically consist of headaches and visual field defects
secondary to compression of the optic chiasm and tracts. In addition,
anterior pituitary dysfunction (growth failure resulting from compres-
sion of the anterior pituitary and the hypothalamic-pituitary portal
system) and hypothalamic dysfunction (usually manifest as diabetes
insipidus) are often noted (8,445,453,454). Hypothalamic dysfunction
at the time of diagnosis, severe hydrocephalus, and age less than 5 years
at presentation are associated with high hypothalamic morbidity (455).
Pathology
Craniopharyngiomas are divided into two histologic types, adaman-
tinomatous and papillary types; some have mixed histology. Ada-
mantinomatous craniopharyngiomas generally occur in children and
adolescents. They are lobulated masses with multiple (often very large)
cysts that often encase the vessels of the circle of Willis (456). Adaman-
tinomatous tumors commonly calcify and are more likely to involve the
hypothalamus (457,458); indeed, most appear to arise in the floor of the
third ventricle (459). They vary greatly in size; small tumors present as
solid or partly cystic nodules in the tuber cinereum, infundibulum, or
sella, whereas large tumors are primarily cystic, often extending upward
into the third ventricle or posteriorly and inferiorly into the interpe-
duncular and prepontine cisterns to the level of the pons. The cyst fluid
may be either straw-colored or a brownish, motor-oil-like substance
that is rich in cholesterol crystals (8,76,445). Papillary craniopharyn-
giomas generally present in adults and will be discussed only briefly.
They are predominantly solid and seem to originate mostly in the sella;
Barkovich_Chap07.indd 721
721
cysts, when present, are small and contain straw-colored fluid (457,458).
Because the tumor commonly originates in the pituitary stalk, both the
dorsum and tuberculum sellae are often eroded. It has been postulated
that lobulated craniopharyngiomas with large, hyperintense cysts on
T1-weighted MR scans are adamantinomatous, whereas the smaller,
round, primarily solid craniopharyngiomas with hypointense cysts on
T1-weighted images are of papillary histology (456).
Surgeons divide craniopharyngiomas into three groups based on the
consequences of their location upon surgical approach: sellar, prechias-
matic suprasellar, and retrochiasmatic suprasellar (453,454). Sellar cran-
iopharyngiomas are usually small; they may involve the pituitary gland
but usually do not distort the optic nerves, chiasm, or anterior cerebral
arteries. Prechiasmatic suprasellar craniopharyngiomas grow anteriorly
between the optic nerves, displacing the chiasm posteriorly and elevat-
ing the anterior cerebral arteries; they rarely compress the third ventricle.
Retrochiasmatic suprasellar craniopharyngiomas can push the chiasm
forward against the tuberculum sellae, fill the third ventricle, and extend
into the interpeduncular and prepontine cisterns. Rarely, craniophar-
yngiomas may develop as clival, nasopharyngeal, or sphenoidal masses
(460,461). Recent work has suggested a possible role of an immune
response in craniopharyngioma cyst formation (462); if further investi-
gations support this, nonsurgical treatment may improve outcomes.
Imaging Studies
The CT appearance of pediatric (adamantinomatous) craniophar-
yngiomas is characteristic (10,463). They are most frequently supra-
sellar in location. Ninety percent will have a cystic component and
90% will be at least partially calcified. The calcification may be a thin,
circumferential rim (usually around the cyst), or chunks of calcium
within the solid portion of the tumor. Intravenous administration of
iodinated contrast results in enhancement of 90% of craniopharyn-
giomas. Therefore, a cystic, contrast-enhancing suprasellar lesion with
calcification is almost certainly a craniopharyngioma (Fig. 7-80). If any
FIG. 7-80. CT of craniopharyngioma. Axial contrast-enhanced CT scan
shows a low attenuation suprasellar mass with multiple areas of calcifica-
tion (arrows). Large chunks of calcified tumor are seen in the posterior
aspect of the tumor but only thin curvilinear calcification is seen in the cyst
walls. In addition, the cyst walls show a rim of enhancement around the low
attenuation cystic center (c).
5/6/2011 9:16:57 PM
 722 Pediatric Neuroimaging

FIG. 7-81. Small craniopharyngioma. A. Axial noncontrast

CT shows a calcified suprasellar mass (arrows). B. Sagit-
tal T1-weighted image shows a loculated multicystic mass
(arrows) in the suprasellar region. C. Coronal FLAIR image
does not show the lesion well. The solid portion of the tumor is
difficult to differentiate from the hyperintense cyst and neither
is well differentiated from the hyperintense edema in the sur-
rounding tissue. D. Axial T2-weighted image shows the solid
component of the cyst (white arrow) as hypointense and an
associated cyst (white arrowhead) as hyperintense compared to
surrounding CSF. E. Postcontrast fat-suppressed T1-weighted
image shows a rim of enhancement (small arrows) around
an inferiorly located cyst and heterogeneous enhancement
(arrowheads) in the more superior portion of the tumor.

two of these components are present, craniopharyngioma is a likely
diagnosis. (Epi)dermoid tumors can have the CT density of a cyst
with foci of calcification but (epi)dermoids, as stated earlier, do not
enhance with IV contrast. Suprasellar arachnoid cysts can be differen-
tiated from craniopharyngiomas by their absence of calcification and
enhancement. Because craniopharyngiomas are often small at the time
of initial presentation, and the solid portion is generally isodense with
brain, small tumors are sometimes difficult to identify on CT.
Pediatric craniopharyngiomas are also characteristic on MR stud-
ies, typically appearing as multilobulated, multicystic suprasellar masses
(Figs. 7-81 to 7-84). The cystic areas may be isointense or may have
high or low signal intensity with respect to brain tissue on T1-weighted

Barkovich_Chap07.indd 722 5/6/2011 9:16:58 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 723

FIG. 7-82. Retrochiasmatic multiloculated craniopharyngioma with extension into interpeduncular cistern. A. Sagittal T1-weighted image shows a
suprasellar mass with multiple areas of hyperintensity extending posteriorly into the interpeduncular cistern and distorting the midbrain. B and C. Sagit-
tal and axial postcontrast T1-weighted images show heterogeneous solid portion of tumor (black arrows in B) immediately superior to the pituitary gland
enhances heterogeneously. A thin rim of enhancement (white arrows in B and C) is seen around the large cysts. Hydrocephalus is present secondary to
obstruction of the foramina of Monro by the tumor. D. Axial T2-weighted image shows the hyperintense cysts (arrows) extending into the interpedun-
cular cistern and splaying the cerebral peduncles. The irregular margin of the tumor with the cerebral peduncles does not necessarily imply invasion by
the tumor.

sequences; the T1 hyperintensity, when present, is the result of very high
protein content (464). Although both the cystic and solid components
tend to have a high signal intensity on T2-weighted sequences, the cys-
tic areas tend to have higher signal intensity than the solid components
(Figs. 7-81 and 7-83) (445,465). In contrast, cystic components and
solid components are difficult to distinguish from flowing CSF in the
prepontine cisterns and from edema in surrounding tissue on 2DFLAIR
sequences. The solid portions of the tumor have a granular appearance
on precontrast T1-weighted images; they may also show heterogeneity
as a result of small cysts and calcifications. The solid portions enhance
heterogeneously after administration of paramagnetic contrast
(Figs. 7-82 and 7-84); the thin walls of the cysts nearly always enhance

Barkovich_Chap07.indd 723 5/6/2011 9:16:59 PM

 724 Pediatric Neuroimaging
(Figs. 7-82 and 7-83) (445). Occasionally, craniopharyngiomas are
entirely solid (Fig. 7-85); the solid tumors are usually of papillary his-
tology and are found almost exclusively in adults. They have a hetero-
geneous appearance and enhancement characteristics that are identical
to the solid portion of cystic craniopharyngiomas.
It is important to realize that craniopharyngiomas extend into
the middle cranial fossa, anterior cranial fossa, or posterior fossa
(prepontine cistern) in about 25% of affected patients (giant cran-
iopharyngiomas, Fig. 7-84) (466,467). This pattern of tumor exten-
sion should therefore suggest a diagnosis of craniopharyngioma;
thus MRI is particularly important in those patients presenting with
symptoms referable to the posterior fossa in order to point to the
proper diagnosis and proper site of tumor origin. Very rarely, cran-
iopharyngiomas can arise primarily in the third ventricle or in the
optic chiasm (468,469). The characteristic lobulated, multicystic
Barkovich_Chap07.indd 724
FIG. 7-83. Multicystic prechiasmatic craniopharyngioma. A. Sagittal
T1-weighted image shows a mass (straight arrows) expanding the sella
and compressing the pituitary gland (curved arrow). The floor of the
third ventricle and optic chiasm are displaced posteriorly and superiorly.
B and C. Postcontrast coronal T1-weighted images show the smaller cyst
(open arrows) to be hyperintense compared to the larger cyst. Both cysts
show thin rims of enhancement. The solid portions of the tumor (closed
arrows) show greater enhancement. D and E. Axial FLAIR image shows
differing intensity of the cysts and lower intensity of the solid tumor por-
tions (arrows).
appearance and the inherent T1 shortening of the cysts, if present,
should aid in this diagnosis.
Proton MR spectroscopy of pediatric craniopharyngiomas differs
from that of other suprasellar tumors (449). The spectra show no nor-
mal metabolites, only a broad lipid spectrum at 1–2 ppm. This should
allow differentiation from suprasellar astrocytomas, which show a large
choline peak and reduced NAA peak (449).
Differential Diagnosis
Rathke cleft cysts and hemorrhagic pituitary adenomas are the only
other lesions that originate in this area and have high signal intensity
on T1-weighted sequences. Since Rathke cleft cysts tend to be small,
intrasellar lesions or small lesions situated immediately anterior to the
insertion of the infundibular insertion into the pituitary gland, and
they are approached transsphenoidally, the differentiation between
5/6/2011 9:17:01 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 725

FIG. 7-84. Giant cystic craniopharyngioma. A. Sagittal T1-weighted image shows very large hyperintense lobulated suprasellar mass. The sella turcica is
enlarged beyond recognition. B. Axial T2-weighted image shows the lobulated cyst to be hyperintense compared to CSF. A fluid-fluid layer (arrows) is pres-
ent. C. Coronal T1-weighted image shows smaller, cysts (arrows) that are hypointense compared with brain. The left temporal fossa is enlarged by the cyst.
D. After administration of paramagnetic contrast, all of the cysts show rim enhancement.

an intrasellar craniopharyngioma and a Rathke cleft cyst is entirely
academic. Hemorrhagic adenomas can generally be differentiated by
the marked hypointensity (from deoxy- or methemoglobin) of the
hemorrhage on T2-weighted spin-echo or susceptibility-weighted
sequences. When the cysts of a craniopharyngioma are dark on
T1-weighted images, differentiation from suprasellar astrocytoma may
be difficult. The presence of calcification, the granular and heteroge-
neous appearance of the solid portion of the tumor, enhancement of
cyst walls, and the enlargement of the sella turcica by extension of the
tumor into the sella all suggest the diagnosis of craniopharyngioma.

Barkovich_Chap07.indd 725 5/6/2011 9:17:02 PM

 726 Pediatric Neuroimaging
Hypothalamic Hamartomas (Hamartomas of
the Tuber Cinereum)
Hypothalamic hamartomas are rare congenital malformations that
are composed of normal neuronal tissue and are located in the tuber
cinereum (the region between the mamillary bodies and the median
eminence of the hypothalamus). Boys are affected more commonly
than girls. The most common presenting symptom is isosexual pre-
cocious puberty; indeed, hypothalamic hamartomas are the most
common cause of central precocious puberty (470). The precocious
puberty usually manifests itself prior to the age of two years in boys
and slightly later in girls (471); the diagnosis, however, is frequently
not made until one or two years later when the MRI is performed. The
other common presenting symptom is epilepsy, typically of the gelastic
type (“laughing seizures”), but patients may initially manifest partial
complex seizures or even infantile spasms, with the result that the hypo-
thalamic region is not adequately examined. Ultimately, most patients
manifest many types of seizures, including atypical absences, gener-
alized tonic-clonic, partial motor, and drop attacks (472,473). Both
Barkovich_Chap07.indd 726
FIG. 7-85. Papillary craniopharyngioma in an adult. A. Axial
contrast-enhanced CT scan shows an enhancing mass in the supra-
sellar region (black arrows) situated between the two posterior cli-
noid processes (white arrows). B. Sagittal T1-weighted image shows
a heterogeneous mass within the sella and extending upward into
the suprasellar region (white arrows). The optic chiasm (open white
arrow) is slightly elevated by the mass. C. Coronal T1-weighted image
shows the mass sitting within the sella turcica and causing a slight
upward displacement of the optic chiasm (open arrows).
precocious puberty and epilepsy appear to be more common when
tumor diameter is more than 10 mm (472,474,475). Some authors
have postulated that precocious puberty is mostly seen in patients
with pedunculated hamartomas suspended from the tuber cinereum,
whereas epilepsy is seen with intrahypothalamic hamartomas (476).
Indeed, gelastic seizures may be present in the presence of smaller intra-
hypothalamic hamartomas and in the absence of precocious puberty
(477). Other symptoms associated with hypothalamic hamartomas
include neurodevelopmental delay, and hyperactivity. The hands and
feet should be examined to look for postaxial polydactyly, which sug-
gests the diagnosis of Pallister-Hall syndrome, an autosomal dominant
disorder related to mutations of the GLI3 gene on chromosome 7p13
(478,479). Affected patients are commonly large for their chronologi-
cal age (480,481). Although therapy is primarily medical, some authors
propose that some patients with medically refractory seizures may be
cured by resection of the tumor (482). Indeed, ictal SPECT studies and
ictal depth electrode recordings indicate that the gelastic seizures origi-
nate from the hamartoma (473,477,483,484). Moreover, there seems to
5/6/2011 9:17:04 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 727

FIG. 7-86. Hypothalamic hama-

rtoma within the floor of the third
ventricle. A. Postcontrast CT scan
shows soft tissue mass (arrows) fill-
ing suprasellar and interpeduncular
cisterns. B. Sagittal T1-weighted
image shows soft tissue mass (arrow)
in the floor of the third ventricle. C.
Coronal FLAIR image shows the
gray matter-intensity mass (arrow-
heads) filling the floor of the third
ventricle. D. Axial T2-weighted
image shows the mass (arrow) in the
floor of the third ventricle remain-
ing isointense to gray matter.

be a strong correlation between the presence/onset of seizures and the Classification

presence/onset of developmental abnormalities in this group of chil-
dren (485). Therefore, surgical therapy is becoming more common in
patients with intractable epilepsy and developmental disorders (486),
particularly with new, safer approaches being developed (487–491).
Pathology
Hypothalamic hamartomas are well defined, round to oval masses that
usually project from the floor of the third ventricle into the lumen of
the third ventricle or into the suprasellar or interpeduncular cistern.
They may be pedunculated, attached to the tuber cinereum or the
mamillary bodies by a thin stalk, or sessile, presenting as a mass within
the hypothalamus. They range in size from a few millimeters to several
centimeters in diameter (492).
Histologically, hypothalamic hamartomas are composed of a het-
erotopic collection of large and small neurons, astrocytes, and oligo-
dendroglial cells in proportion to normal neural tissue. Myelinated
and unmyelinated axons are seen in bundles, suggesting connections
to other parts of the brain (472). They closely resemble the histologic
pattern of the tuber cinereum. Calcification is rare, and hemorrhage is
not described in these lesions (76,480,481).
Valdueza et al. (493) have proposed a clinico-topographical classifi-
cation of hypothalamic hamartomas. Type Ia hamartomas are small,
with a pedunculated attachment to the tuber cinereum, while type Ib
hamartomas are small pedunculated masses attached to a mamillary
body. Both are asymptomatic or associated with precocious puberty.
This group of patients is treated with LHRH analogs.
Type IIa hamartomas are sessile masses, usually larger than 1.5 cm
in diameter, attached to the floor of the third ventricle and mamillary
bodies. Patients typically present with gelastic or generalized seizures.
Type IIb hamartomas are large sessile masses, usually larger than
1.5 cm, that distort the walls and floor of the third ventricle. Patients
have mental and behavioral disorders in addition to gelastic and mixed
epilepsy (493,494).
Imaging Findings
CT is sensitive only to the presence of large hypothalamic hamartomas.
The small, sessile hamartomas arising in the floor of the third ventricle
cannot be seen on axial CT studies. Those hamartomas visible on CT
appear as homogeneous, sharply marginated, round masses within the
suprasellar and interpeduncular cisterns (Fig. 7-86); they are isodense

Barkovich_Chap07.indd 727 5/6/2011 9:17:05 PM

 728 Pediatric Neuroimaging

FIG. 7-87. Pedunculated hypothalamic hamartoma. A. Sagittal T1-weighted image shows a mass (arrow) extending caudally from the tuber cinereum of
the hypothalamus. B. Coronal T1-weighted image shows this pedunculated hamartoma (arrow) clearly outlined by CSF. C. Axial T2-weighted image shows
isointensity of the mass (arrow) to gray matter. D. Sagittal T2-weighted image shows the mass (arrows) as slightly hyperintense compared with cortex;
hamartomas may appear slightly more hyperintense on RARE (FSE, TSE) images compared with conventional spin echo.

with brain tissue. Enhancement does not occur after intravenous
infusion of iodinated contrast (480,481,495). Rarely, cystic compo-
nents can extend into the adjacent temporal fossa; under these cir-
cumstances, the solid, nonenhancing tumor may be difficult to identify
prior to shunting of the cyst.
MRI is the study of choice for patients with precocious puberty
and for patients with epilepsy. The MR appearance of hypothalamic
hamartomas is typically that of a well defined, round to ovoid mass
that lies within the hypothalamus. They typically involve the region of
the mamillary bodies and may extend anterosuperiorly into the third
ventricle (Fig. 7-86), inferiorly to be suspended from the floor of the
third ventricle (Fig. 7-87), or into the lateral wall of the hypothalamus
(displacing the postcommissural fornix and hypothalamic gray matter
anteriorly) (Fig. 7-88) (475). The hamartomas are isointense compared
with gray matter on spin-echo T1-weighted sequences, hypointense
on inversion-prepared gradient-echo T1-weighted sequences (475),
and isointense to slightly hyperintense on T2-weighted sequences
(Fig. 7-87) (496). They range in size from a few millimeters to 3 or 4
cm in diameter (480,492). Larger hamartomas are often heterogeneous
on both T1- and T2-weighted images and regions may be quite hyper-
intense on T2-weighted and FLAIR sequences (Fig. 7-89); the regions
of hyperintensity seem to correspond to an increased glial component
histologically (497). No enhancement is seen after intravenous admin-
istration of paramagnetic contrast (496). Occasionally, large associated
cysts (Fig. 7-90) may be seen in the suprasellar cistern that may extend
into the middle cranial fossa. The diagnosis is made by the characteristic
location, isointensity to normal brain, and lack of enhancement of the
solid portion of the mass (498–500).
We have performed proton MR spectroscopy on a single hypotha-
lamic hamartoma in a neonate; as expected the spectrum was similar

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 729

FIG. 7-88. Hypothalamic hamartoma in the wall of the third ventricle. A. Sagittal T1-weighted image shows a small mass (arrow) in the inferior third
ventricle. B. Coronal T2-weighted image shows that the slightly heterogeneous mass (arrows) sits within the right lateral wall of the third ventricle.

to that of normal immature (neonatal) brain tissue. Reports in the
literature suggest that the myo-inositol is slightly higher and NAA
lower than in normal adjacent brain tissue in the thalamus and fron-
tal lobe (475,501). The increased myo-inositol seems to be associated
with the astrogliosis that is often seen in the hamartomas histologically
(475,497), which may, in turn, be the result of the epileptic seizures that
originate from that hamartomas.
Langerhans Cell Histiocytosis
LCH was discussed briefly in the “Posterior Fossa Tumors” section of
this chapter, pertaining to its involvement of the brainstem, cerebellum,
skull base, and calvarium. In this section, we consider involvement of
the pituitary stalk, the most common intracranial manifestation of the
disorder. Diabetes insipidus develops when more than 80% of neurons
in the paraventricular and supraoptic nuclei of the hypothalamus are
destroyed (502). It is present in 5% of patients with LCH at the time of
diagnosis, but in up to 25% of LCH patients and up to 50% of patients
with multisystemic disease on follow-up examinations (249,503,504).
CNS involvement is most common in patients with multisystemic dis-
ease (249). Involvement of the CNS in LCH starts with the development
of granulomas in the subarachnoid space, with subsequent invasion of
the hypothalamus and infundibulum. These lesions are characterized

FIG. 7-89. Large, heterogeneous hypothalamic hamartoma. A. Axial T1-weighted image shows a large mass in the suprasellar and interpeduncular cisterns
with slight hypointensity (arrows) on the left side. B. Coronal T2-weighted image better shows the heterogeneity of the mass, with marked hyperintensity
(arrows) in its left lateral portion.

Barkovich_Chap07.indd 729 5/6/2011 9:17:07 PM

 730 Pediatric Neuroimaging
by diffuse parenchymal infiltration by CD1a+ histiocytes, CD68+
macrophages, T cells and B cells with surrounding inflammation and
nearly complete loss of neurons and axons (250,504). Ultimately, such
granulomas may develop throughout the brain parenchyma (175,249),
meninges, choroid plexus (505), pineal gland (506), and spinal cord
(507). Brain parenchymal lesions in LCH, which are very rare, are dis-
cussed briefly in the “Posterior Fossa Tumors” section of this chapter.
Calvarial, dural, and plexal lesions are discussed in the section on
“Extraparenchymal Tumors.”
When the pituitary stalk and hypothalamus are involved by LCH,
the involvement varies in size from mild thickening of the infundibu-
lum (508) to a frank hypothalamic mass. Mild thickening of the
infundibulum is difficult to see on CT without the use of intravenous
contrast, especially if images are obtained only in the axial plane.
When images are obtained in the coronal plane, both the thickening
and the enhancement of the infundibulum can be appreciated. MRI
is the imaging modality of choice, as even mild thickening of the
Barkovich_Chap07.indd 730
FIG. 7-90. Cystic hypothalamic hamartoma. A. Sagittal T1-
weighted image shows a mass (white arrows) in the suprasellar
cistern. A low intensity mass (black arrows) elevates the frontal
lobes. B. Axial T2-weighted image shows that the gray matter-in-
tensity mass (black arrows) is surrounded by CSF (white arrows)
in the suprasellar cistern and in the anterior and middle cranial
fossae. C. Coronal postcontrast T1-weighted image shows that
the suprasellar mass does not enhance. A small hypointensity
(arrow), presumably a cystic or necrotic area, is seen within the
mass.
infundibulum (Fig. 7-91) can be appreciated in both the sagittal and
coronal planes (509). Larger hypothalamic masses are easily identi-
fied, generally centered in the superior aspect of the stalk (Fig. 7-92).
Small or large, the mass enhances markedly after intravenous infusion
of paramagnetic contrast (Figs. 7-91 and 7-92). Prior to the onset of
diabetes insipidus, the posterior pituitary retains its normal T1 hyper-
intensity. After the onset of diabetes insipidus, the high signal in the
posterior pituitary on T1-weighted images is not present (Figs. 7-91
and 7-92) (510). Diffusion imaging and spectroscopy have not been
used to aid this diagnosis.
The differential diagnosis of a thickened, enhancing pituitary stalk
or a larger mass centered in the stalk is large, and includes germ cell
tumors, lymphocytic hypophysitis, lymphoma, and granulomatous
diseases such as tuberculosis and sarcoidosis, in addition to LCH. In the
absence of bone involvement by the LCH, the other differential con-
siderations need to be strongly considered in children with diabetes
insipidus (422).
5/6/2011 9:17:09 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 731

FIG. 7-91. Small Langerhans cell histiocytosis and lymphocytic hypophysitis. A and B. Langerhans cell histiocytosis. Sagittal T1-weighted image (A) shows
an enlarged infundibulum (arrows) and absence of the posterior pituitary gland (the “pituitary bright spot”). Postcontrast T1-weighted image (B) shows
uniform enhancement (arrows) of the enlarged infundibulum. C and D. Lymphocytic infundibulohypophysitis. Sagittal T1-weighted image (C) shows an
enlarged infundibulum (arrow). Postcontrast image shows marked enhancement of the infundibular mass. Note that the hyperintense posterior pituitary is
seen despite the presence of the infundibular lesion.

Pediatric Pituitary Tumors
Tumors of the pituitary gland are uncommon in children, with pedi-
atric patients comprising only about 2% of those with pituitary ade-
nomas (511–513). When pituitary tumors do become symptomatic
in the pediatric age group, adolescents are usually affected (512,513).
The most common hormonally active pituitary adenomas in the pedi-
atric age group are prolactin-secreting adenomas (typically result-
ing in delayed menarche), ACTH-secreting adenomas (resulting in
Cushing disease), and growth hormone-secreting adenomas (result-
ing in gigantism) (513). About 25% of pediatric pituitary adenomas
are nonfunctioning (453,512); nonfunctioning adenomas typically
present with delayed puberty, short stature, or (in females) primary
amenorrhea (514). In contrast to adults, pituitary tumors in children
are more commonly macroadenomas than microadenomas. This fact
may reflect a lack of symptoms in boys and premenarchal girls with
prolactin secreting tumors. It might also result from a shorter time to
progression in pediatric pituitary adenomas (512,515,516); the shorter
time to progression suggests that pediatric pituitary adenomas are
more biologically aggressive tumors (515). Children with large pitu-
itary tumors may present with short stature, secondary to compromise
of hypothalamic-pituitary function, or with visual disturbance if the
tumor extends into the suprasellar cistern (453,511,512). Rarely, chil-
dren and adolescents may present with pituitary apoplexy, a condition
caused by sudden enlargement of a pituitary adenoma secondary to

Barkovich_Chap07.indd 731 5/6/2011 9:17:10 PM

 732 Pediatric Neuroimaging
FIG. 7-92. Large Langerhans cell histiocytosis lesion. Precontrast (A) and contrast-enhanced (B) sagittal T1-weighted images show a large hypothalamic
mass (arrows) that uniformly enhances after administration of contrast.
extensive tumor infarction or hemorrhage. Pediatric patients with
pituitary apoplexy manifest acute headache and visual loss, identical to
their adult counterparts (517,518).
Imaging Findings
The imaging appearance of pituitary adenomas in children is identi-
cal to that in adults. MRI is the imaging modality of choice (519,520).
Precontrast and postcontrast thin section (3 mm or less) coronal and
sagittal T1 and T2 images should be acquired through the sella and
suprasellar regions. T2-weighted images are useful to look for cysts
or evidence of hemorrhage. Microadenomas will appear as small
(<1 cm) hypointense masses (Fig. 7-93) within the gland on noncontrast
scans. Secondary signs include deviation of the pituitary stalk to the
side opposite the tumor and upward convexity of the gland. Macroad-
enomas will expand the gland and, if the diaphragma sella is sufficiently
large, will dumbbell into the suprasellar cistern, where the optic chiasm
and infundibulum can be compressed. Lateral extension of the tumor
FIG. 7-93. Pituitary microadenoma in a patient with Cushing syndrome. Postcontrast sagittal (A) and coronal (B) images show a small, nonenhancing
mass (arrows) in the anterior pituitary lobe.
Barkovich_Chap07.indd 732
can result in invasion of the cavernous sinuses (520). After intravenous
contrast administration, microadenomas will typically remain hypoin-
tense compared to the enhancing gland on early images (519). However,
if imaging is delayed, the adenoma will typically become isointense, or
even hyperintense, compared with the surrounding normal gland (521).
Therefore, the patient should be imaged as soon as possible after admin-
istration of contrast. Dynamic scanning, in which multiple images are
acquired through several sections of the pituitary gland during the infu-
sion of contrast, can be useful in detecting enhancing tumors while still
hypointense (before they become isointense) to the surrounding gland
(522,523); we routinely perform dynamic scanning when looking for
microadenomas. Macroadenomas typically enhance uniformly and
intensely (519). Caution must be exercised when examining the ado-
lescent gland, as the hormonal changes during adolescence result in an
enlargement of the gland, with upward convexity of the superior surface
(see Chapter 2 and Fig. 2-18) (524). A focal lesion must be identified
before an adenoma is diagnosed on the basis of the imaging study.
5/6/2011 9:17:11 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 733

In pituitary apoplexy, a sellar mass with suprasellar extension is
identified. The mass shows homogeneous or heterogeneous high sig-
nal intensity on T1-weighted images secondary to the intratumoral
hemorrhage. The diagnosis is made by a combination of the history
and neuroimaging appearance (525). Pituitary apoplexy is an emergent
condition, as permanent visual loss may result if the acute compression of
the optic chiasm is not rapidly relieved. If this appearance is identified, the
referring physician must be contacted immediately or the patient should
be referred to the nearest emergency department.
Rathke Cleft Cysts
Rathke cleft cysts are benign epithelium-lined cysts that arise primar-
ily in the sella turcica and contain mucoid material. They are rare in
children. Although nearly always asymptomatic, they may reportedly
produce symptoms by compression of the pituitary gland or supra-
sellar structures. They are thought to derive from remnants of Rathke
pouch; thus, they may be embryologically related to craniopharyn-
giomas (450,526). Recent experience with high quality neuroimaging
suggests that cysts within the pituitary fossa are common particularly
in children and that most of these cysts (presumably Rathke cleft cysts)
are asymptomatic (527). Indeed, they are reported in up to 33% of
routine autopsy series (528). Of the few with symptoms, it is estimated
that about two thirds present with manifestations of pituitary
dysfunction, ranging from isolated hormonal deficiencies (typically
growth hormone or prolactin) to generalized pituitary hypofunction;
visual disturbances are present in about half and headaches in about
30% (526).
CT scans typically show a round or lobulated intrasellar or supra-
sellar mass with attenuation values similar to CSF and characteristi-
cally without any evidence of calcification (529). MRI shows a round to
ovoid, sharply defined mass that typically lies either between the ante-
rior and posterior pituitary lobes (Fig. 7-94) or immediately anterior
to the insertion of the pituitary stalk into the gland (Fig. 7-95). The
cyst has a variable signal intensity, ranging from isointense to hyperin-
tense compared to CSF on T1-weighted images and from isointense to
slightly hypointense compared to CSF on T2-weighted images (530).
No enhancement is seen after administration of paramagnetic contrast
(Fig. 7-94); however one must be aware of the fact that in some cases the
cyst is surrounded by a layer of stretched enhanced pituitary tissue that
may lead to the wrong diagnosis of enhancing cyst. Not uncommonly,
the cyst is hyperintense compared to normal gland on precontrast MR
images and hypointense compared to enhancing gland on postcontrast
images (Fig. 7-94). When a sharply demarcated mass situated posterior
to the anterior pituitary lobe has these signal characteristics, Rathke

FIG. 7-94. Rathke cleft cyst. A. Sagittal T1-weighted image shows

a mass (arrows), situated between the anterior and posterior pitu-
itary lobes that is slightly hyperintense compared to normal gland.
B. After contrast administration, the mass (arrows) remains unchanged
as the gland enhances. This change from relative hyperintensity to
relative hypointensity is characteristic of a Rathke cleft cyst. C. Coro-
nal T2-weighted image confirms the absence of blood by showing the
lesion (arrows) to be hyperintense (blood would be hypointense).

Barkovich_Chap07.indd 733 5/6/2011 9:17:12 PM

 734 Pediatric Neuroimaging
FIG. 7-95. Rathke cleft cyst. A. Sagittal T1-weighted image shows an ovoid hyperintense mass (arrows) directly anterior to the infundibulum. B. Coronal
T1-weighted image shows the mass (arrows) situated between the pituitary gland and the optic chiasm.
cleft cyst should be strongly considered. It is distinguished from a
hemorrhagic adenoma by the absence of hypointensity on T2-weighted
or susceptibility-weighted images (Fig. 7-94C).
Rarely, Rathke cleft cysts can become infected, resulting in a pitu-
itary abscess (531). Affected patients typically have visual symptoms,
often accompanied by fever. The offending organism may or may not
be identified. On imaging, the characteristic appearance is that of a
rim-enhancing mass with central T1 and T2 prolongation (531).
Lymphocytic Hypophysitis
Lymphocytic hypophysitis is an autoimmune inflammatory infil-
tration of the pituitary gland by lymphocytes and plasma cells that
leads to gradual destruction of the gland. It can be divided into two
major forms: adenohypophysitis, which involves mostly the anterior
pituitary gland, and infundibuloneurohypophysitis, which involves
primarily the posterior pituitary gland, infundibulum, and hypothala-
mus (532,533), although any combination of anterior gland, posterior
gland, and infundibulum may be affected (534). It is primarily a disease
of adults, but children may be affected. A slight female predominance
has been noted, with the mean age of diagnosis being 12 years (534).
Presentation depends upon the portions of the gland that are affected.
Diabetes insipidus is the most common symptom (534), but patients
may present with hypopituitarism, headache or impaired vision.
Hypothalamic-pituitary dysfunction, most commonly diabetes insipi-
dus, elevated prolactin, and reduced gonadotropins, ACTH, and growth
hormone may be found on endocrinologic testing (534–537). MRI (the
neuroimaging study of choice) shows an enlarged median eminence,
infundibulum, and, sometimes, pituitary gland. The enlarged regions
typically show uniform enhancement after administration of para-
magnetic contrast. The imaging findings can be identical to those of
suprasellar germinomas and granulomatous conditions such as LCH
(Fig. 7-91C and D), sarcoidosis, and tuberculosis (534–536,538). Dif-
ferentiation must be made by clinical presentation, laboratory studies,
or biopsy (536,537).
Suprasellar Germ Cell Tumors
Germ cell tumors are discussed in the following section on tumors of the
pineal region, and only their imaging characteristics will be described
Barkovich_Chap07.indd 734
here. Suprasellar germ cell tumors have imaging characteristics similar
to suprasellar LCH and lymphocytic neurohypophysitis. They origi-
nate in the hypothalamus and grow into the infundibulum, most com-
monly causing diabetes insipidus, which is usually the reason affected
patients seek medical attention. Imaging characteristics vary with
histology and with the size of the tumor at the time of imaging. Ger-
minomas, by far, the most common histologic type in the suprasellar
region, have typical imaging features when they are small, appearing
on MR as thickening of the infundibulum and uniformly enhancing
after administration of contrast (Fig. 7-96). When small, they can-
not be differentiated from lymphocytic hypophysitis or LCH. CT is
often normal. With slightly larger germinomas, CT shows homoge-
neous masses of gray matter attenuation that uniformly enhance after
administration of iodinated contrast (Fig. 7-97). MRI shows masses of
gray matter intensity in the midline of the hypothalamus that enhance
uniformly. Typically, the high signal intensity of the posterior pituitary
lobe will not be seen on sagittal T1-weighted images due to block-
age of the infundibulum by the mass. Large suprasellar germinomas
are much more heterogeneous (Fig. 7-98), probably due to necrosis
in the more central regions of the tumor. They are much bulkier and
often extend down the infundibulum into the sella turcica, displacing
the pituitary gland (Fig. 7-98). When large, the MR appearance of a
suprasellar germinoma is very similar to that of a suprasellar astrocy-
toma; however, isointensity of solid portions of the tumor to gray mat-
ter on T2-weighted images, reduced diffusion, and tumor extension
down the infundibulum suggest the presence of a germinoma (445).
The differentiation is more easily made from the history; patients with
suprasellar germinomas nearly always have diabetes insipidus at the
time of presentation, whereas patients with suprasellar astrocytomas
rarely develop diabetes insipidus until later in the course of the disease
(445). Imaging is more helpful in differentiating suprasellar germino-
mas from craniopharyngiomas; germinomas rarely have large cystic
components and rarely calcify (445).
It is important to recognize that at the time that the child pres-
ents with diabetes insipidus, the suprasellar germinoma may be small
(Fig. 7-96) or not yet be visible on an imaging study. In such patients, a
repeat imaging study should be obtained in 3 to 6 months and, if still
negative, a second repeat examination should be obtained after another
5/6/2011 9:17:13 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 735

FIG. 7-96. Small suprasellar germinoma in a patient with diabetes insipidus. Sagittal (A) and coronal (B and C) postcontrast images reveal a slightly thickened
infundibulum, with the enhancing mass (arrows) extending superiorly into the tuber cinereum of the hypothalamus and inferiorly into the pituitary gland.

FIG. 7-97. Moderate sized suprasellar germinoma. A. Sagittal T1-weighted image shows a mass (arrows) in the hypothalamus/floor of the third ventricle.
Note that the pituitary gland is small and the high signal intensity of the posterior pituitary gland is not seen. B and C. Sagittal T2-weighted (B) and coronal
FLAIR (C) images show that the mass (arrows) is homogeneous and has gray matter intensity. D. Coronal postcontrast T1-weighted image shows uniform
enhancement (arrows) of the mass.

Barkovich_Chap07.indd 735 5/6/2011 9:17:14 PM

 736 Pediatric Neuroimaging

FIG. 7-98. Large suprasellar germinoma. A. Axial noncontrast CT image shows the suprasellar mass (arrows) that is hyperdense compared to surround-
ing brain. Small, round cell tumors are typically hyperdense compared to normal brain. B. After administration of intravenous iodinated contrast, the
germinoma uniformly enhances. C. Sagittal T1-weighted image shows the mass (arrows) extending from the inferior third ventricle downward in to the sella
turcica, filling the suprasellar cistern. D. Postcontrast sagittal image shows slightly heterogeneous enhancement of the tumor.

3 to 6 months. A uniformly enhancing mass will often develop in the
infundibulum; biopsy of the mass will show a germinoma (most com-
mon), LCH, or lymphocytic hypophysitis (422).
Suprasellar Arachnoid Cysts
Arachnoid cysts are discussed in Chapter 5.
Pineal Region Masses
Pineal region masses are an important group of pediatric brain tumors
because most affected children present with hydrocephalus when the
tumor is still small; at this stage, many of them are curable with radia-
tion and chemotherapy.
Germ Cell Tumors
Most tumors arising in the pineal region are germ cell tumors, a group
of neoplasms that comprise about 3% to 8% of pediatric brain tumors
(539,540). They are considerably more common among Asian popu-
lations, where they comprise approximately 10% of pediatric brain
tumors, than populations of Europe or North America, where the
figure is closer to 2% to 4% (77,541). The incidence of germ cell tumors
appears to be increased in patients with Klinefelter syndrome (542).

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
Of germ cell tumors, approximately 65% are germinomas (sometimes
incorrectly referred to as atypical teratoma, pinealoma, or dysgermi-
noma), 26% are nongerminomatous (16% teratomas, 6% endodermal
sinus tumors [also called yolk sac tumors] or embryonal cell carcinoma,
and 4% choriocarcinomas), and 9% are mixed (540). Other series
have a greater percentage of mixed histology (541). Germ cell tumors
develop most commonly in the pineal region, with about half of all
intracranial germ cell tumors being found in this region (539–541).
Patients with pineal region germ cell tumors most commonly present
with intracranial hypertension secondary to hydrocephalus, Parinaud
sign, Argyll-Robertson pupillary deficit, or diplopia and possibly in the
first decade, precocious puberty (541). About 30% of germ cell tumors
develop in the suprasellar/hypothalamic region; this group of patients
typically presents with diabetes insipidus, visual disturbances, or amen-
orrhea (541). Other, less common, locations include the basal ganglia
(increased intracranial pressure, hemiparesis, discussed in the section
on “Tumors of Cerebral Hemispheres”), cerebellopontine angle (cranial
neuropathy), cerebellum (increased intracranial pressure), corpus callo-
sum (diplopia), and spinal cord (myelopathy) (402,539–541,543–545).
Germinomas
Germinomas are the most common neoplasm in the pineal region,
accounting for over 50% of neoplasms in this area. Most germinomas
occur in the second and third decades of life, with a peak incidence in
the latter half of the second decade. Patients with pineal germinomas
show approximately a 10:1 male predominance and most commonly
present with hydrocephalus or the Parinaud syndrome (paralysis of
upward gaze), resulting from compression of the aqueduct of Sylvius
and midbrain, respectively (546). Approximately 35% of intracranial
germinomas occur in the suprasellar region. The imaging appearance
of these tumors was briefly discussed in the previous section on “Sellar
and Suprasellar Tumors”; a more wide-ranging discussion is given
here. Suprasellar germinomas affect males and females with equal fre-
quency; they commonly cause symptoms indicative of hypothalamic
involvement such as diabetes insipidus, emaciation, or precocious
puberty. It is of interest that patients with pineal germinomas fre-
quently have symptoms indicative of hypothalamic involvement; these
symptoms most likely result from spread of tumor through the CSF of
the third ventricle to the infundibular recess with subsequent invasion
of the hypothalamus. Some authors, however, believe that the cause of
these symptoms is multifocality of the tumor (8,76,402,539,540,547).
Between 4% and 14% of intracranial germinomas tumors originate in
the basal ganglia or thalamus (discussed earlier in this chapter under
“Tumors of the Cerebral Hemispheres”).
Pathology
Pineal germinomas usually are well-defined lesions restricted to the
pineal gland; rarely they occur in a parapineal location. Occasionally,
adjacent structures, especially the quadrigeminal plate or the thalami,
are infiltrated by tumor. Suprasellar germinomas are round or lobulated
masses that arise in the pituitary stalk and floor of the third ventricle,
subsequently compressing and invading the optic chiasm. They may
extend upward to infiltrate the walls of the third ventricle, mimicking
an infiltrating glioma. Metastatic spread occurs early and frequently via
the CSF, resulting in many pial nodules or, sometimes, a sugar-coated
appearance (8,76,401,408,547,548).
Imaging Studies
The CT appearance of a germinoma is that of an isodense to hyper-
dense, well-marginated mass, typically occurring in either the pineal or
suprasellar region. Occasionally, the tumor may originate in the deep
cerebral nuclei, cerebellum, or other regions. Uniform enhancement
Barkovich_Chap07.indd 737
737
of the solid portions of the tumor is seen after intravenous infusion of
contrast. Germinomas in the suprasellar and basal ganglia regions can
be differentiated from astrocytomas by their high attenuation prior to
contrast infusion (Fig. 7-98) (10,401,408,409).
On MRI, germinomas usually appear as well-marginated tumors,
either round or lobulated, that demonstrate isointensity to hypoin-
tensity compared with gray matter on T1-weighted, T2-weighted,
and FLAIR images (Figs. 7-97 and 7-99) (411). The T2 hypointensity
presumably results from the diminished free water content of these
tumors. Diffusion of solid portions is often reduced compared with
cerebral hemispheric parenchyma on diffusivity maps. The perfusion
and spectroscopy characteristics of these tumors are not known.
When a relatively shortened T2 relaxation time is present in a
pineal region tumor in an adolescent, the diagnosis of germinoma
is suggested; in younger children, pineoblastomas can have a similar
MRI appearance (although with lower Dav than germinoma) (549,550).
Some internal heterogeneity is often seen in large germinomas (Figs.
7-98 and 7-99), probably secondary to focal necrosis or microcystic
change. The solid portions of germinomas strongly enhance after infu-
sion of paramagnetic contrast (Figs. 7-97 to 7-100) (411), as do CSF-
borne metastases to the brain (Fig. 7-100) and spine. When large, the
MR appearance of a suprasellar germinoma is very similar to that of
a suprasellar astrocytoma; however, isointensity of solid portions
of the tumor to gray matter on T2-weighted images, reduced diffusion,
and tumor extension down the infundibulum suggest the presence
of a germinoma (445). The differentiation is more easily made from
the history; patients with suprasellar germinomas nearly always have
diabetes insipidus at the time of presentation, whereas patients with
suprasellar astrocytomas rarely develop diabetes insipidus until later in
the course of the disease (445). Imaging is more helpful in differenti-
ating suprasellar germinomas from craniopharyngiomas; germinomas
rarely have large cystic components and rarely calcify (445).
Teratomas
Although the pineal region is the most common site of intracranial
teratomas, they may also be situated in a parapineal region or in the
suprasellar region. Other than in neonates and infants (see section on
“Tumors in the First Year of Life” later in this chapter) pineal region
teratomas are much less common than germinomas. As with germi-
nomas, pineal teratomas occur almost exclusively in males; however,
in contradistinction to germinomas, teratomas in the suprasellar
location have a marked male predominance. The peak incidence of
presentation is in the second decade. Teratomas are similar to other
pineal region germ cell tumors, in that affected patients may present
with the Parinaud syndrome, hydrocephalus, and hypothalamic symp-
toms, the exact presentation being dependent upon tumor location
(8,408,541,547,548).
Pathology
Benign teratomas are usually sharply marginated, extremely hetero-
geneous masses with a rounded or irregular, lobulated outline. Cystic
areas and recognizable teratoma elements, such as cartilage, bone, hair
and fat, are common. In contrast to those in other parts of the brain,
pineal region teratomas tend to be noninvasive (8,76). Malignant tera-
tomas typically have less well differentiated cells and, therefore, less
well differentiated features. When highly malignant (composed pri-
marily of anaplastic cells), the masses have a much more homogeneous
appearance and may invade surrounding brain (8,76).
Imaging Studies
As with teratomas in other parts of the brain and body, the hallmark of
these tumors is their heterogeneity. On CT, they are sharply marginated
5/6/2011 9:17:17 PM
 738 Pediatric Neuroimaging

FIG. 7-99. Pineal germinoma. A. Sagittal T1-weighted image shows a heteroge-

neous mass in the pineal region (arrows). B. Axial T2-weighted image shows the
tumor mass to have heterogeneous signal intensity with areas of short T2 relax-
ation time (arrows). C. After intravenous infusion of gadolinium-DTPA, there is
marked contrast-enhancement of the tumor (arrows).

masses distinguished by areas of fat and calcification in combination
with cystic and solid areas (Fig. 7-101A). The MR appearance is also
usually one of an extremely heterogeneous mass, usually arising from
the tuber cinereum or infundibulum (Fig. 7-101). The presence of fat,
calcium, cysts, and soft tissue give a variegated appearance on T1- and
T2-weighted images (Figs. 7-101 and 7-102) (445,550). Immature
or malignant teratoma has a similar pattern to that of mature tera-
toma, but the cystic components and calcifications tend to be less and
smaller, respectively. The tumor margins may be obscure in malignant
teratoma, and perifocal edema may be observed in some cases (551).
Enhancement after infusion of intravenous contrast may be seen in
solid portions; its presence does not necessarily indicate malignant
degeneration. An extremely heterogeneous mass in the pineal or supra-
sellar area should be strongly suggestive of a benign teratoma, partic-
ularly if it contains fat or calcium. Highly malignant teratomas have
a very different appearance than their benign counterparts. Highly
malignant teratomas are poorly marginated, homogeneous masses that
have irregular shape and elicit vasogenic edema in surrounding tissues.
Calcification and fat are not seen. Significant enhancement is typically
seen after administration of paramagnetic contrast (237).
Other Germ Cell Tumors
Choriocarcinoma, embryonal cell carcinoma, and endodermal sinus
tumors are highly malignant germ cell tumors that occur in the
pineal region. Affected children typically present with either hydro-
cephalus and/or the Parinaud syndrome. Embryonal cell carcino-
mas and endodermal sinus tumors are heterogeneous masses that do
not have specific findings that allow them to be diagnosed by imag-
ing (237,411,551). Choriocarcinomas are notoriously hemorrhagic;
therefore, a hemorrhagic tumor in the pineal region (where most
tumors have a very low tendency to hemorrhage) is suggestive of a
choriocarcinoma (408,547,550,551). Tumor markers, in particular

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
placental alkaline phosphatase (PLAP), alpha fetoprotein (AFP), and
the beta subunit of human chorionic gonadotropin (b-HCG), are
often secreted by germ cell tumors and can be assessed by serological
and CSF analyses. PLAP is secreted primarily by germinomas, b-HCG
by choriocarcinomas, AFP by endodermal sinus tumors, and both
AFP and b-HCG by embryonal cell carcinomas (552). Therefore, the
specificity of preoperative diagnosis is aided by analysis of the tumor
markers (551–553). An important concept is that 10% (or more) of
germ cell tumors are of mixed histology; for example there may be
components of germinoma, embryonal cell carcinoma, and teratoma
in the same tumor. Therefore, a needle aspiration of the tumor does
not obtain adequate tissue to properly characterize the mass; open
biopsy is necessary (551,553).
Barkovich_Chap07.indd 739
739
FIG. 7-100. Pineal region germinoma
with CSF-borne metastases. A. Sagittal
T1-weighted image shows a large pineal
region mass that has invaded the quadri-
geminal plate (arrows). B. After intrave-
nous infusion of paramagnetic contrast,
heterogeneous enhancement of the pineal
region mass is seen (large white arrows).
In addition, a small focus of enhance-
ment is seen in a thickened infundibu-
lum (small white arrow). The patient had
diabetes insipidus as a result of metasta-
sis of tumor to the pituitary stalk. C and
D. Coronal T1-weighted images show
the enhancing tumor mass in the pineal
region (closed arrows) and a subependy-
mal metastasis in the atrium of the right
lateral ventricle (open arrow).
Pineal Parenchymal Tumors
Pineocytomas and pineoblastomas are both tumors that arise from
pineal parenchymal cells. Both tumor types are considerably less
common in children than pineal germ cell tumors. Pineocytomas
affect both sexes equally; they may be found at any age, but are very
uncommon in children. They are composed of relatively mature cells
and are usually circumscribed, noninvasive, slowly growing tumors.
Because they are rare, the natural history of pineocytomas is not
well-defined (554). Some that remain circumscribed and noninva-
sive are found after several years of clinical symptoms or are dis-
closed at postmortem examination. Others metastasize extensively
through the cerebrospinal fluid and behave more like the primitive
tumor of this group, the pineoblastomas. Some evidence indicates
5/6/2011 9:17:18 PM
 740 Pediatric Neuroimaging

FIG. 7-101. Pineal region teratoma. A. Axial noncontrast CT scan

shows a large mass in the pineal region and extending anteriorly into
the third ventricle (black arrows). Foci of calcification (open white
arrows) and fat (solid white arrows) are present as well. B. Sagittal
T1-weighted image shows the large heterogeneous tumor mass
(arrows) within the third ventricle. The high intensity regions rep-
resent fat. Calcification is not well seen on MR images. Note the
extreme heterogeneity of the tumor. C. Axial T2-weighted image
shows the markedly heterogeneous tumor (arrows) with areas of
high signal intensity, low signal intensity, and intermediate signal
intensity occupying the pineal region and the third ventricle.

FIG. 7-102. Suprasellar teratoma in an

infant with growth delay. A. Axial non-
contrast CT shows a fatty suprasellar mass
(arrow) with a focus of calcification within
it. B. Sagittal T1-weighted image shows a
heterogeneous mass (arrow) extending from
the mammillary body to the infundibulum.
Both fatty components and nonfatty com-
ponents (open arrows) are present. Mild
enhancement of the nonfatty components
was seen on the postcontrast scan.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
TABLE 7-10 Pineal Region Tumors in Children
Tumor
Germ cell tumors
Pineal parenchymal tumors
Dermoids and epidermoids
Pineal region gliomas
Pineal cysts
Vein of galen varices (see Chapter 12)
that pineocytomas in children are aggressive tumors that should be
treated (555). Pineoblastomas are primitive, small round cell tumors
that are highly cellular and are best classified as PNETs, grade IV
embryonal tumors. They are highly malignant, and demonstrate local
invasion as well as distant spread through the cerebrospinal fluid.
They may be found at any age but are more common in the pediatric
age group, with boys affected more frequently than girls (8,76,556).
As with most pineal region tumors (Table 7-10), affected children
are brought to attention by signs and symptoms of hydrocephalus or
Parinaud syndrome (556).
Imaging Studies
On CT, both pineocytomas and pineoblastomas are isodense to hyper-
dense to normal brain prior to contrast infusion (Fig. 7-103). In con-
trast to germinomas, which displace the calcified pineal gland, pineal
parenchymal tumors usually contain areas of calcification within them;
this feature is an important differentiating point (557). Pineoblasto-
mas are usually more lobulated than pineocytomas (558). Both show
marked enhancement, with pineocytomas having generally more uni-
form enhancement, while pineoblastomas have more heterogeneous
enhancement after the infusion of intravenous contrast (554,555,558–
560). In this author’s experience, pineoblastomas more commonly
have hypodense, nonenhancing foci within them and are larger and
more irregular in shape at the time of presentation than pineocytomas
or germinomas (Fig. 7-103). They frequently extend inferiorly into the
posterior fossa and can invade the cerebellar vermis. Moreover, they
can extend anteriorly into the third ventricle or laterally into the walls
of the third ventricle. Pineocytomas tend to be smaller and much less
invasive (10,408,409).
The MR appearance of pineal parenchymal tumors is nonspecific
(550,561,562). However, the diagnosis should always be considered
when a tumor with proper MR characteristics is found in the pineal
region of a girl or woman and suggested if no other predisposing
conditions (other primary malignancy, immunocompromised state)
are present. Pineocytomas are typically hypointense on T1-weighted
images and hyperintense on T2-weighted images compared with gray
matter; they may be isointense with CSF on these sequences. They are
differentiated from pineal cysts by the presence of trabeculae within
the tumor mass and by diffuse, homogeneous enhancement after intra-
venous contrast administration (558,563). Pineoblastomas are usually
larger and more lobulated than pineocytomas (Figs. 7-103 and 7-104);
Barkovich_Chap07.indd 741
741
Key Characteristics
Most common solid pediatric tumor
Germinomas most common: gray matter intensity
Imaging varies with histology
Solid portions: gray matter intensity
Similar to imaging characteristics in other locations
Look for extension from adjacent brain
Most common pineal mass
Cyst with rim of enhancing tissue
Look for signal void from flow
the margins of the pineoblastomas are less sharply demarcated (558).
They are usually isointense to hypointense on T1-weighted sequences
and isointense to hyperintense compared with gray matter on FLAIR
and T2-weighted images (Figs. 7-103 and 7-104); they demonstrate
reduced diffusivity compared with normal brain parenchyma. Necrotic
or cystic areas (hypointense on T1-weighted images and hyperintense
on T2-weighted images) are commonly seen in larger pineoblastomas
(Fig. 7-103). The solid portions of the tumor enhance intensely after
intravenous contrast administration (Fig. 7-104) (561,562). Pineoblas-
tomas very rarely bleed; the author has seen one such case. As with
other pineal region tumors, pineoblastomas are known to metastasize
frequently through the CSF; postcontrast scans of the entire neural
axis are essential to detect and define this subarachnoid tumor, which
enhances markedly (564). The perfusion and spectroscopy characteris-
tics of these tumors are not published. In our limited experience, pine-
oblastomas have significantly increased blood volume compared with
normal parenchyma.
Dermoids and Epidermoids
Dermoids and epidermoids commonly occur in the pineal region.
Their characteristics are described earlier in this chapter.
Pineal Region Gliomas
Gliomas, primarily astrocytomas, can also occur in the pineal region.
Gliomas rarely develop from astrocytes within the pineal gland itself
(565). Much more commonly, the tumors arise from adjacent brain
parenchyma, such as the quadrigeminal plate or thalamus, and grow
into the pineal region secondarily (76,557). Tumors originating from
the quadrigeminal plate are considered a subgroup of brainstem
tumors and are discussed more fully earlier in this chapter. Patients
typically present with headaches, nausea, vomiting, or sleepiness sec-
ondary to hydrocephalus. Other than those from hydrocephalus, they
have few, if any, abnormalities on neurological examination; thus a
significant delay often occurs between the onset of symptoms and the
time of diagnosis (193,566). Histologically, most of the tumors in this
region are pilocytic astrocytomas (566); they are quiescent and rarely
progress (193).
Imaging Studies
Imaging studies reveal a mass, originating most commonly in the
quadrigeminal plate, but sometimes in the thalamus, medial temporal
5/6/2011 9:17:21 PM
 742 Pediatric Neuroimaging

FIG. 7-103. Pineoblastoma. A. Noncontrast CT scan shows a mass in the

pineal region (arrows). A small low attenuation center is seen within the
mass. Pineoblastomas are usually iso- to hyperintense with respect to brain
on CT. B. Sagittal T1-weighted image shows the mass extends from the
pineal region well below the tentorial incisura into the posterior fossa (large
arrows). There are multiple small cystic/necrotic areas within the tumor
(small black arrows). Note the inferior displacement of the fourth ventricle
(small white arrows). C. Axial T2-weighted image shows the solid portion of
the tumor to be isointense with gray matter (arrows).

FIG. 7-104. Pineoblastoma. A. Sagittal

T1-weighted image shows the presence
of hydrocephalus, caused by an iso- to
slightly hypointense mass (arrows) in
the pineal region. B. Axial T2-weighted
image shows the mass (arrows) to be
gray matter intensity with small cen-
tral regions of hyperintensity that likely
represent necrosis

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 743

FIG. 7-104. (Continued)

C. Postcontrast sagittal
T1-weighted image after
shunting of ventricles shows
that the lobulated mass
enhances heterogeneously. A
small cyst is seen inferiorly
(arrow) where the tumor
enters the enlarged Sylvian
aqueduct. D. Axial calculated
Dav image shows reduced dif-
fusion of the mass (arrows)
compared with normal cere-
bral parenchyma.

lobe, or the medial occipital lobe, and growing into the pineal region
(Fig. 7-105). If the tumor is very large at the time of the initial imaging
study, the site of origin may become obscured; under these circum-
stances, differentiation of a primary pineal tumor from a parapineal
tumor growing into the pineal region is impossible. The tumors are
typically hypodense on CT, hypointense on T1-weighted images, and
hyperintense on T2-weighted and FLAIR images prior to contrast
administration. Enhancement is variable; those arising in the tectum
enhance little, if at all, while those arising from the thalamus may
enhance mildly or moderately. Most tumors are stable in size, but
slow enlargement may be seen on sequential studies; it is controversial
whether growth on an imaging study, without the development of clin-
ical symptoms, is in indication for therapy (193,197).
Pineal Cysts
Small nonneoplastic cysts of the pineal gland are common, incidentally
found in up to 40% of autopsies (567–569). These lesions are uncom-
mon in infancy; they seem to develop during adolescence and their
incidence is highest in the third decade (570). Their observation on
imaging studies is nearly always incidental, as they are essentially never
symptomatic unless complications, such as hemorrhage, ensue. Their
cause is not known, and authors have postulated cystic degeneration

FIG. 7-105. Pineal region astrocytoma. A. Sagittal T1-weighted image shows hydrocephalus (note expanded anterior recesses of the third ventricle) and
a hypointense, poorly marginated mass (arrows) in the posterior third ventricle, extending into the aqueduct and tectum to the pineal region. B. Axial
T2-weighted image shows the mass (arrows) to be hyperintense compared to surrounding brain tissue.

Barkovich_Chap07.indd 743 5/6/2011 9:17:23 PM

 744 Pediatric Neuroimaging

FIG. 7-106. Pineal cyst. A. Sagittal T1-weighted image

shows a sharply marginated ovoid mass in the pineal
region (large arrows). The mass is isointense with CSF.
Note that there is some compression of the superior col-
liculi (small arrows). In the absence of the Parinaud syn-
drome or hydrocephalus, such compression should not
cause alarm. These findings are classic for a pineal cyst.
B. After administration of paramagnetic contrast, the
rim of normal pineal gland around the cyst (arrows)
enhances.

of the gland, enlargement of microscopic cysts under hormonal influ- Extraparenchymal Tumors
ence, and enlargement of the embryonic pineal cavity (571).
Although many are too small to see on routine imaging studies, Supratentorial extraparenchymal tumors are rather uncommon in
pineal cysts are, nonetheless, a frequent observation on MR studies of children. By far, the most common are tumors originating from the
the brain. They can be identified in up to 23% of brain MR examinations choroid plexuses of the lateral ventricles and those originating in
(572–575). Pineal cysts are infrequently noted on CT scans, other than the calvarium, the most common of which is LCH. Key features of
in retrospect, because they are isointense with CSF in the surrounding supratentorial extraparenchymal tumors are outlined in Table 7-11.
cisterns. On MRI, they are most commonly appreciated on the sagittal
Choroid Plexus Tumors
images, where they cause pineal enlargement that frequently results in
a slight impression on the superior colliculi or posterior third ventricle Choroid plexus papillomas and carcinomas are rare tumors that
(Fig. 7-106A). Most pineal cysts are small (2–4 mm in diameter) and arise from the epithelium of the choroid plexus in both children and
are incidental findings (575,576). When imaged sequentially, they may
enlarge, shrink, or disappear entirely (576). If the MR appearance is
classic for pineal cyst, these changes should not cause concern. TABLE 7-11 Supratentorial
When larger than 1 cm, pineal cysts may cause some diagnostic Extraparenchymal Tumors
difficulty, especially when hemorrhagic or heterogeneous (577). An
important factor in the differentiation of cysts from neoplasms is Tumor Key Features
that cysts are rarely, if ever, associated with the Parinaud syndrome
and they are essentially never the cause of hydrocephalus (574). In Choroid plexus papilloma Intraventricular origin,
general, the MR appearance of pineal cysts is that of isointensity with lobulated, T2 hypointensity
CSF on T1-weighted images and slight hyperintensity with respect to Choroid plexus carcinoma Intraventricular origin, invasion
CSF on T2-weighted and FLAIR images. The hyperintensity on the of parenchyma, necrosis
T2-weighted sequences is probably the result of loss of phase coher- Tumors of the meninges Meningeal origin
ence of the protons in the moving CSF in the surrounding cisterns;
the phase coherence of the protons within the cysts results in a higher Infantile myofibromatosis Calvarial or dural origin
relative signal intensity. When hemorrhage is present in the cyst, high Sharply marginated
signal intensity is seen in the cyst on both T1- and T2-weighted images Isointense to gray matter
and the cyst may enlarge, resulting in symptoms from local mass effect. Lymphoma/leukemia Gray matter intensity on T2
After intravenous administration of paramagnetic contrast, a crescent Knowledge of systemic disease
or rim of normal pineal gland surrounding the cyst typically enhances
Langerhans cell histiocytosis Dural, skull, or choroid plexus
(Fig. 7-106B). The scan should not be delayed after contrast adminis-
origin
tration as, because no blood–brain barrier is present in the pineal, the
Marked T2 hypointensity
cyst itself may enhance after prolonged delays, making differentiation
from tumors impossible (578). The keys in making the diagnosis of Epidermoids and dermoids Same characteristics as in other
pineal cyst by MRI are the absence of clinical manifestations, normal locations
ventricular size, the characteristic location, the isointensity with CSF Arachnoid cysts (see Chapter 5) Sharp margins, isointense to CSF
on T1-weighted images, the absence of any internal structure within
the lesion, and the presence of the typical rim of enhancement around Calvarial tumors Centered in calvarium
the cyst.

Barkovich_Chap07.indd 744 5/6/2011 9:17:24 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
adults. They comprise approximately 5% of supratentorial tumors
in children and less than 1% of all primary intracranial tumors.
Choroid plexus tumors can occur at any age, but most are found in
infants, or during the first 5 years of life. Papillomas of the choroid
plexus are most often found in the first year of life; they are typically
discovered because of the resultant severe hydrocephalus. A marked
male predominance has been noted for papillomas (8,579–582), but
carcinomas affect males and females more equally (583). Choroid
plexus carcinomas make up 30% to 40% of choroid plexus tumors
in children; affected children tend to present at a somewhat older
age than those with choroid plexus papillomas, but usually within
the first 3 to 5 years of life. Focal neurological deficits secondary to
local brain involvement by tumor are more common than in patients
with choroid plexus papillomas; however, most patients with choroid
plexus carcinomas still present with signs and symptoms of hydro-
cephalus (583).
Pathology
The most common site of origin of choroid plexus tumors in the pediat-
ric age group is the lateral ventricle, the left side being more commonly
involved than the right; tumors are rarely bilateral (579,581). The third
and fourth ventricles are less commonly involved in children, although
the fourth ventricle is the most common site of origin of choroid plexus
tumors in adults. Exceptionally, tumors may originate from chor-
oid plexus in the cerebellopontine angle (584). Grossly, tumors of the
choroid plexus are dark pink or red, globular masses with an irregular
papillary surface resembling a cauliflower. They often cause consider-
able enlargement of the involved lateral ventricle. An important point
is that choroid plexus papillomas are differentiated from carcinomas
based upon histological, not gross pathological, criteria. In general,
papillomas are well-marginated and separate from the surrounding
brain. Small areas of hemorrhage may be present and multiple gritty
foci of calcification are frequently found. Some choroid plexus papil-
lomas show evidence of anaplasia and invasion of the adjacent brain.
FIG. 7-107. Choroid plexus papilloma. A. Axial noncontrast CT images show hydrocephalus and a hyperdense, lobulated mass (arrows) in the left lateral
ventricle. Note surrounding vasogenic edema. B. Sagittal T2-weighted image shows that the very lobulated mass is extremely heterogeneous and has mul-
tiple small areas of hyperintense cysts/necrosis.
Barkovich_Chap07.indd 745
745
Anaplastic papillomas cannot be differentiated from carcinomas based
on gross pathologic features; the distinction is purely based on charac-
teristics of individual cells. Both aggressive papillomas and carcinomas
show a marked propensity to metastasize through the CSF pathways,
sometimes forming large subarachnoid masses (8,75,76).
Imaging Studies
Choroid plexus tumors are usually easy to identify and diagnose, as
few pediatric tumors arise in the lateral ventricles. Although it is usu-
ally easy to differentiate a choroid plexus papilloma from a carcinoma,
it is important to remember that this differentiation is histologic, not
radiologic. Therefore, tumors with a more benign appearance may
ultimately be diagnosed histologically as carcinomas and tumors with
aggressive, invasive imaging characteristics may turn out to be anaplas-
tic papillomas. Nonetheless, it is important to properly characterize the
tumors preoperatively by neuroimaging, as this characterization may
affect surgical approach to the tumor.
On CT, choroid plexus papillomas typically appear as lobulated,
isodense or mildly hyperdense intraventricular masses (Fig. 7-107) with
occasional punctate foci of calcification. The most common location
of the tumor is the trigone, but papillomas may be located anywhere
along the choroid plexus, including the temporal frontal horns of the
lateral ventricle, third ventricle, fourth ventricle, or lateral recess of the
fourth ventricle with extension into the cerebellopontine angle cis-
tern. Homogeneous enhancement is seen after infusion of IV contrast.
Although usually unilateral, bilateral papillomas have been reported
(579). Occasionally, papillomas grow through the ependyma and into
the adjacent white matter, inciting surrounding edema. These aggres-
sive papillomas have a more irregular appearance, more closely resem-
bling a carcinoma; histologically, they show a higher degree of anaplasia
than the less aggressive papillomas. Choroid plexus carcinomas usually
appear much more aggressive than papillomas. Carcinomas have irreg-
ular contours, demonstrate mixed density prior to contrast enhance-
ment and have a prominent, but variable, enhancement pattern. Cysts
5/6/2011 9:17:25 PM
 746 Pediatric Neuroimaging

FIG. 7-107. (Continued) C. Axial FLAIR image show the heterogeneous mass with sur-
rounding edema. The branching areas of central hypointensity are characteristic. Sur-
rounding vasogenic edema does not necessarily imply malignancy, but should inspire
a search for invasion of the cerebral hemispheres. D. Postcontrast axial T1-weighted
image shows robust enhancement of the solid portion of the tumor. Note the character-
istic central, rather low intensity, branches extending outward from the center. The pos-
terior fluid (f) is likely a tumor cyst rather than trapped area of ventricle in light of its
hyperintense signal on FLAIR (in C). E. Calculated diffusivity map shows similar diffu-
sion characteristics to normal cerebral parenchyma. This can help differentiation from
PNET and ATRT which have reduced diffusivity. F. Collapsed view from time of flight
MRA shows enlarged posterior choroidal branches (arrow), indicating a choroid plexus
origin of the tumor. G. Relaxivity curve from dynamic susceptibility-weighted perfu-
sion study shows no return to baseline of curves 1 and 3, which were placed over the
tumor. This indicated absence of blood–brain barrier and strongly suggests an extra-
parenchymal tumor. Contrast with parenchymal curve 2. H. Proton MR spectrum (TE =
135 milliseconds) shows only a choline peak (Ch); absence of NAA also suggests and
extraparenchymal tumor.

Barkovich_Chap07.indd 746 5/6/2011 9:17:25 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 747

and hemorrhage are often present within the tumor. Carcinomas
nearly always grow through the ventricular wall into the brain and
incite vasogenic edema (Fig. 7-108) (10,11,579,582,585,586).
The typical MR appearance of a choroid plexus papilloma
on T1-weighted sequences is that of a homogeneous, lobulated
intraventricular mass (Fig. 7-107C). The surface of the mass typi-
cally has a papillary appearance that distinguishes it from the smooth
surfaces of most other intraventricular tumors such as meningiomas,
ependymomas, or choroid plexus carcinomas. The central portions
of papillomas are usually somewhat hypointense compared to gray
matter on T2-weighted and FLAIR images, often with a well-defined
branching pattern (Figs. 7-107D, E and 7-109B), a characteristic that
may aid in their preoperative diagnosis. Foci of hemorrhage or cal-
cium are occasionally present. Cysts or septations may develop within
the ventricle (Fig. 7-109C); these are likely the result of inflammation
generated by the tumor mass, possibly as a result of recurrent small

FIG. 7-108. Choroid plexus carcinoma. A. Axial noncontrast CT shows a large, high attenuation mass involving the right lateral ventricle and the right
cerebral hemisphere. Foci of calcification (open arrows) and cystic or necrotic areas (closed arrows) are seen within the tumor mass. B. After infusion of
iodinated contrast, there is heterogeneous enhancement of the tumor mass. C and D. Different patient. Axial T1-weighted images show a heterogeneous
mass filling the left ventricular trigone. Foci of hemorrhage and necrosis are present.

Barkovich_Chap07.indd 747 5/6/2011 9:17:27 PM

 748 Pediatric Neuroimaging

FIG. 7-108. (Continued) E and F. Axial T2-weighted images show the extremely heterogeneous tumor mass eliciting vasogenic edema (arrows) in adjacent
white matter. G and H. Postcontrast T1-weighted images show heterogeneous enhancement of the tumor, with both cystic and necrotic regions.

hemorrhages. Uniform, intense enhancement follows intravenous
administration of paramagnetic contrast (Figs. 7-107 and 7-109)
(581,585). Third and fourth ventricular papillomas are more com-
mon in adults but can develop in children (Fig. 7-109). They have an
appearance similar to that of lateral ventricular papillomas, lobulated
intraventricular masses that calcify and cause hydrocephalus. Fourth
ventricular papillomas may originate within or grow through the
fourth ventricular outlet foramina, sometimes presenting as a cerebel-
lopontine angle or cerebellomedullary angle mass (Fig. 7-110).
Choroid plexus carcinomas are typically heterogeneous in appear-
ance, particularly on T2-weighted images, and usually invade the sur-
rounding brain through the ventricular wall, inciting vasogenic edema
(Fig. 7-108) (587). The well-defined branching pattern of the stroma
is not seen. When the surrounding brain parenchyma is extensively
invaded, it is sometimes difficult to determine whether the tumor origi-
nated in the ventricle or in the parenchyma. Under these circumstances,
it is difficult to make the proper diagnosis. Carcinomas often have areas
of high and low signal intensity on both T1- and T2-weighted images,
resulting from hemorrhage and cyst formation. The frontal, occipital,
or temporal horn of the affected lateral ventricle becomes encysted in
more than 80% of patients (37,580). Hydrocephalus is present in more
than 80% of patients at the time of diagnosis and leptomeningeal dis-
semination of tumor is present at the time of diagnosis in nearly half
of affected patients (587).
As with all intraventricular tumors, choroid plexus tumors (papil-
lomas and carcinomas) can spread throughout the neuroaxis via the

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 749

FIG. 7-109. Choroid plexus papilloma of the fourth ventricle.

A. Sagittal T1-weighted image shows a fourth ventricular mass
(large arrows) with associated cysts. The mass is somewhat
heterogeneous and extends inferiorly (small arrows) through the
foramen of Magendie. B. Axial T2-weighted image shows
the mass (arrows) to be heterogeneous, with some areas of very
low signal intensity and other areas (probably cysts) appear-
ing very hyperintense. C. Postcontrast coronal T1-weighted
image shows the tumor mass (large arrows) extending inferiorly
through the foramen of Magendie (small arrows). One of the
walls of the tumor-associated cysts is seen (arrowheads).

FIG. 7-110. Fourth ventricular choroid plexus papilloma extending

through foramen of Luschka. A and B. Postcontrast coronal T1-weighted
images show the lobulated enhancing tumor (arrows) extending out the
left foramen of Luschka into the cerebellomedullary angle cistern and into
the cervical subarachnoid space.

Barkovich_Chap07.indd 749 5/6/2011 9:17:29 PM

 750 Pediatric Neuroimaging
cerebrospinal pathways (588). Therefore, all affected patients should
have a contrast-enhanced scan of the brain and spine with careful
attention for small tumors of the surface of the brain and spinal cord,
and along cranial and spinal nerves.
Proton MR spectroscopy of choroid plexus papillomas is remark-
able for the complete absence of an NAA or creatine/phosphocreatine
peak. Only a choline peak is seen on long TE spectra (Fig. 7-107H),
but a very prominent peak of myo-inositol is seen on short TE (45).
Carcinomas have higher choline levels and show elevation of lactate
(589), but myo-inositol is not increased (45). Perfusion imaging of the
tumor shows high blood volume with persistence of contrast within
the tumor interstitium due to absence of blood–brain barrier within
the mass, resulting in no return of the perfusion curve to baseline.
Differential Diagnosis
Choroid plexus papillomas are easily diagnosed on both CT and MRI
by their characteristic location and appearance. The diagnosis of chor-
oid plexus carcinoma is more difficult because of their resemblance to
PNETs, ATRT, and ependymomas.
Tumors of the Meninges
Intrinsic meningeal tumors are uncommon in childhood, comprising
only 1% to 2% of primary brain tumors. In contrast to adults, in whom
a female predominance exists, males and females seem to be equally
affected in the pediatric age group. No definite age peak is noted
within the pediatric population. The clinical presentation is variable
and depends upon the site of the tumor; headaches and focal neuro-
logical deficits are the most common reasons for initial presentation
(590–594). The presence of a meningioma in a child should raise sus-
picion for neurofibromatosis type 2 (see Chapter 6) and should initiate
a search for other meningiomas or schwannomas.
Pathology
Meningeal tumors of childhood include meningiomas (which are,
by far, the most common), plasma cell granulomas (discussed ear-
lier in this chapter in the section on “Tumors of the Cerebral Hemi-
spheres”), meningeal fibromas and myofibromas (595), meningeal
Barkovich_Chap07.indd 750
sarcomas (594), extraosseous Ewing sarcomas (596), malignant fibrous
histiocytomas (597), and meningeal melanomas (591,598). In addition
to their rarity, several features characterize meningiomas in children.
A higher percentage of meningiomas in the pediatric age group are
intraventricular (590–592). Cystic areas are commonly associated with
pediatric meningiomas, being found in more than 12% of affected
patients (599–601). Meningiomas in childhood sometimes originate
in the Sylvian fissure and lack a dural attachment, a characteristic that
may imply origin from heterotopic meningeal rests within the brain
(602,603). Pediatric meningiomas are often very large, grow rapidly,
and are more frequently malignant than adult meningiomas; in several
series more than 50% of pediatric meningiomas were malignant
(8,76,590,592,604). A high mortality rate and high incidence of sar-
comatous degeneration have been reported (76,590,592). Nonetheless,
outcome is usually good if the tumor is completely resected and if the
patient does not have NF2 (593,602,605).
Extraosseous Ewing sarcomas are very rare tumors that are histo-
logically identical to PNETs but are distinguished by their dural origin/
attachment, by strong membrane expression of the MIC-2 gene prod-
uct (CD99), and by demonstration of the chromosomal translocation
t(11,22)(q24;q12) (606).
Imaging Studies
Meningiomas, plasma cell granulomas, meningeal fibromas and
myofibromas, and meningeal sarcomas have nearly identical imag-
ing features; they can only be differentiated by histologic examination
(220,591,594,607). The diagnosis of malignant fibrous histiocytoma
may be suggested if the child presents with hemorrhage into the tumor
(608). CT studies have revealed a heterogeneous appearance of these
tumors. Approximately one half of patients with meningiomas have
associated hyperostosis and half have intratumoral calcification. All
pediatric meningeal-based tumors are isodense to hyperdense on pre-
contrast CT and the solid portions of the tumor show diffuse contrast
enhancement (Fig. 7-111). Cystic and necrotic changes are more fre-
quent in pediatric patients than in adults (599–601), possibly because
of the larger size at the time of diagnosis. Rapid growth or the pres-
ence of atypical CT features, such as hemorrhage, heterogeneous
FIG. 7-111. Meningioma. A. Axial con-
trast-enhanced CT scan shows a mass
within the atrium of the left lateral ven-
tricle. The periphery (white arrows) is
enhancing whereas the central portion
(open black arrows) is densely calcified.
B. Axial T2-weighted image shows the
meningioma (closed white arrows) in the
atrium of the left lateral ventricle. The
densely calcified center (open arrow) is of
very low signal intensity.
5/6/2011 9:17:31 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
enhancement, cyst formation, or poorly defined margins, suggests a
malignant tumor such as meningeal sarcoma, extraosseous Ewing sar-
coma, or meningeal PNET (594,596); however, benign meningiomas
can have many of these features. Intraventricular meningiomas arise
from the choroid plexuses and have the same CT characteristics as
those originating in the dura (590,591,609).
On MRI, pediatric meningeal tumors are generally large masses
that arise from the dura, the choroid plexuses, or from ectopic dural
rests in the Sylvian fissures. They typically have smooth, well-defined
margins (whether benign or malignant) and are isointense to gray mat-
ter on T1-weighted sequences and isointense to hyperintense to gray
matter on FLAIR and T2-weighted sequences. Cystic and necrotic areas,
if present, are hypointense on T1- and hyperintense on T2-weighted
images compared to the solid portion of the tumor, which shows uni-
form enhancement after intravenous infusion of paramagnetic con-
trast. Hemorrhage, heterogeneity, reduced diffusion (compared with
gray matter), and indistinct margins favor sarcomas or meningiomas
with higher degrees of malignancy (596), but this feature is not reliable.
Densely calcified areas have very low intensity, whereas areas that are
less densely calcified may appear isointense or hyperintense on non-
contrast T1-weighted images (Fig. 7-111B).
As stated in the section on imaging characteristics at the beginning
of this chapter, perfusion imaging may be useful to differentiate men-
ingeal tumors from intraparenchymal tumors in that neuroepithelial
tumors show a return to baseline of relaxivity after the bolus of con-
trast has passed through the tumor, but meningeal tumors show per-
sistence of abnormal relaxivity due to absence of blood–brain barrier.
In addition, meningiomas tend to have large blood volumes compared
to normal brain parenchyma (54).
Long echo time proton MR spectroscopy in meningiomas shows
the normal neoplastic pattern of elevated choline with diminished
creatine/phosphocreatine and NAA. Short echo time spectra show an
increase in alanine (seen as a doublet centered at 1.47 ppm), choline,
and glutamine/glutamate, whereas concentrations of myo-inositol,
creatine/phosphocreatine, and NAA are low (610–612).
Catheter arteriography typically shows a characteristic homoge-
neous tumor blush, along with vascular supply from meningeal vessels.
Surgery may be aided in such cases by preoperative embolization. The
reader should keep in mind, however, that meningeal tumors some-
times parasitize blood flow from intracerebral vessels and may, thus,
incorrectly suggest a primary intracerebral tumor. Similarly, intrac-
erebral tumors can parasitize flow from meningeal vessels to mimic
meningeal tumors.
Infantile Myofibromatosis
Infantile myofibromatosis is a condition in which mesenchymal pseudo-
tumors develop in the skin, subcutaneous tissues, skeletal muscle, bone,
and/or visceral organs of children (595). When infantile myofibromas
involve the skull and brain, they most commonly arise from the calva-
rium or dura (595). By radiologic criteria, these masses are very dif-
ficult to differentiate from meningiomas when they are dural based
and from LCH when they arise within the calvarium. Infantile myo-
fibromas appear on CT and MRI as well-demarcated, homogeneous
calvarial or dural masses that are isodense to gray matter on CT and
isointense to hypointense to gray matter on T1-and T2-weighted MR
sequences. If the calvarium is involved, osteolytic or sclerotic changes
may be identified on plain films or CT. Homogeneous enhancement
is typical after administration of intravenous contrast; if the lesion is
dural-based, a “dural tail” may be present (595,613). Because the imag-
ing characteristics of dural-based infantile myofibromas are nearly
identical to those of meningiomas, differentiation is not possible by
imaging alone. Myofibroma should be considered as a possible cause
Barkovich_Chap07.indd 751
751
of dural-based masses in neonates and infants, an age group in which
meningiomas are extremely rare.
Leukemia and Lymphoma
Tumor deposits in the brain and meninges from systemic malignan-
cies are rare in childhood. The exceptions to this rule are childhood
leukemia and lymphoma. Leukemias account for 30% of all childhood
malignancies and are the most common cancers diagnosed in children
(614). Involvement of the CNS may be asymptomatic or may manifest
with irritability, headaches, vomiting, seizures, or unusual weight gain.
In advanced cases, papilledema or cranial neuropathies (typically uni-
lateral involvement of cranial nerve VII) will be detected (614). The
most common finding in leukemia is enlargement of the ventricles
and sulci. Although some authors have suggested that the enlarged
CSF spaces result from radiotherapy and chemotherapy, Kretchmer et
al. (615) found that 31% of children with acute lymphocytic leuke-
mia have enlarged ventricles before treatment. These findings suggest
that the ventricular enlargement represents hydrocephalus, not atro-
phy, and is caused by the disease, not by the treatment. Meningeal and
parenchymal metastatic disease is far less common than enlargement
of the ventricles and sulci. Children with acute myelogeneous leuke-
mia, may present with focal signs or symptoms due to the develop-
ment of chloromas, aggregates of leukemia cells that often occur in the
calvarium, neck, or spine.
On CT, only 5% of leukemic patients with CNS symptoms
show contrast-enhancement of the meninges (10). When lympho-
mas or aggregates of leukemic cells involve the brain, they appear
on CT as masses of isodense to hyperdense signal prior to contrast
enhancement; they enhance uniformly after contrast administration
(Fig. 7-112) (614). Of interest, leukemic infiltrates may grow through
the calvarium or an orbital wall without any apparent radiologic evi-
dence of bone involvement (Fig. 7-112). On MRI, these masses tend to
be slightly hypointense with respect to brain on T1-weighted sequences
and isointense to slightly hyperintense on FLAIR and T2-weighted
sequences. Almost all lesions show diffuse and prominent enhance-
ment after infusion of IV contrast (Fig. 7-113). There are no character-
istic locations within the brain, and, indeed, the disease can affect the
cerebral parenchyma, meninges, cranial nerves, calvarium, or orbits
(Figs. 7-112 and 7-113). Indeed, when the disease is predominantly or
entirely subarachnoid in location, the only imaging abnormality may
be enhancement of cranial nerves (usually resulting from deposition of
subarachnoid tumor on the nerves) on postcontrast scans. Equally or
more important, and much more frequent than direct involvement of
the disease is the effect of therapy and immunosuppression. Infection
(see Chapter 11), acute neurotoxicity (see Chapter 3), demyelination
(see Chapter 3), hemorrhage and infarction (see Chapter 4) are all-
too-common sequelae of the treatment of leukemia and lymphoma
(614,616,617). The diagnosis of these treatment-related changes can
sometimes be aided by the use of volumetrics, morphometry, perfu-
sion imaging, and DWI (618).
Langerhans Cell Histiocytosis
LCH has been mentioned in nearly every section of this chapter. The
reason for the multiple citations is the fact that LCH can arise nearly
anywhere in the brain and skull. This diagnosis should always be con-
sidered when a mass arises from the bones of the face, skull base, or
calvarium in children. Rarely, LCH may result in masses based in the
cerebral parenchyma, spinal cord, pineal gland (506), dura, or choroid
plexus (504).
The most common imaging finding of calvarial LCH is that of
a well-defined mass involving the calvarium. On CT, a sharply cir-
cumscribed skull lesion is identified with differential involvement
5/6/2011 9:17:31 PM
 752 Pediatric Neuroimaging
of the inner and outer tables (resulting in the classic “beveled edge”
on plain skull films). The lesion is typically of similar attenuation to
cortical gray matter; uniform, moderately intense enhancement is
seen after administration of contrast (Fig. 7-114A and B). MRI shows
the bone lesions as sharply defined soft tissue masses that have sig-
nal intensity comparable to skeletal muscle and enhance markedly
after IV administration of paramagnetic contrast (Fig. 7-114C and D)
(220,241,243,244,246,249,504). The lesion may occasionally displace
the underlying brain.
Barkovich_Chap07.indd 752
FIG. 7-112. Leukemic infiltrate (chloroma) involving the
orbit and frontal lobe. A. Axial postcontrast CT image shows
a mass (arrows) in the anteromedial right orbit, displacing
the ocular globe posteriorly and laterally. No bone destruc-
tion is present. B. Image at a slightly higher level shows the
mass (arrows) extending subcutaneously. C. At a higher level,
a large mass is seen in the right frontal lobe, resulting in sub-
stantial mass effect with subfalcine herniation (arrows) of
the right frontal lobe.
Lesions originating within the dura and choroid plexus tend to
be ovoid masses that are often quite large at the time first detected by
imaging (246). Histologically, these lesions are granulomas consisting
of a mixture of histiocytes, foamy macrophages, multinucleated giant
cells, lymphocytes, plasma cells, and eosinophils (250). On imaging,
the masses are characterized by isointensity to cerebral gray matter
on CT and a marked hypointensity on FLAIR and T2-weighted MR
images (Fig. 7-115). The reason for this marked T2 hypointensity is not
known but it may be related to a severe fibrotic reaction of the choroid
5/6/2011 9:17:32 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 753

FIG. 7-113. Leukemic infiltrate involving the trigeminal nerve. Fat-suppressed postcontrast axial
T1-weighted image shows enhancement of the cisternal portion of the right trigeminal nerve
(arrowheads). Enhancement is also seen within the trigeminal cistern (arrow), which surrounds the
trigeminal ganglion.

FIG. 7-114. Langerhans cell his-

tiocytosis involving the calvarium.
A. Axial CT image using wide win-
dows for optimal evaluation of bone
shows a sharply marginated lytic area
(arrows) in the posterior left frontal
bone. B. Axial contrast-enhanced CT
image shows enhancing soft tissue
(arrows) within the calvarial defect. C.
Axial T2-weighted image of a different
patient shows a well-defined focus of
T2 prolongation (arrows) involving
the right frontal bone. D. Postcontrast
T1-weighted image reveals that the soft
tissue intensity mass (arrows) shows
uniform enhancement.

Barkovich_Chap07.indd 753 5/6/2011 9:17:32 PM

 754 Pediatric Neuroimaging

FIG. 7-115. Langerhans cell histiocytosis of the choroid plexus and tentorium. A. Axial FLAIR image shows heterogeneous isointense and hypointense
masses (black arrows) in the temporal horns of the lateral ventricles. The well-defined hypointense regions (t) anterior to the masses are the trapped tem-
poral horns of the lateral ventricles. The tentorial mass (white arrowheads) is equally heterogeneous, with areas of isointensity and areas markedly hypoin-
tense compared with brain tissue. B. Postcontrast axial T1-weighted image shows somewhat heterogeneous enhancement of both the choroid plexus (black
arrows) and tentorial (white arrowheads) masses. (This case courtesy of Dr. Danielle Prayer, Vienna.)

or meningeal tissue to the LCH involvement. These lesions enhance
intensely and uniformly after administration of intravenous contrast
(Fig. 7-115) (505). The choroid plexus and dural lesions are rarely the
cause of clinical presentation. They are more commonly found inci-
dentally in children with known multisystemic LCH, conditions pre-
viously known as Hand-Schüller-Christian and Letterer-Siwe diseases
(241,246,504).
Extramedullary Hematopoiesis
Extramedullary hematopoiesis refers to the development of hematopoi-
etic tissue (blood cell development) outside of the bone marrow. It is
a compensatory mechanism by which the body attempts to maintain a
level of erythrogenesis sufficient for its demands in the setting of chronic
hemolytic anemias, hemoglobinopathies, and some myeloproliferative
syndromes. The most common locations for this phenomenon are the
liver, spleen, paravertebral and presacral spaces, kidneys, adrenals, lung,
breast, thyroid, maxillary antra, and the falx cerebri (619). Rarely, it can
occur in the epidural space of the head or spine (620), possible due to
transformation of multipotential cells into marrow or direct extension
of hematopoietic cells from marrow into the epidural space (620,621).
Clinically, extramedullary hematopoiesis is usually asymptomatic, but
neurologic signs and symptoms can result from compression of adja-
cent tissue in the brain or spine (see Chapter 10 for discussion of spinal
manifestations). Headaches, seizures, hemiplegia, altered conscious-
ness, and cranial neuropathies are the most common manifestations of
intracranial disease (622).
Imaging studies typically show multiple intracranial dural-based
masses, often with associated enlargement of the diploic space of the
overlying calvarium. The masses are typically isodense to cerebral cortex
on noncontrast CT and show uniform enhancement after intravenous
administration of iodinated contrast. On MRI, the lesions are typically
slightly hyperintense co cerebral cortex and T1-weighted images and
isointense to hypointense on T2-weighted images. Enhancement is dif-
fuse, but heterogeneous (622). Nuclear medicine studies can be useful
to confirm the diagnosis, as sulfur colloid is taken up by macrophages
and, thus, traces the reticuloendothelial system (623). Uptake of 99mTc
sulfur colloid within the masses, therefore, strongly supports the diag-
nosis of extramedullary hematopoiesis.
Calvarial Tumors
Tumors arising from the calvarium were discussed in the “Posterior
Fossa Tumors” section of this chapter and in Chapter 5, under the
section entitled “Fontanel Dermoids and Other Calvarial Masses of
Childhood.” Calvarial masses from LCH were discussed in the previ-
ous section.
Neuroblastoma metastases should also be mentioned again in this
section, because patients with neuroblastoma sometimes present with
a calvarial mass. Neuroblastomas are common tumors of childhood
that can involve the CNS either by direct extension (primarily in the
spine, see Chapter 10) or, more commonly, by blood-borne metastases.
Neuroblastoma metastases rarely involve the brain; instead, they char-
acteristically involve the orbit and calvarium. On CT, calvarial metas-
tases from neuroblastoma show a characteristic appearance of a mass
(or masses) growing inward from the bone with spicules of bone
radiating centripetally within it (Fig. 7-116). Calvarial metastases can
grow centripetally into the intracranial space and mimic intracranial
masses. Coronal images help to verify a dural or extradural origin of
these lesions. On MRI, the metastases appear as soft tissue intensity
masses originating within the calvarium (Fig. 7-117). They enhance
markedly, on both CT and MRI, after administration of contrast.

Barkovich_Chap07.indd 754 5/6/2011 9:17:34 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 755

FIG. 7-116. Metastatic neuroblastoma to calvarium. A. Axial noncontrast CT scan shows multiple intracranial hyperdense masses (arrows), some of
which appear to be intraparenchymal in origin. Bony spicules extend intracranially from the calvarium. B. After intravenous contrast infusion, the masses
heterogeneously enhance. C. Bone windows show the characteristic bony spicules radiating centripetally from the calvarium. Also notice the splitting of the
coronal and sagittal sutures (arrows), another characteristic finding in metastatic neuroblastoma.

FIG. 7-117. Metastatic neuroblastoma

to calvarium and dura. A. Axial contrast
enhanced CT scan shows calvarial metas-
tases with intracranial extension (black
arrows) in the right frontal, right pari-
etal, and midline posterior regions. Note
the displacement of the superior sagittal
sinus from the skull. B and C. Axial T2
(B) and postcontrast T1 weighted (C)
images show extensive extraparenchymal
tumor (arrows) posteriorly. D. Coronal
postcontrast T1 weighted image shows
the involvement of the calvarium and the
heterogeneity of the metastases (arrows).

Barkovich_Chap07.indd 755 5/6/2011 9:17:34 PM

 756 Pediatric Neuroimaging
The elevated periosteum enhances, as well, which may be a helpful sign
in differentiating metastatic tumor from the normal hematopoietic
marrow of childhood.
BRAIN TUMORS IN THE FIRST
YEAR OF LIFE
The histologic distribution of primary brain tumors in the first year of
life (Table 7-12) is different than the distribution of the entire pediatric
period. Although various groups report different incidences of tumors
in infants (10,13–15,624–631) and nearly any histologic type of tumor,
including glioblastoma, can occur in neonates and infants (632,633),
certain definite trends emerge. Supratentorial tumors predominate,
constituting 60% to 70% in most series. Suprasellar lesions seem to
be more common during the first year of life than during the pediatric
age group as a whole. Of these, the most common are suprasellar astro-
cytomas (usually grade II or grade III) arising in the hypothalamus.
Choroid plexus papillomas have a much higher relative incidence in
the first year of life, representing 15% to 20% of all tumors in this age
group.
Among posterior fossa tumors, medulloblastomas (although
known to peak in frequency toward the latter half of the first decade)
are reported to be relatively common among tumors presenting during
the first year of life. However, the recent identification of ATRT as a dis-
tinct group raises the strong possibility that many of the posterior fossa
tumors of infancy previously identified as medulloblastomas were, in
fact, ATRT (118). Therefore, it is likely that ATRT, not medulloblasto-
mas, are common in the first year of life. Posterior fossa ependymomas
also seem relatively more common in younger children, whereas cer-
ebellar and brainstem astrocytomas are uncommon.
Among supratentorial tumors, PNET are reported in some series
to be common within the first year of life, with an incidence nearly
equal to that of choroid plexus papillomas. However, some of these
PNETs may have, in fact, been ATRT because both tumors are com-
posed of sheets of small round cells. The diagnoses of PNET, atypi-
cal teratoid/rhabdoid tumor, and ependymoma should be considered
when intraparenchymal hemispheric tumors are discovered in infancy;
choroid plexus tumor should be a strong consideration if the tumor is
intraventricular.
In other series, teratomas are the most frequent brain tumor diag-
nosed in the first year of life. Teratomas are diagnosed most frequently
TABLE 7-12 Most Common Brain
Tumors in the First Year
of Life
Teratoma
Suprasellar/thalamic astrocytoma
Atypical teratoid/rhabdoid tumor
Ependymoma
Choroid plexus tumor
Craniopharyngioma
Medulloblastoma?
Primitive neuroectodermal tumor?
Barkovich_Chap07.indd 756
in the first few months after birth (Fig. 7-118) and should be consid-
ered congenital tumors, as their incidence of presentation drops off
steadily thereafter. Congenital tumors are usually detected because of an
enlarged head circumference or asymmetric skull growth; the anterior
fontanelle is often tense. Among congenital tumors, which represent
less than 2% of all childhood brain tumors, teratomas constitute 30% to
50%; the remainder most often consist of astrocytomas, choroid plexus
papillomas, embryonic tumors (such as ATRT, PNET, and medullo-
blastoma), ependymomas, and craniopharyngiomas (630,634). Many
congenital tumors are now detected prenatally by ultrasound and MRI
(635). It is not surprising that the histologies of these fetal tumors are
similar to those found in neonates, with teratomas being most com-
mon. Astrocytomas, craniopharyngiomas, embryonal tumors (ATRTs,
PNETs, medulloblastomas), choroid plexus tumors, and ependymo-
mas are also found (635).
The clinical manifestations of tumors presenting in the first year
of life differ from those of older children (15,625,627–631). Focal neu-
rological deficits are almost always absent because of the immaturity
of the CNS. Infants with infratentorial tumors tend to present with
vomiting and increased sleepiness. Increasing head size and develop-
mental delays are noted in more than one-half of affected patients.
Among infants with supratentorial tumors, an increasing head size is
seen in about one half, vomiting and lethargy or irritability develop
in approximately one third, and seizures are seen in approximately
20%. Those infants with hypothalamic/chiasmal gliomas typically
present with decreased appetite, poor weight gain and abnormal eye
movements.
Treatment of very young children also differs from those in the
older age group (15,625,628–631). The treatment of children under
the age of 3 years is compromised by the immaturity of the brain,
the highly malignant nature of the neoplasms, the delay in diagnosis
(because of a low index of suspicion and nonspecific clinical find-
ings), the large bulk of tumor found at presentation, and the reduced
radiation dose used in this age group. A reduced radiation dosage is
necessary because of the immaturity of the brain and the high inci-
dence of subsequent vaso-occlusive disease and developmental retar-
dation that occurs when radiation is given to very young children;
most oncologists try not to use radiation at all in this age group. In
general, a conservative approach is recommended in children with
optic gliomas and low grade supratentorial astrocytomas. Radiation is
deferred until the child is 3 to 4 years old, when its effects on the CNS
are better tolerated; when necessary, modified focal irradiation is used.
Presently, most centers are using surgery, postoperative chemotherapy
(systemic and intrathecal), and delayed radiation; results have been
mixed (636–639).
RADIATION-INDUCED TUMORS OF THE
CENTRAL NERVOUS SYSTEM
One of the unfortunate side effects of radiation therapy for brain
tumors is the development of secondary neoplasms. As the long-term
survival of children with brain tumors increases, so does, unfortu-
nately, the incidence of secondary tumors. Secondary brain tumors in
children differ from those in adults in several ways. Most important,
the latency period appears to be shorter. In adults, the time between
treatment of the primary tumor and detection of the secondary tumor
averages 20 to 25 years, whereas in children it averages 8 years (640). The
second major difference is in the histology of the tumors. Although the
most common secondary tumor in adults is meningioma, malignant
gliomas are, by far, the most common secondary tumor in childhood
(640). Leukemia is another common complication of brain tumor
5/6/2011 9:17:36 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 757

FIG. 7-118. Congenital tumors A and B. Teratoma in a

newborn. Sagittal T1-weighted image (A) shows an enor-
mous, heterogeneous mass involving the frontal, temporal,
and parietal lobes in this newborn infant. There is marked
hydrocephalus. The brainstem is pushed posteriorly and
inferiorly (open arrows) and is kinked at the cervicomedul-
lary junction (closed arrow). Coronal T1-weighted image (B)
shows markedly dilated temporal horns (arrows) in addition
to the huge, extremely heterogeneous tumor occupying the
majority of the intracranial space. (This case courtesy of
Dr. T. Ito.) C–E. Fetal teratoma. Fetal sonogram (C) shows
a transverse view of the brain containing a large echogenic
mass (m) that seems to be centered in the midline. Sagittal
fetal MR view (D) through the brain shows the large midline
heterogeneous mass that seems to be eroding and enlarging
the sella turcica (arrows) suggesting possible origin from
the pituitary gland or stalk. Coronal view of the brain (E)
shows the suprasellar mass lifting and displacing both cere-
bral hemispheres. The margins of the tumor appear sharp,
suggesting displacement rather than invasion of the brain.
Pathology showed craniopharyngioma.

Barkovich_Chap07.indd 757 5/6/2011 9:17:36 PM

 758 Pediatric Neuroimaging

irradiation, with an average latency period of about 10 years. Other
common solid secondary tumors include meningiomas, sarcomas, low
grade gliomas, and PNETs (640).
TUMORS OF THE HEAD AND NECK IN
CHILDHOOD
Masses in the head, neck, and orbit are common indications for imag-
ing in childhood. It is very important, when possible, to differentiate
malignant tumors from developmental and benign masses. The topics
of calvarial and skull base masses have been addressed earlier in this
chapter and in Chapter 5. In this section, I will concentrate on masses
of the ocular globe, orbit, face, and neck.
Ocular Tumors
Retinoblastoma
Retinoblastoma is the most common intraocular malignancy in child-
hood, accounting for 11% of all cancers in the first year of life (641).
It most often presents in early childhood with leukocoria or “cat’s eye
reflex.” Other conditions resulting in this presentation are listed in
Table 7-13. Retinoblastoma is primarily a tumor of infancy; 70% to
80% of retinoblastomas occur in infants less than 2-years-old. There
is no gender or race predilection (641). Multifocal tumors are com-
mon, with a 30% incidence of bilateral tumors and a 30% incidence of
multifocal retinal tumors in affected children (642,643); the incidence
of bilaterality is higher in patients younger than 1 year old at presenta-
tion (641).
Heritable retinoblastoma accounts for 30% to 60% of cases; 10%
to 30% of these are familial and the remainder are caused by sporadic
germline mutations. Both forms are transmitted to offspring in an
autosomal dominant manner with greater than 90% penetrance (641).
Most patients with retinoblastomas have a mutation on the RB1 gene at
chromosome 13q14; this is a tumor suppressor gene that controls cell-
cycle progression. More than 200 distinct mutations of this gene have
been identified. Formerly, about 15% of patients with bilateral retino-
blastomas ultimately developed nonocular neoplasms, most commonly
soft tissue sarcomas (644). The decreased utilization of radiation treat-
ment has resulted in a marked decrease in the incidence of sarcomas;
nonetheless, patients with RB1 germline mutations are predisposed to
the development of additional tumors elsewhere in the body. Whereas
secondary sarcomas occur much more commonly in irradiated patients
(in the radiation field) in the early teenage years, melanomas, carcino-
mas, leukemias, and lymphomas tend to occur in young adults (average
age 27–29 years), often outside of the radiation field and in patients
who did not undergo radiation treatments (645). The deformities of
the face that often occurred secondary to varying degrees of growth
arrest of the maxillary, nasal, and temporal bones following radiation
therapy (644,646,647) are much less commonly seen.
In 2% to 7% of patients with bilateral retinoblastomas, a small cell
tumor will eventually develop intracranially (typically in the midline);
this condition is referred to as “trilateral retinoblastoma.” Patients with
trilateral retinoblastoma present with ocular tumor at an earlier age
(mean 6 months) than those with sporadic or unilateral tumors (648–
650). The incidence of trilateral retinoblastoma is higher in children
with a family history of retinoblastoma than in those with no family
history (651). The intracranial tumor, which is histologically identical
to the intraocular tumors, may develop in the pineal region (classically
the most common), suprasellar region, or fourth ventricle (rare) (650–
654). It is rarely present at the time the ocular tumors are detected,
usually appearing after a latency period of about 2 to 3 years (648,649).
Prognosis of trilateral retinoblastoma is very poor, and the incidence
of subarachnoid tumor spread is high (648,651,655). Recent work sug-
gests that neoadjuvant intravenous chemotherapy might reduce the
incidence of this intracranial complication (656).
A special mention must be made of the diffuse infiltrating retino-
blastoma (DIR), a clinically and pathologically distinct variant that
comprises 1% to 2% of retinoblastomas (657–660). Both clinically
and radiologically, diagnosis of diffuse retinoblastoma is more diffi-
cult than that of the more common nodular type because the tumor
assumes a relatively flat, ill-defined horizontal growth along the retinal
tissue; due to the lack of vertical growth, examination shows little defi-
nition of a mass (660). Patients are typically older (average of ∼6 years)
and present with pain, redness, or decreased vision in the affected eye;
glaucoma can result from neoplastic seeding of the anterior chamber,
causing obstruction of flow of the aqueous humor (660). Leukocoria
is relatively uncommon (24%). Ophthalmologic examination typi-
cally shows a whitish, exudative-appearing, and flocculent material in
the vitreous or anterior chamber, often associated with hemorrhage.

TABLE 7-13 Causes of Leukocoria in Children

Frequency
Condition Leukocoria Age Calcium CT Density Enhancement Size of Eye
Retinoblastoma 58% <12 mo (familial) ++ Very high ++ Normal
>20 mo (nonfamilial)
Persistent hyperplastic 28% Birth – High ++ Small
primary vitreous
Toxocaris infection 16% Childhood – High + Normal
Coats disease 16% Childhood – Very high – Normal to slightly small
Retinopathy of prematu- 5% Infancy ± High +/– Small (bilateral)
rity
Retinal astrocytoma 3% Childhood ± High + Normal
Medulloepithelioma <1% Childhood ± High ++ Normal

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 759

FIG. 7-119. Bilateral retinoblastomas. A. Axial noncontrast CT

through the globes shows calcified masses arising from the retina bilat-
erally (arrows). Two discrete masses are seen in the left globe. There is
no evidence of extension of tumor outside of the globes. The pineal
region was spared in this patient. B. Axial 3D T2-weighted image shows
the masses as regions of hypointensity contrasted by the hyperintense
vitreous. C. Axial fat-suppressed postcontrast T1-weighted image shows
the mass in the left globe (arrow) as an enhancing nodular thickening.
The mass in the right globe is not well seen because of high signal in the
vitreous resulting from hemorrhage and proteinaceous exudate.

The appearance can be mistaken for uveitis, unexplained vitreous
hemorrhage, hyphema, or endopthalmitis (660). No family history can
be elicited in the vast majority of affected patients.
Neuroimaging Findings
The usual CT appearance of retinoblastoma is that of a calcified mass
within the globe. The mass, which may be of any size, arises from the
retina, but the borders may be ill-defined, making the retinal origin
unclear. Calcification, seen in 95% of these tumors, may be large, small,
single, or multiple (Fig. 7-119). Enhancement is usually seen after con-
trast administration. The tumor may extend through the sclera into
the orbital lymphatics or through the optic nerve intracranially; both
pathways of extension are well visualized by CT. Although retinoblas-
tomas can be identified by MRI (Fig. 7-119), the presence of calcifi-
cation is the most important radiological factor in the diagnosis of
these tumors. As modern CT scanners often allow imaging without the
need for sedation, CT should be the primary imaging modality used
in patients presenting with leukocoria (642,661). However, MRI (with
fat saturation and contrast enhancement) shows the tumor well as an
enhancing heterogeneous intraocular mass (Fig. 7-119). In addition,
MRI is more sensitive to spread of tumor along the optic nerve (Fig.
7-120) (seen as enhancement or enlargement along the affected nerve)
(662) and to the presence of subarachnoid intracranial tumor. There-
fore, MRI is an excellent modality for the evaluation of patients with
suspected retinoblastoma. Moreover, MRI should be the study of choice
for children with suspected intracranial spread of tumor and those with
bilateral retinoblastoma should be imaged by MRI, with specific atten-
tion to the suprasellar, pineal, and fourth ventricle regions. In addition,
follow-up imaging studies, which are intended to identify tumor along
the optic nerves or intracranially, should be MR scans of the orbit and
brain. The orbital studies are best performed using precontrast volu-
metric fast spin-echo sequences with thin (<1 mm), overlapping par-
titions and 2 to 3 mm postcontrast axial and coronal fat-suppressed
T1-weighted spin-echo images.
The parenchymal tumor of trilateral retinoblastoma has CT and
MR characteristics identical to that of the intraocular tumor. CT shows
a hyperdense mass that is usually heavily calcified and shows promi-
nent heterogeneous enhancement (663). MRI shows a mass with T1
and T2 relaxation times similar to normal gray matter. The presence
of calcification may cause the mass to appear heterogeneous. Hetero-
geneous enhancement is seen after administration of paramagnetic
contrast (652,653,663).
The appearance of DIR is different, as this form is characterized
by diffuse infiltration of the various layers of the retina. Vitreous inva-
sion is frequent, and extension to the anterior chamber can occur via
the ciliary processes and the iris (664). No discrete nodular retinal
mass, as typically seen in retinoblastoma, is present; instead, a dif-
fuse, homogeneous, infiltrative uniformly enhancing mass is detected
(Fig. 7-121); localized enhancement of the anterior chamber may
mimic medulloepithelioma (664). Calcification may be too minimal to

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 760 Pediatric Neuroimaging

FIG. 7-120. Bilateral retinoblastomas with spread of tumor through the optic nerve. A. Axial T1-weighted image shows retinal detachments in both globes
and enlargement of the left globe. The tumor in the left globe can be seen as a focal hypointensity (arrows) lateral to the optic nerve head. B. Postcontrast
T1-weighted image with fat suppression shows the enhancing tumor in the left globe extending (arrows) posteriorly into the optic nerve.

detect by ocular ultrasound or CT (Fig. 7-121). Typically, only a single
eye is involved. These tumors appear to be less biologically aggres-
sive than typical retinoblastomas; therefore, extension into the optic
nerve or through the sclera is very rare. If any calcification is seen,
the diagnosis of retinoblastoma should be suggested. If no calcifica-
tion is present, the abnormality cannot be radiologically differentiated
from Toxocaris infection or from Coats disease. Careful examination
under anesthesia to search for the yellow-white lipid deposits of Coats
disease within the retina, blood analysis for toxocara titers and other
uveitis laboratory analyses, careful history for episodes of pica, which

FIG. 7-121. Diffuse retinoblastoma. A. Axial CT

image shows a smoothly marginated high attenuation
collection or mass (arrows) in the left ocular globe.
No calcification is seen. B. Axial 3D T2-weighted
image shows the lesion (arrows) to be hypointense
compared to vitreous (isointense to white matter).
C. Homogeneous enhancement (arrows) is seen
after intravenous infusion of paramagnetic contrast
material.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 761

FIG. 7-122. Coats disease.

A. Axial CT image shows cres-
centic hyperdensity (arrow-
heads) in the posterior right
globe secondary to proteina-
ceous subretinal exudate. The
globe is of normal size and no
calcification is present, sug-
gesting the diagnosis of Coats
disease. B. Axial T1-weighted
image shows that the exudate
(arrowheads) is slightly hetero-
geneous and has signal inten-
sity similar to white matter. C.
Axial T2-weighted image shows
a small linear area of marked
hypointensity (arrowheads) in
the exudate, probably repre-
senting hemorrhage. D. Post-
contrast T1-weighted image
shows absence of enhancement
(arrowheads), which helps to
differentiate this lesion from
diffuse retinoblastoma.

are correlated with toxocara canis exposure, and low birth weight (for
retinopathy of prematurity) must then be utilized to make this distinc-
tion (665).

Differential Diagnosis—Medulloepithelioma, Infection,

and Malformations
When bilateral ocular tumors are present in an infant, the diagnosis is
retinoblastoma until proven otherwise. When the tumor is unilateral,
the primary differential diagnosis is Coats disease, which is a degen-
erative proliferative disease of the retina (666). In Coats disease, a
defect is present in the endothelial cells of retinal blood vessels, result-
ing in leakage of secretions that are high in cholesterol content into
the subretinal area and causing retinal detachment and hemorrhage
(Fig. 7-122) (667–670). Absence of calcification helps to differenti-
ate Coats disease from retinoblastoma. Differentiation from diffuse
retinoblastoma is made by the absence of enhancement of the secre-
tions in Coats disease (although the detached retina does enhance) on
postcontrast MR images (Fig. 7-122) and the presence of blood (Fig.
7-122). Another helpful finding is that the affected orbit in Coats dis-
ease is slightly smaller (20% by volume) than the contralateral, nor-
mal globe (671) although this is difficult to determine without the use
of volume measurements. Otherwise, Coats disease has an identical
appearance on CT to larval granulomatosis (Fig. 7-123, also called
ocular toxocariasis or sclerosing endophthalmitis), caused by a Toxo- FIG. 7-123. Larval granulomatosis. Axial CT shows crescentic hyper-
cara canii infection (672). Both are differentiated from retinoblastoma density in the posterior right globe. The appearance is identical to that
by the absence of calcification on CT. Larval granulomatosis, which of Coats disease (Fig. 7-122). (This case courtesy Dr. Sylvester Chuang,
is histologically an eosinophilic abscess, may show focal enhancement Toronto.)

Barkovich_Chap07.indd 761 5/6/2011 9:17:40 PM

 762 Pediatric Neuroimaging
on MRI if granulomas are present in the retina (673). The persistent
hyperplastic primary vitreous is another anomaly that results in leu-
kocoria, retinal detachment, and subretinal hemorrhage (see Chapter
5 and Figs. 7-124 and 7-125). Differentiation from retinoblastoma is
made by the absence of calcification and by the presence of a hypoplas-
tic globe on the affected side (668,674). In contrast to the appearance
of Coats disease, the affected globe in PHPV is visibly smaller than
the contralateral normal globe. Subretinal hemorrhage (Fig. 7-124) is
often present in the affected globe. Occasionally, a persistent hyaloid
canal can be seen as an enhancing linear structure extending from
the posterior aspect of the lens to the optic nerve head, confirming
the diagnosis (Fig. 7-124E). Retinopathy of prematurity (also dis-
Barkovich_Chap07.indd 762
FIG. 7-124. Persistent hyperplastic primary vitreous. A. Axial
CT image shows a small right globe that has an abnormal,
rounded lens and shows abnormal hyperintensity in the region
of the vitreous. B. Postcontrast image at the same level shows
areas of enhancement (arrowheads) behind the lens that may
represent enhancement of the persistent primary vitreous. C
and D. Axial 3D T2-weighted image (C) and T1-weighted image
(D) show crescentic regions of subretinal hemorrhage pos-
terior to the abnormally-shaped lens in the small right globe.
The combination of microphthalmia and retinal detachment is
strongly suggestive of PHPV. E. Persistent hyaloid canal. Axial
CT through the globes shows a hypoplastic right globe. More-
over, a streaky density is seen extending toward the head of the
optic nerve through the vitreous (arrows). This represents a per-
sistent hyaloid canal and confirms the diagnosis of persistent
hyperplastic primary vitreous.
cussed in Chapter 5) is almost always bilateral and symmetric, rarely
calcifies (except in advanced stages), and is usually associated with
microphthalmia (675); a history of low birth weight or prematurity
should be sought if this diagnosis is suspected. Microphthalmia and
leukocoria may sometimes be associated with retinal astrocytic hamar-
tomas of tuberous sclerosis (see Chapter 6). Retinal Hamar-toma may
calcify, making the differentiation from retinoblastoma difficult by
ultrasound and by CT. A search for cortical and subependymal hama-
rtomas in the brain will often help to make the proper diagnosis (676).
A very rare cause of leukocoria is medulloepithelioma, a rare embryo-
nal intraocular neoplasm of young children that arises from the med-
ullary epithelium of the ciliary body. This tumor sometimes calcifies,
5/6/2011 9:17:41 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 763

FIG. 7-125. Medulloepithelioma. Axial T2-weighted image (A) shows a

hypointense mass (arrow) in the anterior chamber near the ciliary body.
Coronal (B) and axial (C) postcontrast T1-weighted images show uni-
form enhancement of the mass and thickening of surrounding soft tissues.
Medulloepitheliomas can mimic inflammatory disease, both clinically and
on imaging.

due to the presence of a hyaline cartilage component found in 30% of
teratoid medulloepitheliomas (677). Medulloepitheliomas can be dif-
ferentiated from classic retinoblastomas if they originate from the cili-
ary bodies but, when they arise from the retina, differentiation may be
impossible. Medulloepithelioma arising from the ciliary body may be
difficult to differentiate from DIR, as discussed above; in the author’s
experience, medulloepithelioma is a more sharply defined mass than
DIR. Ultrasound may be useful, as it can show cystic collections within
the tumor. On CT, medulloepitheliomas appear as dense, irregular,
enhancing masses that may be calcified. On MRI, they are slightly
hyperintense to vitreous on T1-weighted images and hypointense on
T2-weighted images; the solid portions exhibit marked, homogeneous
enhancement after intravenous administration of paramagnetic con-
trast (Fig. 7-125) (670). If cystic areas are present, the enhancement
may appear heterogeneous.
Extraocular Orbital Masses
Extraocular orbital masses in children include a wide range of patholo-
gies, including vascular masses (venolymphatic malformations—
lymphangiomas, varices, venous malformations, and hemangiomas),
rhabdomyosarcomas and (rarely) rhabdomyomas, neurofibromas and
schwannomas, infections, cysts, dermoids, cephaloceles, gliomas, men-
ingiomas, LCH, leukemic infiltrates, lymphoma, Ewing sarcoma, and
metastatic neuroblastoma (678–682). Many of these masses can develop
in any compartment (intraconal, conal, or extraconal) of the orbit, so
they cannot be distinguished by topology. Dermoids and cephaloceles
were discussed in Chapter 5 and infections are discussed in Chapter 11.
Optic gliomas, meningiomas, and LCH were discussed earlier in this
chapter. The remaining pathologies will be discussed briefly.
Vascular Masses
Orbital hemangiomas and venolymphatic malformations are best
thought of as hamartomatous malformations that arise from an anlage
of vascular mesenchyme that is capable of differentiating into both
lymphatic vessels and blood vessels, as well as other mesenchymal tis-
sues (683,684).
Hemangioma
Hemangiomas, formerly referred to as capillary hemangiomas (685),
are the most common vascular masses to present in the orbits of chil-
dren. These malformations, which have a slight (3:2) female predomi-
nance, typically present at birth or in the first few months of life; they
then enter a proliferative phase, with rapid growth that lasts up to
10 months. They typically cease growth during the second year of life
and then slowly involute over the subsequent 5 to 10 years (683,684).
Hemangiomas can develop anywhere in the orbit; anterior lesions are
most common detected clinically, but some retrobulbar hemangiomas
are asymptomatic and may only be detected by imaging. As the mass
enlarges, it may cause complications including proptosis, amblyopia,
optic nerve stretching, bleeding, and corneal ulceration (686). Some
orbital hemangiomas may be associated with cerebral and vascular
anomalies of the PHACES syndrome (see Chapter 6).
CT scans of orbital hemangiomas show a diffuse, lobulated, usually
poorly marginated mass that may be located anywhere in or around the
orbit. The mass may be outside the cone of extraocular muscles (extra-
conal, more common), inside the muscle cone (intraconal, less com-
mon) or both. Rarely, they spread intracranially through the orbital
fissures. Diffuse enhancement is seen after intravenous administration
of contrast. MRI shows the tumor as well-marginated, with slightly
hyperintense signal intensity compared to extraocular muscles and

Barkovich_Chap07.indd 763 5/6/2011 9:17:42 PM

 764 Pediatric Neuroimaging

FIG. 7-126. Orbital hemangioma (formerly capillary heman-

gioma). A. Coronal T1-weighted image shows a mass (arrowheads)
inferior to the right ocular globe, that is both inside and outside of
the muscle cone. B. Coronal T2-weighted image shows the lesion
(white arrowheads) to be of soft tissue intensity. A curvilinear
flow void is present within the mass. C. Postcontrast T1-weighted
image shows that the hemangioma enhances uniformly other than
the curvilinear vascular structures.

hypointense signal intensity compared to fat on T1-weighted images
(Fig. 7-126). Moderate to marked enhancement, usually homogeneous,
is observed after administration of paramagnetic contrast (Fig. 7-126).
On T2-weighted images, hemangiomas are hyperintense compared to
muscle and fat, and hypointense compared to fluid. Curvilinear flow
voids, representing blood vessels, are typically present within and at the
periphery of the mass (Fig. 7-126); this finding is useful in differentiat-
ing hemangiomas from more aggressive lesions, such as rhabdomyo-
sarcomas. Dark, fibrous septa may be seen between the hyperintense
lobules on T2-weighted images. The affected orbit is often enlarged,
probably as a result of the congenital nature of the lesion (684,687). As
the mass involutes, fat develops in the mass, and it becomes more hyper-
intense on T1-weighted images and less hyperintense on T2-weighted
images. Uniform, intense enhancement is typically seen after intrave-
nous administration of paramagnetic contrast (686). Hemangiomas
are most easily differentiated from other orbital tumors by the curvi-
linear flow voids within and at the periphery of the mass.
Combined Venous Lymphatic Malformations—Lymphatic
Malformations (Lymphangiomas) and Venous
Malformations (Cavernous Hemangiomas)
Recent work has shown that orbital lymphatic malformations and
venous malformations are part of a spectrum of disorders involving
both the lymphatic and venous systems (688). Nonetheless, some are
primarily lymphatic while others are primarily vascular; therefore, the
disorders are discussed separately within this section with the under-
standing that these malformations essentially always contain both
components.
Most lymphatic malformations (formerly called lymphangiomas)
present during childhood; they are the most common vascular mass
of the orbit presenting between the ages of 1 and 15 years. Patients
typically present with recurrent episodes of proptosis that result from
recurrent hemorrhages within the mass (possibly due to vascular
thromboses [689]) or from reactions of the lymphatic system due to
upper respiratory infections; other complications include astigmatism,
corneal exposure, hyperopia secondary to pressure on the posterior
globe, strabismus, glaucoma, and compressive neuropathy (690). Such
episodes can result in poor visual outcome (691). The malformation
may involve any part of the orbit, including eyelids, conjunctiva, sclera,
intraconal spaces, and extraconal spaces. Anterior lesions may extend
to the forehead and cheek, while posterior lesions may extend through
the superior orbital fissure into the cavernous sinus or middle cranial
fossa (692,693). This permeation of the intra- and extraconal compart-
ments makes complete resection nearly impossible.
Pathologically, lymphatic malformations are composed of abnor-
mal venous channels that are associated with enlarged lymphatics,

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
FIG. 7-127. Lymphatic malformation (formerly called lymphangiomas).
A and B. Axial noncontrast CT images show an irregular, lobulated mass
(arrows) in both the extra- and intraconal spaces of the left orbit, causing
mild proptosis.
Barkovich_Chap07.indd 765
765
particularly in the eyelids and conjunctiva. Histology shows thin-walled
channels lined by epithelium and containing serous fluid or blood. The
spaces range from large cysts to sponge-like microcystic spaces, often
containing a mixture of both (688).
On CT, lymphatic malformations are lobulated, heterogeneous,
poorly defined lesions that cross anatomic boundaries such as the
conal fascia and orbital septum (Fig. 7-127). Small focal calcifications,
representing phleboliths, are occasionally seen. Areas of hyperdensity,
representing acute hemorrhage, may be present, especially after recent
exacerbation of proptosis. Enhancement is heterogeneous, usually with
weak enhancement along the periphery and in the stromal framework
(678,687). On MRI, lymphatic malformations appear as lobulated
masses containing septa that divide it into multiple cysts and lobules
that have varying sizes and intensities on both T1- and T2-weighted
images. The majority of the mass is typically hypointense to muscle
on T1-weighted images and hyperintense to muscle on T2-weighted
images (Fig. 7-128). The variations of intensity are the result of differ-
ing amounts of blood and protein in the cysts. Fluid-fluid levels may
be present within the cysts (Fig. 7-128); if present, they are strongly
suggestive of lymphatic malformation. Heterogeneous enhance-
ment follows intravenous administration of paramagnetic contrast
(694). Some lesions have multiple components, each with different
appearances; some areas have characteristics suggesting lymphatic
malformations and others more suggestive of venous malformations
(Fig. 7-128) (694).
FIG. 7-128. Lymphatic malformation. A. Sagittal
T1-weighted image shows an irregular mass (arrows),
primarily intraconal, in the right orbit. An extraorbital
component (arrowheads) is seen extending superiorly
above the orbit. B. Axial 3D T2-weighted image shows
two distinct components of the lesion. The intraorbital
component (arrows) is multiloculated and cystic in
appearance with fluid-fluid levels, more compatible with
a lymphatic component, while the supraorbital compo-
nent (arrowheads) is more homogeneous and of lower
signal intensity, more compatible with a venous com-
ponent. C. Postcontrast axial T1-weighted image shows
heterogeneous enhancement (arrows and arrowheads).
5/6/2011 9:17:44 PM
 766 Pediatric Neuroimaging
Venous malformations of the orbit (also called cavernous
malformations, formerly known as cavernous hemangiomas [685])
are uncommonly identified in children, becoming symptomatic more
commonly in young and middle-aged adults (683,695). They typically
present with painless proptosis that remains unchanged with Valsalva
maneuvers, differentiating them from orbital varices, which enlarge
during a Valsalva maneuver (683). When located anteriorly, they pres-
ent earlier and often extend to the forehead, temporal region, or cheek.
On CT, venous malformations appear as homogeneously enhancing
round or ovoid masses that are usually intraconal and spare the orbital
apex. Calcified phleboliths are frequently seen within the mass (687).
On MRI, venous malformations appear as homogeneous, well defined,
round or ovoid, slightly lobulated masses that are usually intraconal
(Fig. 7-129). They are isointense to the orbital muscles on T1-weighted
images and hyperintense to the orbital muscles on T2-weighted
images; often variation in signal intensity is present among the cysts. If
fluid-fluid levels are present, the dependent portion is typically more
hypointense on T2-weighted images. The lesions enhance diffusely, but
somewhat heterogeneously (Fig. 7-129) after intravenous infusion of
paramagnetic contrast (684).
It should be noted that intracranial vascular malformations are
seen very commonly in patients with periorbital lymphatic and venous
malformations; an incidence of up to 70% is reported (690). Therefore
contrast-enhanced study of the brain should be obtained along with
the orbital study. The vascular malformations are most commonly
Barkovich_Chap07.indd 766
FIG. 7-129. Orbital venous malformation (formerly called
cavernous hemangioma). A. Axial T1-weighted image shows an
intraconal mass (m) in the right orbit. Venous malformations can
be intraconal, extraconal, or both. B. Coronal T2-weighted image
shows the mass to be slightly heterogeneously hyperintense. C.
Coronal T1-weighted image after infusion of paramagnetic con-
trast shows diffuse, slightly heterogeneous enhancement.
developmental venous anomalies or cavernous malformations, but AV
malformations and AV fistulae may rarely be found; the intracranial
anomaly may be ipsilateral or contralateral to the orbital lesion (690).
Up to14% of these patients may present with intracranial hemor-
rhage (691). Katz et al. found that the orbital lesions in patients with
(noncontiguous) intracranial vascular anomalies were diffuse with
superficial and deep components (100%) involving the intraconal and
extraconal spaces (57%). The affected orbit and the inferior orbital fis-
sure were expanded with extension into the pterygopalatine fossa in
82%, while the superior orbital fissure was always involved, with exten-
sion into the middle cranial fossa in 43%. Anterior extension into soft
tissues of the face and forehead and palatal involvement were relatively
common. In contrast, lymphatic malformations without intracranial
vascular anomalies were more anterior, less diffuse, less likely to extend
into the soft tissues of the face, have associated vascular lesions, or have
a poor visual outcome (691).
Orbital varices
Orbital varices are venous malformations that occur in the retrob-
ulbar region. They typically present in later childhood or adulthood
with intermittent proptosis that is exacerbated by a Valsalva maneuver,
bending over, or lying prone. On CT and MRI, varices are identified
by a curvilinear configuration, the presence of calcified phleboliths,
intense enhancement after contrast administration, and an increase in
size in the prone position or with a Valsalva maneuver. On occasion,
5/6/2011 9:17:45 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
FIG. 7-130. Coloboma with cyst. Axial T1-weighted image obtained with a
3 cm surface coil shows the shrunken, malformed globe (closed black arrows)
with lens (small white arrows) and posterolateral cyst (large white arrows).
images obtained in a supine position without Valsalva may be normal;
if the proper history is obtained, further scans should be obtained dur-
ing maneuvers. CT is a better study because of the shorter imaging
times that allow scanning to be performed during a Valsalva maneuver
(684,687).
Orbital Cysts
When retro-orbital cysts are seen in infants and children, the most com-
mon cause is a severe colobomatous malformation of the globe. Ocular
colobomas are anomalies of the globe that result from a failure of the
posterior midline of the globe (the choroidal fissure) to close properly,
with consequent localized defects in the uvea, retina, and optic nerve
(682,696). Colobomas and their embryogenesis are discussed in Chap-
ter 5, in the section on “Anomalies of the Eye.” If the malformation
isn’t recognized, the orbital cyst may mimic a more aggressive orbital
mass. The cyst may be small with a normal sized globe, moderate in
size with a slightly small globe, or large with a small, malformed globe
(Figs. 7-130 and 7-131). MRI and CT are useful in making an accurate
diagnosis, in characterizing the cyst, in determining the presence of
defects in the globe, and in assessing the brain for other anomalies.
Both the cyst and globe are isointense to normal vitreous on all imag-
ing sequences. Contrast enhancement is not seen (682,696,697).
Leukemia (Granulocytic Sarcoma, Chloroma)
Granulocytic sarcomas are solid tumors of immature granulocytes that
develop in some patients with myelogenous or myelomonocytic leuke-
mia (698). They most commonly occur in the skin, bones, sinuses and
orbits, but rarely involve the CNS. Although granulocytic sarcomas
arising in other areas usually develop during relapses in children with
known leukemia, those arising in the orbit may be the initial manifes-
tation of leukemia (698,699). After testing, most affected patients are
found to have simultaneous evidence of bone marrow or peripheral
blood disease. Although most patients present with proptosis, some
may have pain and chemosis, suggesting an inflammatory disorder.
CT shows poorly-defined, homogeneous soft tissue masses that may
be intraconal or extraconal. The masses typically infiltrate the orbital
fat and conform to orbital structures; bone erosion is very rare. These
characteristics are typical of all lymphocytic orbital infiltrates; however,
Barkovich_Chap07.indd 767
767
FIG. 7-131. Bilateral colobomas with cysts. Axial T1-weighted image
shows bilaterally small globes with cysts extending from the posterior mid-
line of the globes. The left globe and colobomatous cyst are hyperintense
secondary to subretinal hemorrhage. (This figure courtesy Dr. Sylvester
Chuang, Toronto.)
lymphocytic orbital infiltrates other than granulocytic sarcomas are
uncommon in children. About half are bilateral at the time of presenta-
tion; bilaterality of orbital masses in children is uncommon, so this finding
should arouse suspicion of a granulocytic sarcoma. On MRI, granulocytic
sarcomas are round to oval shaped, slightly lobulated lesions that are
hypointense compared to muscle on T1-weighted images and isoin-
tense to hyperintense compared to muscle on T2-weighted images
(698,699). They enhance intensely and homogeneously after adminis-
tration of intravenous contrast.
Metastatic Neuroblastoma
Metastatic neuroblastoma, although already mentioned twice in this
chapter regarding calvarial and skull base masses, must be discussed
in this section, as well, as it is the most common tumor to metastasize
to the orbit in infants and young children (683). As many as 8% of
patients with neuroblastoma present with orbital symptoms; bilateral
orbital lesions are noted in as many as 40% of patients with metastatic
disease (683,684). Patients typically present with rapidly progressive
proptosis. CT shows a soft tissue mass that typically arises from a par-
tially destroyed orbital wall; the posterior superolateral wall seems to
be involved most commonly, but any site in the orbital wall can be
affected. The bone typically shows a permeated pattern or elevation
of the periosteum secondary to rapid growth of tumor (Fig. 7-132).
MRI shows focal or extensive soft tissue, often partially hemorrhagic,
expanding the orbital wall and growing into the orbit. Tumor growth
is often multidirectional and can extend superiorly into the anterior
cranial fossa or laterally, displacing or invading the temporalis muscle
(Fig. 7-132). Nonhemorrhagic portions of tumor typically remain
isointense to gray matter on both T1- and T2-weighted images (see
Fig. 7-132). The tumor enhances markedly after intravenous infusion
of contrast. A search should be made for other metastases of the calva-
rium, skull base, and petrous pyramids.
Langerhans Cell Histiocytosis
LCH has also been mentioned multiple times in this chapter, as the
disease can affect nearly any part of the brain and any of the bony
structures of the head and neck (241,242,246,250,504). Like metastatic
neuroblastoma, it most commonly involves the posterolateral part of
5/6/2011 9:17:46 PM
 768 Pediatric Neuroimaging

FIG. 7-132. Metastatic neuroblastoma to orbit. A. Axial CT shows a

mass (large arrows) arising within the lateral wall of the orbit. Periosteal
reaction (small arrows) is indicated by irregular thickening of the
bone. B. Coronal T2-weighted image shows the mass to be isointense
to gray matter and to have an intraorbital (small arrows), intracranial
extradural (large arrows) and extracranial (arrowhead) component. C.
Coronal postcontrast fat-suppressed T1-weighted image shows uniform
enhancement of the mass. Note the destruction of bone resulting from
intracranial (large white arrows) and extracranial (arrowhead) exten-
sion of the mass through the orbital walls. Normal orbital structures
are compressed medially by the intraorbital component (small white
arrows) of the mass.

the orbital wall, at the suture between the frontal bone and the greater
wing of the sphenoid bone. Affected children typically present with
either proptosis or a rapidly enlarging periorbital mass. Periorbital
edema or ecchymosis may raise suspicion for child abuse. CT shows a
sharply marginated osteolytic soft tissue mass; the sharp margination
of the bone lesion distinguishes it from the permeative pattern seen
in leukemia or metastatic neuroblastoma. The soft tissue component
typically uniformly enhances after intravenous contrast enhancement.
MRI shows a soft tissue mass that has signal intensity similar to skeletal
muscle and uniformly enhances after intravenous administration of
paramagnetic contrast. If LCH is considered a possible diagnosis, the
brain should be examined to look for involvement, most commonly in
the pituitary stalk (see section on “Sellar and Suprasellar Tumors”), and
the skull and bones in the remainder of the body should be evaluated for
other sharply marginated lytic lesions or, in the spine, vertebra plana. If
other characteristic lesions are found, biopsy might be avoided.
Plexiform Neurofibroma
Plexiform neurofibromas are highly vascular, poorly defined, and dif-
fusely infiltrative masses involving peripheral nerves and connective
tissue that are only seen in the setting of NF1. A more extensive
discussion of the imaging characteristics of neurofibromas is given in
Chapter 6, in the section on “Neurofibromatosis Type 1.” Neurofibromas
tend to grow centripetally along the nerve from the periphery toward the
center. When they involve the orbital region, plexiform neurofibromas
present with proptosis, visual loss, and marked facial asymmetry (683).
They appear on both CT and MRI as serpiginous, irregular, poorly
marginated masses that surround and engulf normal orbital structures
(Fig. 7-133). Neurofibromas cross normal fascial boundaries such as
the orbital septum and, thus, may be periorbital as well as intraorbital.
The involved orbit is often enlarged and the adjacent greater sphenoid
wing is often partially absent; the bone may become progressively more
deficient, suggesting active loss of bone (700). Although any portion
of the orbit may be involved, the superior portion, particularly that
region close to the first division of the fifth cranial nerve, is most often
involved. Such masses may extend through the superior orbital fissure
into the cavernous sinus, which may also be expanded (Fig. 7-133). On
CT, the masses appear as serpiginous lesions, isodense with the extraoc-
ular muscles that do not respect fascial boundaries. On MRI, it is easier
to appreciate the multiple serpiginous enlarged nerve fascicles coursing

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 769

FIG. 7-133. Orbital plexiform neurofibroma. A. Parasagittal T1-weighted image shows numerous irregular curvilinear streaks in the expanded right orbit
of this patient with NF1. B. Postcontrast axial image shows some enhancement of the curvilinear structures. Extension is seen through the enlarged superior
orbital fissure (open arrow) into the cavernous sinus (closed arrows). This patient also had a parenchymal astrocytoma (black arrows).

through the orbit, isointense with muscle on T1-weighted images and
hyperintense compared with muscle on T2-weighted images with fat
saturation. Contrast enhancement is variable and is usually heteroge-
neous (684,687). MRI is the imaging study of choice because of the
ability to analyze for cavernous sinus involvement without the use of
contrast and the ability to analyze the brain for other manifestations of
NF1. In the setting of NF1, no significant differential diagnosis exists.
Dermoids and Epidermoids
Dermoids and epidermoids were discussed extensively earlier in this
chapter. They can develop anywhere in the orbit, but are most com-
monly seen anteriorly, near the ocular globe and near the sutures
between the bones that comprise the orbit. As in other parts of the
head, neck, and brain, dermoids and epidermoids are sharply margin-
ated masses. The presence of fat signal (Fig. 7-134) is quite characteristic

FIG. 7-134. Orbital der-

moids. A and B. Axial image
(A) and sagittal reformation
(B) from a CT scan show a
sharply demarcated fat den-
sity mass (arrows) superior
to the left ocular globe. C
and D. Axial precontrast and
postcontrast fat-suppressed
T1-weighted images in a dif-
ferent patient show the high
signal of the dermoid (arrow)
to be suppressed, confirming
the fatty nature of the lesion.

Barkovich_Chap07.indd 769 5/6/2011 9:17:48 PM

 770 Pediatric Neuroimaging

of dermoids and water signal is very characteristic for epidermoids on and solid masses. CT, which can also generally be performed without
both CT and MRI. sedation, reliably differentiates solid from cystic congenital masses
and often allows characterization of the masses. However, children
Rhabdomyosarcomas/Rhabdomyomas generally have less fat and, without the fat planes, CT provides less
Rhabdomyosarcomas are discussed in the following section. contrast in the pediatric neck than the adult neck. Also, as discussed
many times in this book, exposure of young children to ionizing radi-
ation should be avoided unless medically necessary. Thus, if surgical
Masses of the Face and Neck
intervention is anticipated, children at our institution are usually also
Masses of the pediatric face and neck involve a wide spectrum of both studied by MRI.
congenital and acquired lesions. A full discussion of these masses is A nice review of a large series of masses involving the pediatric face
beyond the spectrum of this book, which is concerned primarily with and neck was given by Vazquez et al. (701). They published a review of
the CNS and its coverings. Readers are referred to books on otolar- 145 pediatric patients from age 1 day to age 18 years who presented to
yngology for more information on these topics. A brief overview of their practice with neck masses. The results of this review are summa-
masses in this region is warranted and will follow, along with brief dis- rized below and in Table 7-14.
cussions of the most common lesions (see Table 7-14). An important Congenital lesions was the largest group, comprising 40% of these
concept is that neck masses in children are most commonly associated masses. These included 19 thyroglossal duct cysts (31%), 15 lymp-
with inflammatory disease, congenital anomalies, and benign neo- hangiomas (25%), 8 branchial cleft anomalies (13%), 6 dermoids
plasms. Malignant neck masses are relatively much less common than (10%), 6 cases of tracheal stenosis (10%), 3 teratomas, 2 lingual thyroid
in adults. glands, and 2 cases of thyroid gland hypogenesis.
Ultrasound is often the first modality used in the evaluation of Benign tumors and tumorlike conditions was the second largest
pediatric neck masses. Ultrasound can be performed without seda- group of pediatric neck and face masses. This group comprised 19% of
tion and is the most reliable method to differentiate between cystic the cases and included 15 cases of fibromatosis colli (56%), 6 aggressive
fibromatoses (22%, most common in the tongue, around the mandible,
or within the infratemporal fossa), 3 cervicothoracic lipoblastomatoses
(11%), 1 parathyroid adenoma, 1 juvenile laryngotracheal papilloma-
TABLE 7-14 Most Common Pediatric tosis, and 1 plexiform neurofibroma.
Neck Masses The third largest group, malignant tumors (18%), was almost
identical in size to the benign tumor group. The most common tumor
in this group was lymphoma (10 tumors, 38%). Other common malig-
Congenital masses (40%)
nant tumors were soft tissue sarcomas (23%, of which two thirds were
Thyroglossal duct cysts
rhabdomyosarcomas), carcinomas (19%, most commonly thyroid car-
Lymphangiomas
cinoma), and neuroblastoma (arising from the cervical sympathetic
Branchial cleft anomalies
chain, 19%).
Dermoid tumor
Inflammatory lesions were the next largest group of masses
Tracheal stenosis
(12%). Cervical adenitis from mycobacterial infections or cat scratch
Teratomas
fever (10 cases, 62%) was the most common cause in this group. In
Lingual thyroid gland
this regard it is important to remember that more than 90% of myco-
Benign Tumors/Tumor Like Conditions (19%) bacterial cervical lymphadenitis in children is due to nontuberculous
Fibromatosis coli mycobacterial (usually Mycobacterium avium-intracellulare); this pre-
Aggressive fibromatosis dilection is in marked contrast to adults in whom tuberculous cervi-
Cervicothoracic lipoblastomatosis (702) cal lymphadenitis is more common (704). The authors also reported
Plexiform neurofibroma 3 cases (19%) each of sialadenitis and retropharyngeal abscess (from
Juvenile laryngotracheal papillomatosis tonsillitis or trauma).
Neoplasms (18%) Masses of vascular origin (10%) comprised the smallest group. Jug-
Lymphoma ular vein varices (fusiform dilatations of the vein secondary to presence
Soft tissue sarcoma (especially rhabdomyosarcoma) of jugular venous valves) accounted for 60% of these vascular masses.
Neuroblastoma Cervical hemangiomas were the only other diagnosis of significant fre-
Carcinoma (especially thyroid) quency, comprising 33% of the masses in this group. The authors note,
however, that a pulsatile cervical mass in a child should raise suspicion
Inflammatory Masses (12%) for a cervical carotid artery aneurysm, which has the greatest clinical
Cervical adenitis significance. Cervical carotid aneurysms may be congenital (usually
Sialadenitis secondary to connective tissue disorder such as Ehlers-Danlos, Marfan,
Retropharyngeal abscess Kawasaki, or Maffucci syndromes), posttraumatic, or postinfectious.
Inflammatory myofibroblastic tumor (plasma cell granuloma,
inflammatory pseudotumor) (703) Thyroglossal Duct Cyst
Vascular Masses (10%) Thyroglossal duct cysts arise from remnants of the embryonic thyro-
Jugular vein varices glossal duct and account for up to 70% of congenital neck masses in
Hemangiomas children (705). The thyroid gland originates in the third week of fetal
Cervical carotid artery aneurysms life from a median endodermal thickening in the floor of the primi-
tive pharynx. The thyroid primordium develops at the foramen cecum,
Adapted from Vazquez et al. (701). a midline depression that is located between the anterior two thirds
and posterior one third of the tongue. The developing gland descends

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 771

FIG. 7-135. Bland and infected thyroglossal duct cysts. A. Axial

postcontrast CT image shows an uninfected cyst (arrows) within
the left thyroid strap muscle. Note the thin, nonenhancing wall.
B. Axial CT image shows a cyst (arrows) that is exophytic, extend-
ing anterior to the strap muscles. C. Postcontrast CT image of an
infected cyst shows a thick, enhancing wall (arrows) with some
obscuration of surrounding fat planes.

along the thryroglossal duct, passing anterior to the hyoid bone and
laryngeal cartilages, then anterior to the thyrohyoid membrane until
it reaches its final position by the seventh gestational week. Thyro-
glossal duct cysts are found along the course of descent of the thyroid
gland, typically found in the midline and occasionally in a parame-
dian position. They are classified by location as above the hyoid bone
(20%–25%), at the hyoid bone (15%–45%), or inferior to the hyoid
bone (35%–65%). Children typically present with a mobile, midline,
nontender mass that elevates with swallowing. If the cyst is infected, a
history of recent growth of the cyst or of local pain and tenderness may
be elicited. Typically, the mass elevates with swallowing or with protru-
sion of the tongue (706).
Imaging studies may show the thyroglossal duct cyst anywhere
along the path of the embryonic thyroglossal duct (from the median
lobe of the thyroid gland to the hyoid bone and then to the foramen
cecum in the midline of the tongue base [707]). Most are in or near
the midline (705). A common paramedian location is within the strap
muscles in front of the thyroid cartilage, where the lesions may be
completely intrinsic (Fig. 7-135A) or exophytic (Fig. 7-135B). These
may extend all the way to the hyoid bone, where they typically termi-
nate at the site of attachment of the duct to the bone. Another com-
mon location is in the midline of the tongue base (708). Ultrasound
shows thin-walled cysts with variable internal echogenicity (usually
hypoechoic). CT shows a low attenuation, well-defined, nonenhanc-
ing mass; the wall may show a thin rim of enhancement (Fig. 7-135A).
MRI usually shows sharply marginated, round or ovoid masses that
manifest hypointensity on T1-weighted images and hyperintensity on
T2-weighted images (Fig. 7-136) (709). Cysts in the tongue base are
best seen on sagittal images, while those in the strap muscles are best
seen on axial images. It is important to remember that if the cyst is
infected, or has hemorrhaged, high signal may be seen on T1-weighted
images and low signal intensity may be present on T2-weighted images.
Hemorrhage and infection may also result in thickening and marked
enhancement of the cyst wall on both CT (Fig. 7-135C) and MRI. A
history of recent discomfort or local edema, indicative of infection, and
the characteristic location of the cyst will usually allow diagnosis, even
after infection has occurred.
If surgery is planned, it is important to ensure that the affected
child has thyroid tissue outside of the cyst. Any type of imaging (ultra-
sound, CT, or MRI) can be used to ensure that the normal thyroid
gland is present.
Branchial Cleft Cysts
Branchial cleft cysts are the result of abnormal development of the
branchial apparatus, which consists of five paired regions on the
ventrolateral surface of the embryonic head between the third and

Barkovich_Chap07.indd 771 5/6/2011 9:17:49 PM

 772 Pediatric Neuroimaging
seventh gestational weeks. The five branchial arches consist of a core
of mesenchyme, covered externally with ectoderm and internally with
endoderm. As a result, adjacent arches are separated by ectodermal
clefts externally and endodermal pouches internally (710,711). Most
anomalies encountered by neuroradiologists are the results of malde-
velopment of the clefts; anomalies of the branchial arches and endo-
dermal pharyngeal pouches can also occur, but usually cause fistulas
that are discovered and recognized shortly after birth (bilateral in up to
30%) and, therefore, are not discussed here. Branchial cleft cysts most
often present in the same manner as thyroglossal duct cysts, typically
with painless swelling or with recent enlargement of a longstanding
soft, mobile, nontender mass. Although they may be discovered at any
age, patients are most commonly discovered in the second to fourth
Barkovich_Chap07.indd 772
FIG. 7-136. Thyroglossal duct cyst. A. Sagittal
T2-weighted image with fat suppression shows a hyperin-
tense mass at the base of the tongue. An extension along the
remnants of the thyroglossal duct (arrow) is seen extending
inferiorly. B. Axial T2-weighted image with fat suppression
shows the ovoid, sharply marginated, thin walled, mark-
edly hyperintense mass (arrow) within the tongue base. C.
Coronal postcontrast T1-weighted image with fat suppres-
sion shows the thin-walled mass (arrows) with complete
lack of enhancement.
decades of life; males and females are equally affected. Rarely, cranial
neuropathies may develop (712).
About 10% of branchial cleft cysts arise from the first bran-
chial cleft, probably as a result of incomplete obliteration of the cleft
between the mandibular process of the first arch and the second arch.
Such cysts typically occur either anterior or posterior to the pinna of
the ear (Fig. 7-137), sometimes extending downward to the angle of the
mandible. It may course lateral to or through the parotid gland in close
association with, and lateral to, the facial nerve. These lesions should
be suspected when a young patient has a cyst adjacent to the external
auditory canal, superficial to or deep within the parotid gland, or adja-
cent to the pinna and extending into the anterior neck to the level of
the angle of the mandible.
5/6/2011 9:17:50 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
FIG. 7-137. First branchial cleft cyst. Axial T1-weighted image shows a
cyst (arrows) anterolateral to the parotid gland in the subcutaneous fat.
Second branchial cleft cysts are by far the most common (90% to
95% of all branchial anomalies). The second branchial cleft runs deep
to the platysma muscle between the second and third arch structures by
ascending along the carotid sheath and passing medially between the
internal and external carotid arteries, above the glossopharyngeal nerve
and below the stylohyoid ligament. A cyst may develop anywhere along
this pathway. They are divided into four types: (a) deep to the plat-
ysma and superficial to the sternocleidomastoid muscle; (b) between
the sternocleidomastoid muscle and submandibular gland (Figs. 7-138
and 7-139), displacing the carotid sheath medially or posteromedially;
(c) between the internal and external carotid arteries, extending to the
lateral wall of the pharynx; and (d) adjacent to the pharyngeal wall
(713–715).
Third branchial anomalies are very rare. They usually consist of
cysts or fistulas. The cysts are most frequently located just proximal
Barkovich_Chap07.indd 773
773
to its external opening at the anterior border of the sternocleidomas-
toid muscle. From here, the fistula passes anterior to the vagus nerve
and above the hypoglossal nerve, but posterior to the glossopharyngeal
nerve and the internal carotid artery. It then crosses over the hypoglos-
sal and superior laryngeal nerve back to the region of the thyrohyoid
membrane, which it crosses to enter the pyriform sinus.
Fourth branchial cleft anomalies occur along a track that starts
along the anterior border of the sternocleidomastoid muscle. Almost
all of these anomalies are fistulas and sinuses, almost always originat-
ing in the pyriform sinus and extending inferiorly, sometimes hooking
around the aortic arch (on the left) or the subclavian artery (on the
right).
On ultrasound, branchial cleft cysts may appear anechoic (∼40%),
homogenously hypoechoic with internal debris (∼25%), pseudosolid
(∼10%), or heterogeneous (∼25%) (716). On CT and MRI, branchial
cleft cysts appear as thin-walled cysts that have signal intensities nearly
identical to that of water. When they occur in characteristic locations
(Figs. 7-137 to 7-139), the diagnosis is straightforward. Pointing of the
cyst medially towards the carotid sheath or posteriorly deep to the ster-
nocleidomastoid muscle (Fig. 7-138) is a characteristic that strengthens
the diagnosis. Difficulties in interpretation result primarily from either
atypical location of the cysts or complications of the cysts, such as infec-
tion or hemorrhage. When assessing cervical cysts in atypical locations,
it is important to keep in mind that second branchial cleft cysts may arise
anywhere from the parapharyngeal space to the anterior wall of the ster-
nocleidomastoid muscle, along a path that extends between the internal
and external carotid arteries (713). When branchial cleft cysts become
infected, the walls thicken and enhance and the contents become more
proteinaceous. Under these conditions, it becomes difficult to differen-
tiate the infected cyst from a necrotic lymph node (709,713). Differen-
tiation can often be made by the fact that infected branchial cleft cysts
incite less surrounding edema than necrotic, infected nodes. However,
lymph nodes from nontuberculous mycobacterial infections can strongly
resemble infected cysts, as they incite relatively minimal inflammatory
reaction and they occur in similar locations (717). Therefore, nontuber-
culous mycobacterial infection should always remain in the differential
diagnosis of any cervical cyst with a thick wall.
FIG 7-138. Second branchial
cleft cysts. Axial CT images show
characteristic location of the cysts
(c) between the sternocleidomas-
toid muscle and the subman-
dibular gland and characteristic
pointing (arrows) of the cysts
medially (A) and posteriorly (B).
Sometimes these lesions extend
medially between the internal
and external carotid arteries to
the pharyngeal mucosa.
5/6/2011 9:17:51 PM
 774 Pediatric Neuroimaging
Thymic Cysts
Thymic cysts are rare remnants of the third branchial pouch and, per-
haps, should be classified as a variant of branchial cleft cysts (709).
During the fifth gestational week, the thymus develops from the
ventral wings of the third branchial pouch. During the seventh and
eighth weeks, thymic primordia detach from the pharynx and migrate
caudomedially to the anterior mediastinum along the thymopharyn-
geal duct, which subsequently involutes. Failure of complete involu-
tion can result in formation of a cyst anywhere along the tract of the
thymopharyngeal duct from the angle of the mandible to the upper
mediastinum.
Affected patients present with dysphagia, respiratory distress,
hoarseness, or an enlarging lower neck mass. Imaging studies reveal a
largely cystic mass; ultrasound often shows intralesional debris if the
fluid is hemorrhagic or proteinaceous (709). Up to 50% are continu-
ous with the mediastinal thymus via direct extension of the cyst or by
connection to a solid cord or vestigial remnant of thymic tissue (718).
Lesions are almost always adjacent to or within the carotid sheath, fre-
quently splaying the carotid artery and jugular vein.
Venolymphatic Malformations
As discussed in the section on “Extraocular Orbital Masses,” the
development of the venous and lymphatic systems is interrelated.
As a result, the entities formerly referred to as lymphangiomas and
cavernous hemangiomas have been found to be strongly interrelated,
with both containing both venous and lymphatic components. As
a consequence, the nomenclature of disorders of these systems has
changed (685). The lesions formerly known as lymphangiomas and
those formerly known as cavernous hemangiomas are now combined
into an entity known as venolymphatic malformation (688). As dis-
cussed earlier, many of these malformations are primarily lymphatic,
while others are primarily venous. Therefore, lymphatic malforma-
tions and venous malformations will be discussed separately, while
keeping in mind that venous malformations nearly always have
Barkovich_Chap07.indd 774
FIG. 7-139. Second branchial cleft cyst.
Axial T1-weighted (A) and T2-weighted
(B) images show a well-defined homoge-
neous lesion (arrows) with long T1 and
long T2 relaxation times lying between
the submandibular gland and sterno-
cleidomastoid muscle.
lymphatic components and lymphatic malformations almost always
have venous components.
Lymphatic malformation is the name given to venolymphatic
malformations with predominantly lymphatic components. They are
malformative lesions, composed of thin-walled sacs of various sizes
containing lymphatic fluid that are generally discovered in infancy.
Clinically, lymphatic malformations present as soft, nontender neck
masses that can develop anywhere in the neck, face, or oral cavity.
The imaging characteristics vary depending on the size of the cysts
and the presence or absence of hemorrhage. Some of the lesions have
very small cystic spaces and may appear solid; these are referred to
as lymphangioma simplex. If the cystic spaces are of moderate size
(several mm to 1 cm), with thin intervening septae, then they are
called cavernous lymphatic malformations (Fig. 7-140). The sep-
tae may enhance on MRI (Fig. 7-141). If the cystic spaces are very
large, the lesion is referred to as a cystic hygroma (Fig. 7-141). One
important characteristic of lymphatic malformations and other con-
genital lesions of the neck (venous malformations, hemangiomas,
neurofibromas, branchial cleft cysts) is that they cross anatomic
fascial boundaries (719). Infections and neoplasms are unlikely to
cross these boundaries until late in the course of the disease; there-
fore, the presence of a mass in multiple fascial compartments suggests
a congenital lesion. Fluid-fluid levels are common in cystic hygromas
(Fig. 7-140). As a result of their crossing of fascial planes, lymphatic
malformations often involve multiple muscles, nerves, and blood ves-
sels. MRI is the preferred method for imaging these lesions because
it allows better assessment of the spatial extent of the lesion and its
relationship to adjacent structures (709); in addition, MRI is better
able to identify intralesional hemorrhage and fluid-fluid levels. As
with other cystic masses of the neck, the diagnosis of lymphatic mal-
formations only becomes difficult if hemorrhage or infection ensue.
Infection causes increased echogenicity (US), increased attenuation
(CT), and T1 and T2 shortening (MRI) as well as enhancement and
thickening of the cyst wall. Hemorrhage results in rapid enlargement
of the malformation. After hemorrhage, echogenicity increases on
5/6/2011 9:17:52 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 775

FIG. 7-140. Venolymphatic malformation. A. Parasagittal

T1-weighted image shows a low signal intensity, lobulated mass
(arrows) in the left side of the neck below the ear. B. Fat-suppressed
T2-weighted image shows the lateral portion of the mass (arrows)
to be very hyperintense (presumably fluid) with multiple septa. A
more hypointense, presumably solid medial component (s) can be
detected. C. Fat-suppressed postcontrast T1-weighted image shows
the medial, presumably solid component (s) to enhance while the
presumably cystic lateral component (arrowheads) does not.

sonography, attenuation increases on CT, and the fluid changes from
water intensity to the intensity of blood-breakdown products on
MRI. When large, lymphatic malformations may be detected in the
fetus; imaging features are nearly identical to those seen postnatally,
except that the cysts are smaller due to surrounding amniotic fluid
(Fig. 7-141).
Venous malformation is the name given to venolymphatic mal-
formations with predominantly venous components. These lesions
were formerly known as cavernous hemangiomas [685]), but they are
not hemangiomas as they do not involute over time and may involve
bone. They are uncommonly identified in children and become
symptomatic more commonly in young and middle aged adults (683).
They typically present with a painless, slow growing mass, often in
the face or in the skeletal muscles of the head or neck (masseter,
pterygoid, trapezius, sternocleidomastoid) that has a bluish discolor-
ation and remains unchanged with Valsalva maneuvers. They range
greatly in size, from a few millimeters in diameter to involvement of
much of the face. When they are large, the airway may be compressed
(720). On CT, venous malformations appear as homogeneously
enhancing round or ovoid masses that often cross fascial planes. Cal-
cified phleboliths are frequently seen within the mass (687). On MRI,
venous malformations appear as heterogeneous, well-defined, round
or ovoid, slightly lobulated masses that are isointense to the muscle
on T1-weighted images, hyperintense to muscle on T2-weighted

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 776 Pediatric Neuroimaging

FIG. 7-141. Large infantile venolymphatic malformation (cystic hygroma).

A and B. Sagittal and axial T2-weighted images of a fetus show a multiloc-
ulated hyperintense lesion (arrows) involving the face and neck. Note the
marked enlargement of the face due to the large lymphangioma. C. Post-
contrast sagittal T1-weighted image shows multiple large loculations in the
lower face, neck and upper chest. The airway appears open. D–F. Axial T1
(D), T2 (E) and postcontrast T1 (F) images show that the septa between
the loculations are best demonstrated on T2 and postcontrast images. Note
the fluid-fluid layer (arrow) in E and F; it is a very characteristic finding in
venolymphatic malformations.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
images, and enhance strongly after intravenous infusion of paramag-
netic contrast (Fig. 7-142) (684). It is important to recall, however,
that variable amounts of lymphatic malformation may result in T1
shortening of part of the venous malformation and the presence of
fluid-fluid levels (Fig. 7-143). These findings should not confuse
the reader but should strengthen the diagnosis of venolymphatic
malformation.
Goyal et al. have proposed a classification for venous malforma-
tions. They define grade 1 as well-defined lesions ≤ 5 cm, grade 2A as
well-defined lesions greater than 5 cm, grade 2B as ill-defined lesions
≤ 5 cm, and grade 3 as ill-defined lesions greater than 5 cm (721).
Barkovich_Chap07.indd 777
777
FIG. 7-142. Venolymphatic malformation. A. Axial
T1-weighted image shows a mass (arrows) in the left maxillary
region. B. Fat-suppressed axial T2-weighted image shows the
lesion to be heterogeneously hyperintense. C. Administration of
contrast shows heterogeneous enhancement.
Response to ethanol sclerotherapy varies with grade, with best response
in grade 1 lesions, and worst response in grade 3 lesions.
Infantile and Congenital Hemangiomas
Hemangiomas have already been discussed in the section on “Extraoc-
ular Orbital Masses.” Referred to as hemangiomas of infancy, juvenile
hemangiomas, or capillary hemangiomas, these are common masses,
occurring in 4% to 10% of white infants. Females are affected more
often than males. They are generally small at birth, and then go through
a proliferative phase during the first year of life, after which they slowly
involute (involuting phase from 1 to 7 years, followed by involuted
5/6/2011 9:17:55 PM
 778 Pediatric Neuroimaging

FIG. 7-143. Venolymphatic malformation. A. Parasagittal T1-weighted image shows a sharply defined hyperintense mass (arrows) in the floor of the
mouth. This suggests a hemorrhagic or proteinaceous cyst. B. Coronal T1-weighted image shows that the lesion has multiple components separated by
septae. Components 1, 2, and 3 are hyperintense, suggesting hemorrhagic or proteinaceous cysts. Component 4, which is hypointense, may be solid or a cyst
filled with transudate. C. Axial T2-weighted image shows marked hyperintensity, which unfortunately does not aid in characterizing the lesion. D. Postcon-
trast coronal T1-weighted image (compare to B) shows enhancement of the septae but not of components 1 to 4. The lack of enhancement of component
4 suggests that it is cystic. E. Axial postcontrast fat-suppressed T1-weighted image at the level of component 4 shows a fluid-fluid level (arrows) confirming
its cystic nature.

phase after age 8 years) (722). Some authors postulate that they result
from emboli of placental cells, because their microvessels share an
unusual set of antigens with placental microvasculature (GLUT1, LeY,
FcgRII, and merosin) (723).
Infantile hemangiomas are often multiple and can develop any-
where on the body. They appear on CT as well-defined masses of
intermediate attenuation; they show intense uniform enhancement
after intravenous administration of iodinated contrast. On MRI,
they are isointense to muscle on T1-weighted images, hyperintense
on T2-weighted images, and show uniform intense enhancement
after paramagnetic contrast administration (Figs. 7-144 and 7-145).
In older children, as the hemangioma involutes, more and more fat is
seen within the mass, resulting in a more heterogeneous appearance
(Fig. 7-145). Curvilinear signal voids can almost always be identified;
they are larger and more numerous in younger patients. As heman-
giomas often involve the parotid gland, assessment of the location of
the facial nerve is important if surgical resection is being considered.
In the last decade, several authors have described a group of
hemangiomas that develop in utero, seem to have an almost equal
gender distribution, are usually solitary and have a predilection for

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
specific cutaneous locations, on the head or on a limb near a joint (685,
722–724). Some of these congenital hemangiomas involute rapidly
(usually within the first 14 months after birth) and are referred to as
rapidly involuting congenital hemangiomas, while others remain very
vascular and do not involute; the latter are referred to as noninvolut-
ing congenital hemagiomas (685,722–724). The precise relationship
among these congenital hemangiomas and infantile hemangiomas is
currently a matter of research (722). From an imaging perspective, it
suffices to say that there are not yet any imaging characteristics that will
definitively separate these lesions.
Hemangiomas of the face are commonly associated with associated
anomalies, a condition that has been called PHACES syndrome (Pos-
terior fossa malformations, facial Hemangiomas, Arterial anomalies,
Cardiac anomalies and aortic coarctation, Eye anomalies, and Sternal
Barkovich_Chap07.indd 779
779
FIG. 7-144. Infantile hemangioma. A. Axial T1-weighted image
shows a large soft tissue–intensity mass (arrows) in the lateral aspect
of the right neck. Multiple foci of signal void, representing blood ves-
sels, are present within the mass. B. Axial T2-weighted image with fat
suppression shows that the hemangioma becomes uniformly hyper-
intense. The margins of the mass are better seen on this image. C.
Postcontrast T1-weighted image with fat suppression shows uniform
enhancement.
clefting and/or Supraumbilical raphe) (725–727) (see Chapter 6).
Therefore, a thorough examination of these patients should always be
carefully performed on these patients and the brain and intracranial
and cervical vessels should be assessed when imaging studies of the
head or neck are performed.
Neurofibromas and Schwannomas
Neurofibromas and schwannomas have been discussed in Chapter 6
and earlier in this chapter. It will briefly be repeated here for the conve-
nience of the reader. Neurofibromas are masses composed of fibroblasts
and nerve cells; they occur most commonly in NF1, but may occur spo-
radically. The neck is a common location for neurofibromas, with an
estimated occurrence of 25% to 30% in patients with NF1 (728). They
are usually ovoid, sharply marginated masses that typically occur in
5/6/2011 9:17:57 PM
 780 Pediatric Neuroimaging
the region of the carotid sheath, although they can develop anywhere
that nerves run. Solitary neurofibromas have slightly greater signal
intensity than skeletal muscle on T1-weighted sequences. On FLAIR
and T2-weighted sequences, the periphery of the lesions tends to be
of high signal intensity with respect to muscle, whereas the center of
the lesions is often of low signal intensity (see Fig. 7-146 and examples
in Chapter 6) (729–731); this has been referred to as the “target sign”
(732). The central area of decreased intensity is probably related to the
known dense central core of collagen within these lesions (729,731).
Collagen has a low mobile proton density and therefore is of low signal
intensity on T2-weighted images. Enhancement is variable, but usually
heterogeneous, after contrast administration.
Schwannomas are tumors of Schwann cells that are most com-
monly sporadic, but are seen with increased prevalence in NF1 and
NF2. Imaging manifestations schwannomas of the neck are similar
Barkovich_Chap07.indd 780
FIG. 7-145. Involuting infantile hemangioma.
A. Axial T1-weighted image shows a well-defined
mass (arrows) in the posterior left neck. Multiple
foci of hyperintensity represent fat from involution
of the hemangioma. B. Axial T2-weighted image
with fat suppression shows heterogeneous hyper-
intensity of the mass. The heterogeneity results
from the fatty degeneration of portions of the mass.
C. Postcontrast T1-weighted image with fat sup-
pression shows nearly uniform enhancement.
to those in other regions of the body. They develop in the same loca-
tions as neurofibromas, being most common in and around the carotid
sheath but may be seen anywhere in the neck. They are well-defined,
usually ovoid, masses that may cross fascial planes. On CT, the masses
are isodense with the neck muscles. On MRI, they are isointense with
muscle on T1-weighted images and hyperintense compared with mus-
cle on T2-weighted and FLAIR images. Contrast enhancement is vari-
able but usually homogeneous.
Plexiform neurofibromas are seen only in the setting of NF1.
They are locally aggressive congenital lesions composed of tortu-
ous cords of Schwann cells, neurons, and collagen in an unorganized
intercellular matrix (733). They tend to progress along the nerve of
origin (usually small, unidentified nerves), causing distortion and
compression of the adjacent structures. On CT, plexiform neurofibro-
mas tend to be of low attenuation and generally do not enhance after
5/6/2011 9:17:59 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 781

FIG. 7-146. Neurofibroma. A. Sagittal T1-weighted image shows an

ovoid, well-defined mass (n) in the region of the carotid sheath. The
mass is isointense to skeletal muscle. B. Axial T2-weighted image with
fat suppression shows the mass (n) to be largely hyperintense with areas
of central hypointensity, presumably the result of collagenous stroma
within the tumor. C. Postcontrast coronal T1-weighted image with fat
suppression shows heterogeneous enhancement of the mass (n).

administration of intravenous contrast. On MRI, the curvilinear masses Teratoma

are heterogeneous, crossing facial boundaries throughout the neck
(Fig. 7-147). They are nearly always surrounded by fat, as nerves in the
neck mostly run through fat. They are mostly of low signal intensity as
compared with brain on T1-weighted images and high signal inten-
sity on T2-weighted images (734). When fat suppression is used, high
quality T2-weighted images nicely show the multiple swirling enlarged
nerves coursing through the tissue (Fig. 7-147B). Enhancement after
administration of paramagnetic contrast is variable, although at least a
portion of the tumor usually enhances (Fig. 7-147C).
Although neonatal head and neck teratomas are reportedly very rare
(735,736), 2 to 3 teratomas of the neonatal head and neck are seen per
year in our department, accounting for up to 10% of all neonatal tera-
tomas (735,736). Most are detected prenatally by obstetrical sonogra-
phy (performed for polyhydramnios due to difficulty in swallowing in
up to 55% of patients); thus, the neonatologists and pediatric surgeons
are usually prepared to deal with the airway compromise that is the
most common complication (up to 50%) of this tumor. As less than
5% of these tumors are malignant (735), early surgery to decompress

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 782 Pediatric Neuroimaging

FIG. 7-147. Plexiform neurofibroma. A. Axial T1-weighted image

shows a heterogeneous mass (arrows) in the posterior right neck.
B. Axial fat-suppressed T2-weighted image better shows the het-
erogeneity of the mass (arrows) and the hyperintense swirls of
thickened, curvilinear nerves that compose the tumor. C. Post-
contrast fat-suppressed T1-weighted image shows heterogeneous
enhancement of the tumor (arrows).

the airway results in a good prognosis for about 90% of affected neo-
nates (737).
Imaging is useful more for assessing the anatomic extent of the
tumor than for establishing a diagnosis. CT may be useful for identi-
fication of fat or calcium, which increases confidence in the diagno-
sis of teratoma. However, MRI is the most useful technique, allowing
imaging in multiple planes and best differentiating of tumor from
surrounding soft tissues. Well-differentiated teratomas are extremely
heterogeneous, with cystic components, soft tissue components (both
fatty and nonfatty, calcified and noncalcified), and bone (Fig. 7-148).
Enhancement is heterogeneous and depends upon the composition of
the tumor. The radiologic diagnosis is easy to establish in these cases.
However, some teratomas are less mature and, as a result, more homo-
geneous. The differential diagnosis is broader in these patients. In
either case, it is important to look for airway compromise, involvement
of the pharynx and tongue, distortion of adjacent osseous structures
(especially the mandible and hard palate), and extension into the skull
base or even the middle cranial fossa.

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 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
FIG. 7-148. Facial teratoma. A. Sagittal T1-weighted image shows a very heterogeneous mass (white arrows) arising from the facial bones. Note the
marked heterogeneity of the tumor, with areas of hyperintensity (presumably fat, black arrows), hypointensity, and isointensity compared to muscle.
B. Fat-suppressed postcontrast T1-weighted image shows suppression (black arrows) of the hyperintense areas, establishing that it is fat. The remainder of
the mass shows mild or moderate, heterogeneous enhancement.
The differential diagnosis varies with the appearance of the tumor
and the precise location. For predominantly cystic masses, the main dif-
ferential considerations are lymphatic malformation (cystic hygroma)
and meningocele. For solid, homogeneous lesions, the differential
diagnosis includes dermoid/epidermoid, neurofibroma, hamartoma,
and rhabdomyosarcoma. For heterogeneous solid lesions, the differen-
tial includes craniopharyngioma, dermoid, encephalocele (is the brain
exiting through the skull defect or being pushed away by an extracra-
nial mass), and sarcoma. If the lesion is largely fatty, dermoids and
lipomas are considerations, although large lipomas and large dermoids
are uncommon in neonates.
Cervical Lymphadenitis
Most patients with cervical lymphadenitis are not imaged, medical
therapy being the treatment of choice. Imaging is indicated if there is
clinical suspicion of suppuration. Either sonography or CT can give a
quick answer, ultrasound showing decreased central echogenicity and
CT showing central hypodensity if central necrosis is present. When
mass effect and surrounding inflammatory changes are minimal,
atypical mycobacterial infections should be considered, particularly if
the nodal masses are located in the parotid or submandibular regions
(738).
Fibromatosis Colli
Fibromatosis colli is a benign condition that is discovered primarily in
neonates and young infants. The infants typically come to attention
between ages 2 and 4 weeks because of torticollis or a mass in the neck.
The mass is typically firm, nontender, and cannot be separated from
the sternocleidomastoid muscle. There may be a history of breech pre-
sentation or forceps delivery, which raises the question of trauma and
hematoma as the cause of the mass (739,740). In the vast majority of
children, the mass spontaneously regresses during the first year of life.
The diagnosis of fibromatosis colli can be suggested by sonogra-
phy, CT, or MRI. Sonography is usually diagnostic, showing focal or
diffuse enlargement of the sternocleidomastoid muscle with variable
echogenicity. Often a hypoechoic rim (thought to represent com-
pressed normal muscle) is present. CT shows a focal enlargement of
Barkovich_Chap07.indd 783
783
the sternocleidomastoid muscle. If contrast is administered, variable
enhancement is seen. On MRI, the mass is isointense to normal muscle
on T1-weighted images, slightly hyperintense on T2-weighted images,
and shows similar enhancement to normal skeletal muscle (Fig. 7-149)
(741). Occasionally, enhancement is heterogeneous; this should not
dissuade one from making the diagnosis of fibromatosis colli if all
other features are consistent with it.
Rhabdomyosarcomas/Rhabdomyomas
Rhabdomyosarcomas are the third most common primary child-
hood malignancy of the head and neck, following intracranial brain
tumors and retinoblastomas in frequency. They comprise 4% to 8% of
all malignant tumors in children less than 15-years-old; 43% of rhab-
domyosarcomas arise before age 5 years, and 78% before age 12 years
(742). Thirty-six percent of rhabdomyosarcomas arise in the head and
neck, with the orbit and nasopharynx/masticator space most com-
monly involved, followed by the paranasal sinuses and middle ear.
Intracranial involvement usually results from extension of extracranial
tumor into the cranial vault through fissures and foramina. However,
very rarely, primary intracranial rhabdomyosarcomas do occur; they
cannot be differentiated radiologically from other primary intra-axial
brain tumors (743–745). Histologically, the embryonal and alveo-
lar rhabdomyosarcomas are most common. Although most cases of
rhabdomyosarcoma appear to be sporadic in nature, some young chil-
dren (age, <3 years) have identifiable constitutional mutations of the
p53 tumor suppressor gene and a possible hereditary predisposition to
cancer (746). Molecular criteria for rhabdomyosarcomas have recently
been described. Approximately 60% of alveolar tumors have a FOXO1
to PAX3 or PAX7 translocation (747); those lacking this characteris-
tic have clinical features more similar to embryonal tumors. This may
have prognostic and therapeutic significance (746).
Rhabdomyomas are much less common than rhabdomyosarco-
mas, comprising only 2% of all tumors of striated muscle in the pediat-
ric age group (748). The fetal type of rhabdomyoma is, by far, the most
common type seen in children. These tumors consist of haphazardly
arranged bundles of immature skeletal muscle fibers intermingled with
undifferentiated spindle-shaped but benign-appearing cells (749).
5/6/2011 9:18:01 PM
 784 Pediatric Neuroimaging
Their most common locations are the head and neck, including the
oral cavity, retroauricular area, and orbit (748,750). Rhabdomyomas
are well-circumscribed, homogenous masses without necrosis or hem-
orrhage. Adjacent bones are remodeled but not invaded or destroyed.
MRI reveals low signal on both T1- and T2-weighted images; admin-
istration of intravenous contrast results in uniform enhancement
(750,751).
Clinically, it is useful to classify rhabdomyosarcomas of the head
and neck by site of origin (752). Three major groups are identified: (a)
parameningeal, (b) orbital, and (c) other head and neck locations. The
Barkovich_Chap07.indd 784
FIG. 7-149. Fibromatosis colli in a 12-day-old infant. A. Axial
T1-weighted image shows a soft tissue intensity mass (arrows)
within the left sternocleidomastoid muscle. B. Axial T2-weighted
image shows that the mass (arrows) is heterogeneously hyperin-
tense compared with muscle. C. Postcontrast T1-weighted image
shows mild uniform enhancement of the mass approximately
equal to that of surrounding muscle.
parameningeal group, consisting of tumors originating in the middle
ear, nasopharynx/masticator space, paranasal sinuses, and nasal cavity,
is of particular importance from the neuroimaging perspective. Tumors
in these locations have the poorest prognosis because they commonly
invade the skull or spread intracranially via skull base foramina. Orbital
rhabdomyosarcomas are most often extraconal in location, but may
be both extraconal and intraconal; they most commonly develop in
the superonasal quadrant of the orbit. They most commonly spread
by local invasion to the paranasal sinuses (20%), but can also spread
intracranially, typically growing through the orbital fissures into the
5/6/2011 9:18:02 PM
 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 785

FIG. 7-150. Rhabdomyosarcoma. A. Axial

contrast-enhanced CT through the mid-
dle of the orbits shows a mass near the
apex of the right orbit and extending
into the posterior ethmoidal air cells. The
mass extends through the superior orbital
fissure into the cavernous sinus (arrows).
B. Image 5 mm higher than A shows the
mass filling and expanding the right cav-
ernous sinus (arrows) and widening the
superior orbital fissure (open arrows).

cavernous sinuses and middle cranial fossa (753). Lymphatic spread
and hematogenous spread is rare other than in advanced disease.
On CT, rhabdomyosarcomas typically appear as irregular, ovoid,
well-circumscribed, homogeneous masses that are usually isodense
with muscle prior to contrast enhancement; they uniformly enhance
after the infusion of contrast (Fig. 7-150). If calcification is present, it
is typically due to destruction of adjacent bone (754). If intracranial
extension occurs, the foramen or fissure through which the extension
has occurred is usually expanded. The extradural mass adjacent to
the expanded foramen usually demonstrates a wide base against the
inner table of the skull; meningeal enhancement indicates a poor
prognosis (755). Usually, an extracranial or petrosal mass is also vis-
ible (743–745,756). The MR findings are usually those of a mass that
is isointense to muscle on T1-weighted images and hyperintense to
muscle (hypointense to brain) on T2-weighted images (Figs. 7-151
to 7-153). The tumors are often heterogeneous on T2-weighted images

FIG. 7-151. Nasopharyn-

geal rhabdomyosarcoma. A.
Sagittal T1-weighted image
shows the mass (arrows) in
the parapharyngeal region
that is isointense to muscle.
B. Axial T2-weighted image
shows the heterogeneous
mass (arrows) to be hyper-
intense compared to skel-
etal muscle.

Barkovich_Chap07.indd 785 5/6/2011 9:18:03 PM

 786 Pediatric Neuroimaging

FIG. 7-151. (Continued) C. Postcontrast T1-weighted image shows homogeneous enhance-

ment (arrows) of the tumor.

FIG. 7-152. Nasopharyngeal rhabdomyosarcoma

with intracranial invasion. A. Sagittal T1-weighted
image shows a mass (arrows) growing upward from
the nasal cavity through the sphenoid bone and into
the inferior anterior cranial fossa. B. Axial T2-weighted
image shows the mass to be slightly hyperintense com-
pared with surrounding muscle. C. Postcontrast axial
T1-weighted image shows moderate homogeneous
enhancement of the mass (arrows).

Barkovich_Chap07.indd 786 5/6/2011 9:18:04 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
due to presence of necrosis and hemorrhage. When tumors invade
the paranasal sinuses, MRI helps to differentiate tumor from retained
secretions, the latter being much more T2-hyperintense. Extension
of tumor through a foramen or fissure is more easily visualized with
MRI than with CT due to the lack of beam hardening artifact from the
skull base. However, erosion or infiltration of the skull base without
intracranial extension is difficult to appreciate on MRI and is better
evaluated with CT. Administration of paramagnetic contrast results in
heterogeneous tumor enhancement, which sometimes gives a pattern
of multiple mildly enhancing nodules separated by enhancing stroma;
this has been called the “botryoid sign” because of the resemblance to a
bunch of grapes (757). This sign may help in specificity of MR diagno-
sis. Contrast enhancement also aids in the identification and localiza-
tion of tumor that extends through the skull base foramina into the
extradural space (743,758). Contrast-enhanced MRI of the neck, there-
fore, should always include fat suppression (Figs. 7-151, 7-153, and
7-154), to aid in differentiation of enhancing tumor from fat. The neck
should be imaged to screen for metastatic cervical lymphadenopathy.
Although the CT and MR findings are not specific, the diagnosis of
Barkovich_Chap07.indd 787
787
FIG. 7-153. Infratemporal rhabdomyosarcoma. A. Axial
T1-weighted image shows a soft tissue intensity mass (arrows)
in the left infratemporal fossa. B. Coronal T2-weighted
image with fat suppression shows the mass (arrows) is
slightly heterogeneous and is hyperintense compared with
muscle. C. Postcontrast T1-weighted image shows that the
mass (small arrows) enhances equally to muscle. No inva-
sion though the foramen ovale (large arrow) is seen.
rhabdomyosarcoma can be suggested from imaging studies because it
is the most common primary extracranial tumor that invades the cra-
nial vault in childhood. Major differential diagnoses depend on the age
of the patient and the location of the tumor; they include lymphoma,
carcinoma (in teenagers), sarcomas, and juvenile nasal angiofibroma
(in teenage boys).
Nasopharyngeal Carcinoma
Although nasopharyngeal carcinoma is rare in children with an inci-
dence of less than 1% of all childhood cancers, carcinoma of the
nasopharynx has a predilection for adolescents and teenagers (759).
Indeed, although rhabdomyosarcoma and lymphoma are more com-
mon causes of nasopharyngeal masses in younger children, nasopha-
ryngeal carcinoma is more common in adolescents (759). These
tumors are typically of the nonkeratinizing variant and are associ-
ated with Epstein-Barr virus (760). Affected children typically pres-
ent with a neck mass, nasal obstruction, nasal bleeding and discharge,
or fever of unknown origin. Unfortunately, these tumors are often
locally advanced by the time of diagnosis because the presentation is
5/6/2011 9:18:05 PM
 788 Pediatric Neuroimaging

FIG. 7-154. Rhabdomyosarcoma with

intracranial invasion. Value of fat
suppression. A. Noncontrast axial
T1-weighted image shows a nasopha-
ryngeal mass (arrows) compressing and
laterally displacing the parapharyngeal
fat stripe. B. Postcontrast fat-suppressed
T1-weighted image 1 cm inferior to (A)
shows the heterogeneously enhanc-
ing mass (arrows) distinctly separate
from infratemporal and marrow fat.
C and D. Postcontrast coronal fat-
suppressed T1-weighted images show
enhancing nasopharyngeal tumor (white
arrows) growing intracranially through
a large hole (curved black arrows) in the
skull base, presumably the expanded
foramen ovale.

nonspecific and the clinical suspicion for tumor is usually low (761).
Only after no response is seen to several courses of antibiotics is biopsy
obtained and diagnosis made. Cervical lymphadenopathy, a common
cause of presentation of nasopharyngeal carcinoma in adults, is so
common in children that it does not cause sufficient alarm among par-
ents of physicians for further investigation.
The main differentiation in diagnosing nasopharyngeal carcinoma
from the benign adenoidal masses that are so common in childhood
and adolescence is asymmetry. Benign adenoidal tissue is nearly always
symmetric, whereas nasopharyngeal carcinoma is almost always asym-
metric (762). Another feature distinguishing carcinoma is local spread
of the mass, typically posteriorly through the pharyngobasilar fascia
towards the clivus or laterally into the parapharyngeal space. Clival
invasion is recognized by loss of the normal high signal intensity of
marrow fat on T1-weighted images and by development of high signal
intensity within the marrow space on T2-weighted images (762). CT
may show erosion of the cortical bone or widening of the petroclival
fissure. Erosion of the surrounding soft tissue structures is most easily
recognized by effacement of the fat planes in the parapharyngeal space
that separate the pharyngeal mucosa from surrounding muscles.
Juvenile Angiofibromas
Juvenile angiofibromas are highly vascular, locally invasive, histo-
logically benign tumors that arise in the sphenopalatine foramen,
nasopharynx, or posterior nasal cavity of adolescent boys. Local spread
into the sphenoid sinus, pterygopalatine fossa, infratemporal fossa,

Barkovich_Chap07.indd 788 5/6/2011 9:18:06 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood 789

FIG. 7-155. A. Axial contrast enhanced CT image shows a right nasal mass (m) that extends posteriorly into and destroys the right pterygoid process (black
arrowheads) and extends laterally (black arrow) through the sphenopalatine foramen into the pterygopalatine fossa. B. Parasagittal reformation shows the
enhancing mass (arrows) in the pterygopalatine fossa.

orbit, and middle cranial fossa is often seen by the time of presentation.
Affected patients typically present with nasal obstruction and recur-
rent epistaxis. In advanced cases, proptosis or cranial neuropathies may
develop (743,763,764). These tumors have an increased frequency in
patients with familial adenomatous polyposis (765).
CT typically shows a sharply marginated, homogeneous soft tissue
mass that arises in the posterolateral wall of the nasal cavity, spreads
anteriorly into the ipsilateral nasal cavity and the nasopharynx and
laterally into the pterygopalatine fossa, causing anterior bowing of the
posterior wall of the maxillary sinus. Expansion through the roof of
the nasopharynx into the sphenoid sinus is common. Homogeneous
enhancement is seen after intravenous infusion of iodinated contrast
(Fig. 7-155) (743,763,764). MRI shows a lobulated mass that is hypoin-
tense to isointense compared with muscle on T1-weighted images;
although most are isointense to slightly hyperintense compared with
muscle on T2-weighted images (Figs. 7-156 to 7-158), the lesions are
occasionally very hyperintense. Marked, fairly uniform enhancement
is seen after intravenous administration of paramagnetic contrast
(Figs. 7-156 to 7-158). Punctate and curvilinear regions of low signal
intensity can be seen on both T1- and T2-weighted images, representing

FIG. 7-156. Small juvenile nasal angiofibroma. A. Axial T1-weighted image shows a muscle-intensity mass (large white arrows) arising in the posterior
nasal cavity and extending laterally to invade the pterygoid process (asterisk). Note that the posterior wall of the left maxillary sinus (small white arrows) is
anteriorly displaced. B. Fat-suppressed axial T2-weighted image shows the nasal mass (large white arrows) growing laterally (small white arrow) into the left
pterygoid process and pterygopalatine fossa.

Barkovich_Chap07.indd 789 5/6/2011 9:18:08 PM

 790 Pediatric Neuroimaging

FIG. 7-156. (Continued) C. Coronal fat-suppressed T1-weighted image shows the brightly
enhancing mass extending from the nasal cavity through the sphenopalatine foramen
(at the large arrow) into the pterygomaxillary fissure and pterygopalatine fossa (small
arrows).

FIG. 7-157. Classic juvenile nasal angiofibroma. A. Axial

T1-weighted image shows a large mass arising in the posterior
nasal cavity and extending laterally through the left spheno-
palatine foramen (large arrow) into the pterygopalatine fossa.
Note that the normal fat in the pterygopalatine fossa seen on the
right (small arrows) is replaced by tumor on the left. B. Axial
T2-weighted image with fat suppression shows a mass that is
slightly hyperintense to skeletal muscle that is centered in the
posterior nasal cavity. The mass extends posteriorly (small white
arrows) into the sphenoid sinus and sphenoid bone, laterally
through the left sphenopalatine foramen into the pterygopalatine
fossa (small white arrowheads), and anteriorly (large arrowheads)
into the nasal cavity. Small hypointensities represent voids from
flow in blood vessels within the tumor. The large white arrows
point to retained secretions in the right ear due to compression
of the Eustachian tube. C. Postcontrast T1-weighted image with
fat suppression shows diffuse, somewhat heterogeneous enhance-
ment. Arrows show extension of tumor into the skull base.

Barkovich_Chap07.indd 790 5/6/2011 9:18:09 PM

 Chapter 7 • Intracranial, Orbital, and Neck Masses of Childhood
the prominent tumor vessels that are characteristic of these tumors;
however, tumor vessels are not always seen by MRI and their absence in
a mass otherwise typical for juvenile angiofibroma should not negate
the diagnosis (743,764). The key findings in making this diagnosis are
the age and sex of the patient (teenage boys are by far the group most
commonly affected) and the location in the posterior nasal cavity with
extension through the sphenopalatine foramen into the pterygopala-
tine fossa. Treatment of choice is by intravascular techniques; details
of intravascular diagnosis and therapy are discussed in Chapter 12.
Melanotic Neuroectodermal Tumors of Infancy
Melanotic neuroectodermal tumors of infancy are tumors of mesoder-
mal origin that typically involve the skull, dura, or face. They often
occur adjacent to cranial sutures and may be initially mistaken for der-
moids. Patients typically present with a mass and discoloration of adja-
cent skin. The tumors secrete high levels of vanillylmandelic acid and
homovanillic acid in the urine, which can be used to make a preopera-
tive diagnosis and to identify tumor recurrence at an early stage. Local
resection is often curative (766,767). CT shows a soft tissue mass that
usually arises in the bones of the face. The bone can show expansion,
hyperostosis, erosion, or osteogenesis; in some reported cases, all of
FIG. 7-159. Fibrous dysplasia of the orbitosphenoid region. A. Sagittal T1-weighted image shows expanded, hypointense, unpneumatized sphenoid bone.
B. Coronal T2-weighted image shows the sphenoid bone (arrows) to be enlarged and markedly hypointense. Compare with Figure 7-158, but note that
there is no nasopharyngeal soft tissue mass in this case. C. After administration of paramagnetic contrast, coronal T1-weighted image shows the expanded
sphenoid bone enhancing dramatically, as is typical for fibrous dysplasia.
Barkovich_Chap07.indd 791
791
FIG. 7-158. Juvenile nasal angiofibroma
with skull base invasion. A. Axial T2-weighted
image with fat suppression shows a mass that
is slightly hyperintense to skeletal muscle
that is centered in the posterior nasal cavity.
The mass extends posteriorly (black arrows)
into the clivus, and bilaterally through the
sphenopalatine foramen into the pterygo-
palatine fossae (small white arrows). Small
hypointensities represent voids from flow
in blood vessels within the tumor. The large
white arrow points to retained secretions in
the right maxillary sinus. Retained fluid is
present in the right ear due to compression
of the Eustachian tube. B. Postcontrast coro-
nal T1-weighted image with fat saturation
shows intense, fairly uniform enhancement.
Black arrows show extension of tumor into
the skull base.
these characteristics have been present in the same patient in different
areas of tumor. MRI shows a soft tissue mass that is isointense to mus-
cle on T1-weighted images and isointense to hyperintense to muscle
on T2-weighted images. T1 shortening from melanin is not reported in
most cases. Rarely, melanotic neuroectodermal tumors of infancy can
originate intracranially, presumably from mesodermal elements within
the stroma of the choroid plexus. These tumors are indistinguishable
from the more common neoplasms that arise in those locations by
radiological criteria (766,767).
Neuroblastoma
Neuroblastoma of the neck is discussed in Chapter 10 in the section of
“Extramedullary Tumors.”
Fibrous Dysplasia of the Skull Base
Fibrous dysplasia is mentioned in this section only because it can mimic
skull base and head-and-neck tumors, such as rhabdomyosarcomas
and juvenile nasal angiofibromas on MRI (Fig. 7-159). Affected bone
is expanded and will enhance dramatically. A noncontrast CT scan
(Fig. 7-160) with bone algorithm will show the classic “ground glass”
appearance of fibrous dysplasia, confirming the proper diagnosis.
5/6/2011 9:18:10 PM
 792 Pediatric Neuroimaging

FIG. 7-160. CT of fibrous dysplasia. A. Axial bone algorithm

CT image of temporal bone shows a diffusely expanded bone,
with attenuation similar to diploic space, lower than that of cor-
tical bone. This appearance is called a “ground glass” appear-
ance. B and C. Different patient. Axial bone algorithm images
through the orbit and supraorbital regions show expanded bone
(arrows) in the lateral wall of the orbit (B) and the supraorbital
portion of the frontal bone (C). Both areas have a “ground glass
appearance.”

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 CHAPTER
Hydrocephalus
8 A. RAYBAUD AND A. JAMES BARKOVICH
Embryology and physiology of CSF dynamics
Choroid plexuses and CSF formation
CSF circulation
CSF absorption
Mechanisms of hydrocephalus
Classical model: obstructive hydrocephalus
Greitz model: communicating hydrocephalus
Classification of hydrocephalus
Obstructive hydrocephalus
Communicating hydrocephalus
Clinical aspects of hydrocephalus
Fetal hydrocephalus
Postnatal hydrocephalus
Radiologic diagnosis of hydrocephalus
The tools
Fetal diagnosis of hydrocephalus
Postnatal diagnosis of hydrocephalus
ydrocephalus may be defined morphologically as a process in
H which the cerebrospinal fluid (CSF) compartment is actively
enlarged at the expense of the brain tissue. It is a common
disorder in all age groups, especially so in children. The basic issue of
hydrocephalus is relatively easy to understand. The ventricles progres-
sively increase in size in conjunction with increasing head size and
progressive compression and, eventually, loss of brain tissue. Some
CSF must be diverted out of the head in order to preserve the brain.
Establishing the diagnosis also is relatively simple in most cases such
as increased ventricular size, effacement of the subarachnoid spaces,
macrocephaly, and typically an obstruction somewhere along the CSF
pathway (e.g., from a posterior fossa tumor or aqueductal stenosis).
But some aspects of hydrocephalus are not so easy to understand. Is
the ventriculomegaly due to increased intraventricular pressure? If so,
why do the ventricles enlarge in communicating hydrocephalus when
the “block” to CSF flow is in the subarachnoid spaces? Brain tissue is
mainly water and, therefore, is not compressible other than some space
provided by the compression of the vascular bed (<4% of the brain tis-
sue) and effacement of the pericerebral spaces. In chronic aqueductal
stenosis, it may take months or years for the ventricular size to increase.
Therefore, the daily CSF production (estimated at 500 mL) must be
somehow resorbed by cerebral parenchyma; why do we see an increase
in ventricular size? The best answer (for now) is that the morphological
pattern that we call hydrocephalus is probably the end result of many
different processes; accordingly, the imaging and pathologic manifes-
808
Barkovich_Chap08.indd 808
Specific categories of hydrocephalus
Hydrocephalus resulting from excessive formation of CSF
(choroid plexus papillomas)
Hydrocephalus secondary to intraventricular obstruction of
Hydrocephalus secondary to extraventricular obstruction of CSF
Benign enlargement of the subarachnoid spaces in infants
Definition
Clinical manifestations
Imaging
Imaging of treated hydrocephalus and resulting
complications
Radiologic assessment of third ventriculostomies
Shunt malfunctions
Shunt infections
Subdural hematoma formation
Slit ventricle syndrome
Imaging of intracranial hypotension
Other complications
tations of hydrocephalus vary considerably. In this chapter, we discuss
many of these processes. In addition, we show that the degree of dila-
tation of the CSF pathways and the amount of damage to the brain
depend upon the cause of hydrocephalus, its severity, and the age of the
patient at the time when the hydrocephalus develops.
EMBRYOLOGY AND PHYSIOLOGY
OF CSF DYNAMICS
Closure of the neural tube in man occurs by about 28 postconceptional
days (see Chapters 5 and 9). Certain portions of the central lumen of
the neural tube then constrict, while others expand to form the basic
pattern of the ventricular system such as enlargement of prosenceph-
alic (forebrain), mesencephalic (midbrain), and rhombencephalic
(hindbrain) vesicles. Some midline dorsal meningeal mesenchyme
invaginates into the lumen of the fourth ventricle during the second
gestational month followed by similar invaginations into the lateral
and third ventricles; these invaginations form the choroid plexuses
of the ventricular system and secrete the early CSF (1,2). Initially, the
plexuses are large relative to the size of the lateral ventricles, filling
approximately 75% of the ventricular lumen during the third month of
gestation. The size of the choroid plexus relative to the lateral ventricle
gradually diminishes as the brain and ventricular system grow.
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Choroid Plexuses and CSF Formation
The choroid plexuses have several functions. They secrete multiple
proteins that are postulated to stimulate and modulate the growth of
progenitor cells in the ventricular zone of the germinal matrices dur-
ing development (see Chapter 5) (3). They act on diverse chemosensi-
tive areas of the ependyma throughout life (4); these small areas in the
walls of the third and fourth ventricle are called the circumventricular
organs; they contain specialized ependymal cells called tanycytes that
form exchange interfaces allowing the brain, mostly the hypothalamus,
to react in response to changing CSF composition. In certain hydro-
cephalic animal models, the progenitor cells in the ventricular walls are
less sensitive to the proliferative effects of certain growth factors than
controls. Thus, fetal hydrocephalus may adversely affect brain develop-
ment (3).
The extracerebral CSF spaces appear near the end of the embryonic
period, resulting from the expansion of the meningeal extracellular
space as the gelatinous primitive mesenchyme that surrounds the brain
(meninx primitiva) undergoes a systematic degeneration to become
the fluid-filled leptomeninges (5,6). The communication between ven-
tricular and subarachnoid CSF results from thinning and opening of
the inferior midline portion of the fourth ventricular roof to create the
foramen of Magendie during the 11th or 12th gestational week, fol-
lowed by opening of the lateral foramina of Luschka (7,8). The function
of CSF in the embryo is not completely understood. However, there is
essentially no intrinsic brain vasculature when the plexuses develop
(9,10), and it is postulated that important chemicals enter the CSF from
the blood vessels of the choroid plexuses and circumventricular organs;
these chemicals may be vital in controlling the early development of the
nervous system along the entire length of the neural tube (11).
In the adult, CSF is secreted at a rate of approximately 0.3 to
0.4 mL/min, resulting in a daily secretion of approximately 500 mL
(12). The choroid plexus produces an estimated 60% to 90% of CSF,
with the other 10% to 40% most likely coming from the parenchyma
of the brain and spinal cord (13,14). CSF secretion by the choroid
plexuses uses ATP hydrolysis to generate unidirectional flux of sodium,
chloride, and bicarbonate ions across the plexus epithelium, driving the
movement of water by osmosis (4). The total volume of CSF was clas-
sically assumed to be 40 to 60 mL in infants, 60 to 100 mL in children,
and approximately 150 mL in adults (12). However, studies using volu-
metric magnetic resonance imaging (MRI) to quantify the CSF volume
have found higher values, with a volume of ∼150 mL in the intracranial
subarachnoid spaces and 100 to 120 mL in the spinal subarachnoid
spaces (15). In addition, the interstitial fluid of the central nervous sys-
tem is estimated to contain 100 to 300 mL of CSF (4). CSF and extra-
cellular fluid in the brain and spinal cord are in continuity with each
other, and exchanges occur constantly across the pial membrane, the
Virchow-Robin perivascular spaces, and the ependyma (16).
CSF Circulation
Classic teaching suggests that CSF flows from the cerebral ventricles
through the ventricular foramina and into the subarachnoid spaces,
ultimately being absorbed into the venous system (13,14); this
movement of water molecules through the ventricles and cisterns is
referred to as bulk flow; it results from a hydrostatic pressure gradi-
ent between the site of its formation (arterial) and its site of absorp-
tion (venous) (17,18). Another mechanism, the coordinated beating of
cilia in ependymal cells, creates a current of CSF along the walls of the
lateral ventricles that likely contributes to bulk flow (19,20). CSF leaves
the lateral ventricles via the foramina of Monro and then circulates
Barkovich_Chap08.indd 809
Chapter 8 • Hydrocephalus 809
through the third ventricle, into the Sylvian aqueduct and the fourth
ventricle. From the fourth ventricle, CSF courses through the foramina
of Magendie and Luschka into the cisterna magna and the basilar cis-
terns, respectively. It is estimated that 80% of flowing CSF then enters
the cisternal system, flowing into the suprasellar cistern and cistern of
the lamina terminalis, the ambient and superior cerebellar cisterns, and
eventually flowing over the cerebral convexities. The remaining 20%
of CSF undergoing bulk flow initially enters the spinal subarachnoid
space but is eventually recirculated into the cerebral subarachnoid
space (21), although some (10%–15%) is absorbed in the spine at the
level of the nerve root sheaths (22–24).
Although the concept of bulk flow in the ventricular system is
generally accepted and serves as an adequate model for most cases of
hydrocephalus, it fails to explain some cases of progressive ventriculo-
megaly (25). It has been demonstrated that the CSF “flow” through the
subarachnoid spaces is quite slow (.35 mL/min) and that subarachnoid
CSF motion is nearly entirely pulsatile; that is, the water molecules
pulsate back and forth, driven by expansion of the intracranial blood
vessels as they fill with blood after each cardiac systole, but very few
CSF water molecules actually follow the rules of bulk flow and actually
circulate through the subarachnoid space from the outlet foramina of
the fourth ventricle to the arachnoid granulations (26). Thus, it appears
that the circulation of CSF results from the combination of two processes.
The secretion-absorption process (bulk flow) is slow and passive,
particularly in the subarachnoid spaces, and may be compared to the
lymphatic circulation. The separate, pulsatile process is fast (~60–80
pulsations/min at rest) and is driven by pressure waves produced by
enlargement of the intracranial arteries as the blood flows into them
after each cardiac systole. These pulsations continuously mix the CSF.
As the cranial cavity is rigid and the brain tissue not compressible, the
pressure waves need to be dampened: the force transmitted through
the subarachnoid space via CSF is dampened by the expansion of the
highly elastic spinal thecal sac, while the force transmitted through the
vascular system is dampened by expansion of the venous sinuses. This
dual dampening process constitutes the compliance of the system. The
loss of thecal elasticity (or restriction of the access to the spinal suba-
rachnoid space) results in less attenuation of the CSF pressure wave;
this force then is fully exerted upon the brain tissue. If the venous pres-
sure is increased, the dampening of the force in the vascular system
is lost and the force of the vascular pressure wave is exerted upon the
parenchyma. In both instances, the pressure waves cause a progressive
loss of brain tissue. Another factor to consider is the anatomic organi-
zation: the arteries surround the brain, which surrounds the ventricles.
Therefore, the force of each arterial pulsation is transmitted centrip-
etally via the parenchyma to the ventricle, pushing CSF toward the
cisterna magna; it is only partly counter-balanced by the small pulsa-
tions of the intraventricular choroid plexuses. Finally, the transmission
of the pressure wave after each pulsation is extremely rapid across the
noncompressible CSF but is slower through the more elastic vascular
bed; as a consequence, the systolic pressure wave results in constriction
of the outlets of the bridging veins before pushing blood into the capil-
lary bed. As a result, the vascular bed expands (through the so-called
“bagpipe” effect), increasing the perfusion pressure and, consequently,
cerebral perfusion (25).
In summary, pressure waves from arterial pulsations are important
for normal CSF flow and cerebral perfusion; however, these pressure
waves need to be dampened for the system to function properly. The
compliance of the system depends on the venous pressure and on the
elasticity of the dura. If the venous pressure is elevated, or if the pressure
waves do not expand the elastic dura, the force of a pressure wave is not
dampened and it pulsates against the parenchyma at full strength. This
5/6/2011 10:25:59 PM
 810 Pediatric Neuroimaging
causes compression of the cerebral tissue, alterations of axonal function
and of cerebral blood flow (CBF), and progressive brain injury.
Neonates and young infants have open fontanelles and sutures,
so both the cranial and the spinal dura contribute to this elasticity,
whereas in the older child and adult, the cranial dura is attached to a
rigid calvarium, so only the spinal dura (long and surrounded by fat
and veins) contributes to elasticity. Thus, in older children, obstruction
of the foramen magnum (which reduces the total elasticity of the CSF-
containing spaces) and any other process that reduces the dampening
of the pressure wave (arachnoid fibrosis and loculation, spinal cord
tumor, suprasellar cyst, high venous pressure) favors the development
of hydrocephalus by reducing the dampening efficacy of the system.
Any factor that increases the pressure wave (any pulsating mass in the
CSF spaces) may also compromise the equilibrium if the compliance
reaches its limit, as was demonstrated experimentally (27).
CSF Absorption
According to the most generally accepted model, CSF absorption
occurs mainly through the arachnoid villi, evaginations of the suba-
rachnoid space into the lumen of the dural and venous sinuses. This
model proposes that the villi behave as one-way valves that have an
opening pressure of between 20 and 50 mm of water; drainage is deter-
mined by hydrostatic pressure differences between CSF and the venous
sinuses (13,14,17). However, several authors have suggested that
approximately half of the CSF may drain via other routes. As the CSF
space and extracellular spaces are in continuity via the ependymal and
pial surfaces and the perivascular spaces, a significant part of the CSF
is presumed to be absorbed by the intracerebral veins, possibly even
as the primary mode of absorption (28–31). The lymphatic system
probably plays a significant role, particularly through the cribriform
plate into the lymphatic vessels located in the nasal submucosa (32–
34), in the perineural spaces (13,35–37), and through the optic nerves
into the orbital lymphatics (38). The anatomical organization of the
dural clefts described where cortical veins join the sagittal and cavern-
ous sinuses, suggests that they could be another pathway of egress of
CSF into the dural sinuses (39,40). Still others contend that the brain,
rather than absorbing CSF, acts as a conduit for fluid to move from
the ventricles into the subarachnoid spaces or into the prelymphatic
channels of the blood vessels (41). CSF may nourish cerebral vessels
through pathways in the adventitia that may be analogous to systemic
vasa vasorum. Another possible route of CSF absorption is through
the epithelium of the choroid plexus to the fenestrated capillaries (4)
and ultimately to the Galenic venous system. Oi and Di Rocco refer
to these routes as the “minor pathways” of CSF absorption and to the
classic route via the subarachnoid spaces and arachnoid granulations
as the “major pathway” (42). Moreover, they and others suggest that
CSF absorption in neonates and infants is predominantly via the so-called
minor pathways and that the major pathway only becomes an important
route of CSF absorption during the middle or end of the first postnatal
year (33,42). This proposal is supported by the observation that third
ventriculostomy is less effective in neonates and young infants than
in older children and adults and becomes progressively more effective
with maturation (42). Others suggest that the “minor pathways” are
recruited in neonates and infants only as auxiliary mechanisms when
intracranial pressures are high (arachnoid villi and granulations are
not formed in neonates and are unlikely to be involved in CSF resorp-
tion) (33,42). It is likely that many or all of the mechanisms described
above function in CSF absorption, some as primary pathways and oth-
ers as alternate pathways. It is also likely that all of these pathways are
involved in the pathophysiology of hydrocephalus when drainage of
CSF through them becomes impaired.
Barkovich_Chap08.indd 810
MECHANISMS OF HYDROCEPHALUS
Classical Model: Obstructive Hydrocephalus
In this concept, hydrocephalus results from an imbalance between CSF
production and absorption. The rate of CSF production tends to be
fairly constant within the brain and, with the exception of hydrocepha-
lus secondary to choroid plexus papillomas, overproduction of CSF is
not a cause of hydrocephalus. (Some authors suggest that diffuse villous
hyperplasia is a very rare cause of hydrocephalus secondary to over-
production (43–45); others claim that these cases represent multifocal
choroid plexus papillomas (46); if choroid plexus hyperplasia exists, it
is very rare and will not be discussed further in this text.) Therefore,
hydrocephalus is almost always the result of impaired absorption of
CSF. The diminished absorption may result from a blockage of CSF
flow within the ventricular system, the cisterna magna, the basilar cis-
terns, or the cerebral convexities. Alternatively, diminished absorption
may result from blockage of the arachnoid villi or the lymphatic chan-
nels associated with the cranial nerves, spinal nerves, and adventitia of
the cerebral vessels. As the intracranial pressure increases, CSF may be
absorbed through the arachnoid membrane, the stroma of the choroid
plexus, or may pass through the extracellular space of the cortical man-
tle to reach the medullary veins or the brain surface (transependymal
absorption of CSF) (13,36,47). Because these new absorption path-
ways open at increased pressure, a new equilibrium can be established
between CSF production and absorption at the higher intracranial
pressure. This situation is referred to as compensated hydrocephalus.
Stenotic or obstructive changes in small blood vessels in the com-
pressed periventricular white matter of hydrocephalic patients cause
neuronal and astrocytic swelling in the deep gray matter and spongy,
atrophic changes in the white matter of the cerebral hemisphere
(46,48–51). The blood flow and cerebral metabolic rate, as measured
by uptake of 18F-fluorodeoxyglucose on positron emission tomogra-
phy, are reduced in the periventricular white matter in hydrocephalic
infants (52). Blood flow is particularly affected in the distribution of
the anterior cerebral arteries, leading to ischemic injury of the basal
forebrain and medial cerebral hemispheres (53). Moreover, the cilia
that normally cover the ependymal surface of the ventricular walls
disappear in hydrocephalic states (54), ependymal cells in the wall of
the ventricle stretch and degenerate (46), the choroid plexuses become
fibrotic (48), and the septum pellucidum undergoes fenestration (48).
Greitz Model: Communicating Hydrocephalus
As mentioned above, an interesting new model of CSF dynamics and
the development of hydrocephalus has been proposed in a series of
articles by Greitz et al. (25,26,30,31,55,56). CSF pulsations have been
observed from the early days of neuroradiology (57), and have been
explained by the transmission of pulsations from intracranial arteries.
These arterial pulsations, occurring in a rigid skull that is filled almost
entirely with incompressible water, transmit blood through capillary
beds and toward the venous sinuses while, at the same time, displacing
some CSF into the spinal subarachnoid spaces, which is encompassed
by more elastic, distensible dura that expands to absorb and dampen
the pressure waves (see Section “CSF Circulation” above). The CSF dis-
placement is greatest at the craniovertebral junction, where it has been
measured at 6 mm per stroke in normal individuals, and at 3 mm in
communicating hydrocephalus (15). If the spinal dural sac does not
expand to dampen the CSF pressure wave (because, e.g., the foramen
magnum is obstructed or the spinal meninges have lost their elasticity),
or if the dampening through the vascular bed is prevented by high
venous pressure, or if the intraventricular choroid plexus pulsations
5/6/2011 10:25:59 PM

are increased, the force of the pulsating arteries is exerted upon the
brain parenchyma. This model leads to three main conclusions:
■ Even if nothing opposes the bulk flow of CSF, hydrocephalus may
develop because the craniospinal meningeal compliance is lost
(communicating hydrocephalus).
■ Even in cases with obstruction of the bulk flow pathway (obstructive
hydrocephalus), part of the problem comes from the fact that the
obstruction restricts the compliance of the system by not allowing
the pressure waves to reach the spinal dura.
■ Even with no obstruction in the ventricles, increased pulsation
waves within the ventricles (e.g., from choroid plexus papilloma or
choroid plexus hyperplasia) may overcome the compliance of the
system and generate hydrocephalus. (Such a situation has been cre-
ated experimentally (27).)
Thus, normal volume and elasticity of the spinal dura are needed for
proper function of the system in older children and adults. As men-
tioned above, the area of the spinal meninges is small in relation to the
volume of the cranium during the first months of life. From the point
of view of compliance, however, the increased elasticity of the skull due
to open sutures and fontanelles compensates for small size of the spinal
canal. The situation in fetuses is not well understood, as the situation is
compounded by high pressure of the surrounding amniotic fluid and
by a blood circulatory system that is different from the postnatal one.
While the bulk flow cannot be detected by noninvasive means,
MR phase-contrast imaging has the ability to evaluate the direction
and velocity of CSF flow. Quantitative data in healthy adult individu-
als have been measured (25). Assuming a CBF of 60 mL/100 g/min,
and a heart rate of 60 beats/min, the volume of the arterial stroke is
15 mL for a 1500 g brain. Of this, 90% flows directly through the vas-
cular bed to the veins, and the expansion of the intracranial arteries
corresponds to 1.5 mL (the sum of the systolic stroke volume of CSF
displaced at the foramen magnum—0.8 mL—and of blood displaced
into the venous sinuses—0.7 mL). The systolic expansion of the brain
capillaries is minimal (0.03 mL, only 2% of the arterial expansion) but
real; it is transmitted inwards to the ventricles, and in the aqueduct,
the displaced volume of CSF is correspondingly 0.03 mL per beat (25).
Given the small section of the aqueduct, this results in a measurable
CSF systolic velocity peak. In another report, the MR-measured sys-
tolic peak aqueductal CSF velocity has been evaluated at 3.4 to 4.1 cm/s
in normal volunteers, corresponding to a mean CSF flow of 0.02 to
0.03 mL/s (58). Using a similar MR phase-contrast imaging method
in volunteers also, another group could measure the CSF production
rate and found 0.305 mL/min ± 0.145 (equivalent to about 430 mL/d),
which is in good agreement with the data obtained with more invasive
methods (58). Using these basic concepts, Greitz et al. have reconsid-
ered the way of approaching hydrocephalus and have devised a new
model that differs from the traditional one. These concepts may be use-
ful in understanding cases of hydrocephalus that cannot be explained
TABLE 8-1 Classification of Obstructive Hydrocephalus
Timing Vasc. Bed Ventr. Size
Hyper-acute Sudden ↓ =
Progressive Weeks/months = ↑
Chronic Years = ↑
Arrested Years = ↑
Barkovich_Chap08.indd 811
Chapter 8 • Hydrocephalus 811
by the traditional models. Examples of the utility of these concepts are
discussed in the section on “Normal Pressure Hydrocephalus.”
CLASSIFICATION OF HYDROCEPHALUS
Although the pathogenesis of hydrocephalus is complex, it is useful
from a clinical and therapeutic point of view to differentiate between
obstructive and communicating hydrocephalus (Table 8-1).
Obstructive Hydrocephalus
Hyperacute obstructive hydrocephalus develops in hours from a sud-
den occlusion of the CSF pathways, with rapid increase of the intra-
ventricular pressure. This may occur after severe head trauma, shunt
obstruction or, rarely, granulomatous meningitis. The brain paren-
chyma has no time to accommodate the increase in ventricular pressure
by loss of tissue, so the ventricles are rounded but minimally increased
in size, making morphological diagnosis difficult. As neither the paren-
chyma nor the CSF is instantaneously compressible, the only part of
the brain in which volume is lost is the vascular bed. This hypoperfu-
sion is worsened by the fact that any expansion of the brain, even slight,
may compress superficial draining veins against the calvarium, while
the deep veins are compressed by high intraventricular pressure, result-
ing in further increase of parenchymal and intracranial pressure. This
vicious circle leads to absence of perfusion of the brain. Only tapping
the ventricles allows relief of the ventricular tamponade.
Progressively acute obstructive hydrocephalus typically develops over
weeks or months, usually from the growth of an intraventricular tumor.
CSF outflow is progressively impeded, due to impaired bulk flow, so the
ventricles progressively enlarge. If the head enlarges as well, the cere-
bral volume may be partly preserved; if not, the ventricular enlarge-
ment will be at least partially due to loss of brain tissue, with the degree
of tissue loss depending on the age of the patient and on the speed of
onset of hydrocephalus. The increased ventricular pressure results in
compression of the subependymal veins; this, in turn, prevents the nor-
mal absorption of interstitial fluid from the deep white matter, result-
ing in development of periventricular interstitial edema and (often)
parenchymal injury, but does not reflect any increased absorption by
the parenchyma (50). If not treated, progressively acute hydrocephalus
will cause brain herniation and/or circulatory arrest.
Chronic obstructive hydrocephalus can be a result of many causes,
such as chronic aqueductal stenosis or leptomeningitis. This chronic
condition causes only mild clinical signs of increased intracranial
pressure (i.e., headaches) and no periventricular interstitial edema,
as the secretion of CSF is presumably compensated by sufficient fluid
absorption via capillaries. However, the ventricles and, typically, the
skull slowly enlarge and the brain slowly loses volume over the years.
An acute decompensation may occur, after trauma for example. The
terms “arrested” and “compensated” hydrocephalus are used when no
Interst. Edema Skull Outcome
No = Arrest
Yes =/↑ Decompensates
No ↑ Slow ↑
No ↑/= Stable?
5/6/2011 10:25:59 PM
 812 Pediatric Neuroimaging
progression can be detected clinically or by imaging over long periods
of time; this seems to be an uncommon occurence.
Communicating Hydrocephalus
The term communicating hydrocephalus describes cases in which no
clear obstruction to CSF flow can be demonstrated; no morphologic
finding explains the development of progressive ventricular dilation with
clinical symptoms of hydrocephalus and good response to CSF diver-
sion. Commonly assumed to be related to obstruction or fibrosis of the
arachnoid granulations, it is better explained by the Greitz model intro-
duced in Section “Greitz Model: Communicating Hydrocephalus” (25).
As explained earlier, free movement of the CSF is impaired by arachnoid
pathology (e.g., fibrosis from a previous history of meningeal infection
or bleed, or brain trauma) or impaired elasticity of the spinal dura. As
a result, the propagation of pulse pressure waves through the CSF is
impaired, and their force is exerted against the brain tissue. It is tempt-
ing to extend this concept to other disorders such as segmental restric-
tion of the meningeal space (significant spinal degenerative changes in
adults, achondroplasia or mucopolysaccharidoses in children, spinal
cord tumors) or the Chiari I deformity where the obstruction of the
foramen magnum may be considered a CSF pathway obstruction that
causes a loss of compliance. This new concept brings into question the
use of the term “normal” pressure hydrocephalus, as many physiologi-
cal studies have shown in adults that the amplitude of the arterial-CSF
pulsation pressure wave (if not the mean pressure) is characteristically
increased (59–62).
CLINICAL ASPECTS OF HYDROCEPHALUS
The most important and most consistent clinical finding in pediatric
hydrocephalus is an excessive rate of head growth. A large head circum-
ference in a child is not, in itself, of concern (it actually allows some
preservation of brain volume). Serial head circumference measure-
ments showing an excessive rate of head growth as compared with nor-
mal standards, however, should raise clinical suspicion of developing
hydrocephalus. Several factors influence the clinical course of hydro-
cephalus. The most important of these are the age of the patient at the
onset of hydrocephalus and the duration of the disease (younger age
and longer duration imply worse prognoses). The rate of increase of
intracranial pressure and the presence of associated structural lesions
are also associated with poor prognosis (63,64).
Fetal Hydrocephalus
Ventriculomegaly is a common indication for fetal MRI or level 3
fetal sonograms (65–67). Fetuses with small heads are unlikely to have
hydrocephalus. However, fetal hydrocephalus is not always associated
with macrocephaly in utero and, thus, normocephalic fetuses may have
hydrocephalus. Associated malformations of the central nervous system
(CNS) or non-CNS viscera are identified in 41% to 78% of fetuses or
neonates in whom hydrocephalus is detected (68,69). The most com-
mon of these are myelomeningoceles, aqueductal stenosis, and callosal
anomalies. Excluding myelomeningoceles, Garel et al. (69) found brain
abnormalities in 44% of fetuses with ventriculomegaly, with many
causes including callosal anomalies (9.5%), ischemic injury (7%), and
posterior fossa anomalies (7%). If treated in utero (by cephalocentesis
or ventriculo-amniotic shunt), only 38% to 55% of survivors will have
normal cognitive function (68,70) and average survival is a little more
than 4 years. It is not known whether the associated brain damage is
the result of the presence of hydrocephalus in the developing brain,
whether a prenatal injury may have caused both the hydrocephalus
Barkovich_Chap08.indd 812
and the associated malformation, or whether the hydrocephalus may
merely be one component of a malformation syndrome.
Postnatal Hydrocephalus
Prior to the age of 2 years, hydrocephalus is almost always accompa-
nied by progressive head enlargement. The Chiari II malformation,
aqueductal stenosis, and aqueductal gliosis account for 80% of hydro-
cephalus in this age group, and 60% of all hydrocephalus regardless
of age (48,71). Other relatively common causes of hydrocephalus in
infancy include intrauterine, perinatal, and neonatal infection, and
perinatal/neonatal hemorrhage. Rare causes of hydrocephalus include
other malformations, congenital midline tumors, choroid plexus pap-
illomas, and vein of Galen malformations (48).
In infants with hydrocephalus, the head tends to grow at an abnor-
mal rate, producing macrocephaly within the first few months of life.
The forehead is disproportionately large (frontal bossing), the skull is
thin, the sutures are separated, the anterior fontanelle is tense, and the
scalp veins are dilated. Ocular disturbances are frequent and include
paralysis of upward gaze, abducens nerve paresis, nystagmus, ptosis, and
diminished pupillary light response. Spasticity of the lower extremities
is common, resulting from disproportionate stretching and distortion
of the corticospinal axons that arise from the medial parts (leg area) of
the motor cortex. These axons have a longer distance to travel around,
and are more directly exposed to pressure from, the dilated lateral ven-
tricle than the more lateral corticospinal and corticobulbar axons that
supply the upper extremities and the face (48,72,73).
Children older than 2 years tend to present with neurologic symp-
toms resulting from increased intracranial pressure or with focal
deficits referable to the primary lesion; these symptoms occur prior
to significant changes in the head size. The most common causes of
hydrocephalus in this age group are posterior fossa neoplasms (see
Chapter 7) and obstruction of the aqueduct. Although each of the
specific lesions that result in hydrocephalus have some special fea-
tures, certain clinical characteristics are common to all hydrocephalic
patients. In most patients, the increased intracranial pressure results
in an early morning headache that improves after being upright for a
while (allowing CSF to re-equilibrate). Papilledema and strabismus are
frequent. Pyramidal tract signs are more marked in the lower extremi-
ties, as described above. Hypothalamic-pituitary dysfunction is prob-
ably caused by compression of the hypothalamus, pituitary stalk, and
pituitary gland by the enlarged anterior recesses of the third ventricle;
affected patients may present with small stature, obesity, gigantism,
amenorrhea or menstrual irregularities, hypothyroidism, or diabetes
insipidus. Perceptual and motor deficits and visual spatial disorgani-
zation result from stretched axons of the parietal and occipital lobes
around the dilated posterior horns of lateral ventricles (48,72,73). Cog-
nitive disorders may also result from compression of the hippocampi
and stretching of the fornices and hippocampal commissure.
RADIOLOGIC DIAGNOSIS
OF HYDROCEPHALUS
The Tools
Magnetic Resonance Imaging
MRI is the best tool to investigate hydrocephalus, its causes, and its
consequences. The imaging protocol must be adapted to the patient,
but thin section sagittal T1, T2FSE, and FIESTA/CISS sequences show
the midline, while coronal T2 best shows the morphology of the lat-
eral ventricles (especially the temporal horns), and axial FLAIR shows
parenchymal lesions and interstitial edema (Fig. 8-1). Signal voids
5/6/2011 10:25:59 PM
 Chapter 8 • Hydrocephalus 813

FIG. 8-1. MRI for hydrocephalus. Normal images. A. Midline sagittal T1, thin sec-
tion (1.5 mm) image shows the commissures, septum pellucidum and fornix. Note
the anterior recesses of the third ventricle (chiasmatic recess in front of the chiasm
and infundibular recess behind) and posterior recesses (pineal recess below the pineal
gland and suprapineal recess above it). Also well seen are the midbrain with tectal plate
and aqueduct, brainstem, fourth ventricle and vermis, cisterna magna, basilar, interpe-
duncular and suprasellar cisterns. B. Midline sagittal T2, thin (3.0 mm) image shows
the same anatomical features. Note in addition the flow void through the aqueduct.
C. Coronal T2-weighted image through the ventricular bodies and temporal horns and
anterior hippocampi. Note the morphology of the third and lateral ventricles, especially
temporal horns and hippocampal commissure. D. Axial FLAIR image is excellent for
evaluation of the parenchyma, especially the periventricular white matter. E. High defi-
nition CISS/FIESTA (1.0 mm or less) image is optimal for depiction of the third ventri-
cle and its recesses, the aqueduct and fourth ventricle. Note the exquisite demonstration
of the membrane of Liliequist (black arrows) extending from the dorsum sellae to the
mamillary bodies. This sequence is not appropriate for demonstrating the flow voids.

Barkovich_Chap08.indd 813 5/6/2011 10:25:59 PM

 814 Pediatric Neuroimaging

due to rapid CSF flow are seen well on T2FSE sequences; these signal
voids can be useful to demonstrate patency of interventricular connec-
tions (foramina or aqueduct) (Fig. 8-1B) or a third ventriculostomy.
Remember, however, that although absence of a signal void suggests
foraminal occlusion, foraminal narrowing without occlusion increases
the velocity and accentuates the signal void. High-definition steady-
state (CISS/FIESTA) imaging better demonstrates morphology; steno-
sis of the aqueduct, cysts and abnormal intraventricular or arachnoid
membranes are seen much better than on conventional sequences
(Figs. 8-1E and 8-2A).
Contrast administration is useful initially to characterize the cause
of hydrocephalus (tumor tissue or infection) but is not useful for fol-
lowing the hydrocephalus itself. Some have safely used intracisternal
contrast (74), but it has failed to gain acceptance as the trend in brain
imaging now is toward minimal invasiveness. Magnetic susceptibility
T2* imaging may demonstrate blood and blood residue. Other MR
sequences are not generally useful in the initial work-up.
MR is not commonly used for follow-up imaging of hydrocepha-
lus, as the need for sedation in young children and the relatively lim-
ited access to MR have resulted in CT being the usual study of choice.
(As discussed in Chapter 1, a low dose CT technique, which does not
allow assessment of subtle parenchymal lesions, is safer for the pedi-
atric patient who will likely have many imaging exams during their
lifetime.) “Fast” MR-scanning (using single-shot, ultrafast imaging
sequences such as those used in fetal imaging) has been suggested as a
potentially useful sequence, as it alleviates the need for sedation/anes-
thesia and the repetitive exposure to significant ionizing radiation (75).
Although these heavily weighted T2 sequences are adequate for assess-
ing the ventricular/cisternal size and morphology, they have poor sen-
sitivity and specificity for parenchymal changes. For various reasons
(not easy to implement, limited diagnostic yield, lack of sensitivity/
specificity, limited access to MR, necessity to reset the magnetic pres-
sure valve), it has failed to gain wide acceptance.
Occasionally, hydrocephalus may be caused by, or associated with,
a spine lesion (tumor or malformation or syringohydromyelia) rather
than an intracranial one. The protocol for spinal MRI in these cases
should include sagittal T2 sequences of the whole spine; if needed, axial
T2, and sagittal T1 and possibly contrast-enhanced T1 sequences may
be acquired though any region of interest. Use of fat suppression allows
better recognition of soft tissue mass, fluid or blood.

FIG. 8-2. Evaluation of the CSF kinetics. A. Midline sagittal

T2-weighted image. Severe hydrocephalus with a prominent flow
void in the aqueduct. B. Cine phase-contrast imaging, systolic
phase (compare with the flow in the straight sinus). Superior
to inferior flow through the aqueduct, similar to the flow void
in (A), is shown by hyperintense signal. C. Cine phase-contrast
imaging, diastolic phase, shows inferior to superior flow as
hypointense signal.

Barkovich_Chap08.indd 814 5/6/2011 10:26:01 PM

 Chapter 8 • Hydrocephalus 815

MR techniques are also able to provide physiologic data on brain
metabolism (single- or multivoxel 1H MR spectroscopy) and brain
perfusion (by either arterial spin-labeling or dynamic susceptibility-
weighted contrast perfusion imaging, see Chapter 1). Qualitative CSF
flow is often demonstrated on routine MR sequences (76–78). On
routine spin-echo MR scans, dynamic CSF flow can be detected by
signal loss in areas of rapid or turbulent flow (76,77). By use of certain
techniques, such as gradient echo and FLAIR, rapidly moving CSF can
be made to appear bright while keeping the signal of stationary or
slowly flowing CSF dark; the patency of the aqueduct can be assessed
in this way (79). Special techniques that take advantage of the relative
change in phase angle of moving spins can be used to quantify the
flow of CSF through the foramina of Monro, aqueduct, foramen of
Magendie, or brainstem cisterns (Fig. 8-2B and C) (80–82). However
CSF motion is dependent on so many physiological factors—arterial
stroke (related to blood pressure, perfusion pressure), distal vascu-
lar compliance (vascular status, pO2, and pCO2), meningeal compli-
ance, CSF pressure, individual anatomy, etc.—that quantification in
individual patients is rarely useful; such measurements are only valid
when obtained from groups of subjects. Practically speaking, func-
tional methods are not useful for individual diagnoses and will not be
discussed in this chapter.
CT Scanning
Together with MRI, CT is the most commonly used modality to evalu-
ate hydrocephalus. It is fast and simple and data is easily reformatted in
multiple planes (Fig. 8-3). Periventricular interstitial edema is readily
apparent on CT, and subarachnoid blood may appear better on CT
than on MR. Mass effects responsible for the hydrocephalus are easily
recognized and contrast enhancement helps in the characterization of
the pathology. However, the diagnostic yield and the versatility of CT
are much less that those of MR, and CT can expose children to signifi-
cant doses of ionizing radiation (see Chapter 1). In our practices, initial
evaluation of the brain and CT is used for follow-up assessment only,
with implementation of a low-dose technique that limits evaluation
mostly to assessment of ventricular size (see Chapter 1).

FIG. 8-3. 3D-CT imaging. Nice demonstration of the ventricu-

lar and cisternal anatomy in the axial (A), sagittal (B), and coronal
(C) planes. Although not as sensitive and versatile as MR, modern
CT is a fast and efficient diagnostic tool, and it is commonly used
for screening or follow-up. Its main disadvantage is the radia-
tion dose delivered, especially concerning in children. In most
instances, a very low dose CT (see Chapter 1) is used to check
ventricular size.

Barkovich_Chap08.indd 815 5/6/2011 10:26:02 PM

 816 Pediatric Neuroimaging

Ultrasonography in children with elevated intracranial pressure. The maximum change

Head ultrasound is the primary modality of choice for the screening of
infants and fetuses suspected of having hydrocephalus. It is noninva-
sive, can be performed at the bedside, and gives a good evaluation of
the ventricular size and morphology. It is also sensitive (if not specific)
to parenchymal abnormalities and, when Doppler is used, can give an
efficient functional assessment of the vasculature. Its use, however, is
limited to the first months of life when the fontanelles are open, and
it does not give nearly as comprehensive a presurgical assessment of
hydrocephalus as MRI.
Monitoring of intracranial pressure is an important factor in
the differentiation of hydrocephalus from atrophy. New innovative
approaches with transfontanelle sonography may allow assessment of
intracranial pressure noninvasively. Taylor and Madsen (83) studied the
hemodynamic response to fontanelle compression in infants with ventric-
ulomegaly. These authors used Doppler sonography to determine resis-
tive indices in the anterior and middle cerebral arteries in premature
neonates who had suffered intracranial hemorrhage. Baseline resistive
indices without fontanelle compression did not correlate with intracra-
nial pressure. However, a statistically significant correlation was found
between the changes in resistive index during fontanelle compression
in resistive index was significantly higher in infants who subsequently
required shunting than in infants who did not (p = 0.001) (83). Thus,
the need for shunt placement may be determined by assessment of
resistive indices with and without fontanelle compression.
Fetal Diagnosis of Hydrocephalus
The prenatal diagnosis of hydrocephalus is currently made almost
exclusively by obstetrical sonography. In fact, the fetal sonogram shows
ventriculomegaly, not frank hydrocephalus, as many of the radiologic
signs of hydrocephalus (see next section) cannot be accurately deter-
mined by fetal sonography. The diagnosis of ventriculomegaly is made
if the fetal sonogram shows that the atrium of the lateral ventricle is
larger than 10 mm (66,84). Fetal MRI gives higher reproducibility and
provides better contrast, allowing a more precise measurement of the
ventricle (69) (Fig. 8-4). The measurement is best made on coronal
images parallel to the brainstem at the level of the choroid plexus (69)
(Fig. 8-4C). This measurement obviously does not determine whether
the ventriculomegaly is the result of increased intraventricular pressure
or destruction of periventricular brain tissue. Thus, some authors have

FIG. 8-4. Fetal ventriculomegaly, 26 weeks GA fetus. A. Sag-

ittal view shows normal midline structures. B and C. Axial
and coronal views show significant ventriculomegaly (14 and
17 mm largest atrial diameter; normal is <10 mm). Note that
the pericerebral spaces are still prominent, which is not con-
sistent with fetal hydrocephalus.

Barkovich_Chap08.indd 816 5/6/2011 10:26:03 PM


proposed use of the ratio between the atrial diameter and the biparietal
diameter (atrio-cerebral ratio); this value progressively decreases dur-
ing gestation (13.6% at 22 weeks, 8% at 38 weeks) (85). Whatever the
cause, the presence of fetal ventriculomegaly suggests that brain devel-
opment may be abnormal and is reason to do a more definitive fetal
neuroimaging study, either a more sophisticated sonogram or a fetal
MR scan (86). The diameter of the atrium of the fetal lateral ventricle
is of some prognostic significance. If the atrium measures larger than
10 mm, it is likely to be abnormal. Moreover, as the size of the ven-
tricle increases, the prognosis worsens (66,84). If the atrium measures
12 mm or less, outcome is normal in 93% (87). If the atrium measures
12.1 to 15 mm, the child has a 21% to 25% chance of developmen-
tal delay (66,87). If the atrium is larger than 15 mm, the chance of
developmental delay increases to greater than 40% (84,87). However,
male fetuses have bigger ventricles than do female fetuses (88); indeed,
some have suggested setting the upper limit of normal ventricular size
in boys at 12 mm instead of 10 mm (89). Therefore, the prognosis for
female fetuses is worse than that for male fetuses with a similar degree
of ventriculomegaly (88). The sizes of the third and fourth ventricles
can also be measured in the fetus; typically, they are measured from
transverse ultrasound images and from coronal (third ventricle) and
sagittal (fourth ventricle) MRI images. The diameter of the third ven-
tricle should be less than 3.5 mm on ultrasound and less than 4 mm on
MR, while the fourth ventricle diameter should be below 4.8 mm on
sonography and below 7 mm on MRI (90).
Differentiating between simple ventriculomegaly and hydrocepha-
lus is not always easy. Hydrocephalic fetuses often have normal head
size (Fig. 8-5A). However, the ventricular expansion effaces the typi-
cally prominent subarachnoid space that is normally observed over
the cerebral convexity in fetuses (Fig. 8-5B, compare with Fig. 8-4B),
especially before 32 weeks (this space progressively becomes filled by
the growing brain in the last weeks of gestation). The ventricular mor-
phology is also useful; in hydrocephalus the ventricles expand sym-
metrically and have a rounded configuration, especially the temporal
horns. If the hydrocephalus is not too severe, the cellular layering in the
cerebral mantle (ventricular zone, intermediate zone, subplate, cortex,
described in Chapter 2) is usually preserved; this layering commonly
FIG. 8-5. Fetal hydrocephalus, twin pregnancy, 21 weeks GA fetuses. A. This image shows the two fetal heads, one which is normal,
and the other hydrocephalic. Note that the head diameter is similar in both, but the pericerebral spaces of the hydrocephalic fetus are
effaced and the ventricles enlarged. B. Axial image of the hydrocephalic brain shows the pericerebral effacement.
Barkovich_Chap08.indd 817
Chapter 8 • Hydrocephalus 817
disappears in cases of destructive ventriculomegaly (91). Aqueductal
occlusion or stenosis is suspected when the posterior fossa appears
normal; this can usually be evaluated on sagittal views of the midbrain.
One complication of hydrocephalus in the fetus is the pressure erosion
of the septum pellucidum, which may be impossible to differentiate
from developmental absence of the septum. MRI is useful in exclud-
ing associated or causative malformations (holoprosencephaly, cal-
losal agenesis, CRASH syndrome, periventricular nodular heterotopia
[92,93]) and in demonstrating the cause of hydrocephalus (aqueductal
stenosis, hindbrain malformations, hemorrhages, infection, vein of
Galen malformation, torcular AV fistula, or rarely tumor).
Therefore, while sonography will likely remain the initial screening
modality for the prenatal detection of ventriculomegaly, MRI of the
fetus has been proved a useful adjunct to look for associated destructive
lesions or parenchymal malformations that may be associated with the
ventricular enlargement (69,85,86,90,92–94).
Postnatal Diagnosis of Hydrocephalus
The Ventricular System
The characteristic triad of hydrocephalus on imaging is the ventricu-
lar rounding and dilation, effacement of the pericerebral spaces over
the convexity, and (at least in children) macrocephaly. Normal lateral
ventricles are typically narrow, encroached upon by the heads of the
caudates, the thalami, the hippocampi, the calcarine sulci, and the
collateral sulci (Fig. 8-1). In hydrocephalus the ventricles are dilated
(Fig. 8-6) and present a rounded appearance on the axial and mostly
the coronal images, notably of the lateral angle (Fig. 8-6C–E). Several
features allow the differentiation between hydrocephalus and ex vacuo
ventriculomegaly in children (Table 8-2). For the frontal horns, bodies
and atria, widening and rounding are not really specific as they can be
similar in atrophy. The appearance of the temporal horns, however,
is quite specific: in atrophy, the roof and the floor of the horn remain
roughly parallel, whereas in hydrocephalus, the horn is rounded with
the choroidal fissure becoming enlarged and the hippocampus being
compressed and displaced inferomedially (95) (Fig. 8-6C and D). The
temporal horns dilate less than the bodies of the lateral ventricles in
5/6/2011 10:26:04 PM
 818 Pediatric Neuroimaging

FIG. 8-6. Triventricular hydrocephalus. Mass in the tectal plate with severe aqueductal
stenosis. A. Midline sagittal T2 image shows stretched corpus callosum and septum
pellucidum; the fornix (black arrows) appears separated from the splenium (compare
with Fig. 8-1A). Anterior third ventricular recesses are massively dilated, and the massa
intermedia effaced. A mass (m) compresses the aqueduct with dilation of its rostral
portion. Normal fourth ventricle with flow voids through its outlet (but not through
the aqueduct). The supratentorial cisterns are effaced. B. FIESTA thin imaging gives
precise depiction of the lesion of the dorsal midbrain and the location of narrowing of
the aqueduct. C. Anterior coronal T2 image shows dilated third and lateral ventricles.
Note the rounding of the temporal horns and the inferomedial compression of the hip-
pocampi. D. Posterior coronal T2 image show that the hippocampal commissure (black
arrows), normally transverse, is vertical and stretched by the enlarged ventricles (com-
pare with Fig. 8-1C). This explains why the posterior fornix seems separated from the
splenium on the midline sagittal cut in (A). E. Axial FLAIR image shows ventricular
dilation; note that the walls of the third ventricle at the level of the thalami are parallel.
The hyperintensity around the frontal and occipital horns is periventricular intersti-
tial edema, resulting from the increased intraventricular pressure that compresses the
subependymal veins, preventing fluid resorption and resulting in the accumulation of
interstitial fluid there.

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 Chapter 8 • Hydrocephalus 819

The ventricular index is the ratio of the ventricular diameter

TABLE 8-2 Imaging Characteristics of
Hydrocephalus (Given in
Order of Utility)
• Enlargement of the anterior or posterior recesses of the third
ventricle
• Downward convexity of the floor of the third ventricle (results
in decreased mamillopontine distance)
• Commensurate dilatation of the temporal horn with the lateral
ventricles
• Narrowing of the ventricular angle
• Widening of the frontal horn radius
• Effacement of cortical sulci
The first three are the most useful signs. Although many measurements can
be derived from these signs (e.g., spleniochiasmal distance, third ventricular
splenial distance, mamillocommissural distance [109]), these measurements
are rarely necessary.
patients with cerebral atrophy, and the hippocampus is not displaced
(96,97) (Fig. 8-7). The rather small size of the temporal lobes and, in
particular, the relatively small volume of white matter in the temporal
lobes, is almost certainly the reason for this (98). The presence of tem-
poral horn enlargement is not reliable in children with significant tem-
poral lobe atrophy, such as those with Down syndrome. The Sylvian
fissures should always be studied to assess the degree of temporal lobe atro-
phy before enlargement of the temporal horns is used to make a diagnosis
of hydrocephalus. If the Sylvian fissures are enlarged, or other evidence
of temporal lobe atrophy is present, enlarged temporal horns are not a
reliable sign of hydrocephalus.
at the frontal horns to the diameter of the brain at the same level
(Fig. 8-8A). The ventricular angle (Fig. 8-8C) measures the diver-
gence of the frontal horns. The angle between the anterior or superior
margins of the frontal horns at the level of the foramina of Monro is
diminished by concentric enlargement of the frontal horns (96). The
diminution of the angle may be appreciated on either axial or coronal
images. The concentric enlargement of the frontal horns eventually
causes them to become rounded, producing an appearance of “Mickey
Mouse ears” on axial scans. This concentric enlargement of the fron-
tal horns also causes enlargement of the so-called frontal horn radius
(Fig. 8-8D), which is determined by measuring the widest diameter
of the frontal horns taken at a 90° angle to the long axis of the frontal
horn (96). Ventricular rounding may be the single feature identified in
hyperacute hydrocephalus (within hours), when the volume of brain
tissue is still preserved, or even becomes swollen.
The dilation and tension of the lateral ventricles modifies the
appearance of the midline. As the lateral ventricles are more dilated
than the third ventricle, the latter is pushed downward. The corpus
callosum is stretched, thinned, arched upward, more than the columns
of the fornix, so that the distance between them increases (Fig. 8-6A);
the septum pellucidum is stretched and may even be torn (Fig. 8-6B).
The part of the fornix that forms the hippocampal commissure (the
psalterium), normally transverse, becomes verticalized on each side of
the midline (Fig. 8-6D, compare with Fig. 8-1C), which explains why
the posterior part of the fornix seems to be detached from the under-
surface of the splenium on the midline sagittal cut (Fig. 8-6A, compare
with Fig. 8-1A).
In rare cases of chronic severe obstructive hydrocephalus (usually
aqueductal stenosis) the ventricular anatomy may be compounded by
a ventricular diverticulum, inferior expansion of the medial wall of
the ventricular atrium through the choroid fissure behind the thala-
mus, into the supracerebellar and quadrigeminal cisterns (Fig. 8-9)
(99–102). The inferomedial atrium is affected because it is the thinnest
portion of the atrial wall and has the largest surface of the ventricular

FIG. 8-7. Brain atrophy in a 4-year-old child, with head circumference below the 25th percentile. A. The third and lateral ventricles
are wide with rounding of the lateral angles. However the temporal horns, although large, are small compared to the bodies of the
lateral ventricles; they retain their normal shape and the hippocampi are not displaced medially. The pericerebral spaces are patent,
notably the sylvian fissures. B. The corpus callosum is thin and the fornix appears lowered. However, the anterior third ventricular
recesses are not dilated, the lamina terminalis and the tuber cinereum are both concave. The pineal recess is prominent, but this may
be a normal variant. The suprasellar cisterns are prominent.

Barkovich_Chap08.indd 819 5/6/2011 10:26:06 PM

 820 Pediatric Neuroimaging

FIG. 8-8. Various methods in the radiographic diagnosis of hydrocepha-

lus. A. The ventricular index is the ratio of the ventricular diameter at the
level of the frontal horns to the diameter of the brain measured at the same
level. This is not a very sensitive or specific measurement in the detection of
hydrocephalus because the ventricular index is enlarged in cerebral atrophy
as well as in hydrocephalus. B. Enlargement of the temporal horns commen-
surately with the bodies of the lateral ventricles is probably the most sensi-
tive and reliable sign in the differentiation of hydrocephalus from atrophy.
There is significantly less dilatation of the temporal horns than the bodies of
the lateral ventricles in cerebral atrophy. C. The ventricular angle measures
the divergence of the frontal horn. In theory, the angle made by the anterior
or superior margins of the frontal horn at the level of the foramina of Monro
is diminished when concentric enlargement of the frontal horns occurs.
Compare the illustration of hydrocephalus (top) with that of atrophy (bot-
tom). The ventricular index in both instances is 39%; however, the ventricu-
lar angle is markedly reduced in hydrocephalus. D. The frontal horn radius
measures the widest diameter of the frontal horns taken at a 90° angle to‘ the
long axis of the frontal horn. The usefulness of this measurement is dem-
onstrated by the markedly increased frontal horn radius in the patient with
hydrocephalus (top) as opposed to the patient with atrophy (bottom). Over-
all, no one measurement is completely accurate in the diagnosis of hydro-
cephalus; the size of the temporal horns, ventricular angle, the frontal horn
radius, and the size of the ventricles as compared to the cortical sulci should
all be assessed. (This figure courtesy Dr. E, Ralph Heinz, Durham, NC.)

FIG. 8-9. Ventricular diverticulum. Axial FLAIR (A),

coronal T2 (B), and sagittal T2 (C) images show expan-
sion of the left lateral ventricle with the posteromedial
aspect of it evaginating through the choroidal fissure
into the ambient cistern behind the third ventricle. This
diverticulum (d) compresses the adjacent structures
such as the tectal plate and the top of the vermis. On
sagittal cuts it may be mistaken for an arachnoid cyst,
but the continuity with the ventricle is well shown on
axial and coronal planes.

Barkovich_Chap08.indd 820 5/6/2011 10:26:07 PM


system and, therefore, has the highest wall tension. If not treated, these
atrial diverticula can compress the mesencephalic tectum with the risk
of significant neurological complications; they can be mistaken for
arachnoid cysts in the region of the quadrigeminal cistern (Fig. 8-9C).
Coronal images are very helpful in the evaluation of these patients,
demonstrating the continuity of the trigone of the lateral ventricle with
the diverticulum (Fig. 8-9B).
The third ventricle is normally slit-like, mildly wider anteriorly
than posteriorly. It is enlarged both in atrophy and hydrocephalus, but
in hydrocephalus, it commonly develops rounded recesses: anteriorly
the chiasmal (supraoptic) and infundibular recesses and posteriorly the
suprapineal recess. This feature is best appreciated on sagittal images
(Figs. 8-6A, B and 8-10A), in which the anterior wall of the third ven-
tricle, normally concave anteriorly, becomes straightened, and the floor
of the third ventricle, usually concave downward, becomes straight-
ened or convex downward. The enlargement and inferior displacement
of these recesses can compress the infundibulum and diminish flow
within the hypothalamic-pituitary portal venous system, resulting in
hypothalamic-pituitary dysfunction (103). When the aqueduct or the
lumen or the outlets of the fourth ventricle are occluded, the tuber
cinereum is characteristically hugely dilated and bulges into the inter-
peduncular cistern (Figs. 8-6A, B and 8-10A) sometimes wrapping the
head of the basilar artery.
The suprapineal recess of the third ventricle is another common
site of ventricular herniation. The dilated recess expands into the pos-
terior incisural space, displacing the pineal gland inferiorly and, occa-
sionally, elevating the vein of Galen. When large, diverticula sometimes
extend inferiorly to compress the quadrigeminal plate, with conse-
quent shortening of the tectum in the rostral-caudal direction (104)
(Fig. 8-10A). The short, thick tectum should not be mistaken for a neo-
plasm; isointensity with normal brain tissue on T2/FLAIR images and
the absence of contrast enhancement exclude a tumor. The suprapineal
recess may also enlarge further posteriorly and compress the tectum
from the posterior direction, resulting in thinning of the tectum and
narrowing of the aqueduct (104).
FIG. 8-10. Aqueductal stenosis caused by a tectal mass. A. Sagittal T2-weighted image shows severe dilation of the third ventricular
recesses, especially the suprapineal recess (S). Dilation of this recess is not consistently seen (see Fig. 8-6A and B); it may depend
on a preexisting prominence of the recess (see Fig. 8-7B), or on the duration or early occurrence of hydrocephalus. B. The anterior
(hypothalamic) portion of the third ventricle presents a more rounded appearance that the more posterior interthalamic portion
(see Fig. 8-6E).
Barkovich_Chap08.indd 821
Chapter 8 • Hydrocephalus 821
The disproportionate enlargement of the recesses of the third ven-
tricle probably results from the relatively small resistance to expansion
provided by the thin hypothalamus and the cisterns that surround the
walls of the recesses. In contrast, the thalami, which form the walls of
the body of the third ventricle, provide a great deal more resistance to
expansion. It is important to note that even with a significant ventricu-
lar enlargement, the lateral walls of the third ventricle (i.e., the thalami)
remain parallel to each other (Fig. 8-6E); a rounded, circular third ven-
tricular lumen indicates the presence of a cyst, usually a suprasellar cyst
with intraventricular expansion (Fig. 8-11). The anterior (chiasmal and
infundibular) recesses seem to enlarge earlier and more severely than
the posterior (suprapineal) recess (105). The pulsating dilated anterior
third ventricle may be so huge that it erodes the dorsum sellae (Figs.
8-6A and 8-10A). On axial images, the dilated anterior recesses of the
third ventricle are best detected by noting that the third ventricle is
larger at the level of the optic chiasm (Fig. 8-10B) than at the level of
the middle of the ventricle. When hydrocephalus is severe and chronic,
the floor of the third ventricle may rupture spontaneously, creating an
internal drainage pathway that allows CSF to escape from the ventricu-
lar system into the subarachnoid space (106).
The cerebral aqueduct (of Sylvius) is a narrow craniocaudal curved
channel that connects the third and fourth ventricles. When narrowed
or occluded, obstructive hydrocephalus develops (aqueductal stenosis)
(Figs. 8-6 and 8-10). Occlusion may be intrinsic (ependymal, usually
postinflammatory) (Fig. 8-12), or extrinsic; the latter may be caused
by a tegmental or a tectal mass lesion (Figs. 8-6 and 8-10), or by an
extrinsic compression of the midbrain. It has been suggested that, in
some instances at least, aqueductal stenosis may result from compres-
sion by expanded temporal lobes (Fig. 8-13); in this situation, the
hydrocephalus may be primarily communicating in nature with aque-
ductal narrowing being a result, rather than a cause, of hydrocephalus
(104,107,108). In contradistinction, the aqueduct typically is dilated
when the fourth ventricle is obstructed, either due to the force exerted
by the CSF pressure or the mechanical effect of a mass expanding the
ventricular lumen (Fig. 8-14).
5/6/2011 10:26:08 PM
 822 Pediatric Neuroimaging

FIG. 8-11. Rounded appearance of the third ventricle; suprasellar cyst. A. Axial T2-weighted image shows the whole third ven-
tricle, including its interthalamic portion appearing rounded. B. Sagittal FIESTA image shows a huge suprasellar cyst displacing the
ventricular floor upward.

Due to the pulse amplitude of the CSF through the normal
aqueductal strictures, a striking flow void is normally observed there
on the sagittal midline T2 image, extending from the posterior third
ventricle to the superior fourth ventricle (76) (Fig. 8-1B). This flow
void disappears if the aqueduct is occluded (Figs. 8-6A and 8-12), but
its presence does not exclude a stenosis; flow velocity is increased, and
therefore signal intensity is decreased, as the aqueductal diameter is
diminished (Fig. 8-15). Flow is also increased in cases of decreased
meningeal compliance (e.g., in communicating hydrocephalus), even
when the aqueduct is patent or large, because the amplitude of the CSF
pulsations is increased (Figs. 8-2A and 8-16 to 8-18).
The fourth ventricle in hydrocephalus ranges from normal to
markedly dilated. It is normal in obstructive hydrocephalus when the
obstruction is located above it (Figs. 8-6, 8-10, 8-12, 8-13, and 8-15). It
is often normal in communicating hydrocephalus, as well (Fig. 8-18),
so it must be remembered that triventricular hydrocephalic dilation
does not necessary mean aqueductal stenosis! In most cases of commu-
nicating hydrocephalus, however, the fourth ventricle is mildly dilated

FIG. 8-12. Intrinsic aqueductal stenosis. A. Sagittal T2-weighted image in an infant with previous perinatal hemorrhage shows
narrowing of the middle portion of the aqueduct (white arrow). Aqueductal stenosis likely develops from ependymal inflammation
in the aqueduct. Note adherent recesses in the anterior third ventricle. Normal tectal plate. B. Sagittal FIESTA image in congenital
hydrocephalus shows obstruction of the aqueduct by a transverse occluding membrane or web (white arrow) in its caudal portion;
note widening of the rostral segment and normal tectal plate.

Barkovich_Chap08.indd 822 5/6/2011 10:26:09 PM


FIG. 8-13. Extrinsic aqueductal stenosis. A. Sagittal T2-weighted image in a patient with congenital hydrocephalus. Note huge dila-
tion of the lateral ventricles and to a lesser degree of the third ventricle. Small posterior fossa. The tectal plate appears compressed by
the expanded lateral ventricle. B. Axial T2. The bilateral ventricular distension results in bilateral compression of the midbrain and
deformity of the tectal plate, likely causing the aqueductal occlusion.
(Figs. 8-2, 8-16, and 8-17). Elevated CSF pressure tends to globally
decrease the volume of the brain, so that all ventricles and cisterns
are large (Fig. 8-19A); anatomy normalizes after shunt placement
(Fig. 8-19B). When both the fourth ventricle and the cisterna magna
are involved, a posterior rotation of the vermis may occur, which is not
a malformation but just hydrocephalus. Finally, the fourth ventricle
may be hugely dilated when both in-flow and out-flow are occluded,
especially if the lateral ventricles are decompressed (isolated fourth
ventricle, discussed in more detail in section Specific categories of
hydrocephalus of this chapter).
Appearances of the ventricular system usually define the type of
an obstructive hydrocephalus. These will be discussed in more detail in
FIG. 8-14. Aqueductal dilation. Large tumor (anaplastic ependymoma)
expanding the fourth ventricle and occluding its outlets results in hydro-
cephalus with a dilated aqueduct.
Barkovich_Chap08.indd 823
Chapter 8 • Hydrocephalus 823
Section “Specific Categories of Hydrocephalus,” dealing with specific
causes of hydrocephalus. Univentricular hydrocephalus occurs when
the obstruction sits at one foramen of Monro; the most common cause
is SEGA in tuberous sclerosis (see Chapter 6). The affected lateral
ventricle is dilated and rounded, and the septum pellucidum bulges
toward the normal side. Biventricular hydrocephalus is caused by
the obstruction of both foramina of Monro; common causes include
bilateral SEGA, colloid cyst of the third ventricular tela choroidea,
suprasellar cyst, or tumor. Triventricular hydrocephalus results from
when the occlusion is in the distal third ventricle, cerebral aqueduct,
or upper fourth ventricle; common causes are inflammatory aqueduc-
tal stenosis and midbrain/pineal, posterior third ventricular tumors.
Quadriventricular hydrocephalus is seen when the four ventricles are
dilated, either because a mass occupies the lower fourth ventricle or
because an obstructive process (typically infection) compromises the
fourth ventricular outlets. A variant of this (“pentaventricular hydro-
cephalus”) is seen when the outlets of the cisterna magna are occluded
(e.g., fibrous arachnoiditis of the posterior fossa cisterns) resulting in
a dilated cisterna magna (the “fifth ventricle”) together with the four
ventricles (Fig. 8-20)
The Cisterns
In hydrocephalus the cisterns may be effaced or dilated, depending on
the specific anatomic/hydrodynamic conditions in each patient. When
the obstruction is intraventricular the cisterns surrounding the por-
tion of the brain that is hydrocephalic tend to be effaced. In case of
aqueductal occlusion, the supratentorial cisterns are effaced, including
the suprasellar and ambient cisterns, the interhemispheric cistern, and
the subarachnoid space over the convexity (Figs. 8-6 and 8-10). In case
of fourth ventricular occlusion, the posterior fossa cisterns (cisterna
magna, cisterns around the brainstem and midbrain) are effaced, as
well (Fig. 8-20).
When the occlusion is cisternal, the cisterns located between the
occlusion and the ventricular outlets are dilated, the cisterns located
between the occlusion and the main absorption sites are effaced. How-
ever cisternal obstructions often result from diffuse arachnoid fibrosis
5/6/2011 10:26:10 PM
 824 Pediatric Neuroimaging

FIG. 8-15. Incomplete aqueductal stenosis. Midline sagittal T1 (A) and T2 (B) images show aqueductal stenosis; the T2-weighted
image demonstrates a striking signal void due to rapid flow. This doesn’t mean that the aqueduct is normal, but that the stricture
results in an increased CSF flow velocity, compatible with obstructive hydrocephalus.

with multiple occlusive arachnoid adhesions; the cisterns appear
multiloculated and sometimes frankly multicystic.
In case of chronic communicating hydrocephalus, all ventricles
and all cisterns tend to be dilated other than the subarachnoid spaces
over the cerebral convexities, which are effaced as a result of the expan-
sion of the lateral ventricles. Note that the sylvian fissures may be quite
dilated in this situation.
Finally, there are instances of hydrocephalus in which the
arachnoid spaces over the convexity are dilated; benign infantile
enlargement of subarachnoid spaces (also called external hydrocepha-
lus and extraventricular obstructive hydrocephalus [EVOH], see sec-
tion “Benign Enlargement of Subarachnoid Spaces in Infants” of this
chapter).
It is generally assumed that increased pressure within the ventric-
ular system causes compression of the brain tissue against the inner
table of the skull and consequent diminution of sulcal size. In pediatric
patients, however, this conclusion may be misleading because both atro-
phy and hydrocephalus can enlarge both the ventricles and sulci (110).

FIG. 8-16. Communicating hydrocephalus with accentuated signal void in widely patent aqueduct. A. Midline sagittal FIESTA
image shows a large aqueduct, mildly dilated fourth ventricle and, likely, arachnoid loculations in the suprasellar cistern (note the
mass effect upon the tuber cinereum and the pituitary stalk). B. Midline sagittal T2-weighted image shows prominent signal void
through the aqueduct, explained by increased pulsatility of the CSF through the aqueduct; restricted cisternal CSF circulation has
resulted in reduced compliance.

Barkovich_Chap08.indd 824 5/6/2011 10:26:11 PM

 Chapter 8 • Hydrocephalus 825

FIG. 8-17. Communicating hydrocephalus. Sagittal T2-weighted image

shows hugely prominent flow void through the aqueduct and the mildly
enlarged fourth ventricle, down to the cistern magna. According to the
Greitz model, this results from a decreased compliance of the theca.

Further complicating the radiologic assessment is the fact that the size
of the ventricles and subarachnoid spaces is quite variable over the first
2 years of life (111). In such a case, the final indicator of hydrocepha-
lus is enlargement of the ventricular system to a degree that is dispro-
portionate to the enlargement of the cortical sulci (98). The failure of
measurements such as the bicaudate index (112,113) and the Evans
ratio (114,115) to accurately differentiate hydrocephalus from atrophy
reflects this difficulty (116). Knowledge of the head size of the infant is
essential; a large or a too-rapidly enlarging head suggests hydrocepha-
lus whereas a small or diminishing head circumference is more com-
patible with atrophy.

FIG. 8-19. Cerebral deformities caused by hydrocephalus. Infant with

macrocephaly. A. At age of 2 months, midline sagittal T1 shows huge dila-
tion of the posterior fossa cisterns, particularly dorsal to the vermis; a
diagnosis of cystic malformation of the posterior fossa was discussed, but
finally a ventriculoperitoneal shunt was inserted in the lateral ventricle.
B. At age of 8 months, midline sagittal T1 shows normal brain anatomy.
Artifact is from the shunt valve.

Acute Parenchymal Changes

FIG. 8-18. Communicating hydrocephalus, Midline sagittal T2 image
shows communicating hydrocephalus with normal fourth ventricle. Note
prominent signal void in aqueduct and fourth ventricle.
Periventricular Interstitial Edema
Acute hydrocephalus is characterized by a periventricular band of low
density on CT, of low T1 and high T2/FLAIR signal on MR, which
reflects periventricular interstitial edema. Rather than an outflow of
fluid from the ventricle to the parenchyma (which in some way would
relieve the ventricular pressure) (47,48), this accumulation of fluid in
the periventricular white matter is felt to represent a failure of normal
parenchymal drainage, with consequent accumulation of fluid within
the interstitial spaces of the cerebrum (50). Current thought suggests
that free exchange of water between the ventricular cavities and the
extracellular spaces of the periventricular white matter is a normal

Barkovich_Chap08.indd 825 5/6/2011 10:26:12 PM

 826 Pediatric Neuroimaging
FIG. 8-20. Quadriventricular hydrocephalus associated with dilated
cistern magna, due to occluded cistern magna outlets.
process. Increased intraventricular pressure prevents the normal flow
of fluid toward the ventricles, and by compressing the subependymal
veins, prevents its absorption by the deep medullary venous channels.
Periventricular interstitial edema, therefore, is not seen in hyperacute
hydrocephalus (water cannot accumulate in a short period of time)
nor in chronic hydrocephalus (the ventricular pressure is not high
enough), but only in acute/subacute obstructive hydrocephalus such
as from an enlarging midline tumor. Periventricular interstitial edema,
therefore, is a complication of hydrocephalus, not a compensatory pro-
cess; it increases the volume of interstitial water, thus increasing the
mass effect upon, and causing damage to, the cerebral parenchyma
(50,51).
FIG. 8-21. Progressive/acute hydrocephalus due to posterior third ventricular tumor: effects on the parenchyma. A and
B. Axial and parasagittal CT. Markedly enlarged lateral ventricles with low attenuation of the periventricular white matter,
reflecting periventricular interstitial edema that results from the compression of the subependymal veins and consequent
lack of absorption of the interstitial fluid from the deep white matter. This parenchymal edema develops in addition to the
hydrocephalus.
Barkovich_Chap08.indd 826
On CT, interstitial edema appears as hypodensity in the periven-
tricular region; the ventricular margins may appear indistinct (Fig.
8-21A and B). On MR, the increase in water appears as a rim of T1
hypointensity and T2/FLAIR hyperintensity surrounding the lateral
ventricles (Fig. 8-21C and D). This rim may be difficult to appreciate
on heavily T2-weighted sequences, where the high signal intensity is
indistinguishable from the ventricular CSF; a proton density or FLAIR
image is much more sensitive. Diffusion-weighted images will reveal
increased water motion in the affected areas. Periventricular interstitial
edema in neonates and young infants may be masked by the normal
high water content of the immature brain.
Structural Parenchymal Changes
With the expansion of the ventricular surface, ependymal cells flat-
ten to maintain the lining but the stretching possibilities are limited
and the ependyma rapidly becomes disrupted, especially over the white
matter and the septum pellucidum (50). Choroid plexuses degener-
ate and become sclerotic, possibly with decreased secretory activity
(50). Multiple experimental and animal studies have demonstrated
that CBF is compromised in hydrocephalus, and may improve after
shunt placement (50,117,118); an evaluation of this phenomenon is
possible using MR technology (118). Impaired cerebral energy metab-
olism in experimental hydrocephalus has been demonstrated by 31P
MRS and 1H MRS (119), but the same group could not show similar
changes with 1H MRS in human hydrocephalus (120). Finally, some
white matter tracts are disrupted in acute hydrocephalus, as the ven-
tricular enlargement stretches the axons of the corpus callosum, the
septum pellucidum (which contains the limbic fibers that connect the
septal cortex to the cingulate cortex), the fornices, the hippocampal
commissure, the occipitofrontal, inferior longitudinal and corticospi-
nal tracts, and the optic radiations. Histologically this stretching has
been shown to be associated with axonal degeneration (50). MRI with
Diffusion Tensor Imaging (DTI) DTI has demonstrated microstruc-
tural changes reflecting compression of the tracts in the white matter
lateral to the ventricles (increased FA, increased longitudinal diffusiv-
ity but unchanged ADC) but not in the corpus callosum (decreased
5/6/2011 10:26:13 PM

FIG. 8-21. (Continued) C and D. Same case, MRI with axial FLAIR (C) and parasagittal T2 (D) images. The MR changes are similar to the CT changes,
but are more easily seen.
FA with increased ADC) (121). The changes reversed after treatment
(121).
Herniation
Increased supratentorial pressure with ventricular dilation may lead to
downward herniation of the mesial temporal structures along the free
edge of the tentorium toward the posterior fossa. In the process, the mid-
brain and the aqueduct are compressed, and the vessels in the adjacent
cisterns are stretched and compressed with resultant ischemia/infarction.
If increased pressure and hydrocephalus occurs in the posterior fossa,
those structures may herniate both upward through the tentorial incisura
and downward through the foramen magnum, with similar effects on the
midbrain and medulla; in addition, occlusion of the foramen magnum
results in a rapid, tamponade-like increase of intracranial pressure.
Circulatory Arrest
Because neither CSF nor brain parenchyma is compressible, the main
complication of a rapid increase of intraventricular/intracranial pres-
sure is vascular compression: the subependymal veins are compressed
within the ventricles, the cortical veins are compressed against the
cranium, and the engorged intracerebral capillaries are compressed in
between. The resulting increased capillary pressure causes brain edema
and consequent herniations; herniated tissue fills the tentorial incisura
and/or the foramen magnum, increasing the pressure even more and
leading to intracranial circulatory arrest as the perfusion pressure can-
not overcome the intracranial pressure. This situation may occur early,
in hyperacute hydrocephalus, or as a later, terminal complication of
progressive hydrocephalus. In hyperacute hydrocephalus, the ventricles
remain small but rounded. In both situations, the pericerebral spaces
are effaced, the parenchyma becomes edematous with loss of gray-
white matter contrast and, if administered, intravenous contrast pools
in the surface vessels but is not able to penetrate the parenchyma.
Chronic Parenchymal Changes
Although many of the acute changes noted in progressive hydrocephalus
(interstitial edema, demyelination, vascular compromise, axonal loss) are
reversible if shunting is performed in a timely fashion, some (ependy-
mal damage, gliosis, and abnormal myelination, including aberrant
Barkovich_Chap08.indd 827
Chapter 8 • Hydrocephalus 827
myelination of glial cells) may persist (50). Demyelination and axonal
degeneration have a similar MR appearance, a ribbon of bright T2/FLAIR
signal in the paraventricular white matter, sometimes accompanied by
loss of brain volume. Axonal degeneration however does not necessarily
imply neuronal loss (122) and damaged axons may regenerate, resulting
in return to a nearly normal appearance of the brain. This may be rather
spectacular in infants whose posterior cerebral mantle was compressed
to a few millimeters thick before shunting. Subependymal fibrosis and
sclerosis is usually found at autopsy (51); it may appear in young infants
as a hypointense ventricular wall interposed between the bright CSF and
bright periventricular white matter on T2-weighted images.
A rare late complication of chronic hydrocephalus is the local rup-
ture of the ventricular wall and the development of a CSF-filled cleft
that dissociates the hemispheric white matter (“ventricular disrup-
tion”). Similar changes have been reported in human fetal hydrocepha-
lus (pseudo-schizencephalies) (123).
SPECIFIC CATEGORIES
OF HYDROCEPHALUS
Hydrocephalus can be divided into major categories (Table 8-3). The
first is overproduction of CSF. Essentially all patients in this category
have choroid plexus papillomas, a rare tumor. A very small number
may have diffuse villous hyperplasia of the choroid plexus, mentioned
earlier in the chapter (43–45). The other major category is obstruc-
tion to normal CSF flow and absorption. This second category, termed
obstructive hydrocephalus, is generally divided into intraventricular
obstructive hydrocephalus caused by intraventricular obstruction of
CSF flow, and EVOH, in which there is cisternal obstruction to CSF
flow or diminished absorption of CSF. In addition to these categories,
the introduction of the Greitz model of CSF hydrodynamics based on
the arterial pulsatile pressure wave leads to the concept of purely com-
municating hydrocephalus, which assumes no physical obstacle to the
flow of CSF but an inability of the thecal sac to appropriately buffer the
systolic pressure waves.
In this section, various causes of hydrocephalus are presented. For
each type of hydrocephalus the most common causes, the mechanisms
by which they cause hydrocephalus, the specifics of the radiologic
5/6/2011 10:26:14 PM
 828 Pediatric Neuroimaging
TABLE 8-3 Categories of Hydrocephalus
A. Hydrocephalus secondary to overproduction of CSF
Choroid plexus papillomas
Diffuse villous hyperplasia of the choroid plexus
B. Hydrocephalus secondary to disturbance of CSF flow or absorption
Intraventricular obstructive hydrocephalus
EVOH
C. Hydrocephalus secondary to a loss of thecal compliance
“Normal-pressure” chronic communicating hydrocephalus
appearance of each cause, and the appearance of the associated
hydrocephalus will be discussed.
Hydrocephalus Resulting From Excessive
Formation of CSF (Choroid Plexus Papillomas)
Choroid plexus papillomas (see Chapter 7) (Fig. 8-22) are large aggre-
gations of choroidal fronds that are microscopically similar to normal
choroid plexus; these neoplasms can produce great quantities of CSF
(124,125). Choroid plexus papillomas account for 2% to 4% of child-
hood intracranial tumors. They usually present during infancy with
signs of increased intracranial pressure; occasionally, however, they are
found incidentally at postmortem examination. In the past, the pres-
ence of hydrocephalus was thought to be related to the mass effect
of the tumor, the presence of proteinaceous CSF, or intraventricular
hemorrhage with subsequent obstruction of CSF flow (obstructive
hydrocephalus). More recent preoperative and postoperative studies
have supported earlier suggestions that, at least in some cases, overse-
cretion of CSF by the papilloma produces hydrocephalus (124,125) by
overcoming the capacity of the system to absorb the fluid. It has also
FIG. 8-22. Hydrocephalus and choroid plexus papilloma. Axial (A) and coronal (B) postcontrast T1 images show a dense, avidly
enhancing mass in the left atrium. It does not obstruct the ventricle. The bilateral, symmetrical hydrocephalus is tentatively explained
by an overproduction of CSF, by the high density of protein usually found in the CSF, and by the increased pulsatility of the tumoral
choroid plexus.
Barkovich_Chap08.indd 828
been hypothesized that, by pulsating into the ventricular lumen, the
papilloma increases the amplitude of the CSF pressure, thus creating
communicating hydrocephalus (27). This theory could apply to hydro-
cephalus associated with choroid plexus hyperplasia as well (Fig. 8-23).
The imaging appearance of choroid plexus papillomas on CT and
MR was discussed and illustrated in Chapter 7. Briefly, the tumors are
frond-like, enhancing masses that are most commonly located in the
trigones of the lateral ventricles, with the bodies and temporal horns of
the lateral ventricles, the third ventricle, and the fourth ventricle being
the next most common sites. In contrast to adults, in whom the fourth
ventricle is the most common site for these tumors, fourth ventricu-
lar choroid plexus papillomas are very rare in the pediatric age group.
Resection of the tumor cures the hydrocephalus in most patients.
Hydrocephalus Secondary to Intraventricular
Obstruction of CSF Flow (Noncommunicating
Hydrocephalus)
Tumors and Cysts
Hydrocephalus may result from obstruction of any portion of the ven-
tricular system from the lateral ventricles to the fourth ventricular out-
flow foramina of Luschka and Magendie. The most common locations
for obstruction are the locations where the CSF pathway is narrowest:
the foramina of Monro, the posterior third ventricle, the aqueduct of
Sylvius, the fourth ventricle, and the fourth ventricular outflow foram-
ina. Tumors are the most common cause of such obstructions in the
pediatric age group.
Tumors and arachnoid cysts can grow into and obstruct the
foramina of Monro from a number of locations. Masses originating
in the lateral ventricles, such as choroid plexus tumors (Figs. 8-22 and
8-23), ependymomas, astrocytomas, or meningiomas, typically cause
obstruction at the foramina of Monro, whereas masses originating in
the third ventricle, such as astrocytomas, choroid plexus papillomas,
craniopharyngiomas, or pineal region tumors, can grow anteriorly
or superiorly to obstruct the foramina of Monro or posteriorly and
inferiorly to obstruct the cerebral aqueduct. Suprasellar tumors and
arachnoid cysts may occasionally grow upward to the foramina of
5/6/2011 10:26:14 PM

Monro, pushing the floor of the third ventricle superiorly (Fig. 8-24).
In children with tuberous sclerosis, giant cell tumors, which originate
adjacent to the foramina of Monro, often grow medially and obstruct
the foramina (see Chapters 6 and 7).
Obstruction of the Sylvian aqueduct is a common cause of hydro-
cephalus. The most common cause of obstruction at this level in chil-
dren is a tumor of the pineal region (see Chapter 7). Germ cell tumors
(germinoma, endodermal sinus tumor, embryonal cell carcinoma,
choriocarcinoma, teratoma), tumors of pineal origin (pineoblastoma,
pineocytoma in young adults mostly but also in teenagers), astrocy-
tomas (from the quadrigeminal plate, thalamus, or the tegmentum
of the midbrain), meningiomas (from the tentorium), supravermian
arachnoid cysts, or varices of the vein of Galen may all cause hydro-
cephalus from compression of the aqueduct (in vein of Galen arterio-
venous malformations, a component of increased venous pressure also
contributes to the hydrocephalus). CT identifies most of these lesions;
however, astrocytomas of the posterior third ventricle or arising in the
quadrigeminal plate are often subtle and difficult to identify on CT.
Both are easier to identify by MR because MR has inherently better
contrast resolution and the ability to image in the sagittal plane. Pos-
terior third ventricular masses are seen as discrete masses within the
ventricle, whereas tumors of the quadrigeminal plate are seen on MR as
bulbous tectal masses with prolonged T2 relaxation and poorly defined
margins (Fig. 8-6A, B, and E). Thus, MR is essential to differentiate
Barkovich_Chap08.indd 829
Chapter 8 • Hydrocephalus 829
FIG. 8-23. Hydrocephalus and choroid plexus hyper-
plasia. Sagittal T2 (A), axial FLAIR (B) and contrast-
enhanced coronal T1 (C) images show massive sym-
metrical enlargement of the ventricles, as well as of the
posterior fossa, suprasellar and anterior interhemispheric
cisterns; choroid plexuses are bilaterally hyperplastic. The
mechanism of the hydrocephalus is assumed to be an
overproduction of CSF.
benign aqueductal stenosis from stenosis secondary to a tumor in chil-
dren with aqueductal narrowing.
Children with tumors of the fourth ventricle and cerebellum fre-
quently have hydrocephalus by the time of presentation. The most
common posterior fossa neoplasms in the pediatric age group are
medulloblastomas, followed by cerebellar astrocytomas and ependymo-
mas (see Chapter 7). Imaging studies show the tumor in the fourth
ventricle, obstructing CSF flow directly (Figs. 8-14 and 8-25), or in
the cerebellum compressing the aqueduct and/or ventricle. In contrast
to cerebellar or ventricular tumors, hydrocephalus is uncommon in
pontine neoplasms.
Rarely, tumors of the spine and spinal cord (see Chapter 10) can cause
hydrocephalus. It is important to think about spinal tumors in all cases
of unexplained new onset hydrocephalus in children and to image their
spines accordingly. The cause of the hydrocephalus in these cases is not
obvious, but a number of hypotheses have been proposed. Among these
are (1) increased viscosity of CSF secondary to elevated CSF protein,
(2) obliteration of cisterna magna due to rostral extension of tumor,
(3) restriction of the thecal space and poor buffering of the systolic
pressure wave, and (4) blockage of spinal subarachnoid pathways of
CSF resorption. All of these mechanisms may have a role in some
cases, although the fact that Chiari I malformations (see Chapter 5)
are inconstantly associated with hydrocephalus makes mechanism (2)
rather unlikely. Because almost all reported cases have very high CSF
5/6/2011 10:26:15 PM
 830 Pediatric Neuroimaging
FIG. 8-24. Third ventricular cyst. A. Midline sagittal T1 image shows triventricular hydrocephalus suggesting aque-
ductal stenosis, although the aqueduct looks patent. B. Midline sagittal FIESTA shows a thin cyst wall (arrowheads),
indicating that a large CSF-filled cyst occupies most of the ventricle, sparing the anterior and posterior portions only. It
blocks CSF flow through the rostral end of the aqueduct and the foramina of Monro.
protein content, it is likely that dissemination of tumor through CSF
probably plays a role in the development of hydrocephalus in these
patients (126).
Aqueductal Stenosis
After the initial closure of the neural tube, its lumen has a relatively
uniform dimension throughout the neural axis. As the brain and spinal
cord mature, the lumen of the neural tube expands in some areas, such
as the cerebral ventricles, but not, or less, in others, such as the spinal
canal and Sylvian aqueduct. The lumen of the aqueduct decreases in
relative size beginning in the second month of fetal life, continuing until
birth (127). This relative narrowing appears to be caused by growth
pressures upon the aqueduct from adjacent mesencephalic structures.
Aqueductal stenosis can be developmental or acquired (128–130)
and is present in approximately 20% of patients with hydrocephalus. Its
incidence ranges from 0.5 to 1 per 1000 births with a recurrence rate in
FIG. 8-25. Fourth ventricular tumor. Midline sagittal postcontrast
T1 image shows triventricular hydrocephalus due to the large fourth ven-
tricular medulloblastoma.
Barkovich_Chap08.indd 830
siblings of 1% to 4.5% (131). The normal mean cross sectional area of
the aqueduct at birth is .5 mm2 with a range of 0.2 to 1.8 mm2 (132). In
aqueductal stenosis, the aqueduct is focally reduced in size; narrowing
generally occurs either at the level of the superior colliculi or at the inter-
collicular sulcus (132). In many instances, aqueductal stenosis is accom-
panied by branching of the aqueduct into dorsal and ventral channels;
the dorsal channel is often divided into a group of several ductules. This
condition has been termed aqueductal forking (133). Forking of the
aqueduct is often accompanied by fusion of the quadrigeminal bodies,
fusion of the third nerve nuclei, and molding or beaking of the tectum.
In some patients, the shape of the molded tectum is congruent with the
shape of the medial aspect of the adjacent temporal lobes, which are
markedly expanded by hydrocephalus. This congruency has motivated
some authors to postulate that aqueductal stenosis may be a secondary
phenomenon in some patients, resulting from communicating hydro-
cephalus and secondary compression of the quadrigeminal plate by the
dilated cerebral hemispheres (107,108,134) (Fig. 8-13).
The onset of symptoms is usually insidious; it may occur at any
time from birth to adulthood. As in all types of hydrocephalus, the
symptoms depend upon the cause of the hydrocephalus and the age of
the patient at the time of onset.
The CT appearance of benign aqueductal stenosis is dilatation of
the lateral and third ventricles with a normal sized fourth ventricle.
This appearance may be misleading, however, since the fourth ventricle
is normal in a significant percentage of patients with communicating
hydrocephalus. Moreover, as stated earlier, tectal tumors that are large
enough to obstruct the aqueduct can be missed on routine CT scans.
In all patients with suspected aqueductal stenosis the posterior third
ventricle should be carefully scrutinized for the presence of a mass; any
asymmetry of the posterior aspect of the third ventricle is indication for
an MR study to rule out the presence of a mass in the mesencephalon or
posterior thalamus. The MR findings in aqueductal stenosis are more
specific but are nonetheless quite variable. Patients with severe hydro-
cephalus generally have a stenosis in the proximal aqueduct, either at
the level of the superior colliculi or at the entrance to the aqueduct
immediately inferior to the posterior commissure (104). In patients
with mild hydrocephalus, the level of obstruction is more often in the
distal portion of the aqueduct. When the distal aqueduct is stenotic,
5/6/2011 10:26:15 PM

the dilated proximal aqueduct tends to displace the quadrigeminal
plate posteriorly. MR can nearly always differentiate benign aqueductal
stenosis from neoplastic aqueductal stenosis. Tectal and tegmental
gliomas that compress and obstruct the aqueduct appear as bulbous
masses that have high signal intensity on T2/FLAIR images (Fig. 8-6E).
These tumors uncommonly enhance (135).
A special case of distal aqueductal stenosis is the aqueductal web.
An aqueductal web is a thin membrane of brain tissue situated in the
distal aqueduct, restricting the flow of CSF into the fourth ventricle. It
has been suggested that the membrane may be the result of a small glial
occlusion of the caudal aqueduct that becomes an attenuated sheet
of tissue secondary to prolonged pressure from and dilatation of the
canal above it (136). The imaging appearance is characteristic, consist-
ing of a thin membrane of tissue separating a dilated aqueduct from
a normal-sized fourth ventricle (Fig. 8-12B). The importance of rec-
ognizing aqueductal webs is that a third ventriculostomy (see section
on “ Imaging of treated Hydrocephalus and Resulting Complications”)
is likely to result in complete resolution of the hydrocephalus. There
also exists a possibility of perforating the membrane via fiberoptic
ventriculoscopy (137–139), another means of obviating the need of an
indwelling shunt. Indeed, in some centers endoscopic aqueductoplasty
is now being performed for aqueductal stenosis of many causes with
promising results (139).
X-linked Hydrocephalus (HSAS, CRASH Syndrome)
X-linked hydrocephalus, also known as Bickers-Adams syndrome,
X-linked aqueductal stenosis and hereditary stenosis of the aqueduct
of Sylvius (HSAS), is a rare hereditary disorder with variable symptoms
that include mental retardation, hydrocephalus secondary to aqueduc-
tal stenosis, spasticity of the lower extremities, and clasped, adducted
thumbs (140). The disorder is caused by mutation of the L1CAM gene
that has been localized to Xq28 (141,142). Identification of this disor-
der is important, not only because of the potential for future siblings
being similarly affected, but also because affected patients have poor
neurological outcome despite early shunting (143,144). This complex
malformation is allelic with (has the same chromosomal location as)
the so-called MASA syndrome, which consists of mental retardation,
aphasia, shuffling gait, and adducted thumbs (145). Some affected
FIG. 8-26. CRASH syndrome, formerly known as X-linked hydrocephalus. Fetal T2-weighted images, sagittal (A) and
coronal (B), show severe ventricular dilatation, thin cerebral mantle, absent or extremely hypoplastic corpus callosum,
compressed aqueduct, and small posterior fossa. The syndrome is related to a developmental failure of the axons to
fasciculate; as a consequence, the white matter is extremely hypoplastic. Hydrocephalus still may develop due to com-
pression of the midbrain.
Barkovich_Chap08.indd 831
Chapter 8 • Hydrocephalus 831
patients have Hirschsprung disease, as well, while others may not have
hydrocephalus (146). Because the malformation is so complex, and
because hydrocephalus seems to be only one small part of the disorder,
Fransen et al. (147) have suggested that the disorder be renamed the
CRASH syndrome (corpus callosum hypoplasia, retardation, adducted
thumbs, spastic paraparesis, and hydrocephalus) and others have sug-
gested that L1CAM should be investigated in any X-linked disorder
associated with corpus callosum anomalies (146). As with many genetic
disorders, the site of mutation within the L1 protein correlates with the
severity of the disease (148,149).
Pathologic studies show that, in addition to hydrocephalus, affected
patients have malformations of cortical development (see Chap-
ter 5) with poor differentiation and maturation of cortical neurons
being identified on histologic examination of the brain (143,144). Of
interest, some authors have suggested that the aqueduct is narrowed by
compression and is not primarily stenotic (150,151). Other pathologic
features include absence or diminution of the size of the corticospinal
tracts, fusion of the thalami, fusion of the colliculi, and absence of the
septum pellucidum. The corpus callosum is typically small and may be
absent (46,152) (see Chapter 5).
Very few reports of MR studies in X-linked hydrocephalus have
been published. The only series of patients with this disorder indicates
that affected patients have enlargement of the massa intermedia (thal-
amic fusion), abnormal flattening of the mesencephalic tectum, a small
brainstem, and diffuse hypoplasia of cerebral white matter. Interest-
ingly, according to this report, the Sylvian aqueduct is usually patent
(153). Others have reported similar findings of large lateral ventricles,
hypoplastic cerebral white matter, thin cerebral cortex with abnormal
sulcation, fused thalami, and hypoplasia/hypogenesis/agenesis of the
corpus callosum. The authors have seen very few cases of X-linked
hydrocephalus and, in those cases, the findings were similar (Figs. 8-26
and 8-27).
Aqueductal Gliosis
Aqueductal gliosis is a postinflammatory process that is usually second-
ary to a perinatal infection or hemorrhage (128,133,154). It is becoming
more prevalent as newborns with bacterial meningitis or intracra-
nial hemorrhage survive at increasing rates. As in benign aqueductal
5/6/2011 10:26:16 PM
 832 Pediatric Neuroimaging
FIG. 8-27. CRASH syndrome, formerly known as X-linked hydrocephalus, in an older child. A. Midline sagittal T1. Small, dysmor-
phic brainstem, with a narrow aqueduct. The lateral ventricles are too large, and the corpus callosum (arrows) is thin and incom-
pletely formed. B. Coronal T1. The thalami (white arrowheads) are small and incompletely separated. The volume of cerebral white
matter is markedly diminished and the cortex has an abnormal gyral pattern with too many sulci that are too shallow.
stenosis, the onset of symptoms, which are those of hydrocephalus,
is insidious. The ependymal lining of the aqueduct is destroyed and
marked fibrillary gliosis of adjacent tissue is evident at autopsy.
On imaging studies, differentiation of aqueductal stenosis from
aqueductal gliosis is not possible. The appearance of the two entities is
identical on ultrasound, MR, and CT.
Congenital Anomalies
Among congenital malformations of the brain, two anomalies are, by
far, the most common causes of hydrocephalus. The more common
of these, the Chiari II malformation, has been extensively discussed
in Chapter 5 (Section “Chiari II Malformations”) and will therefore
be covered only briefly in this section. The Chiari II malformation
accounts for approximately 40% of all hydrocephalus in children (71).
Although there is still some dispute as to the cause of hydrocephalus
in these patients, the most generally accepted theory is that of Russell
(133). Russell demonstrated that adequate flow of CSF exists between
the ventricles and the spinal canal in patients with Chiari II malfor-
mations, but that the connection between the lumbar subarachnoid
space and the subarachnoid space over the cerebral convexities is poor.
The implication is that disturbance in CSF flow is most likely the result
of the abnormal location of the exit foramina of the fourth ventricle
below the foramen magnum, within the cervical spinal canal. Since the
spinal canal absorbs much less CSF, hydrocephalus develops. Recent
experience showing improvement in both posterior fossa herniation
and in the degree of fetal ventriculomegaly after fetal myelomeningo-
cele repair does not contradict this theory (155,156).
It is an important clinical concept that patients with the myelom-
eningocele/Chiari II malformation who develop occipital headaches
at night probably have a shunt malfunction. Fatal shunt malfunctions
may result in brainstem compression and consequent apneic spells.
Symptoms of brainstem compression in patients with the Chiari II
malformation are often interpreted as resulting from compression of
the medulla by the neural arches of C-1 and C-2 or by the foramen
magnum. These patients may be subjected to unnecessary decompres-
sions of the foramen magnum and C-1 and C-2 instead of adjustment
or replacement of the ventriculo-peritoneal shunt. It is important to
Barkovich_Chap08.indd 832
recognize that the fourth ventricle is normally a thin vertical slit in the
Chiari II malformation (see Figs. 5-162 and 5–163). The presence of a
normal-appearing or enlarged fourth ventricle in these patients sug-
gests a shunt malfunction or an isolated fourth ventricle that needs
CSF diversion (see Fig. 5-165).
Hydrocephalus is present in 70% to 80% of patients with the
Dandy-Walker malformation (see Chapter 5, Section “Overview of
Midbrain and Hindbrain Development”) (157,158). It is also common
in children with cobblestone cortex disorders (Chapter 5, Section Mal-
formations of cortical development) and rhombencephalosynapsis
(Chapter 5, Section “Classification of Midbrain-Hindbrain Malforma-
tions”).
The Isolated (Trapped) Fourth Ventricle
When both the aqueduct of Sylvius and the fourth ventricular out-
flow foramina are occluded, the fourth ventricle becomes isolated from
the remaining ventricular system and from the CSF circulation of the
subarachnoid space. Continued CSF production by the choroid plexus
of the fourth ventricle leads to progressive cystic dilatation of the ven-
tricle; the dilated ventricle can then act as an expanding mass in the
posterior fossa. The trapped fourth ventricle appears after shunting of
the lateral ventricles and seems to result from mechanical or inflamma-
tory changes that obstruct the aqueduct and the fourth ventricular out-
let foramina (159). Thus, CSF from the fourth ventricle cannot drain
proximally through the shunt catheter or distally through normal CSF
pathways; the ventricle becomes “isolated.”
The clinical presentation depends upon the baseline neurological
status of the patient. In those patients who have moderate to severe
preexisting neurological deficits, the isolated fourth ventricle accen-
tuates preexisting deficits without causing prominent posterior fossa
signs or symptoms. Patients with normal or near normal baseline neu-
rological examinations tend to present with signs and symptoms of a
posterior fossa mass. A history of a recent ataxia, diplopia, or increas-
ing drowsiness is common (160). Occasionally, patients are mildly
symptomatic or asymptomatic and the isolated fourth ventricle can be
an incidental finding (159). In these asymptomatic patients, a steady
state is presumably reached between production and absorption of the
5/6/2011 10:26:17 PM

FIG. 8-28. Isolated (trapped) fourth ventricle resulting from previous septic meningitis. A. Midline sagittal T2. Huge,
elongated fourth ventricle (V) that herniates toward the supratentorial space; it seems to communicate with the caudal
aqueduct, but not with the cistern magna. Note the multiple loculations in the third ventricle. B. Axial FLAIR. The dila-
tion of the fourth ventricle (V) extends into both lateral recesses (white arrows) presumably because of the obstruction
of both foramina of Luschka.
CSF within the fourth ventricle, resulting in the absence of signs of
increased intracranial pressure. Close follow-up however is justified as
complete lack of evolutivity is uncertain and acute decompensation
may occur.
On imaging studies, the isolated fourth ventricle appears as a
large rounded or pear-shaped midline cystic structure (Figs. 8-28) in
the posterior fossa (159–161). In some cases the lateral recesses may
be ballooned (Fig. 8-28B) (162). The lateral and third ventricles are
small or only moderately enlarged if the ventriculo-peritoneal shunt
is functioning. The aqueduct may be completely occluded or the distal
aqueduct may be dilated (Fig. 8-28A). Treatment is the installation of
a fourth ventricle to peritoneal shunt; endoscopic therapy is currently
experimental (138), as is stenting of the fourth ventricle to allow com-
munication with the subarachnoid space (163). After shunting, there is
usually rapid reversal of posterior fossa signs, if they had been present or
progressive. In children with preexisting neurological deficits, a return
to baseline is generally observed. Occasionally, further treatment, such
as posterior fossa decompression, may be necessary (159,160).
Hydrocephalus Secondary to
Extraventricular Obstruction of CSF
EVOH represents approximately 30% of all childhood hydrocephalus
(131). After leaving the foramina of the fourth ventricle, CSF normally
enters the cisterna magna and basilar cisterns and then progresses into
the cerebral and cerebellar subarachnoid spaces. Normal CSF drainage
is jeopardized if the normal CSF pathways are obstructed by thickened
arachnoid or meninges (Fig. 8-29). (The Greitz model would hypothesize
that the obstruction of the cisterns compromises the dampening of the
systolic pressure wave, and that the full force of the wave is then exerted
against the parenchyma (25,55); see the theory section earlier in this
chapter.) CSF drainage is also impaired if the dural venous sinuses are
obstructed or if pressure in the sinuses becomes elevated. Unless venous
thrombosis is present, it is usually not possible to determine the level of
the extraventricular obstruction to CSF flow from imaging studies.
Impaired flow of CSF through the subarachnoid spaces (or reduced
compliance [55]) may result from recent or remote intracranial
Barkovich_Chap08.indd 833
Chapter 8 • Hydrocephalus 833
hemorrhage, bacterial infections, or granulomatous meningitis. Cer-
tain features seen on imaging studies can help to differentiate the dif-
ferent causes of the hydrocephalus. For example, hemorrhage often
leaves a transient hemosiderin staining of the parenchyma, ependyma,
or pia-arachnoid (superficial siderosis). The hemosiderin will appear
black on T2-weighted spin-echo images (Fig. 8-30B–D) (164,165) and
especially so on T2*-weighted gradient-echo or susceptibility-weighted
images (166,167). Although hemosiderin will remain at the site of
hemorrhage for months or years after parenchymal hemorrhages, it
is absorbed much more quickly from the ependyma and arachnoid.
Both infectious and carcinomatous meningitis may result in meningeal
enhancement (Figs. 8-31 and 8-32) after administration of intravenous
contrast (168–170). Differentiation of subarachnoid tumor from infec-
tion, however, is not possible at this time by radiologic methods.
Hemorrhage
Intraventricular hemorrhage is common in neonates, particularly
in babies with a gestational age of 32 weeks or less (see discussion in
Chapter 4), with hydrocephalus being a frequent complication. Acute
posthemorrhagic hydrocephalus is most commonly the result of red
blood cells obstructing the ventricular system or the arachnoid villi;
this acute hydrocephalus has no prognostic implications. Scarring and
fibrosis begin to appear in the subarachnoid spaces approximately 10
days after the hemorrhagic event (171). The fibrosis tends to be most
prominent in the region of the cisterna magna. This adhesive arach-
noiditis is the cause of the subacute hydrocephalus that occurs after
germinal matrix hemorrhage in premature infants (Fig. 8-30). The pres-
ence of subacute hydrocephalus imparts a poor functional prognosis to
the infant. However, it is important not to mistake ex vacuo ventricular
enlargement secondary to periventricular white matter injury for ventric-
ular enlargement secondary to impaired CSF circulation. Therefore, it is
important to look for evidence of periventricular white matter injury
in all such cases. Irregularity of the ventricular margins, cavitation in
the periventricular white matter and T1 and T2 shortening within the
periventricular white matter (see Chapter 4) all suggest that brain injury
has occurred. Of course, as with all potential cases of pediatric hydro-
cephalus, correlation with head circumference measurements is vital.
5/6/2011 10:26:17 PM
 834 Pediatric Neuroimaging

FIG. 8-29. Extraventricular obstruction of the CSF pathways.

A. Midline sagittal T2. The severe hydrocephalus was initially
explained by the large suprasellar cyst that was felt to obstruct
the foramina of Monro and the third ventricle; however, the
prominent flow void in the aqueduct suggests that the obstruc-
tion must be located somewhere else. The patient was treated by
endoscopic fenestration of the third ventricle and cyst. B. Mid-
line sagittal FIESTA image after surgery confirms the diagnosis
of suprasellar cyst and the patency of the foramina of Monro,
third ventricle and aqueduct, but shows that the suprasellar
cistern remains obstructed and the hydrocephalus persists.
C. Midline sagittal T2 image, acquired in the same study as image
B shows an extremely prominent aqueductal-fourth ventricle-
foramen of Magendie signal void, suggesting hyperdynamic flow
due to reduced compliance. This observation strongly suggests
that the hydrocephalus is a result of restricted cisternal CSF flow
due to the suprasellar location of the cyst. See text for further
explanation.

Subarachnoid hemorrhage in full term infants is most often caused
by trauma (see Chapter 4). The causes of acute and chronic hydro-
cephalus in these infants are similar to the causes of hydrocephalus
in premature infants with intraventricular hemorrhage; however, the
prognostic value of the hydrocephalus is not as great in term infants as
in premature infants.
Meningitis
Inflammation of the leptomeninges may lead to obstruction the CSF
pathways (see Chapter 11, Section “Meningitis”). In the acute phase,
hydrocephalus is caused by blockage of the CSF flow pathways by
purulent fluid. Another component of acute hydrocephalus may be
inflammation of the arachnoid granulations (46,172). In the chronic
phase, organization of exudate and blood results in fibrosis of the suba-
rachnoid spaces with subsequent obstruction to normal CSF flow and
resultant hydrocephalus (46,172).
Clinically significant hydrocephalus is less common in bacterial
meningitis than in granulomatous and fungal meningitides. Indeed,
hydrocephalus is almost always present at the time of presentation in
granulomatous and fungal meningitis. Hydrocephalus appears to be
related to the duration and severity of the meningeal infections; in gen-
eral, the longer the delay in treatment, the worse the prognosis for the
patient. As a general rule, bacterial meningitis tends to produce cerebral
cortical arachnoiditis, whereas granulomatous or parasitic meningiti-
des produce cisternal obstruction (Fig. 8-31) (46). Viral meningiti-
des may result in obstruction at either point, albeit rarely. Ventricular
dilatation, which presumably results from transiently diminished CSF
absorption, is the most common finding on ultrasound, CT scans, or
unenhanced MR scans in patients with bacterial meningitis. Contrast-
enhanced MR scans often show localized or diffuse meningeal enhance-
ment in bacterial and fungal meningitides (see Fig. 8-31 and examples
in Chapter 11) (169). Arachnoidal scarring from meningitis may also
result in arachnoid loculations, which may be indistinguishable from
arachnoid cysts.
CSF Seeding of Tumor
A number of neoplastic processes can involve the subarachnoid space
diffusely (see Chapter 7). The most common of these in children are

Barkovich_Chap08.indd 834 5/6/2011 10:26:18 PM

 Chapter 8 • Hydrocephalus 835

FIG. 8-30. Post hemorrhagic hydrocephalus in a former premature infant. A. Midline sagittal FIESTA image shows severe hydro-
cephalus, dehiscent septum pellucidum, and an obstructed aqueduct. Low signal intensity around the brainstem and inferior vermis
suggests hemosiderin from intraventricular hemorrhage. B–D. Axial T2*-weighted images show hypointensity (black arrows) from
magnetic susceptibility effects of blood on the surface of the brainstem and cerebellum (B), choroid plexuses and walls of the lateral
ventricles (C and D).

medulloblastoma, germinoma, leukemia, and lymphoma; it can also be Venous Hypertension

seen in a variant of pilocytic astrocytoma, the pilomyxoid astrocytoma
(173). This is in contrast to adults where adenocarcinoma is the most
common tumor to show diffuse meningeal involvement (174).
Older patients with CSF seeding of tumor (also called carcinoma-
tous meningitis) typically present with headache, stiff neck, and cranial
nerve palsies. Hydrocephalus occurs only later in the course of the dis-
ease. As with infectious meningitis, ventricular enlargement is the most
common manifestation of this process on ultrasound, CT, and unen-
hanced MR scans. Occasionally, diffuse meningeal enhancement may
be seen on contrast-enhanced CT scans. Significant enhancement of
the subarachnoid spaces and cranial nerves (particularly cranial nerves
5 and 8) is typically seen on contrast-enhanced MR scans (Fig. 8-32)
(168,170,175).
Obstruction of the cerebral veins and sinuses is thought to be a cause of
communicating hydrocephalus in infants (176–178). It appears that the
increased intracranial venous pressure may produce either hydroceph-
alus or pseudotumor cerebri, depending upon the patient’s age (176).
Hydrocephalus is more likely if the patient is less than 18th months
of age, whereas pseudotumor cerebri is noted if the patient is more
than 3 years of age. This difference is thought to result from an expan-
sile calvarium and softer, less myelinated parenchyma in the infant;
both of these factors allow greater ventricular dilatation under high
pressure (179–182). Once the cerebrum is myelinated and the sutures
are fused or the calvarium is otherwise prevented from expanding,
intracranial hypertension occurs without ventricular enlargement and
results in pseudotumor cerebri (176,179). The hydrodynamic theory

Barkovich_Chap08.indd 835 5/6/2011 10:26:19 PM

 836 Pediatric Neuroimaging

FIG. 8-31. Hydrocephalus associated with tuberculous menin-

gitis. Midline sagittal (A), coronal (B), axial (C) T1 images after
contrast administration. The thickened, inflamed leptomeninges
show diffuse enhancement over the surface of the brainstem,
hypothalamus, cerebellum, and cranial nerves, associated with
significant triventricular dilation.

of Greitz would suggest that, in infant with an elastic skull, CSF would
accumulate immediately above the obstruction, in the pericerebral
subarachnoid spaces, much more than in the ventricles (25).
Ventricular enlargement results from skull base abnormalities
in a number of syndromes. These include achondroplasia (183,184)
(Fig. 8-33), craniofacial syndromes that result in multisutural cranio-
synostosis (Apert syndrome, Carpenter syndrome, Pfeiffer syndrome,
Crouzon syndrome, and others described in Chapter 5, Section “Cran-
iosynostosis”), and the Marshall-Smith syndrome (a syndrome of accel-
erated osseous maturation and CNS malformations) (178,185–187). It
has been postulated that the ventricular enlargement in all of these syn-
dromes results from diminished venous outflow through the small jugu-
lar foramina that, in turn, result from hypoplasia of the skull base (188)
(Fig. 8-33D). These theories are supported by experimental evidence in
the case of achondroplasia (189,190) and Crouzon syndrome (191). The
mechanism of this ventricular enlargement is believed to be an increase
in superior sagittal sinus pressures, leading to a decreased pressure gra-
dient across the arachnoid villi, from the subarachnoid spaces to the
superior sagittal sinus. (The hydrodynamic theory would suggest that
the arterial systolic inflow not being properly buffered because of the
increased pressure in the dural sinuses and, thus, the compliance of the
system is decreased (25).) The resultant increased intracranial pressure
results in expansion of the calvarium and ventricles in infants until the
pressure normalizes (186,187) or the hydrocephalus becomes compen-
sated (192). Typical imaging signs of hydrocephalus are not reliable in
these patients. For example, temporal horn enlargement results from
expansion of the middle cranial fossa and frontal horn enlargement may
be the result of the enlarged anterior fontanelle, not necessarily from
increased intraventricular pressure. Also, because of the sutural synos-
tosis, the bodies and trigones of the lateral ventricles may not enlarge
until a cranial expansion has been performed (193). The indication
for shunting in these patients seems to be based primarily on the pres-
ence of severe ventricular dilation or evidence of persistent intracranial
hypertension such as papilledema (193). A recent study suggests that the
intracranial pressure normalizes in patients with craniosynostosis syn-
dromes at the age of approximately 6 years as a result of the enlargement
of stylomastoid emissary veins (transcalvarial veins that allow venous
drainage into the stylomastoid venous plexus) (194).

Barkovich_Chap08.indd 836 5/6/2011 10:26:20 PM

 Chapter 8 • Hydrocephalus 837

FIG. 8-32. Hydrocephalus associated with leptomeningeal tumoral dissemination (high risk medulloblastoma). Postcontrast
T1-weighted axial (A) and coronal (B) images show a thick enhancing layer of leptomeningeal carcinomatosis (carcinomatous men-
ingitis), mainly overlying the cerebellar folia.

Progressive head enlargement in infants can also result from
thrombosis of the dural venous sinuses, presumably via the same mecha-
nism. MR venography can be helpful to detect obstruction of the dural
venous sinuses in children with increased CSF pressures with no other
obvious cause. As two-dimensional (2D) time-of-flight MR venogra-
phy may show apparent narrowing of the distal transverse and sigmoid
sinuses that are caused by complex flow (sometimes by the presence of
an arachnoid granulation or flow from the vein of Labbé) in those areas,
time-resolved contrast-enhanced MR venography (see Chapter 1, Section
“Magnetic Resonance Angiography and CT Angiography”) is the study
of choice to evaluate the venous sinuses. However, MR venography can-
not determine pressure differential across foci of narrowing in the dural
venous sinuses. In difficult cases, it may be necessary to do a catheter
venogram and measure pressures in the sinuses.
Normal Pressure Hydrocephalus
Normal pressure hydrocephalus (NPH) is a form of hydrocephalus in
which a pressure gradient exists between ventricle and brain paren-
chyma, despite the fact that CSF pressure is within the normal range
at the time of lumbar puncture. Intermittently high pressure probably

FIG. 8-33. Hydrocephalus from venous hypertension in a 15 month old infant with achondroplasia. A. Midline sagittal T1-weighted
image shows the frontal bossing characteristic of the disease. Supratentorial ventricles are large, the posterior fossa is small, the
cranio-vertebral junction and cervical spinal canal are narrow. B. Coronal T2 image shows supratentorial ventricular dilation with
typical rounding of the temporal horns compressing the hippocampi, and a prominent suprapineal recess (black arrow).

Barkovich_Chap08.indd 837 5/6/2011 10:26:21 PM

 838 Pediatric Neuroimaging
FIG. 8-33. (Continued) C. Axial FLAIR image shows diffuse ventricular dilation with prominent subarachnoid spaces over the
frontal lobes and anterior interhemispheric fissure (associated subrachnoid enlargement). D. MR venogram shows both sigmoid
sinuses to be interrupted in the jugular foramina. Prominent collateral venous flow can be seen through emissary veins and the
venous plexuses around the foramen magnum (white arrows).
results in a compromise of normal compensatory pressure mechanisms
(195,196); this is called a loss of compliance in the hydrodynamic the-
ory (25). The fluctuating high pressures may combine with impaired
regional CBF to cause ventricular enlargement and parenchymal
destruction (131). The most common cause of NPH is communicating
hydrocephalus with unidentified arachnoidal damage interfering with
normal CSF dynamics, or loss of elasticity of the dural sac. Primary
events leading to NPH include neonatal intraventricular hemorrhage,
spontaneous subarachnoid hemorrhage, intracranial trauma, infec-
tions, and surgery (197). Among the pediatric population, it is most
commonly seen in those who have underlying neurological pathology
such as complications of meningitis or germinal matrix/intraventricu-
lar hemorrhage (198). NPH, therefore, is not merely a disease of adults
but occurs in children, as well.
The ultrasound, CT, and MR appearance of NPH in children is
indistinguishable from that of other forms of communicating hydro-
cephalus. However, measurements of CSF flow with flow-sensitive
MRI methods have demonstrated that the CSF stroke volume (vol-
ume of CSF displaced with each cardiac systole) is reduced by 50% at
the craniovertebral junction and the venous stroke volume is reduced
by 33% in the dural sinuses in communicating hydrocephalus. At the
same time, intracranial pressure monitoring reports a 6-fold increase
of the CSF pulse pressure (25). This association of decreased stroke
volume and increased pressure wave reflects the loss of compliance.
It means that the arterial expansion resulting from cardiac systole is
decreased and that the arterial pulse wave, instead of being transmit-
ted to the CSF, is transmitted directly to the vascular lumen. Thus, the
intravascular pressure is increased in capillaries and veins, preventing
the appropriate absorption of CSF by the parenchyma. Because the
pulse wave is transmitted into the vessels rather than via the pericere-
bral CSF, the brain expands, compressing the cerebral ventricles. The
ventricular compression, in turn, causes increased amplitude of the
pressure wave within the ventricles and, especially, in the aqueduct.
The increased pressure in both the vessels and the ventricles results
in a slowly progressive loss of brain tissue. In addition the compres-
sion of the draining veins by the pericerebral CSF pulse pressure is lost;
Barkovich_Chap08.indd 838
therefore, the venous backpressure that keeps open the venules and
capillaries is lost, compromising the optimal perfusion and exchange
conditions that prevailed between the vessels and the brain (25). This
model has been confirmed by several reports in which the registration
of the velocity curve at the aqueduct using cine phase-contrast imaging
in cohorts of patients demonstrated a significant increase of the CSF
stroke amplitude as compared with normal controls (59–62). On con-
ventional diagnostic this is expressed by a significantly increased signal
void at the aqueduct on sagittal T2 FSE/TSE imaging.
BENIGN ENLARGEMENT OF THE
SUBARACHNOID SPACES IN INFANTS
Definition
A pattern of enlarged CSF spaces with normal to slightly increased
ventricular size in infants (Fig. 8-34) is fairly common. The affected
children are usually neurologically normal infants without evidence
of prior brain injury (199). This appearance rarely causes clinical
concern and, indeed, is rarely noticed unless the infant has macro-
cephaly or rapid head growth; under these circumstances, the large
CSF spaces often raise concerns for hydrocephalus (200–203). This
phenomenon of large CSF spaces in developmentally and neurologi-
cally normal children with macrocephaly has been variously called
benign extra-axial collections of infancy, benign idiopathic external
hydrocephalus, EVOH, benign subdural effusions of infancy, benign
macrocephaly of infancy, and benign enlargement of the subarachnoid
spaces (200,202,203). The term benign enlargement of the subarach-
noid spaces probably is most appropriate and can be applied to neuro-
logically normal infants with large CSF spaces whether macrocephaly
is present or not.
Clinical Manifestations
In the absence of other anomalies, children with benign enlargement
of the subarachnoid spaces develop normally (203). If macrocephaly is
5/6/2011 10:26:22 PM
 Chapter 8 • Hydrocephalus 839

FIG. 8-34. Benign enlargement of the subarachnoid spaces.

This 1-year-old infant was referred for macrocephaly, with head
circumference above the 95th percentile. A–C. Axial, coronal and
sagittal T2 images show significant widening of the subarachnoid
spaces over the anterior convexity. With proper windowing, the
bridging veins are clearly seen coursing from the brain surface to
the inner layer of the dura. The lateral ventricles are only mildly
dilated, and the temporal horns are normal. D. Midline sagittal
T2-weighted image shows diffusely prominent CSF spaces. A
faint flow void can be seen through the aqueduct. E. Midline
sagittal FIESTA image shows normal midline anatomy other than
the prominence of the CSF spaces.

Barkovich_Chap08.indd 839 5/6/2011 10:26:22 PM

 840 Pediatric Neuroimaging
present, the head circumference tends to be in the high normal range
at birth and increases rapidly during the first few months of life; it
is generally well above the 95th percentile at the time of presenta-
tion (usually between the ages of 2 and 7 months). It is important to
recognize that this rapid head growth does not necessarily represent
hydrocephalus or the presence of subdural hematomas, particularly in
the absence of developmental delay or signs or symptoms of increased
intracranial pressure. In fact, when followed without intervention,
the head growth curve of affected infants tends to stabilize along a
curve parallel to the 95th percentile by the age of 18 months. Both
the size of the subarachnoid spaces and the head circumference typi-
cally return to normal after the second birthday (202). Cisternogra-
phy has demonstrated slow flow over the cerebral convexities in these
patients (201); the enlarged subarachnoid spaces, therefore, are pro-
posed to result from delayed maturation of the arachnoid villi or other
absorption sites such as the nasal mucosal-lymphatic pathway under-
lying the cribriform plate (34,40). The fact that this same pattern of
enlarged subarachnoid spaces may be found also in association with
high venous pressure lends credence to this tentative explanation. In
most cases, however, benign enlargement of the subarachnoid spaces
is idiopathic; it is sometimes familial (204). Histologic examination in
affected patients has shown thickening of the arachnoid, which may
be a normal developmental phenomenon or perhaps a reactive change
that helps to increase resorption of CSF (205).
Imaging
The mere presence of enlarged subarachnoid spaces is not sufficient
to make this diagnosis. Enlarged subarachnoid spaces can be caused
by a number of factors, including ACTH and corticosteroid therapy
(206,207), dehydration, malnutrition (208), total parenteral nutrition,
and cancer chemotherapy, in addition to the mechanisms discussed
previously in this chapter. The presence of these factors should be ruled
out before the diagnosis of benign enlargement of the subarachnoid
spaces (or atrophy, or hydrocephalus) is considered.
Typical imaging findings in patients with benign enlargement of
the subarachnoid spaces include slightly enlarged lateral and third
ventricles, and subarachnoid space that is wider than normal in
frontal region, anterior interhemispheric fissure, and Sylvian fissures
(Fig. 8-34) (199). The chiasmatic cistern is also typically enlarged
(Fig. 8-34D and E). The degree of dilation of the lateral ventricles is
roughly proportional to the width of the frontal subarachnoid space.
Imaging studies may not be helpful in the distinction of benign enlarge-
ment of the subarachnoid spaces from hydrocephalus or, for that mat-
ter, from atrophy. As discussed earlier, scrutiny of the anterior and
posterior recesses of the third ventricle and the temporal horns (see
figures in the early sections of this chapter) may be helpful in the dif-
ferentiation from hydrocephalus. Symmetry of the extraparenchymal
fluid is an important finding, especially on CT; asymmetry is unusual
in benign macrocephaly and may indicate the presence of traumatic
subdural collections (209). Both MR and ultrasound can differentiate
subdural collections from enlarged subarachnoid spaces by visualiza-
tion of cortical veins (Fig. 8-34A–C). On MR, examining the first echo
of a T2-weighted sequence or a FLAIR image is optimal. In benign
enlargement of the subarachnoid spaces, veins are identified as curvi-
linear structures that are adjacent to the inner table of the calvarium;
with subdural collections, the veins are displaced from the inner table.
Also most subdural collections have high protein content and have
higher signal intensity than CSF on T2-weighted or FLAIR images. On
cranial ultrasound, differentiation is made by angling the transducer
to follow the veins into the superior sagittal sinus. In infants with sub-
dural collections, the echogenic pia-arachnoid is displaced from inner
Barkovich_Chap08.indd 840
table with veins medial to it. In patients with enlarged subarachnoid
spaces, the veins course directly into superior sagittal sinus (210,211).
Occasionally, patients with clinical courses and CT scans strongly
suggestive of benign enlargement of the subarachnoid spaces have had
bloody subdural collections, superimposed upon large subarachnoid
spaces, detected on MR scans or ultrasound (208,210) (Fig. 8-35).
Wilms et al. have reported that infants with bloody subdural collec-
tions have a higher incidence of difficult births or postnatal traumatic
incidents and are more likely to have symptoms of increased intracra-
nial pressure, such as vomiting and somnolence (210). However, many
reports describe infants with mildly hemorrhagic subdural collec-
tions superimposed upon large subarachnoid spaces in which exten-
sive investigations have revealed no evidence of significant trauma
(212–214). It is postulated that the large CSF spaces in these patients
may make these infants more susceptible to subdural hematoma forma-
tion secondary to rather mild trauma, similar to the condition encoun-
tered in patients with middle cranial fossa arachnoid cysts (215,216).
All babies with hemorrhagic subdural collections should, nonetheless,
be carefully screened by child protective services, as most will be found
to have suffered some sort of trauma (217).
IMAGING OF TREATED HYDROCEPHALUS
AND RESULTING COMPLICATIONS
As discussed in Sections Classification of hydrocephalus and Clinical
aspects of hydrocephalus, severe long-lasting hydrocephalus will cause
damage to the brain. In dogs, the brain is not permanently damaged
until the cerebral mantle is compressed to a thickness of less than 4
mm (218). Persistent compression of the brain results in gliosis, cor-
tical distortion, damage to neurons, tearing of axons in the internal
capsule, and myelin destruction (46,218,219). Therefore, treatment of
uncompensated hydrocephalus is mandatory.
In hyperacute hydrocephalus, ventricular tapping with external
ventricular drainage relieves the ventricular tamponade and prevents
the circulatory arrest caused by the compression of the vascular bed
(see section Clinical aspects of hydrocephalus). Follow-up imaging,
FIG. 8-35. Benign enlargement of the subarachnoid spaces with small
subdural hematoma. Axial CT of a 1-year-old infant with head circumfer-
ence above the 95th percentile shows prominent subarachnoid spaces over
the frontal convexity. The right frontal subdural collection of intermediate
attenuation (black arrows) is highly suggestive for a subdural hematoma.
5/6/2011 10:26:23 PM

typically restricted to the acute period, assesses the ventricular size, the
morphological features associated with high intraventricular pressure,
and the related condition of the parenchyma.
In less acute situations, hydrocephalus may be treated by endo-
scopic third ventriculostomy or by CSF diversion in the form of a ven-
triculo-peritoneal or a ventriculo-atrial shunt. Third ventriculostomy
is a popular treatment because it eliminates the necessity of having an
indwelling shunt, which can become obstructed and can be the cause
of hemorrhage, infections, foreign body reactions, slit ventricle syn-
drome, and other complications listed in this section. In third ventricu-
lostomies, a fiberoptic endoscope is used to create a hole in the floor of
the third ventricle, immediately anterior to the mamillary bodies. This
hole allows the intraventricular CSF access into the interpeduncular
and suprasellar cisterns, from where it can flow laterally and upward
over the cerebral convexities to sites of CSF resorption. Thus, the
obstructions are bypassed. Third ventriculostomies appear to be most
useful in obstructive hydrocephalus; as discussed earlier, obstructive
hydrocephalus in children is most often the result of obstruction in the
region of the Sylvian aqueduct, fourth ventricular outflow foramina,
cisterna magna, or basal cisterns. Third ventriculostomy may also be
used in cases of communicating hydrocephalus, as by-passing the cau-
dal ventricular channels (aqueduct, fourth ventricle) might increase
the compliance (220). However, third ventriculostomy is not effec-
tive when loculations are present in the subarachnoid spaces, such as
the prepontine, interpeduncular or suprasellar cisterns. Studies have
shown that third ventriculostomies result in successful resolution of
hydrocephalus in 80% of children so treated (221). If the third ven-
triculostomy does not result in adequate resolution of hydrocephalus,
a ventricular shunt is placed. Advantages of endoscopic third ventricu-
lostomy include a more physiologic CSF circulation, lower incidence of
infections, and better response of infection to antibiotic therapy.
Third ventriculostomies are less useful in young infants, in whom a
higher incidence of parenchymal injury and vascular injury is reported;
in addition, the communication through the floor of the ventricle is
more likely to spontaneously close (222). In countries where appro-
priate follow-up of patients is difficult for economic or geographic
reasons, third ventriculostomy associated with cauterization of the
FIG. 8-36. Appearance of a ventriculoperitoneal shunt (white arrows) on MR (A and C) and CT (D). On MR the shunt appears
as a hypointense linear structure extending from the ventricle to the extracranial soft tissues. It appears as a high attenuation linear
structure on CT.
Barkovich_Chap08.indd 841
Chapter 8 • Hydrocephalus 841
choroid plexuses is the procedure of choice, provided the cisterns are
patent (223,224).
Shunt systems are composed of a ventriculostomy tube, a reservoir
(optional), a valve, and a peritoneal tube. The ventriculostomy tube is
inserted either into the frontal or occipital horn of the lateral ventricle
through a small hole in the calvarium. This is attached to the reser-
voir, which lies subcutaneously over the calvarial defect. The valve is
set to a certain pressure that must be attained before drainage occurs;
the presence of the shunt system restores the compliance of the system
and allows both dampening of the systolic pressure wave and drain-
age of the accumulated fluid. Some valves are pressure-adjusted with
an external magnetic device; although these magnetic devices are not a
contraindication to MRI, it is almost always necessary to reset the valve
after the study. The peritoneal tube is run subcutaneously from the valve
into the peritoneal cavity. The radiologist is usually asked to assess the
function of the shunt by determining the position of the tip of the ven-
triculostomy tube and the reduction in ventricular size resulting from
its placement. In general, the tip of the ventriculostomy tube should lie
within the lateral ventricle in the region of the foramen of Monro. The
tube is hypointense on T1- and T2-weighted and FLAIR MR images
(Fig. 8-36A–C) and has high attenuation on CT (Fig. 8-36D). Some
diminution in ventricular size should be apparent soon after the place-
ment of a shunt; if the ventricular size is unchanged after 2 to 3 days, the
patency of the shunt system should be questioned. It has been shown
that if the cerebral mantle measures 2 cm or more in thickness after
shunting, patients usually attain average intellectual development (46).
Surgical cannulation of the aqueduct was proposed in the 1970s
to 1980s for treating aqueductal stenosis (128,225) and reintroduced
in the past decade using fiberoptic ventriculoscopy, with or without
stenting (139,226). It is uncommonly used and the reader is unlikely to
encounter such cases.
Radiologic Assessment of Third
Ventriculostomies
Although sonography, CT, or MR can be used to assess shunted hydro-
cephalus, MR is the study of choice for the assessment of patients
5/6/2011 10:26:24 PM
 842 Pediatric Neuroimaging
FIG. 8-36. (Continued)
treated with third ventriculostomy, as only by MR can one assess the
surgically induced defect in the floor of the third ventricle and the CSF
pulsing through it.
In children who have undergone successful third ventriculostomies,
the reduction in ventricular size is usually slower and less dramatic
than in those who have been treated using ventricular shunts (227).
The ventricular size after third ventriculostomy usually decreases over
several months, instead of several days as in patients with ventricu-
lar shunt catheters (228). On follow-up, the ventricles remain larger
than they would usually be after shunt placement. This difference in
magnitude of ventricular size reduction is likely related to the fact that
indwelling ventriculostomy catheters dampen the pulsations of CSF
emanating from the choroid plexus or possibly to a reduced absorp-
tion capacity in the affected children (229).
Imaging assessment of the third ventriculostomy is aimed at
demonstrating flow passing through the hole in the floor of the third
ventricle. This can be best accomplished noninvasively by the use of
MR. Lev et al. used phase-contrast MR flow studies to determine ratios
of CSF flow velocities in patients with third ventriculostomies (230).
They found that the ratio of velocity of CSF in the prepontine space
to that in the anterior cervical spinal subarachnoid space was signifi-
cantly higher in patients with patent third ventriculostomies than in
normal patients. Those patients with velocity ratios lower than normal
needed revisions (230). Fischbein et al. found that sagittal 3 to 4 mm
fast spin-echo sequences show hypointensity in the region of the ven-
triculostomy secondary to rapid pulsatile flow. In their study, the fast
spin-echo studies were as sensitive as cine phase-contrast studies (227)
(Fig. 8-37). Kim et al. used a combination of T2-weighted images and
phase-contrast images (228). Hoffman et al. used a steady-state free
precession sequence and consistently found loss of the steady state (and
consequent loss of signal) in the inferior third ventricle and suprasellar
cistern in patients with patent third ventriculostomies but no loss of
the steady state (persistent high signal intensity in the inferior third
ventricle) in patients with occluded third ventriculostomies (231) (Fig.
8-38). As all of these techniques rely on detecting flow in the inferior
third ventricle and suprasellar/interpeduncular/prepontine cisterns, it
is likely that all of them work. Therefore, choice of the precise tech-
nique to be used should depend upon which techniques are available on
the MR scanner being used and with which technique(s) the imaging
Barkovich_Chap08.indd 842
physician is most comfortable. In addition, detailed morphological
analysis can be provided by using CISS/FIESTA submillimeter imag-
ing. This sequence is not sensitive to flow but demonstrates the ventric-
ulostomy well and can identify occlusive septations in the surrounding
cisterns better that flow-sensitive sequences.
Shunt Malfunctions
Shunt malfunctions are manifested clinically by symptoms of increased
intracranial pressure, persistent bulging of the anterior fontanel, exces-
sive rate of head growth in the infant, or seizures (131,232). On imag-
ing studies, shunt malfunction is usually manifested by increasing
ventricular size (Fig. 8-39A and B). In infants, this is usually assessed
by sonography. In older children, CT is the standard study, but devel-
opment of fast imaging (half-Fourier single-shot RARE sequences and
PROPELLER sequences) now allow rapid assessment of ventricular size
by MR without sedation and without ionizing radiation (233–236). If
time is available on the MR scanner, serious consideration should be
given to using these techniques. Shunt failure does not always result
in ventricular enlargement, however. Some patients have considerable
scarring in and around the ventricular walls, causing decreased com-
pliance of the brain and no enlargement or minimal enlargement of
the ventricular system in the presence of shunt malfunction (see sub-
sequent section on the “Slit Ventricle Syndrome” [237,238]). The most
common cause of malfunction is occlusion of the ventricular catheter
by choroid plexus or glial tissue that grows into the lumen of the cath-
eter. This diagnosis can only be inferred from imaging studies, which
will show enlarging lateral ventricles in spite of a well-placed ventricu-
lostomy tube and intact connections of the shunt system.
Disconnection of the shunt components can occur at any point
within the system; it most commonly occurs where the various compo-
nents are joined. Although the site of shunt malfunction (ventricular
portion versus peritoneal portion) can often be determined clinically,
plain film studies of shunt components (Fig. 8-39C), positive contrast
plain film radiography, or radionuclide studies are sometimes neces-
sary (239–243). If radionuclide studies are performed, both dynamic
and static studies should be obtained (239). The “scout” film from a
CT scan will sometimes show a disconnection at the valve that is not
appreciated on the axial images; therefore, the scout film should always
5/6/2011 10:26:24 PM
 Chapter 8 • Hydrocephalus 843

FIG. 8-37. Endoscopic third ventriculocisternostomy (ETV) efficacy assessment. A. Midsagittal FIESTA image shows a wide defect
(black arrow) in the anterior part of the floor of the third ventricle. B and C. Cine phase-contrast imaging demonstrates good CSF
flow (hypointensity in [B], hyperintensity in [C]) across the defect in the floor of the ventricle. D. Sagittal T2-weighted image dem-
onstrates a prominent signal void (black arrow) at the ventriculostomy site. FSE T2 is felt to be similarly diagnostic as cine phase-
contrast imaging for evaluating the patency of an ETV.

be analyzed. In addition to showing the location of obstruction or dis-
connection, shunt function studies are of value when symptoms of
shunt malfunction are vague and clinical testing of shunt function is
equivocal. Note that the reservoir is not always radio-opaque and, there-
fore, may appear as a discontinuity of the shunt system on plain radio-
graphs. It is essential to communicate with the treating neurosurgeon
or perform a positive contrast or radionuclide study in order to dif-
ferentiate a disconnection from the presence of a radiolucent shunt
component.
Using special techniques described in Chapter 1, CSF flow can be
analyzed by MR techniques (81,82). When used properly, the CSF flow
techniques can be used to analyze flow in ventricular catheters and
in connecting tubing (244,245); when done properly and calibrated
carefully, flow rates within the shunt can be calculated (246). Parameters
are set to detect flow with velocity greater than a certain minimum. If
flow is seen within the shunt tubing, therefore, one may confidently
conclude that a rate of flow above that minimum is present within the
shunt system. However, CSF production and, therefore, CSF flow, vary
from minute to minute (247); therefore, a negative study (a study show-
ing no flow) is indeterminate. CSF may be flowing through the shunt
at a velocity below the minimum detectable rate (245). In addition,
the amount of CSF flowing through the shunt may vary with position
(e.g., upright versus supine). As a result of these considerations, a lack
of detection of CSF flow on an MR study is not necessarily diagnostic
of shunt failure. Therefore, if no flow is detected, a more conventional
radionuclide or positive contrast study becomes necessary.

Barkovich_Chap08.indd 843 5/6/2011 10:26:25 PM

 844 Pediatric Neuroimaging
Shunt Infections
The risk of infection resulting from ventricular shunting has decreased
steadily over the years and is now generally between 1% and 5%
(131,248,249); the rate is higher in infants (249,250). Most shunt infec-
tions develop shortly after insertion; however, as many as 10% develop
months to years later, usually as a result of systemic infection, peri-
tonitis, trauma, or surgery (252,2002). The major clinical manifesta-
tion of shunt infection is fever, which is usually intermittent and low
grade. Anemia, dehydration, hepatosplenomegaly, and stiff neck can
also be presenting signs. Shunt infection may also be manifested by
swelling and redness over part or all of the shunt tract or by such gen-
eralized symptoms as peritonitis. The only aspect of shunt infection
that is visualized on imaging studies is that of ventriculitis, which is
seen on contrast-enhanced imaging studies as enlarged lateral ventri-
cles with an irregular, enhancing ventricular wall. Occasionally, after
severe ventriculitis, multiple fluid loculations develop and distort the
brain, resulting in a confusing image; fortunately, these appear to be
increasingly uncommon. In the vast majority of these cases, the fluid
Barkovich_Chap08.indd 844
FIG. 8-38. Failed endoscopic third ventriculocisternostomy.
A. Coronal T2 image shows persistent evidence of hydrocepha-
lus, with large ventricular bodies and temporal horns. B. Sagittal
FIESTA image shows wide opening in the third ventricular floor
(arrows). C. Sagittal T2-weighted image shows no signal void
through the opening.
loculations are within the brain parenchyma, not in the ventricles; they
result from ischemic or toxic parenchymal damage that causes cavita-
tion of the white matter (see section on “Complications of meningitis”
in Chapter 11). Patients with multiple loculations are more difficult to
treat because each loculation must be drained separately. The use of the
fiberoptic ventriculoscopy to fenestrate the loculations has aided the
treatment of these cases (252). In order to guide the ventriculoscopy, it is
essential to image the affected patients in 3 orthogonal planes; ideally a
3D image is acquired and multiple contiguous images can be viewed
in three orthogonal planes at a workstation. Therefore, sonography or
MR is the study of choice; intraoperative sonography or neuronaviga-
tion using MR may be a useful adjunct in identifying and localizing
each loculation within the ventricular system.
Subdural Hematoma Formation
Subdural, clinically significant collections are uncommon. They develop
in the weeks or months following the treatment of the hydrocephalus.
It is hard to tell if they develop directly as subdural blood collections,
5/6/2011 10:26:26 PM

or primarily as simple hygromas which may themselves become
hemorrhagic (Fig. 8-40). It is difficult to understand why the ventricu-
lar collapse would result in a late subdural collection. The pericerebral
spaces typically become mildly dilated, and one would expect efface-
ment of (noncommunicating) ventricles without brain restoration to be
accompanied by a simple expansion of the subarachnoid spaces. A pos-
sibility is that the arachnoid septations have not enough time to adapt
and therefore are pulling the inner dural cellular layers inward, inducing
the inner dural vessels to bleed. In the case of a hygroma, interstitial
fluid would accumulate instead of blood; then, like during the evolution
of posttraumatic hygromas (253), neoangiogenesis could take place in
the inner membrane of the collection and secondarily bleed (Fig. 8-40).
Whatever their mechanism, these collections tend to attenuate and
characteristically disappear spontaneously. Rarely, they may become
chronic; they have been suspected of being the origin of the occasionally
observed fibrous meningeal thickening, but the pathophysiology could
also be that of the chronic intracranial hypotension.
When present, the appearance of the subdural collections is similar
to that of traumatic subdural hematomas (see Chapter 4) (Fig. 8-41);
Barkovich_Chap08.indd 845
Chapter 8 • Hydrocephalus 845
FIG. 8-39. Ventriculoperitoneal shunt disconnection. (Early
infantile hydrocephalus.) A. Axial CT from a routine follow-up
study shows small ventricles, with the interhemispheric fissure
clearly patent. B. Follow-up axial CT due to complaints of new
headaches. Significant bilateral ventricular enlargement with
effacement of the interhemispheric CSF spaces. C. Plain film
evaluation of the shunt. Disconnection of the tube (white arrow)
in the right lateral the neck.
however, surgical decompression of post-shunt subdural hemato-
mas is very uncommon, as the ventricular decompression results in a
considerable buffer to increases in intracranial pressure. Because it is
very sensitive to the presence of very small fluid collections, MR will
often show small subdural hematomas in children who have recently
been shunted. These small hematomas are almost never of clinical sig-
nificance. Large subdural hemorrhages which can result in increased
intracranial pressure, are usually seen in children over 3 years of age
after drainage of markedly enlarged ventricles. The use of high-pres-
sure valves in the shunting of these patients has reduced the incidence
of significant subdural hematomas. Hygromas or hemorrhagic hygro-
mas may develop secondarily within weeks and are usually not con-
cerning, as they evolve and disappear over months (Fig. 8-40).
Using contrast-enhanced MR or CT, chronic subdural hematomas
can be distinguished from postshunt meningeal fibrosis (meningeal
callus [254]), in which a thick collagenous scar develops in the sub-
dural space, presumably as a reaction to chronic subdural hematoma
(254–256) (Fig. 8-42). Whereas the liquid portions of chronic sub-
dural hematomas will not enhance after administration of contrast,
5/6/2011 10:26:27 PM
 846 Pediatric Neuroimaging

FIG. 8-40. Development and evolution of subdural collections

after ventriculoperitoneal shunt placement in an eight month old
infant with Chiari I related hydrocephalus. A. T2-weighted axial
MR 1 month after shunt placement shows persistent ventricular
enlargement with a subdural hygroma over the right convexity.
B. Axial CT 2 months after shunt placement shows that the size
of the ventricles has clearly decreased. Bilateral subdural collec-
tions of intermediate attenuation, higher on the right than on the
left. C. Three months post surgery, the CT shows that the ven-
tricles have enlarged, but both collections are much smaller. Their
attenuation remains increased. D. Four months post surgery, the
CT shows the collection on the left to have completely resorbed.
The collection on the right now has high attenuation. Ventricles
are unchanged. E. Nine months post surgery, the collections have
completely resolved. Ventricles are slightly larger, commensurate
with the amount of subdural fluid resorbed.

Barkovich_Chap08.indd 846 5/6/2011 10:26:28 PM

 Chapter 8 • Hydrocephalus 847

FIG. 8-41. Subdural hematomas after shunt placement. A. Axial CT shows bilateral large subdural collections of intermediate
attenuation associated with ventricular compression. B. Axial MR FLAIR in a different patient shows bilateral moderate-sized col-
lections of different signal intensity, associated with ventricular compression.

meningeal fibrosis enhances dramatically, presumably as a result of
vascular granulation tissue intermixed with the collagen bundles in the
subdural space (256).
Slit Ventricle Syndrome
Definition
Shunted hydrocephalic patients may become symptomatic from shunt
failure without evidence of ventricular enlargement on ultrasound, CT,
or MR. Patients who exhibit this phenomenon have been labeled as
having the “slit ventricle syndrome” (238,257–261). Some debate exists
as to what constellation of clinical and/or pathological findings define
this syndrome (238,262). It has become clear that there are multiple
different entities lumped together under this name; therefore, affected
patients may require several different treatments (263).
Di Rocco has divided slit ventricle syndrome into three groups:
(1) patients with inability of the ventricles to expand due to stiff-
ness at the subependymal level (normal intracranial pressure),
(2) patients with chronic low pressure from overdrainage or siphoning
of CSF through a shunt catheter or chronic CSF leak (low intracranial

FIG. 8-42. Post shunt meningeal fibrosis and calvarial thickening. Constellation of findings in chronic intracranial hypotension.
Child with congenital hydrocephalus. A. At 5 years of age, axial CT shows prominent ventricles, but the pericerebral spaces in the
sulci and interhemispheric fissure are visible. B. At age 7 years, contrast-enhanced CT showed much smaller ventricles. The skull is
markedly thicker than at 5 years. There is a thick layer of intermediate density (white arrows) between the subarachnoid space and the
skull. It could be mistaken for a fluid collection but its irregular, enhancing inner margin suggests meningeal fibrosis.

Barkovich_Chap08.indd 847 5/6/2011 10:26:29 PM

 848 Pediatric Neuroimaging

FIG. 8-42. (Continued) C. At the age of 16, axial FLAIR shows marked bone thickening especially the frontal bone. The ventricles
are small and surrounded by a thin band of white signal, presumably periventricular gliosis/fibrosis. A thick layer of tissue (white
arrows) is interposed between the brain and the calvarium and between the occipital lobes, most likely dural fibrosis. D–F. T1 post
contrast axial (D and E) and sagittal (F) images from the same study show that the thick fibrotic calvarial, tentorial, and falcine dura
enhances avidly. The dural venous sinuses are prominent. The cerebellar tonsils are low and compressed. The pituitary gland is
prominent.

pressure), and (3) patients with craniocerebral disproportion second-
ary to early suture fusion (high intracranial pressure) (264). Rekate
(257) has a different classification of the various disorders composing
the slit ventricle syndrome. He divides them into (1) extreme low pres-
sure headaches, probably from siphoning of CSF from the brain by
the shunt; (2) intermittent obstruction of the proximal shunt catheter;
(3) normal volume hydrocephalus (in which the buffering capacity
of the CSF is diminished, see following paragraph); (4) intracranial
hypertension associated with working shunts (probably linked to
venous hypertension); and (5) headaches in shunted children unre-
lated to intracranial pressure or shunt function. Thus, shunted patients
may experience a number of disorders, with very different treatments,
that can cause headaches without detectable ventricular enlargement.
Other than Rekate’s category no. 3, which may show calvarial thicken-
ing, imaging cannot differentiate these categories. Bruce and Weprin
suggest that patients with symptoms of shunt malfunction in the
absence of ventricular enlargement require an emergency shunt func-
tion study, followed by shunt revision with revision of the ventricular
catheter and valve (261).
Pathophysiology
The syndrome most commonly referred to by the name “slit ventricle
syndrome” is the result of a combination of decreased intracranial
volume; resultant diminished CSF buffering capacity (diminished

Barkovich_Chap08.indd 848 5/6/2011 10:26:30 PM

 Chapter 8 • Hydrocephalus 849

ability to compensate for the normal variations in intracranial pres- Diagnosis

sure); diminished brain compliance; and, possibly, intermittent or
partial shunt obstruction (237,238). Intracranial volume decreases
because shunting causes an immediate reduction in ventricular, and
hence brain, size. Thus, the brain expansion that maintains the patency
of the cranial sutures is temporarily reversed and the sutures close. By
the time the brain grows enough to once again fill the calvarium, the
sutures have fused and the calvarium cannot enlarge as rapidly as the
brain. When the overlying calvarium is too small, the CSF spaces are
not large enough to provide adequate buffering of normal variations
in intracranial pressure. Thus, unless the shunt is functioning perfectly,
patients have recurrent episodes of increased intracranial pressure.
However, because of the small size of the CSF spaces and the compres-
sion of the brain, the lateral ventricles do not enlarge significantly dur-
ing these episodes of increased pressure.
Affected patients typically present with recurrent, transient symptoms
of shunt failure. Imaging studies, however, will show small ventricu-
lar size (Fig. 8-43). Shunt function studies show the shunt system to
be patent, although flow may be reduced. Treatment is shunt revi-
sion or replacement with a valve having higher opening pressure (Fig.
8-43D). If this fails, bilateral temporal craniotomies are performed
in order to expand the volume of intracranial CSF. Theoretically, the
expanded intracranial space is better able to compensate for the tran-
sient changes in intracranial pressure that accompany the variations
in CSF production.
One finding on imaging studies that may help in the determination
of which patients have diminished buffering capacity is that of progres-
sive calvarial thickening. Such thickening may or may not be associ-
ated with premature synostosis of the cranial sutures; either way, the

FIG. 8-43. Slit ventricles. A. Initial CT scan demonstrating significant hydrocephalus. B. First post surgery CT shows that the
ventricles are still large, with rounded temporal horns but markedly improved. C. Two years later the child complains of headaches.
A new CT demonstrates almost completely effaced ventricles and pericerebral spaces (sulci and cisterns). D. After shunt revision,
headaches have resolved. The CT shows normal-looking ventricles.

Barkovich_Chap08.indd 849 5/6/2011 10:26:31 PM

 850 Pediatric Neuroimaging

result is a diminished reservoir of CSF to buffer the normal variations

in intracranial pressure (238).
It is less important for the radiologist to know all the possible
causes of small ventricles in a symptomatic patient than to realize that
the presence of very small ventricles after placement of a ventriculo-
peritoneal shunt is not diagnostic of, or even suggestive of, the “slit
ventricle syndrome.” This syndrome is a clinical, not a morphologic syn-
drome. Small ventricles are not, in the majority of cases, a problem;
they are the desired result of many surgeons after treatment of hydro-
cephalus and, even when extremely small, their only implication in the
vast majority of patients is that the shunt is functioning.

Imaging of Intracranial Hypotension

Beside the early development of subdural collections and the isolated
delayed “slit ventricle”, too much depletion of the ventricles may lead to
the progressive development of the imaging constellation characteris-
tic of intracranial hypotension, findings identical to those observed in
idiopathic cases, iatrogenic cases or cases related to pathologies such as
Marfan syndrome. Intracranial hypotension is important to recognize
as its clinical symptoms are similar to those of intracranial hyperten-
FIG. 8-44. Iatrogenic Chiari I secondary to placement of lumboperito-
sion, while the therapeutic goals are diametrically opposed. The main neal shunt. Midline sagittal T2-weighted image shows elongated cerebellar
symptom is a postural headache exacerbated by standing and relieved tonsils herniating through the foramen magnum.
by reclining. Other nonspecific neurological manifestations may be
observed, including cranial neuropathies and, in severe cases, coma.
When the condition is chronic, head MRI is diagnostic, showing a Other Complications
characteristic constellation of nonspecific abnormalities (265) (Fig.
8-42). The most typical findings are diffuse pachymeningeal (dural) Other complications resulting from ventriculo-peritoneal shunting
enhancement and thickening (PME/PMT) (100%) (Fig. 8-42B, C, E, are much less common. Complications within the abdomen typically
and F), and the venous distension sign (VDS) (100%) which reflects result from the shunt becoming too short while the child grows, and its
venous engorgement resulting from the low intracranial pressure (265) peritoneal end remaining in the same area instead of being displaced
(Fig. 8-42D and F). PMT may be seen without contrast administra- by the bowel displacements; they include ascites, pseudocyst formation,
tion on FLAIR images. VDS may be recognized on T1 imaging without perforation of a viscus or of the abdominal wall, intestinal obstruction
contrast as well, from observing the convexity of the sinus walls (265); (241,269), and catheter degradation (270). Very rarely, patients may
it is the first anomaly to resolve after normalization of the intracra- develop a granulomatous reaction adjacent to the shunt tube either
nial pressure (265). Other features may include subdural hygromas within or near the ventricle (271). These granulomatous lesions appear
or hematomas, effacement of the cisterns, and downward brain her-
niation (which can mimic the Chiari 1 malformation, Fig. 8-42F). An
increased height of the pituitary gland with convex upper border is
commonly observed as well (265) (Fig. 8-42F).
Another presentation of chronic intracranial overdrainage is that of
the complicated acquired Chiari I malformation (266). As mentioned
before, CSF diversion produces a major reduction of intracranial capac-
ity due to calvarial thickening, premature closure of the sutures (pos-
sible induced), and expansion of the paranasal sinuses and mastoid air
cells. The craniocerebral disproportion may be further complicated by
the development of intracranial hypertension with tonsillar herniation
that can only be relieved by a decompressive supratentorial craniotomy
(266). Imaging in this situation shows a small posterior fossa with ton-
sillar herniation through the foramen magnum, small ventricles, mark-
edly reduced pericerebral CSF spaces and prominent thickening of the
calvarium (266). As in all instances of intracranial hypotension, there
may be a pachymeningeal thickening, avidly enhancing after contrast
administration, and prominent widening of the dural venous sinuses.
Clinical features suggest intracranial hypertension with symptoms
pointing to the lower brainstem (266).
This is different from another variety of “acquired Chiari I malfor-
mation” (more accurately, another form of intracranial hypotension)
that is a fairly common complication of lumboperitoneal shunting FIG. 8-45. Interstitial edema and cyst formation secondary to shunt
(267) (Fig. 8-44). It is assumed to result from a CSF pressure differen- malfunction. A. Axial FLAIR image in a shunted 12-year-old hydrocepha-
tial between the cranium and the spine, but this explanation has been lic child shows the normal hypointensity of the ventriculostomy catheter
challenged (268). (arrow) coursing through the cerebrum.

Barkovich_Chap08.indd 850 5/6/2011 10:26:32 PM


FIG. 8-45. (Continued) B. Two years later, an area of edema surrounds the shunt. The central focus of low signal (arrow) likely
represents a cyst forming around the shunt. The child still is asymptomatic. C. At the age of 17, both the edematous area and the cyst
have increased in size, leading to a shunt revision.
as irregular, contrast-enhancing masses along the course of the shunt
tube. Calcification may be noted within the mass.
One final appearance of shunt malfunction should be mentioned.
Rarely, when the ventricular end of the shunt becomes partially
occluded, CSF may track along this shunt and enter the interstices of
the centrum semiovale. On these occasions, the CT and MR appear-
ance is that of edema (low density in the white matter on CT, pro-
longed T1 and T2 relaxation time in the white matter on MR) in the
area around the shunt. Eventually, an actual cyst may form in the white
matter surrounding the ventricular catheter (Fig. 8-45). It should be
recognized that the presence of edema in these patients is not the result
of infection or tumor but is a sign of shunt malfunction. The edema
and cyst will resolve after shunt revision.
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 CHAPTER
Congenital Anomalies
9 of the Spine
ERIN SIMON SCHWARTZ AND A. JAMES BARKOVICH
Normal and abnormal embryogenesis of the spine:
an overview
Gastrulation and neurulation
Canalization and retrogressive differentiation
Formation of the vertebral column
Anomalies of spinal formation: concepts
Clinical manifestations of spinal anomalies
Terminology
Counting anomalous vertebrae
Imaging techniques
Imaging of patients with idiopathic scoliosis
Abnormalities of neurulation (disorders in which the spinal
cord does not completely fuse posteriorly)
Disorders resulting from nondisjunction
Disorders resulting from premature disjunction—spinal lipomas
Anomalies of the caudal cell mass
Normal conus medullaris and filum terminale
The terminal ventricle
Anomalies of the filum terminale/tight filum terminale
(a simple spinal dysraphism)
Syndrome of caudal regression (a complex spinal dysraphism)
Terminal myelocystocele (a closed spinal dysraphism with a
subcutaneous mass)
NORMAL AND ABNORMAL
EMBRYOGENESIS OF THE SPINE:
AN OVERVIEW
An understanding of the normal embryonic developmental sequence
of the spine is invaluable to the understanding of spinal anomalies.
Furthermore, combining knowledge of embryology with understand-
ing of the anatomic relationships in the mature congenital lesion allows
insight into the time and stage of development at which the normal
sequence was altered; this insight leads to a better understanding of
developmental lesions. Normal development of the spine will therefore
be discussed in some detail.
Gastrulation and Neurulation
On about the 15th day of embryonic life, ectodermal cells proliferate
to form a plate, the primitive streak, along the surface of the embryo.
A rapidly proliferating group of cells forms at one end of the primi-
tive streak; this nodular proliferation, surrounding a small primitive
pit (known as Hensen node), defines the cephalic end of the primitive
Barkovich_Chap09.indd 857
Anterior sacral meningocele
Sacrococcygeal teratoma
Anomalies of development of the notochord
The split notochord syndrome spectrum (complex spinal
dysraphisms)
Split cord malformation (diastematomyelia and diplomyelia—
complex spinal dysraphism)
Malformations of unknown origin
Segmental spinal dysgenesis (a complex spinal dysraphism)
Dorsal meningocele (a closed spinal dysraphism with a
subcutaneous mass)
Lateral meningocele
Congenital tumors of the spine
Teratoma
Dermoid and epidermoid tumors
Hamartoma
Syringohydromyelia
Definition
Clinical presentation and course
Classification and causes
Theories of pathogenesis
Imaging
streak. At days 15 and 16, cells enter the primitive pit and migrate
inward between the ectoderm and endoderm and then course laterally
and undergo epithelial-to-mesenchymal transition, to form the inter-
posed mesoderm. Initially, no cells migrate in the midline; later, these
mesodermal cells will join in the midline to form the notochordal pro-
cess, which will eventually roll into a tube, separate from the endoderm,
and become the notochord. During a process known as intercalation,
the notochordal process fuses with the endoderm, creating a commu-
nication of the central canal of the notochordal process with the yolk
sac. As the central canal is already in communication with the amniotic
cavity through the primitive pit, a transient communication is present
all the way from the yolk sac to the amniotic sac; this communica-
tion is called the primitive neurenteric canal. Once formed, the noto-
chord induces the formation of a plate of ectodermal cells in the dorsal
midline, beginning immediately cephalad to Hensen node (Fig. 9-1).
Under the influence of bone morphogenetic proteins (BMPs), most
of the ectoderm is prevented from differentiating into neuroectoderm
(1). However, suppression of the BMPs by antagonists such as chor-
din, noggin, and follistatin, emanating from the primitive node, allows
neuroectoderm to form in the midline (1,2). The lateral edges of this
857
5/6/2011 10:28:20 PM
 858 Pediatric Neuroimaging
midline structure, now known as the neural plate, are contiguous with
the ectoderm from which the plate has differentiated, now known as
superficial or cutaneous ectoderm.
After the neural plate is formed, it is shaped into an elongated
structure that is broad at the anterior (cranial) end and narrow at the
posterior (caudal) end. The major driving force of the shaping is a
mediolateral elongation of a group of cells, along with development of
polarized cellular protrusions that enable the cells to migrate medially
and intercalate with neighboring cells close to the midline (3). This
midline convergence of cells causes an anterior-posterior elongation
and narrowing of the neural plate (4,5). This process is strongly related
to the development of cell polarity (4,5). Along with the process of
shaping, the neural plate also bends. At approximately 17 days of gesta-
tion, the lateral portions of the neural plate begin to thicken bilaterally,
forming the neural folds; the process of bending elevates these folds
and brings them to the dorsal midline (6). The process involves the for-
mation of “hinge points” at two sites: the median hinge point (MHP)
in the ventral midline and extending over the rostrocaudal extent of
the neural plate and the paired dorsolateral hinge points (DLHPs),
which form mainly at the levels of the developing brain (2) and lower
spine. The formation of these hinge points is controlled by secretion of
the signal transduction protein sonic hedgehog by the notochord (7),
as well as an inhibitory interaction between BMP2 and noggin, par-
ticularly in the lower spine (8). After formation of the hinge points, the
more lateral aspects of the neural plate are elevated around the MHP,
bringing the DLHPs upward and toward the midline (Fig. 9-2). This
elevation is accomplished by a poorly understood process called apical
constriction, in which columnar cells of the neural tube are converted
into wedge-shaped cells (9). Eventually, the lateral folds contact one
another in the dorsal midline and adhere to one another, with their
fusion forming the neural tube (neurulation). Neurulation seems to
begin separately at at least two different levels in humans, when cel-
lular protrusions (possibly cilia) project medially from the most dorsal
cells of the neural folds on either side. Cell recognition and adhesion
occur under the influence of many molecules (Ephrin-A5, EphA7,
neural cell adhesion molecule, and neural cadherin among them [3]),
closing the tube at each point. Immediately following closure, the
Barkovich_Chap09.indd 858
FIG. 9-1. Schematic showing the development of the neu-
ral plate. The primitive streak forms along the surface of the
embryo by about 15 days of embryonic life. A small primitive
pit lies at what will become the cephalic end of the primitive
streak; a nodular proliferation of cells surrounding the primi-
tive pit becomes known as Hensen node. On about days 15
and 16, cells enter the primitive pit and migrate cephalad in
the midline to form the notochordal process, which will even-
tually become the notochord. The notochordal process and
notochord induce formation of a plate of ectodermal cells
dorsally in the midline; this is the neural plate.
overlying ectoderm separates from the neural tissue and the edges of
the ectoderm meet in the midline and fuse, forming a continuous ecto-
dermal covering of the neural structures, with the mesenchymal cells of
the neural crest migrating between the cutaneous and neural ectoderm
layers (2). Progressive folding and closure of the neural structures and
separation from ectoderm then proceed both cranially and caudally
from each point of initial closure, ultimately resulting in complete
closure (10–13). The initial closure of the neural tube in humans, the
posterior neuropore, is believed to be at the hindbrain-cervical junction,
from which closure extends in both directions. A second site of closure
in mice is at the forebrain-midbrain boundary; this site has not been
confirmed in humans. The necessity of this site even in mice is ques-
tionable, as about 80% of mice that lack the second closure point still
achieve complete cranial closure (14). The “third” site of closure occurs
at the most rostral extremity of the forebrain, the lamina terminalis
(2). The exact site of the most caudal end of the neurulation-formed
neural tube has been debated, but most experts believe that it is at the
S-2 level (12,15–21).
Canalization and Retrogressive Differentiation
A portion of the neural tube develops caudal to the posterior neu-
ropore. This elongation is not due to primary neurulation but is the
result of another process known as canalization (or secondary neu-
rulation). In this process, a caudal cell mass (also called the tail bud),
composed of undifferentiated, pleuripotential cells (the residua of the
primitive streak [2,21]), forms in the tail fold as a result of fusion of
neural epithelium (at the caudal end of the embryo) with the noto-
chord. Ventral to the caudal cell mass, with the notochord interposed,
lies the cloaca, which will form the cells of the anorectal and lower
genitourinary tract structures.
By the time the embryo is 30 days old, multiple microcysts and
clumps of cells begin to appear in the caudal cell mass. These micro-
cysts coalesce to form an ependyma-lined tubular structure that unites
with the neural tube above (Fig. 9-3). This process is not as organized as
the process of neurulation; the multiple accessory lumina and ependy-
mal rests in the normal filum terminale and distal conus medullaris
5/6/2011 10:28:20 PM
 Chapter 9 • Congenital Anomalies of the Spine 859

FIG. 9-2. Normal and abnormal neurulation. A–E. Normal neurulation. The neural plate is composed of neural ectoderm, which is continuous with
cutaneous ectoderm on either side. The cells at the junction of the neural ectoderm and cutaneous ectoderm will eventually differentiate into neural crest
cells (A). At approximately 17 days of gestation, the lateral portions of the neural plate begin to thicken, forming the neural folds (B). Contractile filaments
located in the neuroepithelial cells in the neural folds contract, causing the neural folds to bend dorsally along the entire length of the neuroaxis, bringing the
edges of the neural folds toward one another in the midline (C). Neurulation (closure of the neural tube) begins when the neural folds meet in the midline.
At the time of closure, the overlying ectoderm separates from the neural tissue and fuses in the midline, forming a continuous ectodermal covering of the
neural structures. At the same time, the neural crest cells are extruded from the neural tube to form a transient structure immediately dorsal to the tube
(D). Eventually these neural crest cells will migrate to form dorsal root ganglia and multiple other structures (E). F–G. Abnormal neurulation. When there
is premature disjunction of neural ectoderm from cutaneous ectoderm, the surrounding mesenchyme gains access to the inner surface of the neural tube.
When mesenchyme comes in contact with this primitive ependymal lining, it evolves into fat. This is believed to be the process underlying the formation
of spinal lipomas (F). Complete nondisjunction of cutaneous ectoderm from neural ectoderm results in the formation of myelomeningoceles (Fig. 9-4).
Focal nondisjunction results in a persistent epithelium-lined connection between the central nervous system and the skin (G). This persistent connection
has been labeled a dorsal dermal sinus.

of the adult are believed to result from the disorder of this process.
Several neuronal markers expressed in vertebrate embryos are thought
to modulate the differentiation of structures derived from the caudal
cell mass and be involved in the maturation of the caudal spinal cord.
These include N-CAM, synaptophysin, 3A10, and NeuN (22). The
final stage in the formation of the distal spinal cord begins at about
38 days of gestation, at which time the cell mass and central lumen
of the caudal neural tube decrease in size as a result of programmed
cell death (apoptosis) of the portion derived from primary neurula-
tion (21) and necrosis of the portion derived from secondary neuru-
lation (23). This process has been named retrogressive differentiation
(Fig. 9-3). The caudal segment (formed by canalization and retrogres-
sive differentiation) eventually becomes the most caudal portion of
the conus medullaris, the filum terminale, and a focal dilatation of the
central canal (within the conus medullaris) known as the ventriculus
terminalis (15–20,24).

Barkovich_Chap09.indd 859 5/6/2011 10:28:21 PM

 860 Pediatric Neuroimaging

FIG. 9-3. Canalization and retrogressive differentiation. After formation of the neural tube, a caudal cell mass forms in the tail fold as a result of fusion of
neural epithelium at the caudal end of the embryo with the notochord (A). By the age of 30 days, multiple cysts and clumps of cells appear in the caudal cell
mass (B). These cysts coalesce to form a tubular structure that unites with the neural tube above (C). At about 38 days, the cell mass and central lumen of the
caudal neural tube decrease in size through cell necrosis in a process known as retrogressive differentiation. The segment formed by this process eventually
forms the distalmost conus medullaris, the filum terminale, and the terminal ventricle (D).

Formation of the Vertebral Column
Formation of the vertebral column was discussed in Chapter 2 and
illustrated in Figure 2-23. A review of the subject is given here, as well,
for convenience of the reader. Development of the vertebral column
can be divided into three periods. The first of these is membranous
development. At about the 25th gestational day, the notochord sepa-
rates from the primitive gut and neural tube to create two zones, the
ventral subchordal and dorsal epichordal zones. These zones are filled
with mesenchyme, which migrates to them from its initial position lat-
eral to the neural tube.
The mesenchyme lateral to the closing neural tube organizes into
somites, which are separated by small intersegmental fissures. Somite
formation progresses from rostral to caudal (25). Each somite is
divided into a medial (medial sclerotome) and a lateral (lateral myo-
tome) portion. The medial sclerotome contributes to the formation of
the vertebrae, while the lateral myotome gives rise to the paraspinous
musculature. After the neural tube has closed and becomes separated
from the superficial ectoderm, mesenchyme also migrates dorsal to the
neural tube to form the precursors of the neural arches (in addition
to the meninges and paraspinous muscles). Differentiation of the ven-
tral and dorsolateral mesenchyme, which will form the vertebral body,
results from induction by the sonic hedgehog protein, whereas the dif-
ferentiation of the dorsal mesenchyme, which will form the posterior
elements, results from induction by a protein called BMP4 (26). Sub-
sequently, the sclerotomes separate transversely along the previously
mentioned intersegmental fissures. The inferior half of one sclerotome
then fuses with the superior half of the subjacent sclerotome across the
fissure to form a vertebral body. This process proceeds bilaterally and
symmetrically so that the fusion of the sclerotomes on each side forms
half of the vertebral body on that side. As a consequence of this reseg-
mentation, the intersegmental arteries and veins become located in the
center of the new vertebral bodies.
During the second (chondrification) stage of vertebral development,
chondrification centers appear within sclerotomes at the cervicotho-
racic junction region during the sixth embryonic week and then extend
rostrally and caudally. Six centers will form each vertebral level, with
two in the vertebral centrum, two forming the posterior vertebral arches
and spinous process, and two within the transverse processes and cos-
tal arch (27). Notochordal remnants persist between the newly formed
vertebral bodies and become incorporated into the intervertebral discs
as the nuclei pulposi. Portions of the thoracic sclerotomes later migrate
ventrolaterally to form ribs. The anterior and posterior longitudinal
ligaments form during chondrification, from mesodermal cells.
In the final stage of vertebral development (ossification), the chon-
dral skeleton ossifies to complete the formation of the vertebrae. Ossi-
fication starts in three centers, one in the middle of the vertebral body
and one in each vertebral arch. The thoracolumbar junction region is
the first to ossify, with rostral and caudal ossification to follow. The
formation of the vertebrae at the caudal end of the embryo proceeds
by a different, less organized process. A mass of cells composed of

Barkovich_Chap09.indd 860 5/6/2011 10:28:22 PM


notochord, mesenchyme, and neural tissue merely divides into somites
to form the sacral and coccygeal levels. Regression results in reduction
and fusion of most of these segments. As in development of the caudal
neural tube, this apparent disorganization of the caudal cell mass leads
to frequent anomalous development. Caudal regression syndromes,
lipomas, and teratomas can result (28,29).
Anomalies of Spinal Formation: Concepts
Embryological Concepts and Theories
Embryological explanations of anomalies of the developing spine are
continually evolving. As new facts are discovered, old theories some-
times have to be discarded and new theories developed. In contrast
to mathematical theories, embryological theories cannot be proved
correct; they can only be verified or disproved. In clinical medicine, a
theory is useful if it explains observations and helps to organize a clas-
sification; the ability to predict future observations is an added bonus.
The classification scheme used in this chapter is based primarily upon
a theory of spinal dysraphism developed by David McLone, MD, PhD
and Thomas Naidich, MD when they worked together at the Children’s
Memorial Hospital in Chicago, Illinois; this work was based on original
concepts by Della Rovere (30). The more recent clinical-radiological
classification scheme proposed by Tortori-Donati et al. (31) incorpo-
rates much of the work of the older classification schemes and adds a
clinical component; however, it is not entirely in agreement with the
earlier works. This chapter discusses aspects of both classifications,
as they are the most useful theories we have found for classifying and
explaining anomalies of the spine.
Developmental neurogenetics are largely ignored in the discussion
of spine anomalies in this chapter. This is not in any way an attempt
to minimize the value of developmental neurogenetics. Indeed, spi-
nal anomalies result from a multitude of factors and genetic fac-
tors are likely among the most important (interested readers can see
[2,3,9,32–37]). However, despite many major advances in genetics over
the past 10 years, the details of developmental neurogenetics of normal
and abnormal spinal development are still being worked out, and the
inclusion of the bits and pieces that are known would likely prove more
confusing than enlightening to most practicing clinicians.
Neurulation Anomalies
The process of separation of the neural tube from the cutaneous
ectoderm during closure of the neural tube is known as disjunction.
FIG. 9-4. Open spinal dysraphism (Myelocele and Myelomeningocele). A. Myelocele. The neural placode is a flat plaque of neural tissue that is exposed to
the air. The dura is deficient posteriorly; the pia and arachnoid line the ventral surface of the placode and dura, forming an arachnoid sac that is continuous
with the subarachnoid space superiorly and inferiorly. Both the dorsal and ventral roots arise from the ventral surface of the placode. B. Myelomeningocele.
This is identical to the myelocele with the exception that there is an expansion of the ventral subarachnoid space, which posteriorly displaces the placode.
Barkovich_Chap09.indd 861
Chapter 9 • Congenital Anomalies of the Spine 861
After disjunction, the cutaneous ectoderm fuses in the midline,
dorsal to the closed neural tube. At the same time, perineural mes-
enchyme migrates into the newly created space between the neural
tube and cutaneous ectoderm, surrounds the neural tube, and is
induced to form the meninges, the bony spinal column, and the
paraspinous musculature (38). The mesenchyme normally remains
isolated from the newly formed central canal of the spinal cord
because the neural tube closes immediately prior to, or simultane-
ously with, disjunction.
Defective disjunction can explain a number of diverse patho-
logic lesions. For example, focal unilateral premature disjunction of
the neural ectoderm from the cutaneous ectoderm (prior to clo-
sure of the neural tube) allows the perineural mesenchyme to gain
access to the neural groove and come in contact with the primi-
tive ependymal lining of the groove. Mesenchyme that is exposed
to the interior of the neural tube seems to develop into fat, either
by receiving signals promoting adipocyte (fat cell) production or by
the blockage of signals that prevent adipocyte production (39,40).
Therefore, focal premature disjunction of neural ectoderm from the
superficial ectoderm could explain the development of spinal lipo-
mas and lipomyelomeningoceles (41) (Fig. 9-2F). Spinal lipomas
situated rostral to the filum terminale seem to be formed in this
manner. Lipomas caudal to the conus medullaris more likely form
as a result of other processes, such as abnormal development of the
caudal cell mass.
Other anomalies of the spine can be explained by failure of dis-
junction. Dermal sinus tracts may be the consequence of focal failure
of disjunction, resulting in a focal ectodermal-neural ectodermal tract
(Fig. 9-2G). A related entity has been recently described, the dermal-
sinus-like stalk, in which there is a solid stalk composed of fibrous
tissue and fat (with or without nervous tissue) rather than the epithe-
lium-lined tract of the typical dermal sinus (42). The tract should pro-
hibit mesenchyme from migrating between the neural ectoderm and
cutaneous ectoderm at that site, forming a focal spina bifida as is com-
monly seen in children with dermal sinus tracts. Moreover, the adhe-
sion between the ectoderm and neural ectoderm could explain the
correlation of the dermatome level of the cutaneous lesion with the
neuroectodermal level of the central nervous system termination of
the tract. Open spinal dysraphism (OSD) (myelocele and myelomenin-
gocele) can be explained as a large area of nondisjunction (Figs. 9-2
and 9-4). These concepts are discussed in more detail in later sections
of this chapter.
5/6/2011 10:28:23 PM
 862 Pediatric Neuroimaging
Association of Spinal Anomalies with Other
Systemic Anomalies
Spinal malformations are very commonly associated with anomalies of
the viscera, as well as those of the spinal column. As discussed previ-
ously, the caudal cell mass forms in close anatomic proximity to the
cloaca, the region of origin of the lower genitourinary tract and ano-
rectal structures. As a result of this close embryological relationship,
patients with anorectal and urogenital anomalies have a high incidence
of lumbosacral hypogenesis, terminal myelocystoceles, and tethered
spinal cords (and vice versa) (43–45). Moreover, the notochord is
associated with the induction of normal formation of thoracic and
abdominal viscera, as well as the neural tube. Therefore, patients with
spinal anomalies secondary to abnormal formation of the notochord
will often have anomalies of the upper gastrointestinal tract or the
respiratory tract. Finally, it is important to remember that the devel-
opment of the vertebral column is influenced by many of the same
factors that influence development of the spinal cord. Therefore, any
condition that results in vertebral anomalies, such as the VACTERL
syndrome (46), the Klippel-Feil syndrome (47), and lumbosacral
hypogenesis (48,49) should be investigated for associated anomalies
of the spinal cord.
CLINICAL MANIFESTATIONS OF SPINAL
ANOMALIES
Many patients with spinal anomalies present either with external
manifestations of the anomaly or with the tight filum terminale (teth-
ered cord) syndrome. The external manifestations vary with the type
of anomaly and are described in more detail in the sections on the
specific anomalies themselves. They include cutaneous hemangiomas,
dimples, hairy patches, atypical scoliosis, and large subcutaneous
lipomas. The syndrome of the tight filum terminale, also known as the
tethered spinal cord syndrome, denotes a complex of neurologic and
orthopedic deformities. This clinical syndrome may be associated
with split cord malformation (SCM), with spinal lipoma, or with a
short, thick filum terminale; frequently the conus medullaris is in a
low position. Patients may present with new onset of symptoms at
any age (50); the authors have seen patients in nearly every decade
of life (as late as the eighth decade) become suddenly symptomatic
from their tethered spinal cords. Patients suffer from difficulty with
locomotion, ranging from muscle stiffness to actual weakness; some
exhibit abnormal lower extremity reflexes. The patients can also
exhibit bladder dysfunction (usually manifest as a low-pressure, drib-
bling urine stream), sensory changes with abnormal somatosensory
evoked potentials, orthopedic deformities of the lower extremities
(most commonly clubfoot), and back pain (particularly with exer-
tion). Urodynamic studies are typically abnormal. Bowel dysfunc-
tion is uncommon. Although scoliosis frequently accompanies this
syndrome, it is rarely the sole complaint (20,51–53). Symptoms are
frequently worse in the mornings and after exercise. An increased
incidence of tethered spinal cords is seen in lumbosacral hypogenesis,
in the VACTERL syndrome (46,49), and in anorectal malformations
(imperforate anus), including low lesions (54).
Adults with tethered spinal cords may present somewhat differently
than affected children. Adults present more often with pain, possibly
because of accompanying degenerative changes, and less commonly
with incontinence, weakness, or scoliosis (50,53). Indeed, it has been
suggested that tethering of the spinal cord accelerates disc degenera-
tion. Adults who present with symptoms of lumbar disc degeneration
without magnetic resonance imaging (MRI) evidence of disc disease
should be investigated for a tight filum terminale (55).
Barkovich_Chap09.indd 862
TERMINOLOGY
The term spinal dysraphism refers to a heterogeneous group of spinal
anomalies. In spite of their heterogeneity, all lesions within this group
have incomplete midline closure of mesenchymal, osseous, and nervous
tissue (20).
Spina bifida refers to incomplete closure of the bony elements of
the spine (lamina and spinous processes) posteriorly (56,57).
OSD includes the myelocele, a midline plaque of neural tissue that
lies exposed at and is flush with the skin surface, and the myelomenin-
gocele, a myelocele that has been elevated above the skin surface by
expansion of the subarachnoid space ventral to the neural plaque.
Closed spinal dysraphisms are a group of lesions that develop
beneath an intact dermis and epidermis; that is, there is no exposed
neural tissue (58). The clinical-radiological classification system of
Tortori-Donati, Rossi, and Cama subdivides this group into lesions
with a subcutaneous mass (usually the result of a subcutaneous lipoma
or a simple meningocele) and those without a subcutaneous mass (31)
(Table 9-1). Included in the category of closed spinal dysraphism with
a subcutaneous mass are lipomas with dorsal defect of the bony spi-
nal canal (lipomyelocele and lipomyelomeningocele), meningocele,
and myelocystocele. Anomalies with closed spinal dysraphism lacking
a subcutaneous mass include the simple dysraphic states (fatty and/or
fibrous thickening of the filum terminale, intraspinal lipoma, spina
bifida, and persistent terminal ventricle) and the complex dysraphic
states (SCM, dorsal dermal sinus, caudal regression syndrome, segmen-
tal spinal dysgenesis, neurenteric cyst, and dorsal enteric fistula).
TABLE 9-1 Clinical-Radiological
Classification System
for Spinal Dysraphism
Open Spinal Dysraphism
(Hemi-)myelomeningocele
(Hemi-)myelocele (also known as myeloschisis)
Closed Spinal Dysraphism
With a Subcutaneous Mass
Lipoma with dorsal defect (lipomyelomeningocele and
lipomyelocele)
Myelocystocele (terminal or cervical)
Meningocele
Cervical myelomeningocele
Without a Subcutaneous Mass
Simple Dysraphic States
Spina bifida
Persistence of the terminal ventricle
Intraspinal lipoma (intradural or filum terminale)
Tight filum terminale (fibrous thickening)
Complex Dysraphic States
Dorsal dermal sinus
Caudal regression syndrome
Split notochord syndrome (dorsal enteric fistula and neurenteric cyst)
Split cord malformation (diastematomyelia and diplomyelia)
Segmental spinal dysgenesis
Adapted from Tortori-Donati et al. (31).
5/6/2011 10:28:24 PM

Counting Anomalous Vertebrae
Identifying the specific level in patients with vertebral anomalies, such
as hemivertebrae and butterfly vertebrae, can be challenging. One way
to approach this is to count all of the vertebrae (normal ones, butter-
fly vertebrae, and hemivertebrae) in the numbering, but to designate
the hemivertebra as being extra by adding an “h” and the butterfly by
adding a “b.” For example, if C-6 is a hemivertebra, it is referred to as
C-6h. A butterfly T-8 would be T-8b. A report of a patient with these
two segmentation anomalies would state that the spine is not a C-7/T-
12/L-5/S-5 (i.e., normal) spine, but a C-8(1h)/T-12(1b)/L-5/S-5 spine
with the hemivertebra at C-6 and the butterfly vertebra at T-8. This
system can be useful for transmitting the necessary clinical data to the
referring physician. Accurate determination of vertebrae can only be
performed by labeling from the craniocervical junction and proceed-
ing inferiorly.
IMAGING TECHNIQUES
The spine can be imaged using a variety of techniques. Sonography,
x-ray computed tomography (CT), and MRI can all give exquisite
images of the diverse anatomic anomalies that characterize these enti-
ties (40,47,48,58–89). Therefore, an understanding of the characteristic
anatomic features that distinguish these various entities may be more
important than the imaging modality for the diagnosis and presurgical
planning of these entities.
An important concept to remember, however, is that a single
patient may have multiple spinal anomalies. For example, a patient
with a lipomyelomeningocele may have, in addition, SCM, a tight filum
terminale, or a dorsal dermal sinus. Therefore, it is important to image
the entire spine if a cutaneous anomaly or vertebral anomaly suggests
the presence of a malformation. The ability to noninvasively perform
high-resolution imaging of the entire spine in the sagittal and coronal
planes in a very few sequences without ionizing radiation is an advan-
tage of MR that other modalities cannot match. For example, one study
comparing MR and ultrasound in the infant spine found that, while a
normal ultrasound was sufficient to rule out most spinal pathology,
additional pathology is picked up by MR in 20% of cases (90). Detec-
tion of a thick or fatty filum terminale in a patient whose conus medul-
laris terminates at a normal level may be difficult with sonography but
is easy on axial MR images. Finally, sonography becomes progressively
less useful as ossification of the posterior elements proceeds during the
first year of life while MR remains superb. Typical MR sequences for
spine imaging are discussed in Chapter 1. It should be added that spiral
CT, with the rapid scanning time and easy curvilinear and planar ref-
ormations (in any plane) allow excellent evaluation of osseous spinal
anomalies and, if intrathecal contrast is administered, good evalua-
tion of intraspinal lesions. In our practices, MRI is currently the initial
imaging modality of choice because it is noninvasive and does not use
ionizing radiation but, for some cases, CT myelography gives impor-
tant supplementary information.
Imaging of Patients with Idiopathic Scoliosis
While the necessity of preoperative imaging with MRI was previously
controversial, there is now general agreement that patients with scolio-
sis should have their spinal columns imaged by MR before undergoing
distraction and instrumentation of their spines (91). This is particu-
larly true in any patient presenting with clinical deterioration, atypi-
cal features of scoliosis (rapid progression, abnormal location of the
curve, or a left thoracic curve), neurological signs or symptoms (92),
age less than 11 years (93), or severe scoliosis (Cobb angle > 45°–50°)
Barkovich_Chap09.indd 863
Chapter 9 • Congenital Anomalies of the Spine 863
(92,94). In these patients, MRI should be used to look for neoplasm,
Chiari I malformation, syringohydromyelia, tethered spinal cord or
other cord anomaly, and intradural or extradural cysts. Any of these
conditions can lead to scoliosis; more importantly, surgical treatment
of the scoliosis before treatment of the underlying disorder may result
in increased neurologic disability.
ABNORMALITIES OF NEURULATION
(DISORDERS IN WHICH THE SPINAL
CORD DOES NOT COMPLETELY FUSE
POSTERIORLY)
Disorders Resulting from Nondisjunction
Open Spinal Dysraphism—Myelocele and
Myelomeningocele
Myeloceles and myelomeningoceles most likely result from a localized
lack of closure of the neural tube, resulting from a lack of expression of
specific receptors on the surface of the neuroectodermal cells (34,95).
Most authors use the term “myelomeningocele” to refer to any OSD; we
use the term OSD to encompass the myelocele and myelomeningocele.
All other anomalies are considered closed spinal dysraphisms.
Open neural tube defects cause neurological disabilities, including
paraplegia, hydrocephalus, incontinence, sexual dysfunction, skeletal
deformities, and, often, cognitive impairment (96). Experimental evi-
dence suggests that the neurological deficits of patients with OSD are
not entirely caused by the open neural tube defect, but also by chronic
mechanical injury and amniotic fluid-induced chemical trauma that
progressively damages the exposed fetal neural tissue during gestation
(97,98). Early in utero repair of OSD in fetal sheep has been shown
to interrupt the spinal cord injury and improve spinal cord function
at the time of birth (97). Several institutions have performed in utero
OSD repairs in human fetuses; reports suggest postoperative improve-
ment of the associated Chiari II malformation, ventriculomegaly,
lower extremity function, and brainstem function (99–102) in fetuses
treated before 25 gestational weeks. Thus, prenatal diagnosis of OSD
by ultrasound or MRI (Fig. 9-5) has made postnatal diagnosis much
less common, in regions where these modalities are widely available.
The ongoing prospective multi-institutional study will determine the
benefits of prenatal repair of this spinal anomaly on neurological and
functional outcome.
The exact cause of the impaired closure of the neural tube in
patients with OSD has not been discovered. Environmental factors
implicated in increasing the risk include socioeconomic class, mater-
nal age, maternal diet, maternal diabetes and obesity, and exposure
to antiepileptic drugs. Genetic components include association with
trisomy 13, 18, and 21; association with genetic syndromes (Meckel
syndrome and anal stenosis); racial differences in incidence rates;
increased risk for a second affected child (3–5×) for couples who have
one affected infant; and a tenfold increase in risk for siblings of affected
children compared to the general population (103,104). Strong evi-
dence has accumulated for a protective role of folate in this disorder.
Animal work suggests that the folate deficiency impairs biosynthesis
of pyrimidine, the presence of which may help to compensate for an
underlying genetic predisposition (105). Localized differences in folate
metabolism exist early during neural tube formation, and it is believed
that folate may modulate proliferation in the midline via effects on
Aldh1l1+ cells (106). Offspring of women whose diet is supplemented
with folate have a significantly reduced incidence of neural tube defects
(10,107–109). This has led to investigations of genes involved in folate
metabolism as being potentially related to development of OSD.
5/6/2011 10:28:24 PM
 864 Pediatric Neuroimaging

FIG. 9-5. Prenatal imaging of an OSD (myelomeningocele). A. Sagittal sonogram using 4-MHz transducer shows a focal loss of the normal echogenicity
of the posterior elements of the vertebrae, indicating a bony spina bifida. The meningocele is seen as a hypoechogenic region (arrows) extending dorsally
at the level of the spina bifida. B. Higher resolution image using 8-MHz transducer shows curvilinear echoes (arrows) representing neural tissue running
through the meningocele. C. Sagittal image through the spine shows the lumbosacral spina bifida with the dorsal myelomeningocele (small white arrows).
The Chiari II malformation (larger white arrows) is seen at the craniocervical junction. Note the massive hydrocephalus. D. Axial image shows the dorsal
bony spina bifida. At this level, the placode (black arrows) is still within the spinal canal.

Two identified polymorphisms (C677T and possibly A1298C) in
the homocysteine remethylation gene MTHFR are associated with a
1.8-fold increase in the risk of an open neural tube defect (14). Interest-
ingly, although offspring of obese women (defined as weighing more
than 70 kg) have an increased incidence of neural tube defects, no risk
reduction has been found among these women after administration of
folate (110,111), possibly because women with high body mass indi-
ces have low folate levels compared with nonobese women, even when
controlling for folate intake (112).
In patients with OSD, the neural folds do not fuse in the midline
to form a neural tube in the affected zone; instead, the neural tube
remains open and the neural folds remain in continuity with cutane-
ous ectoderm at the skin surface (nondisjunction). The region of open
spinal cord, located at the skin surface and open to the air in the pos-
terior midline, is a region of reddish tissue referred to as the neural
placode. The posterior (dorsal) surface of the placode is made up of the
tissue that would normally form the internal, ependymal lining of the
neural tube. The anterior (ventral) surface of the placode corresponds
to what would normally be the external surface of the spinal cord
(pia mater) (Fig. 9-4).
The lack of separation of the placode from the cutaneous ectoderm
prevents the mesenchyme from migrating into the area posterior to the
neural ectoderm; it is forced to remain anterolateral to the nervous tis-
sue. Thus, the pedicles and lamina (which are formed from this mesen-
chyme) are everted, facing posterolaterally instead of posteromedially
(Fig. 9-4). As a result of the external rotation of the lamina and pedi-
cles, the spinal canal undergoes a fusiform enlargement throughout
the extent of the posterior osseous defect. The maximum enlargement
of the canal occurs when the laminae are in the sagittal plane; further
rotation of the lamina diminishes the size of the canal (20).

Barkovich_Chap09.indd 864 5/6/2011 10:28:24 PM

 Chapter 9 • Congenital Anomalies of the Spine 865

The vertebral bodies can be nearly normal or can have anomalies
of segmentation ranging from a single hemivertebra to a jumbled
mass of malsegmented vertebral components. Segmentation anoma-
lies result in a short radius kyphoscoliosis in approximately one-third
of patients with myelomeningoceles (20). Another 65% of affected
patients develop a (less severe) kyphoscoliosis as a result of a neuro-
muscular imbalance (113,114).
In children with lumbar or lumbosacral OSD, the spinal cord is
always tethered. The nerve roots in affected patients radiate in a spoke-
wheel pattern as they leave the placode and travel rostrally, laterally,
and caudally to their respective neural foramina.
Imaging studies are rarely required in the newborn with an OSD
(Fig. 9-6). The exposed placode is obvious upon visual examination
and is usually repaired within 48 hours. After repair, the infants typi-
cally have a neurological deficit that is stable. They should not further
deteriorate if the accompanying hydrocephalus, which is almost always
present unless the patient has had a prenatal repair, is controlled. Neu-
roradiologic examination of the spine is indicated if patients deterio-
rate neurologically in spite of adequate treatment of hydrocephalus or
if they have an unusual neurological examination, such as an asymmet-
ric lower extremity neurological deficit, which should raise suspicion
that the patient has a SCM and hemiOSD.

FIG. 9-6. Myelomeningocele in a neonate. A and B. Sagittal T1-weighted (A) and T2-weighted images (B) show the spinal cord coursing caudally within
the spinal canal to the sacral level. The cord is expanded by syringomyelia (s), with some air (small white arrows) producing some susceptibility artifact
within the syrinx. The neural placode (p) extends dorsally through the bony spina bifida. The asterisks mark a wet cloth covering the placode. C. Axial
T1-weighted image shows the spinal cord (arrows) traversing the subarachnoid space from the spinal canal to the skin surface where it will form a placode.
D. Axial T1-weighted image at a lower level shows the placode (p) at its dorsal extent, covered by the wet cloth (asterisk).

Barkovich_Chap09.indd 865 5/6/2011 10:28:26 PM

 866 Pediatric Neuroimaging

FIG. 9-7. Hemimyelocele. A. Sagittal T1-weighted image shows a repaired myelomeningocele (curved arrows) at the thoracolumbar level and focal syrin-
gohydromyelia (straight arrows) in the cervicothoracic spinal cord. B. Axial T1-weighted image reveals a SCM in the thoracic region. The right hemicord
(arrow) is dilated by hydromyelia. C. At the level of the myelomeningocele repair, the right hemicord is a flattened placode (small arrows), which is tethered
to the dura and epidural fat. The smaller left ventral hemicord (large arrow) was not appreciated at the time of repair.

HemiOSD
Cameron (115), Emery and Lendon (116), and Pang (117) have shown
that between 31% and 46% of patients with OSD have associated SCM.
The spinal cord may be split above (31%), below (25%), or at the same
level (22%) as the OSD (116). In addition to the patients with frank
SCM, 5% of patients with OSD have a duplication of the central canals
of the spinal cord cephalic to and at the level of the placode, indicating
a mild form of splitting that is insufficient to affect the gross contour
of the cord (116).
The hemiOSD, a special form of OSD with SCM, is observed in
less than 10% of patients with OSD (116,118). In the hemiOSD, one
of the two hemicords exhibits a small OSD that tends to lie on one
side of the midline, whereas the other hemicord is either normal, teth-
ered by a thickened filum terminale (Fig. 9-7), or has a smaller OSD
at a much lower level. The two hemicords usually lie in separate dural
tubes that are separated by a fibrous or bony spur. Occasionally, the two
hemicords lie within a single dural tube, which becomes deficient at the
level of the hemiOSD. In general, affected patients have impaired neu-
rological function on the side of the hemiOSD but normal or nearly
normal function on the normal side (118). Imaging studies (Fig. 9-7)
will show the splitting of the spinal cord, the extent and symmetry (or
lack thereof) of the OSD, the presence or absence of the bony spur,

Barkovich_Chap09.indd 866 5/6/2011 10:28:27 PM


and any other anomalies that may alter the surgical approach. SCM is
discussed more fully later in this chapter.
Postoperative Complications
After repair of an OSD, patients usually have a stable neurological defi-
cit. Deterioration in neurologic function, therefore, suggests the pres-
ence of a complication. There are five major causes of postoperative
neurological deterioration in this group of patients: (i) the spinal cord
and placode may be tethered by scar or by a second, previously unrec-
ognized malformation; (ii) the dura may be pulled too tightly when
approximated over the placode, forming a constricting dural ring; (iii)
the spinal cord may be compressed by a dermoid or epidermoid tumor
or an arachnoid cyst; (iv) ischemia may occur because of vascular com-
promise; (v) there may be syringohydromyelia (119,120).
Retethering of the cord by scar is a diagnosis that essentially can
only be made by exclusion of other causes. The purpose of imaging
patients after the repair of OSD is to identify one of these causes.
If no other cause for neurological deterioration is identified, the
clinical diagnosis of retethering is made. It is possible that the diag-
nosis of retethering may be suggested or verified by demonstrating
diminished motion of the cervical spinal cord by phase contrast MRI
(121,122). The normal spinal cord moves caudally at a velocity of
Barkovich_Chap09.indd 867
Chapter 9 • Congenital Anomalies of the Spine 867
1 cm/s during CSF diastole (at which time, CSF is moving rostrally
at a velocity of up to 2 cm/s) and moves rostrally during CSF systole
(122). In patients with spinal cord tethering, this motion is damped
and the cord velocity is reduced (121,122). However, it is not trivial
to calibrate your MR scanner in order to make these measurements
accurately. In addition, the presence of scoliosis may reduce cord
motion in the absence of tethering. Moreover, the sensitivity and
specificity of the phase contrast examination in making this diagno-
sis has still not been established in large scale trials. Therefore, this
technique is not widely used at the time that this edition is being
written.
Associated malformations are common. SCM (Figs. 9-7 and 9-8)
or dermal sinuses are seen in up to 46% of patients with OSD. Hydro-
cephalus and the Chiari II hindbrain malformation frequently develop
in the absence of prenatal repair. Therefore, patients with neurological
deterioration after OSD repair must have their entire craniospinal axis
evaluated. We typically perform sagittal and axial T1- and T2-weighted
study of the brain, followed by a coronal study of the entire spine (to
assess for vertebral anomalies and a split spinal cord malformation).
Finally, sagittal T1- and T2-weighted images are obtained of the entire
spine, with sagittal FLAIR and axial T1- and T2-weighted imaging of
the lumbar spine.
FIG. 9-8. Patient with multiple causes of
neurologic deterioration after myelom-
eningocele repair at birth. A and B. Sagittal
T1-weighted images show multiloculated
hydromyelia (arrows) in the lower cervical
and upper thoracic spinal cord. C and D.
Sagittal T1-weighted image in the lower
thoracic region shows thinning of the cord
(small arrows), another possible cause of
neurologic deterioration, and a large
bony spur (large arrow). E and F. Axial
T1-weighted images show SCM, with two
hemicords (black arrowheads) and a bony
spur (white arrow). The right hemicord is
dilated by hydromyelia.
5/6/2011 10:28:28 PM
 868 Pediatric Neuroimaging
Dermoids and epidermoids can appear as developmental tumors or
as tumors that result from lumbar puncture or OSD repair (119,123–
126). They may be more common following in utero OSD repair (101);
however, this cannot be confirmed until the results of the multicenter
prospective trial are available. On imaging studies, dermoids and epi-
dermoids appear as intraspinal masses that may be intramedullary or
adherent to the spinal cord, the roots of the cauda equina, or the wall of
the thecal sac (64,66,127,128). It is not possible to distinguish between
dermoids and epidermoids by CT or myelography; on MRI, some
dermoids will show a markedly shortened T1 relaxation time. More
commonly, both epidermoids and dermoids are difficult to identify by
MRI because they can be isointense with cerebrospinal fluid (Fig. 9-9);
however, compression of the adjacent cord or displacement of nerve
roots by the tumor will indicate presence of the mass (64). The mass
can be confirmed by imaging using a FLAIR sequence, on which CSF
is hypointense and the dermoid/epidermoid is hyperintense, or by dif-
fusion-weighted imaging, on which the dermoid/epidermoid will have
high signal intensity in contrast to the hypointense CSF.
Arachnoid cysts can be congenital (true cysts) or acquired (arach-
noid loculations), as described in Chapters 5 and 10. They can occur
at any level and may be dorsal or ventral to the cord. Because they are
filled with CSF, they are isointense to the subarachnoid space and must
be identified on MRI by their mass effect upon the adjacent spinal cord
(Fig. 9-10). Although cysts too small to exhibit mass effect will not be
detected, myelography is rarely necessary, as cysts that do not have
mass effect will not produce symptoms.
Segmental ischemic injury of the spinal cord is identified by an
abrupt diminution in caliber of the cord at the level of the ischemic
Barkovich_Chap09.indd 868
insult. Sonography, CT myelography, or MRI can be used to locate this
abrupt narrowing. A narrowing of the dural sac, suggesting that the
meninges have been approximated too tightly at the time of the closure
of the lesion, may be difficult to demonstrate by MRI and is more easily
seen by myelography and sonography.
Hydromyelia develops in between 29% and 77% of patients with
OSD (Figs. 9-7 and 9-8) (115,116,129). The exact frequency depends
upon the efficacy of treatment of the patient’s hydrocephalus (129–
132). The hydromyelia in repaired OSD is likely a result of the pas-
sage of CSF through the obex from the fourth ventricle into the central
canal of the spinal cord: hydromyelia is not usually seen caudal to
the placode. Hydromyelia is most easily diagnosed by MRI, where it
appears as a dilated (CSF-intensity) central canal, causing a fusiform
enlargement of the cord, most frequently in the lower cervical or upper
thoracic region. The hydromyelia can also involve a short segment,
typically beginning a small distance above the site of the placode, or
may involve the entire central canal from the cervicomedullary junc-
tion down to the placode.
Untreated hydromyelia can cause the rapid development of sco-
liosis (83,129–133). In patients with OSD and hydrocephalus, rapidly
progressive scoliosis may be the sign of a nonfunctioning shunt or an
encysted fourth ventricle. Because scoliosis in these patients may result
from shunt malfunction, encystment of the fourth ventricle, or hydro-
myelia unrelated to the above, all patients with scoliosis that is rapidly
progressive, has an atypical curve, or is associated with neurological
deficits should have imaging studies of the entire craniospinal axis to
eliminate these treatable causes of scoliosis. MRI is the imaging study
of choice in these circumstances (83,133,134).
FIG. 9-9. Epidermoid tumor in a patient who under-
went fetal myelomeningocele repair. A–D. The epi-
dermoid (arrows) can be difficult to detect by routine
sagittal and axial T1 and T2 MR sequences. E. Sagit-
tal FLAIR with fat suppression shows the epidermoid
clearly (arrow). Diffusion imaging can also be valuable
(see Chapter 7).
5/6/2011 10:28:29 PM
 Chapter 9 • Congenital Anomalies of the Spine 869

FIG. 9-10. Patient who had myelomeningocele repair at birth, now with worsening neurologic exam secondary to arachnoid scarring/loculations.
A. Sagittal T2-weighted image shows the conus medullaris (white arrow) extending caudally to the L-5 level. Based on this image, it cannot be determined
whether the neurologic symptoms are the result of retethering or another process. This patient emphasizes the need to image the entire spinal cord. The
levels of spina bifida (white arrowheads) are those without spinous processes. B. Sagittal T2-weighted image of the cervical and upper thoracic spine shows
a thin spinal cord (black arrows) that is dorsally displaced due to scarring and arachnoid loculations. C. Axial T1-weighted image at the midthoracic level
shows the spinal cord (white arrows) to have a crescentic shape, being displaced by the scarring and loculations.

Barkovich_Chap09.indd 869 5/6/2011 10:28:30 PM

 870 Pediatric Neuroimaging

The Chiari II Malformation ascent through the sinus tract (144–146); meningitis is a risk factor for
The Chiari II malformation is an anomaly of the cervical spinal cord, poor outcome (147). Occasionally, the meningitis is chemical in nature,
brainstem, and hindbrain that is observed in varying degrees in all resulting from the release of cholesterol crystals or other contents of
patients with myelomeningoceles. Because of the close association of dermoid or epidermoid cysts into the cerebrospinal fluid (147,148).
Chiari II malformations with OSD, a brief discussion is appropriate A related entity, the spinal dermal-sinus-like stalk, was recently
in this section, in spite of the fact that this malformation is discussed reported as a discrete entity in a small cohort of patients (42). These
extensively in Chapter 5. patients did not have a tract with an epithelium-lined lumen commu-
The Chiari II malformation can be best considered as an entity in nicating with a cutaneous orifice, but rather a solid stalk of connective
which the posterior fossa is too small (135) due to collapse of the ven- tissue, fat, and occasionally neural tissue that ran from a skin dimple
tricular system from leakage of CSF through the open neural tube. As without an ostium to the intradural space or spinal cord. The dural
a result of the small bony posterior fossa and the reduced pressure of sleeve associated with the stalk was directed towards the skin surface,
the spinal subarachnoid space from the CSF leakage, normal contents unlike the dural sleeve of the dermal sinus, which is directed towards the
of the posterior fossa are distorted as they are squeezed out through an spinal cord; this observation suggests an etiology distinct from that of
enlarged foramen magnum. The brainstem is stretched inferiorly and the dermal sinus. The authors postulate that disjunction between cuta-
narrowed in the anteroposterior diameter, often lying at the level of the neous and neural ectoderm occurred, but that intervening mesodermal
foramen magnum or in the cervical spinal canal. The cervical spinal cord cells may have formed a tight, persistent connection between the two.
is displaced inferiorly and the upper cervical nerve roots have to ascend
Pathology
toward their respective neural foramina. The medulla is also displaced
inferiorly. In 70% of patients, it folds caudally at the cervicomedullary Pathologically, dermal sinuses are thin, epithelium-lined channels
junction, dorsal to the cervical spinal cord (which is tethered by the den- that course inward from the skin surface through the subcutaneous
tate ligaments and therefore limited in its vertical descent), forming a tissues, extending into the spinal canal in 50% to 70% of cases. The
characteristic cervicomedullary kink (Figs. 5-162 and 5–163). The cer- sinus may reach the dura without passing through it; in such cases,
ebellar vermis often herniates inferiorly, forming a tongue of tissue pos- the dura and arachnoid are tented dorsally at the attachment of the
terior to the medulla that usually extends down to the C-2 or C-4 level. sinus tract to the dura. This tenting may be the only manifestation
Rarely, it extends down into the upper thoracic segments of the canal. of the sinus tract on myelography. If they pass through the dura, the
The cerebellum wraps around the brainstem (Fig. 5-163). The fourth sinuses may empty into the subarachnoid space or may traverse the
ventricle is vertical in orientation (Figs. 5-162 and 5–163), extending subarachnoid space to terminate within the conus medullaris, filum
inferiorly between the medulla and cerebellar vermis; occasionally, it terminale, a nerve root, a fibrous nodule on the dorsal aspect of the
extends down below the medulla, posterior to the cervical spinal cord, cord, or a dermoid or epidermoid tumor (Fig. 9-11) (149–151). About
in a cyst-like fashion. The quadrigeminal plate is stretched posteriorly half of dorsal dermal sinuses end in dermoid or epidermoid tumors.
and inferiorly (Figs. 5-161 and 5–162). The small posterior fossa and the
downward herniation of its contents result in a low-lying, abnormally
vertical tentorium cerebelli (136–141). Many of these changes resolve
after fetal repair of the OSD, as discussed in Chapter 5.
Dorsal Dermal Sinuses (also considered as a complex
spinal dysraphism)
Clinical Features
Dorsal dermal sinuses are epithelium-lined tubes that extend inward from
the skin surface for varying distances and frequently connect the body
surface with the central nervous system or its coverings. This anomaly
seems to result from a focal area of incomplete disjunction of cutaneous
ectoderm from neural ectoderm during the process of neurulation (Fig.
9-2). When the spinal cord later becomes surrounded by mesenchyme and
undergoes its relative ascent with respect to the spinal column, this adher-
ence remains and forms a long, epithelium-lined tract. The incidence of
dermal sinuses is low in the cervical region where the neural folds first
fuse into the primitive neural tube, and relatively great in the lumbosacral
and occipital regions, which are the last portions of the neural tube to
close. In a series of 120 cases of dorsal dermal sinuses, 1 was sacrococ-
cygeal, 72 were lumbosacral, 12 thoracic, 2 cervical, and 30 occipital; the
remaining 10 were mostly ventral to the skull and spinal column (142).
Dermal sinuses in the frontonasal region are discussed in Chapter 5.
Dorsal dermal sinuses occur equally frequently in males and females
and are usually detected any time from early childhood through the
third decade of life. Physical examination reveals a midline (rarely para-
FIG. 9-11. Schematic of dorsal dermal sinus. A tuft of hair, nevus, or heman-
median) dimple or pinpoint ostium that is frequently associated with
gioma frequently marks the ostium of the sinus. The dura is often tented when
a hyperpigmented patch, hairy nevus, or capillary angioma (143). The the sinus penetrates the dura. The sinus may terminate in a CNS structure, the
patients become symptomatic either by infection or because of com- dura, or external to the dura. Dermoid or epidermoid tumors develop along
pression of neural structures by an associated dermoid or epidermoid the course of the sinus in 50% of affected patients. (Reprinted from Barkovich
tumor. Meningitis or abscesses in the subcutaneous, epidural, subdural, AJ, Edwards MSB, Cogen PH. MR evaluation of spinal dermal sinus tracts in
subarachnoid, and/or subpial spaces may develop as a result of bacterial children. Am J Neuroradiol 1991;12:123–129, with permission.)

Barkovich_Chap09.indd 870 5/6/2011 10:28:31 PM


Conversely, 20% to 30% of dermoids and epidermoids are associated
with dermal sinus tracts (150–154). Dermal sinuses can be midline or
paramedian in location. Those with midline orifices are usually associ-
ated with midline dermoid tumors. Paramedian orifices are more com-
monly associated with epidermoids, which can be located laterally in
the epidural, subdural, or subarachnoid spaces. In some patients, the
dermal sinus courses horizontally beneath the skin to the dura mater.
In others, it courses subcutaneously for some distance before reaching
the dura and then ascends within the spinal canal to the level of the
conus medullaris. The exact course of the sinus seems to vary from
patient to patient. Therefore, the complete course of each dermal sinus
must be determined by narrow, contiguous sections above and below
the level of the external orifice.
The bony abnormalities associated with dermal sinuses are vari-
able. Bone abnormalities may be absent if the dermal sinus extends
intraspinally through a ligamentous defect at the interspace between
Barkovich_Chap09.indd 871
Chapter 9 • Congenital Anomalies of the Spine 871
two spinous processes. In other cases, the sinus may be associated with
a groove in the upper surface of the spinous process and lamina of the
vertebra, a hypoplastic spinous process, a single bifid spinous process,
focal multilevel spina bifida, or a laminar defect (145,150,152).
When a dermoid or epidermoid tumor is present, adjacent nerve
roots are frequently bound down to the capsule of the cyst. The
cord may be displaced and compressed by extramedullary dermoids
or epidermoids, or expanded by intramedullary lesions (20,64).
Nerve roots may be clumped because of adhesive arachnoiditis from
previous infections or rupture of a dermoid. If abscesses form, they
may remain confined near the tract and entry site of the sinus or may
extend cephalad and caudad for considerable distances (64,146,155).
Imaging
Sonography, CT, and MRI can all demonstrate the subcutaneous and
extracanalicular extent of the dermal sinus tract (Figs. 9-12 to 9-14).
FIG. 9-12. Dorsal dermal sinus with dermoid
adjacent to conus medullaris. A. Sagittal
T1-weighted image shows the dermal sinus
(black arrowheads) coursing through subcu-
taneous fat and into the subarachnoid space.
Part of the subarachnoid portion of the tract is
bright (white arrowheads) because it contains
fat. The hyperintense circle (white arrow) at the
skin surface is a vitamin E capsule marking the
opening of the sinus. B. Sagittal T2-weighted
image shows the sinus tract (large black arrow-
heads) more clearly as it courses through the
subarachnoid space. Incidentally noted is a
thickened filum terminale (small black arrows),
likely related to the low level (bottom of L-3, one
full vertebral body level too low) of the conus
medullaris. C and D. Axial T1-weighted images
show smudgy soft tissue intensity (white arrows)
dorsolateral to the conus medullaris. At surgery,
this was found to represent dermoid tumor.
5/6/2011 10:28:32 PM
 872 Pediatric Neuroimaging

FIG. 9-13. Lumbar dorsal dermal sinus with intramedullary

dermoid. A and B. Sagittal T1-weighted and T2-weighted
images show an intramedullary mass (asterisk) that has sim-
ilar signal intensity to CSF. Note that the sinus tract is not
within the portion of the spine visualized on these images.
C. Sagittal T2-weighted image of the lumbar spine shows a
hypointense curvilinear structure (black arrowheads) cours-
ing down the dorsal aspect of the subarachnoid space, then
terminating (black arrow) at the mid-L-5 level. As seen in (D),
this is the level where the tract exits through the dermal sinus.
D. Sagittal T1-weighted image shows the dermal sinus cours-
ing (white arrowheads) below the L-5 spinous process and
(black arrowheads) through the subcutaneous fat. The ostium
is marked by the small white arrow.

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 Chapter 9 • Congenital Anomalies of the Spine 873

FIG. 9-14. Dorsal dermal sinus with infected dermoid and epidural abscess.
A and B. Sagittal T1-weighted images show the importance of proper windowing.
In (A), filmed with wide windows, the subcutaneous portion of the sinus (black
arrows) is easily seen. In (B), windowed to see the intraspinal portions of the sinus
and dermoid, the subcutaneous portion of the tract cannot be identified. In (B),
the lower aspect of the thecal sac (arrows) is very heterogeneous. However, it can-
not be determined from this study whether the heterogeneous signal is the result
of clumping of nerve roots from infection or from (epi)dermoid tumor. At surgery,
this patient was found to have a large, infected epidermoid at the L-5 to S-1 levels
and an epidural abscess at the L-3 to L-4 levels. C and D. Sagittal T2-weighted (C)
and fat-suppressed postcontrast T1-weighted (D) images allow better distinction
between the epidural (e) and intradural (i) components of the infection. E. Axial
T1-weighted image at the L-5 level. The contents of the thecal sac (white arrows)
are of heterogeneous high signal intensity. This was found to be an infected der-
moid tumor at surgery. The black arrowhead points to the sinus tract coursing
through subcutaneous fat.

MRI best demonstrates intramedullary dermoid and epidermoid
tumors (Figs. 9-13 and 9-14). T1-weighted images with wide window
settings best show the subcutaneous portion of the sinus tracts; nar-
row windows may make the tract impossible to see (Fig. 9-14). The
intrathecal portions of the tracts are small and hypointense; therefore,
they are essentially invisible on noncontrast T1-weighted MR images
unless fatty tissue is present (Fig. 9-12). Thin section T2-weighted
RARE (fast spin echo, turbo spin echo) images in the sagittal and axial
planes best show the sinus tract as a hypointense linear or curvilinear
structure on MRI (Figs. 9-12 and 9-13) and will show the deviation of
nerve roots around any mass, giving a strong indication of its presence.
The use of strongly T1-weighted images (64), FLAIR images (156,157),
or diffusion-weighted images (157,158) will help to identify intraspinal
extramedullary (epi)dermoids, which may have signal intensity identi-
cal to CSF on standard T1- and T2-weighted images. The administration
of paramagnetic contrast (which results in enhancement of some sinus
tracts [60]) and use of fat-suppression techniques may help to identify
the sinus tract if granulation tissue is present due to prior infection or
inflammation (Fig. 9-15). Carefully performed ultrasound can show
the intradural portion of the sinus in young infants. CT with intrathecal

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 874 Pediatric Neuroimaging

FIG. 9-15. Contrast enhancement of thoracic dermal sinus. A and B. Sagittal T2-weighted images show the hypointense dermal sinus (white arrows)
coursing through the subcutaneous fat and the distortion of the dorsal spinal cord (black arrows) where the sinus tract inserts. C. Sagittal postcontrast
T1-weighted image with fat suppression shows the enhancement of the deeper portion of the oblique sinus (white arrow). D and E. Axial T2-weighted
images show the lack of complete closure of the dorsal thoracic spinal cord just above the level of the tract, (black arrow in D) and the hypointense tract
through the subcutaneous fat (black arrows in E).

contrast best demonstrates the intraspinal portion of the dermal sinus
and small extramedullary (epi)dermoids in older children. Thus, in
those rare cases in which the intraspinal anatomy is not clearly defined
after high-quality MRI, a CT myelogram should be considered.
As mentioned, extramedullary (epi)dermoids may be difficult to
visualize with MRI using standard T1- and T2-weighted sequences;
ruptured and infected dermoid and epidermoid tumors are even more
difficult to identify, as no distinct mass is seen. Instead, the subarach-
noid space has a “smudgy,” slightly heterogeneous appearance (Fig.
9-14) that cannot be differentiated from arachnoiditis by MR tech-
niques. FLAIR and diffusion-weighted images can be very helpful in
this setting (156,157); they will help the surgeon know where to look to
remove as much tumor as possible.
For detection of associated intraspinal abscesses, precontrast and
postcontrast MRI is the imaging study of choice (Fig. 9-14). The abscess
may be intradural, extradural, or both. On T2-weighted MR images of
the spinal cord, abscesses appear as areas of high signal intensity, often
with a ring of low signal intensity. T1-weighted images show low signal
intensity; these areas are usually poorly defined on precontrast images
because of surrounding edema. Administration of paramagnetic con-
trast reveals ring-enhancing masses (159). Diffusion-weighted images
show reduced diffusion within the abscess. Every attempt should be
made to show the associated dermal sinus.
Cervical Myelocystocele and Cervical Myelocele (may
also considered as CSD with a subcutaneous mass)
The myelocystocele is a malformation in which a dilated central canal
protrudes dorsally through a bony spina bifida (Fig. 9-16). Although some
authors consider these to be synonymous with cervical myelomeningo-
celes (160) or to be part of a continuity with cervical meningocele in

Barkovich_Chap09.indd 874 5/6/2011 10:28:35 PM


FIG. 9-16. Schematic of myelocystocele. This is an occult, skin-covered,
spinal dysraphism in which the spinal cord (which has a syringohydromy-
elia) and the arachnoid are herniated through a posterior spina bifida. The
cyst is in continuity with the central canal of the spinal cord. Myelocysto-
celes can occur at any level. Localized expansion of the subarachnoid space
is not a necessary component and is uncommon in myelocystoceles that
occur at locations other than the cord terminus.
which a fibrovascular stalk extends from a nearly normal-looking spinal
cord through a spina bifida to form a skin-covered mass (161), we con-
sider the latter to be a true cervical myelocele and an entity distinct from
the myelocystocele. The latter, by definition should be an encysted spinal
FIG. 9-17. Cervical myelocystocele. A. Sagittal T1-weighted image through the cervical spine shows syringohydromyelia of the cord with multiple septa-
tions within the syrinx (white arrowheads). The ependyma-lined cyst is seen to extend posteriorly through a spina bifida into the subcutaneous tissues (black
arrowheads) forming a skin-covered dorsal mass (white arrows). B. Axial T1-weighted image at the lower level of the dorsal cyst shows the loculations within
the spinal cord and the cord extending dorsally through a bony spina bifida. The subarachnoid space ventral to the spinal cord is expanded.
Barkovich_Chap09.indd 875
Chapter 9 • Congenital Anomalies of the Spine 875
cord. Other authors differentiate cervical myelocystoceles from cervical
myeloceles, but consider the latter to be meningoceles (162). However,
meningoceles by definition do not contain neural tissue, and the cervical
myeloceles clearly have a stalk of neural tissue extending through the spi-
nal bifida, as shown by Rossi et al. (161). Cervical myelocystoceles should
also be differentiated from terminal myelocystoceles, which are anoma-
lies of the caudal cell mass and are located at the lumbosacral level. Ter-
minal myelocystoceles are discussed later in this chapter.
Patients with cervical myelocystoceles and those with cervical
myeloceles present as neonates with a dorsal midline cystic mass, usu-
ally at the cervical or cervicothoracic level. Most of the mass is covered
by full-thickness skin, whereas a tough, violaceous membrane covers
the apex. The neonates are typically alert and vigorous, with normal
neurologic exams and no evidence of extraneural congenital malfor-
mations (163). Occasionally, infants have mild abnormalities of muscle
strength or of tone (160,162). These deficits become more noticeable
during the first year of life, the patients becoming spastic or weak in
the arms or legs (164). By the end of the first decade, some sort of
motor deficit is usually present, often requiring orthopedic interven-
tion (164). The head size is often enlarged (162).
The diagnosis is made by identification of spinal cord tissue pro-
truding dorsally through a bony spina bifida into the dorsal subcutane-
ous soft tissues (Fig. 9-17). In a myelocystocele, the central canal of the
spinal cord is enlarged, and the area containing this syrinx protrudes
posteriorly through the spinal bifida. Fluid may not be continuous all
the way into the subcutaneous region, but dysplastic neural tissue will
be found within the leptomeninges in the subcutaneous tissue beneath
a thickened layer of squamous epithelium. The fluid in the enlarged
central canal may be multiloculated. In cervical myeloceles, soft tissue
and fluid may be present in the dorsal sac that protrudes through the
spina bifida, but no cyst is seen within the spinal cord (161,162). Care
should be taken to examine the entire spinal axis, as other malforma-
tions, such as dermal sinuses, SCMs, and Chiari II malformations may
be present (162,165). The diagnosis can be made by MR or by ultra-
sound. CT myelography is less useful, because of its invasive nature and
radiation exposure and because it does not detect the focally enlarged
central canal.
5/6/2011 10:28:36 PM
 876 Pediatric Neuroimaging

Disorders Resulting from Premature Intradural Lipomas (Also classified as a simple

Disjunction—Spinal Lipomas dysraphic state)
Intradural lipomas, which constitute slightly less than 1% of primary
Concepts of Lipomas
intraspinal tumors, are juxtamedullary masses that are totally enclosed
Spinal lipomas are masses of fat and connective tissue which appear in an intact dural sac. They are slightly more frequent in females.
at least partially encapsulated and which have a connection with Affected patients present at three age peaks: the first 5 years of life
the leptomeninges or the spinal cord (166). Grossly, the lipomas are (24%), the second and third decades (55%), and the fifth decade (16%)
homogeneous masses of mature fat cells that are separated into glob-
ules by strands of fibrous tissue. The proportion of fibrous tissue is
much greater near the interface of the cord and lipoma and consider-
ably less near the skin surface (151,167). Calcification and ossification
are sometimes seen (151,168), as are muscle fibers, nerves, glial tissue,
arachnoid, ependyma, and many other types of tissue (169).
Spinal lipomas can be divided into three principal groups: (a) intra-
dural lipomas (3%–5%); (b) lipomas with dorsal defect, encompassing
lipomyeloceles and lipomyelomeningoceles (75%–85%); and (c) lipomas
deriving from the caudal cell mass (10%–15%). Group 2 can be divided
into dorsal, caudal, and combined or “transitional” lipomyeloceles/lipo-
myelomeningoceles (170,171). Group 3 can be further divided into (a)
terminal lipomas, which are at the caudal part of the thecal sac and are
always associated with a thickened filum terminale, and (b) fibrolipo-
mas of the filum terminale. Both are almost always associated with teth-
ering of the spinal cord. Terminal lipomas and fibrolipomas of the filum
terminale are best classified as anomalies of the caudal cell mass. Termi-
nal lipomas are discussed in this section because their lobulated, fatty
appearance is so similar to that of intradural lipomas and lipomas with
dorsal defect. Fibrolipomas are discussed later in this chapter, in the sec-
tion on “Anomalies of the Caudal Cell Mass.” In contrast to the anoma-
lies of the caudal cell mass, intradural lipomas and lipomas with dorsal
defect are postulated to result from a premature separation of cutaneous
ectoderm from neural ectoderm during the process of neurulation (Fig.
9-2). This premature separation permits the surrounding mesenchyme
to enter the ependyma-lined central canal of the neural tube, which has
not yet closed. The presence of the mesenchyme impedes the closure
of the neural folds and results in an open neural placode at the site of
premature disjunction. Moreover, the mesenchyme that enters the cen-
tral canal differentiates into fat. This same mesenchyme, if exposed to
the exterior of the cord, differentiates into meningeal tissue, bone, and
paraspinous muscles. The junction between the internal and external
surfaces of the cord therefore determines the junction between the
meninges and the fat. The faulty disjunction between neural ectoderm
and cutaneous ectoderm that results in the formation of spinal lipomas
may also explain the frequent association of lipomas with dorsal dermal
sinuses, which result from a focal area of faulty disjunction.
An important concept in the imaging evaluation of spinal lipomas
is that these lipomas are largely but not exclusively composed of nor-
mal fat (169). More importantly, fat cells dramatically increase in size
during infancy (172). In fact, the proportion of body fat increases from
14% of body weight at birth to 25% at age 6 months (173). As a result, FIG. 9-18. Schematic illustrating spinal lipomas and lipomyelomenin-
lipomas may be missed or be considered inconsequential when imaging is goceles. A. Subpial-juxtamedullary lipoma. The spinal cord is open in the
performed in the fetal or neonatal period, only to be found much larger at midline dorsally with the lipoma situated between the nonapposed lips of
a subsequent imaging study (174). This potential for growth should be the placode. B. Lipomyelocele. This lesion is very similar to a myelocele with
kept in mind when deciding on the optimal time for imaging neonates two additional characteristics. The lipoma lies dorsal to and is attached to
with spinal anomalies. Another aspect of this concept is that a spinal the surface of the placode. This lipoma is continuous with subcutaneous
lipoma can diminish in size if the patient loses weight (175). There- fat. Equally important is the fact that an intact skin layer overlies the lesion,
making this an occult spinal dysraphism. C. Lipomyelomeningocele with
fore, control of body weight may, in some instances, be a conservative
rotation of the neural placode. When the lipoma is asymmetric, it extends
method of managing affected patients (175). into the spinal canal and causes the ventral meningocele to herniate pos-
MRI is the imaging modality of choice for the evaluation of teriorly and the dorsal surface of the placode to rotate to the side of the
patients with spinal lipomas. The short T1 relaxation time of fat results lipoma. This rotation brings the contralateral dorsal root (in this case the
in characteristic high signal intensity of the lipoma on T1-weighted right dorsal root) into the midline posteriorly, putting it at increased risk
sequences. MRI allows the full extent of the lipoma, and its relationship for surgical trauma. Moreover, the left roots are markedly shortened by this
to the neural placode, spinal cord, and roots of the cauda equina, to be rotation, limiting the mobility of the cord and impeding the neurosurgeon
fully evaluated. from completely untethering it.

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 Chapter 9 • Congenital Anomalies of the Spine 877

(176). Patients harboring cervical and thoracic intradural lipomas most

frequently present with a slow, ascending monoparesis or paraparesis,
spasticity, cutaneous sensory loss, and defective deep sensation. Radic-
ular pain is uncommon. Patients with lumbosacral intradural lipomas
may present with flaccid paralysis of the legs and sphincter dysfunction
(176) or predominately pain (177). Symptoms may be exacerbated by
pregnancy (178). The skin and the adjacent subcutaneous tissues over-
lying the lipoma are most often normal.
Intradural lipomas develop most commonly in the cervical and
thoracic spine (cervical 12%, cervicothoracic 24%, thoracic 30%) but
may develop anywhere in the spinal cord or cauda equina (171,179,180).
Most develop along the dorsal aspect of the cord, but 25% are lateral or
anterolateral (151,153,168,176,181,182). Hydromyelia and syringomy-
elia are present in approximately 2%.
Intradural lipomas are actually subpial in location (Fig. 9-18)
(176). The spinal cord is open in the midline dorsally with the lipoma
situated in the opening between the unopposed lips of the placode.
The lipoma fills the space between the central canal and the pia, which
is frequently lifted from the cord surface as the lipoma projects into the
subarachnoid space. In the 45% of patients in whom the lipoma is exo-
phytic, the exophytic component tends to be at the upper or lower pole
of the lipoma. Although “intramedullary” lipomas have been rarely FIG. 9-19. Intradural lipoma. Axial CT image shows a low-attenuation
reported, no lipoma has been described that is fully encompassed by mass (arrows) in the dorsal aspect of the spinal canal.
cord (20,176).
Although the bony spinal canal can be normal in patients with
intradural lipomas, focal enlargement of the spinal canal and, occa- on T1-weighted MR images by their lobulated shape and high signal
sionally, the adjacent neural foramina is more common (40). Some- intensity (Fig. 9-20). Their fatty nature can be confirmed, if necessary,
times, a localized, narrow spina bifida is observed at the level of the by use of fat-suppression pulses. MRI best identifies compression of
lipoma; however, the bony spinal canal is usually intact (178), aiding in the spinal cord.
the distinction from lipoma with dorsal defect. There are generally no
Lipoma with Dorsal Defect (Lipomyeloceles and
segmentation anomalies of the vertebral bodies.
Lipomyelomeningoceles)
Intradural lipomas appear on imaging studies as focal, round to
oval masses that most often lie dorsal to the spinal cord (Figs. 9-19 Description and Presentation
and 9-20) and may expand the spinal canal (Fig. 9-20). Lipomas have a Lipoma with dorsal defect occurs when a lipoma that is tightly attached
very low attenuation on CT and, therefore, can be detected on studies to the dorsal surface of a neural placode extends dorsally through a
without intrathecal contrast (Fig. 9-19). They are easily identified bony spina bifida to be continuous with subcutaneous fat (40,169,183).

FIG. 9-20. Intradural lipoma. Sag-

ittal (A) and axial (B) T1-weighted
images show the hyperintense lipoma
(arrows) dorsal to the compressed spi-
nal cord. The spinal canal is expanded
by the mass.

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 878 Pediatric Neuroimaging

Terminal lipomas are probably identical to caudal lipomyelocele; these
lipomas attach to the cord at the conus medullaris, which is almost
invariably low in position due to tethering, and then extend dorsally
through a sacral spina bifida. They constitute approximately 20% of
skin-covered lumbosacral masses and between 15% and 50% of cases
of closed spinal dysraphism (31,184,185); they account for about 75%
to 85% of spinal lipomas (31). Patients are typically female. Affected
patients most commonly present with a rather soft lumbosacral mass,
less commonly with sensory loss in the sacral dermatomes, bladder
dysfunction, lower extremity weakness, orthopedic deformities of the
foot, scoliosis, and/or leg pain (169,171,186,187). When a lumbosacral
mass is present, patients typically come to medical attention before the
age of 6 months. If the mass is subtle, or no mass is present, clinical pre-
sentation is typically the result of neurologic or urologic deficits that
are noticed between the ages of 5 and 10 years; patients may occasion-
ally go undetected into adulthood (171,187). As children with lum-
bosacral masses are usually detected early, 40% to 45% of such children
are neurologically normal on initial examination (40,169,183). It is not
clear how many of these asymptomatic patients will eventually become
symptomatic, with different series reporting that as few as 16% and
as many as 88% of such children eventually develop progressive neu-
rologic symptoms if untreated (169,171,186,187). There is no debate
that most symptomatic patients will have progression of symptoms if
untreated (169,171,186,187).
Lipomas with dorsal defect usually occur in the lumbosacral region
of the cord and tether the cord at that level. Anatomically, lipomyelom-
eningoceles and lipomyeloceles are very similar to myelomeningoceles
and myeloceles, respectively, with two important additional character-
istics: (a) a lipoma is attached to the dorsal surface of the placode, and
(b) an intact skin layer overlies the lesion (closed spinal dysraphism).
Imaging Characteristics
Patients with lipomyeloceles have a normal-sized subarachnoid space
ventral to the placode; the cord and the junction between the placode
and the lipoma, therefore, are within the spinal canal (Figs. 9-21 and
9-22). The lipoma extends dorsally through the spina bifida and is con-
tinuous with subcutaneous fat. The focus of continuity with extraspinal
fat is sometimes quite small (Fig. 9-21) but is always present. The lipoma
appears as an echogenic mass on ultrasound, as a mass of very low atten-
uation on CT, and as a mass with short T1 and T2 relaxation times on

FIG. 9-21. Dorsal lipomyelocele containing well-formed bone. A and B. Sagittal T1-weighted and T2-weighted images show a low-lying conus medullaris
and a lipoma (white arrows in A) dorsal to the spinal cord at the L-2 level. There is a dorsal spina bifida at L-2 to L-4 (white arrows in B). C and D. Axial SE
T1-weighted images show the lipoma (white arrows) lying immediately dorsal to the spinal cord, which is flattened in appearance. The black arrows in D
point to a bony structure better identified in E.

Barkovich_Chap09.indd 878 5/6/2011 10:28:39 PM


FIG. 9-21. (continued) E. Lateral plain film of the spine shows a well-
formed bone (arrow; surgery showed it to be a digit) arising within the
lipoma, dorsal to the L-2 vertebra (white arrow).
FIG. 9-22. Transitional lipomyelocele. A. Sagittal T1-weighted image shows a large fatty mass (arrowheads) over the lumbosacral spine and a large intraspi-
nal lipoma (L). The conus medullaris is low-lying, at the L-4 level. B–D. Axial T1-weighted images show the placode (white arrowheads in B) as a curvilinear
region of tissue ventral to the lipoma.
Barkovich_Chap09.indd 879
Chapter 9 • Congenital Anomalies of the Spine 879
MRI. The spinal cord can have a number of different shapes depending
upon the morphology of the lipoma. It is usually crescent-shaped, arch-
ing over the ventral surface of the lipoma. However, if the intracanalicu-
lar portion of the lipoma extends laterally on both sides of the cord, the
placode may appear pointed, with the tip of the point directed posteri-
orly between the lateral extensions of fat. Rarely, well-formed bones (Fig.
9-21) or hamartomatous masses (188) are found in the lipoma.
In patients with lipomyelomeningoceles the spinal subarachnoid
space is expanded ventrally, and the placode, cord, subarachnoid
space, and dura extend dorsally through the spina bifida (Figs. 9-23
and 9-24). Similar to lipomyeloceles, a lipoma is attached to the dorsal
aspect of the placode; this lipoma extends posteriorly to blend with the
subcutaneous fat. Depending upon the degree of posterior herniation
of the spinal cord, the junction between the placode and lipoma may
be entirely posterior to the spinal canal, or partly within and partly
posterior to the canal. The dura is deficient in the zone of the spina
bifida and does not pass posterior to the neural elements to form a
closed dural tube as it does elsewhere. Instead, the dura is attached to
the lateral border of the neural placode, posterior to the dorsal nerve
roots as they emerge from the cord (Fig. 9-18). A continuous layer of
pia-arachnoid is continuous superiorly and inferiorly with the suba-
rachnoid space, lining the deep surface of the dura and the ventral
surface of the placode (Fig. 9-18). The dorsal surface of nervous tissue
is, therefore, attached to the lipoma, external to the dural sac and sub-
arachnoid space (40,168,183). The dorsal and ventral nerve roots exit
from the ventral surface of the placode (Fig. 9-18B). The nerve roots
may course through fat as they course toward their neural foramina
(169,171).
5/6/2011 10:28:40 PM
 880 Pediatric Neuroimaging

FIG. 9-22. (Continued) In C, the lipoma (white arrows) is seen to herniate dorsally out of the spinal canal through the bony spina bifida. In D, the fat of
the lipoma merges with subcutaneous fat; the white arrows demarcate the point of merging.

FIG. 9-23. Transitional lipomyelomeningocele. A and B. Sagittal T1-weighted and T2-weighted images show the spinal cord tethered by a large lipoma
that extends from the subcutaneous fat through a spina bifida into the dorsal subarachnoid space. A portion of the dilated subarachnoid space can be seen
extending into the subcutaneous fat (arrows). Note the hydromyelia (black arrowheads in B), seen in about 25% of patients with tethered spinal cords. C and
D. Axial T1-weighted images show the subcutaneous fat (white arrows) herniating into the spinal canal through the spinal bifida. The placode (black arrows)
is rotated to the right, contralateral to the fat, which is invaginating on the left (white arrows in D). E. Axial T2-weighted imaging at a slightly more rostral
level shows the superior portion of the placode-lipoma interface, as well as dorsal and ventral nerve roots (black arrowheads) arising from the placode.

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 Chapter 9 • Congenital Anomalies of the Spine 881

FIG. 9-24. Lipomyelomeningocele. A and B. Sagittal T1- and T2-weighted

images show the tethered spinal cord which is attached to a dorsal lipoma
through a posterior osseous defect. The meningocele (m) can be seen extend-
ing into the subcutaneous fat. Fat extends into the spinal canal (black arrow in
A) and adheres to the dorsal surface of the cord. The central canal of the spinal
cord is dilated. C. Axial T1-weighted image rostral to the lipoma shows the
hydromyelia (arrow) within the spinal cord. D. The intraspinal lipoma (white
arrow) is present at this more caudal level. The dorsal and ventral nerve roots
are seen originating from the placode coursing ventrally toward their neural
foramina. The posterior elements are bifid at this level and the meningocele
(black arrow) extends in to the subcutaneous fat.

The dorsal surface of the placode, adjacent to the lipoma, has no
ependymal lining; instead it is covered by a relatively thick layer of con-
nective tissue mixed with islands of glial cells and smooth muscle fibers
(168). The lipoma lies immediately external to the connective tissue
in the extradural space; it may be localized to the levels of the spina
bifida or may extend upward along the dorsal placode and underlie an
outwardly normal-appearing spinal canal. Moreover, the lipoma can
enter the central canal of the spinal cord and pass upward within it
to form an apparently isolated intramedullary lipoma at higher levels.
The lipoma can also extend upward within the extradural portion of
the spinal canal, forming an apparent epidural lipoma. In both of these
situations, the use of MR, especially in the sagittal plane, helps to trace
the lipoma to its caudal origin near the myeloschisis (Fig. 9-25).
At the level of the placode, the spinal canal is generally large and
is associated with a posterior osseous defect (189). Butterfly vertebrae
and segmental anomalies of the vertebral bodies may be found in as
many as 43% of affected patients, and abnormalities of the sacrum,
including confluent sacral foramina and partial sacral agenesis, are
present in up to 50% (180,189).
The lipoma is asymmetric in approximately 40% of patients. If
the asymmetric lipoma extends into the spinal canal, it causes the
meningocele to herniate posteriorly and the dorsal surface of the pla-
code to rotate to the side of the lipoma (Fig. 9-23). Such rotation and
herniation brings the contralateral dorsal roots and dorsal root entry
zones into the midline posteriorly, putting them at increased risk for
surgical trauma (Figs. 9-23 and 9-24). Moreover, the nerve roots are
unequal in length; those that originate posterior to the spinal canal
are very long, whereas those that originate from the intracanalicular
portion of the placode are very short. These short nerve roots limit
the mobility of the cord and impede complete untethering of the cord
(169,171).
Some lipomas attach to the spinal cord at the level of the conus
medullaris and course caudally through the lumbosacral spinal canal,
exiting through a bony spina bifida, usually at the lower lumbar or sacral
level, to become continuous with subcutaneous fat (Fig. 9-26). The
conus is almost invariably abnormally low and the distal spinal cord is
almost invariably thin from being stretched inferiorly (Fig. 9-26). Rota-
tion of the spinal cord and anomalies of vertebral body segmentation
are uncommon in this malformation, which is often called a terminal
lipoma, or a caudal form of lipoma with dorsal defect. As with tethered
spinal cords of all causes, the central canal of the spinal cord is dilated
in about 20% of affected patients (82,169).

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 882 Pediatric Neuroimaging

FIG. 9-25. Rostral extension of lipoma through the central canal of the spinal cord. A. Sagittal T1-weighted image of the cervical spine shows a lipoma (arrows)
within the spinal cord. B. Axial proton density image confirms the location of the lipoma (arrows) within the central canal of the spinal cord. C. T1-weighted
image of the lumbar spine shows a marked spinal deformity at the site of repair of a lipomyelomeningocele. The lipoma (arrows) entered the cord at the level of
the placode and extended upward through the central canal of the spinal cord, thereby mimicking the appearance of a purely intramedullary lipoma.

Associated Malformations hamartomas, angiomas, or arachnoid cysts may be present. Thus, it is

Lipomas with dorsal defect are commonly associated with other
anomalies; an active search for these anomalies should always be per-
formed when evaluating the imaging studies of affected patients. Sacral
hypogenesis is seen in about 25% of patients with lipomas affecting the
conus medullaris (169). Anorectal malformations (including imperfo-
rate anus, anorectal stenosis, and anal malposition) and genital and
urinary tract anomalies are seen in 5% to 10% of affected patients.
If anal or genitourinary anomalies are present, the incidence of
sacral anomalies increases to more than 90% (169); these patients are
best classified as having anomalies of the caudal cell mass. Terminal
SCM may accompany lumbosacral lipomas in up to 10% of affected
patients (169). Less commonly, (epi)dermoid tumors, dermal sinuses,
crucial to look for other anomalies whenever lipomyelomeningoceles and
lipomyeloceles are identified.
ANOMALIES OF THE CAUDAL CELL MASS
As discussed in the embryology section at the beginning of this chapter,
the lowest portion of the spinal cord (the conus medullaris), the filum
terminale, and the lower lumbar and sacral nerve roots form from the
caudal cell mass by a process referred to as canalization and retrogres-
sive differentiation. The nearby anorectal and lower genitourinary tract
structures form from the cloaca, which develops simultaneously and
in close topological proximity to the caudal cell mass. As a result, the

FIG. 9-26. Terminal lipomas. A. Sagittal high-resolution

ultrasound image of the lumbosacral spine in an infant
where the echogenic fatty mass (white arrows) tethers the
low-lying spinal cord. Note the associated hydromyelia.
B. Different patient. Sagittal T1-weighted image shows a fatty
mass attached to the tip of a low-lying conus medullaris. The
most caudal three levels of the cord are abnormally thin.

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 Chapter 9 • Congenital Anomalies of the Spine 883

FIG. 9-26. (Continued) C. Axial T1-weighted image at the level of the sacrum shows the continuity of the lipoma (black arrows), through the bony spina
bifida and paraspinous muscles, with the subcutaneous fat. D. Different patient. This newborn was imaged because of the large subcutaneous lumbosacral
fatty mass. The terminal lipoma (black arrows) is seen caudal to the low-lying conus medullaris.

anomalies listed in this section are commonly associated with anorec-
tal and genitourinary anomalies (45). Anomalies of the caudal spine
should always be suspected in patients with anorectal and genitourinary
anomalies and vice versa.
Normal Conus Medullaris and Filum Terminale
Early in embryogenesis, the spinal cord extends to the caudal end of the
spinal canal. At that time, each neural segment is at exactly the same
level as the corresponding segment of spinal canal. Each nerve root
courses directly laterally towards its neural foramen. As the embryo
matures, the most distal portion of the cord undergoes retrogressive
differentiation; moreover, the vertebral bodies grow more quickly than
the spinal cord. This combination of factors produces a relative ascent
of the spinal cord within the spinal canal.
The exact level of the conus medullaris at the time of birth is
debated; however, most recent evidence indicates that the conus should
be no lower than the L-3 level by 24 weeks of gestation (190) and at its
normal (adult) level by 40 postconceptional weeks (191,192), that is, at
the time of birth. It has been well established that the conus medullaris
is usually positioned above the middle of the L-2 vertebral level by the
age of 3 months (68,89,193). In several series involving a total of more
than 1,000 patients, the most caudal aspect of the conus was observed
above the L-2 to L-3 level in greater than 98% of cases and at the L-3
level in less than 2% (68,89,194,195). However, in more recent work,
where complete spine MRI was performed in asymptomatic oncology
patients, allowing counting from the craniocervical junction, no nor-
mal conus medullaris terminated below the level of the midbody of
L-2. Therefore, if the conus medullaris terminates below the level of L-2
inferior endplate, it should be considered abnormal, and a search should
be made for a tethering mass (usually lipoma), bony spur, or thick filum.
The normal filum terminale measures 1 mm or less in diameter at
the L-5 to S-1 level (20); previous editions of this book have stated the
upper limit as 2 mm, but that was based on the poorer spatial resolu-
tion of early MR scanners (82). Some even believe that if the filum can
be seen at the L-5 to S-1 level on axial T2-weighted RARE sequences, it
is abnormal, but this is certainly not a widely accepted belief.
The Terminal Ventricle
During the development of the spinal cord, the central canal is widest
at the level of the conus medullaris; this widening is referred to as the

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 884 Pediatric Neuroimaging
FIG. 9-27. Terminal ventricle. A and B. Sagittal ultrasound and sagittal
T2-weighted image show a focal prominence (arrows) of the caudalmost
portion of the central canal of the spinal cord, at the level of the conus
medullaris. If cystic and asymptomatic, the lesion should be treated as an
anatomic variant.
terminal ventricle or ventriculus terminalis. This feature may persist
into infancy, childhood, or even adulthood; in one series it was found
in 2.6% of children examined (196). Occasionally, the terminal ven-
tricle takes on a cystic appearance that can mimic a frank cyst or mass
(Fig. 9-27). Our experience and the cases reported in the literature
(196–202) indicate that these are incidental findings and are rarely,
if ever, associated with signs or symptoms. After confirmation of the
purely cystic nature of the lesion by ultrasound (in infants) or MRI
(FLAIR and diffusion-weighted MRI are preferable), it should be con-
sidered as an anatomical variant.
Anomalies of the Filum Terminale/Tight Filum
Terminale (a simple spinal dysraphism)
The normal filum terminale is a long thin fibrous filament that is both
intra- and extradural. It starts at the tip of the conus medullaris and
extends caudally, through the bottom of the subarachnoid space and
the dura mater, to insert on the dorsal aspect of the first coccygeal ver-
tebra (166). Fibrolipomas and cysts of the filum likely result from minor
anomalies in the sequence of canalization and retrogressive differentia-
tion; the pleuripotential caudal cell mass produces fat cells or does not
properly connect areas of cavitation to the central canal. The fibroli-
pomas may be limited to the intradural filum, may be limited to the
extradural filum, or may involve both portions. Cysts may be found by
ultrasound in up to 12% of young infants who are referred for spinal
sonography (203); they are most commonly seen dorsally in the rostral
portion of the filum, just caudal to the tip of the conus medullaris.
They appear to be asymptomatic and are associated with normal devel-
opment during the first postnatal year (203).
It is likely that the tight filum terminale results from failure of invo-
lution (apoptosis and/or necrosis) of the terminal cord and/or failure
of lengthening of the nerve fibers that form the filum. When the filum
terminale is too short, the tethering effect is transmitted to the spinal
cord. However, because the dentate ligaments secure the cord rostral to
T12, the effect of the tethering is limited to the conus medullaris and
Barkovich_Chap09.indd 884
the symptoms limited to the lower extremities, urinary bladder, and
bowels. The clinical symptomatology is believed to be due to stretch-
ing of nerve fibers, resulting in abnormal oxidative metabolism in the
conus medullaris and nerve roots (204).
Small amounts of fat in the filum terminale may be asymptom-
atic. Emery and Lendon (166) found incidental fat (which they termed
fibrolipomas) in the filum terminale of 6% of autopsied patients with
presumably normal spines. Fibrolipomas are also sometimes seen inci-
dentally on imaging studies of both children and adults referred for
other reasons (88,205). However, patients with filum fibrolipomas may
become symptomatic at nearly any age (52,169) (indeed, at UCSF, we
have seen patients of all ages become symptomatic from tethered spi-
nal cords with one patient developing symptoms at age 70 years), and
the percentage of asymptomatic patients decreases rather dramatically
with increasing age (169). Thus many authorities currently believe
that fibrolipomas of the filum terminale are not a normal variant, that
patients with this finding should have a careful neurological examina-
tion and urodynamic testing, and, if abnormalities are found, should
be treated surgically (169,186). There is no information available con-
cerning long-term outcome in filar cysts.
Plain radiographs may be normal, although they typically show a
small defect in the posterior elements; scoliosis is present in approxi-
mately 20% of affected patients (51,182,206,207). Filum fibrolipomas
appear on CT as small foci of hypoattenuation and on T1-weighted
MRI as areas of high signal intensity and low signal intensity on
T2-weighted images within an enlarged filum (Figs. 9-28 to 9-30). The
normal filum should measure 1 mm or less in diameter. Often, the
lipoma will be in the caudal portion of the filum. Therefore, if the patient
has any manifestations that raise the possibility of a tethered cord (atypi-
cal scoliosis, urologic abnormalities, signs or symptoms of lower extremity
dysfunction), it is critical to acquire axial T1- and T2-weighted images all
the way from the conus medullaris to the bottom of the thecal sac to ensure
that a fibrolipoma is not missed. The conus medullaris is often, but not
always, low-lying, being tethered by the tight filum (71,82). It is impor-
tant to remember that the conus may be at a normal level (L-2 inferior
endplate or above) in symptomatic patients (82). An area of prolonged
T1 and T2 relaxation, probably representing a dilated central canal, is
seen in the center of the spinal cord on T1-weighted MR images in
approximately 20% to 25% of affected patients (Fig. 9-31). It is not
known whether this area represents a mild hydromyelia or myelomala-
cia resulting from the metabolic abnormalities within the conus as a
result of the tethering (82,208). However, the fact that this finding may
disappear after release of the filum suggests that it represents hydromy-
elia and is caused by the tethering (209).
The dural sac is frequently widened and the dorsal dura may be
tense and tented posteriorly by the filum. The filum may be so closely
applied to the dura posteriorly that it cannot be detected by myelogra-
phy (20). Therefore, MR with thin sagittal and, especially, axial sections
is the study of choice. The thickness of the filum must be measured from
axial images and should always be measured at the L-5 to S-1 level, as the
filum may be stretched, and therefore of normal thickness, at more rostral
levels. In addition, the level of the conus medullaris is best determined
from axial images, as the roots of the cauda equina may obscure the pre-
cise level of the conus when the sagittal images are viewed (82). In a series
of 31 patients operated for the tethered cord syndrome, 55% had an
obviously thick, fibrotic filum, 23% had a small fibrolipoma within the
thickened filum, and 3% had a small filar cyst. In 13% of patients, no
distinct filum was seen; rather, the spinal cord was markedly elongated,
extending downward to the lower end of the dural sac and ending in
a small lipoma at the caudal end of the thecal sac (Fig. 9-31) (210).
Increased awareness of the signs and symptoms of spinal cord tether-
ing have prompted some neurosurgeons to section the filum terminale
5/6/2011 10:28:45 PM
 Chapter 9 • Congenital Anomalies of the Spine 885

FIG. 9-28. Fibrolipoma of the filum

terminale in an adolescent. A. Sagittal
T1-weighted image shows a thickened
filum terminale (arrows) demonstrating a
short T1 relaxation time indicative of fat.
Note that the conus medullaris is at the
normal level. B. Axial T1-weighted image
through the filum shows a thickened, fatty
filum diagnostic of a fibrolipoma.

FIG. 9-29. Fibrolipoma of the filum terminale in an infant; importance of axial images through the L-5 to S-1 levels. A. Sagittal T1-weighted image shows
the conus terminating near the bottom of L-2. No fat is seen in the filum. B. Axial T1-weighted image at the L-3 to L-4 level shows normal cauda equina
without any abnormality of the filum terminale. C. Axial T1-weighted image at the L-5 level shows the thick, fatty filum (arrow) in the dorsal aspect of the
thecal sac. D. Different patient. Axial T2-weighted image at the L-5 level shows the enlargement and hypointensity (arrow) from fibrous thickening of the
filum terminale. If the filum terminale appears larger than the roots of the cauda equina on axial T2 images, it is probably too thick.

Barkovich_Chap09.indd 885 5/6/2011 10:28:45 PM

 886 Pediatric Neuroimaging

FIG. 9-30. Fibrolipoma of the filum terminale; use of axial T2-weighted images. A. Sagittal T1-weighted image shows normal level of the conus medullaris.
B. Axial T1-weighted image shows a thick, fatty filum terminale (white arrow) at the sacral level. C. Axial T2-weighted image shows the filum (black arrow)
as abnormally thick.

FIG. 9-31. Tethered spinal cord (tight filum terminale syndrome). A and B. Sagittal T1- and T2-weighted images show a very thin, elongated spinal cord
extending all the way down into a terminal lipoma (white arrow in A). The thickness of the filum at the L-5 to S-1 level is always greater than 1 mm in these
patients. Note the dilated central canal (black arrows in B), present in 20% to 25% of patients with tethered spinal cord. C. Axial T2-weighted image at the
S-1 level shows nerve roots as linear hypointense structures exiting ventrally, indicating that this is spinal cord, not a thick filum. D–F. Tethered spinal cord
with a tail.

Barkovich_Chap09.indd 886 5/6/2011 10:28:47 PM


FIG. 9-31. (Continued) D. Sagittal T2-weighted imaging shows the markedly elongated distal spinal cord, extending all the way to the abnormally low
termination of the thecal sac at the S-4 level (small white arrow). The normal thecal sac should terminate at the S-2 level. A portion of the 13 cm tail can be
seen behind the lumbar spine soft tissues (large white arrowhead). E and F. Axial T1-weighted images at the L-4 and S-3 levels show the low termination of
the spinal cord but no apparent fat deposition. The tail (arrows) can be seen posteriorly in both images.
more frequently, even in the setting of a normal MRI (55,211); the
results of an ongoing prospective, randomized trial were not available
at the time of this writing (212).
Phase-contrast MRI may be useful to detect diminished motion
of the cervical spinal cord in patients with cord tethering (121,122).
The normal spinal cord moves caudally at a velocity of 1 cm/s during
CSF diastole (at which time, CSF is moving rostrally at a velocity of up
to 2 cm/s) and moves rostrally during CSF systole (122). In patients
with spinal cord tethering, this motion is damped and the cord veloc-
ity is reduced (121,122). After release of the tethering, normal motion
returns in about one third of patients (122).
Syndrome of Caudal Regression
(a complex spinal dysraphism)
The syndrome of caudal regression is composed of a spectrum of
anomalies, including sirenomelia (fusion of the lower extremities),
absence of the caudalmost vertebrae and spinal cord (lumbosacral
agenesis), anal atresia, malformed external genitalia, exstrophy of the
urinary bladder, renal aplasia or ectopia, and pulmonary hypopla-
sia with Potter facies (213,214). The syndrome seems to result from
disturbances of the caudal mesoderm, including the caudal cell mass
and cloaca, before the fourth week of gestation (213,214). Two cases
have been described in association with deletion of the short arm of
chromosome 18 (215,216). The lack of formation of the caudal spi-
nal cord and spinal column in patients with lumbosacral agenesis has
been postulated to result from maldevelopment of the lower portions
of the spinal cord and notochord due to a toxic, infectious, or isch-
emic insult. This insult presumably impairs the normal migrations of
neurons, paraxial mesoderm cells (somites that form the vertebrae),
and the lateral mesoderm cells that form the lower digestive tract
(39,217). Another possibility is that the notochord is injured, resulting
in abnormal neurulation and maldevelopment of the vertebral bodies.
The abnormal neural tube subsequently causes abnormal development
of the vertebral arches (218). Other possibilities include abnormality
of glucose transporter genes (219), mutation or lack of expression of
the genes that code for the development of the lowest segments of the
spine, or induction of apoptosis in these segments for reasons that are
not currently understood.
The incidence of caudal regression syndrome is approximately
1 in 7,500 births (214). The milder forms, including isolated sacral
Barkovich_Chap09.indd 887
Chapter 9 • Congenital Anomalies of the Spine 887
hypogenesis or anal atresia, are more common than the more severe
forms. Approximately one sixth of infants with caudal regression syn-
drome have diabetic mothers (220). As would be expected from the
embryology, a high incidence of lumbosacral hypogenesis is found in
patients with anomalies of the lower gastrointestinal and genitouri-
nary systems, particularly those with anal atresia (43,44). Moreover,
the higher the level of the anal atresia, the more severe is the lum-
bosacral hypogenesis (43,49,221). Therefore, the sacrum and lower spi-
nal cord should be carefully scrutinized in all patients with anomalies of
the lower GI and GU systems. About 10% of patients with lumbosacral
hypogenesis have OEIS (concurrent omphalocele, cloacal exstrophy,
imperforate anus, and spinal deformities) and another 10% have the
VACTERL syndrome (vertebral anomalies, anorectal malformations,
cardiac malformations, tracheoesophageal fistulae, renal anomalies,
and limb anomalies) (49).
Clinical signs at presentation range from isolated deformities of the
feet or minor distal muscle weakness to complete sensorimotor paraly-
sis of both lower extremities (49,218). Motor deficits, almost always
more severe than the sensory loss, correspond to the level of vertebral
loss (within one level) unless an associated myelomeningocele is pres-
ent. In most patients, sensation is intact caudally for several segments
below the vertebral loss; therefore, perineal sensation can be preserved
despite severe leg weakness, sphincter disorder, and sacral agenesis.
Almost all patients have a neurogenic bladder (49). The clinical sce-
nario of sphincter dysfunction and lower extremity motor deficits
results in a tentative clinical diagnosis of tethered spinal cord in many
of the less severely affected patients. Indeed, as many as 60% of patients
with lumbosacral hypogenesis, particularly those with progressive neu-
rologic symptoms, have cord tethering superimposed upon agenesis of
the lower sacral nerve roots (49,221).
The degree of spinal agenesis is variable, ranging from a partial or
total unilateral sacral agenesis (with an oblique lumbosacral joint) to
total agenesis of the lumbar and sacral spine (48). The caudalmost two
or three vertebral bodies are often fused and dysplastic (Figs. 9-32 and
9-33). The bony canal immediately rostral to the last intact vertebra
may be severely narrowed as a result of bony excrescences originat-
ing from the vertebral bodies, from fibrous bands connecting the bifid
spinous processes, or from stenosis of the dural tube. Surgical release
of such dural stenosis and duroplasty may achieve an improvement
of neurologic function (218). The major neural anomaly is hypopla-
sia of the distal spinal cord, which is typically more severe ventrally
5/6/2011 10:28:48 PM
 888 Pediatric Neuroimaging

FIG. 9-32. Severe caudal regression with VACTERL syndrome. A. Coronal T1-weighted image shows scoliosis, absence of the right kidney, and vertebral
anomalies at the apex of the spinal curvature (asterisk marks a hemivertebra). The sacrum is absent. White arrow points to the level of a neurenteric cyst.
B. Sagittal T1-weighted image of the cervical and upper thoracic spine shows a gap in the vertebral bodies (white arrows) at the level of the neurenteric cyst
and the cyst (white arrowheads). C. Sagittal T1-weighted image shows the blunted cord terminus (arrows) at the midthoracic level.

than dorsally, resulting in a characteristic blunted or “wedge” shape of
the cord terminus (Figs. 9-32 and 9-34) (48). Such blunting is seen in
essentially all children with partial or complete sacral agenesis and ter-
mination of the spinal cord above the level of the first lumbar vertebra
(49). It is the result of diminished numbers of anterior horn cells in
the distal cord and abnormally small sacral nerve roots. Below the level
of the last intact vertebra, scattered nerve fibers pass through dense
fibrous tissue (151,222).
The spinal cord may be tethered in sacral agenesis; Pang et al.
(49) found tethering of the spinal cord in all patients with lumbosacral
hypogenesis in whom the conus terminated below the L-1 level. They also
found a correlation with level of the conus and severity of the sacral
hypogenesis. Termination of the conus above L-1 is highly correlated
with sacral malformations ending at S-1 or above, whereas conus ter-
mination below L-1 is highly correlated with sacral malformations
ending at S-2 or below (49). Therefore, tethering is more common in
milder sacral agenesis. It is important to note the presence of spinal
cord tethering in patients with lumbosacral hypogenesis, as release of
the tethered cord may result in improved urinary function, even if the
neurologic deficit remains static (223); at the very least, the release of
the tethered cord is likely to prevent neurological worsening (169).
Tethering may be associated with a thick filum terminale (65%), ter-
minal myelocystocele (15%), terminal hydromyelia (10%), or terminal
lipoma/lipomyelocele (10%) (49). When the spinal cord is tethered in
lumbosacral hypogenesis, the cord terminus is not wedge-shaped, but
elongated, like a typical tethered spinal cord (Fig. 9-33).
On imaging studies, the diagnosis of caudal regression is easily
made. Plain films allow diagnosis of the bony hypogenesis but do not
show associated cord tethering or dural stenosis, if present. Sagittal and
coronal MR images are helpful in detecting hypogenesis or dysgenesis
of the caudal vertebral bodies (Figs. 9-32 and 9-33). Moreover, assess-
ment of the level and shape of the conus medullaris will determine
whether tethering is present. MRI reveals a characteristic blunted or,
often, “wedge-shaped” appearance of the terminus of the spinal cord
in those patients in whom the cord is not tethered; in these cases, the
cord terminus will generally be located above the L-1 level (Figs. 9-32
and 9-34) (44,48). When this appearance is seen on sagittal images,
the sacrum should always be scrutinized to assess for the presence and
degree of hypogenesis. As discussed above, the distal cord has a tapered
appearance when tethered (Fig. 9-33); typically, the cord will terminate
below the L-1 level in these patients. Axial T1- and T2-weighted images
should be obtained through the levels immediately adjacent to the level
of regression to look for thickened or fatty filum terminale (Fig. 9-30),
a lipomyelocele, terminal hydromyelia (Fig. 9-34), lipoma, or the pres-
ence of bony spinal stenosis (44,48).
Terminal Myelocystocele (a CSD with a
subcutaneous mass)
The terminal myelocystocele (also known as syringocele) is the least
common form of spinal dysraphism with posterior osseous defect
(224). This anomaly is an occult spinal dysraphism in which the hydro-
myelic spinal cord and the arachnoid are herniated through a posterior
element defect, creating an unusual type of skin-covered myelomenin-
gocele (Fig. 9-35). Affected patients present with midline cystic masses
in the lumbosacral region. They have no bladder or bowel control, and

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 Chapter 9 • Congenital Anomalies of the Spine 889

FIG. 9-33. Caudal regression with a tethered cord.

A. Sagittal T1-weighted image shows a low-lying cord
terminus that is tapered, not blunted, as seen when
caudal regression is associated with tethering of the
spinal cord. Black arrows point to a terminal lipoma.
B. Coronal T1-weighted image shows a small, dysplas-
tic sacrum (black arrows), which is fused with the lower
lumbar vertebrae.

FIG. 9-34. Mild caudal regression. A. Sagittal T1-weighted

image shows that the cord terminus is blunted, ending at the
mid T11 level. The central canal appears dilated. The spinal col-
umn is normal except for the sacrum. S-2 is dysplastic and the
S-3, S-4, and S-5 segments and the coccyx are absent. B. Axial
T1-weighted image shows substantial dilatation of the central
canal of the spinal cord.

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 890 Pediatric Neuroimaging
FIG. 9-35. Schematic of terminal myelocystocele. Hydromyelia is always
present in the spinal cord. At the cord terminus, the central canal opens
into a large cyst (c). This cyst is below a region of bony spina bifida and
expanded subarachnoid space (sas) that surrounds the distal spinal cord.
Barkovich_Chap09.indd 890
lower extremity function is typically severely impaired (225). As with
other anomalies of the caudal cell mass, the terminal myelocystocele is
often associated with anomalies of the anorectal system, lower genito-
urinary system, and vertebrae, such as anal atresia, cloacal exstrophy,
lordosis, scoliosis, and partial sacral agenesis (45,225). Myelocystoceles
in other locations are more likely anomalies of disjunction and are dis-
cussed in that section, earlier in the chapter.
In the terminal myelocystocele, the spinal cord partially or com-
pletely traverses a meningocele and inserts within its lateral or poste-
rior wall (Fig. 9-35). At the junction line between the placode and the
meninges, the pia covering the spinal cord is reflected along the wall
of the meningocele, creating a closed cavity filled with cerebrospinal
fluid. In all forms of myelocystocele, a hydromyelic cavity lies within
the cord. At the level of the myelocystocele, this hydromyelic cavity
dilates into a large ependyma-lined cyst that protrudes beyond the
reflection of the pia in such a manner that it can be extra-arachnoidal
in location (Fig. 9-35). On occasion, the dorsal mesoderm is fatty in
these patients (169); in this situation, the malformation is termed a
lipomyelocystocele.
Imaging studies demonstrate direct continuity of the meningo-
cele with the subarachnoid space and the presence of a cyst in conti-
nuity with the central canal of the spinal cord (Fig. 9-36) (77,79,224).
Because the cyst does not communicate with the meningocele, myel-
ography will demonstrate only the meningocele (if present), which
is much smaller in volume and at a different level than the clinically
apparent mass. Imaging studies show that the clinically apparent mass
is a second cyst, which is thin-walled and has no internal structure
(Fig. 9-36) (77,79,80,224,226). The cyst may show delayed opacifi-
cation with water-soluble intrathecal contrast, similar to a hydromy-
elia. The ependyma-lined (hydromyelia) cyst is frequently the larger
of the two cysts; it is typically situated posteriorly and inferiorly to
the meningocele, but will occasionally extend rostrally outside the
meningocele.
FIG. 9-36. Terminal myelocystoceles; infants with sacral
masses. A. Sagittal T1-weighted image in a 2-day-old neonate
shows an expanded, syringohydromyelic spinal cord, which
appears to terminate at the midsacral level (white arrow). A
large cystic mass is seen caudal to the apparent cord termina-
tion (black arrows). At surgery, this terminal cyst was found to
communicate with the dilated central canal of the spinal cord,
resulting in the classification of this anomaly as a myelocysto-
cele. B. Sagittal T1-weighted image shows the myelocystocele
(c) in direct contact with the syringomyelic cavity (s) in the
distal spinal cord. The walls of the cavity (arrows) are seen to
separate as they lead into the cyst.
5/6/2011 10:28:51 PM
 Chapter 9 • Congenital Anomalies of the Spine 891

Anterior Sacral Meningocele
Anterior sacral meningoceles are anomalies characterized by focal
erosion or hypogenesis of sacral or coccygeal segments with herniation
of a cerebrospinal fluid-filled meningeal sac through the defect into
the pelvis. They account for approximately 5% of retrorectal tumors
and are usually diagnosed in the second and third decades of life. In
children, males and females are equally affected (20,76). Symptoms
are produced as a result of pressure on the pelvic viscera, causing con-
stipation, urinary frequency and incontinence, dysmenorrhea, dys-
pareunia, or pain in the lower back or pelvis. Furthermore, pressure
may be exerted on nerve roots, resulting in sciatica, diminished rectal
and detrusor tone, or numbness and paresthesia in the lower sacral
dermatomes. Finally, fluid shifts between the sac and the spinal suba-
rachnoid space can cause intermittent high-pressure headache (when
supine), nausea, vomiting (especially during defecation), or low-
pressure headache (while in the erect position).
The embryogenesis of anterior sacral meningoceles is not deter-
mined. A relatively simple form arises in patients with neurofibromatosis
Type 1 and in patients with Marfan syndrome. A more complex famil-
ial form, which is associated with a partial sacral agenesis, imperforate
anus or anal stenosis, and a tethered spinal cord, has been described
(227). The sacral dural sac is usually widened; it communicates with
the pelvic cyst through a (usually) narrow neck that is situated within
the sacral defect. The meningoceles may be large or small, simple or
multiloculated, devoid of neural tissue or traversed by nerve roots
within the wall or lumen of the sac (76,227–229). The identification
of traversing nerve roots is crucial, since the neck of the meningocele
cannot be simply ligated in their presence.
Bony anomalies consist of a widened sacral canal, scalloping of
the anterior wall of the sacrum, and sacral scoliosis (229). The curved
appearance of the residual sacrum, which is scalloped beneath the
defect, gives the appearance of scimitar sacrum or a sickle-shaped
sacrum on sagittal images; this appearance is highly suggestive of an
anterior sacral meningocele (228).
Imaging studies show a deficient sacrum and a variably sized cyst
extending into the pelvis through an enlarged sacral foramen. Conti-
nuity of the cyst with the thecal sac must be demonstrated in order to
make the diagnosis. On MR studies, the continuity is best demonstrated
in the sagittal plane (Fig. 9-37) (76). If CT is used, contrast should be
injected intrathecally to optimally show the continuity of the meningo-
cele with the subarachnoid space. Whatever imaging technique is used,

FIG. 9-37. Anterior sacral meningocele. A and B. Lateral view and sagittal CT
reformation from a lumbosacral myelogram show the extension of the intrath-
ecal contrast through an anterior sacral osseous defect and into the presacral
space (arrows). C. Axial bone window from a CT myelogram shows the dysplas-
tic appearance of the left hemisacrum (h) and absence of the right hemisacrum
anteriorly. Note the contrast extension into the presacral space (white arrow). D
and E. Sagittal T1- and T2-weighted images show the anterior sacral meningocele
(arrows) coursing under the hypoplastic sacrum. It is important in these anoma-
lies to determine whether nerve roots of the cauda equina are floating within the
meningocele before the meningocele is ligated.

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 892 Pediatric Neuroimaging
the most important features to demonstrate are (a) tethering of the
cord and the associated tethering lipoma or dermoid, if present, and
(b) whether nerve roots traverse the sacral defect.
Sacrococcygeal Teratoma
Sacrococcygeal teratomas are rare congenital tumors that develop in
the lower sacrum. They are thought to arise from rests of totipotential
cells in the caudal cell mass. Females are affected more commonly than
males by a four to one preponderance. Sacrococcygeal teratomas may
present as external masses protruding from the gluteal cleft or from
the perineum, or may intrude into the pelvis, causing radicular pain,
constipation, or urinary frequency and incontinence. Histologically,
approximately two thirds are mature teratomas; the other one third
is split relatively evenly between immature teratomas and anaplastic
carcinomas (20). The vast majority of these teratomas are large, well-
encapsulated, lobulated masses, having both solid and cystic portions.
Approximately 5% are predominantly cystic.
Sacrococcygeal teratomas have been classified by their location
(230–232). Type I tumors (47%) are situated almost entirely exteriorly
and have only a minimal presacral portion. Type II tumors (35%) are
also largely exterior in location, but have a significant pelvic extension.
Type III tumors (8%) are visible from the exterior as a mass but are
mainly in the pelvis and abdomen. Type IV teratomas (10%) are entirely
presacral without any external mass. The sacral canal is involved in 2%
of affected patients.
If a sacral malformation is associated with a sacrococcygeal tera-
toma, it suggests the rare familial form of tumor, which has an auto-
somal dominant inheritance, a slight female preponderance, and
prominent sacrococcygeal defects. Anorectal stenosis, vesicoureteral
reflux, and cutaneous stigmata are frequently present in children with
the familial form.
The sporadic and familial forms are indistinguishable on imag-
ing studies. Bony erosions in the sacrum, when present, outline
the entire soft tissue component, whether dorsal to the sacrum or
intrapelvic. Depending upon the percentage of solid components, cystic
FIG. 9-38. Sacrococcygeal teratoma in a 27-week fetus. A. Sagittal imaging shows the heterogeneous mass (Type 3 teratoma) with the large intra-abdominal
and pelvic component and the smaller external component. This particular tumor was of an aggressive, immature histology and invaded the spinal canal
(arrows). B. Coronal image shows the widening of the pedicles by the invasive spinal component (arrows). C. A more anterior coronal image shows the
obstructive hydronephrosis and displacement of kidneys due to the large pelvic mass.
Barkovich_Chap09.indd 892
components, and calcification, the tumors are variably heterogeneous.
Adequate CT evaluation necessitates opacification of the bowel, the ure-
ters, and bladder by the use of contrast agents to evaluate the relation-
ship of the tumor to the pelvic viscera. Contrast agents are not necessary
if MR is used. The MR appearance of the tumor is variable, depending
upon its composition. Most often, the solid portions of these lesions are
extremely heterogeneous as a result of high signal from fat, intermedi-
ate signal from soft tissue, and low signal from calcium on T1-weighted
images (Figs. 9-38 and 9-39). The tumors are usually lobulated and
sharply demarcated. When they are mostly cystic (Fig. 9-39), intrave-
nous contrast administration may be necessary to identify a solid com-
ponent in the wall of the cyst.
ANOMALIES OF DEVELOPMENT
OF THE NOTOCHORD
The Split Notochord Syndrome Spectrum
(complex spinal dysraphisms)
Embryology
A review of some embryology aids in the understanding of split
notochord malformations. During the second week of gestation, the
embryo consists of a flat, two-layered disc. The developing ectoderm
lies dorsally, in contact with the amniotic cavity. The primitive endo-
derm lies ventrally, in contact with the yolk sac. During the third
week of life, a thickening occurs in the dorsal midline as a result of a
focal rapid proliferation of cells; this area has been called the Hensen
node. Cells proliferate and migrate from Hensen node, separating the
ectoderm from the endoderm; these cells course in predefined routes
lateral to the midline. Subsequently they will join in the midline to
form the notochordal process, which will eventually roll into a tube
and separate from the endoderm to form the definitive notochord. If
the ectoderm fails to completely separate from the endoderm (leav-
ing a strand or adhesion), the notochord must either remain split
around the adhesion or deviate to the left or right of it (31,233,234).
Moreover, the primitive neurenteric canal, formed by the process of
5/6/2011 10:28:53 PM

FIG. 9-39. Cystic sacrococcygeal teratoma. A. Sagittal T1-weighted image shows a cystic mass (Type 3 teratoma, arrows) centered at the coccyx. B. Post-
contrast T1-weighted image with fat suppression shows a small solid portion of tumor (arrows). The high signal intensity focus in the tumor seen in C
disappears, proving that it represents fat. No enhancement is present. C. Precontrast T1-weighted image shows the presence of high signal intensity fat
within the solid portion of the tumor (arrows).
intercalation, may not regress, leaving a residual connection between
endoderm and ectoderm. The mesoderm, which normally surrounds
the notochord to form the vertebral bodies, is split or deviated by the
anomaly, resulting in a persistent connection between the dorsal sur-
face of the gut and the dorsal, midline surface of the body. As the
embryo grows and the gut migrates, the adhesion can become quite
long and the structures connected by it may become quite topo-
graphically distant. Because the notochord may remain split or devi-
ate around the adhesion, the connection of the cyst to the vertebrae
may be in the midline or paramedian. Moreover, because all or part
of the connection may involute, only portions of the connection may
be present (233,234).
Classification
The term “split notochord syndrome” refers to a spectrum of anoma-
lies that are believed to result from splitting or deviation of the noto-
chord with a persistent connection between the ventrally located
endoderm and the dorsally located ectoderm (235). The most severe
form of this syndrome is a fistula (the dorsal enteric fistula) through
which the intestinal cavity communicates with the dorsal skin surface
in the midline, traversing the prevertebral soft tissues, the vertebral
bodies, the spinal canal and its contents, and the posterior elements
of the spine (235–237). The most extreme form of the dorsal enteric
fistula is a dorsal bowel hernia in which a portion of bowel is herniated
into a skin- or membrane-covered dorsal sac after passing through a
combined anterior and posterior spina bifida. Often, the bowel lumen
is open to the skin surface. Because any portion of the dorsal enteric
fistula may become obliterated or persist, apparently isolated diver-
ticula, duplications, cysts, fibrous cords, and/or sinuses may be present
at any point along the tract. The dorsal enteric sinus is the remnant of
the posterior part of the tract and forms a blind tract with a midline
opening to the dorsal external skin surface (235,236). Dorsal enteric
(enterogenous) cysts (which are derived from the intermediate part of
the tract) are enteric-lined cysts which may be prevertebral, retrover-
tebral, or intraspinal (235,236). Dorsal enteric diverticula are tubular
Barkovich_Chap09.indd 893
Chapter 9 • Congenital Anomalies of the Spine 893
or spherical diverticula that arise from the dorsal mesenteric border
of the bowel. These diverticula represent a persistence of a portion of
the tract between the gut and the vertebral column. Because the bowel
segments migrate inferiorly and rotate, it is not uncommon to trace
dorsal enteric diverticula far upward from the small bowel through
the mesentery and diaphragm into the mediastinum. Occasionally, the
diverticula will extend to the anterior surface of the vertebra or into
the spinal canal (235). If there is involution of the portion of the diver-
ticulum near the gut, a prevertebral dorsal enteric cyst is formed (236).
Finally, in some patients, the dorsal enteric fistula may close at mul-
tiple sites. In these patients, one may find combined, noncommunicat-
ing elements of the split notochord syndrome; for example intestinal
diverticula, mediastinal enteric cysts, and intraspinal enterogenous
cysts may be present.
Clinical and Imaging Characteristics
Patients with dorsal enteric fistula usually present as newborns with a
bowel ostium or an exposed pad of mucous membrane in the dorsal
midline. These openings pass meconium and then feces. Associated con-
genital tumors have been reported (238). Patients with dorsal bowel her-
niations present with large, midline, dorsal sacs that are partly covered
by skin and partly covered by mucous membrane; the vertebral column
around the sac is duplicated (Fig. 9-40) (237). Patients with extraspinal
enteric cysts present with masses either in the mediastinum or in the
abdomen. Children with the above-mentioned lesions do not present
with neurological problems as their chief problem and, therefore, will
not be further discussed in this book. The reader is referred to standard
pediatrics and pediatric radiology texts for further information.
Patients with dorsal enteric diverticula typically come to medical
attention because of gastrointestinal complaints, but can present with
neurologic problems if the diverticulum extends into the spinal canal.
The imaging clue in this diagnosis is the abnormalities of the vertebral
bodies on plain films and the extension of intra-abdominal structures
through the vertebral body defects on cross-sectional imaging studies
(Fig. 9-41).
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 894 Pediatric Neuroimaging

FIG. 9-40. Dorsal enteric fistula. A. Coronal T1-weighted image shows a split spinal column and spinal cord (arrows) framing the bowel. B. Axial GE image
shows two spinal columns (open curved arrows), two spinal canals (open straight arrows), and the high intensity bowel extending dorsally between them to
open (solid arrows) at the skin surface. (This case courtesy Rosalind Dietrich, M.D. San Diego, CA).

FIG. 9-41. Dorsal enteric diverticulum. A. Coronal T1-weighted image shows

abnormal vertebrae (arrows) and abnormal narrowing of the spinal cord in the
lower thoracic region. B. Sagittal T1-weighted image shows a deficiency (arrows)
in the vertebral bodies in the lower thoracic region. C. Sagittal T2-weighted
image shows the dorsal enteric diverticulum (black arrows) coursing toward the
vertebral body deficiency. D. Axial T2-weighted image shows a cleft separating
the two halves of a vertebral body (v). The diverticulum (white arrows) courses
between the vertebral bodies. A small cyst (c) is present within the spinal canal,
dorsal to the diverticulum.

Barkovich_Chap09.indd 894 5/6/2011 10:28:55 PM


Intraspinal Enteric Cysts (Neurenteric Cysts,
Endodermal Cysts)
Intraspinal enteric cysts (also called neurenteric cysts and endodermal
cysts) infrequently cause signs or symptoms in newborn infants; when
neonates are symptomatic, the cyst is typically quite large. More com-
monly, affected patients present as adolescents or young adults with
intermittent or progressive local and radicular pain that is worsened
by elevating intraspinal pressure. Eventually, myelopathy ensues as spi-
nal cord compression causes both local and distal long tract symptoms
(239). By the time these patients are imaged, marked compression of
the spinal cord is usually evident (65,240). Acute presentation is rare,
and usually follows infection or illness (241).
Enteric cysts are usually single, smooth, and unilocular, occurring
primarily in the lower cervical and thoracic regions. Rarely, they occur
in the lumbar spine or intracranially in the pons, prepontine cistern,
or cerebellopontine angle (see Chapter 5) (242–244). The fluid within
them may be nearly identical to cerebrospinal fluid or may be milky,
cream-colored, yellowish, or xanthochromic. Enteric cysts are usually
intradural, extramedullary, and situated ventral or ventrolateral to the
cord; less frequently, the cyst may be dorsal or dorsolateral to the cord
or within the cleft of a diastematomyelia (240,244). An intramedullary
component is present in 10% to 15% (245). The cord is usually nar-
rowed and displaced by the mass when symptoms develop.
Spine radiographs may show an enlarged spinal canal at the site
of the enteric cyst. Newborns and infants who are symptomatic from
intraspinal enteric cysts sometimes exhibit vertebral anomalies includ-
ing hemivertebrae, lack of segmentation, partial fusions, and sco-
liosis in the region of the cyst (such changes are more common with
mediastinal or abdominal dorsal enteric cysts). Older patients usually
exhibit no vertebral changes other than focal enlargement of the canal
resulting from local pressure effects (240).
Some neurosurgeons believe that both CT and MRI are required
for proper preoperative imaging analysis of a neurenteric cyst (246).
CT shows vertebral anomalies in about 50% of affected patients; verte-
bral body clefts, butterfly vertebrae, and anomalies of segmentation are
most common (245). The spinal canal may be focally expanded. MRI,
however, shows most of the vertebral anomalies and, more importantly,
shows the cysts and their relationship to the spinal cord (Figs. 9-42 to
9-45). MRI typically shows a cyst lying ventral to and compressing the
adjacent spinal cord (Figs. 9-43 and 9-44) (65,240,244). However, the
Barkovich_Chap09.indd 895
Chapter 9 • Congenital Anomalies of the Spine 895
cyst may lie dorsal to the cord (Fig. 9-44) or partially or completely
within the cord (Figs. 9-42 and 9-45); it is most important to define the
cyst and its relationship to the spinal cord. The cyst contents may be
similar to CSF (Figs. 9-42 and 9-45) or may be proteinaceous, short-
ening the T1 relaxation time and resulting in relatively (compared
to CSF) high intensity on T1-weighted images (Figs. 9-43 and 9-44)
(246). If the cyst is creamy or has xanthogranulomatous changes, it
may have a heterogeneous appearance on both T1- and T2-weighted
images (239,247). Occasionally, this heterogeneity may mimic a nodule
and suggest the presence of a neoplasm (248); in such cases, admin-
istering contrast will help in differentiating cyst (no enhancement of
nodule) from tumor (nodule usually enhances). The identification of
anomalies of the adjacent vertebral bodies aids in identification of the
abnormal level. The abnormal vertebrae and the cysts can be identified
by myelography. Similar information can be obtained from MRI. Cor-
onal images through the vertebral bodies (Figs. 9-44 and 9-45) identify
abnormal vertebrae. The cyst may be difficult to detect if it is small and
its contents are very similar to cerebrospinal fluid; FLAIR imaging may
be helpful. However, the displacement and distortion of the spinal cord
by the cyst facilitates detection (Fig. 9-42). In addition to evaluating the
spine, it is important to look for associated fistulae and mediastinal or
abdominal cysts.
Split Cord Malformation (Diastematomyelia and
Diplomyelia—complex spinal dysraphism)
Definition
The term diastematomyelia, a form of SCM, refers to a sagittal division
of the spinal cord into two symmetric or asymmetric hemicords, each
containing a central canal, one dorsal horn (giving rise to a dorsal nerve
root), and one ventral horn (giving rise to a ventral nerve root). Each
hemicord is invested by its own layer of pia (20,63,151,249–252). The
division may involve the entire thickness of the cord or may only affect
the anterior or posterior half of the cord (partial diastematomyelia or
“horseshoe cord”) (47,234,253). Partial division is frequently observed
in the transitional zones superior and inferior to an area of complete
diastematomyelia (20,74,234,252). Although one can find a number of
definitions of the rare diplomyelia in the medical literature, it is most
commonly used to refer to a duplication of the spinal cord, with each
cord containing a central canal, two dorsal horns (giving rise to two
FIG. 9-42. Neurenteric cyst. A. Sagittal T1-weighted
image shows the characteristic anterior spinal defect
associated with the neurenteric cyst, as well as a T1-
hyperintense cyst (white arrows) in the dilated spinal
canal. Segmentation anomalies of the vertebral bodies
and posterior elements are also present at this level. B and
C. Coronal T2-weighted imaging demonstrates the ante-
rior osseous defect (d) and the hyperintense cyst (arrow
in C) resulting in lateral deviation of the spinal cord.
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 896 Pediatric Neuroimaging

FIG. 9-43. Neurenteric cyst associated with SCM. A and B. Sagittal T1-weighted images show a hyperintense neurenteric cyst (small solid white arrows)
ventral to a dysplastic upper cervical spinal cord. The cyst points toward a space (small open white arrows) between the dysplastic upper cervical vertebrae.
C. Axial T1-weighted image shows a dysplastic vertebral body and a nearly complete sagittal cleft (solid white arrow) of the spinal cord. The cyst (open white
arrows) presumably contains proteinaceous, possibly inspissated, fluid. (This case courtesy of Dr. Michael Brant-Zawadzki).

dorsal nerve roots), and two ventral horns (giving rise to two ventral
nerve roots). As diastematomyelia and diplomyelia cannot always be
distinguished from one another and may be incorrectly used as syn-
onyms, the term SCM is preferred (234).
Clinical Presentation
The signs and symptoms of SCM may appear at any time of life. Females
are affected much more commonly than males (74,117,254). Cutane-
ous stigmata such as hairy patches (hypertrichosis, the most common
stigma), nevi, lipomas, dimples, and hemangiomas overlie the spine in
more than half of cases; these signs often lead to diagnosis in infancy
(255). Half of affected patients manifest orthopedic problems of the
feet, particularly clubfoot. A specific neuro-orthopedic syndrome (251),
consisting of weakness and muscle wasting in one leg, often associated
with an ipsilateral clubfoot, is seen in about half of patients with lum-
bar SCM (256). Scoliosis is common in older children and adults (257)
and is a common reason for clinical presentation in these age groups,
along with low back pain, sciatica, and perianal dysesthesias (255,258).
SCM is responsible for approximately 5% of congenital scolioses (254).
Neurologic symptoms are nonspecific and may be indistinguishable
from other causes of cord tethering (20,74,117,234,254,258–260).
Embryology
SCM most likely develops as a result of splitting of the notochord
(234,253). If the cells forming the notochord, in the course of their
migration from Hensen node, encounter an obstacle such as an adhe-
sion between ectoderm and endoderm, the notochordal cells must
course laterally around the obstacle on one side or split and go around
on both sides at the same time. As a consequence of this detour, the
notochord develops either a lateral notch or a central cleft. Because
the notochord influences the development of the vertebral bodies,
any alteration of the notochord could result in an abnormality of the

FIG. 9-44. Dorsal intraspinal enteric cyst. A. Sagittal

T1-weighted image shows a mass (arrows) dorsally in the
cervical subarachnoid space compressing the spinal cord.
B. Coronal T1-weighted image shows several hemiverte-
brae (arrows) at the level of the cyst.

Barkovich_Chap09.indd 896 5/6/2011 10:28:57 PM


FIG. 9-45. Intramedullary neurenteric cyst. A. Sagittal T2-weighted image shows an apparent cyst (solid black arrow) within the dorsal aspect of the spinal
cord. The upper cervical vertebral bodies (open white arrows) appear small and possibly dysplastic. B. Axial T1-weighted image shows the cyst (solid white
arrows) within the dorsal spinal cord. C. Coronal T1-weighted image shows the multiple malsegmented vertebrae (white arrows) of the cervical and upper
thoracic spine.
vertebral bodies such as a hemivertebra (if the notochord were notched)
or a butterfly vertebra (if the notochord had a cleft). Similarly, a split
notochord could induce the formation of two neural plates, which may
go on to form two hemicords. Surrounding mesenchyme can migrate
into the space between the hemicords, forming a fibrous, cartilaginous,
or bony spur. Moreover, one can imagine in this setting that the distal
notochord could be split, resulting in two separate foci of canalization
and retrogressive differentiation; this sequence of events could explain
the rare cases of SCM affecting only the conus medullaris and filum
terminale.
Pathology and Imaging
Imaging of SCM can be difficult, because patients commonly have
severe scoliosis, often with a rotatory component. MR is the best tech-
nique if 3DFT volumetric techniques are used or if oblique images
are acquired in planes parallel and perpendicular to each relatively
straight segment of spine. These techniques are described in Chapter 1.
T1-weighted images are optimal to visualize the spinal cord and to
look for fibrolipomas of the filum terminale. Exiting nerve roots and
thickening of the filum terminale are best imaged by axial T2-weighted
RARE images. Bony and cartilaginous spurs are most easily identified
on axial T2- or T2*-weighted images or on CT. However, if the patient
has difficulty in holding still during the MR exam or if the scoliosis
is particularly severe, CT myelography with reformations in multiple
planes, parallel and perpendicular to the course of the spinal cord, may
be extremely useful to assess the course of the spinal cord and the pres-
ence or absence of a fibrolipoma of the filum.
The level of the cleft is variable but it is most commonly (more than
80%) in the lumbar region (258). Upper thoracic clefts are unusual and
cervical clefts are rare (117,258,261,262). It is possible that cervical and
upper thoracic SCM are more common than is generally accepted but
remain asymptomatic because they are less likely to cause symptom-
atic tethering of the cord than are clefts that are located more caudally.
(Tethering is less likely because the segmental level of the spinal cord
much more closely coincides with the segmental level of the adjacent
vertebrae in the cervical and upper thoracic levels.) The two hemicords
Barkovich_Chap09.indd 897
Chapter 9 • Congenital Anomalies of the Spine 897
usually reunite caudal to the cleft (74). Occasionally, however, the cleft
will extend unusually low and the hemicords remain distinct with two
separate coni medullaris and two fila terminale.
In 40% to 70% of patients, the arachnoid and the dura split into
two separate arachnoid and dural tubes, each surrounding the corres-
ponding hemicord (258). Thus, each hemicord has its own pial, arach-
noid, and dural sheath for several spinal sections; this is referred to as
Type I SCM (234,251,263). Patients with two separate dural sheaths
nearly always have a bony or cartilaginous spur at the most inferior
portion of the cleft; this is often better seen on axial and coronal images
than on sagittal images (Fig. 9-47). The spur may originate from a lam-
ina or from the vertebral body (Figs. 9-46 and 9-47). If the myelogram
or imaging study appears to show the spur at a more rostral level, a sec-
ond spur, present in approximately 5% of patients with SCM, is likely
to be present (Fig. 9-46) (84,234,251,263). The bony spur forms from
cartilage and has multiple ossification centers. Therefore, depending
upon the age of the patient and the number of ossification centers,
the spur can be nonossified cartilage, cartilaginous with multiple small
ossification centers arranged linearly between the two hemicords, a
bony strut attached to the wall of the spinal canal by a synchondrosis,
or a complete osseous bridge joining the vertebral body with the pos-
terior elements (252). The spur may be isointense or slightly hyperin-
tense compared to CSF on T1-weighted images if nonossified; it will
be hyperintense on T1-weighted images if ossified (Fig. 9-46) because
of the high signal from the marrow. Bony, cartilaginous, and fibrous
spurs all appear hypointense on T2-weighted spin-echo and gradient-
echo (Fig. 9-46) images. The CT attenuation will vary, depending upon
how much of the spur is bone, how much is cartilage, and how much
is fibrous tissue; the appearance of the bony/cartilaginous section will
vary with the stage of ossification.
Usually, the bony spur is in the midline sagittal plane and divides
the canal into two fairly equal halves. However, scoliosis may rotate
the spur such that the two hemicanals are oriented more anteriorly
and posteriorly (Fig. 9-48) (251). Occasionally, the spur may cross the
spinal canal obliquely and insert into an externally rotated lamina or
a pedicle creating a significant asymmetry in the two hemicanals; in
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 898 Pediatric Neuroimaging

FIG. 9-46. SCM with spurs at two levels. A. Sagittal T1-weighted image shows a spur (curved arrow) at the midthoracic level. This spur is several levels
rostral to the lowest level of the split spinal cord, suggesting that a second spur is present. B. Adjacent image shows a possible spur (curved arrow) at the
lower thoracic level. C. Axial T1-weighted image at the level of the upper spur shows the two hemicords (arrows) separated by a poorly defined spur. D. The
spur (arrows) is better demonstrated by this GE image. E. Axial T1-weighted image shows the lower spur (arrows). Note that the posterior part of the spur
is fibrous and, therefore, poorly seen by MR.

these patients, the larger canal is usually posterior. MRI is especially
helpful when patients have rotoscoliosis (Fig. 9-48). An initial coronal
image is obtained. Oblique sagittal and oblique axial planes of imaging
are then defined parallel and perpendicular, respectively, to the straight
segments of spine, as described in Chapter 1. Alternatively, a volume
image may be obtained and reformatted in multiple planes. In our
experience, more artifact is present on volume images because of more
motion (due to greater time for the sequence) and the presence of two
phase encoding gradients.
It must be emphasized that even osseous spurs can be missed
on T1-weighted spin-echo MR images. Therefore, patients with two
hemicords should be imaged using T2- or T2*-weighted images (which
facilitate identification of bone) in the axial plane or with CT. Resec-
tion of the spur is critical for proper untethering of the cord (117).
In 30% to 60% of patients with diastematomyelia, the two hemi-
cords, each invested by an intact layer of pia, travel through a single
subarachnoid space surrounded by a single dural sac; this malforma-
tion is referred to as Type II SCM (117,257,258,263). Each hemicord
has its own anterior spinal artery. This form of SCM is not accompa-
nied by a bony spur but always has a fibrous band coursing through the
most inferior portion of the cleft, inserting in the dura (234). Patients
with this type of SCM are rarely symptomatic unless hydromyelia or
tethering (Figs. 9-49 and 9-50) is present (117,194,234). Imaging stud-
ies in these patients show the split cord and the vertebral anomalies, if

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 Chapter 9 • Congenital Anomalies of the Spine 899

FIG. 9-47. SCM with bony spur, scoliosis, and vertebral anomalies.
A. Coronal T1-weighted image shows thoracic dextroscoliosis with multiple
anomalies of vertebral segmentation (asterisks) including hemivertebra and
lack of segmentation. B. Coronal T1-weighted image adjacent to (A) shows
the hyperintense spur (white arrows) between the two hemicords. C. Sagit-
tal T1-weighted image shows the segmentation anomalies (white arrowheads)
and two areas of hydromyelia (arrows) but does not show the spur. D. Axial
T1-weighted image shows the hyperintense spur (white arrowheads) coursing
between the two hemicords.

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 900 Pediatric Neuroimaging

FIG. 9-48. SCM with rotoscoliosis. A. Coronal image showing the oblique plane prescribed for axial images. B and C. Coronal T1-weighted images show
vertebral anomalies (arrows) at the level of the most severe spinal curve. D and E. Images posterior to those in (B) and (C) show the spinal cord splitting
into two hemicords (arrows). F and G. Oblique axial T1-weighted images show the hemicords (curved arrows) aligned anterior and posterior to each other,
split around a spur (small white arrows) that is nearly horizontal. Note the markedly thick laminae (straight black arrows).

present, but rarely show the fibrous band (117). In the authors’ experi-
ence, the fibrous band is most often seen on sagittal T2-weighted RARE
images (Fig. 9-49).
Associated spinal anomalies are very common, being present in
up to 85% of affected patients (257). The conus medullaris is situ-
ated below the L-2 level and the filum thickened in more than 75%
of patients with SCM (Figs. 9-49 and 9-50) (117,264). Myeloceles/
myelomeningoceles (of the undivided spinal cord) are present in 15%
to 25%, whereas hemimyeloceles (myeloceles/myelomeningoceles of
one of the hemicords) are present in 15% to 20% of affected patients
(117). Lipomas, dermal sinuses, (epi)dermoid tumors, and tethering
adhesions (meningocele manqué) are reported commonly, but in less
than 20% of patients (117,255). The meningocele manqué (Fig. 9-50)
is a very subtle finding on imaging studies and will only be seen if the
radiologist is actively looking for it (117,260,265,266). The appearance
is that of a small band of tissue extending from the hemicord to the
dorsal dura and mimicking a nerve root; only a portion of the band
may be visible on the imaging study (117,265). This band of tissue can
cause persistent tethering of the cord after resection of the spur and
transection of the filum, so its identification is important. Hydromyelia
is found in about half of patients with diastematomyelia. When pres-
ent, the hydromyelic cavity may extend from the spinal cord above the
cleft into one or both hemicords (264). The importance of the high
incidence of associated anomalies is that the radiologist cannot be sat-
isfied with identification of the diastematomyelia, but must scrutinize
the imaging examination in an attempt to identify other lesions that
may lead to neurologic deterioration in the patient.
The spinal column is nearly always abnormal in patients with
SCM (Figs. 9-47 and 9-49) (74,194). The laminae are often thick and
may be fused with the ipsilateral or contralateral laminae of adjacent

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 Chapter 9 • Congenital Anomalies of the Spine 901

FIG. 9-49. SCM with fibrous spur. Value of sagittal T2 image and CT. A. Coronal T1-weighted image shows dextroscoliosis and shows the cleft (white
arrows) between the two hemicords. B. Sagittal T2-weighted image shows the fibrous spur (white arrowhead) coursing obliquely upward from the dorsal to
the ventral aspect of the spinal canal, through the tethered spinal cord. C. Axial T2-weighted image shows the bony prominence (white arrow) from which
the fibrous spur arises. The cord is not split at this level. D. The fibrous band is not seen on this axial image at the proper level because of the oblique course
of the band. E. Axial T1-weighted image at the sacral level shows a fibrolipoma of the filum terminale (arrowhead).

Barkovich_Chap09.indd 901 5/6/2011 10:29:03 PM

 902 Pediatric Neuroimaging

FIG. 9-49. (Continued) F. Coro-

nal reformation of a noncontrast
CT scan shows interlaminar fusion
(white arrows), a common find-
ing in SCM. G. Axial image at the
same level as (C) shows the bony
prominence (black arrow) from
which the fibrous band arises. The
band was not seen on CT.

FIG. 9-50. SCM with single dural tube and meningocele manqué. A. Sagittal T1-weighted image shows an abrupt kyphosis at the (T-8) level of the SCM
(large white arrowhead). Focal hydromyelia (small white arrows) is seen two levels higher. B. Axial T1-weighted image shows the hydromyelia above the level
of the split cord.

Barkovich_Chap09.indd 902 5/6/2011 10:29:04 PM


FIG. 9-50. (Continued) C. Axial GE image shows the two hemicords with small fibrous bands (meningocele manqué, black arrows) coursing posteromedi-
ally from each hemicord. These bands can cause local tethering of the spinal cord(s). D. Axial T1-weighted image shows a fibrolipoma (white arrow) of the
filum terminale at the sacral level.
vertebrae (Fig. 9-49); fusion with contralateral laminae of the adjacent
level is known as intersegmental laminar fusion. Spina bifida is almost
always present. The association of an intersegmental laminar fusion
with spina bifida is seen in approximately 60% of patients with SCM
and is essentially pathognomonic for this anomaly. The intersegmen-
tal laminar fusion is almost always at the level of the SCM (74,250).
Anomalies of the vertebral bodies (Fig. 9-47) including hemiverte-
brae, butterfly vertebrae, block vertebrae, and decreased disc height
are observed in a high proportion of cases. Kyphoscoliosis (Figs. 9-48
and 9-50) resulting from the osseous anomalies is seen in more than
half of patients.
Another anomaly of the spinal column that is associated with par-
tial or complete SCM is the Klippel-Feil anomaly, a condition defined
as two or more consecutive unsegmented vertebrae at the cervical
level (267,268). The Klippel-Feil anomaly has been divided into three
categories: Group 1 in which patients have a short, webbed neck with
low hairline and complete lack of cervical segmentation; Group 2 in
which the lack of segmentation (most commonly called “fusion”) is
isolated and which most commonly involves C-2 to C-3 or C-5 to C-6;
and Group 3, in which patients have separate thoracic or lumbar levels
of nonsegmentation in addition to cervical involvement (47,267,269).
Neurologic impairment can result from several aspects of the Klippel-
Feil malformation. Probably the most common cause of neurologic
dysfunction or neck pain is accelerated disc degeneration resulting
from the restricted motion at the level of the unsegmented vertebrae
(267). A second cause is malformation of the spinal cord; up to 50%
of patients with the Klippel-Feil anomaly have at least partial dorsal
splitting of the cord (47,267,269). In such patients, anomalies have
been identified in the decussation of the corticospinal tracts (270),
and mirror movements may be detected on physical exam (267).
A third cause is associated bony abnormalities of the craniocervical
junction (271). Other causes of neurologic dysfunction are associ-
ated CNS anomalies, which are reported to include occipital encepha-
loceles, Chiari malformations, Dandy-Walker malformations, Duane
syndrome, nasofrontal and posterior fossa (epi)dermoids, and syrin-
gohydromyelia. Associated visceral anomalies include Sprengel defor-
mity (congenital elevation of the scapula, often associated with an
omovertebral bone), cervical ribs, supranumerary digits, tracheal and
proximal bronchial stenosis, sickle sacrum, cleft palate, and various
renal anomalies (47,267,269,271).
Barkovich_Chap09.indd 903
Chapter 9 • Congenital Anomalies of the Spine 903
MALFORMATIONS OF UNKNOWN ORIGIN
All of the anomalies described in this chapter are actually of unknown
origin. Those anomalies discussed up to this point can be explained
by reasonable theories, permitting a classification based upon their
embryogenesis. At this time, however, no reasonable theory has been
proposed that explains segmental spinal dysgeneses, simple meningo-
celes, and lateral meningoceles, which can develop anywhere along the
spinal canal.
Segmental Spinal Dysgenesis
(a complex spinal dysraphism)
Segmental spinal dysgenesis is a malformation that is probably the
result of embryonic segmental malformation (272,273) or focal injury
to the developing spine in utero (274). In utero detection is possible;
however, affected children are typically identified at the time of birth
by a kyphotic deformity (often sharply angled), anomalies of the lower
extremities (usually equinovarus deformities of the feet and flexion
contractures of the hips and knees), hyperreflexia of the lower extremi-
ties, and bladder dysfunction. The skin overlying the deformity may
be bluish (273–275). One reported patient had dextrocardia and situs
inversus (274).
Imaging reveals a marked focal hypoplasia of the vertebral column,
thecal sac, and spinal cord, typically at the thoracolumbar junction.
Plain films show a kyphotic deformity with hypoplasia or absence of
one or more vertebral bodies. Myelography shows smooth tapering of
the thecal sac and spinal cord with a complete or nearly complete block
of contrast at the most severely affected level(s). Caudal to the narrow-
ing, a round or oval intradural mass represents the lower segments of
the spinal cord. CT myelography shows marked bony narrowing of the
spinal canal with the small remnant of subarachnoid space running
through the extraspinal soft tissues. MR may show a variable degree of
tapering of the spinal cord to a point of marked narrowing or complete
focal absence of the cord. However, in most cases, the termination of
the upper segment of the spinal cord is abrupt (Figs. 9-51 and 9-52),
and in some cases it appears quite blunted (Fig. 9-52). Both of these
appearances are similar to the appearance of the spinal cord in patients
with caudal regression/lumbosacral hypogenesis. (Indeed, this blunt-
ing is one reason that Tortori-Donati et al. (276) have postulated that
5/6/2011 10:29:05 PM
 904 Pediatric Neuroimaging
segmental spinal dysgenesis and lumbosacral hypogenesis have similar
causes; see the section on “Syndrome of Caudal Regression (a complex
spinal dysraphism)” earlier in this chapter.) Below the segmental agen-
esis, the bony spinal canal, thecal sac, and spinal cord resume a nor-
mal appearance (Figs. 9-51 and 9-52). Evaluation of the entire spinal
column is essential, as affected patients may have associated lipomas,
dermal sinuses, or hydromyelia (276).
Surgery to decompress the bony narrowing at the site of dysgenesis
does not seem to help the patient regain any neurological or urological
function, but may prevent further neurological deterioration (273–275).
Dorsal Meningocele (a CSD with a subcutaneous
mass)
Dorsal meningoceles are dorsal herniations of dura, arachnoid, and
cerebrospinal fluid that extend into the subcutaneous tissues of the
back. The overlying skin is intact unless secondary skin ulcerations
arise. By definition, the simple meningocele does not contain nervous
tissue, although, occasionally, a nerve root may enter the sac before
leaving it to reenter the spinal canal en route to its respective neural
foramen (151). Rarely, a nerve root may become adherent to the wall of
the sac. The conus medullaris tends to be in its normal position within
the spinal canal. The filum terminale occasionally extends into the neck
of the sac. Complex meningoceles differ from simple meningoceles by
the presence of significant associated anomalies of the spine and, usu-
ally, spinal column.
Barkovich_Chap09.indd 904
FIG. 9-51. Segmental spinal dysgenesis. A. Sagit-
tal T1-weighted image shows a high termination of
the spinal cord (white arrow) at the T-2 to T-3 level.
Note how the spinal canal and thecal sac taper rap-
idly (black arrowheads) caudal to the cord termina-
tion. B. Sagittal T1-weighted image in the lower half
of the spine shows a normal-appearing segment of
spinal cord (arrows) in the midlumbar region below
a level where the spinal canal appears again.
By definition, meningoceles are lined with arachnoid. Arachnoi-
dal adhesions occasionally occur within the sac and, when unusually
thick, may partially obliterate the neck of the sac (277). Because the sac
communicates with the subarachnoid space, it may change in size with
patient position or with Valsalva maneuver.
The bony abnormalities accompanying meningoceles are usually
limited. They may range from absence of a single spinous process to a
localized spina bifida or to a multisegmental spina bifida with enlarge-
ment of the spinal canal.
The purpose of imaging studies in patients with meningoceles is
(a) to detect the meningocele, (b) to determine its shape, (c) to define
associated anomalies of the spinal cord and the bony spinal canal,
(d) to determine the presence or absence of nervous tissue within the
sac, and (e) to assess the relationship of the sac to the conus med-
ullaris and the filum terminale. Although sonography demonstrates
most of these details, MR and CT myelography give the most infor-
mation. Because it is noninvasive, MRI is the imaging procedure of
choice in the evaluation of these patients. High-resolution images
with white CSF, either by T2 weighting or steady-state techniques,
are ideal to show the location of nerve roots. MR of patients with
simple dorsal meningoceles shows an empty meningocele sac, a nor-
mal spinal cord, a normal or nearly normal spinal column, a normal
termination of the conus medullaris, and a normal filum terminale
(Fig. 9-53). MR of patients with complex dorsal meningoceles shows
the presence of anomalies within the spinal cord, spinal canal, or
spinal column (Fig. 9-54).
5/6/2011 10:29:06 PM
 Chapter 9 • Congenital Anomalies of the Spine 905

FIG. 9-52. Segmental spinal dysgenesis with blunted

termination of the upper segment of the spinal cord:
MR and CT appearances. A. Sagittal T1-weighted
image of the spine shows a blunted cord terminus
(white arrows) in the thoracolumbar region. B. Sagit-
tal T2-weighted image shows the marked narrowing
of the spinal canal (white arrows) and vertebral body
dysgeneses and fusions caudal to the termination of
the upper spinal cord segment. A distal cord segment
(asterisk) is seen below the region of abnormal spi-
nal column. C. Sagittal reformation of a noncontrast
CT scan shows vertebral body dysgenesis and lack of
segmentation with narrowing of the spinal canal and
offset of the upper and lower vertebrae in the lower
lumbar region. D. Axial noncontrast CT image shows
the dysplastic vertebral body and very narrow spinal
canal secondary to dysplastic posterior elements in
the dysgenetic segment of spine.

Barkovich_Chap09.indd 905 5/6/2011 10:29:07 PM

 906 Pediatric Neuroimaging

FIG. 9-53. Simple dorsal meningocele.

A. Sagittal T1-weighted image shows a large
ovoid dorsal meningocele (arrows) in the
midthoracic region. The vertebral column
and spinal cord appear normal. B. Axial
T1-weighted image shows absence of neural
tissue within the meningocele sac.

Lateral Meningocele slight weakness. Type 1 neurofibromatosis is present in approximately

Thoracic Lateral Meningocele
Thoracic lateral meningoceles are cerebrospinal fluid-filled protrusions
of dura and arachnoid that extend laterally through an enlarged neu-
ral foramen. They then course anteriorly through the adjacent inter-
costal space into the extrapleural aspect of the thoracic gutter. Males
and females are equally affected and most commonly present during
the fourth and fifth decades of life. Although usually asymptomatic,
affected patients may have pain, vague sensory deficits, hyperreflexia, or
85% of patients with lateral thoracic meningoceles (277,278). The
preferential thoracic location has been postulated to result from lesser
development of the paraspinal musculature at this level and the rela-
tively high pressure differential between the negative thoracic pressure
and the pressure of the CSF in the thoracic subarachnoid space (279).
Less common predisposing conditions include Marfan and Ehlers-
Danlos syndromes.
Patients with lateral thoracic meningoceles may have a sharply
angled scoliosis in the upper thoracic spine, convex toward the

FIG. 9-54. Complex dorsal meningocele. A and B. Sagittal T1-weighted images show a lumbar dorsal meningocele (large white arrows). The conus med-
ullaris is abnormally low. A cyst (small white arrow) is present in the cord just above the meningocele. C and D. Coronal T1-weighted images show the
intramedullary cyst (small white arrows in C) and multiple lumbar vertebral anomalies (large black arrows).

Barkovich_Chap09.indd 906 5/6/2011 10:29:08 PM


meningocele, which is located near the apex of the curvature (278).
Scalloping of the pedicles, laminae, and vertebral bodies adjacent to the
meningocele often result in an enlarged spinal canal (see Fig. 6-22).
The size of the meningocele varies markedly from small, nearly
undetectable meningeal protrusions to enormous cystic masses. Large
thoracic meningoceles may fill an entire hemithorax and compromise
ventilation, particularly in neonates. Most remain static in size, but
occasionally they show slow growth. The meningocele may disappear
after shunting of hydrocephalus (280).
The position of the cord with respect to the meningocele sac is
variable. When scoliosis is present, the cord tends to be situated on the
side opposite the sac. More rarely, the cord may be pulled toward the
sac or into the sac by nerve roots at that level (20).
Lumbar Lateral Meningocele
Lumbar lateral meningoceles are protrusions of dura and arachnoid
through one or several enlarged lumbar neural foramina into the lum-
bar subcutaneous tissue and retroperitoneum. They often occur in
a setting of Marfan syndrome or type 1 neurofibromatosis, but may
be seen as isolated anomalies. The meningoceles may be unilateral or
bilateral, may involve a single neural foramen or multiple adjacent
neural foramina, and may displace adjacent structures (Fig. 9-55).
Lumbar meningoceles are similar to those in the thorax in that they
are commonly associated with an expanded spinal canal, erosion of the
posterior surface of the vertebral bodies, thinning of the neural arches,
and enlargement of the neural foramina (Fig. 9-55).
CONGENITAL TUMORS OF THE SPINE
Teratoma
Teratomas are neoplasms containing tissues belonging to all three ger-
minal layers at sites where these tissues do not normally occur. Exclud-
ing sacrococcygeal teratomas (discussed earlier in the chapter), these
FIG. 9-55. Lumbar lateral meningoceles in a patient with Marfan syndrome. A and B. Coronal T2-weighted images show multiple bilateral hyperintense
meningoceles extending laterally into the pelvis and lumbar paraspinous muscles through enlarged neural foramina. C. Axial T1-weighted image shows the
bilateral meningoceles (arrows) extending laterally through expanded neural foramina. The spinal canal is enlarged.
Barkovich_Chap09.indd 907
Chapter 9 • Congenital Anomalies of the Spine 907
neoplasms constitute 0.15% of all intraspinal tumors (20). Males and
females are affected equally, usually presenting with pain and myelopa-
thy. All ages are affected.
Two basic theories have been proposed for the pathogenesis
of teratomas. They may arise by multiplication of displaced germ
cells or of cells left behind during the migration of the Hensen
node that can give rise to any of the three germinal layers of tis-
sue (185,281,282). Alternatively, teratomas might arise from rests
of tissues that have escaped the control of those factors in early
embryonic development that determine cell line. Tissue growth
therefore produces diverse tissues that can be more or less well dif-
ferentiated (283).
The appearance of spinal teratomas is extremely variable. The
tumor may be solid, partially or wholly cystic, unilocular, or multiloc-
ular. In general, the more immature the histology, the more the lesion
resembles astrocytomas and ependymomas, with fairly homogeneous,
enhancing soft tissue and associated cysts (284) (see description of
spinal cord tumors in Chapter 10). Mature tumors show evidence of
fat (hyperintense on T1-weighted images) and calcification; bone and
cartilage may be present, sometimes in the form of a well-defined bone
or tooth. When cysts are present, they may be thin or thick walled, and
the fluid within them may be clear, milky, or dark. Teratomas may be
intramedullary or extramedullary; whatever their location, they usu-
ally fill the spinal canal at the time of presentation and will produce a
complete block at myelography. When extramedullary, the tumors are
often closely adherent to the cord with a poorly defined cleavage plane
formed by tumor, connective tissue, and reactive astrogliosis. In such
cases, it is difficult to differentiate the extramedullary tumor from an
intramedullary one. When teratomas occur in the lumbar region, the
roots of the cauda equina frequently adhere to the walls of the tumor
as they are draped over it. Syringomyelia may appear above the level
of the tumor secondary to restricted CSF flow. Malignant teratomas
are rare and cannot be differentiated from the more common benign
variant by imaging.
5/6/2011 10:29:10 PM
 908 Pediatric Neuroimaging

The spinal canal may be normal or may be focally widened by erosion
of the pedicles and laminae. Other bony anomalies are uncommon.
Dermoid and Epidermoid Tumors
Dermoids are round, ovoid, or multilobular tumors, sometimes cystic,
that are lined by a squamous epithelium containing skin appendages,
such as hair follicles, sweat glands, and sebaceous glands. Epidermoids
are tumors lined by a membrane composed of only the superficial (epi-
dermal) elements of the skin (151). Dermoids usually cause symptoms
before the age of twenty; they occur equally in males and females. Epi-
dermoids develop slightly more slowly, begin to manifest symptoms in
early adulthood (third to fifth decade), and are more common in males
(153). Together, dermoid and epidermoid tumors constitute approxi-
mately 1% to 2% of spinal cord tumors at all ages and 10% of spinal
cord tumors below the age of fifteen. Approximately 20% develop in
association with dermal sinuses; of those not associated with dermal
sinuses, epidermoids are slightly more common than dermoids (153).
When not associated with dorsal dermal sinuses, dermoids and epider-
moids may present as a slowly progressive myelopathy or as an acute
onset of a chemical meningitis secondary to rupture of the inflam-
matory cholesterol crystals from the cyst into the cerebrospinal fluid
(148,153).
Dermoid and epidermoid tumors most commonly arise from con-
genital dermal or epidermal rests or from focal expansion of a der-
mal sinus. They may also be acquired as iatrogenic lesions resulting
from implantation of viable dermal and epidermal elements by spinal
needles not provided with trocars (124,285) or as a result of surgery
(119,126).
Epidermoids are distributed fairly uniformly along the spine (upper
thoracic 17%, lower thoracic 26%, lumbosacral 22%, and cauda equina
35%) (153). Dermoids, on the other hand, are much more common
in the lumbosacral area (60%) and cauda equina (20%), but are quite
infrequent in the cervical and thoracic regions (153). Sixty percent of
epidermoids are extramedullary and 40% intramedullary (154).
Although they range in size from tiny subpial growths to huge
mass lesions, at the time of clinical presentation, dermoid and epi-
dermoid tumors almost always cause a complete spinal block to
intrathecal contrast when myelography is performed (154). On
imaging studies, dermoids almost always have the appearance of fat
on CT, showing low attenuation. However, the appearance is vari-
able on MRI, sometimes showing high intensity on T1-weighted
images, but more commonly having low to intermediate intensity
on T1-weighted images and high intensity on T2-weighted images
(see Fig. 9-13 in section on “Dosal Dermal Sinuses” in this chap-
ter). The lack of a fatty signal may be a result of secretions from
sweat glands within the tumor causing increased water content.
Epidermoids also have variable signal intensity on MRI (Fig. 9-56),
most commonly isointense to CSF but sometimes hyperintense or
hypointense; this variability is similar to that seen in intracranial
epidermoids, as described in Chapter 7. Small epidermoids are dif-
ficult to diagnose on both MRI and CT because they are difficult to
differentiate from surrounding cerebrospinal fluid on both imag-
ing modalities. Using MRI, larger extramedullary epidermoids can
be identified by slightly altered signal intensity and the displace-
ment of the spinal cord or nerve roots by the mass (Fig. 9-56F–H).
It can be confirmed by FLAIR or diffusion sequences (156–158).
FLAIR will demonstrate the epidermoid as a hyperintense mass sur-
rounded by hypointense CSF, while diffusion images will show soft
tissue, not fluid, characteristics of water motion (Fig. 9-56D and E)
(156–158,286). If FLAIR or diffusion sequences are available, CT
myelography should no longer be necessary to detect these tumors.
Neither dermoids nor epidermoids enhance after administration of
intravenous contrast unless they are or have been infected. Infection
is much more common if the tumors have developed in association
with dermal sinuses.

FIG. 9-56. Intraspinal epidermoid and dermoid. A–E. Recurrence 12 years after resection of an epidermoid and dorsal dermal sinus. A and B. Sagittal
T2-weighted images from the initial presentation show the focal tethering of the spinal cord by a hypointense band (white arrows) which traverses the tho-
racic posterior osseous defect and communicates with the hypointense tract through the subcutaneous tissues. The associated epidermoid (black arrow) is
slightly more hyperintense than CSF. C–E. Sagittal T2-weighted imaging (C), diffusion-weighted imaging (D), and the apparent diffusion coefficient map
(E) performed 12 years later show the recurrent epidermoid (e) with its central T2 prolongation, peripheral T2 shortening, and reduced diffusion. Adjacent
spinal cord edema is also present.

Barkovich_Chap09.indd 908 5/6/2011 10:29:11 PM


Hamartoma
Hamartomas are malformations composed of an abnormal mixture of
those tissue elements that normally occur at the tumor site. Because
they grow and develop at the same rate as normal tissues, hamartomas
are unlikely to result in compression of adjacent parenchyma; there-
fore, neurologic deficits and hydrocephalus are usually not present
(20,287).
Hamartomas are composed of mesodermal elements such as
bone, cartilage, fat, and muscle. They appear as midline, dorsal, skin-
covered masses, usually found at birth, that are located in the midtho-
racic, thoracolumbar, or lumbar regions and may be associated with
cutaneous angiomas (288). Posterior element deficiency is present in
approximately 60% of patients and the spinal canal is widened in 80%.
Heterotopic bone formation is seen in about half of cases (288). On
MRI, they are reportedly isointense with spinal cord on both T1- and
T2-weighted images (289). Rarely, hamartomas may contain function-
ing choroid plexus and present with syringohydromyelia (Fig. 9-57).
SYRINGOHYDROMYELIA
Definition
Although syringohydromyelia is usually a disease of adults, it can
occur in children and, furthermore, is often associated with (and likely
the result of) a congenital anomaly of the spine or the cervicomedul-
lary junction. Therefore, we have included the topic in this chapter.
Syringohydromyelia is characterized by the presence of longitudinally
oriented cerebrospinal fluid-filled cavities and astrogliosis within the
spinal cord. When the cavity is a dilated central canal of the spinal cord,
the term hydromyelia has been applied, reserving the term syringomy-
elia for spinal cord cavities extending lateral to, or independent of, the
central canal. On detailed pathologic or radiologic exam, most cavi-
ties are found to involve both parenchyma and central canal. The term
syringohydromyelia reflects this difficulty in classification. Some have
used the terms syringomyelia and syrinx in a general manner to repre-
sent any spinal cord cyst. We shall use these terms in the same general
sense in this chapter, recognizing that in some patients the term is not
a precisely correct one (85,290–292).
An important point is that not all patients with dilation of the central
canal of the spinal cord have a pathologic condition. Petit-Lacour et al.
(293) found that 12/794 patients (1.5%) had a focal filiform enlargement
Barkovich_Chap09.indd 909
Chapter 9 • Congenital Anomalies of the Spine 909
FIG. 9-56. (Continued) F–H. Dermoid associated
with fibrofatty infiltration of the filum terminale.
F and G. Sagittal and coronal T1-weighted images
show the large dermoid (d) at L-3 to L-4 with a
hyperintense proximal and distal filum terminale
(white arrows). H. Sagittal T2-weighted imaging
shows slightly heterogeneous T2 prolongation in the
dermoid and the hypointense proximal and distal
filum terminale.
of the central canal, exclusive of terminal ventricles (see section “The
Terminal Ventricle” of this chapter). It was located at the junction of the
ventral 1/3 and dorsal 2/3 of the cord, except when located at the level
of the lumbar enlargement, when it was located centrally. The cavities
were most typically located at the lower cervical or midthoracic level.
The authors recommend that such cavities, when found incidentally,
do not require follow-up. We have had similar experiences and concur,
although we typically perform a single follow-up examination with
contrast at 12 months after discovery of an asymptomatic dilation of
greater than 2 mm, to ensure that this is not the earliest phase of a cord
neoplasm or syrinx. We also make sure that a craniovertebral or spinal
anomaly that might predispose to syrinx formation is not present.
Clinical Presentation and Course
Patients with syringomyelia are uncommonly symptomatic from their
syrinx during childhood. Indeed, many childhood cases of syringomy-
elia are discovered due to the progressive scoliosis found in about 30%
of such children (294). The presence of progressive scoliosis, levosco-
liosis (a curve convex to the left), or back pain suggests an underlying
abnormality such as syringomyelia, tumor, or dysraphism (295) and
are indications for an MRI study. Syringes discovered in children are
most commonly enlarged central canals of the spinal cord (true hydro-
myelia) and associated with postnatally repaired Chiari II (more com-
monly) or Chiari I (less commonly) malformations (129). In patients
who are symptomatic, presentation is similar to that in adults, with
anesthesia and weakness of the upper limbs, scoliosis, and unsteadiness
of gait (129,296). Children may also develop slightly dilated central
canals in association with the tight filum terminale syndrome; how-
ever, the central canal does not seem to be under increased pressure in
this group of patients and, therefore, the term syringomyelia does not
seem appropriate. Children with spinal cord tumors can develop asso-
ciated syringomyelia or hydromyelia, not to be mistaken for tumoral or
peritumoral cysts; typically, the syrinx will resolve after resection of the
tumor. Spinal cord tumors of childhood are discussed in Chapter 10.
Most commonly, symptoms of syringomyelia begin in late ado-
lescence or early adulthood and progress irregularly with long inter-
vening periods of stability. Sometimes, the syrinx may be picked up
incidentally; such cases present a therapeutic dilemma, as such patients
may remain asymptomatic for 10 years or more (297). In traumatic
syringomyelia, a latent period of 20 to 30 years is common before
5/6/2011 10:29:12 PM
 910 Pediatric Neuroimaging

FIG. 9-57. Spinal cord hamartoma with associated syringomyelia. A and B. Coronal T1-weighted images show a dilated spinal cord with CSF intensity
within it (open arrows), both rostral and caudal to a focal heterogeneous narrowing of the cord at the midthoracic level (solid white arrow). The hamartoma
was located at the site of the narrowing. C. Axial T1-weighted image at the level of the hamartoma shows heterogeneity of signal and a bilobed appearance
to the cord resulting from the tumor and the associated syringomyelia. This hamartoma, which contained functioning choroid plexus, is believed to be the
cause of the severe syringomyelia. D. Axial T1-weighted image in the lower thoracic region. The ventral aspect of the spinal cord is markedly thinned and
expanded by the syrinx cavity (open arrows). The dorsal cord (solid arrows) is compressed and displaced posteriorly by the syrinx.

the onset of symptoms is noted (298). Signs and symptoms are vari-
able, depending upon the cross-sectional and vertical extent of cord
destruction. The classical presentation is of segmental weakness with
atrophy of the hands and arms, loss of tendon reflexes, and segmen-
tal anesthesia of the dissociative type (loss of pain and temperature
sense with preservation of the sense of touch) over the neck, shoul-
ders, and arms (299). Pain is often severe and may be most intense
in an analgesic limb (anesthesia dolorosa). In practice, symptoms are
often unilateral, confined to the lower extremities, or absent (300,301).
Dysesthesias may be present; they are almost always the result of exten-
sion of the syrinx into the dorsolateral quadrant of the spinal cord
(302). The clinical course is unpredictable. Long periods of stability of
symptoms can be followed by acute deterioration. Narrowing of the
subarachnoid space is nearly always found in patients with syringo-
hydromyelia. The narrowing is most commonly found at the level of
the foramen magnum. The Chiari I malformation, arachnoiditis, bony
narrowing of the foramen magnum or spinal canal, intramedullary
tumors, and extramedullary tumors can all be found in patients with
syringomyelia (301,303–308).
Occasionally, syringomyelia undergoes spontaneous decompres-
sion, with the appearance of the spinal cord returning to normal
(309–311). The reasons for this spontaneous cure are unknown; per-
haps spontaneous myelotomy occurs, with drainage of the syrinx into
the subarachnoid space or perhaps the abnormal fluid dynamics (see
below) revert to normal. Whatever the cause of the regression, it does
not appear to lessen the symptoms of the patient (309,310).

Barkovich_Chap09.indd 910 5/6/2011 10:29:12 PM


Classification and Causes
Syringomyelia has many causes, just as cystic spaces in the brain may be
of diverse origin. The shape and structure of the spinal cord and spinal
canal have a strong influence on the appearance of the syrinx, making
the pathological (and imaging) appearance of the cavities and the clini-
cal signs similar, regardless of the underlying cause (85,312).
Milhorat et al. (313) has proposed a classification system for syrin-
gohydromyelia based upon histopathology. These different types of
syringomyelia can be differentiated by axial T1-weighted MR images
(314), making this a useful classification for radiologists. In type 1
syringes, the dilated central canal is in direct communication with the
fourth ventricle. Type 1 syringes are found in association with hydro-
cephalus; patients are asymptomatic or have nonspecific neurologic
signs. Type 2 syringes are dilations of the central canal below a syrinx-
free segment of spinal cord. Type 2 syringes are found in patients who
have alterations of cerebrospinal fluid dynamics in the subarachnoid
space, such as Chiari I malformations and arachnoiditis. (Note that the
foramen magnum can also be blocked by tumors, cysts, or tonsils that
are pushed downward due to chronic downward pressure from hydro-
cephalus, cyst, or mass. Similarly, if the tonsils are pulled downward by
a CSF leak, blockage of the foramen by the cerebellar tonsils can occur;
see Chapter 5, section on “Anomalies of the craniocervical junction.”)
Type 2 syringes are more likely than type 1 to dissect into parenchyma
outside of the central canal of the spinal cord. These dissections most
commonly extend into the posterolateral quadrant of the spinal cord;
their development may correlate with onset of clinical symptoms, most
commonly dysesthesias. Type 3 syringes are extracanalicular cysts that
arise in the spinal cord parenchyma and do not communicate with the
central canal. Type 3 syringes are typically found in the watershed area
of the cord (in the central gray matter, dorsal and lateral to the central
canal, between the anterior and posterior spinal artery distributions).
Associated myelomalacia is commonly present. The most common
causes of Type 3 syringes are trauma, infarction, spontaneous hemor-
Barkovich_Chap09.indd 911
Chapter 9 • Congenital Anomalies of the Spine 911
rhage, and transverse myelitis. Clinically, patients have various com-
binations of long tract and segmental signs that can be related to the
level, side, and specific quadrant of spinal cord cavitation (313,314).
Another classification system is based upon the way the syrinx com-
municates with the central canal (315). Communicating syringomyelia
is postulated to communicate with the fourth ventricle via the obex at
some time during the development of the spinal cord cyst, allowing
fluid transmission to the syrinx cavity via this communication. Thus,
communicating syringes should be centrally located; however, in real-
ity, these hydromyelic cavities often dissect into, and are thus eccentric
within, the surrounding spinal cord tissue (85,291). Communicating
syringomyelia is the form that is associated with the Chiari malforma-
tions (Fig. 9-58) and with syndromes with decreased size of the foramen
magnum, such as achondroplasia (Fig. 9-59) (316,317). Dandy-Walker
malformations (see Chapter 5) can also be associated with syringo-
hydromyelia, in particular when the posterior fossa cyst enlarges and
interferes with flow of CSF through the foramen magnum (318).
Theories of Pathogenesis
Gardner (319,320) has postulated that continued communication
between the fourth ventricle and central canal is the result of a failure of
the foramina of the fourth ventricle to open at the eighth or ninth week
of fetal life. He describes a “water hammer effect” (caused by cerebro-
spinal fluid pulsations) that is transmitted to the central canal through
the obex, causing the canal to dilate. Rupture of the ependymal lin-
ing results in cyst extension into the substance of the spinal cord (Fig.
9-60B). Gardner’s theory was modified by Williams (321,322), who
favored a pressure differential between the intracranial and spinal cere-
brospinal fluid as the cause for formation of the syrinx (Fig. 9-60C).
Williams speculated that coughing and other maneuvers that produce
increased intrathoracic and intra-abdominal pressure result in spinal
epidural venous distention. Distention of the veins within the confined
space of the spinal canal causes a rapid rostral displacement of spi-
FIG. 9-58. Syringohydromyelia second-
ary to Chiari I malformation. A. Sagittal
T2-weighted image shows a well-defined,
multiloculated segment of hyperintensity
(white arrowheads), representing a syrinx
in the center of the dilated spinal cord.
The intermediate intensity between the
syrinx and normal spinal cord likely rep-
resents astrogliosis or interstitial edema.
The patient has a Chiari I malformation
with the cerebellar tonsils (white arrows)
extending below the foramen magnum.
B. Axial T2-weighted image through the
cervical spine shows the hyperintense
syringohydromyelic cavity causing expan-
sion of the cervical spinal cord.
5/6/2011 10:29:14 PM
 912 Pediatric Neuroimaging
nal fluid. In patients with the Chiari I malformation, or other causes
of obstruction within the cerebrospinal fluid spaces, the initial surge
forces cerebrospinal fluid into the intracranial space; however, the cere-
brospinal fluid does not drain out immediately because of a ball-valve
effect resulting from the obstructing lesion. The result of the fluid shift
is craniospinal pressure dissociation. According to Williams, the higher
intracranial pressure forces fluid through the obex into the central
canal of the spinal cord (321). Furthermore, Williams speculated that
the engorgement of the epidural veins by increased thoracoabdominal
pressure compresses the subarachnoid space and spinal cord, forcing
fluid upward within the syrinx cavity (Fig. 9-60C). If enough fluid is
forced upward with sufficient force, the syrinx cavity will be extended.
A rapid upward acceleration of contrast within syrinx cavities and in
the subarachnoid space has been demonstrated with coughing, Valsalva,
and respiration (321,323).
Ball and Dayan (324) have speculated that cerebrospinal fluid
enters the central canal via the perivascular spaces. They postulated that
increased pressure in the spinal subarachnoid space is generated by an
obstructing lesion (such as the ectopic cerebellar tonsils in the Chiari I
malformation) acting as a one-way valve, allowing cerebrospinal fluid
to escape from the basal cisterns into the spinal canal, but blocking
its return. They proposed that the increased intraspinal pressure then
drives cerebrospinal fluid into the central canal (Fig. 9-60D), resulting
in an increased intraspinal CSF pressure compared to the brain. The
finding of increased pressure within syrinx cavities in a large series of
patients by Milhorat et al. (312) supports this concept, as does animal
work showing the development of intramedullary edema and subse-
quent cyst formation after constriction of the thecal sac (325).
Aboulker (326) proposed a theory somewhat analogous to that
of Ball and Dayan. Referring to animal experiments demonstrating
that 30% of cerebrospinal fluid is produced in the central canal of the
cord, he postulated that stenosis at the foramen magnum or elsewhere
in the canal inhibits cerebrospinal fluid flow toward intracranial areas
of resorption and causes increased cerebrospinal fluid pressure in
the spinal canal. The cerebrospinal fluid, driven by high intraspinal
pressure, then filters into the spinal cord, either through the paren-
chyma or along the posterior nerve roots. Long-standing spinal cord
edema may eventually cause cavitation within the cord parenchyma
(Fig. 9-60D).
Barkovich_Chap09.indd 912
FIG. 9-59. Syringomyelia secondary to
achondroplasia. A. Sagittal T1-weighted
image shows small clivus, long infundibu-
lum, and big ventricles as described in
Chapter 8. A focal well-defined region of
hypointensity (arrows) is seen extending
from the foramen magnum to the bottom
of C-2. The craniocervical junction is com-
pressed by the narrow foramen magnum.
B. Axial T2-weighted image confirms the
intramedullary cyst (arrow) at the cranio-
cervical junction.
More recently, Heiss et al. (327) have emphasized the importance
of the ectopic, compressed cerebellar tonsils in the progression of
syringomyelia. They suggest that the tonsils partially occlude the fora-
men magnum, then act as pistons to create large cervical subarachnoid
pressure waves that compress the spinal cord and drive the syrinx fluid
caudally with each heartbeat. Heiss et al. do not speculate on how the
syrinx is initially formed.
The other forms of syringomyelia that have been described are trau-
matic syringomyelia, tumor-associated syringomyelia, syringomyelia sec-
ondary to arachnoiditis, and “idiopathic” syringomyelia (315). Clearly,
communication with the fourth ventricle via the obex is not the underly-
ing mechanism of the formation of the syrinx in all cases. However, exten-
sion of the cavity within the cord (or even into the brainstem or thalami, a
condition known as syringobulbia [328,329]) may well occur via the same
mechanism once the cavity is established. Williams’ proposed mechanism
of (a) an obstructing lesion causing pressure dissociation in the subarach-
noid spaces above and below it, and (b) extension of the cavities as a result
of CSF accelerations from increased thoracoabdominal pressure and dis-
tention of the epidural venous plexus (Fig. 9-60C) explains the clinical
observation that these cavities frequently extend after severe coughing,
straining, or sneezing. This mechanism might also explain the astrogliosis
seen in the spinal cord at the caudal and rostral ends of syringes and the
edema seen in cord at the rostral end of the syrinx (Figs. 9-61 and 9-62)
before the syrinx extends rostrally (85) (the “pre-syrinx” [330]). More-
over, the observation that foramen magnum decompression often cures
the syringomyelia without any other therapy supports the theory that
syringes are primarily caused by disturbed CSF dynamics.
Supporting these observations, Koyanagi and Houkin (331) have
proposed that reduced compliance of the posterior spinal veins due
to blocking of the CSF pulse wave after cardiac systole (see the hydro-
dynamic theory of hydrocephalus in Chapter 8) results in reduced
absorption of CSF via the intramedullary venous channels and that
this lack of resorption plays an important part in the development of
cord edema (presyrinx [330]) and subsequent syrinx formation.
Imaging
MR is unquestionably the diagnostic modality of choice in the diagno-
sis of and the evaluation of treatment of syringohydromyelia and syrin-
5/6/2011 10:29:15 PM
 Chapter 9 • Congenital Anomalies of the Spine 913

FIG. 9-60. Diagrammatic representations of

pathophysiologic theories concerning syringohydro-
myelia. A. In the normal situation, CSF flows from the
aqueduct into the fourth ventricle, out the fourth ven-
tricular foramina and into the cisterna magna, basilar
cisterns and spinal subarachnoid space. The central
canal of the spinal cord is usually incompletely pat-
ent in older children and adults. B. Gardner’s theory
(319,320) suggests that there is a lack of perforation of
the foramen of Magendie (blocked arrow in inset) that
forces CSF through the obex into the central canal of
the spinal cord. C. Williams (321) suggests that there is
CSF flow cephalad from the spinal subarachnoid space
into the intracranial cisterns but that flow is partially
blocked in the cephalocaudal direction. He suggests
that this cranial-spinal pressure association leads to CSF
being “sucked” into the central canal of the cord from
the fourth ventricle, initiating the syrinx. He further
proposes that the fluid within the syrinx moves both
rostrally and caudally as a result of changes in epidural
venous pressure; when engorged, these veins compress
the subarachnoid space and spinal cord, forcing fluid
upward within the syrinx cavity. Rapid accelerations
result in extension of the syrinx cavity. D. Both Ball
and Dayan and Alboulker believe that the craniospinal
pressure dissociation is present but reversed in direc-
tion from that proposed by Williams. These authors
believe that increased CSF pressure in the spinal CSF
space results in CSF filtering from the subarachnoid
space into the central canal through the spinal cord.

Barkovich_Chap09.indd 913 5/6/2011 10:29:15 PM

 914 Pediatric Neuroimaging

FIG. 9-61. Holocord syringohydromyelia with septations due to a Chiari I malformation. A–C. Sagittal T1 FLAIR images of the cervical, thoracic, and
lumbar spine performed at 3T show the enlargement of the entire spinal cord and a large syrinx with multiple septations. D. Axial T2-weighted image shows
increased signal intensity (white arrow) within the syrinx cavity, probably secondary to pulsations of the fluid within the cavity.

FIG. 9-62. Syringomyelia resulting from arachnoiditis. A. Sagittal T1-weighted image shows that the ventral thoracic subarachnoid space (black arrow-
heads) is enlarged. In the kyphotic thoracic region, the dorsal subarachnoid space is usually enlarged and the ventral subarachnoid space is small. The lower
cervical/upper thoracic spinal cord (large white arrows) is enlarged and hypointense, suggesting a “presyrinx” state. B and C. Sagittal T1-weighted (B) and
T2-weighted images a year later show a frank syrinx cavity (s) with an intermediate signal intensity area (presyrinx, p) rostral and caudal to the cavity. In
addition, there has been development of a small syrinx in the midthoracic spinal cord (white arrowhead). The arachnoid loculation ventral to the thoracic
spinal cord can still be seen and appears to have grown.

Barkovich_Chap09.indd 914 5/6/2011 10:29:17 PM

 Chapter 9 • Congenital Anomalies of the Spine 915

is diagnosed. The process usually enlarges the affected region of spinal

FIG. 9-63. Posttraumatic syringomyelia. Sagittal T1-weighted image
shows a holocord syrinx with multiple septa. The spinal canal is narrowed
in the upper lumbar region by a fractured vertebral body (arrows) from a
motor vehicle in the past.
gobulbia (85,328). In order to properly assess syringes by standard MRI,
it is necessary to obtain thin (≤3 mm) sagittal T1-weighted images, fol-
lowed by axial T1-weighted images. The syrinx cavity can be missed if
only sagittal images are obtained. The syrinx appears on MR images
as a CSF-intensity collection within the cord (Figs. 9-58, 9-62, and
9-63). If the cavity extends into the medulla (Fig. 9-64), syringobulbia
cord or medulla. Often, there will be multiple incomplete septations
within the syrinx cavity, giving a “beaded” appearance (Figs. 9-61 and
9-63). If T2-weighted sequences are used, increased signal intensity
may be seen within the parenchyma at the rostral or caudal end of
the cavity (Figs. 9-61 and 9-62). This high signal intensity should not
be misinterpreted as tumor; the prolonged T2 relaxation time results
from microcystic or astrogliotic changes at the end of the syrinx cav-
ity, presumably caused by the pulsations of the cyst upon the adjacent
cord. The edema is reversible, so this appearance is sometimes referred
to as a “presyrinx” (330). If flow compensation techniques are not
used, the syrinx cavity may be hypointense on T2-weighted sequences
(Fig. 9-61) as a result of CSF pulsations within the cavity (85,332).
Cine high-resolution imaging techniques, particularly with high field
strength systems, have been reported to increase the visualization of
arachnoidal adhesions (333).
If MR is unavailable or contraindicated, CT myelography can
be used to evaluate the spinal cord; this technique, however, requires
acquisition of delayed images to visualize the cavity. The patient should
be scanned 4 hours after infusion of the water-soluble contrast. After
4 hours, contrast will usually have diffused into the cavity. If a syrinx
is suspected clinically, and it is not detected on the initial scan or the
4-hour delayed scan, a 12-hour delayed or even a 24-hour delayed scan
should be obtained. Even with delayed imaging, however, CT myelog-
raphy is much less sensitive to syringomyelia, does not show the rostral
and caudal extent as well as MR, and is insensitive to associated spinal
cord pathology.
Syringes can be eccentric within the spinal cord, even exophytic,
in all forms of syringomyelia (Fig. 9-57) (73). When very eccentric, a
syrinx may be difficult to differentiate from an extramedullary (arach-
noid) cyst. In less severe cases, examining consecutive axial images can
differentiate the lesions. In an intramedullary cyst (a syrinx) the rostral
and caudal portions of the cyst are clearly intramedullary. When very
eccentric or very large and rounded, the remnant of compressed spinal
cord peripheral to the syrinx cavity may be impossible to see on an MR
scan and, therefore, the syrinx may be impossible to differentiate from
an arachnoid cyst. In practice, the differentiation is not important for
the treating physician, however.
Techniques have been developed that allow assessment of CSF flow
in the cerebral ventricles and at the foramen magnum by phase-contrast

FIG. 9-64. Syringobulbia and presyrinx. A and B. Sagittal T2-(A) and T1-(B) weighted images of the brainstem and cervical spine show syringohydro-
myelia in the cervical spinal cord, extending to the medulla (syringobulbia, white arrowheads). Regions of T2 prolongation—interstitial edema—are seen
in the upper medulla and upper thoracic spine (white arrows in A). These areas of “presyrinx” indicate potential extension of the cavity. Artifact from
hardware placed during previous foramen magnum decompression for Chiari I malformation is present posteriorly. C. Coronal T2-weighted imaging of
the brainstem shows the presyrinx (white arrows) above the syringobulbia. D. Axial FLAIR image through the medulla shows the area of presyrinx (white
arrows) within the upper medulla.

Barkovich_Chap09.indd 915 5/6/2011 10:29:19 PM

 916 Pediatric Neuroimaging
MR (334–336). The technique used at UCSF is described in Chapter 1
and illustrated in Chapter 5 (in the section on “Chiari I Malforma-
tions”). Using this and similar techniques, flow dynamics of CSF
through the foramen magnum or past an obstructive lesion within the
spinal canal can be evaluated and quantified (337). This technique is
most useful if a syrinx is not already present, as it helps to identify
which patients with Chiari I malformations have altered CSF dynamics
at the foramen magnum and are, therefore, at risk to develop syrin-
gomyelia (338). It has been demonstrated that the foramen magnum
obstruction in Chiari I malformations may be reduced when the head
is in extension (339). We have also seen patients in whom CSF flow
improves with flexion. Therefore, in patients in whom a Chiari I mal-
formation is present and CSF flow at the craniocervical junction is
normal in the neutral position, additional sequences with the patient’s
head in flexion and extension may be valuable.
Gated phase-contrast CSF flow studies are also useful when syringes
are idiopathic or associated with arachnoidal scarring. Such scarring may
be the result of prior trauma, infection, surgery, or hemorrhage; as dis-
cussed above, scarring probably causes syrinx formation by altering CSF
flow dynamics. Impaired CSF flow appears as lack of pulsatile CSF flow
in the affected region. If MR is contraindicated or is difficult because of
extensive metallic instrumentation of the spine, myelography can be used
to demonstrate the scarring, which usually appears as a myelographic
block. The location of the scarring is important, as adequate treatment
requires microsurgical dissection of the arachnoid scar and decompres-
sion of the subarachnoid space with a fascia lata graft (340).
Static MRI and MR CSF flow studies can also be used to assess
the foramen magnum after decompression. The MR appearance of the
decompressed foramen magnum is that of a widened foramen; the pos-
terior margin of the foramen is located high above its normal position
secondary to removal of bone. Some “kinking” of the cervicomedullary
junction and “slumping” of the cerebellum into the enlarged foramen
magnum is commonly seen (341,342). Some CSF should be seen ante-
rior to the cervicomedullary junction and posterior to the cerebellum
at all levels. The CSF flow study should show unimpeded flow through
the foramen with the head in the flexed position.
In all patients in whom a syrinx is discovered radiologically, a
search should be made for the underlying cause of the syrinx. First, the
foramen magnum should be evaluated; the position of the cerebellar
tonsils should be noted. The tonsils should have a rounded appear-
ance and should lie no more than 6 mm below the level of the fora-
men magnum as measured on sagittal images (343,344). MR of the
craniocervical junction may also show stenosis of the foramen mag-
num, as in achondroplasia, masses at the level of the foramen mag-
num, such as schwannomas and meningiomas, cysts, herniated tonsils,
or arachnoidal loculations. Any mass or narrowing at the foramen mag-
num can cause craniospinal pressure dissociation. If arachnoiditis, either
from previous trauma or infection, is the cause of syringohydromyelia,
arachnoid loculations can usually be identified at some point within
the spinal canal. Although the loculations are isointense with free-
flowing cerebrospinal fluid, they can be identified by their mass effect
upon the spinal cord (Fig. 9-62). The cord will be slightly displaced and
deformed by adjacent loculations.
As mentioned earlier in this section, MRI shows mild dilatation
of the central canal in up to 25% of patients with a tethered spinal
cord (Fig. 9-31) (82). The exact cause of this dilatation is not known.
However, the mild dilatation of the central canal in these patients is
not felt to be significant, and the cause of the tethering should be dealt
with primarily. Indeed, the central canal typically returns to normal
once the cord is untethered (209). Only if symptoms persist after the
release of the tethered cord, should the dilated central canal be evalu-
ated further.
Barkovich_Chap09.indd 916
If patients do not have a known history of prior severe trauma and
an obstructing lesion cannot be demonstrated, they should be studied
by MR with intravenous contrast. Some patients previously diagnosed
with “idiopathic” syringomyelia harbor small spinal cord neoplasms
that can be shown by contrast-enhanced MR. Moreover, a small but
significant number of patients with syringomyelia and cerebellar ton-
sillar ectopia (the Chiari I malformation) have spinal cord neoplasms
as well (85). Such patients will not improve unless the neoplasm, which
is the primary cause of their syrinx, is treated. If the patient has not
improved after foramen magnum decompression, paramagnetic con-
trast should always be given on the follow-up MR scan.
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 CHAPTER

Neoplasms of the Spine

10 A. JAMES BARKOVICH

Spinal tumors—introduction