Professional Documents
Culture Documents
Neuroimaging
SIXT H ED IT ION
A. James Barkovich, MD
Professor
Radiology, Neurology, Pediatrics, and Neurosurgery
University of California at San Francisco
Chief, Pediatric Neuroradiology
UCSF Medical Center/Benioff Children’s Hospital
San Francisco, California
Sixth Edition
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Contributors
A. James Barkovich, MD
Professor
Radiology, Neurology, Pediatrics, and Neurosurgery
University of California at San Francisco
Chief, Pediatric Neuroradiology
UCSF Medical Center/Benioff Children’s Hospital
San Francisco, California
Matthew J. Barkovich, MD
Fellow in Neuroradiology
University of California at San Francisco
San Francisco, California
Van V. Halbach, MD
Clinical Professor of Radiology and Neurological Surgery
University of California at San Francisco
San Francisco, California
Gary L. Hedlund, DO
Adjunct Professor
Department of Radiology
University of Utah
Director
Pediatric Neuroradiology
Department of Medical Imaging
Primary Children’s Medical Centre
Salt Lake City, Utah
Steven W. Hetts, MD
Associate Professor
University of California, San Francisco
Chief of Interventional Neuroradiology
Mission Bay Hospitals
University of California, San Francisco
San Francisco, California
Philip M. Meyers, MD
Professor
Radiology, Neurological Surgery, and Neurology
Co-Director, Neuroendovascular Service
Colombia University Medical Center/New York-Presbyterian Hospital
New York, New York
Gilbert Vézina, MD
Professor of Radiology and Pediatrics
George Washington University
Director of Neuroradiology
Children’s National Medical Center
Washington, District of Columbia
It is a little hard to believe that this is the sixth edition of Pediatric Neuroimaging. However, imaging continues to evolve, as
does the sophistication of the imaging machines and techniques used to evaluate the brain, head, neck, and spine of children
with abnormal neurodevelopment or neurological function. New diseases continue to be discovered and described, along with
improved understanding of normal processes of neurodevelopment (genetics, molecular biology, and biochemistry), what can
(and does) go wrong with the developmental processes, and new ways to classify them based upon our knowledge of these
factors. Imaging continues to improve; it is faster, and more accurate, allowing assessment, in many cases, of function as well
as anatomy. Once again, I have called upon my highly knowledgeable and esteemed colleagues to help in the writing of this
book by sharing their experience and knowledge. Charles Raybaud and Jim Barkovich have again written much of it and edited
the work of eight other respected authors (Christopher Hess, Duan Xu, Matthew Barkovich, Zoltan Patay, Erin Schwartz,
Gilbert Vézina, Gary Hedlund, James Bale, and Steven Hetts), who have generously graced this edition with information and
insights from their areas of expertise. As the reader will notice, this is a complete book, which shares the experience and
opinions of many dedicated pediatric physicians, some with many decades of experience in many different locations, in
addition to some insights from younger colleagues with newer insights. As in the fifth edition, the contributions of the many
authors have blended together to give a more informative book, while minimizing confusing differences and maintaining a book
that is 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 many images to illustrate them.
Chapter 1 on imaging techniques and Chapter 2 on normal developmental features seen by imaging have been updated. In
Chapter 1, concepts of imaging children with ultrasound, CT, and MRI are discussed, with discussion of sedation, monitoring,
and many recently developed imaging techniques and their role in pediatric neuroimaging. The main focus is on MRI of the
brain, blood vessels, and spine, along with suggested protocols for both routine imaging and more sophisticated studies.
Techniques for Fetal MRI are also discussed, as well as those for microstructural, physiologic, and metabolic imaging;
assessment of blood flow, perfusion, and CSF flow; and sections on MR spectroscopy and functional MRI. Chapter 2 has
updated figures of normal development, including new MR images of fetal brain development.
As in prior editions, Chapters 3 to 12 address imaging findings in specific categories of disease. Some of these chapters
have been extensively revised to reflect changes in concepts of the disorders; others, with fewer advances, have been updated
with a few newly described or newly defined entities in a chapter whose organization remains largely the same, with
discussions of new techniques integrated into the discussion of the disease entity accompanied by images of the disease.
Images of fetal brains are included when early diagnosis will alter care, mostly illustrating patients with malformations,
hydrocephalus, brain injury, occasionally, tumors.
Chapter 3 on metabolic diseases includes new information on diffusivity, spectroscopy, and clinical/genetic manifestations.
The mitochondrial disorders section has been significantly updated, now discussing new classification by which respiratory
chain complex is affected (when known). However, the field is changing very quickly with new genetic discoveries, so we
have not attempted to classify all such disorders according to respiratory chain complex affected, but focused mainly on
imaging phenotypes. 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 discusses perinatal and postnatal injuries to the brain and spine and has more up to date information and images
of pediatric brain and spine imaging and causes of stroke, perinatal injury (premature and term), and traumatic brain injury
(accidental and inflicted). It includes new images and new sections on abusive trauma and brain concussion.
Chapter 5 has again been extensively updated with new concepts of normal development and newly described
developmental disorders, in addition to new categories of disease and new concepts of developmental pathways that, when
disrupted, cause specific disorders. This chapter remains organized according to the part of the brain primarily involved by the
disease process (dorsal forebrain [cerebral cortex and commissures], ventral forebrain [base of the brain],
midbrain/hindbrain, craniocervical junction, brain coverings) in order to help the reader to locate the disorder within the text;
we hope readers will find this useful. Chapter 6 (Phakomatoses) has been updated with new genetic information, new
classifications, many new images, and several new disorders being described.
Chapter 7 has been updated extensively, with many new images, as brain tumor discoveries have exploded over the past
several years. However, much of the new Brain Tumor Classification concerns adult tumors; our changes concern new
classification of specific pediatric tumors (e.g., medulloblastomas, supratentorial white matter tumors, supratentorial cortical
tumors, tumors of central gray matter, etc.) and updated figures and discussions of a broader range of pediatric tumors than has
been previously discussed.
Chapter 8 on hydrocephalus has been significantly modified and upgraded to include new theories of development and
physiology of the ventricles and other CSF spaces, CSF dynamics, and new methods of assessing 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 once again been greatly expanded and
improved by Drs. Hedlund and Bale, who again have added many new disorders and images, including disorders that were
very localized 10 to 15 years ago, outside of North America and Europe, but have become prevalent elsewhere as a result of
modern travel. This work will facilitate the diagnosis of these disorders as they spread to new continents, perhaps stopping
their spread.
Despite the many changes in this edition, we hope the reader will notice that the philosophy of the book remains the same. A
large number of disorders are discussed and illustrated, as it is much easier to recognize a disorder by seeing imaging than by
reading about imaging features. The cause of the disorder, the main clinical features, and the underlying pathophysiology are
discussed whenever possible because it is easier to remember disorders when the genetic or embryologic 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 previous 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 myelomeningoceles 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.
Preface to the First Edition
New techniques for pediatric brain and spine diagnoses have rapidly developed over the past 10 years. Computed tomography
(CT), ultrasound, and magnetic resonance (MR) imaging have opened a new window to the pediatric central nervous system.
Through the use of these imaging modalities, an increased understanding 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 notable lack of textbooks on the subject, particularly in dealing with CT and MR. In this book, I attempt, at
least in part, to fill the gap of knowledge that exists in pediatric neuroimaging.
This book strongly emphasizes CT and MR in pediatric neurodiagnosis. 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 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. Specifically, this includes the diagnosis of intracranial pathology in premature 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 deemphasized 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 interpretation. 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.
List of Disorders
Neurocutaneous Disorders
I. Neurofibromatosis Type I
II. Neurofibromatosis Type II
III. Other Forms of Neurofibromatosis
IV. Tuberous Sclerosis
V. Sturge-Weber Disease
VI. von Hippel-Lindau Disease
VII. Ataxia–Telangiectasia
VIII. Neurocutaneous Melanosis
IX. Incontinentia Pigmenti
X. Hypomelanosis of Ito
XI. Basal Cell Nevus Syndrome
XII. Cutaneous Hemangioma–Vascular Complex Syndrome (PHACE Syndrome)
XIII. Chédiak-Higashi Syndrome
XIV. Progressive Facial Hemiatrophy (Parry-Romberg Syndrome)
XV. Epidermal Nevus Syndrome
XVI. Encephalocraniocutaneous Lipomatosis
XVII. Other Overgrowth Syndromes
Hydrocephalus
I. Congenital Infections
1. Cytomegalovirus
2. Congenital neonatal herpes
3. Lymphocytic choriomeningitis
4. Rubella
5. Syphilis
6. Toxoplasmosis
7. Varicella–Zoster
8. Zika
9. Parecho
10. Human immunodeficiency
11. Disorders mimicking infections
II. Meningitis and Complications
1. Neonatal meningitis
2. Meningitis in infants, children, and adolescents
3. Pathophysiology of meningitis
4. Imaging manifestations
III. Empyema Secondary to Sinusitis and Otomastoiditis
IV. Bacterial, Spirochetal, and Rickettsial Infections
1. Bacterial cerebritis
2. Brain abscess
3. Cat-scratch disease
4. Lyme disease
5. Rocky Mountain spotted fever
V. Viral Infections
1. General concepts
2. Herpesvirus family—herpes simplex, varicella zoster, Epstein-Barr, human herpesvirus-6
3. Nonpolio enteroviruses
4. Arthropod-borne viruses—eastern equine encephalitis, western equine encephalitis, Venezuelan equine
encephalitis, Japanese encephalitis, St. Louis encephalitis, West Nile, dengue virus, LaCrosse encephalitis
virus, California encephalitis viruses, Colorado tick fever virus
5. Influenza-associated encephalitis/encephalopathy
6. Acute cerebellitis
7. Rabies
8. Chronic viral infections—AIDS encephalopathy, progressive multifocal leukoencephalopathy, Rasmussen
encephalitis, postrubella panencephalitis, subacute sclerosing encephalitis, variant Creutzfeldt-Jakob disease
VI. Fungal Infections
1. Neonatal candidiasis
2. Aspergillosis
3. Coccidioidosis
4. Cryptococcus
VII. Parasitic Infections
1. Neurocysticercosis
2. Visceral larva migrans
3. Cerebral malaria
VIII. Sarcoidosis
IX. Infections of the Spine
1. Discitis/osteomyelitis
2. Spinal empyemas
X. Emerging Infections of the CNS
1. Nipah virus
2. Dengue virus
3. Chikungunya virus
Cover
Title Page
Copyright
Dedication
Contributors
Preface
List of Disorders
Normal Development of the Fetal, Neonatal, and Infant Brain, Skull, and Spine
MATTHEW J. BARKOVICH AND A. JAMES BARKOVICH
3a
3b
3c
A. JAMES BARKOVICH AND ZOLTAN PATAY
4a
4b
ERIN SIMON SCHWARTZ AND A. JAMES BARKOVICH
5a
5b
5c
A. JAMES BARKOVICH AND CHARLES RAYBAUD
Neurocutaneous Disorders
6a
GILBERT VÉZINA AND A. JAMES BARKOVICH
7a
7b
7c
CHARLES RAYBAUD, ZOLTAN PATAY, AND A. JAMES BARKOVICH
Hydrocephalus
8a
CHARLES RAYBAUD
9a
ERIN SIMON SCHWARTZ AND A. JAMES BARKOVICH
11a
GARY L. HEDLUND, JAMES F. BALE JR., AND A. JAMES BARKOVICH
Index
Techniques for Pediatric Neuroimaging
Christopher P. Hess, Duan Xu, and A. James Barkovich
Ultrasound
Computed Tomography
MRI: Anatomic Imaging
Brain
Vascular Imaging
Spine
Fetal MRI
Abbreviated Protocols
MR Neurography
Summary
The past two decades have seen tremendous advances in the field of pediatric neuroimaging. Improvements in technology,
broader recognition of the risks of sedation and radiation, and enhanced access to high-quality imaging across the medical
community have significantly altered referral patterns and imaging strategies for evaluating disorders of the brain, head, neck,
spine, and peripheral nervous system. In addition, in the United States, overall shifts in the payment landscape for national
health care have renewed focus on achieving best practices for neuroradiology, and the term “value” has entered the routine
lexicon of academic and community practices for medical diagnostics. Although the same principles that have been used to
guide the use of imaging for many years still apply, the future of pediatric neuroradiology must now be viewed more carefully
through the lenses of quality, safety, and cost efficiency.
Radiologists have long appreciated the significant differences between imaging children and imaging adults. The pace and
magnitude of developmental changes that occur in the brain and spine, nuanced by the different spectrum of neurologic disease
in children, require tailoring of imaging protocols to optimally detect and show the anatomic, physiologic, and metabolic
changes in pediatric disorders. Coils, scanning parameters, and approaches for sedation and monitoring differ significantly for
imaging the fetus, the newborn, the infant, and the adolescent. Far from “one size fits all,” the choice of modality and specific
imaging technique that should be applied depends upon the age and medical condition of the patient, the indication for imaging,
the urgency of diagnosis, and the cost of imaging.
This chapter outlines techniques for safe, high-quality, and effective neuroimaging in pediatric patients. First, we outline
special considerations for imaging, including sedation, selection of appropriate imaging modality, and the use of intravenous
contrast agents. The use of cranial ultrasound and CT is then reviewed. Given the narrow window of situations in which these
modalities are now applicable, these sections are brief. The remainder of the chapter focuses on MR, the current clinical
standard for evaluation of the brain and spine. We consider first anatomic imaging and then pivot to physiologic and metabolic
MR techniques. Specific approaches to pediatric disease that are used in our own practice at UCSF are outlined. The
techniques that are discussed in this chapter will be referred to throughout the remainder of this book.
Neonates
Premature infants present the special problems of small size and inability to maintain constant body temperature. In general,
premature infants should be imaged initially with ultrasound in the neonatal 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-frequency transducers is excellent
for the detection of edema, blood, or infarction in deep structures of the brain, the location of most central nervous system
pathology in the premature infant, 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 (1,2) and these
abnormalities are of prognostic significance (3–6).
When an MR examination is necessary, special precautions must be observed to ensure the safety of the neonate. It is best to
enlist the assistance of neonatologists and/or neonatal nurses 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 (7). 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
(8). 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 (9,10).
We have found that when the baby is minimally disturbed in the incubator, we can perform MRI without sedation in as many
as 70% of premature neonates; this should be attempted before sedation is administered (11). 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 prewarmed towels and an air bag that is warmed to body temperature. Alternatively, chemical “blankets”
containing mixtures of chemicals that maintain a temperature of 37°C when mixed can be used to maintain body heat beneath
the airbag. A stockinet hat may be used to prevent heat loss from the head. Earplugs and earmuffs (we use both) reduce noise
exposure and further reduce heat loss. Vital signs in these infants are monitored during both transportation and in the magnet.
The child should be disturbed as little as possible (11).
Sedation
In modern clinical practice, sedation is rarely an issue for ultrasound or CT. Ultrasound is inherently “hands-on,” and excellent
images can usually be obtained by targeted imaging and light restraints to movement. For CT, multidetector CT (MDCT)
technology has significantly accelerated acquisition times, such that fewer than 1.5% of patients now require sedation with this
modality (12,13). The use of soft restraints, although not usually necessary with MDCT, can further limit the movement of
younger children to achieve satisfactory image quality.
The issue of sedation gains importance when considering MRI in young children. When children are unable to remain still,
motion artifacts are likely to obscure important information and render exams clinically nondiagnostic. Sedation can be
essential to achieve sufficient quality for diagnosis. At the same time, there is an increasing focus on the risks of sedation in the
pediatric population and, as a result, a general decline in the use of sedation over the past decade. Currently, we use sedation
only when infants need a rather extensive MRI (with multiple sequences), such as preoperative for suspected tumor or
metabolic disease, and the child has been unable to lie sufficiently still to allow an adequate exam (11). Although several
animal and in vitro studies have demonstrated immediate and in some cases longer-lasting or even permanent neuroanatomical
and functional effects of common sedatives, clinical studies have been more reassuring, and the larger-scale studies that have
been performed have not shown adverse effects of anesthetic exposure in terms of neurodevelopmental outcome. Nevertheless,
the potential for neurotoxic effects of anesthesia led the U.S. Food and Drug Administration to issue a “Drug Safety
Communication” in December 2016, stating that anesthesia for longer than 3 hours or repeated use of anesthetics in pregnant
mothers or children less than 3 years of age “may affect the development of children’s brains.”
It is important to recognize that in most parts of the world (Europe, Asia, and South America as examples), the risk of
sedation is considered to be much less than the risks associated with underlying injuries and diseases for which MRI is being
performed, and sedation is used routinely in neonates, infants, and young children. Given its declining use, however, sedation
is not covered in this chapter in the same detail that it has been in prior editions of this text. When sedation is necessary, the
practitioner should be familiar with the guidelines published by the American Academy of Pediatrics (14,15), the American
Society of Anesthesiologists (16), and the American College of Radiology (17). Again, at our institution, sedation in neonates
has been largely supplanted by the feed-and-swaddle technique, which induces natural sleep and can usually be accomplished
without any sedatives, occasionally supplemented with small amounts of morphine and/or sodium pentobarbital (11); however,
this technique limits imaging to 4 or 5 relatively short sequences (11). When MRI is critical to diagnosis that will significantly
change management, we rely upon the expertise of our pediatric anesthesiologists for longer examinations. In young children,
we have also found that using MR-compatible video projection goggles and sound systems to display movies or videos during
examinations suffices to distract these patients sufficiently to achieve a diagnostic examination. Age-appropriate scanner
settings and antecedent education using child life specialists and MRI mock-ups to prepare children can also significantly
reduce the need for sedation in this age group.
Monitoring
The American Academy of Pediatrics and the American Society of Anesthesiologists recommend that heart and respiratory
rate, blood pressure, and arterial oxygen saturation be monitored in all sedated infants and children (14–16).
Monitoring a patient in the CT suite is relatively simple. A patient undergoing MRI is more difficult to monitor because of
the safety issues and because biomonitoring devices (a) may not work properly in the magnetic environment and (b) may cause
distortion of the magnetic field, especially within the narrow confines of the bore of the magnet. Monitoring must be performed
using equipment composed of diamagnetic metals (e.g., aluminum) and/or plastics or composites. Several MRI-compatible
monitoring devices are commercially available and are the best option for patient safety and optimal imaging at the present
time. 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 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 without 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 practitioner 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 shielding configurations will allow life-support equipment to be in close
proximity to the patient, most high-field MR suites require significant modifications to achieve intense, close-in electronic
monitoring. MR-compatible pediatric ventilators are now commercially available and in broader use; in their absence,
respirator-dependent patients must be manually ventilated. In extreme circumstances, significant respiratory or hemodynamic
instability may require that the physician or nurse crawl into the bore of the scanner and observe the child from this extremely
uncomfortable position to ensure the safety of the patient through the duration of the examination.
A brief mention should be made of the impact that monitoring and sedation can have on image quality. One example of
this is T2 FLAIR hyperintensity in cerebrospinal fluid (CSF) that is seen in patients who are administered supplemental oxygen
in high concentration during MRI. In this situation, oxygen in the blood diffuses across a concentration gradient into the CSF,
effectively increasing its oxygen concentration. With its two unpaired electrons, oxygen is weakly paramagnetic and effectively
shortens the T1 relaxation time of the CSF, often to a sufficient degree to compromise the CSF nulling pulse and cause
abnormal hyperintensity within CSF on T2 FLAIR images that might otherwise be mistaken for hemorrhage, pus, or
carcinomatosis. Unlike these CSF diseases, oxygen-related CSF hyperintensity on T2 FLAIR images is typically diffuse and
involves the entirety of the CSF rather than concentrated locally in sulci or cisterns. The effect is further potentiated by certain
anesthetics, notably propofol. Thus, if CSF hyperintensity is seen in the cisterns on T2 FLAIR sequences, any sedation and
the concentration of supplemental oxygen must be researched before the scan is interpreted as abnormal. Using lower
concentrations of supplemental oxygen (50%–60% works well) eliminates this artifact (18,19).
Contrast Media
The indications for administration of intravenous contrast media in CT for neuroradiology are declining and limited now
primarily to angiographic studies and studies outside of the brain, for example in the head and/or neck. Occasionally, when a
noncontrast CT of the head reveals an acute abnormality, such as subdural empyema, the decision to administer contrast can be
made when MR cannot be obtained in a timely fashion in order to obtain an accurate diagnosis or more completely delineate an
abnormality. However, very little information is gained, in general, by administration of CT contrast unless a vascular
lesion is suspected (20).
When CT is necessary, nonionic, iso-osmolar, or low-osmolar contrast media have been shown to be safer and less
uncomfortable for the patient. The exact type of iodinated contrast is not important, as long as the concentration 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. In view of their
rapid heart rate, children should be scanned as soon as possible after contrast has been administered. Thankfully, adverse
reactions to iodinated contrasts are rare in the pediatric population and exceptionally infrequent in the youngest patients (21).
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 (21).
For almost all indications, MRI can be performed without intravenous contrast with no compromise in examination quality.
There are several situations, however, in which intravenous gadolinium-based contrast agents (GBCAs) can improve
diagnostic accuracy and lesion detection. These include some MR angiographic and perfusion techniques and for disorders
such as primary and metastatic brain and spine tumor, infection (abscess, empyema, cerebritis, meningitis), and certain
neurocutaneous disorders (neurocutaneous melanosis, neurofibromatosis type II, Sturge-Weber syndrome) (22,23).
Administration of contrast to infants or children undergoing evaluation for developmental delay or epilepsy is unlikely to be of
benefit unless a space-occupying lesion is identified or a cutaneous lesion suggesting one of the neurocutaneous disorders
mentioned above is present. Similarly, no advantage is gained by administering GBCAs to children with developmental
malformations of the brain or spine, with the exception of dermal sinus tracts.
From the standpoint of diagnostic efficacy, there does not appear to be a significant difference among commercially
available paramagnetic contrasts. All are given intravenously; for most neurologic applications, the standard dose is 0.1
mmol/kg. It is important to note that agents now exist in different concentrations, such that volume of contrast administered for
the same dose depends upon the GBCA that is used. After infusion of contrast, any pulse sequence sensitive to T1 contrast will
be sensitized to the effects of the agent. GBCAs also have a T2*-shortening effect that is exploited for some MR-based
cerebral perfusion techniques. Fat suppression may be useful if meningeal disease is suspected (24) or if suspected pathology
lies in the orbits or neck, where fat may obscure the enhancing lesion. Similarly, postgadolinium FLAIR imaging can be
particularly useful in the assessment for abnormalities of the CSF.
Once widely administered in the setting of impaired renal function, GBCAs are now known to be associated with
nephrogenic systemic fibrosis (NSF) in patients with renal insufficiency (25,26). This rare but serious systemic disorder
causes fibrosis of the skin and other tissues, thereby leading to considerable morbidity or even death. All reported cases in
children (27,28) have occurred in patients with estimate glomerular filtration rate (eGFR) less than 30 mL/min. A
proinflammatory state (systemic infection, limb or major tissue injury, recent transplant surgery, or thrombosis) may further
increase the risk of developing this complication.
More recently, it has been noted that exposure to multiple doses of some GBCAs may cause increased T1 signal intensity in
certain brain structures, such as the globus pallidus and deep cerebellar nuclei (29–31). Although the mechanism underlying
this phenomenon is still under investigation, brain autopsy studies documenting retained gadolinium within the endothelial
walls and interstitium indicate that the metal likely becomes dissociated from the chelate to which it is bound before it is
eliminated from the bloodstream. Gadolinium deposition has been most convincingly described in patients receiving linear
GBCAs. However, gadolinium deposition has also been reported with macrocyclic GBCAs and in our opinion likely occurs to
varying degrees with all GBCAs. Pathological studies have not shown evidence of neuronal injury, and there are no known
clinical conditions associated with these findings. Nevertheless, this “brain stain” from gadolinium underscores the need to
carefully consider whether gadolinium contrast is necessary for diagnosis when performing MRI in children. If used, the
macrocyclic agents are preferable, as the gadolinium ion may be more tightly chelated (32).
With the recognition of the relationship between gadolinium and NSF and the observation of gadolinium deposition, there is
no longer justification for administering contrast to every sedated patient to avoid the need to resedate the child for a
repeated scan with contrast. When gadolinium is necessary, screening for diminished GFR is essential and the relative risks
and benefits in patients with renal failure should be considered in consultation with referring physicians. The reader should be
aware, however, that as of the date of this revision, there have been no new reported cases of NSF since 2009. Limited use of
GBCAs in patients with low GFR, the adoption of more stable macrocyclic agents, and restricting the maximum dose to 0.1
mmol/kg together most likely account for the decline in the incidence of NSF.
Other reported side effects of gadolinium are exceptionally rare. Allergic reactions are even less common with GBCAs than
they are with iodinated contrast. In one study of 13,344 examinations in which gadolinium was given to children, the rate of
acute allergic reaction was 0.04%. With respect to its use in pregnancy, intravenous GBCAs cross into the placenta and are
excreted into the amniotic fluid. In high and repeated doses, intravenous gadolinium is teratogenic in animal studies (33).
Although no similar effects have been observed in human studies of teratogenicity, it has been our practice to avoid the use of
gadolinium in pregnancy except when absolutely essential. There are no indications for which maternal paramagnetic
contrast agent administration is necessary for fetal MRI.
Another class of paramagnetic contrast agent that may be used in some situations are the ultrasmall superparamagnetic iron
oxide (USPIO) compounds. Ferumoxytol is increasingly being reported as an alternative to GBCAs for vascular imaging,
particularly in patients with renal insufficiency. This medication, first investigated over a decade ago, enjoys much stronger T1
relaxation effects than do GBCAs. Moreover, because of its size and carbohydrate coating, the agent has a long intravascular
residence of more than 12 hours and can be used to achieve higher-quality vascular imaging than the GBCAs. However,
ferumoxytol is used “off-label” as a contrast agent as the primary indication for the medication is iron deficiency anemia in
chronic kidney disease. Moreover, the FDA issued a boxed warning for the medication in 2015, citing the incidence of severe
anaphylactic reactions in a small number of patients, recommending that it should be used only for patients who require
intravenous iron therapy. Nevertheless, ferumoxytol is still useful as a contrast agent in a subgroup of patients and occasionally
used at academic medical centers (34), particularly for the study of vascular disease (35,36).
Ultrasound
Ultrasound is always the first study of choice in the fetus. It is also nearly always the first in neonates, as it is noninvasive,
inexpensive, and portable (can be performed at the bedside); requires no sedation; and produces no ionizing radiation. The
modality has improved in recent years with more widespread availability 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 high-quality ultrasound examination. Indeed, measurements
of brain structures with ultrasound and MRI are nearly identical (37), with small observed differences (mainly cortical
thickness and interhemispheric fissure size) most likely due to inability to accurately differentiate the cortex from the overlying
leptomeninges on ultrasound. The peripheral aspects of the brain may also be difficult to visualize, particularly when small
fontanelles limit the size of the acoustic window; this limitation has been markedly reduced, however, with current equipment.
After the first few months of life, however, as the brain grows and the sutures/fontanelles close, ultrasound rapidly becomes
less useful for brain and spine, and MR becomes the imaging modality of choice.
Meticulous technique on the part of well-trained sonographers must be used to optimize ultrasound studies. Imaging should
always be performed using multiple transducers functioning at variable frequencies. Vector, curved, and linear array
transducers should all be used. Resolution and depth penetration can be optimized by adjusting the frequencies (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.
Abnormalities will be shown best if images are acquired in sagittal, parasagittal, coronal, and axial planes. Real-time images
allow an excellent appreciation of subtle changes in echogenicity and have, essentially, replaced static images at UCSF. Major
arteries and veins should be assessed by Doppler techniques, looking for peak systolic velocities, end-diastolic velocities, and
resistive indices.
Computed Tomography
Medical radiation is a particularly important consideration in pediatric radiology, as younger patients have a greater chance of
developing radiation-associated diseases (38–40) and, possibly, developmental impairment (41). Overutilization of CT in the
past decade (2000–2010) among the entire US population, including pediatric patients, and the variability in scan parameters
for CT (42) resulted in an increased focus on the need to consider alternative modalities first (43). When CT is necessary, one
must also consider whether dose reduction techniques (44,45) should be used, recognizing that the diagnostic quality of the
imaging study may suffer when image contrast to noise is reduced by dose reduction (46,47). Institutional approaches based on
systematic consideration of clinical indications and prior history of exposure to ionizing radiation may help to increase the
consistency with which specific parameters are used for pediatric CT scanning and to reduce overall radiation exposure (48).
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 an magnetic resonance angiography (MRA) or magnetic
resonance venography (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 imaging 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 (49). If the purpose 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 tube voltage or tube current. By reducing
CT dose from 220 to 80 mA, one study showed a reduction in radiation dose of 63% while maintaining diagnostically
acceptable images (50); as noted above, however, the reduction of signal to noise that accompanies the dose reduction severely
limits assessment of brain parenchyma. At UCSF, we have chosen to acquire a fast MR sequence as our initial study if a child
is too old for ultrasound. Initially, we use single-shot fast spin echo (ssFSE) or half-Fourier acquisition single-shot turbo spin
echo (HASTE), or a periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) sequence,
thereby eliminating ionizing radiation altogether. In the age of magnetically adjustable pressure valves, however, the use of MR
in a child with shunted hydrocephalus requires a visit to the neurosurgeon after the scan to readjust the valve.
If, after careful consideration, CT is considered necessary based on the indication and the condition of the patient, 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 (44,45). 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 ≤3-mm slice thickness; an eye shield may be used, and the plane of section
should be chosen to minimize 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 signal to noise diminishes with decreasing slice thickness and this must be compensated with increased tube voltage
or tube current, which increases dose. To mitigate that issue, the thinner sections can be reformatted as thicker (4–5 mm)
sections, improving signal to noise and allowing reformation of thinner sections (e.g., when looking for fractures) if desired
(44). 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 (51). 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 tube current 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 nonsedated 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 techniques 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 reformations. Software that allows three-dimensional surface- and
volume-rendered reconstructions of the bones of the face and skull is available from most manufacturers; these have significant
value in assessing suture patency and in the planning of reconstructive surgery.
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 with a window of approximately 60
and level of approximately 20. Use of normal adult brain windows will result in pathology being missed.
Brain
The primary pulse sequences used for the evaluation of brain structure are summarized in Table 1-1. T1- and T2-weighted
images are obtained using gradient-recalled echo (GRE) and fast spin-echo (FSE) techniques. Although it sometimes provides
the best contrast, single-echo spin-echo acquisition requires longer scan times and is now less commonly used. Given its short
imaging time and sensitivity to a broad range of diseases, diffusion-weighted imaging (DWI) is included in almost all brain
protocols. Although state-of-the-art DWI is also capable of depicting brain anatomy in high detail, we defer discussion of this
technique until the next section, which focuses on physiologic and metabolic MR techniques. In our practice at UCSF,
susceptibility-sensitive (T2*-weighted) imaging is also included for most indications.
High-quality T1-weighted imaging is essential for accurate identification of structural brain abnormalities. Volumetric 3D
T1 GRE techniques such as spoiled gradient echo (SPGR) and magnetization-prepared rapid gradient echo (MP-RAGE) (52)
are favored as, unlike conventional 2D FSE, the resulting images can be reformatted in any plane, exhibit strong contrast
between gray and white matter, and allow high spatial resolution to be achieved within clinically feasible scan times using
short TR and TE (typically 35 ms for TR and minimum TE). Using a sagittal prescription oriented such that the longest
(craniocaudal) axis is the readout direction, the total acquisition time for this sequence is approximately 5 minutes for 3 T
scanners. The FOV and matrix size for 3D T1 imaging in children should be set so that the voxel size is no greater than 1 × 1 ×
1 mm.
Table 1-1 Sequences Used for Evaluation of Brain Anatomy in Most Children
Axial T2 FSE (dual echo) 4-mm thickness TR/TE = 3000/60, 120 ms for <12 mo
2-mm interslice gap TR/TE = 2500/30, 80 ms for ≥12 mo
Vascular Imaging
Both CTA and MRA are accurate and easy; both show the vessels 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 considered 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.
Although exquisite images of the vascular lumen can be achieved using multidetector CTA (51), the use of CTA 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 intravenous catheter (usually 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 acquisition begins after the bolus injection is
begun. Alternatively, when obtained as a part of the examination, perfusion CT can be used to estimate the optimal timing of the
bolus. Helical acquisition CTA on our scanners consists of 64 sections at 1.25-mm collimation, 0.4-second rotation time, and
pitch of 1 using a small (typically 10–15 cm, depending upon patient size) FOV (51). Two- and three-dimensional reformations
can then be constructed to optimally show the blood vessels of interest.
For studies of the intracranial vasculature with MRI, fast imaging times and the lack of a need for exogenous contrast make
three-dimensional Fourier transform time-of-flight (3D TOF) studies using multiple overlapping time-of-flight acquisitions
(MOTSA) most useful for screening purposes (66,67). For 3D TOF, a GRE (TR/TE = 45 ms/minimum) sequence is performed
with flip = 20°, partition thickness 0.9 mm, and 128 partitions. A superior saturation band is applied to eliminate, as much as
possible, contamination of the images by flowing blood from venous structures for MRA. Similarly, arterial flow can be
suppressed using an inferior saturation band for 3D TOF MRV. In either case, 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 drawing a region of interest around each and creating maximum-intensity projections (MIP) (68). 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 (69,70) and that, therefore, the individual partition
images should always be scrutinized 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, two-dimensional Fourier transform time-of-flight (2D TOF)
images are fast and efficient (66,71,72) and are usually quite adequate in children because the vessels are typically straight and
stenoses (which make flow more complex 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 excessive patient motion, although it is primarily used for
imaging of vessels in the neck and for venography. We perform 2D TOF studies using a GRE TR/TE = 4.5/minimum sequence.
Axial MR images are obtained through the entire brain with a section thickness of 1.5 mm, flip = 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, contrast-enhanced MRA with using either view-sharing or bolus-timed techniques allows production of high-
resolution MRA images with minimization of saturation and dephasing artifacts (73). 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 children, we
are not aware of any work on its utility for imaging the pediatric cervical vessels. It is expected that the results would be
similar to 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. Techniques for balancing spatial and temporal resolution may prove useful for arterial–venous separation
(74) and have found some application in the assessment of pediatric vascular malformations (75).
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 (66,76). In pediatric 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 GRE
TR/TE = 27/4.5 ms sequence with matrix = 192 × 256, slice thickness 5 mm, flip = 20°, and NEX = 15. The image is obtained
using a presaturation band technique. Encoding 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 can be obtained using 2D TOF or contrast-enhanced MRA techniques described above.
2D TOF venograms (77) are frequently used but are less reliable, as complex or in-plane flow can give equivocal 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 GRE TR/TE = 45 ms/4.9 ms images are obtained using flip = 60°, matrix = 256 × 160, and NEX = 1. Note
that shorter values of TE result in less in-plane saturation of protons and, therefore, in fewer apparent “flow gaps” within the
sinuses (78). 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 contrast-enhanced 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.
Given its high sensitivity to thrombus and spatial resolution, we now perform contrast-enhanced 3D venography using a
dynamic, bolus-triggered 3D gradient echo T1 acquisition technique (TR/TE = 1.74/0.64 ms, flip = 15°, matrix 128 × 128,
FOV = 25 cm, 64 sagittal 2-mm sections with zero filling of k-space in the partition direction) (79,80). The first dataset is
discarded and magnitude subtraction of the subsequent 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 dataset 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 reconstructing axial slabs.
Most vascular techniques currently used in practice focus on evaluation of the anatomy and flow within the lumen of arteries
and veins. This is sufficient for diagnosis of occlusive vascular disease and most aneurysms, but limited for other disorders in
which abnormalities arise within the vessel wall, such as vasculitis or vasculopathy. There is growing interest in using high-
resolution MR to visualize the diseased vessel wall, made possible by 3T pulse sequences implemented with submillimeter
spatial resolution and contrast properties that delineate vessels as distinct from blood within the lumen and surrounding CSF,
bone, or brain parenchyma. The most promising approaches for vessel wall imaging are based on 3D CUBE/SPACE or VISTA
variable flip angle FSE T1-weighted acquisition with fat suppression. High spatial resolution is essential, with isotropic voxel
sizes 0.5 to 0. 7 mm (81). Both pre- and postcontrast images are usually acquired, the former compared to the latter to better
discriminate between mural enhancement and intrinsic T1 shortening due to intramural hematoma from dissection. VWI can be
particularly useful for the evaluation of transient cerebral arteriopathy of childhood, and in our practice, the presence of long-
segment, concentric arterial enhancement in a child with a recent infarct now prompts our neurologists to initiate treatment with
steroids to prevent further arterial compromise and the associated complications (82).
Spine
A normal ultrasound is sufficient to exclude most developmental spine abnormalities in neonates and young infants but becomes
less useful in older infants and children as the posterior elements of the spinal column ossify. Moreover, it is still not clear that
sonography can consistently detect a fatty filum if the conus medullaris is at a normal level (83). Moreover, even if sonography
detects a developmental spine anomaly, additional pathology is picked up by MR in 20% of cases (83).
The scope of indications for using CT to evaluate the spine is also limited. CT is frequently used in the setting of acute
trauma without neurological deficits, in order to evaluate for injuries to the osseous structures of the spine. Also, when the
spine has been instrumented for scoliosis, CT with intrathecal contrast (CT myelography) may also be necessary to evaluate
the spinal cord as metallic hardware may sometimes render MR images useless. Review of the operative record is
recommended in these cases, however, as fusion hardware constructed from titanium or certain alloys does not give rise to the
same susceptibility artifacts as traditional stainless steel, and MRI may still yield diagnostic information. When CT is
necessary, multidetector helical CT should be performed to increase speed while still allowing adequate coverage and
multiplanar reformations (51). 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 (51). However, when neurological deficits are present, CT is
only useful after intrathecal contrast injection and is, therefore, more invasive and more difficult.
MR is the clear study of choice for imaging the pediatric thecal sac, spinal cord, and nerves. Different techniques may be
used depending upon the clinical situation. When scanning a child with suspected or confirmed spinal dysraphism, sagittal T1-
weighted images (TR/TE = 600/minimum) should be obtained initially using 3-mm slice thickness. Axial images should then
be obtained through any areas of abnormality or suspected abnormality visualized on the sagittal study. We acquire both T1 and
T2 FSE axial images (note, however, that use of FSE sequences at 3 T in infants may result in high surface absorption rates,
which slows acquisition). T1-weighted images depict the spinal cord without the associated artifacts from circulating CSF that
are so common on T2-weighted images of the spine and will nicely show lipomas; the T2 FSE clearly depicts the cauda
equina, the filum terminale, adhesions (such as meningocele manqué), and any bony or fibrous spurs. If high spatial resolution
is required to resolve fine anatomic detail, we have also found 3D constructive interference in the steady-state (CISS)
acquisition that is targeted to structures of interest to be highly useful for troubleshooting.
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 associated 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 (84).
Patients with scoliosis present a technical challenge for acquisition with any imaging modality. Initially, a coronal T1- or
T2-weighted image should be obtained to assess vertebral anomalies and look for a split-cord malformation. Oblique sagittal
(parallel to a straight segment of spine) and oblique axial (perpendicular to a straight segment of spine) planes can then be
defined based on the coronal images in order to give optimal information. If a split spinal cord is seen, thin-section (≤3 mm)
axial T2- or T2*-weighted GRE images should be obtained through the entirety of the split to look for a fibrocartilaginous or
calcified spur. Alternatively, a 3D CISS sequence can be obtained; each segment of the spine can be displayed quite well after
postprocessing.
Patients who present with myelopathy but no suspicion of dysraphism should have sagittal 3 mm FSE T2-weighted images
(TR/TE = 3500/102 ms) through the entire spinal cord, in addition to the T1-weighted sagittal images. Targeted axial T2-
weighted FSE or T2*-weighted GRE images can then localize any abnormal region of T2 prolongation within the cord. We
prefer the GRE (TR/TE = 600/25 ms) images in the cervical and upper- to midthoracic spine, where rapid CSF flow causes
considerable artifact on axial FSE images. Axial FSE is usually better in the low thoracic and lumbar spine. In either case,
flow-compensating readout gradients should be used to reduce these artifacts. T1-weighted images after infusion of gadolinium
contrast are often very helpful for evaluating intrinsic spinal cord pathology, particularly when neoplasm is suspected based on
the unenhanced images. Standard 2D FSE T1 images are most often used for the postcontrast scans; however, when patient
motion is not a problem, 3D gradient echo postcontrast images with multiplanar reformations may be slightly more sensitive to
small foci of CSF tumor spread (60).
To evaluate for bone and ligamentous injuries (pars interarticularis stress reaction or edema from a fracture) or for tumors
involving the vertebrae, sagittal 3 mm STIR sequences are very useful. In our experience, they are more sensitive than fat-
suppressed FSE or contrast-enhanced T1 images and well worth the slightly longer imaging time. We use TR/TE/TI =
5000/58/150 ms with ETL = 8 and NEX = 2.
Fetal MRI
MRI has become clinical standard of practice as the second step in evaluation after fetal sonography shows (definite or
potential) abnormalities. The value in this situation is both to verify the presence of a suspected abnormality and to specify its
severity and extent (85–88). With careful attention to detail, excellent images of the fetal brain and spine can be obtained
through proper patient preparation. The study begins before the gravid mother arrives at the MR scanner, as it is important that
she remain NPO for 4 hours prior to the MR examination. The lack of food reduces intestinal peristalsis, which in turn reduces
artifacts from moving bowel that alias over the fetus. It also seems to reduce the amount of fetal motion. Upon arriving, the
mother is asked to lie supine in the scanner, and a multichannel 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
problem until after 30 weeks), the exam can be performed with her in the left lateral decubitus position. In our practice,
excellent studies are routinely possible without using maternal or fetal (via the umbilical cord) sedation (89).
Once the mother is comfortably positioned, a series of ultrafast T2-weighted ssFSE/HASTE images are acquired,
complemented by echo-planar T2*-weighted gradient echo, diffusion, and, whenever possible, T1-weighted imaging. The
ultrafast T2 ssFSE 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 acquisition. An initial localizer is obtained using T2 HASTE in three orthogonal
planes with respect to the mother, using 6- to 8-mm thick slices, 1- to 2-mm interslice gap, and a large 40-cm FOV. The
localizer is used to visualize the position of the fetus, determine the location of the placenta within the uterus, and determine
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 T2
HASTE images of the fetal brain are prescribed from this localizer. Each subsequent image set is prescribed from the
preceding set by determining a plane orthogonal to that set. In this manner, axial, sagittal, and coronal image sets of the fetal
brain are obtained. We routinely obtain at least two image sets of good quality in each plane.
Some manufacturers have developed interactive scanning programs that can be applied to fetal MRI. These programs allow
“real-time” adjustment of scanning parameters, such as slice angle and orientation (87,90). Such programs allow the
technologist to adjust the angle of a prescribed image stack without having to exit and reprogram a new sequence and can be
invaluable when the fetus is moving during the scan. This ability is particularly critical when trying to acquire high-quality
images of midline structures. In cases of aliasing artifact, the FOV can be increased, and/or the phase-encoding and frequency-
encoding directions can be changed directly during image acquisition. Overall, image quality is improved, and scan time is
reduced when this program is utilized.
When evaluating the fetal brain, the optimal slice thickness is 3 mm with no interslice gap. This slice thickness allows
adequate SNR without excessive volume averaging in the small fetal brain. For the fetal spine, we have found that a slice
thickness of 2 mm is better for identifying small structures such as the spinal cord, bony spurs, and myelomeningoceles. Images
are acquired during free maternal breathing, although we have found respiratory triggering useful in decreasing motion. The
FOV is typically kept small, although must be adjusted for increased fetal and/or maternal size and when aliasing artifacts
obscure important structures. Our routine imaging parameters are as follows: TR/TE = 4000/90 ms, BW = 25 kHz, matrix =
192 × 160, FOV = 24 cm, and NEX = 0.5. Images are acquired in an interleaved manner in order to obtain contiguous slices
without signal loss from crosstalk between slices.
DWI provides quantitative information about water motion and tissue microstructure. With modern clinical gradients,
single-shot echo-planar DWI can be performed within 18 seconds during a single maternal breath-hold (91,92). Scanning
parameters include TR/TE = 4500/minimum ms, FOV = 32 cm, matrix = 128 × 128, slice thickness = 5 mm, interslice gap = 2
mm, and BW = 167 kHz. Gradients are applied in three orthogonal directions 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 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.
Whenever possible, T1-weighted images should be obtained to supplement the ssFSE/HASTE T2 images. However, these
are generally of limited value, especially in fetuses less than 27 gestational weeks, due to their limited SNR. Fast, multiplanar,
SPGR techniques are primarily used, mainly to detect hemorrhage or calcification (both of which are 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). Typical scanning parameters are TR/TE = 120/minimum ms, flip = 70°, FOV = 24 cm, matrix =
256 × 160, NEX = 1, slice thickness = 5 mm, interslice gap = 1 mm, and BW = 31.25 kHz, which yield 8 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) motion. 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 SNR). Gradient echo echo-planar T2- weighted images are routinely acquired and can be useful in
detecting hemorrhage.
Advanced MR techniques such as diffusion tensor imaging (DTI) and spectroscopy are being successfully applied to fetal
MRI, although their development is still in the early stages (91,92). DTI is currently only applicable when the fetal head is
already engaged in the pelvis (93), because otherwise too much fetal motion occurs during the acquisition time. Similar
troubles, in addition to the large size of the voxel relative to the fetal brain size, plague fetal MR spectroscopy (MRS).
Therefore, 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.
Abbreviated Protocols
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 sedation. These include the previously
mentioned techniques ssFSE/HASTE (59,60) and PROPELLER (61,62). These techniques are currently useful only for gross
anatomic assessments such as ventricular size in patients with hydrocephalus 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 (61). In our experience, tissue contrast also is not as good in PROPELLER sequences as in conventional FSE or STIR
sequences. For ssFSE images, we use TR/TE = 20,000/90 ms, NEX = 0.5, FOV = 24 cm, matrix = 256 × 256, and 4-mm slice
thickness. For PROPELLER FSE, we use TR/TE = 4000/83 ms, NEX = 2, FOV = 24 cm, matrix = 224 × 224, and 4 to 5 mm
slice thickness.
MR Neurography
For MR neurography (MRN), high-resolution, water-sensitive T2, and STIR sequences are necessary 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. MRN is also useful to identify birth-related brachial plexus
injury. The utility of these sequences relies upon their high spatial resolution and their high sensitivity to edema. High-
resolution T1-weighted images are less sensitive to slow flow in vessels, and useful anatomically to identify relevant nerves
within fat and evaluate muscle bulk. Detecting edema and other nerve abnormalities requires heavily T2-weighted imaging
with fat suppression. We use T2 FSE acquisition with long TR/TE = 4000–5000/100–110 ms and flow suppression on all
sides of the imaging volume to suppress high signal from incoming flow; a technique for fat saturation that achieves uniform fat
suppression across the imaging volume is essential.
In general, STIR sequences work better for the neck and brachial plexus, where fat suppression pulses are often affected by
bulk susceptibility, resulting in heterogeneous fat saturation and water suppression. STIR alleviates these problems. In our
practice, we use a modified Dixon technique (IDEAL, iterative decomposition of water and fat with echo asymmetry and least
squares estimation) to achieve more homogeneous fat suppression (94). The resultant images highlight nerve bundles as
longitudinal bands of high signal intensity within suppressed dark fat and low signal muscle. T2-weighted sequences are
excellent for searching for intrinsic pathology in peripheral nerves (95,96).
MRN requires very close attention to technique and often long imaging times. For both T1- and T2-weighted 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,
and if possible, a matrix size of 512 × 512 should be used. With improvements in DWI outside of the head, we are now
routinely acquiring DWI sequences in our MRN protocols, which we have found further heightens sensitivity to edema and
nicely depicts infiltrative nerve disease. It should also be mentioned that CISS can be added in cases of nerve root avulsion, as
this sequence can depict nerve discontinuity and associated pseudomeningocele with high accuracy. This additional
information is useful to the surgeon for surgical planning in nerve repair procedures. Postcontrast T1-weighted acquisition with
fat suppression is added in the case of suspected malignancy.
Diffusion
At UCSF neuroradiology, DWI is obtained in nearly every patient that we scan. The technique is a single-shot, echo-planar
spin-echo technique that uses TR/TE = 5000/minimum ms, BW = 250 kHz, FOV = 25.6 × 25.6 cm, matrix = 128 × 128, and
slice thickness 3 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. For clinical DWI, it is necessary to apply
diffusion gradients in only three directions to minimize acquisition time. The geometric mean along the three directions is
calculated and presented as a diffusion trace, “combined,” or “isotropic” image that depicts signal intensity as a weighted
combination of both T2 and diffusion effects. Removing the T2-weighted contrast results in images of mean diffusivity (Dav)
or equivalently apparent diffusion coefficient (ADC) maps. These images are inherently quantitative, with each pixel
numerically representing the average rate of proton diffusion (in mm2/s). For visual review, it is helpful to view trace images
and ADC maps together, the former depicting abnormal signal intensity with greater visual contrast and the latter to confirm
that mean diffusivity is truly reduced.
It is important to be consistent in selection of the diffusion gradients, especially if quantifying the ADC. Work has shown
that the magnitude of the ADC varies with the b-value utilized when the number of acquired directions is small (97). In
addition, absolute ADC measurements should be interpreted with the knowledge that numerical values may vary between 4%
and 9% depending on scanner vendor, field strength, and sequence parameters (98). Despite this variability, quantitative values
of ADC are especially useful in detecting diffuse abnormalities of the brain, as with severe traumatic, metabolic, toxic, or
hypoxic–ischemic injury. Early after injury, the brain may be visually normal; it may be possible to identify the injury only by
reviewing the numerical values in regions of interest on ADC maps.
Because diffusion-weighted images can be acquired so rapidly, there is little time penalty incurred by measuring mean
diffusivity (Dav) in 6 or more directions to improve the numerical accuracy of ADC measurements and allow calculation of
diffusion tensors, which, unlike simple DWI, can be processed to study orientational heterogeneity (anisotropy) of tissue.
Images of anisotropy are directly reviewed or used in the construction of white matter pathways (99). The quantitative
evaluation of anisotropy and white matter tractography were originally made possible by the observation that diffusion data
can be conveniently represented mathematically using a tensor, for DTI (100,101).
To determine the diffusion tensor, it is necessary to acquire diffusion-weighted images in a minimum of six different
directions, along with an image acquired without diffusion weighting (i.e., b = 0 s/mm2). Unlike simple DWI, the preferential
directions of water diffusion within each voxel can be derived from the tensor. The degree to which diffusion preferentially
occurs along a single direction is referred to as anisotropy. As it is difficult to display tensor data with images, the concept of
diffusion ellipsoids is often used. An ellipsoid is a three-dimensional representation of the distance and direction traveled in
space by the average water molecule in a voxel during a given time Td. The axes of the ellipsoid are directed along the three
orthogonal eigenvectors (ν1, ν2, and ν3, the principal diffusion orientations), and the lengths of the vectors are scaled by the
corresponding eigenvalues (λ1, the primary eigenvalue—sometimes also called the parallel eigenvalue, a measure of
longitudinal diffusivity; λ2, the intermediate or median eigenvalue; and λ3, the minor eigenvalue—note that (λ2 + λ3)/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 fractional anisotropy (FA), which is sensitive to small differences among white
matter tracts when anisotropy is low (as in neonates and infants) (102). Three features of DTI are of interest in pediatric
neuroimaging. First, diffusion characteristics can be used to assess brain maturation (102) because both the ADC and FA vary
with maturation in both immature white matter and in immature cerebral cortex (57,103). In premature neonates, water
molecules in the cerebral cortex move more radially (perpendicular to the surface of the cortex) than horizontally (parallel to
the surface of the cortex) (104); this anisotropy disappears with maturation. In white matter, the rate of diffusion parallel to
axon fascicles is faster than the diffusion perpendicular to them (105,106). This anisotropy increases as the axons myelinate
although, interestingly, anisotropy is present even before myelination (105,106)
Diffusion characteristics can be used to differentiate different layers of the developing cerebral mantle in fetuses and
prematurely born neonates (107). 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 different characteristics than the intermediate zone (the layer of developing axons and glia
between the subplate and the germinal zones, also known at the ventricular and subventricular zones) (107). The ability to
distinguish these layers on imaging studies may be crucial to unraveling the cause of developmental difficulties in premature
neonates.
Importantly, DTI can also be used with connectivity algorithms to permit axonal tracts to be mapped in the brain (108).
Although currently a research tool, this diffusion tractography has tremendous potential to identify the causes of neurologic
defects in children (99,109) and to help us to better understand white matter anomalies associated with developmental brain
disorders (110–113). More recently, diffusion imaging has moved beyond tensor with methods using higher orders of
mathematical models to describe it in a more precise manner. The tensor model, while simple and easily understood, lacks the
ability to properly describe fiber crossings in the brain. The technical details of these approaches are beyond the scope of this
text, and interested readers are referred to a definitive text that reviews the subject (114).
In the last few years with the worldwide initiative in human brain mapping, there is a push toward visualizing and
understanding the human brain as a network, similar to the Internet or any other connected networks; this is being referred as
“connectomics.” By using diffusion imaging, the method of tractography can be employed to generate a mathematic model of
the axons throughout the entire brain. With parcellation of brain regions (nodes) and computing the connections between these
nodes, a connectivity matrix can be derived and quantified. Then, using simple graph theory, metrics can be computed and
evaluated. Our group has performed some of the initial work to study newborns with injuries in comparison to those who have
normal outcomes (115–119). While promising, the physiological correlation with the mathematical representation of the brain
network remains unclear; further research efforts are needed to elucidate the clinical significance and the predictive values of
their network metrics.
Perfusion
Perfusion MR techniques aim to detect and/or quantify the delivery of blood to the microcirculation within the brain at the
capillary level. There exist several techniques that are capable of measuring classic perfusion parameters including mean
transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV) using CT and MRI. All are very difficult in
children, due to the rapid rate of blood flow and the small size of the structures in the young brain. In addition to these
biological obstacles, implementation of perfusion is further challenged technically by difficulty in gaining peripheral venous
access in young children, the use of small intravenous catheters that limit injection rates and prolong injection times, the
necessity of using low doses of contrast for some perfusion methods, 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.
Enhanced by the rapid acquisition of multidetector helical CT, CT perfusion (CTP) imaging is now commonly used in adults
(120,121). However, the limitations outlined above and concerns for radiation exposure have limited the application of this
technique among young children. The few studies employing this technique in children have focused on the variation in
perfusion parameters with age (122) or on the use of the CTP in the emergency setting (123). Risk–benefit considerations of
radiation with CTP suggest that there is limited application of this tool in children. In our own practice, its use is limited to
combined CT/CTP/CTA protocols obtained in some children with acute neurologic deficit due to suspected vascular
occlusions. Even so, MRI is obtained prior to CT when possible in this situation.
Most approaches to measuring perfusion in children have used MR imaging after administration of a contrast agent
(124–127). One method is the use of fast gradient echo sequences such as fast spoiled GRE (FSPGR). This sequence allows
strongly T1-weighted sequences to be acquired in as little as 1 second. In this dynamic contrast-enhanced (DCE) perfusion
approach, the influx of paramagnetic contrast results in an increase in brain signal intensity of the images. Alternatively, T2*-
weighted pulse sequences can be used, exploiting the T2* shortening effects of parametric contrast for dynamic susceptibility
contrast (DSC) perfusion. If echo-planar imaging is available, it should be used for DSC, 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, DSC is more sensitive to small changes in CBV than DCE. Therefore, the
majority of the literature for tumor imaging favors using a echo-planar GRE sequence to estimate CBV. 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 (128). Region-
of-interest intensity measurements are acquired from the images sequentially to generate a curve in which relaxivity (ΔR2*) is
plotted versus time. From the ΔR2* curve, the voxelwise MTT, CBV, and CBF can be deduced. The ΔR2* curve can be used to
differentiate low-grade from high-grade gliomas, recurrent tumor from treatment-related injury, intraparenchymal from
extraparenchymal tumors, and abscesses and demyelinating plaques from parenchymal tumors (129–131).
With DSC perfusion, patients are imaged during infusion of paramagnetic contrast given intravenously as a bolus injection.
In most settings, a gadolinium chelate is used, although other contrast agents such as superparamagnetic iron oxide agents can
also be injected. For echo-planar imaging, we use a single-shot GRE technique with TR/TE = 1250 /54 ms, BW = 178 MHz,
FOV = 26 × 26 cm, 4 mm slice thickness, matrix = 256 × 128, and NEX = 1. 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
ms, flip = 10°, NEX = 1, 10 mm slice thickness, and matrix = 256 × 64. 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 timing. Data analysis can provide local blood
volume, approximate local blood flow, and perfusion delay measurements (125,127). Although most of our experience with
pediatric perfusion imaging has been in older children, the method can also be safely applied when specifically tailored for
infants (132,133).
Perfusion imaging can also be performed using blood water as an endogenous tracer. This technique is referred to arterial
spin labeling (ASL) (124,134,135). It is entirely noninvasive and is theoretically quantitative. For these reasons (and because
it requires less manual intervention for analysis), our group has shifted most of our perfusion imaging to ASL. With this
technique, an excitation slab placed below the skull base inverts the moving protons in arterial blood. A series of images
through a section in the brain downstream is 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 magnetization is a function of
perfusion of the tissue in that plane. Although this technique works with spin-echo techniques (136), the change in signal
intensity as a function of tissue perfusion is small; measurements are, therefore, easily impaired by head motion or instability of
instrumentation. Spin tagging is therefore better performed using echo-planar techniques, which reduce instrumental drift and
head motion artifacts (137), making the results more reproducible. Pseudocontinuous arterial spin labeling, in which arterial
spins are continuously or pulsed labeled to achieve a steady-state condition, is now the most widely used sequence for ASL,
other than in neonates, where difficulty arises from the extremely short distance from the position in the neck where the protons
are magnetically labeled to the point where they are read.
As computational resources increased, a number of acquisition schemes of varying nature have appeared and compounding
the clinical use of the technique. As a result, in 2015, the perfusion study within the International Society of MR in Medicine
organized a meeting, which produced a consensus paper to improve the adoption of ASL for clinical applications (138). The
paper detailed typical hardware needs, labeling approaches, postlabeling delay, background suppression, readout strategies,
and quantitation methods. At UCSF, we employ a version of the pseudocontinuous ASL using a postlabeling delay of 2000 ms
for neonates and 1500 ms for young children. With spiral echo-planar readout, the total imaging time is approximately 5
minutes.
CSF Flow
The movement of CSF can be visualized and quantitatively analyzed using phase-contrast techniques (139). MR studies of CSF
flow are most useful when looking for interruptions of normal flow patterns. For example, we use these studies in patients with
craniocervical junction malformations (e.g., Chiari I and Chiari II) when they are being considered for foramen magnum
decompression surgery. We have also used them occasionally to evaluate the patency of the cerebral aqueduct or of an
endoscopic third ventriculostomy. We use phase-contrast sagittal studies because the CSF flow can be both visually assessed
and numerically quantified (139,140). For studies of patients with Chiari malformations, images are centered at the level of the
foramen magnum. Our typical parameters include Venc of 5 cm/s, TR/TE = 27/11.7 ms, flip = 30°, FOV = 22 cm, matrix = 128
× 256, and NEX = 2. Peripheral cardiac gating is used, as CSF systole and diastole are synchronous with the cardiac cycle.
If only qualitative information is desired about CSF flow, other flow-sensitive sequences can be used. Steady-state free
procession sequences (CISS) using three-dimensional Fourier transformation can be very useful to show rapid CSF flow that
disturbs the steady state and, therefore, appears as low signal intensity. For this technique, we use TR/TE = 30/14 ms, flip =
40°, and 200 phase-encoding steps. With 128 partitions and FOV = 18 cm, a partition size of 1.4 mm is typical. Because of the
3D acquisition, the images can be formatted in any plane. FSE and FLAIR sequences are also motion sensitive and can be used
to qualitatively evaluate CSF flow.
Magnetization Transfer
Magnetization transfer contrast (MTC) is occasionally added to T1-weighted sequences for indications that require
assessment of myelination and demyelination (141,142). MTC relies on detecting differences in relaxation properties of free
and bound water (142–144). 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. However, a constant exchange occurs between free water molecules and 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 molecules. The measured relaxation times of the entire population of water protons will be
shortened by this process, which is known as magnetization transfer (MT). The amount of MT 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, therefore, will negate any contribution of bound water protons to the overall T1 and T2 relaxation times.
Subtraction of the image obtained with the off-resonance RF saturation pulse will show the contribution from the bound
protons, that is, the amount of MT. MT can be assessed qualitatively or quantitatively (145).
Magnetization transfer images can be obtained by acquiring two sets of gradient echo scans with gradient spoilers. Data are
best acquired using TR/TE = 300/7 ms, flip = 20°, 3-mm partition thickness, and FOV = 12 cm. An RF saturation band applied
to the second set at 5 kHz off the resonance frequency of free water will saturate the pool of bound protons. Subtraction of the
second dataset 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 the brain (MTR = (Mo − Ms)/Mo, where MTR is the magnetization transfer ratio, Mo is the magnitude of
signal without saturation by an off-resonance radiofrequency pulse, and Ms is the magnitude of tissue signal with the saturation
pulse on).
MR Spectroscopy
Proton MRS is useful in the assessment of encephalopathic neonates (146,147), in detection and diagnosis of some inborn
errors of metabolism (148,149), in developmental delay (150), and in pre- and posttherapeutic assessment of intracranial
tumors (151,152). Single-voxel spectra are obtained from volumes of approximately 6 cm3, but two-dimensional and three-
dimensional chemical shift imaging allows acquisition of spectra from larger volumes, which can be parcellated into smaller
voxels sized 1 cm3 or smaller. The voxel is prescribed from anatomic images obtained in an imaging sequence during the same
examination.
For most implementations of MRS, chemical shift selective pulses are used for spatial localization and water suppression,
yielding signal restricted to the region of interest at the intersection of spatially selective pulses. Most MR scanners now have
“push button” MRS sequences that include automatic shimming and water suppression. Multiple averages are obtained to
achieve adequate SNR. Long TE spectra (TR/TE = 2000/272–288 ms) are typically acquired using point-resolved
spectroscopy (PRESS) and are more useful in injury states, in which optimal evaluation and quantification of lactate and NAA
are needed (146,153), and in tumors, in which quantification of choline, creatine, and NAA is needed (154). Short TE spectra
(usually TE < 45 ms) can be acquired using either stimulated echo acquisition mode (STEAM) or PRESS; they allow
assessment of the peaks of many metabolites and are most useful for assessing patients with inborn errors of metabolism (148).
With STEAM, it is possible to achieve shorter TEs, such that protons with short T2 relaxation times can be reliably detected,
at the expense of half of the SNR that can be achieved with PRESS.
With 2D and 3D spectroscopic imaging, multiple spectra from a variety of locations can be acquired during a single
acquisition. The location of the smaller voxels within a larger acquisition area can be modified retrospectively, allowing a
great deal of flexibility in the regions sampled. 2D MRS is nearly as fast as single-voxel acquisition, but the 3D still increases
the acquisition time considerably (155,156). The use of higher field strength MR scanners with echo-planar and spiral
acquisition techniques has allowed faster acquisitions, often within 5 to 6 minutes depending on the size of the coverage and
voxel size.
As the scanner performance has improved dramatically over the past decade, previously long scan times of MRS using
editing techniques such as MEGA (157–159) or others (160,161) to resolve J-coupled metabolites (such as lactate, GABA,
and glutamate) have become available for clinical use. Editing involves excitation of the coupling spins in one acquisition
cycle and not another, which enables using the difference to extract the metabolite of interest. In newborns diagnosed with
hypoxic–ischemic encephalopathy, lactate has been demonstrated as a key biomarker for long-term outcome. Long TE MRS is
usually employed to quantify lactate due to its spectral overlap with lipids in the 1.3 to 1.4 ppm range as well as it being a
coupled species. By leveraging shorter TE and editing techniques, accurate quantitation of metabolites such as glutamate and
myo-inositol in addition to lactate is possible. This will no doubt have great impact on measuring steady-state metabolic
concentrations in pathological conditions or as a monitoring mechanism for interventions that directly impact metabolism.
Functional MRI
A number of different techniques can be used to map the spatiotemporal 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, MSI), electroencephalographic mapping, positron emission tomography (PET), 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 administered 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 CBV, local CBF (perfusion, see above), or blood oxygenation. As the blood oxygenation-
based methods are the most widely used, they will be briefly discussed.
The capillary and venous blood in the vascular network around the normal resting cerebral cortex has a relatively high
concentration 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 reduces the local
concentration of deoxyhemoglobin. The reduction of local deoxyhemoglobin results in an increase in local signal intensity.
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 (162), is the
primary technique used for functional MR. Because the sensitivity to changes in the oxyhemoglobin/deoxyhemoglobin ratio is
increased at higher magnetic field strength, BOLD imaging is likely to become more widely used as more 3 T MR scanners
become available.
fMRI in older children is performed in a manner identical to that in adults (162–164). At 1.5 T, we use a single-shot
gradient echo echo-planar sequence with TR/TE = 2000/60 ms, matrix = 256 × 128, 10 mm slice thickness, and NEX = 20. At
3 T, we use the similar sequence with TE of 28 ms and voxel resolution of isotropic 3 mm. For fMRI with tasks, a minimum 15
repetitions of the blocks are needed and 200 repetitions for resting state to achieve sufficient data quality. 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 studies of children, as motion artifacts are typically more of a problem in children
than in adults (165). Patient cooperation becomes a problem in younger children, particularly those below the age of 8 years
and those with developmental delay or mental retardation (166). In this group, conditioning of the patients to the experimental
situation by going through the necessary tasks in a mock MR scanner can save considerable time when the actual experiment is
performed (167). Pediatric fMRI shows particular promise in the evaluation of disorders of language acquisition (168). In
infants and young children, resting state fMRI shows particular promise as a means of assessing normal and abnormal brain
function.
Summary
The many differences between the pediatric and adult nervous systems require that different strategies be used for diagnostic
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, MRI, and CT 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; in general, sonography is the initial study of choice in infants and
MRI in children older than approximately 4 months. 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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Normal Development of the Fetal, Neonatal, and Infant Brain,
Skull, and Spine
Matthew J. Barkovich and A. James Barkovich
Introduction
Normal Prenatal Brain Development
Embryology
Imaging of the Preterm Brain (Premature Infant and Fetus)
Grading of Brain Maturation in Premature Infants
Introduction
The brain matures in an organized, predetermined pattern that correlates with the functions as the newborn or infant performs at
various stages of development. Prior to the development of modern neuroimaging techniques, it was not possible to analyze
normal brain maturation 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, MR supplies the most information. MR
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; myelination can be studied by the changes in
the T1 and T2 relaxivity of the brain tissue, by assessing changes in magnetization transfer or, indirectly, by assessing changes
in the degree and direction of microscopic motion (diffusion) of water in the brain. Magnetic resonance spectroscopy (MRS)
allows us to assess some of the chemical changes that occur as the brain develops. Finally, changes in regions of brain activity
may be determined by looking at changes in local cerebral blood oxygenation resulting from the activity through the use of
blood oxidation level–dependent (BOLD) imaging (sometimes called functional MRI or fMRI). Imaging correlations of these
changes that occur during normal brain maturation will be described in this chapter.
Embryology
The bilateral cerebral vesicles that will form the cerebral hemispheres first appear at about 35 days of gestation as
outpouchings of the telencephalon from the regions of the foramina 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 subventricular 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 near the developing third ventricle,
GABAergic neurons generated, including cortical interneurons, hippocampal interneurons, and globus 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 bottom of
the developing third ventricle, GABAergic neurons generated, including cells to the preoptic area, amygdala, posterior globus
pallidus, and cortex); (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, initially in an incomplete form that is often called the preplate. As the neurons migrate, they develop
axonal connections with other cortical and subcortical (subplate) neurons. The axons 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 developing
cortex. In addition to afferent and efferent axons, the intermediate 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 temporary neuronal circuits, particularly with the thalamus (9); this zone is known as the subplate. The
subplate is largest at the 30th postconceptional week (10). At that time, it is about four times thicker than the cortex, occupying
up to 45% of the telencephalon, and is easily seen on fetal MRI as an area of T1 hypointensity and T2 hyperintensity between
the intermediate zone and cortex (10–12). It gradually disappears after the 30th gestational week, as definitive cortical
connections are established (10,11) but remains functional, in part, possibly for as much as the first half of the first postnatal
year (10). Details of the development of the hemispheres are described in more detail in Chapter 5. For the purposes of the
discussion to follow, it is sufficient to understand that the 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 are smooth. The fetal sulci appear in an orderly sequence; the phylogenetically older sulci appear first, and the
more recently acquired sulci appear later. The principal sulci and gyri form the characteristic pattern of the human cortex that
can be identified in the full-term infant (Table 2-1). The primitive sylvian fissure, the earliest fetal sulcus, is usually present
when the fetus is imaged in the fourth gestational month. The next sulci to appear are the calcarine, parieto-occipital, and
cingulate sulci during the fifth month (by 20–22 weeks); the Rolandic (central), interparietal, and superior temporal sulci that
appear toward the end of the sixth month (by 25 weeks); and the precentral, postcentral, superior frontal, and middle temporal
sulci that appear during the seventh gestational month (24–28 weeks) (13) (Fig. 2-1 and Table 2-1). In the medial temporal
lobe, the hippocampal sulci are variable and often asymmetrical; asymmetry is also often seen in the formation of the collateral
sulcus (14). Because sulcal formation occurs so late in gestation, imaging studies of premature infants show sulci that are
shallow and few in number. It is, therefore, important to know the postconceptional age of a child before assessing the
sulcal pattern. Otherwise, a false diagnosis of lissencephaly may be made. In addition, as will be discussed in more detail
later in the chapter, sulcation, myelination, and corpus callosum development are often delayed in prematurely born
neonates compared to fetuses of the same postconceptual age.
van der Knaap et al. (20) have devised a method by which gyral development can be divided into five stages: (a) before 32
weeks, (b) 33 to 34 weeks, (c) 35 to 37 weeks, (d) 38 to 41 weeks, and (e) beyond 41 weeks. The gyral maturity is determined
by measurements of the width of the gyri and depth of the sulci. The stage of gyral development is then assigned based upon the
degree of gyral maturity in seven different regions of the brain. Battin et al. (21) and Ruoss et al. (22) have also developed
systems of assessing sulcal development based on ratios of the width and depth of the sulci and gyri. Gyral development
proceeds most rapidly in the area of the sensorimotor and visual pathways. These are also the areas in which myelination
occurs earliest ((23) and following section), in which glucose uptake increases earliest (24), in which relative cerebral
perfusion increases earliest (25), in which cortical microstructure matures most rapidly (26), and in which brain chemistry
matures most rapidly (27). Gyral development takes place most slowly in the frontobasal, frontopolar, and anterior temporal
regions, which are also the slowest regions to myelinate and to mature metabolically (24,25,27). It is important to evaluate the
sulcal pattern of neonates and infants, as abnormal sulcation predicts abnormal functional development (28).
Table 2-1 Chronology of Sulcation of the Brain (15–19)
Medial Surface
Ventral Surface
Lateral Surface
Insular sulci 34 wk
Cerebellum
In general, the earlier numbers are from pathology studies and the later ones from radiology studies. Imaging numbers (later numbers) indicate when the
sulcus is seen in more than 75% of studies.
Fetal MR imaging has been successfully utilized in a large number of centers for the past two decades (12,29–35). Studies
have shown that the cerebral cortex and deep gray structures are relatively large before 20 weeks (Fig. 2-2) but that the
cerebellum and cerebral white matter grow disproportionately during the last 20 weeks (36). Improvements in coil technology
(particularly the use of multiarray-phased array coils), improved pulse sequences, and development of higher–field strength
MRIs have allowed progressive improvement in the quality of the images. Studies (19,33,37–39) indicate that brain
development follows a similar progression of sulcation in fetuses as in prematurely born infants; sulci are increasingly
identified with increasing postconceptional age. However, it appears that sulcal development occurs earlier in utero than ex
utero. In other words, sulci are seen slightly earlier in fetuses still in the uterus than in neonates of similar
postconceptional ages that have been born prematurely (40). This may result from the fact that the subarachnoid spaces are
considerably bigger in fetuses than in newborns of the same postconceptual age (40), allowing the sulci to be more easily seen.
The reasons for this are not yet clear, nor are the precise differences in timing. Studies also show that the cerebrum and its
components grow largely proportionally. For example, the volume of cortical gray matter, basal ganglia volumes, and
ventricular volume parallel that of supratentorial volume, while supratentorial white matter volume grows more rapidly than
overall supratentorial volume (41).
Prior to 20 weeks of gestation, the cerebral mantle is quite thin and the ventricles are relatively large (Fig. 2-2).
Supratentorially, the T2 hypointensity of the germinal matrices lining the walls of the lateral ventricles is thicker than that of the
cortex at 16 weeks (Fig. 2-2D); it is roughly equivalent in thickness to the cerebral white matter layer. The germinal matrix is
thickest at the region of the caudate heads and should not be mistaken for a germinal matrix hemorrhage at this location. The
more central ventricular zone and adjacent subventricular zone cannot be distinguished by in vivo imaging. Between the
germinal zones and the cortex, MR also shows a layer of intermediate signal intensity, separated from the more peripheral
cerebral cortex and more central germinal matrix (Fig. 2-2C–E). Although previously believed to represent migrating glial
cells, this layer has recently been identified as the intermediate zone or the developing fetal white matter (11). Projection and
commissural axons are present, as are some late migrating neurons and many migrating astrocyte and oligodendrocyte
precursors (42). Immediately peripheral to the intermediate zone and deep to the cerebral cortex is a region of T1
hypointensity/T2 hyperintensity (Fig. 2-2F), known as the subplate, a region composed of loosely spaced neurons where
thalamocortical afferent axons, basal forebrain cholinergic afferent axons, and callosal and ipsilateral corticocortical axons
accumulate for a variable period before entering the cortical plate to establish definitive thalamocortical and corticocortical
synapses (10,43–45). These zones are most prominent in younger fetuses (<20 gestational weeks). Before 20 weeks, the
sylvian fissures are extremely shallow and no operculization can be identified. The basal ganglia can be identified and are
intermediate in signal between the darker cortex and germinal zone and the lighter white matter (Fig. 2-2D). The cerebellum
remains quite small at this age, barely bigger than the pons on axial images and smaller than the mesencephalic tectum on the
midline sagittal image (Fig. 2-2A and B).
Figure 2-2 MR images of a fetus at 16 postconceptional weeks. A. Sagittal SSFSE image shows the small size of the cerebellar vermis
(large black arrow) and the corpus callosum (small black arrow) at this age compared with the quadrigeminal plate (large white arrow). B. Axial
SSFSE image shows the relatively small size of the cerebellum (white arrows) at this age compared with the pons (black arrow). C. Axial image
at the level of the diencephalon shows a very small fourth ventricle (black arrow) between developing thalami and developing temporal horns.
D–F. Axial images at the level of the basal ganglia (D) and above show the large hypointense germinal zones of the ganglionic eminences
(black arrows in D) and in the walls of the frontal horns and trigones at all levels. Note the thin layer of hyperintense white matter (the white w in
F) at this age between the hypointense germinal zones and cortex.
Figure 2-3 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).
At 20 (Fig. 2-3) to 24 (Fig. 2-4) weeks of gestation, the cerebrum has grown considerably (especially the white matter; Fig.
2-3B–D), but it remains essentially agyric with the exception of the wide, vertically oriented sylvian fissures. The size of the
brain is very small and the cerebral cortex is extremely thin, so thin imaging sections (≤3 mm) must be used for optimal
evaluation. MR images show the cortex to be very hyperintense with respect to the underlying white matter on T1-weighted
images and very hypointense compared to white matter on T2-weighted images (Figs. 2-3 and 2-4). The germinal matrix has
not yet involuted and can still be seen as a stripe in the walls of the lateral ventricles that is isointense to the gray matter of the
cortex on T1- and T2-weighted images (Fig. 2-2) and very hypointense on echo-planar T2 imaging; it is, however, thinner than
in younger fetuses (18–20 weeks) and becomes thinner and discontinuous with further maturation (Fig. 2-4). At this age (23–24
weeks), the germinal matrices remain large and conspicuous as areas of relative hyperintensity between the cerebral cortex and
the white matter on T2-weighted imaging studies (12,46), but they seem to begin to disappear rapidly after 25 weeks. The
lateral ventricles and the cisterns around the brain stem and cerebellum are visible and more prominent at this age than in the
mature infant; they are relatively smaller at 23 to 24 weeks (Fig. 2-4) than at 18 to 20 weeks (Fig. 2-3). When imaging at 3T,
the third and fourth ventricles are easily visualized at this age unless a lot of motion artifact is present; if difficulty is
encountered, waiting a few minutes for the fetus to calm down usually results in good images. The globi pallidi typically
appear hyperintense on T1-weighted images starting at about 20 weeks. This likely represents premyelination changes, such as
the appearance of proteolipid protein in oligodendrocyte processes (47).
Figure 2-4 Fetal MR at 23 postconceptional weeks. A. Sagittal SSFSE image shows a thin corpus callosum (black arrows) and an enlarging
cerebellar vermis (compare with Fig. 2-2A). B–E. Axial T2 FSE images through the cerebrum. 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 2-3. Note also that the subplate
and intermediate zones, although still visible, are less conspicuous at this age than at 20 weeks.
Between 24 and 30 weeks, the cerebral cortex shows development of shallow Rolandic (central), calcarine,
pericallosal/callosomarginal, interparietal, and superior temporal sulci (Figs. 2-5 and 2-6); in some patients, the precentral,
postcentral, superior frontal, and middle temporal sulci may be visualized. The subplate is still seen in the subcortical white
matter as a layer of T1 hypointensity/T2 hyperintensity; it becomes difficult to see on imaging in the posterior frontal and
parietal lobes at about 28 weeks but remains visible in less mature areas such as the anterior frontal and temporal lobes for
some time thereafter (12,46). Myelination is seen in some brain stem structures during this period, including the median
longitudinal fasciculus (MLF; bright at 25 weeks on T1-weighted images, dark at 29 weeks on T2-weighted images), the
lateral lemnisci (bright at 26 weeks on T1-weighted images, dark at 28 weeks on T2-weighted images), the medial lemnisci
(bright at 27 weeks on T1-weighted images, dark at 30 weeks on T2-weighted images), and the superior and inferior
cerebellar peduncles (bright at 28 weeks on T1-weighted images, dark at 29 weeks on T2-weighted images) (48). The basal
ganglia and thalami are better seen at this age on MR imaging 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 (Fig. 2-
5I–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, mostly due to its high
cellularity and, possibly, to early myelination. 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 development
of the calcarine sulci.
Figure 2-5 MR of 28-week fetus (A–D) and of 28-week postconceptional age prematurely born neonate (E–H). A–D are FSE, E–H are SE T1
MR images, and I–L are SE T2 images. Note that sulcation is 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 shallow Rolandic (central),
calcarine, pericallosal/callosomarginal, 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 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 development of the calcarine sulci.
Figure 2-6 MR of normal 31-week fetus (images A–D) and a 31-week postconceptional age premature infant (images E–H are T1 weighted
and I–L are T2 weighted). Note that there is not much difference in brain development between the postnatal and prenatal images. More sulci
have developed by this age, although they are still rather shallow. The myelinated dorsal brain stem is contrasted by the unmyelinated ventral
pons (E and I) and the thalami and globi pallidi are contrasted by the completely unmyelinated internal capsule (F, G, J, and K). 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, G, and K); 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 brain stem, superior and inferior cerebellar peduncles, far lateral putamen, and ventrolateral thalamic nucleus. The cerebral white matter
still appears completely unmyelinated.
By 31 to 32 weeks, an increased number of gyri and shallow sulci become visible in the cerebral cortex of prematurely born
neonates (Fig. 2-6). The sylvian fissures retain their immature appearance, although some development of the opercula can be
detected. The cisterns around the brain stem and cerebellum remain large at this age, and the cerebrospinal fluid (CSF) spaces
in the occipital region and in the interhemispheric fissure remain prominent, although the interhemispheric fissure is more
variable in size. The cavum septi pellucidi and cavum vergae are prominent and will remain so throughout the first 40
postconceptual weeks (29,32). The dorsal brain stem (relatively hyperintense on T1-weighted images and hypointense on T2-
weighted images) is contrasted by the unmyelinated ventral pons (Fig. 2-6E and I). The thalami and globi pallidi are contrasted
by the unmyelinated (relatively hypointense on T1-weighted images and hyperintense on T2-weighted images) internal capsule
(Fig. 2-6F and J). 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. However, some curvilinear T2 hypointensity is seen extending
along the lateral walls of the frontal horns of the lateral ventricles to the medial tip of the frontal lobes and into the olfactory
sulci at this age (Fig. 2-6G and K); previously thought to be regions of residual germinal matrix (49), these areas turn out to be
migrating GABAergic neurons that are present until about 6 postnatal months (50). The dorsal brain stem 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 brain stem (predominantly due to
the MLF, medial and lateral lemnisci), superior and inferior cerebellar peduncles, nuclei of the inferior colliculi, far lateral
putamen, and ventrolateral thalamic nucleus (51) (Fig. 2-6). The white matter of the centrum semiovale still appears
completely 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 (51). On T1-weighted MR, the posterior limb of
the internal capsule remains hypointense as compared to the lentiform nucleus (Fig. 2-7C and D); some patients will show a
small dot of hyperintensity in the posterior aspect of the posterior limb at 39 weeks (48). On T2-weighted images, the posterior
limb of the internal capsule remains entirely hyperintense compared with surrounding structures (Fig. 2-7J). The sylvian
fissures and, to a lesser extent, the CSF spaces in the posterior parietal area remain prominent (Fig. 2-7C–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 (29,32).
Figure 2-7 Normal 34/35 week premature infant. Images A–F are T1 MR images, and G–L are T2 MR images. More sulci are forming, as can
be seen along the interhemispheric fissure and over the convexities. Sulcal development varies considerably at this age. The sylvian fissures
have markedly diminished in prominence due to opercular development. Notice that the dorsal brain stem and globi pallidi have increased in
signal intensity on the axial T1-weighted MR (A–F). The posterior limb of the internal capsule remains completely unmyelinated at this age. On
T2-weighted images, the brain stem nuclei, the periphery of the cerebellar dentate nuclei, and the cerebellar vermis are relatively hypointense
structures in the posterior fossa (G and H). The subthalamic nuclei (arrows in I) have become hypointense.
By 38 to 40 weeks, the brain has a nearly normal adult sulcal pattern (Fig. 2-8); the sulci are largely formed but are not as
deep as they will become in the next several weeks. On T1-weighted MR studies, the dorsal brain stem, posterior portion of
the posterior limb of the internal capsule, and the central portion of the corona radiata (the corticospinal tracts) are
hyperintense compared to the rest of the brain. On T2-weighted images, the dorsal brain stem is hypointense and, at 39 to 40
weeks, a characteristic spot of hypointensity is present in the posterior 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 matter and parieto-occipital white matter remain relatively low in attenuation compared to the gray matter
(Fig. 2-8A–E). This probably results from the known high water content of the newborn brain, related to 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. The 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 from back to front.
The cisterna magna and basilar cisterns are relatively large throughout infancy, as the cerebellum continues to grow
considerably (compared to the cerebrum) during the first postnatal year. 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.
Measurement 20 wk 21 wk 22 wk 23 wk 24 wk
Maturation
From the perspective of T1 and T2 relaxation times, postnatal brain development consists primarily of changes in signal
intensity associated with the process of myelination. A multiparametric imaging approach to assessing brain maturation showed
that it correlated well with postmortem studies (53). Postmortem studies showed that myelination of the brain begins during the
fifth fetal month with the myelination of the cranial nerves and continues throughout life. Perhaps the best way to think about 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. In the brain stem, the medial longitudinal fasciculus, lateral and medial
lemnisci, and inferior and superior cerebellar peduncles, which transmit vestibular, acoustic, tactile, and proprioceptive sense,
are myelinated at birth, whereas the middle cerebellar peduncles, which transmit motor impulses into the cerebellum, acquire
myelin later and more slowly. Similarly, in the cerebrum, the geniculate and calcarine (optic), postcentral (somesthetic), and
precentral (propriokinesthetic) regions acquire myelin early, whereas the posterior parietal, temporal, and frontal areas, which
are association areas that integrate the sensory experience, acquire myelin later (23,54–56). On MRI, the sensory and motor
pathways mature before association bundles. The spinothalamic tract is the most advanced in maturation, followed by the optic
radiations, the middle portion of the corticospinal tract, and the fornix. Most projection bundles (except the anterior limb of the
internal capsule) thus mature earlier than limbic, commissural, and association bundles. Within the limbic and commissural
bundles, the fornix tends to mature earlier than the cingulum, while the splenium and genu of the corpus callosum seem to
mature before the callosal body. The arcuate and superior longitudinal fasciculi, the anterior limb of the internal capsule, and
the external capsule all mature late (53). Yakovlev and Lecours (56), 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 in the anterior frontal and anterior temporal lobes continue
to myelinate well into the third and fourth decades of life.
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 (63) and brain stem (57).
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) (59). As discussed above, the small foci of gray matter intensity seen just
anterior and lateral to the tips of the frontal horns and extending downward to the base of the anterior frontal lobe in premature
and term neonates (Fig. 2-8P–T) represent migrating inhibitory neurons that originate in the ganglionic eminences (50); they are
a normal finding during the first 2 to 3 months after term birth. The cerebellar vermis (Fig. 2-8K) and the flocculi cerebellum
are also of low signal intensity. The ventral brain stem becomes of similar low intensity to the dorsal brain stem at about the
fifth postnatal month. The middle cerebellar peduncles begin to decrease in signal intensity during the second month of life and
are of uniform low intensity by age 3 months (64). The cerebral peduncles become low in intensity by 4 months and the red
nuclei by 5 months (64). 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.
Figure 2-10 MR of the brain of a normal 4-month-old. A–E. T1 images show rostral progression 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 and G. Note the relative lack of change on the T2-weighted image from the neonate (Fig. 2-
8).
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 (59). By less
than 1 month of age, the cortex in the pre- and postcentral gyri has lower intensity than the surrounding cortex (Fig. 2-8). By age
2 months, patches of low signal intensity 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 pre- and
postcentral gyri is indistinguishable from that of adjacent gyri, which have also diminished in signal intensity (Fig. 2-10). 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 posteriorly 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. 2-11 and
2-13). The internal capsule matures in a posterior-to-anterior fashion. The more anterior 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 internal 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 posterior limb. The corpus callosum matures grossly from posterior to anterior; the inferior portion of the
splenium (most of which is actually the hippocampal commissure) may change earlier, but most of the splenium shows low
signal intensity by age 6 months and the genu by age 8 months (Figs. 2-11 and 2-12). The basal ganglia begin to diminish 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. 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, which
will be described later in this chapter.
Figure 2-11 MR of the brain of a normal 6-month-old. A–E. T1 images show further progression 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 paracentral regions. F–J. T2 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 intensity within the callosal genu.
The subcortical white matter (other than in the calcarine and Rolandic areas) matures last, proceeding from the occipital
region anteriorly to the anterior frontal and temporal lobes. In the past, subcortical white matter maturation was described as
being complete by about 24 months (23). With improved signal-to-noise and thinner imaging 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 frontally (Figs. 2-
13 and 2-14); deep white matter in the anterior temporal lobe matures last. Extension of the low signal intensity into the
subcortical white matter begins at about 1 year in the perirolandic region and gradually extends into the subcortical white
matter in the subfrontal and anterior temporal regions; the process is essentially complete, even on modern images, by 24 to 28
months (Figs. 2-15 and 2-16). Thus, with the exception of the so-called terminal zones (see following section), white matter
maturation, as assessed by visual inspection of MR imaging (quantified parameters, such as relaxation times and diffusion
metrics, continue to evolve), is complete in the middle 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.
Figure 2-12 MR of the brain of a normal 8-month-old. A–E. T1 images at this age show essentially an adult appearance 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. F–J. On T2-weighted 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.
Figure 2-13 T2-weighted MR of the brain of a normal 12-month-old. A–D. 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.
Terminal Zones
As maturation in the centrum semiovale progresses, nearly all subjects 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. 2-17A–C). The areas may be homogeneous or they may be patchy (and made more so by dilated
perivascular spaces that are common in this region [Fig. 2-17D–F]). They are more difficult to identify on the first echo of the
long TR sequence than on the second and usually appear isointense to surrounding white matter on a proton density image; they
may be visible on FLAIR images, depending upon the exact imaging parameters and machine. The primary cause of this high
signal intensity is probably the known delayed myelination of the fiber tracts involving the association areas of the posterior
and inferior parietal and posterior temporal cortex. As noted above, large perivascular spaces probably contribute to the high
signal intensity, particularly in the peritrigonal area (see subsequent paragraph in this section). Yakovlev and Lecours called
these regions the “terminal zones” because some of the axons in these regions do not stain for myelin until the fourth decade
(56). These areas of persistent high signal intensity are seen throughout the first decade and, in some patients, into the second
decade of life.
Figure 2-14 T2-weighted MR of the brain of a normal 15-month-old. A–D. 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 temporal lobes.
Figure 2-15 T2-weighted MR of the brain of a normal 22-month-old. A–D. The appearance of the brain is essentially identical to that of an
adult. Notice, however, that there is still some patchy high signal intensity in the anterior frontal white matter and in the white matter parallel to
the lateral ventricles. This is most prominent dorsal to the bodies and trigones of the lateral ventricles.
Figure 2-16 T2-weighted MR of the brain of a normal 24-month-old. A–D. The brain has a near adult appearance with minimal patchy high
signal in the anterior frontal white matter, diminished from the 20-month-old.
Figure 2-17 Terminal zones and large perivascular spaces. A–C. Axial (A), coronal (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 mildly and more strongly T2-weighted
(D and E) images show curvilinear periventricular areas that are isointense to CSF on all imaging sequences. This is the classic appearance
for perivascular spaces. G and H. Axial T2-weighted 4-mm thick image (G) shows hyperintensity (white arrow) in the white matter of the
superior frontal gyrus. On this image, it is difficult to differentiate from a mass or injury. Higher-resolution imaging using a steady-state
sequence with 1-mm imaging shows clearly the presence of multiple small perivascular spaces (large white arrow). Note a similar, smaller
area in the parietal lobe (smaller white arrow).
It is important to differentiate the terminal zones from white matter injury resulting from prematurity (see Chapter 4),
hydrocephalus (see Chapter 8), and metabolic disorders (see Chapter 3); all can be associated with areas of T2 hyperintensity
in the peritrigonal region. In general, the white matter injury of prematurity is more sharply defined and is situated more
inferiorly, lateral to the trigones and near the optic radiations. Injured white matter is of very high intensity and is typically
bright on FLAIR images and on “proton density” (long TR [>2 seconds] short echo time [TE] [<60 ms]) sequences. More
importantly, white matter injury is commonly associated with loss of brain tissue, typically resulting in irregularity of the
ventricular wall; abnormally deep cortical sulci, with the cortex sometimes extending down to the ventricular surface; and
thinning of the posterior body or splenium of the corpus callosum (see examples of white matter injury of prematurity in
Chapter 4). The difficult differentiation between normal areas of peritrigonal high signal intensity and white matter injury
of prematurity is aided by identification of a layer of myelinated white matter between the trigone of the ventricle and the
terminal zones in normal patients (Fig. 2-17C) (65). When the peritrigonal high signal is due to periventricular leukomalacia,
this layer of normally myelinated white matter is absent. Differentiation from hydrocephalus is made easier when a shunt or
third ventriculostomy (see Chapter 8) can be detected on the MR study (or when ventricles are still enlarged from unshunted
hydrocephalus). White matter disease due to metabolic disorders is typically much more extensive than peritrigonal; details are
described in Chapter 3.
Milestones
Just as sulcation develops in an orderly manner, white matter signal changes associated with maturation and myelination of
axons appear as shortening of T1 and T2 relaxation times in an orderly and predictable manner (23). These should be assessed
on all brain MRIs of infants and young children (Table 2-3). As the white matter matures, T1 shortening occurs, resulting in
increasing hyperintensity of the white matter on T1 images, and is followed by T2 shortening, which results in decreasing
signal intensity (23,68); these changes vary little with field strength or specifics of the sequence (conventional spin echo, fast
spin echo, inversion recovery, spoiled gradient echo, etc.) as long as the sequence is related to T1 and T2 relaxation. During
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 matter 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 pattern 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 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.
Table 2-3 Ages When Changes of Myelination Appear
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 (94), probably because normal infants vary more in head size and shape
than in head enlargement 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 constant in infants throughout the first year of life (94). Some authors have investigated the
relationship of the area of the corpus callosum to maturity (101). Although analysis of callosal area on midline sagittal images
is an accurate method of quantification of white matter maturation, 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 (93). As
described earlier, similar delays of maturation have been found in sulcation and myelination of prematurely 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 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 anterior lobe of 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. 2-19A) (102–104), possibly because of
the high concentration of proteins within it. The T1 signal intensity and size diminish slowly and linearly until approximately 2
months after birth (Fig. 2-19B), 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 intensity of normal gray matter on T1-weighted spin-echo images
(105,106). Of note, the evolution of signal is similar in infants born at term and in those born prematurely, indicating that the
changes result from adjustments to extrauterine life and are not related to the infant’s developmental stage (107). The low
signal of the anterior pituitary gland in the older infant and child 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 (108). During childhood, the
pituitary gland slowly grows in all dimensions, 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. On
T2-weighted images, the signal of the pituitary gland is typically that of gray matter and does not undergo significant temporal
signal changes.
Figure 2-19 Development of normal pituitary gland. A. Normal newborn pituitary (35 weeks). The gland is upwardly convex and is uniformly
bright on T1-weighted images. B. Normal infant (3-month) 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 more easily identified as a separate
structure.
Although the normal size of the developing pituitary stalk (infundibulum) has never been determined, the size of the mature
infundibulum is established and this number can be used in children. The infundibulum should be no more than 2.6 mm in its
thickest portion on coronal and sagittal MR images; greater thickness is highly suspicious for pathologic infiltration (see the
section on suprasellar tumors in Chapter 5) (109,110). 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 (111).
With the arrival of puberty, the pituitary gland increases dramatically in size and (in girls, but only mildly in boys)
demonstrates a marked upward convexity (Fig. 2-20). Of note, the gland is homogeneous on all imaging sequences, both prior
to and after contrast administration; this aids in differentiation from an adenoma or a Rathke cleft cyst. The height of the gland
may reach 10 to 12 mm in girls and 7 to 8 mm in boys (112,113). The appearance then slowly evolves into that of the adult
gland over the subsequent 5 to 8 years.
Figure 2-20 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.
Embryology
At the end of the second gestational week, the normal human embryo is a bilaminar structure comprised of a flat sheet of cells
adjacent to the amnion, termed the epiblast, and a second layer adjacent to the yolk sac, known as the hypoblast. The hypoblast
will eventually be replaced by the endoderm, which is believed to be a derivative of the epiblast. Soon after, cells in the
caudal midline of the embryo proliferate to form a primitive knot (also known as Hensen node, which defines the cephalic
end) and the primitive streak caudal to it. By about embryonic day 16, the primitive streak begins to regress and cells at the
rostral lip of the primitive knot migrate between the epiblast and hypoblast, forming the 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 paraspinous muscles and overlying skin, and sclerotomes, which will form the cartilage, bones, and ligaments of the
vertebral column (124,125). As discussed in Chapter 5, the rostral notochordal process eventually becomes the prechordal
plate, which induces formation of the ventral forebrain, and, as discussed in Chapter 9, the notochord likely induces formation
and closure of the neural tube. This process is rather complex, particularly at the junction of the primary neural tube (formed by
neurulation of the neural plate, defects of which cause open neural tube defects) and the secondary neural tube (defects of
which cause closed neural tube defects) (126).
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 sclerotome separate from the cranial half (of
the same sclerotome) at the sclerotomal cleft and then fuse with the cranial half of the inferior sclerotome (Fig. 2-21) to form a
new, primitive vertebral body (124,125). 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 pulposus. The mesenchymal vertebrae
then undergo chondrification, starting at specific chondrification centers within the vertebrae, 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 (124,125). The ossification centers in the vertebral bodies of the thoracolumbar spine are
separated from those in the vertebral arches by the neurocentral synchondroses, small linear cartilaginous regions located at
the junction of the pedicle and the vertebral body (127).
The newborn vertebral body has a membranous central (in the rostral–caudal dimension) component, 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 (128). 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–marrow 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
spinal arteries (129,130).
Figure 2-21 Diagram of formation of vertebral bodies. A. Each sclerotome consists of a cranial mass of loosely packed cells (anterior
sclerotome, 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.
CT of Spine Development
In the spine, the major developmental process that is demonstrated by CT is the ossification of the synchondroses between
ossification centers. The persistence of these synchondroses in infants and children can create problems in the interpretation of
CT scans. Therefore, it is important to recognize their normal sequence of closure (Table 2-4). As briefly discussed above, all
of the vertebrae (except for C2) develop from three primary ossification sites: the body (anteromedial) and the two neural
arches (posterolateral), with the neural arches separated from the body by the neurocentral synchondroses (127). At C1, the
anteromedial ossification center is the anterior arch. C2 differs from the other vertebrae in that it has four ossification centers:
the body, the two neural arches, and the dens. The dens forms in utero from two separate paramedian ossification centers that
fuse in the midline, usually by the seventh fetal month; the synchondrosis between the two ossification centers may persist in
infancy and should not be mistaken for a fracture (131).
At birth, nonossified synchondroses are present within the anterior arch of C1, within the posterior arch of C1, and between
the two arches. The anterior arch synchondrosis typically ossifies between the 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 between the ages of 7 and 9
years (132). At the C2 level, the synchondrosis between the two posterior ossification centers ossifies between the ages of 4
and 7 years. The center between the C2 vertebral body and 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 years and fuses with the odontoid between the
ages of 11 and 12 years. Below the level of C2, the vertebral bodies consist of one anterior ossification center and two
posterolateral ossification centers (Fig. 2-22). At C3 and below, the ossification of the synchondroses is fairly constant. The
posterior synchondrosis ossifies between the ages of 4 and 7 years; the synchondrosis between the vertebral body and the
posterior ossification center ossifies between the ages of 3 and 7 years (132).
MR of Spine Development
The neural synchondroses (between the neural arches and the vertebral body) can be assessed by MR as well as by CT. These
synchondroses 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 images (Fig. 2-23), appearing on the sagittal images as low-intensity lines running from the superior
endplate to the inferior endplate and on axial images as oblique low-intensity lines. The lines are seen from infancy and
presumably represent dense cortical bone plus cartilage. The synchondroses disappear from MR at a different time than they do
on CT and plain films, suggesting that MR and CT visualize different aspects of the process. On MR, the lines begin to
disappear laterally, at a point about midway between the superior and inferior endplates (133,134). In the lumbar spine, the
synchondroses appear approximately 75% closed at age 4 years. Complete disappearance of the lines begins in the mid- and
lower cervical region at about age 6 years. In the lumbar region, the lines disappear between the ages of 10 and 14 years,
while in the thoracic region, they disappear between the ages of 10 years (upper thoracic) and 15 to 16 years (midthoracic)
(127,133,134).
The MR appearance of the vertebral bodies and intervertebral discs of the infant spinal column has been described as
evolving through three stages (135). 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 represents the vertebral
body ossification center (Fig. 2-24A). The cartilaginous 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 osseous portion. T2-weighted images show the vertebral body ossification centers to be hypointense centrally and
slightly more hyperintense peripherally (Fig. 2-24B). Administration of paramagnetic contrast at this age will result in mild to
marked enhancement of both the vertebral body and the cartilaginous endplates. The intervertebral disc does not change
significantly during childhood, appearing hypointense on T1-weighted images and hyperintense on T2-weighted images and
showing minimal to no enhancement (135,136).
Figure 2-23 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.
Figure 2-24 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 basivertebral venous plexuses. The cartilaginous 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 muscle 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.
Stage II (Fig. 2-25A–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 centrally, eventually affecting the entire vertebral
body. Thus, the upper and lower portions of the vertebral body are more hyperintense than the central portion (Fig. 2-25A). A
band of hypointensity (the exact correlate of which is not known) separates outer portions of the vertebral body from the
cartilaginous endplate. The intervertebral disc is hypointense. Note that the cartilaginous synchondrosis between the body of
C2 and the dens, the cartilaginous apical dens, and the sphenooccipital synchondrosis (in the clivus) are all hyperintense on
T1-weighted images during this stage (Fig. 2-25E). 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.
2-25B–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. 2-25C) (135,136).
Stage III (Fig. 2-25F–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 incorporated into the vertebral body, which becomes rectangular in shape by about
age 2 years. T2-weighted images (Fig. 2-25G) 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. 2-25H) is seen in the endplates and vertebral bodies in most children up to the age of 9 or 10 years, during which time the
hematopoietic marrow is being slowly replaced (135,136).
Figure 2-25 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 arrows) located within the centers 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 cartilaginous endplate of the vertebral bodies; these are markedly hyperintense compared with the central osseous portion 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 hyperintense (large black arrow) and
the markedly hypointense cartilaginous 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 vertebral body ossification center is less well differentiated
from the surrounding cartilaginous 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 surrounding peripheral vertebral
body (black arrowheads). However, the hyperintense cartilaginous endplate and intervertebral disc are both hyperintense (white arrows) and
cannot be differentiated. E. Sagittal T1-weighted image of the craniocervical junction shows that the synchondroses between the body of C2
and the dens (white arrowhead), the cartilaginous apical dens (large white arrow), and the sphenooccipital synchondrosis (small white arrows)
are all hyperintense compared to bone at this stage. F. Sagittal noncontrast image at age 9 months. The vertebral bodies now appear nearly
homogeneous and the cartilaginous 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 cartilaginous endplates remain hypointense,
while the intervertebral disc remains hyperintense. H. Postcontrast sagittal T1-weighted image shows nearly uniform enhancement of the
vertebral bodies.
MR Spectroscopy
The Normal MR Spectrum
Before dealing with specifics of changes in spectra during development, some important concepts need to be discussed. The
first is that the observed spectra vary with the TE used in acquiring them. As discussed in Chapter 1, many more peaks are seen
on short (20–30 ms) TE than on intermediate (135–144 ms) or long (270–288 ms) TE spectra. The reason for this is that
excited protons lose coherence at variable rates, depending of their chemical surroundings (T2 relaxation). As they lose
coherence, their respective MRS peaks broaden and the peak amplitude is decreased. In general, short TE spectra are used in
our practice to assess patients with suspected metabolic disorders, where one needs to analyze as many peaks as possible and
look for the appearance of new, unexpected ones; some groups use short echo MRI in brain tumors, where the smaller voxels
are useful (a) to evaluate the very heterogeneous tissue of the obvious mass and (b) to assess tissues around the obvious mass
for areas of (less obvious) tumor infiltration; in addition, elevation of myo-inositol can help to identify low-grade gliomas in
untreated patients (138). Long TE spectra generally detect peaks from only four compounds (N-acetylaspartate, choline,
creatine, and lactate). A mass with high-choline levels and low NAA levels is very suspicious for a higher-grade tumor
(lower-grade tumors can have normal spectra or elevated lactate [from anaerobic glycolysis within the tumor]). In addition,
long echo spectra are easier to quantify and are used in our institution (and many others) to assess patients with brain injury
(139–142) in addition to brain tumors (143,144).
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 brain stem, the basal ganglia have different spectra than the cerebral white matter,
and the thalamus has a different spectrum than the putamen. Beyond that, each thalamic nucleus has a slightly different
spectrum, and within each nucleus, different areas have slightly different spectra depending upon their connectivity.
Furthermore, the spectra change with maturation. Infants have high choline and myo-inositol and relatively low creatine and N-
acetylaspartate peaks; as they grow, the choline and myo-inositol 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 (145), but a study of sufficient size to establish definitive norms and
their variations with age (and possibly other parameters) will require many years. Moreover, in the opinion of the authors, it is
likely that the spectra change with changes in brain activity. Therefore, one can get important information from spectra by
looking at patterns of peak heights and peak ratios in different parts of the brain to determine whether gross abnormalities are
present, but the tool is not sensitive enough, using the imaging coils currently available, to perform detailed studies of neuronal
function. Some patterns give important information; before discussing these patterns, however, let us first discuss the different
peaks seen on proton (1H) MR spectra (Fig. 2-26), 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.
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 (146,147). The “choline”
contribution is a sum signal from several choline-containing compounds (i.e., phosphorylcholine, phosphorylethanolamine,
glycerophosphorylcholine, glycerophosphorylethanolamine, 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 spectrum; it decreases
with age along with phosphorylcholine (166); both of these compounds are precursors for membrane synthesis (167).
Glycerophosphorylethanolamine and glycerophosphorylcholine are products of membrane breakdown; they increase in
concentration with postnatal age (166). Membrane-bound choline compounds may not be visible by MR (168); however, when
the cell membranes are broken down in disease processes, the bound choline is released and becomes visible (168). The
choline reflects the structural components of cell membranes, especially myelin sheaths (146,147). Thus, the choline peak
tends to be enlarged in highly cellular processes such as high-grade tumors and in neurodegenerative disorders. Focal
inflammation, 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 cerebellum 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-amino butyrate, lysine, and glutathione (146,147). A second, smaller creatine peak is seen at 3.94 ppm (169,170).
Phosphocreatine appears to be a crucial molecule in maintenance of energy-dependent systems in all brain cells (171).
Creatine is synthesized mainly in the kidney and liver and cannot get into the brain without functional creatine transporters. In
the brain, its concentration is highest in the cerebellum, followed by the thalami, basal ganglia, cortical gray matter, and white
matter (172). Its concentration remains largely constant throughout the brain throughout life, other than minimal decrease in the
frontal white matter, corpus callosum, and caudate nucleus (148); therefore, Cr is used as a standard for comparison with other
metabolites. In rats, Cr concentrations are higher in astrocytes than in neurons; therefore, Cr may be elevated in injured tissue
(173). Very small Cr peaks may be an indication of a creatine synthesis disorder or a creatine transport disorder (see Chapter
3).
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 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 (27).
However, lactate is a normal finding on 1H MRS in the CSF of premature and term neonates, with a concentration up to 2.7
mm/L (27,174–176). 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 propan-1,2,-diol (ethylene glycol), an injection solvent for the administration of
anticonvulsants given to neonates, has a spectroscopic appearance nearly identical to lactate (177). Propan-1,2-diol appears as
a doublet centered at approximately 1.1 ppm (Fig. 2-27) (177). 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.
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 glutamate (Glu) are seen in the 2.1- to 2.4-ppm region (146,171). A second peak, at 3.75 ppm, can be
seen and is from resonance of the alpha CH moiety. Glutamate is an excitatory neurotransmitter that is released from excited
axons into the synapse, where it binds to postsynaptic glutamate receptors. Some of the released glutamate is then transported
into adjacent glial processes, while the rest is taken up into pre- and postsynaptic neuronal processes. The glutamate absorbed
into glial cells is converted into glutamine by the enzyme glutamine synthetase or metabolized to oxoglutarate (by glutamate
dehydrogenase) and aspartate (by aspartate aminotransferase) (178). Glu is an important molecule in brain injury, from
hypoxia–ischemia, seizures, and possibly trauma (179). 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 7 Tesla. 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 (180). 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.
Figure 2-27 Presence of propan-1,2-diol in neonatal spectrum. (A) is a proton spectrum (TE = 270 ms) from the basal ganglia. (B) is a proton
spectrum from the frontal watershed white matter. Note that two doublets are present, the one centered at 1.1 ppm (p) representing propan-
1,2-diol and the one centered at 1.3 ppm (la) representing lactate.
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 (152,181); its concentration remains largely constant in all regions of the brain during development (148). Myo-inositol
is an essential growth factor (182) and is the precursor of phosphatidylinositol, a constituent of phospholipid membranes
(146). It is located primarily in glial cells, with particularly high concentrations in astrocytes (167) and, therefore, may be a
specific marker for astrogliosis. Other possible roles include osmoregulation, cell nutrition, and detoxification (152,181).
Minor contributions to the peak at 3.56 ppm come from glycine and inositol-1-phosphate (168). Scyllo-inositol is a
nonmetabolized isomer of myo-inositol that may inhibit the transport and incorporation of myo-inositol into phospholipids
(183,184). 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 spectra of mammalian brain in vivo and in vitro (172,184). 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 (185).
Taurine is an amino acid that is reported to act as an osmoregulator and as a modulator of the action of neurotransmitters
(186). It is found at high concentration in infants, but the concentration drops with maturation, to approximately 1.5 mmol in
adults. The spectrum contains two triplets centered at 3.25 and 3.42 ppm (186). 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 (138).
Two broad peaks are typically seen in short echo spectra of infants, one between approximately 0.5 and approximately 1.0
ppm and another between approximately 1.0 and 1.6 ppm. These are commonly referred to as “macromolecular peaks.” They
are composed primarily of methylene (centered at about 1.3 ppm) and methyl (centered at about 0.9 ppm) protons 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 degenerative process. In the authors’ experience, these
peaks are somewhat larger in inborn errors of metabolism and in child abuse than in the “normal” infant population.
Most commercially available MR spectroscopy programs do not allow phosphorus MRS to be performed. However, some
knowledge of (31)P MRS is useful. Presently, the progressive decrease of phosphomonoester and the complementary increase
of phosphodiester, caused by lipid metabolism, seem to be the best indicators of brain development on (31)P MRS (187).
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 precursors). 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 (188), glycerophosphorylethanolamine, and glycerophosphorylcholine (166).
Additionally, the correlation of (31)P MRS and neurologic exam (examination of reflexes, motor and sensory functions) in
newborn dogs demonstrated that exponential increases in phosphocreatine, inorganic phosphate, and phosphodiesters, with
maintenance of the phosphocreatine/inorganic phosphate ratio, preceded maturational changes in the neurological examination
(189). The spectroscopic evolution is postulated to result from increasing ATP turnover in the maturing mitochondria.
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 (202). 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 (138,171,181,198,203). However, different groups obtain slightly different values, even using these
“absolute” measurements (171,204–206). One reason for these differences is that the spectra of different parts of the brain
mature at different times and different rates (see Fig. 2-30A–F) (192,198). 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 proton spectra (192,205,206). On phosphorus spectra, the more mature areas will give lower values of
phosphomonoester and higher values of phosphodiester, phosphocreatine, and ATP (188). Using absolute measurements, myo-
inositol has been found to be the dominant peak in neonates, with a concentration of 10 to 12 mmol/kg (171,204). Choline, with
a concentration of 2.5 to 3.5 mmol/kg, is the dominant peak in older infants (171,204). 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 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 (171,204).
Figure 2-29 Changes in short echo time (26 ms) (1)H 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. The arrow and arrowhead in (A) point to so-called “macromolecular peaks” from chemical groups present in
neonates that decrease in size (as in B) over the first postnatal year and then disappear.
Although the brains of near-term and term neonates, infants, and children show no anisotropy of gray matter, DTI of very
preterm neonates and infants shows an interesting phenomenon of anisotropic water diffusion in the cerebral cortex (Fig. 2-33).
This anisotropy is believed to result from the radial organization of the immature cerebral cortex (235). 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 oriented basal dendrites and horizontally oriented thalamocortical axons invade the cortex
(235). 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 perirolandic region of the cortex, where it is no
longer seen after about 30 postconceptional weeks (236). Anisotropy persists the longest in the anterior temporal and
prefrontal cortex, where is seen as late as 37 postconceptional weeks (Fig. 2-33B) (236). This loss of cortical anisotropy 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 premature neonates.
Figure 2-32 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 preterm (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, representing reduced water motion, is now
present in the corticospinal tracts within the corona radiata (H). I–L. Three-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. Nine-month-old infant. At this
age, most hemispheric white matter is isointense to cortex. In the regions that mature late (anterior frontal and parietal, P), the white matter
remains slightly hyperintense. 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 cortex except for some patchy hyperintensity (in W) posterior and superior to the ventricular trigones.
Figure 2-33 Diffusion anisotropy of the premature cerebral cortex. A. Fractional anisotropy 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. Fractional
anisotropy 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.
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 matter). Many thalamocortical and corticocortical axons that will eventually synapse with neurons in the
cortex temporarily synapse with neurons in the subplate until the cortex is sufficiently mature to receive it. 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 (237). 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.
Perfusion Imaging
Perfusion imaging is uncommonly performed in children. It is occasionally necessary in children with vasculopathies such as
moyamoya, where revascularization is contemplated. Dynamic susceptibility-weighted perfusion imaging (DSC), as described
in Chapter 1, is often 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 (267,268). However, age-related changes require the use of a quantitative method
such as arterial spin labeling (we use pseudocontinuous arterial spin labeling, pCASL) (269–272); at the time of writing of this
chapter, ASL is still not widely available and gives rather inconsistent results in infants. However, significant preliminary
work suggests that pCASL can be used reliably in infants and children and that cerebral blood flow increases with age in both
gray matter and white matter (269,273,274). The cerebral blood flow appears to suddenly decrease in adolescence (275). At
UCSF, we use it routinely in children with suspected ischemia or vasculopathy. 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 MR Imaging
Blood oxygenation level–dependent (BOLD) fMRI has been a powerful research tool for mapping human brain activity for the
past two decades (276,277). 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
development 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 functionally 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 (278). Currently, two different methods 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 region of interest on the area to be studied and calculating the temporal correlations of the BOLD signal
with those of other regions of interest in the brain (278). 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
(279).
Figure 2-34 Magnetization transfer images in a neonate. A and B. SE 550/15 images show T1 shortening in the dorsal brain stem 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.
Examples of resting-state networks, also known as intrinsically connected networks, computed from ICA of BOLD fMRI at
3T are shown in Figure 2-35. More than a dozen such cortical networks have been identified in the human brain to date
(280,281). 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
(282,283).
Resting-state fMRI has begun to be used in the research setting to investigate the process of human brain development,
although the authors’ search of the literature suggests that it is used more in psychiatric than neurologic diseases (284); child
neurology studies have been performed mainly to assess regional brain function in epilepsy and effects of neonatal injury
(285,286). The hypothesis 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 abnormalities 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
premature infants scanned at term-equivalent age (287), indicating that cortical 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 cortical regions of the two
cerebral hemispheres (288). The DMN could not be detected in premature newborns but was identified in term-born infants
(288). 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 (289). 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 (290). 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 reported that children
showed more short-range functional connectivity and less long-range functional connectivity than adults (291). 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 development from more local to more distributed. However, research into the
development of brain networks using functional connectivity information 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.
Figure 2-35 Resting-state functional MRI (fMRI) 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. Independent
component analysis of resting-state fMRI reveals correlated BOLD activity of bilateral regions of the posterior cingulate and adjacent
precuneus, inferior parietal lobules, ventromedial prefrontal cortex, and lateral temporal cortex. These comprise the default mode network,
those areas that are maximally activated in the resting state. B. Independent component analysis of resting-state fMRI reveals correlated BOLD
activity of bilateral regions of the occipital lobes corresponding to visual cortex. C. Independent component analysis of resting-state fMRI
reveals correlated BOLD activity of bilateral regions of the superior temporal gyri corresponding to auditory cortex. D. Independent component
analysis of resting-state fMRI reveals correlated BOLD activity of bilateral perirolandic regions corresponding to motor and somatosensory
cortex.
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Metabolic, Toxic, and Autoimmune/Inflammatory Brain
Disorders
A. James Barkovich and Zoltan Patay
Introduction
Imaging Techniques in Metabolic Disorders
A Simple Pattern Approach to Metabolic Disease
White Matter Versus Gray Matter
White Matter Disorders
Gray Matter Disorders
Disorders Affecting 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, which impairs the function 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; 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 protein that is necessary
for normal function of a metabolic pathway or from formation of an abnormal protein that disrupts normal function or is
otherwise, directly or indirectly, toxic to the brain. Sometimes, the disruption of metabolism (usually fetal, occasionally
maternal) affects in utero brain development, resulting in a malformation (Table 3-1). Much more typically, however, toxic
chemicals are removed and necessary chemicals supplied via the placenta; thus, the brain forms normally and 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 metabolic 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 diseases that affect the nervous system, often present with nonspecific
behavioral, cognitive, psychiatric, or neurologic dysfunction and subtle imaging findings that can be difficult to diagnose
without a high index of suspicion, while diagnosis of brain injury from radiation or chemotherapy can usually be suggested if
the history of treatment is known. In all of these groups, a combination of a good history combined with clinical, laboratory,
and imaging findings is necessary to make the diagnosis.
The diagnosis of the disorders discussed in this chapter is challenging 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 cognitive and behavioral disorders, hypotonia, seizures, spasticity, ataxia, movement disorder, delay in achieving
developmental milestones, or focal neurologic deficits. The imaging study is most often suggestive of a certain type of disorder
—impaired development, focal or diffuse injury, degeneration, or inflammatory injury—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, 40% to 50% of children with inborn metabolic errors never receive a specific diagnosis despite
extensive investigations (1,2). Even if a diagnosis is made, the expectations for outcome may be uncertain, as the precise
distinctions among the various mitochondrial disorders or the various autoimmune inflammatory disorders are far from clear,
especially in children (3–7).
In order to establish a diagnosis, some method of organizing the diseases from an imaging perspective is helpful, as
narrowing the differential diagnosis facilitates the clinical workup, saving time and expense. In the future, all of these
disorders may be diagnosed, classified, and treated according to how specific gene mutations affect the activity of their protein
products in the various metabolic pathways in which that protein is involved. However, our understanding of genetics,
epigenetics, and metabolic pathways is not yet good enough to accomplish these goals. Therefore, we are a long way from a
useful classification of these diseases.
Table 3-1 Malformations of the CNS Described in the Context of Inborn Errors of Metabolism
Cerebral dysgenesis Glutaric acidemia type 2 (warty protrusion of the surface of the cerebral cortex)
Neonatal carnitine palmitoyltransferase 2 deficiency
In this chapter, the disorders are classified by the most typical MR pattern of brain involvement, which frequently coincides
with the initial clinical presentation. Discussion will center mainly on the pattern of brain involvement (“pattern recognition”),
as detected by morphologic MRI, diffusion imaging, susceptibility-weighted images, and proton MR spectroscopy (MRS)
(Table 3-2). Perfusion imaging (using PcASL; see Chapter 1) may be useful in selected patients. By proper neuroimaging
analysis of the early pattern of brain involvement, many disorders may be identified and differentiated from others with similar
clinical presentations (1,8). It is important to recognize that the patterns of injury are dynamic (they change over time). Initial
imaging findings may be very subtle or may not be detected until the disease progresses. Moreover, many
toxic/metabolic/inflammatory brain disorders may have a nonspecific imaging appearance, particularly if imaged early
(nonspecific white matter changes) or in the late stages (diffuse white matter injury or diffuse atrophy) of the disease.
Therefore, if magnetic resonance is to have a role in the diagnosis of inborn metabolic errors, the study should be performed
early in the course of the disease and it should include T1- and T2-weighted images, T2 FLAIR imaging, susceptibility-
weighted imaging (SWI, to detect calcium and iron), diffusion imaging, and proton spectroscopy. Follow-up studies should be
performed if the disorder progresses.
MTR − − − −− NL
T2 + + ++ +++ NL
Dav NL + ++ +++ NL
FA − −− −−− −− NL
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.
After van der Voorn JP, Pouwels PJW, Hart AAM, et al. Childhood white matter disorders: quantitative MR imaging and spectroscopy. Radiology
2006;241:510–517.
Another important concept concerns the definition of the disease. In the past, diseases were defined by the clinical
phenotype: How did the patient present and progress? In the early 21st century, the definition changed, and the diseases began
to be defined by the genotype. Recently, however, it has become clear that different mutations of the same gene can cause
different phenotypes. An excellent example of this is seen in mutations of GFAP. Some patients with GFAP mutations develop
macrocephaly in infancy and have severely impaired early neurodevelopment caused by edematous changes of the frontal lobes
and basal ganglia; this is called infantile Alexander disease. Other patients with GFAP mutations are normal until adulthood,
when they develop slowly progressive medullary and spinal cord degeneration; this is called adult Alexander disease. Clearly,
these are two different diseases caused by different mutations of the same gene. As our knowledge of genetics and metabolic
pathways improves, we see this phenomenon more and more commonly. It is particularly true in mitochondrial disorders,
where the maternal inheritance of mitochondria results in very different mutations of patients with similar phenotypes and very
different phenotypes of patients with similar mutations (4,9–11).
The first part of this chapter is a listing of many toxic/metabolic/inflammatory disorders based solely upon their imaging
characteristics; 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 overview 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 (39), Epstein et al. (44), Valle et al.
(45), or Saudubray et al. (46).
Table 3-3 Disorders Involving White Matter Only (References Given for Some Disorders Not Otherwise Discussed in the Chapter)
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. Succinate dehydrogenase deficiency
f. Profound neonatal hypotensive encephalopathy
g. 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—cavitary, 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
3. Primarily striatal involvement
a. Leigh syndrome (frequent inferior olivary and subthalamic nuclei)
b. MELAS—usually cortical involvement
c. Wilson disease (thalami later)
d. Alexander disease (with frontal white matter)
e. Ethylmalonic acidemia (39)
f. Propionic acidemia (39)
g. Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency)—with anterior temporal lobe hypoplasia
h. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (39)
i. Molybdenum cofactor deficiency (often cerebral cortex) (40)
j. Mitochondrial ATP synthetase deficiency (39)
k. 3-Methylglutaconic aciduria (incomplete striatal injury) (41)
l. Beta-ketothiolase deficiency (39)
m. Malonic acidemia (39)
n. Biotinidase deficiencies (39)
o. Biotin-responsive basal ganglia disease (42)
p. Toxins (39)
q. Hypoxic–ischemic injury in older child or adult
r. Hypoglycemic injury in older child or adult
s. Cockayne disease (43)
t. Hypomyelination with atrophy of basal ganglia and cerebellum—often with atrophic caudate, putamen, and cerebellum
References given for some disorders not otherwise discussed in the chapter.
Age of Onset
The age of onset of metabolic diseases is a very useful clinical pattern element. Depending on the 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–3 years), early and
late childhood–juvenile (3–6 and 6–16 years), and adult (16 and over). It is important to recognize that the onset of
recognizable clinical signs and symptoms does not necessarily correspond to the onset of the metabolic derangement.
As a clear manifestation of their considerable phenotypic variations, almost all neurometabolic diseases have several
clinical forms depending on the age of onset. Within the same disease category, earlier onsets usually suggest a more profound
derangement of the affected metabolic pathway(s), whereas later onset often reflects clinically milder (but not necessarily
benign) variants. Most metabolic disorders of neonatal onset fall into the category of so-called devastating metabolic diseases
of the newborn. The underlying metabolic disturbances 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 “devastating 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 (hypo- or hypertonia)
are common. If the disease is not diagnosed and treated promptly, the progressive toxicity leads to irreversible neurological
deficit or death. Most devastating metabolic diseases of the newborn are organic or aminoacidopathies (Table 3-6).
If a “devastating metabolic disease” is suspected in a newborn or young infant, in addition to anatomical MR imaging,
advanced MR techniques are useful. Diffusion-weighted imaging may be pathognomonic in MSUD; MRS may be diagnostic in
some disorders (HMG coenzyme A lyase deficiency (59) and glycine encephalopathy (60)) or suggestive in energy metabolism
disorders (elevated lactate) and urea cycle defects (increased glutamate).
Propionic acidemia
Methylmalonic acidemia
Isovaleric acidemia
Pyroglutamic aciduria
Menkes disease
Nesidioblastosis
Maple syrup urine disease Congenital disorders of glycosylation Creatine transporter deficiency
Menkes disease
Peroxisomal disorders
Stroke-like events associated with metabolic disorders probably represent episodes of regional metabolic decompensation
with subsequent functional disturbances within brain parenchyma, which may or may not lead to permanent structural damage.
Stroke-like episodes with hemiparesis or hemianopsia are characteristics of some disorders caused by mutations of one of
several mitochondrial genes; these are commonly referred to as mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes (MELAS, OMIM #540000). Occasionally, extrapyramidal movement disorders (dystonia,
choreoathetosis, or tremor) may develop suddenly and mimic stroke, typically in organic acidurias (e.g., glutaric aciduria type
1, methylmalonic acidemia), and are usually associated with severe basal ganglia disease, 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. Nonketotic hyperglycinemia (also called glycine encephalopathy, OMIM 605899) and propionic academia (OMIM
606054) can cause hypotonia as a result of increased blood glycine levels, caused by the inhibitory effect of glycine on spinal
ventral motor neurons. In fatty acid oxidation disorders, and perhaps in many of the mitochondrial cytopathies, affected
children are hypotonic because of associated myopathy. Hypertonia is typical of Krabbe disease and methylmalonic and
isovaleric acidemia, while muscle contractures are seen in rhizomelic chondrodystrophia punctata. Alternating muscle tonus
(hypo- and hypertonia, presenting with opisthotonos) is typical of MSUD.
Figure 3-1 Metachromatic leukodystrophy. A. Axial T2-weighted image shows abnormal hyperintensity in the deep and periventricular white
matter; the subcortical white matter (white arrowheads) is spared. Note the nearly horizontal stripes of relatively spared (darker) white matter
(white arrows). B. Axial diffusion-weighted image shows patchy abnormal hyperintensity of the white matter, indicating reduced diffusivity. C.
Axial postcontrast T1-weighted image in a different patient shows enhancement (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).
DTI may be useful in the early diagnosis of Krabbe disease, because affected neonates have significantly lower FA than
age-matched controls (102). Diffusion-weighted images show reduced diffusion early in the course of the disease in areas of
active inflammation/demyelination, 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 (81,82). Other studies have
shown, not surprisingly, reduced FA and increased RD in affected regions of white matter (92).
Few reports of proton MRS of patients with Krabbe disease have been published. In infantile Krabbe disease, reports show
marked elevation of choline and myo-inositol, moderate elevation of creatine, moderate to marked NAA reduction, and
inconsistent lactate elevation in the white matter (Fig. 3-2F); these changes were less marked in gray matter (103–105). 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 “macromolecular peaks,” broad peaks centered at 0.9 and 1.3 ppm
(Fig. 3-2F). Changes in juvenile Krabbe disease were much less marked and consisted mainly of elevated myo-inositol in
white mater and normal spectra of gray matter (104). In adults, MRS of white matter shows mild decrease in the concentration
of NAA and mild elevations of creatine, choline, and myo-inositol (87,104).
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 (106,107).
About 40% of male children with these mutations will convert to the rapidly progressive inflammatory demyelinating condition
that we recognized as childhood adrenoleukodystrophy (108). Recent work suggests that ABCD1 is highly expressed in human
brain microvascular endothelial cells and that silencing of the ABCD1 gene in these cells results in upregulation of adhesion
molecules and decrease in tight junction proteins (109); the result of this is greater adhesion and transmigration of monocytes
across the endothelium and blood–brain barrier (109), with a possible secondary failure of oligodendrocytes (110). Whatever
the mechanism (a topic of active research), plasma analysis for very long-chain fatty acids is the best initial biomarker for the
disease, allowing unambiguous diagnosis in males (although false-negative results are found in about 20% of obligate
heterozygote carriers (111,112)). So far, more than 500 different mutations of the ABCD1 gene have been described (112);
despite decades of research, there is no clear correlation between location of the mutation and phenotype (110,113).
Histologically, this disorder is characterized by two major pathophysiologic components, a severe inflammatory
demyelination that predominates in the cerebral white matter and an axonal degeneration that predominates in the posterior
fossa and spinal cord (114). The axonopathy and inflammation are associated with accumulation of very long-chain fatty acids
in the nervous tissue; normal cells are protected by plasmalogens (structural phospholipids in nervous tissue), but
plasmalogens are also affected in many patients with ABCD1 mutations (115). Pathologic analysis shows three different zones
of white matter involvement are identified within the cerebrum; these are identifiable by MRI as discussed in the imaging
section below. A central burned-out zone (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 MRS is performed (116).
Although many different clinical forms of adrenoleukodystrophy have been described (Table 3-8) (117,118), 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 demyelination of the cerebrum. Affected patients are almost exclusively boys, who usually present between
ages 5 and 12 years (mean 7.2 years) (117); all ethnic groups are affected with no apparent difference in frequency (112).
Many children present with learning difficulties at school and are initially given a diagnosis of attention deficit hyperactivity
disorder. Other early features of the disorder include impaired visuospatial 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 present acutely with
seizures, acute adrenal crisis, acute encephalopathy, or coma (119). Progression of this form of the disease is usually fairly
rapid and may be associated with moderate to severe head trauma (120). 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 (121–123).
Figure 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 hyperintensity of the pontine corticospinal tracts (white arrows). E
and F. Axial T2-weighted images show more pronounced involvement of the corticospinal tracts (small arrows, compare with A–C), increased
extent of white matter involvement in the periventricular and deep cerebral white matter (large arrows in E and F), and loss of volume (enlarging
sulci and ventricles, with diminished white matter volume compared to B and C). G–I. Axial T2-weighted images show resorption of damaged
tissue. Hyperintensity of the corticospinal tracts is no longer visible in the pons and the volume of white matter in the parietal lobes (H and I) is
much reduced. Note the posterior insular cortex (black arrows in H and I) abutting the ventricular walls.
Table 3-8 Phenotypes of X-ALD Carriers
Asymptomatic (MRI Patients between 2 and 10 y old. Usually initially diagnosed as another leukodystrophy Increasing as
abnormal) diagnostic tests
improve
Cerebral (mild) without Patients usually between 3 and 10 y, but up to 21 y. Present with behavior changes, school failure, and 45%
adrenomyeloneuropathy dementia. Typically initially diagnosed as ADHD, autism, or Asperger syndrome
(AMN)
Cerebral (severe) Onset between 5 y old and adulthood. Progressive behavioral, cognitive, and neurologic (epilepsy, visual 2%–3%
without AMN 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 Onset 28 ± 9 y. Paraparesis, sphincter disturbances, sensory changes, incoordination, pain, impotence. 35%
adrenomyeloneuropathy Progressive over decades. Involves primarily spinal cord with loss of myelin but minimal or no inflammatory
(AMN) 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 disturbances, psychosis, epilepsy, aphasia, visual 15%
involvement loss bulbar palsy
Cerebellar Cerebellar/brain stem involved in adolescence or adulthood. Patients present with ataxia, cranial 2%–3%
neuropathies, or long tract signs
Addison only Onset usually before 10 y. Adrenal insufficiency without neurologic signs or symptoms. Rarely brain MRI 20%
abnormal
Asymptomatic Biochemical and gene abnormality without demonstrable adrenal or neurologic deficit. ~50% will become Common <4 y
symptomatic within 10 y. Rare >40 y
Mild myelopathy Increased deep tendon reflexes and distal sensory changes in lower extremities Increases with
age. ~30% of
women >40 y
Moderate to severe Resembles AMN, but later onset and milder Increases with
myeloneuropathy age. ~15% of
women >40 y
Cerebral involvement Rare in childhood. Slightly more common in middle age or later ~2%
Source: Adapted from Moser HW, Raymond G, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 2005;294:3131–
3134.
The other major form of this disorder is characterized mainly by axonal degeneration in the brain stem and spinal cord; this
form is called adrenomyeloneuropathy (AMN) (124). Adrenomyeloneuropathy typically presents in young adults (mean age 28
years) with incontinence, progressive paraparesis, or progressive cerebellar dysfunction (118); peripheral neuropathy may be
detected (112). Affected patients can develop inflammatory demyelination in the cerebrum at any age; this often (in 63% of
males with AMN in a recent study (125)) occurs in the third or fourth decade, about 10 years after the onset of the
spinal/cerebellar dysfunction, and is referred to as “cerebral AMN” (112). 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
(118,126). 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.
Imaging studies show several characteristic patterns. Eighty percent of affected patients with cerebral ALD have
predominant posterior white matter involvement (127); the first area affected in this group is the middle of the callosal
splenium and/or hippocampal commissure (Figs. 3-4 and 3-5). CT reveals low attenuation starting in the splenium of the
corpus callosum and extending into the deep and (subsequently) 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. 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 (128), characteristically with enhancement of the inflammatory leading edge of demyelination (Zone B,
Fig. 3-4C) if paramagnetic contrast is administered. The enhancing areas typically show reduced diffusivity (Fig. 3-4D)
because of the increased cellularity resulting from the inflammatory infiltrate. The presence of contrast enhancement seems to
be associated with clinical worsening of the disease (129) and with more guarded prognosis after treatment with hematopoietic
stem cell transplantation (HSCT) (130). In early phases of the disease, the subcortical white matter is spared on standard
imaging sequences (Figs. 3-4 and 3-5) (57,58), but DTI may show mildly increased water diffusivity and reduced anisotropy
(128). The corticopontine and corticospinal tracts in the pons and medulla often show T2 hyperintensity (Fig. 3-6) (131) and
enhancement. The splenium of the corpus callosum appears low signal intensity on the midline sagittal, T1-weighted image
(132); in chronic disease, it is small and atrophic. Less common patterns have been described (58,133,134), including
calcification in the parietooccipital white matter.
The second most common pattern is predominantly frontal involvement (Fig. 3-7) (135), seen in about 15% of affected
patients (127). In this pattern, the genu of the corpus callosum, frontal white matter, anterior limbs and genus of the internal
capsules, and, occasionally, the cerebellar white matter are predominantly involved. Contrast enhancement is seen on the
peripheral margins (Zone B), as in the posterior form. Other patterns include predominantly unilateral involvement restricted to
an entire hemisphere, both frontal and occipital (involving both callosal splenium and genu; Fig. 3-6) (136), and a pattern with
supratentorial involvement restricted to the genus of the internal capsules (131).
Figure 3-4 Adrenoleukodystrophy; classic imaging appearance. A. Axial noncontrast CT shows low attenuation in the callosal splenium (s),
peritrigonal white matter (p), and posterior thalami (t). B. Axial FLAIR image shows abnormal hyperintensity involving the callosal splenium,
posterior periventricular and deep white matter (sparing subcortical white matter), posterior thalami, and posterior aspect of the posterior 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 inflammatory zone is slightly hyperintense (white
arrowheads), indicating reduced diffusivity; note that administration of contrast is not necessary to detect inflammation! 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).
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 (126).
Proton MRS shows decreased NAA; increased choline, glutamine, and glutamate; decreased myo-inositol; and increased
lactate resonances in areas of active disease (137,138). In more chronic disease, or with longer echo times, findings may be
limited to low NAA and elevated choline (Figs. 3-4 and 3-7). MRS shows abnormalities before the MR imaging study
becomes abnormal in some children (137) 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 (139). Therefore, proton MRS should be
performed in all individuals with ALD, particularly in those with stable MR imaging 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 (126).
Figure 3-5 Evolving ALD. A. Sagittal FLAIR image shows hyperintensity (white arrow) localized to the mid callosal splenium. B. Axial T2 image
shows abnormal hyperintensity (white arrows) localized to the central splenium. C. Axial ADC map shows central splenial hyperintensity
(increased water motion) with some hypointensity (arrows), suggesting some inflammatory cells, in the tissue surrounding it. D. Postcontrast
axial T1 image shows enhancement in the periphery of the splenium, supporting the presence of inflammation. E and F. Sagittal FLAIR images
8 months later shows that the area of splenial involvement (arrows) has more than doubled in size and extending beyond the callosum. G and
H. Arrows on axial ADC (G) and postcontrast T1 images (H) show more reduced diffusivity (G) and more extensive and diffuse enhancement
(H), all compatible with progression of disease.
Figure 3-6 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 (white arrows) of both the genu and splenium of the corpus callosum. D. Coronal T2-weighted image shows
extension of abnormal hyperintensity from the internal capsules (white arrowheads) inferiorly into the pontine corticospinal tracts (black arrows).
The imaging findings in adrenomyeloneuropathy (Fig. 3-8) 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 brain stem) are more commonly involved (Fig. 3-8) (108,124). Lesion progression appears
to be slower than in ALD (108). No inflammatory component is present (when inflammation develops, the diagnosis changes to
ALD) and, therefore, no enhancement is seen.
No extensive radiologic differential diagnosis exists for the classic pattern of ALD. Another peroxisomal disorder, acyl-
CoA oxidase deficiency, 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 (140). However,
the clinical presentation is quite different, as both boys and girls are affected, often with delayed cognitive and motor
development, followed by developmental regression during the third year of life (140).
Leukoencephalopathy with vanishing white matter
Leukoencephalopathy with vanishing white matter (VWM, OMIM 603896, also called childhood ataxia with diffuse central
nervous system hypomyelination, CACH) is a disorder in which patients typically have normal development in early childhood
and then develop progressive ataxia and spasticity with relapsing–remitting phases, development of bulbar symptoms, variable
optic atrophy, and epilepsy (141,142). Involvement of the peripheral nervous system is uncommon (141).
Figure 3-7 Atypical adrenoleukodystrophy with predominant frontal involvement. 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.
Figure 3-8 Adrenomyeloneuropathy. A. Axial T2-weighted image through the midpons shows abnormal hyperintensity in the lateral pons
(arrowheads) and cerebellar white matter (small arrows). B. Axial FLAIR image at the level of the bodies of the lateral ventricles is normal.
Onset of VWM usually occurs from early childhood to early adulthood (143,144) or even middle age (145); rarely, patients
may present as neonates (146) or infants/fetuses with severe encephalopathy and rapidly fatal courses (146,147). The disorder
previously known as Cree leukoencephalopathy (148) is an early form of VWM, with onset between 3 and 9 months (147);
affected children typically present with abnormalities of tone (hypotonia or spasticity) and then progress to seizures, posturing,
and death within a few months (148). In the childhood and adult-onset forms of VWM, normal or mildly delayed early
development is followed by episodes of deterioration, often after episodes of trauma or infection (142,149,150) or sometimes
fright (151). Rarely, extreme macrocephaly may develop (152,153). Analysis of CSF, serum, or urine may show elevation of
glycine (154). Adult variants are also described, usually presenting in the teenage years or twenties with occasional seizures
or psychiatric symptoms or dementia (155); some affected adult women have associated ovarian failure (156).
This autosomal recessive disorder can be caused by mutations in any of the five genes encoding subunits of the eukaryotic
translation initiation factor eIF2B guanine exchange factor: eIF2B1 at 2p23.3, eIF2B2 at 14q24, eIF2B3 on chromosome 12,
eIF2B4 at 1p34.1, or eIF2B5 at 3q27 (29,157). The mechanism of cell injury is incompletely understood but is believed to be
related to stress conditions (heat stress, head injury) that result in a reduction in protein synthesis within affected cells
(141,155); glial cells appear to be selectively vulnerable. The effect of the mutation on the function of the protein probably
determines the severity of the disease (155,158); most patients have residual guanine exchange factor activity of 30% to 80%,
while carriers have normal activity (159).
Diagnostic criteria, as suggested by van der Knaap et al. (142,143), include the following: (a) There is normal or mild
delay of initial motor and mental development. (b) Neurologic deterioration has a chronic progressive 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 spasticity. 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 3-9.
On histopathologic analysis, affected brains shows axonal loss, hypomyelination, demyelination, gliosis, and “foamy”
oligodendrocytes, primarily in the deep white matter (149,160,161). The cortical gray matter, subcortical U fibers, corpus
callosum, and internal capsules are relatively spared (160,161). 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 tegmental tract and the superior central nucleus on both sides. Whereas
some studies suggest that this is a primary axonopathy, with myelin being secondarily affected (143), others suggest a primary
disease of oligodendrocytes, resulting in excessive oligodendroglial apoptosis with secondary axonal degeneration
(141,160,161) or impaired astrocyte function (162).
MR imaging shows diffuse white matter signal abnormality (T1 hypointensity and T2 hyperintensity) in which the white
matter ultimately cavitates to become CSF intensity on T1- and T2-weighted images (Figs. 3-9 and 3-10). Diffusivity is
variably reduced compared to CSF on diffusion-weighted images; tissue in the process of cavitating has reduced diffusivity
(163), whereas cavitated white matter has increased diffusivity, with signal identical to CSF (Fig. 3-10). Cavitated (cystic)
white matter is hypointense on FLAIR and proton density images and thus can be differentiated from the hyperintense rarefied
(but noncavitary) white matter (Fig. 3-9). Subcortical axons may be spared at the time of presentation (Fig. 3-9B).
Degeneration to CSF intensity starts in the central white matter (Fig. 3-10) but eventually involves the entirety of the white
matter in the cerebrum; only the ventricular lining is spared at this point (Fig. 3-11). 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. 3-11), but cavitation is not seen in the cerebellum or brain stem (155). Cerebellar atrophy
varies from mild to severe and primarily involves the vermis (142). In the brain stem, abnormal hyperintensity is seen initially
in the pontine central tegmental tracts but ultimately involves the ventral pons as well (143,164). Later stages of involvement
are characterized by nearly complete loss of white matter, with ex vacuo ventricular enlargement.
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.
When presentation is in neonates, the initial MRI may be normal (163) or the cerebral gyri may appear slightly broader than
normal, indicating either delayed sulcation or slight white matter swelling (Fig. 3-12) (146,155); 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) (165). On proton density
and FLAIR images, white matter signal intensity is lower than normal in some regions of cerebral white matter, suggesting
white matter rarefaction, and possible impending cystic degeneration. No evidence of myelination is seen at term.
Figure 3-9 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 appreciate 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.
Proton MRS is normal early in the disease. As rarefaction and cavitation ensue, white matter spectra show a progressive
decrease and, ultimately, complete disappearance of all “normal” signals; some lactate and glucose remains and may become
more evident as the amplitude of the other signals decreases (142,149,150). NAA progressively decreases, whereas Cr is
decreased but stable (83). Cortex maintains a more normal spectrum, apart from a decrease in NAA and a variable elevation of
lactate and glucose (143,150,166).
Giant axonal neuropathy
Giant axonal neuropathy (OMIM 256850) is a rare, autosomal recessive chronic polyneuropathy caused by a disorder of
cytoplasmic intermediate filaments that results in the accumulation of ovoid aggregates in many different cell types (167). The
responsible gene (GAN1) has been mapped to chromosome 16q23.2 and encodes a ubiquitously expressed protein that has
been named gigaxonin (168,169). Affected patients initially present in childhood with features of a peripheral sensory and
motor neuropathy and extremely curly hair (170). However, central nervous system involvement is an important component of
the disease (171,172). Typically, muscular hypotonia is noticed early in life, along with delayed motor development. Walking
may be eventually achieved but is broad based and ataxic, and then regresses until the child becomes wheelchair bound.
Ultimately, the neurologic exam shows hypotonia, muscle weakness and wasting, absent reflexes, and contractures. Optic discs
are pale, and visual acuity is diminished. Variability is seen, even among patients with the same mutation (173).
Imaging is nonspecific, showing T1 and T2 prolongation of the white matter, with sparing of the subcortical U fibers in both
the cerebrum and cerebellum. The posterior limbs of the internal capsules are commonly involved early (Fig. 3-13A), as is the
cerebellar white matter (Fig. 3-13B). On noncontrast T1-weighted images, the ependymal lining of the lateral ventricles is
often hyperintense compared to surrounding white matter (39). Later in the course of the disease, the corticospinal tracts in the
brain stem show T2 hyperintensity and will enhance after paramagnetic contrast administration (39). Thus, this disease has an
MR appearance somewhat similar to X-linked adrenoleukodystrophy. Thalami may show T2 hyperintensity (174). MRS shows
reduced NAA but increased choline and myo-inositol (175). Creatine values are roughly normal.
Figure 3-10 Severe vanishing white matter disease in a 14-year-old adolescent. A. Sagittal T1 image shows a paucity of white matter and
ventriculomegaly. Note cavitating white matter (white arrows) in the frontal lobe. B. Axial FLAIR image shows multiple foci of CSF-intensity
cavitation (white arrows) in abnormally hyperintense white matter. C. Axial ADC map shows varying degrees of hyperintensity in the abnormal
white matter. The very hyperintense frontal white matter (black arrows) has diffusivity identical to CSF; the degree of hyperintensity reflects the
loss tissue structure as cavitation progresses.
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 12q23.2 (176). This mutation causes phenylalanine hydroxylase (PAH) deficiency, although
other biochemical defects can cause hyperphenylalaninemia and manifest similar signs and symptoms (177,178). A report in
2007 calculated a total of 548 mutations of the PAH gene have been identified (179,180), partially accounting for the marked
clinical, biochemical, and neuroimaging variability. In addition, about 2% cases are caused by mutations of genes encoding
enzymes that control synthesis and recycling of tetrahydrobiopterin (BH4) (181). Most PAH missense mutations cause
misfolding of the PAH protein, resulting in increased protein turnover and loss of enzymatic function (180), with consequent
production of compounds (phenylpyruvic and phenylacetic acids and phenylacetylglutamine) that are toxic to the developing
brain (74,182). Untreated patients are characterized by growth retardation, global developmental delay, eczematous dermatitis,
hypopigmentation, and a peculiar musty odor of the urine, skin, and hair (176,182). Treatment is by dietary control and,
occasionally, dietary supplements (182–184); benefit from control of diet is variable, probably due to the heterogeneity of the
disease.
Imaging studies show primarily abnormally increased water in the periventricular white matter, corresponding to delayed
and defective myelination. In older patients, ventriculomegaly develops as a result of white matter degeneration (185). MR
shows T2/FLAIR hyperintensity that is initially seen in the periventricular white matter of the cerebral hemispheres (Fig. 3-14)
(74,186). 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 (187). In the acute phase, diffusion is reduced in the affected white matter,
possibly due to spongiotic changes of myelin (188); some studies suggest a relationship between the serum phenylalanine level
and degree of reduced diffusion (189). Contrast enhancement has not been reported. The volume of the cerebral hemispheres is
reduced (190).
In the minority of cases caused by dihydropteridine reductase deficiency or defect in the synthesis of BH4, the frontal
cortex, occipital cortex, subcortical white matter, and putamina are affected. Putaminal and frontal/occipital subcortical
calcification is often seen in these cases on CT (176). MR imaging shows cortical and subcortical atrophy, particularly in the
intervascular boundary zones (“watershed zones”) (39). T1 shortening (T1 hyperintensity) may be present in damaged regions
of cortex.
Figure 3-11 End-stage vanishing white matter disease. Axial (A) and coronal (B) FLAIR images show enlarged ventricles and minimal
remaining very hypointense white matter (white arrows).
Figure 3-12 Vanishing white matter disease in an infant. Axial T2-weighted images (A and B) show abnormal white matter hyperintensity and
volume of white matter with widening of posterior gyri due to increased interstitial water. (Images are courtesy of Prof. Nancy Fischbein,
Stanford, CA).
Proton MRS shows the presence of a peak from elevated phenylalanine at 7.37 ppm (187,191). The size of this peak may be
useful for monitoring treatment, although it is currently not trivial to assess this peak, which is far “downfield” on most clinical
MR scanners. Other peaks seem to be normal. Diffusion imaging reveals reduced diffusivity of water in the affected regions of
the brain (188) in younger children while it shows increased diffusivity and increased FA (indicative of tissue damage) in the
deep parietal and occipital white matter in children older than 3 years (192).
Maple syrup urine disease
Maple syrup urine disease (OMIM 248600) is a genetically heterogeneous disorder; the three known causative genes
(BCKDHA at 19q13.2, BCKDHB at 6q14.1, and DBT at 1p21.2) 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 (193). Treatment requires lifelong dietary restriction and monitoring of branched-chain amino
acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of
catabolic stress associated with nonspecific illness (194). The mechanisms 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 (195). 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 (182). If the disease is not recognized and treated,
infants develop signs of increased intracranial pressure, become comatose, and may die in a few weeks (196). The severity of
neurologic sequelae is strongly correlated with the duration of the acute toxic phase in the neonatal period (197). The less
severe forms of the disease, with higher residual enzymatic activity, can present later in childhood with metabolic crises
resulting in lethargy, irritability, nausea, and vomiting that may progress to stupor or coma (196).
Figure 3-13 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 are courtesy of Dr. Susan Blaser,
Toronto.)
Figure 3-14 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.
Imaging is normal in the first few days of life. Because classic MSUD 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 periventricular white matter, basal ganglia, and thalami in the
acute stage (198). The CT and MR findings are quite characteristic, revealing profound localized edema (low density on CT,
hypointense T1, hyperintense T2/FLAIR on MR) in the deep cerebellar white matter, dorsal brain stem, cerebral peduncles,
posterior limb of the internal capsule, sensorimotor tracts in the centrum semiovale, and, sometimes, globi pallidi (Fig. 3-15A–
D) (74,199). 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 abnormalities (200), particularly in the
first weeks of life. Diffusion imaging may be very useful at this stage of the disease, as the areas with (intramyelinic (201))
MSUD edema (cerebellar white matter, dorsal brain stem, cerebral peduncles, corticospinal tracts, and globi pallidi) show
reduced diffusivity during the acute phase of the disease (Fig. 3-15E–G), with ADC values falling to 20% to 30% of their
normal values (202). When relapses occur after the brain has fully or nearly fully myelinated, reduced diffusion will be seen in
most of the white matter of the cerebral and cerebellar hemispheres (200), 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 (182,199).
Figure 3-15 Maple syrup urine disease, neonatal form. 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 brain stem (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 show reduced diffusivity in the brain stem (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.
Figure 3-16 Maple syrup urine disease, infant form, during an exacerbation of disease. A. Axial FLAIR images show high signal intensity in
periphery of ventral pons and in pontine tegmentum (white arrows) as well as in peripheral cerebellar white matter (black arrows). B. At the
basal ganglia level, high signal intensity is seen in the callosal genu (white arrows) and the white matter between putamina and globi pallidi
(black arrows). C. Diffusion-weighted image shows slightly reduced diffusivity in the same regions (white arrows) as the increased FLAIR
signal.
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 superimposed upon damage to the dorsal brain stem,
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 (Fig. 3-16). From the imaging perspective, the intermittent form of MSUD may
resemble early Canavan disease (including diffusion findings, 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 MSUD shows slight reduction of NAA and slight elevation of
lactate; these abnormalities disappear after treatment. More importantly (and more specific), a somewhat broad peak at 0.9
ppm (Fig. 3-16H and I) is also present, on both long and short echo spectra; it is believed to represent resonances of methyl
protons from branched-chain amino acids and branched-chain alpha ketoacids that accumulate as a result of defective oxidative
decarboxylation of leucine, isoleucine, and valine (203,204). 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 a sharper peak than the macromolecule peak and it is
present on both long echo (TE = 270–288 ms; Fig. 3-15I) and short echo spectra (Fig. 3-15H) (203). 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). Homocysteine may be either recycled into methionine (remethylation pathway) or catabolized into
cystathionine, cysteine, and sulfate (transsulfuration pathway). The three key enzymes involved in the pathogenesis of
hyperhomocysteinemia are cystathionine beta-synthetase (on the transsulfuration pathway), methionine synthetase (also
known as 5-methylhydrofolate:homocysteine methyltransferase), and 5,10-methylene 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 deficiency (“classic” homocystinuria), methionine synthetase deficiency, folate deficiency, defect of folate metabolism
(5,10 methylene tetrahydrofolate reductase deficiency), cobalamin (vitamin B12) deficiency, and defects of cobalamin
metabolism (methionine synthetase deficiency in isolated methylcobalamin and combined methyl- and adenosylcobalamin
deficiencies) (205).
The major clinical manifestations of hyperhomocysteinemia are ophthalmological (lens dislocation), vascular (steno-
occlusive arterial and venous disease), and neurological (demyelination in brain and spinal cord).
Cystathionine beta synthase deficiency
Cystathionine beta synthase deficiency (OMIM 236200) is caused by mutations in the cystathionine beta synthase (CBS) gene at
21q22.3. The resulting biochemical 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), prevents small arteries from dilating (increasing likelihood of obstruction), and causes proliferation of smooth
muscle cells in arterial walls (206). Patients have characteristic clinical abnormalities, including dislocation 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 retardation, seizures, and dystonia. Outcome is markedly improved in
vitamin B6–responsive patients and nonresponsive patients who are compliant with treatments (207). In most cases,
neuroimaging studies reveal multiple small infarcts of different ages throughout the brain. Demyelination, white matter
vacuolization, and spongy degeneration have been observed only rarely (176,208); this phenotype may result in increased
intracranial pressure, with MRI findings of diffuse white matter edema with T2 hyperintensity and reduced diffusivity of the
cerebral white matter and globi pallidi, effacement of sulci, and papilledema (209).
5,10 Methylenetetrahydrofolate reductase deficiency
5,10 Methylenetetrahydrofolate reductase deficiency (MTHFRD) (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 (210). There is a direct correlation between methylenetetrahydrofolate
reductase activity in fibroblasts and clinical severity of the disease (211). This disorder has less pronounced vascular
pathology than cystathionine beta synthase deficiency and cerebral infarcts are rare; however, children with abnormal MTHFR
activity may be predisposed to cerebral infarction (212), particularly due to venous thrombosis (213). Patients with this
disorder most commonly present 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 (214). 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 childhood stroke) and for cervical
arterial dissections (215). Treatment with betaine, folic acid, and cobalamin is recommended to prevent or mitigate symptoms
(216).
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 commonly, demyelination of the dorsal and lateral columns of the spinal cord may be present.
MR imaging shows infarctions, when they occur, in addition to nonspecific white matter abnormalities ranging from small
foci of high signal intensity (predominantly medial and bifrontal) to more diffuse, generalized white matter T1 hypointensity
and T2 hyperintensity (Fig. 3-17) (176,208,214). Proton MRS is reported to show reduced NAA in the white matter (217).
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 of reduction of these compounds is a
buildup of methylmalonic acid and homocystine and their increased excretion in the urine (218). The different forms of the
disorder are classified according to complementation groups of cells in vitro: cblC (OMIM 277400, the most common,
resulting from mutations of the MMACHC gene at 1p34.1), cblD (OMIM 277410), and cblF (OMIM 277380) (219). These
disorders differ from the isolated forms of methylmalonic acidemia and homocysteinemia, which have different biochemistry,
different genetics, and different clinical–neuroradiological attributes. Cerebral infarcts and vascular thrombosis have not been
reported, although intimal thickening and fibrosis are generally present. Not surprisingly, affected patients have a variable
clinical picture (219–222). Some present in infancy with feeding difficulties, hypotonia, failure to thrive, seizures,
microcephaly, megaloblastic anemia, or developmental retardation; some develop hemolytic–uremic syndrome (HUS). Others
may present later in childhood or in adolescence or adulthood with dementia, progressive gait disturbance, acute neurologic
dysfunction, or myelopathy (176,218,223). 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 homocystine,
and hypomethioninemia (219). Confirmation of an intracellular defect of cobalamin metabolism is made by analysis of cultured
fibroblasts (219) or by identification of mutation of a causative gene (224). Treatment includes hydroxocobalamin, betaine, and
carnitine, but response and outcome vary (219,220). Pathologic analysis of the brains of affected patients typically shows
spongiform demyelination of the white matter.
Figure 3-17 Hyperhomocysteinemia (5,10 methylenetetrahydrofolate reductase deficiency) in a 10-month-old infant. Axial T1-weighted (A)
and T2-weighted (B) images show marked hypomyelination throughout the brain.
Neuroimaging is variable, reflecting the heterogeneity of the disorder. It may be normal early in the course of the disease,
particularly when presentation is in adulthood (225). MR 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 subcortical U fibers (176,208,218,219). Other reports describe hydrocephalus with diffuse white
matter swelling, patchy cavitation of the basal ganglia, and loss of T2 hypointensity of white matter (226). In the single case of
cobalamin C deficiency at our institution, the MR features were of enlarged cortical sulci, mildly enlarged lateral ventricles,
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 (226).
Collagen 4A1 and 4A2 mutations presenting as white matter disease
Described in Chapter 4 as a cause of intraparenchymal hemorrhage in fetuses and children secondary to missense mutations of
COL4A1 and COL4A2, frameshift mutations that result in premature termination of transcription and result in non–sense-
mediated decay of the mutant messenger RNAs can cause small vessel disease resulting in areas of T2/FLAIR hyperintensity,
which may be symmetrical (227). Sometimes, these areas may be seen in association with regions of porencephaly (228), or
the patients have relatives who have had intracerebral hemorrhages in childhood or early adulthood that can give clues to the
genetic cause.
Mitochondrial disorders
Mitochondrial disorders are among the most common inborn errors of metabolism presenting in childhood. At the time of
presentation, MRI may show exclusive cerebral white matter involvement (deep or subcortical), exclusive basal ganglia or
thalamic involvement, exclusive brain stem involvement, or a combination of the above. More details on mitochondrial disease
are discussed in the section on Disorders Affecting Both Gray Matter and White Matter, later in this chapter.
Methionine adenosyltransferase I/III deficiency
Methionine adenosyltransferase (MAT) I/III (OMIM 250850), expressed solely in liver, catalyzes the biosynthesis of S-
adenosyl methionine from methionine. MAT I/III deficiency, caused by autosomal recessive mutations in the MAT1A gene at
10q22, is characterized by persistent isolated hypermethioninemia (229–231); more than 37 mutations have been reported
(230). Clinical manifestations are variable and poorly understood. Patients with moderate impairments in MAT I/III activity
have no clinical manifestations, but those with severe impairments of MAT I/III activity have neurological signs and symptoms
(delayed development or epilepsy) and MR findings of abnormal cerebral white matter (230,231). 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 (229).
On imaging studies, patients with MAT I/III deficiency show variable imaging findings, ranging from normal to abnormal
with T1 and T2 prolongation in the cerebral white matter, and sparing of the subcortical U fibers (Fig. 3-18A). Diffusion
images show reduced diffusivity (Fig. 3-18B). Proton MRS findings have not been reported.
Oculocerebrorenal syndrome (Lowe syndrome)
Lowe syndrome (oculocerebrorenal syndrome, OMIM 309000) is an X-linked recessive disorder that predominantly affects
males. In addition 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-bisphosphate-5 phosphatase that is located in the Golgi complex
(232–234) and is postulated to play a role in mediating trafficking of proteins from endosomes to the trans-Golgi network
(235). Primary clinical manifestations include congenital cataracts, glaucoma, mental retardation, renal tubular dysfunction
(Fanconi syndrome–proteinuria, generalized amino aciduria, carnitine wasting, and phosphaturia), and metabolic bone disease
leading to arthropathy (236,237). Mild cases have been reported with cataracts and glomerular disease but lacking renal
tubular defects and mental retardation (238).
Imaging studies are characteristic. CT shows nonspecific hypodensity in the cerebral white matter; calcification of the lens
(cataract) may be apparent if the scan is performed prior to surgery (Fig. 3-19A). MR shows three distinct lesions: (a) dilated
perivascular spaces in the periventricular and deep white matter (Fig. 3-19B), (b) confluent regions of T2/FLAIR
hyperintensity that spare the subcortical white matter in the early course of the disease (Fig. 3-19D), and (c) later in the disease
course the appearance of multiple small spherical cysts in deep and periventricular white matter (Fig. 3-19C and D)
(239–241). The cysts may be the result of progressive enlargement of the perivascular 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-inositol (242,243). This may
represent accumulation of phosphatidylinositol 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 (242).
Figure 3-18 Methionine adenosyltransferase I/III deficiency in a 3-year-old boy. A. Axial T2-weighted image shows abnormal hyperintensity in
the cerebral 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 is courtesy of Dr. Jun-ichi Takanashi, Chiba, Japan.)
Sjögren-Larsson syndrome
Sjögren-Larsson syndrome (OMIM 270200) is an autosomal recessive disorder characterized by congenital ichthyosis, mental
retardation, and progressive spastic tetraplegia (265). The severity of the disorder varies markedly even within families (266).
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 alcohols (267). The
gene (ALDH3A2) has been mapped to chromosome 17p11.2 (267), but mutations of many different aldehyde dehydrogenase
genes can cause the syndrome (55). 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 (176).
Figure 3-21 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 brain stem and spinal cord (268).
Imaging shows delayed myelination during the first years of life, with T2/FLAIR hyperintensity developing in the deep
white matter (Fig. 3-22A) (269). 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 (270,271). Of note, small areas of
subcortical white matter remain incompletely myelinated for many years, even into adulthood (269). Mild cerebral atrophy is
found in most patients older than 10 years (269). DTI shows normal diffusivity values but reduced FA in the affected white
matter (272), likely representing impaired formation or impaired maintenance of myelin.
Proton MRS of the occipital white matter shows a fairly characteristic, 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. 3-22B) (270) and,
therefore, can be differentiated from the broader “macromolecular” peaks (probably methyl and methylene proton resonances,
respectively) with those chemical shifts that are often seen in infants (269,270,273). These peaks are smaller in other regions
of the brain and are not seen in gray matter (269). It has been postulated that these peaks are the result of accumulation of long-
chain fatty alcohols (270); 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
(266). Choline, creatine, and myo-inositol peaks are slightly elevated in the white matter (269).
Brain injury from radiation and chemotherapy
Radiation and chemotherapy have long been mainstays in the treatment of tumors of the central nervous system. A number of
factors affect patient response, including duration of survival after treatment, age of patient during treatment, the specific
chemotherapeutic agent, and whether therapy is single (radiation or chemotherapy) or combined (radiation and chemotherapy)
(274). Treatment-related injury of the nervous system may be due to radiation or chemotherapy treatment of tumors of the brain,
head, neck, or spine and is a common cause of long-term morbidity and of abnormalities seen on imaging studies of those
regions (275,276). It has become apparent in recent years that radiation induces an inflammatory response that is induced by
the treatments and continues after radiation treatment has ceased, generating recurring waves of reactive oxygen species,
cytokines, chemokines, and growth factors with associated inflammatory infiltrates (276). In addition, the radiation-induced
damage to normal tissues continues over time due to the onset of various regulatory immune mechanisms associated with
wound healing (274,277). Some work even suggests that proinflammatory responses with highly oxidative stress may
contribute to tumor heterogeneity, making treatment more difficult (276,278). Other variables relevant to damage potential
include total radiation dose, size of radiation field, size of radiation fractions, and the number and frequency of radiation
doses, while other (279,280). Recent studies also implicate chemotherapy as a cause of cognitive deficits, with the memory,
attention, school performance, and psychosocial function being the most commonly affected functions (275,281). Although
these factors may have little importance in patients with tumors associated with short life expectancy, prolonged survival may
be associated with development of significant functional deficits and significant reductions of memory and learning (280).
Certain individuals may display unusual sensitivities to radiation or chemotherapies. It is well known that syndromes
caused by impaired DNA damage repair (e.g., Fanconi anemia, ataxia–telangiectasia, etc.) predispose to childhood brain
tumors, but affected patients are at increased risk for treatment-related toxicities, as well (282). For example, patients with
dual mutations in breast cancer susceptibility gene (BRCA2) may develop symptomatic neurotoxicity (leukoencephalopathy),
myelosuppression, and poor immune response after “regular” (usually nontoxic) therapeutic doses of chemotherapeutic agents
(283). Patients with other genetically determined cancer syndromes (e.g., Gorlin syndrome) show excessive sensitivity to
ionizing radiation (282). If such patients develop brain tumors and require radiation therapy, conventional radiation doses may
not be tolerated and could actually be fatal. These data need to be taken into account prior to planning therapeutic strategies in
such “high-risk” patients.
Figure 3-22 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.
White matter injury
With a few exceptions, the clinical and imaging manifestations of white matter injury secondary to radiation 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 treatment) (284,285).
Acute and early delayed reactions are mild, often asymptomatic, and self-limiting, consisting of mild localized interstitial
edema (secondary to transient vasodilatation with variable changes in capillary permeability) or perhaps transient myelin
injury due to radiation effects on oligodendrocytes (286,287). 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. DTI studies show 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 (288). White matter damage is more widespread than in patients treated with
chemotherapy alone, but it is unclear whether the lower FA is due to loss of axons, disruption of axons, delay of white matter
maturity, or individual vulnerability to neurotoxicity of the treatment (289). 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 (290).
Late delayed injury is believed to result primarily from permanent damage to blood vessels, perhaps associated with
inflammation (276,287). 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 (276,285). All of these effects seem to be exacerbated when the
patient also receives chemotherapy, particularly methotrexate (MTX) (287). Pathologically, the white matter exhibits areas of
necrosis, with rarefaction and fragmentation of myelin, and cellular disruption. Patients may develop localized neurologic
deficits or obtundation (281,289).
In the early postirradiation period (6–12 months), the brain may show reduced Dav and substantial edema but the blood–
brain barrier may remain intact and perfusion tends to be reduced (Fig. 3-23). Over time, substantial white matter injury may
appear on imaging (Fig. 3-24). In addition to differences due to timing of imaging with respect to time of treatment, imaging
studies show variable patterns of injury, ranging from localized lesions (Fig. 3-23) to diffuse white matter abnormality (Fig. 3-
25). Signal abnormalities reflect the edema and loss of myelin, as CT shows low attenuation and MR shows T1 hypointensity
and T2/FLAIR hyperintensity (Figs. 3-23 and 3-24) (291,292). If tissue is injured, diffusivity may be reduced (Fig. 3-25).
Contrast enhancement is variable and may be transitory, due to temporary blood–brain barrier injury. Significant mass effect
can be present. Central necrosis within the lesions is uncommon in children (292). Petechial hemorrhage may be present,
appearing as multifocal areas of T1 hyperintensity/T2 hypointensity superimposed upon the edema. Hemorrhage is much more
common following radiation therapy and is uncommon if treatment is limited to chemotherapy (293). 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 DTI may allow detection and quantification of treatment-induced white matter injury
(275,294). Compared with age-matched controls, decrease of the FA 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 (294). Susceptibility-weighted perfusion imaging shows
reduced blood volume compared to unaffected white matter (295); this is particularly useful in differentiation between
radiation injury and recurrent tumor in children treated for CNS malignancies.
Hemorrhagic vasculopathy secondary to radiation
Hemorrhagic lesions may be seen in white matter of children who have been irradiated (293,296,297). The pathophysiology of
these lesions has not been ascertained; capillary damage is a likely candidate. The imaging and surgical appearance is that of
occult vascular malformations or cavernomas (298): 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)
(296,298). Affected children may present up to 19 years after therapy (mean 8.1 years, earliest 2–3 years) (297,299).
Presenting symptoms may be headaches, seizures, or focal neurologic signs and symptoms; others are asymptomatic and found
incidentally (293,296,297). The lesions may develop after a wide range of radiation doses; in the series of Young-Poussaint et
al. (297), the range was 1800 to 6000 cG. Although there was no clear correlation between dose and development of these
lesions in the series of Koike et al. (299), Chan et al. (293) found a correlation between the number of hemorrhages and the
radiation dose, while Zeng et al. (300) found that use of susceptibility-weighted imaging substantially increases the number of
hemorrhagic lesions identified. Pathologic examination shows locally abnormal blood vessels. Currently, the lesions are only
resected if they are symptomatic or have caused symptomatic hemorrhage (301,302).
Occlusive vasculopathy secondary to radiation
Young children are more susceptible than adults to radiation injury of the large vessels 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/suprasellar/parasellar region
for supratentorial midline tumors (303–306) (patients with neurofibromatosis type 1 seem particularly susceptible (307,308)),
but vasculopathy has been shown to develop after whole-brain irradiation for posterior fossa tumors such as medulloblastoma
or ependymoma (309) or for CNS involvement by leukemia (306). Rarely, the vasculopathy has developed as early as 15
months after radiation (309), although it is more commonly seen after many years (305). Fortunately, improvements in
chemotherapy regimens and increased awareness of the susceptibility of children to vascular injury has resulted in a reduction
of radiation use (and reduction of doses when used) and, at the same time, recognition of the importance of upregulation of
VEGF as a cause of radiation vasculopathy has led to the use of anti-VEGF antibodies such as bevacizumab to reduce
morbidity (310). As a result, the incidence of occlusive vasculopathy has diminished.
Figure 3-23 Localized acute radiation necrosis in a child treated for a frontal lobe glioma. A. Axial noncontrast T1 image shows cortical and
subcortical hyperintensity rostrally (arrow) and less hyperintense tissue with thickening of the callosal genu causing mass effect upon the
frontal horn posteriorly in the right frontal lobe. B. Axial postcontrast T1-weighted image at the same level shows little enhancement anteriorly
and rim enhancement (arrows) in the posterior margin of the mass. C. Average diffusivity map shows large, lobulated areas of markedly
reduced diffusivity (arrows) in the posterior and lateral frontal lobe, as well as the callosal genu, suggesting an acute process. D–F. Regions of
interest (ROIs) within the right frontal white matter (ovals 1, 2, and 3 in D) show no increase in blood volume (lack of change in susceptibility in
F), while the left frontal ROI shows normal white mater perfusion (small reduction in susceptibility in F). Perfusion map (E) shows marked
decrease in white matter perfusion (black being the absence of signal) in the right frontal lobe. All these findings suggest necrosis rather than
tumor.
Figure 3-24 Delayed white matter injury from radiation treatment of tectal glioma. A. Sagittal T2-weighted image shows a large tectal mass
(arrows) blocking CSF flow in the distal cerebral aqueduct. Note the thick calvarium resulting from shrinkage of the hydrocephalic brain as a
result of previous CSF shunts. B–D. Axial FLAIR images 5 years after radiation to tectal mass shows extensive new hyperintensity (arrows) in
the cerebellar white matter, pons and midbrain (in B and C), and in the thalami, internal capsules, callosal splenium, and peritrigonal white
matter (in D).
Patients develop intimal hyperplasia and fibrous thickening of the adventitia, leading to progressive narrowing of the
supraclinoid carotid artery (Fig. 3-26) 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 (311).
Imaging shows multiple small infarctions (Fig. 3-26), 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 a rare occurrence and it is
difficult to prove causation (291). Of radiation-induced tumors in adults reported in the literature, 70% are meningiomas (Fig.
3-26D), 20% are gliomas, and 10% are sarcomas (312). The risk for meningioma is not affected by sex, age at exposure, time
since exposure, or attained age. However, risk for gliomas is stronger in younger age groups and malignant gliomas seem to be
much more common than meningiomas in children (313); moreover, a significant risk for sarcomas and low-grade gliomas have
been noted in irradiated children (314). 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 (313,314). The
neuroimaging appearance of radiation-induced tumors does not differ from that of those not associated with radiation. The
neuroimaging appearance of brain tumors is discussed in Chapter 7.
Figure 3-25 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 shows 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.
Figure 3-26 Radiation-induced vasculopathy in an 18-year-old girl with history of radiation for her suprasellar tumor. A. Axial FLAIR image
shows abnormal hyperintensity in the basal ganglia and external/extreme capsules. Note also pial hyperintensity (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 lenticulostriate arteries in the basal ganglia. Solid white arrows point 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 moyamoya-like collaterals (black arrows).
Figure 3-27 Focal acute white matter injury from methotrexate. A. Axial T2-weighted image shows faint hyperintensity (white arrows) in the left
hemispheric 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).
Combined radiotherapy and chemotherapy
An important concept is that the combination of chemotherapeutic agents and radiotherapy often results in more severe injury
than either chemotherapy or radiotherapy alone (287,310,332). 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) (325,342).
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, often multiple regions that are located several centimeters away from the tumor resection site
or even contralaterally; common locations include the corpus callosum and corticomedullary junctions (342). Tumor is more
often solitary and located immediately adjacent to the surgical site; correlation with radiation ports is critical to making the
correct diagnosis. More chronically, the changes from combined radio- and chemotherapy appear as widespread multifocal or
diffuse cortical injury and diffuse deep cerebral and cerebellar nuclear injury with calcification. Examination of the white
matter shows impaired myelination, diffuse injury with punctate calcifications, and volume loss (Fig. 3-29). Fortunately, this
complication has become rare.
Figure 3-28 Chronic extensive methotrexate injury. Axial T2-weighted image shows extensive white matter hyperintensity (arrows) in both
cerebral hemispheres. Note the sparing of the subcortical white matter.
White Matter Disorders with Abnormal Signal Initially Affecting Subcortical Cerebral White Matter
Megaloencephalic leukoencephalopathy with subcortical cysts
Megaloencephalic 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 neurologic signs and symptoms in the setting of a very abnormal imaging study. Patients may
present during first year of life with macrocephaly (although head growth becomes normal after the first year, with head
circumference paralleling the 98th or 99th percentile) or during the second year of life with delay in attaining developmental
milestones. After several years, slow neurologic deterioration ensues with gradually increasing ataxia and, to a lesser extent,
spasticity; they often become wheelchair bound during their teen years (343). Head circumference stabilizes after the first year
and then parallels the normal curve. Most patients are wheelchair bound within 8 to 10 years (344), 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 (345). Slow cognitive deterioration is noted from midchildhood in older patients, but communication and social skills
remain essentially unaffected (343). Diagnosis is based upon a combination of clinical and MR criteria.
MLC phenotypes
About 75% to 80% of cases are caused by mutations of the MLC1 (also called KIAA0027) gene at 22q13.33. The gene encodes
a transmembrane protein that associates with the Na,K-ATPase beta-1 subunit (ATP1B1) in a multiprotein complex; MLC1
regulates the assembly and response of the Na,K-ATPase complex to osmotic stress (346). The other 20% to 25% of patients
with MLC have mutations of the HEPACAM gene at 11q24.2, which encodes a molecule called GlialCAM that functions as a
chaperone for MLC1 (347,348). Most have homozygous or compound heterozygous mutations and a typical MLC phenotype;
these patients are classified as having MLC2A (343). A third subtype of MLC, referred to as MLC2B, is seen in a group of
patients with heterozygous mutations of HEPACAM (347,349). MLC2B patients also develop macrocephaly during the first
year of life, with normal or mildly delayed development; head circumference rarely normalizes. Their motor capabilities may
normalize or they may remain clumsy but do not become spastic or ataxic; cognition may be normal or slightly decreased
(349).
Figure 3-29 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 myelination, enlargement of subarachnoid spaces, and focal cortical injury (white arrows) in the left parietal
lobe.
Figure 3-30 Diffuse necrotizing leukoencephalopathy. A. Noncontrast CT scan soon after symptoms shows white matter edema and
multifocal cortical and subcortical calcifications. B. Axial T2-weighted image a few months later shows 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 postcontrast T1-weighted images show marked diffuse enhancement secondary to extensive injury to the blood–brain
barrier.
Physiology/pathology/imaging
GlialCAM and MLC1 are proteins that combine to regulate cell volumes by activating astrocytic volume-regulated anion
currents (VRACs), particularly moving potassium and chloride ions (343,350). Mutations in either gene cause dysregulation of
VRAC activity and result in disrupted chloride channel activity with consequent impaired disposal of excessive potassium and
water from myelin interstices and at astrocytic end feet (343). Thus, the T2 hyperintensity of the brain and the megaloencephaly
found in affected patients are not related to impaired myelination but to excessive interstitial water (343).
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 and blood vessels by the
vacuoles (351,352).
Neuroimaging studies in MLC1 and MLC2A are remarkable for a nearly complete absence of the T2 hypointensity (and,
often, the T1 hyperintensity) normally seen after myelination in most subcortical and deep cerebral white matter. Some central
white matter is spared, particularly in the corpus callosum, internal capsules, brain stem, and the occipital lobes (Fig. 3-31),
but this varies from patient to patient. The subcortical white matter appears swollen, with enlargement of the gyri in affected
regions (Fig. 3-31C). A characteristic feature is the presence of subcortical cysts that initially develop in the anterior temporal
lobes (Fig. 3-31A and B) and may eventually arise in the frontal and parietal lobes (Fig. 3-31D and E). (Note that anterior
temporal cysts are an uncommon imaging finding; when they are seen, one should consider congenital cytomegalovirus
infections, Aicardi-Goutières syndrome (AGS), and some cobblestone malformations (see Chapter 5) in addition to MLC
(353)). 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. 3-31A and C) (345). Mild cerebellar atrophy is usually
present (344). As would be expected from the physiology of the disease (increased interstitial water), diffusion studies show
increased diffusivity in the cerebral white matter (dark on diffusion-weighted images, bright on ADC maps) (354). 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 (83).
Figure 3-31 Megaloencephaly with leukoencephalopathy and cysts. A–C. A 16-month-old girl with megaloencephaly and mild developmental
delay. Axial FLAIR image at the fourth ventricle (A) 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). At a slightly higher level, FLAIR
image (B) shows hyperintense unmyelinated white matter in the temporal lobes with right anterior temporal cyst (black arrows). Coronal T2-
weighted image (C) shows diffuse 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. Megaloencephaly with leukoencephalopathy 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 round, sharply delineated hypointensity (white arrows) on the
axial T1 image (E).
Patients with MLC2B have less subcortical swelling and better preserved cerebellar white matter on initial MR scans than
those with MLC1 or MLC2A; subcortical cysts are often present but are limited to the anterior temporal lobes. Cerebellar
white matter is typically normal, even on the earliest studies. On follow-up scans, MR shows spectacular improvement over
the course of a few years with progression of myelination such that only a few minor signal abnormalities remain, usually in the
subcortical regions; subcortical cysts in the temporal lobes regress and may disappear (343,349).
Differentiation of this disorder from Canavan disease 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), white matter less T2 hyperintense than in Canavan disease, proton MRS
(large NAA peak in Canavan disease, small NAA in MLC), and the diffusion characteristics (reduced diffusivity in Canavan
disease (39), increased diffusivity in MLC (354)).
Cystic leukoencephalopathy without megaloencephaly
Patients with cystic leukoencephalopathy without megaloencephaly present during the first year of life with psychomotor
impairment, seizures, sensorineural hearing impairment, and progressive microcephaly. These findings typically raise the
possibility of congenital cytomegalovirus infection, but they do not test positive for CMV by PCR on blood spots of neonatal
Guthrie cards or serologic CMV markers (355). In addition, study of families of these patients show a pattern of autosomal
recessive inheritance, primarily in persons of central and eastern European descent (356). Linkage analysis and candidate gene
sequencing have identified mutations in RNASET2 at chromosome 6q27 (355). In addition to the psychomotor delay and
seizures, nystagmus, athetoid hand movements, or dystonia may develop (356,357).
Brain CTs and MRIs of affected patients look very similar to those of patients with congenital cytomegalovirus infection,
showing patchy involvement of the subcortical supratentorial white matter and cystic lesions in the anteriormost part of the
temporal lobes (Fig. 3-32). The cysts do not communicate with the ventricular system, which is typically mildly or moderately
enlarged (355–357). In our experience, peritrigonal white matter is involved from the ventricular surface to the deep white
matter, showing T2/FLAIR hyperintensity and increased diffusivity; subcortical white matter is typically spared. Proton MRS
is typically normal.
Figure 3-32 Cystic leukoencephalopathy without megaloencephaly. 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).
Aicardi-Goutières syndrome
For many years, Aicardi-Goutières syndrome (AGS) was defined as a genetically heterogeneous disorder that initially is
manifested in infancy with irritability, poor feeding, progressive microcephaly, spasticity, and dystonic posturing; profound
psychomotor retardation ensues, often with death in early childhood (358,359). All patients show findings of chronic CSF
leukocytosis and basal ganglia calcifications, which raise the possibility of congenital infection, but testing is negative. Studies
revealed causative genes that expanded the clinical diagnosis to the point where many patients did not fit the paradigm as
initially delineated (360). It was subsequently shown that a minority of patients present during the later part of the first year of
life, while less than 10% present after the first year (360). As a result, many authors have recommended the use of a more
generic term, type I interferonopathy (IFN), to refer to this group of monogenic diseases in which upregulation of type I
interferon is considered a key aspect of pathogenesis (361). Currently, seven 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, the most common cause (360), autosomal recessive caused by RNASEH2B on 13q14-21), AGS3 (OMIM
#610329, autosomal recessive caused by RNASEH2C on 11q13.2), AGS4 (OMIM #606034, autosomal recessive caused by
RNASEH2A on 19p13.13), AGS5 (OMIM #612952, a form with unknown inheritance caused by mutation of SAMDH1 on
20q11.2), AGS6 (OMIM #615010, autosomal recessive caused by mutation of ADAR on 1q21.3), and AGS7 (OMIM #615846,
autosomal dominant caused by mutation of IFIH1 on 2q24.2) (360). All of these genes encode proteins that are involved in
nucleic acid metabolism and/or signaling. Testing of spinal fluid and serum shows increased levels of interferon activity due to
increased expression of interferon-stimulated genes in the peripheral blood (362).
The finding of multiple punctate basal ganglia calcifications and white matter abnormalities (T2 hyperintensity or
calcifications) in the clinical setting of an early-onset encephalopathy should raise the possibility of AGS (360). The putamina
are most commonly involved (Fig. 3-33A), but the globi pallidi, thalami, deep and subcortical white matter, and, sometimes,
cerebellar dentate nuclei may also show punctate or globular calcification (363); these may or may not be visible on MRI.
TREX1 mutations tend to have particularly severe calcifications (>90%) (364). The subcortical and deep white matter
typically are abnormally hypodense on CT and show T1 hypointensity and T2/FLAIR hyperintensity on MR (Fig. 3-33B);
subcortical white matter is involved early in the course of the disease (365). Imaging studies also show ventriculomegaly,
usually progressive, secondary to progressively reduced volume of white matter in the cerebral hemispheres (Fig. 3-33B)
(365). In later stages of the disease, white matter may have signal intensity similar to CSF, particularly in the frontal and
anterior temporal lobes, a common location for fluid accumulation; this appearance is strongly associated with TREX1
mutations and an early age of onset (353,364). The cerebellum and brain stem may be small (366–368), 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, especially if
there is a family history of neurodegeneration in childhood, then testing for AGS should be performed.
Cockayne syndrome
The Cockayne syndromes (type A:OMIM 216400 [80%] and type B:OMIM 133540 [≤20%]) are autosomal recessive
disorders that are characterized by cutaneous photosensitivity, dwarfism, pigmentary retinopathy, optic atrophy, cataracts,
premature aging, and progressive neurological dysfunction; joint contractures may develop. Type A is caused by truncating
mutations in the ERCC8 gene on chromosome 5q11 (369), while type B is caused by mutations of ERCC6 at 10q11.23. Both
genes encode (group 8 or group 6) excision repair cross complementing proteins that eliminate a broad spectrum of structural
DNA lesions; affected patients have impaired transcription-coupled repair of damaged nuclear and mitochondrial DNA, which
inhibits resumption of replication and transcription (370). Affected patients typically present with psychomotor retardation
between the ages of 6 and 12 months. Both development and growth progressively fall farther and farther from the norm
(371,372). Patients are further characterized by accentuated thoracic kyphosis, lumbar lordosis, and characteristic facies
(183,371).
Figure 3-33 Aicardi-Goutières syndrome. A. Axial noncontrast CT scan shows calcification of the basal ganglia (white arrows) with diffuse
cortical 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 calcification. (This case is
courtesy of Dr. Susan Blaser, Toronto.)
Figure 3-34 Cockayne syndrome. A. Axial noncontrast 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 calcifications. Diffuse hyperintensity of the white matter is
present (black arrows).
CT in Cockayne syndrome reveals brain calcification, most commonly in the basal ganglia (Fig. 3-34A), cerebellar dentate
nuclei, the deepest part of cortical sulci, and in subcortical white matter; cerebral and cerebellar atrophy are nearly always
present (373,374). MR shows diffuse atrophy (involving both cerebral and cerebellar hemispheres) and T2 hyperintensity,
initially in the periventricular white matter, basal ganglia, and cerebellar nuclei (374). The subcortical U fibers can be
involved early in the disease but are more commonly affected only in later stages (56). Susceptibility-weighted, gradient echo,
and (sometimes) spin echo or FLAIR (Fig. 3-34B) images will show hypointensity within calcified deep cerebral and
cerebellar nuclei (375).
Many other disorders have radiologic findings of cerebral calcifications and abnormal myelination. These include many
mitochondrial disorders (376), GM1 gangliosidosis (377), biotinidase deficiency (378), pseudo-TORCH syndromes (366),
Aicardi-Goutières syndrome (353,364), tuberous sclerosis (see Chapter 6), congenital cytomegalovirus, congenital
toxoplasmosis, congenital rubella, 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.
Galactosemia
Galactosemia (OMIM 230400) is an autosomal recessive disorder that results from defective conversion of galactose to
glucose by a pathway 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 (379). Affected
patients typically present as newborns or young infants with failure to thrive, signs of increased intracranial pressure, and
vomiting. If untreated, patients develop severe liver disease, profound mental retardation, epilepsy, language production
impairments, and choreoathetosis (380). Treatment is dietary restriction of galactose, which prevents or resolves the acute
manifestations of the disease; however, even compliant patients go on to develop neurologic and neuropsychologic
complications including memory impairment, slower information processing, and voice, motor, and language impairments
(apraxia and dyspraxia of speech) (381).
CT scans of patients with galactosemia are nonspecific, showing extensive low attenuation in the cerebral white matter
(74). MR studies seem somewhat more specific, showing delayed myelination (persistent high signal) and consequent blurring
of the cortical–white matter junction on T2-weighted images (Fig. 3-35) (382,383). Cerebral and cerebellar atrophy is seen in
older patients, with severe loss of white matter resulting in marked ventriculomegaly (383). Focal white matter lesions are
occasionally seen and appear to be areas of cavitation, mostly in the subcortical white matter (383).
Proton MRS of the brain in patients with galactosemia is reported to be normal by some authors (384), but others report
resonances at 3.67 and 3.74 ppm, corresponding to galactitol, in newborns with very high urinary galactitol levels (383,385).
These peaks are not specific 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 (386). Galactitol can be distinguished from
myo-inositol, which precesses at nearly the same chemical shift, by the presence of J-coupling, which results in inversion of
the peak when using an echo time of 135 to 144 ms. A large peak at 3.6 ppm on a short echo spectrum strongly supports a
diagnosis of galactosemia (387). Galactosemic patients who have been following a galactose-restricted diet for several years
do not have galactitol peaks (385).
Figure 3-35 Galactosemia. This noncontrast axial T2-weighted image shows hyperintensity in the subcortical white matter secondary to
delayed myelination. Note the consequent diffuse blurring of the cortical–white matter junction. (This image is courtesy of Dr. Susan Blaser,
Toronto.)
Mitochondrial disorders
Mitochondrial encephalopathies can cause white matter injury, often with cavitation in the affected cerebral white matter.
However, mitochondrial diseases can have many different appearances. It is probably easiest to discuss all such diseases in
one section. Therefore, mitochondrial disorders are discussed in the section “Metabolic diseases that affect gray matter and
white matter.”
Figure 3-36 Connatal Pelizaeus-Merzbacher disease at age 2 months and 4 years. A and B. Axial T1-weighted (A) and T2-weighted (B)
images at age 2 months 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 capsules (see Chapter 2). C. Follow-up T2-weighted image at age 4
years shows that there is still no myelination, even in the posterior limbs of the internal capsules.
Figure 3-37 Evolution of Pelizaeus-Merzbacher disease. A–C. Axial T1, T2, and ADC images at age 3 months show some T1 shortening
(hyperintensity, white arrows in A) and reduced diffusivity (hypointensity, white arrows in C) in the posterior limbs of the internal capsules. Normal
hypointensity is not seen on T2 image (B). D–F. Axial T1, T2, and ADC images at age 9 months show no progression and possible regression
of the earlier indications of myelin.
Figure 3-38 Atrophy in Pelizaeus-Merzbacher disease. A and B. Axial T1- and T2-weighted images at age 2 years show hypomyelination but
normal ventricular size. C. Proton MRS (TE = 144 ms) shows large NAA peak. D and E. Sagittal and axial FLAIR images of the same patient at
age 8 years show marked volume loss with markedly diminished white matter volume, thinning of the corpus callosum, and atrophy of the
anterior cerebellar vermis.
Hypomyelination can also be demonstrated by use of magnetization transfer (MT) imaging, DTI, and proton MRS. The
magnetization transfer ratio is reduced in hypomyelination, mean diffusivity and RD are increased, and the NAA, Cr, Glu, and
myo-I peaks are increased on proton MRS in many cases (51,414). The size of the NAA peak on MRS differs with the
mutation; to understand this, it is important to understand that NAA is synthesized within mitochondria and metabolized in
oligodendrocytes by the action of aspartoacylase (415). Several reports have shown that the NAA peak is increased in PMD
(Fig. 3-38C) (402,414). Takanashi et al. (416) showed that this enlarged NAA peak is a result of oligodendrocyte death from
the folded protein response. NAA is not metabolized (because oligodendrocytes are reduced in number and have impaired
function) and the excess NAA binds to glutamate to form NAAG, which is not resolved from NAA on routine clinical proton
MRS but can be detected as a separate peak on higher-resolution imaging (416). Therefore, presence of the enlarged NAA
peak supports the diagnosis of PMD, but a normal NAA peak does not exclude it.
Hypomyelination of early myelinating structures
A group of patients with a variant of PMD present with nystagmus or cerebellar dysfunction in the first of second year of life;
motor development progresses but remains delayed as they grow. MRI shows that they have hypomyelination that is not diffuse
but is isolated to the dorsal medulla oblongata, the pons, the hila of the cerebellar dentate nuclei, the optic radiations, the
thalami (other than the ventrolateral nuclei), and the internal capsules (dark centrally but with hyperintensity of the medial and
lateral portions) (417). Genetic analyses showed that all patients in the group had mutations of PLP1 that were located in exon
3B or intron 3 of the gene (417). This variant is referred to as “hypomyelination of early myelinating structures.”
Pelizaeus-Merzbacher–like disease
Some patients have been described with clinical features identical to that in patients with Pelizaeus-Merzbacher disease but
without PLP1 mutations. These patients appear to have different Pelizaeus-Merzbacher–like diseases, also called
hypomyelinating leukodystrophies 2 (HLD2, OMIM #608803) and 3 (HLD3, OMIM #260600).
Patients with HLD2 have autosomal recessive mutations of the GJC2 gene at 1q42.13 (22,389). GJC2 (OMIM 608804)
encodes the gap junction connexin protein (Cx46.6), which is highly expressed in oligodendrocytes and appears to play a role
in a myelinogenesis (418). Affected patients have a similar phenotype to those with classic PMD, but patients with GJC2
mutations have been found to show better cognition, better receptive language (419), and earlier signs of axonal degeneration
(420). MR imaging and MRS appear to be nearly identical to those in PMD due to PLP1 deletions (389).
Patients with HLD3 (caused by autosomal recessive mutations of the AIMP1 gene at chromosome 4q24, OMIM #603605)
present as young infants with severe global developmental delay, lack of development, lack of speech acquisition, and
peripheral spasticity with kyphoscoliosis (393). The patients have seizures and soon after develop an epileptiform EEG
pattern suggesting cortical disease rather than a white matter disease. Several authors have argued that the disorder may be a
primary neuronal degenerative disease with secondary hypomyelination (421). This is a very plausible hypothesis, but we keep
the disorder in the belief that, this way, the imaging appearance will lead to the consideration of the proper diagnosis.
Patients with HLD4 (caused by autosomal recessive mutations of the HSPD1 gene at 2q33.1, OMIM #612233) present with
hypotonia, nystagmus, and psychomotor developmental delay before age 3 months; the appearance of spasticity follows soon
after and then developmental arrest and regression (422). MRI shows no evidence of normal myelination in affected patients.
The corpus callosum is thin and the CSF spaces (ventricles, sulci, subarachnoid spaces) show progressive enlargement; their
size is correlated with worsening severity of symptoms (422). Autopsy results have not been reported.
Hypomyelination with congenital cataracts
Hypomyelination with congenital cataracts (HLD5, OMIM #610532) is a rare, autosomal dominant disorder that is caused by
deficiency of a membrane protein of unknown function called hyccin, which is encoded by the FAM126A gene located at
chromosome 7p15.3 (33). Affected patients are typically recognized at birth, or during the first month after birth, when they are
discovered 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 (32). Scoliosis slowly develops and progresses, along with hyperactive deep tendon reflexes,
extensor plantar responses, dysarthria, cerebellar signs, and truncal ataxia (32). Cognition is impaired, with mild to moderate
impairment in all patients described to date (32). More recent studies revealed that the cataracts may not become detectable
until early childhood (423) and that the motor findings are extremely variable in time of onset, despite the presence of similar
mutations (424).
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 (32). Overall, the impression is that
little myelin is actually formed and that this is subsequently broken down such that the disease is probably best considered a
combination of hypomyelination and demyelination (425).
Neuroimaging with MRI shows more severe white matter abnormalities compared to other hypomyelinating disorders. On
T1-weighted images, cerebral and cerebellar white matter may be slightly hyperintense, isointense, or slightly hypointense
compared with gray matter; white matter is hyperintense compared to gray matter on T2-weighted images (32). Subcortical
white matter may be partially spared early in the course of the disease (Fig. 3-39). Some patients have more severe T1 and T2
prolongation in the periventricular and deep white matter, which may show hypointensity on FLAIR images, suggesting
cavitation. These regions seem to start anteriorly and progress posteriorly; they decrease in volume over time (32,425). There
is no enhancement after intravenous administration of paramagnetic contrast (425). Cerebellar white matter is less severely
affected than cerebral white matter. The pons is moderately hypoplastic, sometimes showing T2 or FLAIR hyperintensity in the
corticospinal tracts and transverse pontine fibers (424–426).
Diffusion-weighted imaging shows increased diffusivity (Fig. 3-39D) in affected white matter, with slightly increased Dav
values in the unmyelinated white matter and higher values (by ~20%) in the cavitating white matter (425). 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 (425).
Figure 3-39 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 (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 sparing 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.
Allan-Herndon-Dudley syndrome
The Allan-Herndon-Dudley syndrome (OMIM #300523) describes boys who have hypotonia at birth but otherwise develop
normally until midway through the first year of life when they lose the ability to hold up their heads. They subsequently have
reduced motor development, generalized muscle atrophy, joint contractures, and hyporeflexia (427). Subsequent studies
showed that serum T3 is elevated and T4 levels somewhat low in affected patients and that many patients developed nystagmus
and impaired gaze and hearing (428). Several authors eventually concluded that SLC16A2 (OMIM #300095; also called
MCT8) mutations are a major cause of this disorder (429). MRI shows classic hypomyelination with some T1 and T2
shortening in the internal capsules, callosal splenium, and deep white matter, but a significant myelin delay is present in the
deep white matter and the white matter volume is significantly diminished (430).
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
leukodystrophy 6) is a newly described disorder that results from mutations of the beta-tubulin gene TUBB4A, which is
important in the formation of microtubules (431). The location of the c.745G>A mutation at the intradimer interface between
alpha-tubulin and beta-tubulin suggests that it results in reduced microtubule polymerization or reduced microtubule stability
(431). Clinical presentation varies with the severity of the disease. Most affected children with the initially described
phenotype and genotype 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, increasing
spasticity, and ataxia (29,432). Severely affected children are noted to have poor vision or oculogyric eye movements and
absent motor development when they are only a few months old (433). Variable nystagmus, decreased hearing, short stature,
and microcephaly have been reported (432). Cognitive deficits are variable, but all affected children appear to have learning
difficulties and require special education (29,432). EEG reveals slowing of background activity in all patients. However, more
recent studies have shown wider variability of phenotype ranging from neonatal to childhood disease onset, normal to delayed
early development, and a variable rate of neurological deterioration (434). Not surprisingly, the clinical phenotype appears to
be related to the genotype (434–437).
MR imaging vary with genotype. The mildest MR phenotypes have isolated hypomyelination (438). Others also have mild
cerebellar atrophy, with or without atrophy of the basal ganglia (usually less severe than that of the cerebellum) (434–438).
The most severe forms show diffuse hypomyelination, with hyperintense cerebral white matter compared to gray matter on T2-
weighted images (Fig. 3-40); progressive loss of myelin is seen on sequential scans (432). 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 (432). These findings of hypomyelination, probably due to both
lack of deposition and further myelin loss, have been confirmed by histopathology (432). The corticospinal tracts are most
severely affected and appear hyperintense in the pons and midbrain, highlighted by the hypointensity of the surrounding
structures (29). Depletion of corticospinal tract axons in the brain stem was confirmed by histopathology (432). The cerebral
white matter has mildly reduced volume (Fig. 3-40), which seems to diminish over time. In many patients, the putamen and, to
a lesser degree, the caudate nucleus are small and show progressive atrophy on sequential scans; globi pallidi and thalami
appear to be spared. The cerebellum usually undergoes progressive atrophy (Fig. 3-40A), with the vermis being more severely
involved than the hemispheres (29); histopathology shows the most severe involvement to be in the internal granular layer of
the cerebellar cortex (432). 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 matter (29). The effects of this disorder on water diffusion, as measured by diffusion-weighted
imaging and DTI, has not been reported.
Pol III–related leukodystrophies
Pol III–related disorders constitute a genetically defined group that has recently been recognized as a specific group of HLD.
Clinically, these disorders are characterized by varying combinations of three major clinical findings: motor dysfunction
(progressive gait abnormalities due to spasticity, cerebellar ataxia, or tremor), abnormal dentition (delayed dentition,
hypodontia, oligodontia, and abnormally placed or shaped teeth), and hypogonadotropic hypogonadism (439). Five
overlapping conditions (4H [hypomyelination, hypodontia, and hypogonadotropic hypogonadism] syndrome, ataxia with
delayed dentition and hypomyelination [ADDH], leukodystrophy with oligodontia [LO], tremor–ataxia with central
hypomyelination [TACH], and hypomyelination with cerebellar atrophy and callosal hypoplasia [HCAHC]) have all been
related to mutations in POLR3A (which results in HLD7, OMIM #607694) or POLR3B (which results in HLD8, OMIM
#614381). These genes encode subunits A and B of the polymerase III gene, a DNA-directed RNA polymerase that transcribes
genes encoding ribosomal, nuclear, mitochondrial, and transfer RNAs (390,439,440); POLR3A mutations are detected in about
80% and POLR3B mutations in the remaining 20% of cases (441). Patients with these disorders have varying combinations of
hypomyelination, oligodontia, cerebellar hypoplasia/atrophy, and hypogonadotropic hypogonadism; they are believed to
represent different variations of a continuum of manifestations of the same disorder (442).
MRIs of these patients show limited, but variable, T1 hyperintensity and very little T2 hypointensity in the cerebral white
matter with maturation. When present, T2 hypointensity of the white matter is seen predominantly in the posterior
periventricular white matter (optic radiations and adjacent tapetum in up to 90%), the posterior limb of the internal capsules
(~40%), and the hila of the cerebellar nuclei (70%); T2 hypointensity is also common in the globi pallidi and anterolateral
thalami (442). The other common findings on imaging are cerebellar atrophy (90%) and a thin corpus callosum (Fig. 3-41)
(443). The presence of all criteria—T2 hypointensity of the globi pallidi, anterolateral thalami, pyramidal tracts, and hila of
the dentate nuclei together with cerebellar atrophy—is strongly suggestive of this diagnosis (442).
Figure 3-40 Hypomyelination with atrophy of the basal ganglia and cerebellum in a 2-year-old child. A. Sagittal T2-weighted image shows a
very thin corpus callosum (black arrows) reflecting diminished cerebral white matter and prominent vermian fissures (white arrows), indicating
cerebellar atrophy. B. Axial T2-weighted image at the level of the basal ganglia shows nearly complete absence of the putamina (arrows) and
diminished volume of white matter, which also shows a complete absence of the hypointensity (relative to cortex) expected from myelination.
Figure 3-41 Pol III–related leukodystrophy in a 14-year-old. A. Sagittal T1-weighted image shows a thin corpus callosum (large white arrows)
with moderate atrophy of the anterior > posterior cerebellar vermis (small white arrows). B. Coronal T2-weighted image shows complete
absence of supratentorial myelination with diminished white matter volume. Moderate cerebellar atrophy is again noted, with slight hypointensity
of the hila of the dentate nuclei (arrows). These images are courtesy of Junichi Takanashi, Tokyo.
Figure 3-42 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.
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. 3-43A). 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 (Fig. 3-43B and C) (28). The subcortical white matter
never seems to myelinate. In patients with more severe symptomatology, enlarged ventricles and subarachnoid spaces are seen
(28). In some patients, the cerebellar white matter is affected, as well (472,473). The basal ganglia appear normal (474), but
mild atrophy of the cerebellum is often apparent (Fig. 3-43A). As the disorder progresses slowly, there is no need for
sequential MRI so it is difficult to know whether the myelination abnormality or enlargement of the CSF spaces is progressive
(28).
Figure 3-43 Sialuria (Salla disease). A. Sagittal T1-weighted image shows a markedly thin corpus callosum (small white arrows), indicating
markedly reduced white matter volume and superior vermian atrophy (larger white arrow). B and C. Axial T1-weighted (B) and T2-weighted (C)
images show markedly diminished white matter volume; note the presence of 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 are courtesy of Dr.
Susan Blaser, Toronto.)
MRS of patients with Salla disease shows enlarged Cr and NAA peaks with 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 (474). The
reason for the increased area under the “NAA” peak appears to be that the acetyl protons from N-acetylneuraminic acid
process at the same frequency as the acetyl protons from N-acetyl aspartate (474).
Fucosidosis
Fucosidosis (OMIM #230000) is a rare, autosomal recessive lysosomal disorder resulting from a deficiency of alpha-L-
fucosidase, the enzyme that hydrolyzes fucose from 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 (475). The disease is caused by mutations of the FUCA1
gene at 1p36.11 (475). Clinically, this disease is divided into two forms, infantile (type I) and juvenile (type II), although a
continuous spectrum of the disease exists, dependent upon the severity of the enzyme deficit (476). 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%) (476). Skeletal findings are
of dysostosis multiplex, which shows characteristic abnormalities of spine, pelvis, and hips (476,477). Pathology shows
prominent neuronal loss in gray matter, especially the thalamus, hypothalamus, cerebral cortex, and the Purkinje cells and
dentate nuclei of the cerebellum (478).
Imaging studies show findings characteristic of diffuse gray matter loss. CT shows atrophy and hypodensity in white matter
and globi pallidi. MR reports indicate variable findings (475,477). Abnormal T1 hypointensity and T2/FLAIR hyperintensity
typical of hypomyelination are present in the white matter of patients in late infancy and early childhood (Fig. 3-44); this may
be the only finding in late infancy (479). Associated 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 and lateral thalami (Fig. 3-
44) (30,479). Hyperintensity of the hypothalami may be seen (475). These features are somewhat reminiscent of findings in the
GM2 gangliosidoses. In patients with more long-standing disease, MR shows diffuse atrophy with nonspecific T2 prolongation
in periventricular white matter and T1 and T2 shortening (T2 hypointensity) in the globi pallidi (477). The appearance is
nearly identical to that in the NCLs. Proton MRS of the affected white matter shows the presence of a doublet centered at about
1.3 ppm on both long and short echo spectra (referred to, in error, as lactate in the early literature) and a broad “hump”
corresponding to multiple peaks from about 3.4 to 3.8 ppm (30,480). The combination of imaging and MRS findings is
probably specific.
Figure 3-44 Infantile fucosidosis. Axial T2-weighted image in a 13-month-old child shows diminished white matter volume with abnormal
hyperintensity, most notably in the peritrigonal regions (larger arrows). Note the thin rim of hypointensity in the posterior limbs of the internal
capsules (smaller arrows), the marked hypointensity of the globi pallidi (white arrowheads), and the relative hypointensity of the lateral thalami.
White Matter Diseases with Nonspecific Patterns
Glycine encephalopathy (nonketotic hyperglycinemia)
Glycine encephalopathy, also called nonketotic hyperglycinemia (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 glycine, which may result from mutations of several different genes in the mitochondrial glycine cleavage
system; loci for these genes have been identified at 16q23.2, 9p24.1, and 3p21.31 (55). 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 (481)) with myoclonic
encephalopathy (lethargy, hypotonia, and myoclonic jerks, progressing to apnea and often death) (482,483). Those patients who
recover spontaneous respiration develop seizures, dystonia, and pronounced developmental delay (482). 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 (182,482,484). A transient neonatal form has also been described
(485), identified with homozygous mutations of the GLDC gene (486). These atypical/mild forms of the disease are more
phenotypically heterogeneous, which makes diagnosis more difficult (487).
CT studies have revealed cerebral and cerebellar volume loss with hypoattenuation of the periventricular white matter
(488). Early MR studies show a thin corpus callosum, severely delayed myelination, and white matter edema (Fig. 3-45A–E).
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 (Fig. 3-45G) with the corpus callosum remaining small (489). A few studies
have reported reduced proton diffusivity in the dorsal brain stem and corticospinal tracts (posterior limbs of internal capsules,
central corona radiata) on diffusion-weighted imaging (Fig. 3-45C and E), probably reflecting the known pathological finding
of vacuolating myelinopathy in the acute phase of the disorder; imaging at this stage can resemble that of MSUD, which is also
due to a vacuolating myelinopathy. Anisotropy of the white matter may be normal (490,491). As atrophy develops over time,
however, diffusion normalizes and then increases while anisotropy decreases, probably as a result of the known axonal
degeneration (491). An increase in magnetic susceptibility has been reported in the putamina in some cases (492).
Proton MRS studies are critical for making the diagnosis, showing an abnormally high glycine peak at 3.56 ppm (Fig. 3-
45F) (489). Abnormal spectra are reported in patients with normal MR imaging 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 (489). In order to separate the glycine peak from that of myo-inositol, which has a similar chemical
shift, the spectra should be obtained with a long echo time (272–288 ms). The myo-inositol 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 (489).
Dihydropyrimidine dehydrogenase deficiency
Dihydropyrimidine dehydrogenase deficiency (DPD, OMIM #274270) is caused by mutation of the DPYD gene located at
1p21.3 (493); DPD is the rate-limiting enzyme in the 3-step pathway of uracil and thymidine catabolism and in the pathway
leading to the formation of beta-alanine (55). It has been reported mainly in patients of European or Turkish ancestry. Affected
children have had a variable clinical phenotype ranging from unaffected to severe neurologic involvement (493,494). Because
of the presence of unaffected individuals, including asymptomatic siblings, with biochemical and molecular findings similar to
affected patients, it appears that DPD deficiency is a necessary, but not sufficient, prerequisite for the development of clinical
abnormalities (493,495). Seizures and mental and motor retardation are common features, affecting 45% of individuals (493).
Ocular abnormalities (23%), autism (18%), growth retardation (18%), microcephaly (14%), and mild dysmorphic features
(14%) are relatively frequent findings (493). Ophthalmologic findings in DPD-deficient patients include megalocornea, optic
atrophy, iris and choroidal colobomata, and fundus hypopigmentation (493). The mechanism of neurologic injury in DPD has
not been clearly elucidated, although decreased levels of the neurotransmitter (alanine) and increased central nervous system
concentrations of uracil and/or thymine may be contributing factors (496).
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 (493). 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 (497). The T2-weighted axial images
show abnormally prominent CSF spaces. Abnormal T2 hyperintensity is present in the periventricular cerebral white matter
and may be seen in the brain stem, specifically in the pontomedullary portions of the medial lemnisci and median longitudinal
fasciculi, and in the inferior olivary nuclei (494). The ventral superficial reticular area of the medulla and the parvocellular
reticular area of the pons may also be involved (Fig. 3-46).
3-Hydroxy-3-methylglutaryl-coenzyme a lyase deficiency
3-Hydroxy-3-methylglutaryl-coenzyme A lyase is an important compound in both the breakdown of L-leucine and in fatty acid
oxidation; the latter process is important in the production of acetylcoenzyme A and acetoacetate, both of which are important
compounds in energy production within the brain. In addition, excess HMG coenzyme A inhibits the process of
gluconeogenesis. Biochemically, deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (OMIM 246450) is characterized
by tissue accumulation and high urinary excretion of 3-hydroxy-3-methylgutarate, 3-methylglutarate, 3-methylglutaconate, and
3-hydroxyisovalerate (498), while its deficiency is characterized clinically by recurrent episodes of severe metabolic
derangement, including hypoglycemia, metabolic acidosis, and, sometimes, hyperammonemia (499,500). It is caused by
mutations of the HMGCL gene at chromosome 1p36.11 (501). 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 confirmed by demonstration of deficient activity of 3-hydroxy-
3-methylglutaryl-coenzyme A lyase in leukocytes and cultured fibroblasts (499,500).
CT of patients with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency show diffusely low attenuation of the white
matter (34). MR imaging 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 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. 3-47),
but some cases have shown involvement of the subcortical axons, as well (34,500). In patients who suffer episodes of severe
hypoglycemia, the characteristic neuroimaging findings of hypoglycemic brain injury (caudate and putaminal injury (502); see
Chapter 4) may be superimposed upon the baseline findings of the 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency
(500).
Figure 3-45 Nonketotic hyperglycinemia in a neonate. A. Sagittal T1 image shows an extremely thin corpus callosum (arrows). B and C. Axial
T2-weighted and diffusion-weighted images show T2 hyperintensity (B) and reduced diffusivity (C) in the cerebellar white matter (large black
arrows) and central tegmental tracts (small black arrows). D and E. Axial T2-weighted and diffusion-weighted images at the level of the basal
ganglia show diffuse white matter hyperintensity (D) with reduced diffusivity (E) in the posterior limbs of the internal capsules (black arrows),
the myelinated part of the white matter. F. Proton MRS (TE = 144 ms) shows abnormally elevated glycine peak (Gly) at 3.6 ppm. Myo-inositol
also processes at this frequency but is not seen at echo times this long. G. Follow-up axial T2-weighted image at age 2 years shows enlarged
ventricles and subarachnoid spaces with a reduced volume of hypomyelinated white matter, indicative of atrophy from severe cortical and white
matter injury.
Figure 3-46 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 is courtesy of Dr. Greg Enns, Stanford, CA.)
Proton MRS of patients with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency shows reduced NAA/Cr, increased
Ch/Cr, and increased myo-inositol/Cr ratios, suggesting enhanced membrane turnover and gliosis in the white matter of
affected patients (500). Broad peaks are consistently seen at 1.3 and 2.4 ppm during metabolic decompensation, possibly due
to accumulation of 3-hydroxy-3-methylglutaryl-CoA; however, the precise biochemical explanation is not yet clear (59).
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 premature birth, perinatal brain injury, twin–twin transfusion
syndrome, metabolic disease, or congenital infection (72). 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 matter hypoplasia is probably very heterogeneous in cause, the end result of a number of processes, including genetic
disorders of white matter development and prenatal injury/infection. Genetic causes are sometimes classified as familial
spastic paraplegia (254,264,503) (see earlier in this chapter); many different genetic loci have been associated with these
disorders (504) and the pathophysiology is only beginning to be worked out (254,505,506).
Figure 3-47 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).
Imaging findings are similar in all cases, probably because the imaging appearance is used to confirm the diagnosis. The
volume of white matter 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 brain stem might be
thin. Basal ganglia, cerebral cortex, and cerebellum are normal. Diffusion imaging and proton spectroscopy are normal or
show slightly reduced diffusivity or NAA, respectively.
Single-voxel proton MRS (Fig. 3-49D) may also be useful; short echo spectra demonstrate elevated glutamate and glutamine
in the lesion, while both long and short echo spectra show elevated choline, elevated lactate, elevated lipid, and decreased
NAA (531). 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 multiple sclerosis in such
children (527). Readers interested in further information concerning imaging findings in multiple sclerosis 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 syndrome, systemic lupus erythematosus [SLE],
Takayasu disease, or even arterial dissection), monophasic inflammatory/demyelinating diseases (such as acute disseminated
encephalomyelitis or NMOSD), migraine, and infections/inflammatory disorders such as Lyme disease or neurosarcoidosis
(532). When only a single lesion is identified, tumor is the most concerning differential diagnosis; perfusion imaging is the
most useful technique in differentiating these two entities (533), as blood flow is increased in tumors and decreased in plaques
(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 (516,534,535).
More advanced MR techniques in MS
Although pre- and postcontrast T1, T2, FLAIR, and diffusion imaging are standard sequences for the evaluation of MS, many
other MR techniques may be useful in the evaluation of patients with multiple sclerosis, particularly in the research setting. The
use of magnetization transfer techniques improves visibility of enhancing multiple sclerosis 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 (518).
Quantification of white matter injury can be accomplished via the calculation of magnetization transfer ratios and DTI (see
Chapters 1 and 2) (536,537). Although FLAIR is somewhat limited in the detection of posterior fossa and spinal cord lesions
(48,521,522), double inversion recovery, in which the signal of both CSF and white matter are suppressed through the use of
two separate inversion pulses (538), seems to be useful in these regions (539).
The ability of DTI techniques to assess damage to the microstructure of the brain makes it potentially the most useful
technique for assessing brain injury in this disorder (magnetization transfer is more specific for myelin damage), as axonal
injury results in reduced average diffusivity and reduced FA (537). Although these findings seem to be less severe in pediatric-
onset disease than in adult-onset MS (540), early results suggest that disease in white matter pathways is widespread, with
increased diffusivity and reduced FA, even in normal-appearing white matter (541). Within the plaques themselves, highest
diffusivity values are found in T1 hypointense lesions, representing long-standing destructive damage. Diffusivity values in
enhancing and nonenhancing plaques are variable, although anisotropy is always lower in enhancing than in nonenhancing
plaques, suggesting that the inflammatory effects have a more variable impact on diffusivity than on anisotropy and that blood–
brain barrier breakdown probably varies during these active periods (542).
Magnetization transfer techniques are also useful in differentiating the inflammation associated with MS (little reduction of
magnetization transfer) from actual demyelination (more marked reduction of magnetization transfer) (543). Magnetization
transfer ratios diminish more rapidly in the acute phase and are overall lower in secondary progressive multiple sclerosis than
in relapsing–remitting multiple sclerosis; this observation may indicate a difference in the nature of these forms of the disease
(544). Detection of small lesions of the cerebral cortex can be improved by increasing signal-to-noise with parallel imaging or
higher field strength or by the use of sequences that suppress both the signal of white matter and that of CSF (545). Techniques
based upon susceptibility changes (fMRI and SWI) are being explored in pediatric MS patients as a method to assess effects of
the disease on brain connectivity; early results suggest preserved connectivity (537,546).
Localized proton spectroscopy from white matter plaques of children with MS shows a decrease in NAA and creatine and
an increase in choline and myo-inositol relative to age-matched controls (138). Adjacent white matter is normal, but adjacent
cortical gray matter shows reduced NAA. These data are supported by reports in the adult literature suggesting that acute MS
plaques have increased choline and normal NAA (indicating inflammation but no cell loss), whereas chronic lesions have
decreased choline and decreased NAA (indicating resolution of inflammation but loss of neurons or axons) (547). Reduced
NAA (548) and elevated lactate (548,549) may also be seen in acute plaques (Fig. 3-49). 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 (549). 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 (533)), 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 dysfunction. Such global analysis allows inclusion of disease in normal-appearing white
matter that might otherwise be missed (542).
Neuromyelitis optica spectrum of disorders
Neuromyelitis optica was initially characterized by sequential or concomitant optic neuritis and transverse myelitis, with
females much more commonly affected and onset at practically any age. As more experience with the disease accumulated, it
became evident that other areas of the CNS were often affected: unexplained hiccups or nausea and vomiting caused by
involvement of the area postrema (near the obex) (550), diencephalic syndrome/acute endocrinologic syndrome (551) causing
abnormalities of hypothalamic/pituitary function, symptomatic narcolepsy, or an acute cerebral syndrome with typical brain
lesions in the periphery of the brain abutting ventricular walls (ependyma) and cerebral walls (pia) (19). A recent consensus
statement has broadened the diagnosis of neuromyelitis optica, renaming it the neuromyelitis optica spectrum of disorders
(NMOSD) and dividing it into two major categories: (a) NMOSD with serum antibodies that target the water channel
aquaporin-4 (AQP4-IgG) and (b) NMOSD without AQP4-IgG or unknown AQP4-IgG status (19). Diagnostic criteria are listed
in Table 3-10. Pediatric NMOSD criteria are identical with two small exceptions: (a) presence of a longitudinally extensive
transverse myelitis is less specific for NMOSD in children; and (b) the presence of AQP4-IgG in a child with ADEM favors a
diagnosis of NMOSD (19).
Table 3-10 Neuromyelitis Optica Spectrum of Disorders
Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status
1. At least 2 core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:
a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis lesions or area
postrema syndrome.
b. Dissemination in space (2 or more different core clinical characteristics)
c. Fulfillment of additional MRI requirements, as applicable
2. Negative tests for AQP4-IgG using best available detection method or testing unavailable Moser
3. Exclusion of alternative diagnoses
1. Optic neuritis
2. Acute myelitis
3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
4. Acute brain stem syndrome
5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Adapted from Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
Neurology 2015;85:177–189.
As in adults, pediatric NMOSD is more common in females and in nonwhite populations (552–554), with a viral prodrome
occurring before the initial presentation in up to 84% of patients. Initially, most pediatric patients present with optic neuritis
(75%), with transverse myelitis being less common (30%); many patients (~10%) are initially diagnosed as having ADEM
(552). In the acute phase, swelling of optic nerves and the affected part of the spinal cord is seen but optic nerve atrophy and
spinal cord necrosis ultimately develop. CSF studies reveal intrathecal oligoclonal bands in 20% of patients; blood tests may
reveal the presence of the neuromyelitis optica immunoglobulin G (NMO IgG), the presence of which is considered specific
for a diagnosis of NMOSD (19,555,556). A large study in Great Britain found that 60% of pediatric patients with this classic
clinical onset were AQP4-IgG positive at presentation (552). Prognosis is better in children (complete recovery in 77%) than
adults (18%). The disease may be multiphasic, with recurrences occurring from less than 6 months up to 5 years after initial
presentation (553–555).
As optic neuritis is a common presenting symptom, identification of lesions within the optic nerves or suprasellar optic
pathways should be pursued in the imaging workup. This may be challenging and requires high-resolution imaging, including
thin section (3 mm or less) fat-suppressed T2-weighted or FLAIR images (3D FLAIR with fat suppression and 1 mm partition
size, reformatted in three planes, is best for detecting subacute or chronic optic neuritis) and fat-suppressed postcontrast T1-
weighted images (the most sensitive techniques to detect acute optic neuritis) (Fig. 3-50). 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 clinical presentation and evolution usually allow a confident differentiation. The spine should always be
examined, as simultaneous optic neuritis and transverse myelitis are reported at presentation in 15% (552). Detection of spinal
cord lesions (Fig. 3-51) is generally easy by MRI. The T2 hyperintense lesion, often occupying almost the entire cross-
sectional area of the cord (which is often swollen), is usually more extensive (3–17 segments) than MS-related cord lesions,
and enhancement after intravenous administration of paramagnetic contrast is seen in approximately 20% of patients (557).
Intracranial lesions are detected during the course of the disease in up to 25% of all patients and in up to 75% of children
(552,557,558). Especially commonly involved are the dorsal brain stem/area postrema (Fig. 3-51), which can be associated
with episodes of hiccupping and nausea/vomiting (550), and the hypothalamus (Fig. 3-52), resulting in hypothalamic–pituitary
dysfunction and causing an acute diencephalic syndrome (551). The presence of parenchymal brain findings should not alter the
diagnosis of NMOSD, as they are seen in about one-third of patients at presentation (552).
Figure 3-50 Neuromyelitis optica spectrum disorder in a 2-year-old girl with sudden loss of vision. Initial postcontrast T1 image (A) shows
markedly swollen, enhancing optic nerves (arrows) causing papilledema. Follow-up T2-weighted image (B) shows the swelling to have abated
somewhat and reveals hyperintensity of the anterior pons (black arrows). NMOSD parenchymal lesions tend to occur adjacent to CSF-filled
spaces.
Figure 3-51 Neuromyelitis optica spectrum disorder in a 14-year-old with acute onset of myelitis accompanied by nausea and vomiting. A and
B. Sagittal T2 (A) and postcontrast T1 (B) images show T2 prolongation and patchy enhancement involving the entire cervical spine and
extending into the obex (black arrows). The most caudal ventral medulla is also involved (white arrow in A). Note the normal dorsal pons. C and
D. Two years later, cranial neuropathies developed; sagittal and axial FLAIR images show minimal disease in the spinal cord (small arrows in
C) but new involvement of the dorsal pons (large arrows in C and D). NMOSD parenchymal lesions commonly occur adjacent to CSF-filled
spaces.
The shape and character of the brain and spine lesions may be useful to differentiate NMOSD from MS by MRI. In contrast
to cerebral MS lesions, in which long axes run perpendicular to the ventricles (along the veins), NMOSD brain lesions tend to
run parallel and adjacent to the walls of the ventricles, particularly in the brain stem (19). Spinal cord lesions in NMOSD tend
to involve the entire cord thickness for long segments (three vertebral bodies or more) (19), which helps to differentiate them
from lesions of MS but not from ADEM; therefore, the spinal findings are less specific in children than in adults.
Acute disseminated encephalomyelitis
Children may develop acute encephalitis late in the course of a viral or bacterial infection (commonly mycoplasma); less
commonly, encephalitis may occur after a vaccination or drug ingestion or with no history of a preceding event (559,560). This
disorder is called acute disseminated encephalomyelitis (ADEM) or parainfectious encephalomyelitis. A T-cell–mediated
cross-activation and response against myelin proteins, particularly myelin basic protein, PLP, and myelin oligodendrocyte
protein, is currently considered the predominating pathogenic mechanism of disease expression, resulting from molecular
mimicry of the infectious agents (560).
The most common clinical presentation is the onset of focal neurological signs a few days to several weeks after the clinical
onset of an infection. These are usually severe and indicate multifocal involvement of the CNS. Headache of rapid onset is
common, followed by vomiting (32%–35%), impairment of consciousness (45%–69%), seizures (13%–35%), and often
nuchal rigidity. Encephalopathy with behavioral changes (confusion, excessive irritability) or alteration of consciousness is
virtually always present; 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 (561). CSF cultures are
repeatedly negative for bacteria, fungi, or viruses, and typically (although not always) no oligoclonal bands are found;
elevation of proteins and white cell count (pleocytosis) are frequent (561). 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 (562).
Patients usually respond well to immunosuppressive therapy with intravenous high-dose methylprednisolone; intravenous
immunoglobulin (IVIG) serves as a second-line treatment in corticosteroid-resistant or refractory patients, and plasmapheresis
is sometimes used successfully. The neurological findings evolve and then resolve over a period of a few weeks up to 2 to 3
months (560,563). The majority of individuals make a complete recovery with no neurological sequelae; 10% to 30% will
have some permanent neurological sequelae (559).
Figure 3-52 Neuromyelitis optica spectrum disorder in an 11-year-old girl with vomiting and diencephalic syndrome. A. Axial T2-weighted
image shows hyperintensity (arrows) in the posterior pons along the anterior wall of the fourth ventricle. B. Axial T2-weighted image at the level
of the third ventricle shows multiple foci of hyperintensity: along the external capsule/insulae (arrowheads), in the globi pallidi (small arrows),
and in the thalami at the third ventricle ependyma (large arrows). C. Coronal FLAIR image shows hypothalamic involvement bilaterally (left >
right, white arrows), explaining the diencephalic syndrome. D. Coronal FLAIR image posterior to (C) shows more of the thalamic involvement
(large arrow) and shows involvement of the area postrema in the medulla (small arrows), likely responsible for the vomiting.
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 (564). Monophasic ADEM is defined as a multifocal clinical
syndrome in patients without a prior demyelinating event. Symptoms may evolve over a period of up to 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. Although no differences are found
between patients with recurrent or multiphasic ADEM (565), a significant number of patients who receive an initial diagnosis
of ADEM eventually receive a diagnosis of multiple sclerosis; this number could be as high as 25% (516,566). 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 multiple sclerosis (see paragraph on imaging findings below) on the initial MRI, or have an optic nerve
lesion. Chances of a second attack are lower in patients with myelitis (symptoms of spinal cord involvement) or mental status
changes (encephalopathy) (567).
Like the other disorders discussed in this section, ADEM is likely caused by an autoimmune response; it is postulated that
the precipitating illness induces a host antibody response against a central nervous system antigen. Although a specific
etiologic agent is inconsistently recognized in this disorder, a recent viral or mycoplasma infection or, less commonly,
vaccination is frequently noted (559,560). In addition, the gross pathological and histological manifestations of ADEM closely
resemble those of experimental allergic encephalitis, an experimentally induced autoimmune disease induced in laboratory by
exposure to antibodies to myelin. Pathologically, a diffuse perivenous inflammatory process causes confluent areas of
demyelination. In the brain, cortical and deep 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, the cortex, white matter, and deep gray nuclei may all be involved by the inflammatory process (568),
with moderate to large areas of demyelination (low density on CT, T1 hypointensity, and T2/FLAIR hyperintensity on MR)
seen in one or both hemispheres, usually asymmetrically (Fig. 3-53A and B) (568). CT, which may be 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 >90%
involvement in multiple sclerosis, and the corpus callosum is much more commonly involved in multiple sclerosis than in
ADEM; these criteria might be useful in differentiating ADEM from an initial episode of multiple sclerosis (516,563,569)
(factors that favor a diagnosis of MS are absence of a diffuse bilateral pattern of involvement and the presence of black holes,
sharply marginated regions of T1 hypointensity (516)). In the subacute phase, the lesions may show various patterns of
enhancement (nodular, diffuse, a complete ring, or a partial ring) after infusion of contrast (Fig. 3-53B and D) (570,571). MR
of ADEM reveals abnormalities of the basal ganglia/thalami in more than 50% (up to 80%) of affected pediatric patients
(563,568,572). The brain stem, spinal cord, and cerebellar white matter are each involved in about 30% to 50% of affected
patients (Fig. 3-53C and D) (563,573). Spinal cord lesions often are located in the central gray matter; long segments of the
cord (>3 vertebral bodies) are commonly affected in ADEM, another differentiation point from MS (but not from NMOSD).
Petechial hemorrhage may be present within the lesions; this is best demonstrated by T2-weighted gradient echo images or
susceptibility-weighted images. Diffusion imaging typically shows a short period (days) of reduced diffusivity in the acute,
inflammatory phase (574), followed by increased diffusivity in the foci of demyelination in both the acute and the subacute
phase, a factor that is useful in differentiating ADEM from vasculitis (lesions from vasculitis show reduced diffusion only in
the acute phase); however, rather prolonged reduced diffusivity is reported in up to 12% of cases (demonstrating the
heterogeneity of lesions in ADEM) (568). Perfusion imaging may 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 (575). Although ADEM may recur, as mentioned earlier, the clinical
exam and CSF analyses are more indicative of the course of the disease than the MR results.
Figure 3-53 Acute disseminated encephalomyelitis in a 13-year-old. A. Axial FLAIR image shows multiple foci of subcortical (white arrows)
white matter hyperintensity in the frontal and parietal lobes. B. Postcontrast T1 images at the same level show patchy subcortical
enhancement in the regions of FLAIR hyperintensity. C and D. T2 and contrast-enhanced T1 sagittal images of the cervicothoracic spine show
ventral T2 hyperintensity and patchy enhancement (arrows).
Other disorders may present with neurologic and imaging findings that resemble those of ADEM; these disorders include
viral encephalitis, collagen vascular diseases, Whipple disease, Behçet disease, neurosarcoidosis, and multiple sclerosis
(527,532,576–578). These alternative diagnoses must always be kept in mind when patients present with acute neurologic
deficit and imaging findings compatible with ADEM, which is diagnosed after exclusion of other possibilities.
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, influenza A, varicella-zoster, human herpesvirus 6,
and Epstein-Barr virus infections, although the inciting infection is often not identified (579–581). A genetic predisposition has
been suggested, as well (559). 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 brain stem (pons). Microscopically, widespread injury of astrocytes is associated with
swelling of their end feet and degeneration of both their processes and cell bodies in the absence of demyelination (582). Later
in the course of the disease, fibrinoid necrosis of vessel walls (both arteries and veins) is found in conjunction with
perivascular tissue necrosis 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 after onset (583,584). The few survivors have serious neurologic sequelae (585).
Imaging findings in acute hemorrhagic encephalomyelitis are of multiple or large unilateral or bilateral hemorrhagic lesions
of the cerebral white matter, most commonly involving the frontal and parietal lobes. The basal ganglia, thalami, brain stem,
cerebellum, and spinal cord may be involved. Overall, the lesions are similar to those in ADEM except that the lesions are
larger and hemorrhagic and have more associated edema and mass effect (39,183,586).
Systemic lupus erythematosus
Although commonly categorized as a collagen vascular disease, SLE fits into our discussion of autoimmune disorders, as
neuropsychiatric lupus (NPSLE) is a result of autoantibody stimulation and production, associated with (and possibly causing)
microangiopathy, intrathecal production of proinflammatory cytokines, and premature atherosclerosis (587). Neurological
involvement appears to be severe in children, who may accrue permanent organ damage at higher rates than adults (588,589).
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 (590). Males are more commonly affected in childhood (591); 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 (592,593). The most prevalent NPSLE symptoms in a recent longitudinal study were headaches
(in 72% of children), mood disorder (57%), cognitive dysfunction (55%), seizure disorder (51%), acute confusional disorder
(35%), peripheral nervous system impairment (15%), psychosis (12%), and stroke (12%) (590). A more recent prospective
study of 256 children with SLE confirmed the substantial contribution of both glomerulonephritis and CNS manifestations to
SLE-related morbidity over time (593).
In 32% to 47% of children with NPSLE, the neurologic manifestations either precede the diagnosis of SLE or are coincident
with the diagnosis; another 30% manifest neurologic signs or symptoms within 1 year of time of diagnosis (594). A variety of
pathologic findings have been identified in the brains of patients with SLE, including cerebral atrophy, cerebral infarcts due to
emboli or vasculitis (often associated with the antiphospholipid antibody syndrome (595,596)), petechial hemorrhages, and
areas of demyelination; these are attributed to angiopathy, direct autoimmune damage to brain, demyelination, and ischemia
from thromboembolism (597), all of which are believed to result from the action of cytotoxic antibodies that vary in their
composition and antigenicity and, thus, attack various vulnerable parts of the central nervous system (596).
Few prospective neuroimaging studies have been performed in children with SLE. In our experience, imaging studies may
show a variety of findings that vary with the indication for imaging. Unless there has been an acute onset of neurologic
signs/symptoms, CT and MR are usually negative or show large CSF spaces (598); morphometric analyses show both cortical
and white matter involvement (599). In patients with seizures, MR/CT may show focal lesions (25%) or may be normal. The
focal lesions are typically areas of low attenuation (CT) or T1 hypointensity and T2/FLAIR hyperintensity (MR) in the white
matter of the cerebrum, cerebellum, brain stem, or spinal cord (Figs. 3-54 and 3-55) (600). The basal ganglia may be involved;
if so, angiography should be performed to look for vasculitis. Spinal cord lesions (seen in 1%–5% of adults (601)) are often
rather long (spanning up to 8–10 vertebral bodies (Fig. 3-56) (601)); these typically have moderate associated edema and
expand the affected areas of spinal cord when acute but in the chronic phase often show cord atrophy with an enlarged central
canal. The MR lesions are believed to represent either autoimmune cerebritis/myelitis or parenchymal edema and injury
secondary to small vessel vasculitis. Depending on the underlying process, DWI may show normal or reduced diffusivity
acutely, evolving into increased diffusivity in the chronic phase. Some peripheral enhancement after intravenous administration
of paramagnetic contrast may be present in the subacute phase. Cerebral hemispheric lesions tend to involve subcortical white
matter, with or without overlying cortical involvement (Figs. 3-54 and 3-55), and may revert to normal on subsequent scans.
When the lesions are paramedian in location, it is not clear whether they represent areas affected by SLE (vasculitis or
cerebritis) or those that are abnormal because of recent episodes of hypertension or seizures, both common in SLE, with
consequent disturbance of the blood–brain barrier and resultant subcortical white matter (and sometimes cortical) T2/FLAIR
hyperintensity (602,603). These changes have, unfortunately, been given the name posterior reversible encephalopathy
syndrome (604,605). They are, in fact, regions of interstitial edema resulting from a mild breakdown in blood–brain barrier
related to transient hypertension with endothelial dysfunction (605,606). Most commonly, these abnormalities are bilateral,
symmetrical, and 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) (602,607). For uncertain reasons, they can be more
extensive; may involve the temporal lobes, thalami, or cerebellum; and are sometimes asymmetric (605). Although these
abnormalities are most often reversible, they can sometimes result in permanent brain injury (605,608). It is important to
perform diffusion imaging in such cases; those areas with normal or increased diffusivity will completely resolve without
residua, while those areas with reduced diffusion have suffered permanent injury and will undergo atrophy (607). 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 to 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 (irregularity
of arterial lumens; Fig. 3-54), arterial occlusions, or venous occlusions, 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 (609). The NAA/Cr ratios appeared to correlate with the course of the disease in one study (610).
Figure 3-54 Systemic lupus erythematosus vasculitis in a 10-year-old girl. A. Axial T2-weighted image shows abnormal hyperintensity
(arrows) in cortex and subcortical white matter of the bilateral occipital poles. B. Images from CTA of the intracranial vessels show extensive
vasculitis, manifested as multiple areas of vascular narrowing and occlusion along the pericallosal (anterior arrows in B) and callosomarginal
branches (superior arrows).
Figure 3-55 Multiple lesions due to antiphospholipid antibody syndrome in a 14-year-old with systemic lupus erythematosus. A. Axial FLAIR
image shows bilateral cerebellar (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.
Figure 3-56 Lupus affecting the spinal cord and medulla. Sagittal T2-weighted image shows a long segment of abnormal hyperintensity
(arrows) extending from the medulla down to the midthoracic spinal cord. Spinal cord lesions in SLE are often rather long (spanning up to 8–10
vertebral bodies) and typically have moderate associated edema.
Finally, at UCSF, we have admitted a number of children of varying ages (generally 5–15 years) who develop medically
refractory epilepsy after a minor (likely viral) illness and no specific antibodies have been identified. Many of these patients
are eventually put into a barbiturate coma in order to reduce excitotoxic brain injury from the autoantibody-induced injury. MR
imaging of these patients generally shows T2/FLAIR hyperintensity (sometimes transient) of the hippocampi, regions of the
cerebral (and sometimes cerebellar) cortex, and basal ganglia/thalami (Fig. 3-57F and G). If the epilepsy remains
uncontrolled, volume loss ensues in the affected areas.
Differential diagnosis of autoimmune disorders
The differential diagnosis of autoimmune encephalopathy/encephalitis of childhood includes viral/bacterial/spirochetal
encephalitides, toxic exposure (drug ingestion such as alcohol, ketamine, phencyclidine, and organophosphates), epileptic
disorders, inflammatory vasculitides (SLE), Beçhet disease, and some inborn errors of metabolism (Wilson disease, PKAN,
glutaric aciduria type I, creatine transport disorders, urea cycle disorders, and mitochondrial diseases).
Toxic/Nutritional Encephalopathies
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 triethyltin, hexachlorophene, cuprizone, actinomycin D, and isoniazid (183,623–625). All of these disorders
cause bilateral symmetric white matter injury that involves the subcortical U fibers early in the course of the clinical illness. A
similar pattern is described after ingestion of toxic heroin (Fig. 3-58) (626). Other drugs that can cause brain injury include
amphetamines (including methylenedioxymethamphetamine/ecstasy (627)), oxycodone (globus pallidus, cerebellum, corpus
callosum (628)), and medications such as MTX (central deep cerebral white matter), tacrolimus (cerebral cortex),
metronidazole (cerebellar nuclei), and vigabatrin (deep cerebral/cerebellar nuclei) (629).
Osmotic demyelination syndrome in childhood
The term osmotic demyelination syndrome refers to osmotic myelinolysis in any regions of the brain; it is most widely
described in adults but is common in children, as well (630). 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, but current theory suggests a hyperosmotically induced
demyelination process resulting from rapid intracellular/extracellular to intravascular water shifts producing relative glial
dehydration, myelin degradation, and/or oligodendroglial apoptosis (631). In children, central pontine myelinolysis has been
reported to occur with various disorders including fulminant hepatitis, hypophosphatemia, liver transplantation, diabetic
ketoacidosis, chronic debilitation, treatment of hyperammonemia and craniopharyngioma, and malnutrition often associated
with severe fluid and electrolyte disturbances (632–635).
Figure 3-58 Acute leukoencephalopathy from toxic heroin ingestion. A and B. Axial T2-weighted images show abnormal hyperintensity 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 ganglia. 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 macromolecular 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 doublet at 1.3 ppm) due to impaired mitochondrial production of ATP.
Extrapontine myelinolysis (EPM) may be found concurrently with (~15%) or in the absence of (~20%) pontine disease
(630). Patients become symptomatic after rapid shifts in fluids, usually the result of overly rapid treatment of hyponatremia in
many clinical situations (630,636); the causes are almost certainly similar to those of central pontine myelinolysis (637).
Affected children may manifest a variety of neurologic signs and symptoms, including akinesis, ataxia, catatonia,
choreoathetosis, rigidity, dysarthria, dystonia, emotional lability, mutism, myoclonus, myokymia, parkinsonism, and tremor
(637).
The imaging appearance of childhood myelinolysis is identical to that in adults, with a focus of low attenuation (CT) or T1
hypointensity and T2/FLAIR hyperintensity (MR) in the central pons (Fig. 3-59A); the corticospinal tracts are
characteristically spared. Diffusion is reduced in the affected area(s) (Fig. 3-59B) (638). Both the patient and the MR scan may
return to normal after slow treatment of nutritional and electrolyte abnormalities (634,639). It is important to remember that
osmotic myelinolysis can develop in other areas, including the basal ganglia (640), thalami (641), external and extreme
capsules, cerebral cortex (usually at the cortical–white matter junction) (631,642), and middle cerebellar peduncles (643)
(Fig. 3-59C). (Relatively few disorders cause abnormalities of the middle cerebellar 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 (644,645).)
Lead encephalopathy
Special mention must be made of lead encephalopathy. The developing fetus and child are more sensitive to lead exposure than
adults because of the immaturity of the blood–brain barrier, increased gastrointestinal absorption, and hand to mouth behaviors
of childhood, all of which increase exposure (646). Although lead encephalopathy has been recognized for many years, recent
studies have shown that exposure to relatively low levels of lead can lead to specific impairments such as fine motor skills,
attention, and visuoconstruction (647,648); boys appear to be more sensitive than girls (647). The typical clinical presentation
of children with lead intoxication is abdominal cramping, nausea, and vomiting. Neurologic signs and symptoms vary from
mild behavioral change to frank obtundation, with occasional ataxia, aphasia, or psychological disturbance (647–649). The
most common imaging finding is edema (swelling and T2/FLAIR hyperintensity) in the external and extreme capsules (Fig. 3-
60) (650). Rarely, lead intoxication may lead to localized edema in the cerebellum causing hydrocephalus and presentation as
a posterior fossa mass (649,651). CT and MR in these cases show localized cerebellar edema with mass effect and mild
enhancement after intravenous contrast infusion (649,651). The appearance is identical to that of acute cerebellitis from viral
illnesses (see Chapter 11).
Solvent abuse
Solvent abuse is a serious problem in some cultures, particularly in adolescents and young adults (652). Toluene and other
forms of organic materials (trichloroethane, methylchloroform) are inhaled and rapidly absorbed into the bloodstream, from
where they can cross the blood–brain barrier and involve the central nervous system (652). Patients may present with acute
encephalopathy or with chronic mental and neurologic deterioration. Insomnia, forgetfulness, anosmia, and tinnitus are reported
to be common (653). Neurologic exam reveals cerebellar ataxia (50%), tremors of the extremities (35%), increased deep
tendon reflexes (25%), and rigidity (25%) (653). Pathologic studies of the brains of affected patients show neuronal and
axonal loss with associated demyelination: diffuse demyelination of the cerebral 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 (652,654). MR shows loss of gray-white discrimination, diffuse mild T2 prolongation of the
(deep greater than subcortical) cerebral and cerebellar white matter, often some T2 shortening of the putamina, and generalized
atrophy of cerebrum and cerebellum (626,654,655). In severe cases (associated with a longer duration of abuse (653)), T2
shortening (hypointensity) may be seen in the thalami, substantia nigra, and cerebral cortex (656).
Figure 3-59 Osmotic demyelination syndrome in two patients. A and B. Axial T2-weighted image (A) and ADC map (B) from a child with
lymphoma show central pontine myelinolysis in T2 prolongation (arrow in A) and reduced Dav (arrow in B) in central pons. C. Axial T2-weighted
image in a 3-year-old child shows extrapontine demyelination, with T2 prolongation in the claustra, lateral putamina, anterior limbs of internal
capsules, and central thalami.
Figure 3-60 Lead encephalopathy in a 9-year-old child. Axial T2-weighted image shows hyperintense edema (black arrows) in the external
and extreme capsules.
Gray Matter Disorders Primarily Involving the Deep Gray Cerebral Nuclei
Neurodegeneration with brain iron accumulation
The term neurodegeneration with brain iron accumulation (NBIA) refers to a group of heterogeneous neurologic disorders
characterized by progressive accumulation of iron in the basal ganglia, mainly in the globus pallidus and substantia nigra,
resulting in physical and neuropsychiatric deterioration. So far, 10 genes are implicated with these disorders. PANK2 (MIM
606157) causes pantothenate kinase–associated neurodegeneration (PKAN), also known as INAD, and accounts for 35% to
50% of all cases (657). PLA2G6 (MIM 256600) causes phospholipase A2–associated neurodegeneration (PLAN) and accounts
for 20% of cases (658). C19orf12 (MIM 614297) causes mitochondrial membrane protein–associated neurodegeneration
(MPAN) and accounts for 6% to 10% of cases (658,659). More recently, WDR45 (MIM 300894), coding for a protein with a
putative role in autophagy and causing beta-propeller protein-associated neurodegeneration (BPAN), was reported, accounting
for 1% to 2% of cases (660,661). Other rare forms of NBIA are caused by several other genes: FA2H (MIM 611026) causing
fatty acid hydroxylase-associated neurodegeneration (FAHN) (662,663), ATP13A2 (MIM 610513) causing Kufor-Rakeb
syndrome (664,665), FTL (MIM 134790) causing neuroferritinopathy (666), CP (MIM 604290) causing aceruloplasminemia
(667), DCAF17 (MIM 612515) causing Woodhouse-Sakati syndrome (668,669), and most recently, COASY (MIM 609855)
coding for CoA synthase (670). These 10 genes account for <70% of patients with NBIA, leaving a significant number without
a known genetic defect.
The hallmark clinical manifestations of NBIA are progressive dystonia, dysarthria, spasticity, and parkinsonism later in life.
Retinal degeneration and optic atrophy are common. Onset ranges from infancy to adulthood. Progression can be rapid or slow
with intermittent stability, and cognitive abnormalities vary among subtypes. All are inherited in an autosomal recessive
manner, except the subtypes due to WDR45, which is associated with X-linked dominant de novo mutations with suspected
male lethality, and FTL, which is inherited in an autosomal dominant fashion. Although NBIA disorders are defined on the
basis of iron deposition in the brain, not all mutations in NBIA genes lead to iron deposition (671).
Pantothenate kinase–associated neuropathy (neurodegeneration with brain iron accumulation 1, formerly Hallervorden-Spatz disease)
Pantothenate kinase–associated neuropathy (PKAN, also called neurodegeneration 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 disorder, dysarthria,
and mental deterioration (672,673). Optic atrophy or retinitis pigmentosa may develop (673). Although the age of onset varies
considerably, most patients begin to show some neurological deterioration during the last half of the first decade or first half of
the second decade of life (674); however, the age of onset can vary greatly (674). 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 (675); this has been found to
be a novel pantothenate kinase gene (PANK2) (676), the protein product of which localizes to mitochondria in animal models
(677).
Two forms of PKAN have been defined (678). The classic form is characterized by disease onset before the age of 10 years
(mean 3.4 ± 3.0 years), manifested as extrapyramidal signs (dystonia, dysarthria, and choreoathetosis, seen in >95%),
pyramidal signs (spasticity, hyperreflexia, and extensor toe signs, seen in 25%), cognitive decline (29%), and retinopathy
(68%); most of these patients have mutations of PANK2 (657). 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
retinopathy (20%); pyramidal signs are about equally common (18%) as in the classic form (657); these patients are less likely
to have mutations of PANK2 and are referred to as having neurodegeneration with brain iron accumulation (678).
The striking pathologic finding in affected patients is rust-brown pigmentation of the globus pallidus and zona reticulata of
the substantial 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 pallidus (particularly the
internal segment) and substantia nigra (679).
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. MR shows hypointensity in the globus
pallidus on T2-weighted images (Fig. 3-61, more pronounced hypointensity than is normally seen in the second decade; see
Chapter 2), resulting from iron deposition (680–682); this finding may appear before clinical symptoms develop (683). 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 (3 T), the sign will appear on T2-weighted spin-echo, FLAIR, and diffusion-weighted images
(Fig. 3-61). Foci of T2 hyperintensity of variable size are typically present within the area of T2 hypointensity (Fig. 3-61B);
these foci presumably represent pallidal destruction and gliosis (681). This imaging sign, called the “eye of the tiger sign”
seems to be much more common in those cases with PANK2 mutations (657) (but it is not always present (684,685) and one
report describes this characteristic sign disappearing during the course of the disease (686)). Susceptibility-weighted imaging
using high-pass filtered phase images can differentiate calcium from iron deposition only if the user knows whether the MR
imaging system is “right handed” or “left handed” (687,688). This sequence should be obtained if the presence of iron is in
question. The study will show marked loss of signal in regions of iron deposition (Fig. 3-62). However, as noted in Chapter 2,
iron accumulates early in the globi pallidi and substantia nigra (and, to a lesser extent, the red nuclei) (691); the presence
of hypointensity in these areas on susceptibility-weighted images (SWI) at 3 T in the second decade or later is usually
normal and should not, in itself, stimulate a workup for NBIA! Diffusion imaging shows increased FA and mean diffusivity in
the globi pallidi and substantia nigra of affected patients compared with age-matched controls (692).
Figure 3-61 Pantothenate kinase–associated neuropathy (neurodegeneration with brain iron accumulation, type 1). A. Axial T2-weighted
image shows marked hypointensity in the bilateral globi pallidi (arrows). B. Coronal FLAIR image also shows bilateral globus pallidus
hypointensity but shows, in addition, some central hyperintensity (arrows), likely representing tissue destruction and astroglial response. C.
Axial diffusion-weighted image also shows hypointensity in the globi pallidi (arrows), likely as a result of susceptibility artifact.
Patients with NBIA without PANK2 mutations (678) also have T2 hypointensity in the globi pallidi but are less likely to
have the central T2 hyperintensity (685). Although oculodigital dental dysplasia (693) 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 3-11 to 3-13).
Juvenile Huntington disease
Huntington disease (OMIM 143100) is a chronic progressive degenerative disease characterized by choreiform movements,
mental deterioration, 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 (697). The CAG segment on the gene is
unstable when transmitted to the next generation, with a propensity toward further expansion, particularly during
spermatogenesis (698). Larger segments of CAG repeats are associated with earlier onset; juvenile Huntington disease is
reported to be associated with 80 to 100 CAG repeats (699), although a recent publication suggests that maternal transmissions
and expansions of fewer than 60 CAG repeats are more common than has been reported (700). Less than 6% of patients present
prior to age 14 years (701). 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, often with psychiatric difficulties (700),
whereas those presenting at age 10 years or older most commonly present with oropharyngeal dysfunction (702). 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 (702). Patients in both
groups developed gait, cognitive, and behavioral disorders 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 (702). Presentation with
progressive myoclonus epilepsy has been described (703).
Figure 3-62 Use of susceptibility-weighted imaging (SWI) in identifying calcium and iron. A. Axial T2-weighted image shows hypointensity
around the perimeter of the globi pallidi (arrows), but the center is somewhat hyperintense. B. Susceptibility-weighted image shows darkening
of the regions of T2 hypointensity (arrows) but does not entirely prove the presence of iron. C. Processed SWI shows hypointensity (arrows); on
a “left-handed system,” this is definitive for iron.
Table 3-11 Childhood Diseases Involving the Deep Cerebral Nuclei
Acute
Hypoxia
Hypoglycemia
Toxins (carbon monoxide, cyanide)
Hemolytic–uremic syndrome
Osmotic myelinolysis
Encephalitis (think streptococcus [Sydenham chorea]; Epstein-Barr virus; if thalami think West Nile virus or acute necrotizing encephalopathy, often
from HHV-6)
Vasculitis (especially from varicella-zoster virus)
Parainfectious encephalomyelitis
Tegretol toxicity
Chronic
Degenerative diseases
Other diseases
Neurofibromatosis type 1
Chronic liver disease of any cause
Aicardi-Goutières syndrome
Table 3-12 Disorders Resulting in Deep Cerebral Nuclear Calcification
Endocrine
Hypoparathyroidism
Pseudohypoparathyroidism
Pseudopseudohypoparathyroidism
Hyperparathyroidism
Hypothyroidism
Metabolic
Mitochondrial disorders
Aicardi-Goutières syndrome
Fahr disease (familial cerebrovascular ferrocalcinosis)
Pantothenate kinase–associated neuropathy
Carbonic anhydrase deficiency type II
Wernicke encephalopathy
Griscelli disease (694)
Fried syndrome (695)
Organic acidurias
Congenital or developmental
Inflammatory
Toxoplasmosis
Congenital rubella
Cytomegalovirus
Measles
Chickenpox
Pertussis
Coxsackie B virus
Cysticercosis
Systemic lupus erythematosus
Acquired immunodeficiency syndrome
Toxic
Hypoxia
Cardiovascular event
Carbon monoxide intoxication
Lead intoxication
Radiation therapy
Methotrexate therapy
Nephrotic syndrome
Table 3-13 Anatomic Distribution of Some Diseases Affecting Basal Ganglia
Acute Disorders
Cyanide intoxication ++ + + −
Hemolytic–uremic syndrome + + +
Viral encephalitis + + + +
Leigh syndrome + + ++ +
Canavan disease ++ − − ++
GM2 gangliosidoses − ++ − +
Wilson disease ++ + ++ +
Fried syndrome + ++ +
Ethylmalonic encephalopathy + ++ ++ −
Methylmalonic acidemia + − − +
Propionic acidemia − ++ ++ +
Isovaleric acidemia ++ − − −
L-2-Hydroxyglutaric aciduria ++ + + ++
Kearns-Sayre syndrome ++ − − ++
β-Ketothiolase deficiency ++ − − −
Alpha-ketoglutaric aciduria + + ++ −
Aicardi-Goutières syndrome + + ++ ++
3-Hydroxyisobutyric aciduria + ++ ++ −
Imaging studies are normal early in the course of the disease. As the disease progresses, the striatum atrophies and develops
T2 hyperintensity; atrophy of the caudate heads results in a characteristic enlargement of the frontal horns of the lateral
ventricles, which become convex laterally (Fig. 3-63) (701). Atrophy in the putamen, seen better by MR than by CT, is equal to
or more severe than in the caudate (702,704). Cortical atrophy is most prominent in the frontal lobes. As in many other
metabolic diseases, F-18 fluorodeoxyglucose PET scanning identifies decreased glucose uptake in the striatum before CT or
MR scans become positive (705). Comparisons of the sensitivity of PET to that of MR have not been published. A single
report of proton MRS found reduced NAA and increased myo-inositol 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 (706).
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 (707,708).
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
periodic attacks of severe ketoacidosis (typically provoked by infection) occur with asymptomatic intervening periods (709).
Patient outcomes are inversely related to the age at diagnosis but not to the number of catabolic episodes (710). The
abnormalities 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 (Fig. 3-64) (711).
Figure 3-64 Isovaleric acidemia. T2-weighted images at ages 7 (A) and 17 months (B) show hyperintensity in the bilateral globi pallidi (white
arrows).
Figure 3-65 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.
Figure 3-66 Creatine deficiency secondary to guanidinoacetate methyltransferase deficiency in 10-month-old child. A. Axial T2-weighted
image is normal; some cases show bilateral T2 prolongation of the globi pallidi. B. Single-voxel proton MRS (TE = 26 ms) of the basal ganglia
also shows absence of the creatine peak. The finding 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. C. 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.
β-Ketothiolase deficiency
Also known as mitochondrial acetoacetyl-CoA thiolase deficiency (OMIM 203750), this rare autosomal recessive disorder
affects isoleucine and ketone body catabolism (738). It is caused by mutations of the ACAT1 gene, which encodes
mitochondrial acetyl-CoA acetyltransferase at chromosome 11q22.3. The disorder is sometimes not identified by newborn
screening. Affected patients have intermittent episodes of metabolic ketoacidosis associated with vomiting and
unconsciousness, often triggered by infections; no clinical symptoms are detected between episodes (739). MRI shows reduced
diffusivity in swollen putamina during the acute phase, followed (if damage has occurred) by low diffusivity and shrunken
putamina (Fig. 3-67A) between episodes of decompensation (740). Proton MRS of the basal ganglia can be supportive and
increase specificity, showing enlarged peaks of 3-hydroxybutyrate at 1.2 ppm, acetone and acetoacetate at 2.25 ppm, and a
second acetoacetate peak at 3.4 ppm (Fig. 3-67B) (741).
Infantile beriberi/Wernicke encephalopathy
Wernicke encephalopathy (OMIM 277730, also called Wernicke-Korsakoff syndrome, Gayet-Wernicke encephalopathy, and
alcohol-induced encephalopathy) and infantile beriberi are degenerative conditions caused by a chronic deficiency of thiamine
(vitamin B1) (37,742). Infants who receive insufficient thiamine present with altered mental status (confusion, somnolence,
stupor, or coma), systemic signs/symptoms of vomiting/reflux, fever and diarrhea, tachycardia, and neurologic findings of
altered sensorium, irritability, ptosis, seizures, and lack of response to external stimulation (37,742,743). In adults who receive
a large percentage of their calories from alcoholic beverages, a classical clinical triad of oculomotor abnormalities, mental
status changes, and ataxia has been described; few patients present with the full triad. Ocular signs (ophthalmoplegia or
nystagmus) are present in more than two-thirds of patients (74%) at presentation, but ataxia is less common (39%) (742).
Affected patients are typically malnourished, most commonly from malignancy, gastrointestinal disease, or food allergy (743).
Figure 3-67 β-Ketothiolase deficiency in a 12-month-old child. A. Axial T2-weighted image shows bilateral putamina hyperintensity (arrows).
Myelination is normal. B. Short echo (26 ms) proton MRS shows multiple extra peaks (arrows): enlarged peaks of 3-hydroxybutyrate at 1.2
ppm, acetone and acetoacetate at 2.25 ppm, and a second acetoacetate peak at 3.4 ppm.
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. The most common MR imaging findings are T2/FLAIR
hyperintensity and atrophy of the dorsomedial thalami and mamillary bodies, with the periaqueductal area involved in about
two-thirds (sometimes including the tectum); about half show enhancement after administration of intravenous contrast
(626,742). Increased diffusivity is seen in the affected areas (744). Reported cases of affected infants and children show
involvement (low attenuation on CT, T2/FLAIR hyperintensity on MR) of the medial thalami (most common finding; Fig. 3-68),
putamina, caudate nuclei, and frontotemporal cerebral cortex (37,743,745,746). MRS is reported to show lactate in affected
areas, together with decreased NAA and choline (747).
Figure 3-68 Pediatric Wernicke encephalopathy in an anorexic 12-year-old. Axial T2-weighted image shows abnormal T2 hyperintensity
(white arrows) of the medial thalami.
Hemolytic–Uremic syndrome
The HUS is a thrombotic microangiopathy that results in a multisystemic disorder, characterized clinically by hemolysis, renal
insufficiency, thrombocytopenia, and a microangiopathic hemolytic anemia that follow a prodrome of acute afebrile
gastroenteritis, often with bloody stools (748,749). (Thrombotic microangiopathies are defined by thickening of the walls of
arterioles and capillaries, prominent endothelial swelling and detachment, and subendothelial accumulation of proteins and
cellular debris that result in fibrin and platelet-rich thrombi obstructing vessel lumina with resultant tissue ischemia (748).) In
HUS, the renal vasculature is the predominant site of microangiopathy, with the brain (20%–50%), heart, lungs, and GI tract
also commonly affected. Central nervous system involvement is most commonly caused by infections with Stx-producing
strains of Escherichia coli; these result in altered mental status, personality changes, seizures, long tract signs, and loss of
vision. 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 (750,751). The mutation of several genes that regulate the complement
alternative pathway causes a variant of the disease called atypical hemolytic–uremic syndrome (OMIM 235400) (752), 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 ischemic 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. MRI in the
acute phase shows reduced Dav in the basal ganglia and deep subcortical white matter, which may resolve completely or
evolve into increased Dav in the chronic stages of the disorder (Fig. 3-69) (753,754). In the more subacute phase, FLAIR- and
T2-weighted MR images show hyperintensity in the affected areas of the deep gray cerebral nuclei, particularly thalami,
putamina, brain stem, cerebellar vermis, and cerebral cortex (Fig. 3-69) (753). The adjacent white matter, particularly the
internal and external capsules in the case of putaminal involvement and the subcortical white matter in cases of cortical
involvement, may be involved (Fig. 3-69B) (751,753,754). T1-weighted MR images may show hyperintensity in the basal
ganglia (Fig. 3-69), resulting from coagulative necrosis secondary to microthrombosis without hemorrhage or calcification
(751). These areas of T1 hyperintensity may persist on follow-up imaging (Fig. 3-69E) (753) and may continue to enhance for
many weeks (Fig. 3-69F). When the cerebral cortex is involved, similar signal characteristics are seen (751).
Figure 3-69 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 hyperintensity (white arrows) in the posterior putamina
and globi pallidi. Contrast enhancement in (F) shows that the blood–brain barrier injury has not fully healed.
Sydenham chorea
Sydenham chorea, also called chorea minor, St. Vitus dance, or rheumatic encephalitis, is a presumed autoimmune phenomenon
that results from streptococcal infections. Most common in children between ages of 7 and 12 years, it may be isolated (20%–
30%) or be associated with other manifestations of rheumatic fever (carditis, migratory polyarthritis, subcutaneous nodules)
(755,756). Affected patients develop a hypotonic, hyperkinetic syndrome that is characterized clinically by involuntary and
uncoordinated movements, muscular weakness, frequent 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–compulsive disorder, anxiety, and depression
may develop, as well (756). Neuropathological studies have revealed degeneration of neurons and alteration of blood vessels
in the cerebral cortex, basal ganglia, and cerebellum (757), as well as antibodies reactive against dopamine D2L (D2R)
receptors on neurons of the corpus striatum (756,758,759).
Imaging findings may correlate with outcome. The basal ganglia are by far the region in which abnormalities are most
commonly recognized, in particular the caudate nuclei, putamina, and cerebral white matter. Localized low attenuation is seen
on CT, while T2 prolongation is seen on MR (Fig. 3-70A–D) (760–762). These changes may be permanent (762), but they
generally resolve over weeks to months (761). When MR changes are permanent (Fig. 3-70A–D), they seem to be associated
with prolonged clinical course of disease and recurrent episodes of neurological impairment (760). Reduced volume of the
basal ganglia is seen on volumetric studies, even in patients with apparently normal MR imaging studies (763). Proton MRS
shows elevated choline/creatine and reduced NAA/creatine (764).
Figure 3-70 Sydenham chorea with permanent injury to basal ganglia after a severe streptococcal infection. A and B. Early phase of disease
shows T1 hyperintensity of the right lentiform nucleus (arrow in A) with some volume loss already present in the right corpus striatum (arrows in
B). C and D. Later phase showing marked volume loss and scarring in bilateral basal ganglia. E. Axial T2-weighted image shows small, slit-like
lentiform nuclei (white arrows) in a patient with an ARX mutation.
Clinical presentation depends upon the type of NCL and the age of presentation (785,786). Infants with the congenital form
(almost exclusively CNL10) are characterized by primary microcephaly, respiratory insufficiency, neonatal (or prenatal)
epilepsy, and death in early infancy (787). Patients with infantile forms (usually CNL1) typically are brought to attention
because of deceleration of head growth and muscular hypotonia between the ages of 6 and 24 months. Ataxia and motor
clumsiness develop together with psychomotor regression irritability, sleep disturbance, and visual failure leading to a rapid
developmental deterioration, usually during the second year of life (787,788). In late infantile forms, the first symptoms begin
around the third year of life (rarely as late as 6 years), typically an unexpected delay of psychomotor development or epilepsy
(myoclonic, tonic, absence, and tonic–clonic) of sudden onset; they may soon become resistant to drug treatment (787,788).
The first symptom of patients with juvenile forms is usually failure of vision between the ages of 4 and 7 years, followed after
several years by progressive dementia, seizures, and progressive impairment of speech and motor function (788,789).
Definitive diagnosis is made by genetic testing or by electron microscopic analysis of lipopigments from the skin, which shows
characteristic ultrastructral characteristics (789). 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 development, analysis for PPT1 and TPP1 activity (see Table 3-14) has been recommended (786).
Findings on imaging studies (Figs. 3-71 and 3-72) 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 hyperintense rims around the ventricles (Fig. 3-71) and T2 hypointensity in the thalami and globi
pallidi (95,790–793). The T2 changes appear to correlate with loss of myelin and gliosis of unknown origin (794); thalamic
atrophy develops, suggesting that the thalamic T2 changes may be primary rather than secondary. Cortical hypoperfusion is
shown by SPECT (793). Atrophy of both cortex and deep structures develops more rapidly in the infantile form (Fig. 3-71)
than in the late infantile form (Fig. 3-72) and earlier in the late infantile form than in the juvenile form (790,795). In the late
infantile and progressive epilepsy with mental retardation forms, cerebellar atrophy is an early finding; indeed, these patients
often present with motor delay secondary to cerebellar atrophy (787,788), but it may not progress as rapidly as supratentorial
atrophy (Fig. 3-72). In the other forms, cerebellar and cerebral atrophy seem to progress at similar rates (Fig. 3-71). 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 (790,794).
Proton MRS in the infantile form of the disease shows a complete absence of the NAA peak (suggesting markedly reduced
mitochondrial function), marked reduction of creatine and choline, and elevation of myo-inositol and lactate in gray and white
matter (793). In the late infantile form, reduced NAA has been noted in gray and white matter; myo-inositol, creatine, and
choline are elevated in white matter (Fig. 3-57D) (796,797). On short TE spectra, the level of myo-inositol elevation is
reportedly concordant with the severity of disease (797). Lactate elevation is reportedly seen in some patients (796). In
juvenile NCL, spectra are reportedly normal (796). 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.
Figure 3-71 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 is
courtesy of Dr. Lara Brandao, Rio de Janeiro, Brazil.)
Figure 3-72 Progressive disease in late infantile neuronal ceroid lipofuscinosis. A–C. Sagittal T1, coronal FLAIR, and axial T2 images at age 5
years show diffuse cerebral and cerebellar atrophy with enlarged ventricles and sulci and loss of myelin in (C). D–F. Same patient 3 years
earlier (age 2 years), when atrophy was very mild and myelination was age-appropriate.
PET and SPECT may be useful in establishing diagnosis in NCL. 18 FDG PET studies show severe reduction of
metabolism in all the cortical and subcortical structures. Regional analysis shows marked bilateral hypometabolism,
particularly in calcarine, lateral occipital, and temporal cortices and in thalami (798). In infantile NCL, SPECT using 99m-Tc
HMPAO showed bilateral anterior frontal, posterior temporoparietal, and occipital hypoperfusion. Initially, hypoperfusion was
localized and symmetric, whereas atrophy on MR was more generalized. 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 MR (799). SPECT in juvenile NCL shows diffuse hypoperfusion, most severe in the temporal lobes
and less so in the parietal, occipital, and cerebellar regions. Interestingly, epilepsy does not correlate well with involvement of
any region by SPECT (800).
Aspartylglucosaminuria
Aspartylglucosaminuria (AGU, OMIM 208400) is a hereditary lysosomal storage disorder caused by defective activity of the
enzyme aspartylglucosaminidase in various body tissues and fluids (801). The AGA gene on chromosome 4q32-33 has been
cloned and several mutations causing AGU have been identified (802). Characteristic neurological manifestations are mildly
dysmorphic facial features, slowly progressive mental retardation, delayed speech, hyperkinesia, motor clumsiness, and slight
truncal ataxia (802–804). 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)
(805) 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 (803). It seems that this white matter abnormality may be reversed by
bone marrow transplant (806). As the patients mature, cortical–white matter differentiation improves but cortical atrophy
develops, manifested as shrunken gyri and enlarged sulci (803).
Infantile neuroaxonal dystrophy/NBIA2A/PLAN
Three names are listed for this disease because some consider it a form of neurodegeneration with brain iron accumulation
(i.e., NBIA type 2A) (671), others name it after the affected gene (PLA2G6-associated neurodegeneration or PLAN) (807), and
others still call it infantile form of neuroaxonal dystrophy (INAD, OMIM 256600) (808). Patients usually present during 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 (807). 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 (809) (note that other PLA2G6 mutations have also been associated with early-onset dystonia–
parkinsonism and with mitochondrial dysfunction (810), more evidence that proteins participate in multiple pathways and that
different mutations of the same gene can cause very different diseases). 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 common (671,807). As with most metabolic disorders, severity of the disease seem to correlate
with the effect of the mutation on protein function: loss of function leads to a severe INAD profile, while increasing degrees of
protein function result in progressively less severe phenotype (671,811). Among patients with the “typical” infantile form of
the disease, about 30% present following an intercurrent illness (807). Initial physical exam typically reveals axial hypotonia,
four-limb spasticity, and bulbar signs. Patients eventually develop ataxia, dystonia, optic atrophy and blindness, muscular
atrophy, severe dementia, and, eventually, complete lack of motor function. Epilepsy develops in some patients (671,807,812).
A later onset form of the disease (sometimes called atypical NAD) is characterized by progressive spasticity, ataxia, and
dystonia, progressing to optic atrophy, peripheral neuropathy, and impaired cognition (813).
Pathology shows atrophy of the cerebellar and cerebral cortices, degeneration of Purkinje cells, and cerebellar granule cell
loss, with marked astrogliosis, extensive axonal swelling, and spheroids in the axoplasm of the pontine tegmentum, midbrain,
periaqueductal gray matter, and trochlear nuclei; iron deposition with swollen axons, depleted myelin, and swollen
mitochondria is seen in the basal ganglia, mainly in the globus pallidus. The medulla is affected, as well, with diminished size
of the corticospinal tracts and enlargement of the dorsal nuclei resulting in expansion of the medulla immediately beneath the
level of the obex (808,813).
Imaging with MR reveals prominent sulci in the cerebral and cerebellar cortices, diminished cerebral white matter, and
marked T2 prolongation of the cerebellar cortex (Fig. 3-73). Sequential scans will show progressive cerebellar atrophy in
most patients (807,814), which usually starts to develop during the second half of the second postnatal year preceding the
appearance of susceptibility and, often, T2 hypointensity (corresponding to iron deposition) in the globi pallidi (807,813,815);
this is most notable in children with more severe forms of the disease. Some patients show thinning of the optic nerves and
chiasm (814). Proton MRS shows progressive loss of NAA and, in some patients, slightly elevated lactate in the basal ganglia
(813,816).
Niemann-Pick disease
Niemann-Pick disease is an autosomal recessive disorder that is characterized by progressive hepatosplenomegaly,
lymphadenopathy, edema, and, in some patients, neurologic degeneration. The underlying problem 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 manifestations, which consist primarily of loss of motor and intellectual function. Onset in early infancy and rapid
deterioration are characteristic of type A variant, which is caused by mutations of the SMPD1 gene at chromosome 11p15.1-4
(817). Onset in the late infantile or early childhood periods (less commonly in adolescence) with slower progression is seen in
type C1 (265), caused by mutation of the NPC1 gene at chromosome 18q11-12 (818) and (much less commonly), type C2,
caused by mutation of NPC2 at 14q24.3, which have similar phenotypes (819). 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 (819,820).
Figure 3-73 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 are courtesy of Dr. Susan Blaser, Toronto.)
Figure 3-74 Niemann-Pick disease, type C, in an 11-year-old. A. Sagittal T1-weighted image shows marked superior vermian atrophy
(arrows), with markedly narrow folia resulting in enlarged fissures. B. Axial T2-weighted image at the level of the basal ganglia shows hazy
white matter, lacking its normal T2 hypointensity, with resultant extensive blurring of the cortical–white matter junction, most prominent in the
frontal and perisylvian cortex in this patient.
Imaging findings reflect the pathologic descriptions of nonspecific progressive gray matter atrophy, which is most prevalent
in the cerebellum (Fig. 3-74A) and the frontal lobes, when present. The cortical sulci and ventricles are enlarged. The corpus
callosum is often thin. The underlying white matter shows diffuse, hazy T2 hyperintensity, and, to a lesser extent, T1
hypointensity that results in blurring of the cortical–white matter junction (Fig. 3-74B). Proton MRS shows progressive
diminution in the amount of NAA (821,822).
Rett syndrome
Rett syndrome (OMIM 312750 (823)) was established as an internationally defined syndrome in 1983 (824). It is a
progressive neurodevelopmental 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 (825,826). Although the
mutation is usually fatal in boys, some 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 (827) or an extra X chromosome (828). Note that so-called
congenital Rett variant appears to be a separate disorder, caused by mutations of FOXC1 (829) or MECP2 (830) (see next
section).
Typically, affected patients have a normal pre- 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 regression 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 (826). Seizures develop in up to 80% of affected patients (831,832). Pathology shows global decrease in
the size of neurons with increased packing density and decreased melanin in the large neurons of the pars compacta of the
substantia nigra (833).
Rett syndrome is extremely uncommon in boys. When boys are affected, they may have a typical presentation of a Rett
syndrome phenotype (seen with somatic mosaicism (834) or with X-inactivation in an XXY karyotype (828,835,836)).
Alternatively, they may have severe neonatal encephalopathy (835,837) or severe mental retardation with progressive
spasticity (838). Autopsy of one patient with a small deletion in MECP2 who presented with neonatal encephalopathy showed
bilateral perisylvian polymicrogyria (839).
Although qualitative neuroimaging studies of girls with Rett syndrome 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 matter volumes are reduced
uniformly through the brain (840). Proton MRS shows decreased NAA in older patients, more pronounced in gray matter than
in white, with reduction of the glutamate/glutamine ratio (841). Frontal and parietal lobes and insular cortex seem
predominantly involved (842).
Congenital variant of Rett syndrome
Patients with Rett syndrome may have early developmental findings that are difficult to recognize using the standard criteria
(843). However, the term “congenital Rett syndrome” seems to be commonly used to refer to patients with normal body
measurements at birth but mildly slow growth thereafter, resulting in low weight (−1.5 to 2.5 SD) and significant microcephaly
(−4 to −6 SD) by age 2 years (844). Global developmental delay is detected early, evolving into severe mental retardation.
Few learn to walk or even sit independently. None develop speech or adequate social interactions. Exam shows muscular
hypotonia and, often, spasticity, with frequent dyskinesias and features of chorea, athetosis and dystonia (844).
MRI of the brain shows a fairly characteristic appearance of hyperintense frontal white matter with diminished volume,
often with thinning of the anterior frontal cortex, and a diffusely thin corpus callosum with more marked thinning of the genu
(Fig. 3-75). Ventriculomegaly may be seen, usually associated with (and possibly caused by) reduced cerebral white matter.
Figure 3-75 Congenital variant of Rett syndrome in a 1.5-year-old child, caused by FOXG1 mutation. A. Sagittal T1 image shows very thin
anterior body and genu (arrows) of the corpus callosum. B. Axial T2-weighted image shows diminished volume of frontal white matter with
abnormal hyperintensity (at tips of arrows), suggesting degeneration.
Toxins
Certain toxins affect primarily gray matter. Therefore, toxic exposure should always be considered in children, particularly
adolescents, with acute neurological symptoms and bilateral, symmetric gray matter involvement. Carbon monoxide poisoning
(Fig. 3-76), cyanide poisoning (Fig. 3-77), intoxication with drugs such as ecstasy (845), and exposure to organic solvents
(626,845) can all result in damage to the deep gray matter (CO to the globi pallidi and substantia nigra (846), cyanide to the
globi pallidi and striatum) and, sometimes, to the cerebral or cerebellar cortex (particularly with cyanide; Fig. 3-77)
(626,847,848). Delayed injury may develop in the cerebral white matter (“postanoxic encephalopathy”) by mechanisms that
are unclear (849,850). Most of these injuries will show reduced diffusion if MR imaging is performed in the acute phase
(846).
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.
Figure 3-76 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.
Figure 3-77 Cyanide poisoning. Axial T2-weighted image (A) shows abnormal hyperintensity (white arrows) of the globi pallidi. Coronal FLAIR
image (B) shows diffuse severe swelling and hyperintensity of the cerebellar cortex.
Proton spectroscopy (Fig. 3-79C) reveals elevated levels of the NAA peak in both mild and severe cases (859,870), a
finding that is strongly suggestive of this disorder. The NAA is less elevated in milder cases (871). Reduced
glutamate/glutamine is found on short echo proton MRS (872).
Occasionally, patients have typical involvement of the supratentorial white matter seen in infantile Alexander disease, in
addition to the dorsal medulla and cerebellar nuclei, manifested as T2/FLAIR hyperintensity and, sometimes, contrast
enhancement (Fig. 3-83), likely reflecting that the functions of different portions of the GFAP protein are affected by the
mutations that cause the infantile/juvenile and adult forms and that (not surprisingly) some mutations affect the functions of both
portions.
Mucopolysaccharidoses
The mucopolysaccharidoses (MPS) are lysosomal storage disorders that result from mutations of genes that encode lysosomal
hydrolases, compounds that are involved in the degradation of mucopolysaccharides (glycosaminoglycans or GAGs).
Deficiency of any of the enzymes involved in this process results in the accumulation of GAG storage material within
lysosomes and, consequently, progressive, multisystemic disease (892). Incompletely degraded mucopolysaccharides
accumulate in the tissues and are excreted in the urine as dermatan sulfate, heparan sulfate, and keratan sulfate. Typical
symptoms include growth delay, organomegaly, cardiopulmonary disease, skeletal dysplasias, airway obstruction, and, in some
disorders, severe neurocognitive decline; clinical manifestations vary with the mutation (892,893). Diagnosis is made by
combining the clinical picture with characteristic urinary mucopolysaccharides. Recent advances in the use of allogeneic
HSCT and recombinant enzyme replacement therapy (ERT) have shown promise in the treatment of affected patients (893).
Table 3-15 summarizes the main genetic and biochemical aspects of the various MPS.
Figure 3-83 Alexander disease, mixed form. A. Sagittal T2-weighted image shows abnormal hyperintensity in the dorsal medulla (black arrow)
and cervical spinal cord (white arrow) as well as the anterior portion of the very thin corpus callosum. B. Axial T2 image through the medulla
shows the two dorsal foci of hyperintensity (black arrows) commonly seen in the juvenile form of the disease. C and D. Axial T1-weighted (C)
and T2-weighted (D) 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; the garlands and the extensive abnormal white matter signal intensity are
considered typical of the infantile form of the disease.
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 (primary and secondary involvement) is characteristic (819). 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. It should be noted that HSCT and ERT are both being used in the treatment of MPS. Extraneural manifestations of
MPS respond well to HSCT, with rapid phenotypic correction (893), reducing damage to the craniocervical junction and
spinal cord. However, neurological outcomes are dependent upon the age and severity of the disease at the time of transplant:
earlier transplant has a better chance of preventing lysosomal accumulation of GAG and associated secondary storage
materials within the brain (894), but the results are inconsistent, incomplete, and variable (893,895). Intravenous ERT has
provided benefits for some symptoms of MPS I, MPS II, and MPS IIIA, but medical treatment of central nervous system
disease is still a difficult challenge (896), with most reports of human therapy anecdotal at this time.
The most frequent imaging substrates of direct central nervous system involvement are enlarged perivascular spaces and
white matter abnormalities. Enlargement of perivascular spaces are likely related to mucopolysaccharide deposition in
leptomeninges, impairing outflow of interstitial fluid from the parenchyma. Enlarged perivascular spaces are therefore filled
with interstitial fluid (and mucopolysaccharides), as described in classic pathology texts (897). These seem to be reduced in
number and in size since HSCT and ERT have become successful clinical treatments for MPS patients (898,899). Cerebral
white matter remains abnormal, likely 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.
Gene Type OMIM#/Eponym/ Inheritance Enzyme Deficiency Urinary GAG Neurologic Signs
Gene
Genetic heterogeneity. II 309900/Hunter X-linked Iduronate sulfatase Dermatan or heparan Mild to moderate
Locus at Xq28 recessive sulfate
SGSH 17q25.3 IIIA 252900/Sanfilippo AR Heparan N-sulfatase Heparan sulfate Mental deterioration
A
OMIM#, Online Mendelian Inheritance in Man disease number; AR, Autosomal recessive inheritance; GAG, glycosaminoglycan.
Indirect CNS damage in mucopolysaccharidoses often results from hydrocephalus or compression of the upper cervical
spinal cord in the craniocervical junction area; this has decreased as a result of ERT in very young cases, but response seems
more limited in older children and adults (900). Hydrocephalus in mucopolysaccharidoses 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; these are somewhat improved after HSCT and ERT (898,900,901).
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 ligament laxity) and mucopolysaccharide deposits within synovial and dural structures. Ligamentous
hypertrophy may develop in response to chronic subluxation at the C1-C2 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 central 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 (902). Attention deficits are present in MPS-II (903).
Sanfilippo (MPS-III) disease presents with neurological abnormalities only (hepatomegaly or dysostosis is 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 (819)
with resultant stenosis, cord compression, and myelopathy.
Imaging studies of the brain in the mucopolysaccharidoses are usually ordered when secondary CNS involvement due to
hydrocephalus, craniocervical instability, or spinal cord compression is suspected (904–907). CT and MR usually reveal
delayed myelination, atrophy, varying degrees of hydrocephalus, enlarged perivascular spaces, and white matter changes
(908–910). In all types of mucopolysaccharidoses, 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. 3-84 to 3-86). 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. 3-84 to 3-86) (74). With progression of the disease, the
lesions become larger and more diffuse and resemble a leukodystrophy (Fig. 3-84) (911), 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 underlying white matter (Fig. 3-86) (909,912). The atrophy and white matter changes occur earliest in
types I, II, III, and VII, usually becoming visible 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 (908–910,913); these patients
typically have normal intelligence (914) and present for medical care with reduced exercise tolerance and myelopathy (915).
Affected patients are commonly macrocephalic, probably from a combination 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 long-standing, the latter may result in optic nerve atrophy (Fig. 3-86B). A high incidence of
intracranial arachnoid cysts may also contribute to the macrocephaly (908,916).
Figure 3-84 Mucopolysaccharidosis IH, 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 basiocciput (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 myelination 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).
Figure 3-85 Mucopolysaccharidosis IIIA (Sanfilippo). A. Sagittal T1-weighted image of a patient with Sanfilippo syndrome shows two cysts
(black arrows) in the body of the corpus callosum. Note that the basiocciput (small white arrows) is small and the odontoid process of C1 (large
white arrow) is absent. The ligaments connecting the odontoid to the basiocciput (smallest white arrows) are enlarged, from either hypertrophy
or mucopolysaccharide deposition. B. Axial T2-weighted image of the same patient shows additional cysts in the corpus callosum (white
arrows) and show slight hyperintensity of the cerebral white matter, resulting in indistinct cortical–white matter junctions.
Figure 3-86 Mucopolysaccharide VI (Maroteaux-Lamy) syndrome illustrating narrowing of the upper and lower spinal canal. A. Sagittal T1-
weighted image shows an abnormally thick clivus (large white arrows) compressing the pons. Abnormal soft tissue (t) surrounding the dens is
probably a combination of mucopolysaccharide and hypertrophied ligaments. The hypointense vertebral bodies (smaller white arrows) are
small, hypointense, and pointed anteriorly, separated by large intervertebral discs. The calvarium is thick, the posterior fossa is small, and there
are dilated perivascular spaces (smallest white arrows) in the corpus callosum. B. Axial T2-weighted image shows large sylvian fissures (s)
and dilated optic sheaths (white arrows) containing atrophic optic nerves due to increased intracranial pressure. The right globe has retinal
detachment. C. Axial T2-weighted image at the upper level of the lateral ventricles shows multiple slightly enlarged perivascular spaces with
poor differentiation of the cortex from underlying white matter. D and E. Axial (D) and sagittal T2-weighted (E) images show bony narrowing at
the foramen magnum/C1 with compression and distortion (arrows) of the spinal cord. F. Sagittal T2-weighted image of the thoracolumbar spine
shows spinal stenosis secondary to intervertebral disc enlargement, likely due to the deposition of mucopolysaccharides.
The spine abnormalities in the mucopolysaccharidoses consist 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 compression (compressive myelopathy; Fig. 3-86), which occurs frequently in mucopolysaccharidoses types IV
and VI due to GAG deposits in the dura and supporting ligaments (901). The most common location for the cord compression
is at the atlantoaxial (C1-C2) joint (Fig. 3-86A). 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 (Figs. 3-85A). Flexion/extension views are often
necessary to demonstrate the laxity of the transverse odontoid ligament. Ligamentous hypertrophy (Figs. 3-85A and 3-86A)
may develop in response to chronic subluxation at the C1-C2 level, causing additional compression on the upper cervical
spinal cord. MR of the craniocervical 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 (914). 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 enhancement is seen. Another cause of
cord compression at the C1-C2 level is dural thickening resulting from intradural deposition of collagen and
mucopolysaccharides. This is seen as a thickening of the soft tissue posterior to the dens, resulting in narrowing the
subarachnoid space at that level; it is difficult to differentiate from ligamentous hypertrophy (Fig. 3-85A). 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. 3-86F) and is most common in Morquio disease (mucopolysaccharidosis
type IV) (74,913,917,918). Meningeal thickening may result in cyst formation in mucopolysaccharidoses types 1H and II (74).
Proton MRS results have been reported in a few of the mucopolysaccharidoses (919). 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 (920). 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 MLD (819); therefore, it is listed here as a subcategory of mucopolysaccharidoses. As its name
indicates, multiple sulfatase enzymes (those involved in MLD 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 childhood, but rare neonatal and juvenile forms also exist (819).
Clinically, facial dysmorphia (similar to that seen in mucopolysaccharidoses), hepatosplenomegaly, microcephaly
(macrocephaly in the neonatal form (921)), delayed development, progressive spasticity, blindness, and deafness are usually
found. Imaging findings in multiple sulfatase deficiency represent the combination of abnormalities seen in MLD and
mucopolysaccharidoses, notably variable patterns of white matter disease and diffuse brain atrophy; occasionally, these are
associated with enlarged perivascular spaces and craniocervical junction abnormalities (922,923).
Peroxisomal Disorders
Peroxisomes are small cellular organelles containing multiple compounds that are essential for normal growth and
development of the organism. More than 40 enzymatic functions have been identified in peroxisomes (924); the most important
are beta-oxidation 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 (924–927). Some authors classify peroxisomal
disorders into three major groups, based upon the severity of the enzyme dysfunction, whereas others divide them into two
groups (Table 3-16): deficiencies in peroxisomal biogenesis and single peroxisomal protein deficiencies (926,927). These are
described below in greater detail.
Peroxisomal disorders show remarkable clinical phenotypic heterogeneity, with dysmorphic features, hepatointestinal
dysfunction, and CNS involvement being common in many of them; therefore, peroxisomal diseases should always be
suspected in a neonate presenting with a polymalformative syndrome associated with severe neurological disturbances. The
imaging abnormalities in peroxisomal disorders have a wide spectrum of patterns, but the most characteristic patterns include
cortical malformation (resembling polymicrogyria) with abnormal myelination (e.g., Zellweger syndrome, neonatal
adrenoleukodystrophy, D-bifunctional protein deficiency) or symmetrical demyelination that most typically involves the
corticospinal tracts, corpus callosum, and posterior greater than anterior white matter structures (e.g., pseudoneonatal
adrenoleukodystrophy, acyl-CoA oxidase deficiency, X-linked adrenoleukodystrophy–adrenomyeloneuropathy complex).
Classic X-linked adrenoleukodystrophy has already been discussed in the section of this chapter on white matter disorders
with deep white matter involvement. This section will briefly discuss peroxisomal biogenesis disorders (PBDs), with focus
primarily on imaging characteristics. Interested readers are referred to review articles or texts in child neurology or metabolic
disorders for further details (926–928).
1. Refsum disease
2. Alpha-methylacyl-CoA racemase (AMACR) deficiency
3. Peroxisomal sterol carrier protein X (SCPx) deficiency
After Poll-The BT, Gärtner J. Clinical diagnosis, biochemical findings and MRI spectrum of peroxisomal disorders. Biochim Biophys Acta 2012;1822:1421–
1429.
Patients with infantile Refsum disease (IRD) usually have no facial dysmorphia but may have external features (such as
Down syndrome–like facies) that are reminiscent of Zellweger syndrome (931). Their cognitive and motor development range
from being severely handicapped to having a moderate learning disorder with deafness and visual impairment (related to
retinopathy). Survival is better than in Zellweger or NALD and some patients reach childhood (and rarely adulthood) (931).
MRI may be normal, but most patients have a progressive loss of normal white matter signal (starting in sensorimotor pathways
from brain stem to cerebral cortex) and volume (Fig. 3-89) (931,940).
Imaging differential diagnosis of peroxisomal biogenesis disorders
Several disorders can have a similar neuroimaging appearance to that of the PBDs. These include peroxisomal D-bifunctional
enzyme deficiency (see discussion below) (941) and peroxisomal thiolase deficiency (pseudo-Zellweger) (942), which have
hypomyelination with germinolytic cysts and perisylvian polymicrogyric–type cortical malformations (943), and acyl-CoA
oxidase deficiency (see below) (944), which has a similar MRI appearance to IRD. In addition, patients with these disorders
have neonatal courses and phenotypic manifestations that resemble those in PBDs (945). Other differential considerations from
a neuroimaging perspective include the congenital muscular dystrophies with brain malformations (see Chapter 5) and
congenital cytomegalovirus infections (see Chapter 11). All of these disorders have hypomyelination associated with cortical
malformations. Differentiation is made by associated findings, which include brain stem and cerebellar anomalies in congenital
muscular dystrophies (Chapter 5) and white matter gliosis with diffuse or multifocal polymicrogyria (if present) in congenital
cytomegalovirus infection (Chapter 11).
Figure 3-89 Infantile Refsum disease, progression of white matter disease. A–C. Images at age 16 months with worsening developmental
delay. Some delay in myelination is present in genu of corpus callosum (arrow in A), deep frontal white matter (small arrows in B), posterior
limbs of internal capsules (arrowheads in B), and along superior aspects of corticospinal tracts in centrum semiovale (arrows in C). D–F. By
age 5 years, there is edema, but no myelin, in the dorsal brain stem (arrows in D), loss of myelin and abnormal hyperintensity along the
posterior limbs of the internal capsules and optic radiations (arrows in E), and abnormal hyperintensity (likely representing edema and/or
astrogliosis) in the sensorimotor pathways of the centrum semiovale (white arrows in F).
Wilson Disease
Wilson disease, also known as hepatolenticular degeneration (OMIM 277900), is an autosomal recessive disorder in which a
deficient transport 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 with resultant free radical formation
and oxidative damage in multiple organs (liver, brain, kidney, eye) (957). The responsible gene is called ATP7B and is located
at chromosome 13q14.3 (958); the protein product encodes a copper-transporting P-type ATPase (959). Initial symptoms in
children are often related to liver failure (jaundice or portal hypertension). When neurologic symptoms predominate, the
appearance of the illness is delayed until the second or early third decade and progression is slower than in the hepatic form
(960). Several clinical phenotypes have been identified. The classic form is characterized by extrapyramidal signs (a jerky,
dystonic tremor 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 (960,961). Psychiatric
symptoms may be present, and deterioration in school performance and behavior or intellectual impairment may also be
observed (960). In patients with neurologic presentations, the diagnosis 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.
CT findings of Wilson disease consist of low density in the basal ganglia and variable cerebral white matter atrophy (962).
Brain MRI in clinically symptomatic patients is usually, but not always, abnormal. Indeed, in some young patients with mild
neurological manifestations, conventional MRI may be normal; conversely, subtle abnormalities may be found in about one-
third of clinically asymptomatic patients (963,964). Patients presenting with hepatic failure in childhood are usually found to
have bilateral, symmetric T1 shortening (high intensity on T1-weighted images) in the globus pallidus (Fig. 3-93A) and dorsal
midbrain, secondary to the hepatic failure and portosystemic shunting (965,966). 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 are usually abnormal but don’t always show the classic “giant panda face” (960). Typical findings 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. 3-93) (967); T2 hyperintensity may be seen in the pons
(960). Some of the T2 changes may resolve after chelation therapy (961). Lesions of the claustra are inconsistently seen but,
when present, are very suggestive of Wilson disease. Reduced diffusivity may be seen in actively involved regions (Fig. 3-
93E). The presence of deep gray nucleus involvement seems to correlate well with neurologic disability, striatal lesions with
pseudoparkinsonism, and putaminal lesions with dystonia (968). Cortical and white matter atrophy are present in up to 70% of
patients as the disease advances (Fig. 3-93D) (967) and, occasionally, areas of abnormal signal intensity are seen in the
cerebral hemispheric white matter, primarily in frontal and temporal lobes (960); subcortical white matter is typically affected
more than deep white matter (967). Although cerebral involvement is most commonly bilateral and symmetrical, asymmetric or
unilateral involvement can occur (969). Proton spectra are normal in treated patients (970). 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. 3-93F) (971). Myo-inositol/creatine ratios were increased in the basal ganglia on short echo
spectroscopy (972).
Mitochondrial Disorders
Mitochondria are important organelles that are involved in many intracellular functions, including production of much of the
adenosine triphosphate (ATP) necessary for normal electrical activities of neurons and synaptic transmission as well as
neurotransmitter synthesis, calcium homeostasis, redox signaling, production and modulation of reactive oxygen species, and
neuronal death (973,974). Although some of the disorders discussed in this section are reasonably well defined and
understood, the reader should recognize that it is only a partial listing and, although tremendous advances in the understanding
of these disorders have taken place in the past 10 to 15 years, neither mitochondrial function nor mitochondrial disease is
understood completely at this time. Indeed, the level of understanding has reached a point where classification is more difficult
than ever.
Figure 3-91 Rhizomelic chondrodysplasia punctata. A. Anteroposterior radiograph shows irregularity and abnormal stippling of multiple joints
(white arrows), including shoulders, elbows, hips, and costovertebral joints. Note also the abnormal, stippled appearance of the vertebrae. B.
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. C. Sagittal T2-weighted image at the craniocervical junction shows an edematous upper cervical
spinal cord (black arrow) that is compressed by the posterior arch of C1 (white arrow). Foliation of the cerebellar vermis (Cb) appears abnormal
and the ventral pons (P) appears small. D. 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 arrow) is thick. The combination of low
conus, thick filum, and distended urinary bladder (B) suggests a tethered spinal cord.
Figure 3-92 Rhizomelic chondrodysplasia punctata. A. Axial T2-weighted image shows patches of subcortical T2 prolongation (open white
arrows) and a periventricular nodular heterotopion (open black arrow). B. Axial T2-weighted image at a higher level shows asymmetrical patchy
white matter hyperintensities (open white arrows). A venous malformation is present in the parietal region. (This case is courtesy of Dr. Curtis
Sutton.)
Figure 3-93 Wilson disease. A. Coronal T1-weighted image shows abnormal hyperintensity 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 abnormal 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 diffusivity (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.
DiMauro et al. have suggested that mendelian mitochondrial defects can affect six components of mitochondrial biology:
subunits of respiratory chain complexes, mitochondrial assembly proteins, mtDNA translation, phospholipid composition of the
inner mitochondrial membrane, mitochondrial dynamics, and defects of mtDNA maintenance (975). As mitochondrial
respiratory chain disorders (MRCD; Tables 3-15 and 3-16) seem to be the most common cause of neurologic morbidity in
childhood (4) and are reasonably well understood, MRCD will be the main focus of this section, although other disorders
caused by mitochondrial dysfunction will be briefly discussed. MRCDs are characterized by disorders of mitochondrial
function that result in (a) elevated NADH/NAD+ ratio in cells, (b) impaired ATP production in affected cells, (c) increased
superoxide radical formation, and (d) functional impairment of numerous metabolic pathways (4,976). They are relatively
common metabolic disorders of childhood, with recent demonstration of a birth prevalence of inherited MRCD to be greater
than 1 in 5000, making them the most frequent cause of metabolic abnormalities in childhood (977,978). Single or multiple
organs (brain, heart, muscles, kidney, liver, endocrine glands, bone marrow) can be involved, with the striated muscles and
brain most commonly affected (4,973,979,980). MRCD should be suspected in patients presenting with an unexplained
combination of neuromuscular and/or nonneuromuscular symptoms, a progressive course, and involvement of seemingly
unrelated organs or tissues (4,980), particularly if associated with certain “red flags” such as short stature, neurosensory
hearing loss, progressive external ophthalmoplegia, axonal neuropathy, diabetes mellitus, hypertrophic cardiomyopathy, or
renal tubular acidosis (981). It should also be suspected in severely ill newborns when (a) there is little evidence to suggest an
intrapartum or peripartum insult or (b) MR features are unusual for hypoxic–ischemic injury (982).
Classification of MRCDs
Classification of these MRCDs is difficult. Classification neither by phenotype nor by morphology is satisfactory, particularly
in children in whom classic “syndromic” findings tend to be absent (981). Classification by metabolic pathway involved has
been similarly unsatisfactory. As 71% of a cohort of 113 pediatric patients with mitochondrial disease (based upon clinical,
pathological, molecular, enzymation, and metabolic parameters) had significant functional defects in respiratory chain
components (983), it seems reasonable to use the affected MRC complex as a tool for classification. The most frequently
identified functional MRC defects were in complex I (32%), followed by combined complexes I, III, and IV (26%), complex
III (16%), and complex II (7%). Patients presenting with cardiac disease as a part of the initial diagnosis had a survival rate of
18% at 16 years, while those presenting with neuromuscular features without cardiomyopathy had a survival rate of 95%
(983). Attempts have been made to classify MRCDs according to the site of the mutations (mitochondrial DNA mutation vs.
nuclear DNA mutation (4)) and according to the enzyme complex of the MRC affected by the causative mutations (4,979). A
combination of these methods will be utilized in this chapter despite the knowledge that, at this time, no classification is
completely satisfactory.
Components of the mitochondrial respiratory chain
Practically all fundamental cell functions of living organisms are dependent on energy, most of which is supplied by
mitochondria in the form of ATP. This energy is used for such diverse cellular functions as synthesis of molecules, transporting
these molecules against concentration gradients, and migration of cells in developing tissues (974). ATP is produced almost
exclusively in the MRC via the process of oxidative phosphorylation (4). The MRC contains five enzyme complexes, called
complexes I to V, plus two other complexes known as coenzyme Q10 or ubiquinone (which carries electrons from complexes
I and II to complex III) and cytochrome C (between complexes III and IV); all are embedded in the inner mitochondrial
membrane (Table 3-17). Mitochondrial disorders can result from dysfunction of any of the subunits. The energy released by
electrons flowing through the MRC is used to transport protons across the inner mitochondrial membrane. Two factors, the
proton gradient that is generated by this electron translocation and the ensuing inward (negative) membrane potential across the
inner mitochondrial membrane, provide the energy required for ATP synthesis, which takes place in complex V (4,984). More
details of MRC function help to understand why mutations in specific complexes result in different diseases (although the
details of the individual components of the MRC are still not well understood).
Complex I (reduced NADP-CoQ reductase) is the largest complex of the respiratory chain, consisting of 47 polypeptides,
of which 7 are encoded by mitochondrial DNA (mtDNA) (979). Patients with complex I deficiency can be subclassified as
having either myopathy or multisystemic disorder (985). The myopathy, manifested as exercise intolerance and limb weakness,
typically develops in childhood or early adult life. The multisystemic involvement can be manifested as a fatal infantile
disorder with congenital lactic acidosis, weakness, hypotonia, delayed development, and cardiopulmonary failure leading to
early death. The other major multisystemic presentation is that of Leigh syndrome; indeed, complex I deficiencies seem to be
the major causes of Leigh syndrome (see discussion later in this section) (985). Imaging findings in patients with complex I
deficiencies vary greatly with the exact severity and location of the causative mutation. Areas of reduced diffusivity in the
acute phase, with T2 hyperintensity, and, often, cavitation may occur in cerebral white matter (including corpus callosum),
basal ganglia, ventral or dorsal midbrain, ventral or dorsal medulla, dorsal pons, or cerebellum. A fairly consistent pattern of
injury is seen in NUBPL mutations (986) and is described later in this section.
I. Complex I deficiency
A. Myopathy
B. Multisystemic disorder
1. Fatal infantile disorder
2. Leigh syndrome
V. Complex V deficiency
A. Multisystemic forms
1. Leigh syndrome
2. NARP (neuropathy, ataxia, retinitis pigmentosa)
3. Familial bilateral striatal necrosis
4. Fatal infantile multisystemic disease
Complex II (succinate-CoQ reductase) is composed of four subunits, all encoded by nuclear DNA (979). Deficiencies of
this complex are less common; patients typically present with encephalomyelopathy. Succinate dehydrogenase deficiency (see
discussion later in this section) belongs to this group, as does CoQ10 deficiency. The latter can cause a myopathy
characterized by recurrent myoglobinuria and CNS dysfunction that includes seizures, ataxia, or mental retardation. When
ataxia predominates, significant brain stem involvement or cerebellar atrophy may be present (see section on cerebellar
atrophy in this chapter for more details).
Complex III (coenzyme Q-cytochrome-c oxidoreductase) consists of 11 subunits, one of which is encoded by mtDNA (979).
Disorders caused by complex III defects are divided into three forms. The first is a generalized multisystemic disorder
manifested by limb weakness, exercise intolerance, and various neurologic signs (985). The second is a tissue-specific
syndrome manifested as a pure myopathy with childhood onset (985). The third is a pure cardiomyopathy manifested in early
infancy (985). In addition, a rapidly fatal infantile disorder called GRACILE (growth retardation, aminoaciduria, cholestasis,
iron overload, lactic acidosis, early death) has been described in Finland (987).
Complex IV (cytochrome c oxidase) is composed of 13 protein subunits, 3 encoded by mtDNA (979). Defects of this
complex can also be divided into myopathic and systemic forms (988). Myopathies include a fatal infantile syndrome and a
benign infantile syndrome. The main multisystemic presentation is Leigh syndrome, particularly associated with cytochrome
oxidase (COX) deficiency; 25% to 75% of COX-deficient Leigh patients have mutations of SURF1 I (979). Alpers disease has
also been associated with complex IV deficiency, but these cases are not well characterized.
Complex V (mitochondrial ATP synthase) is composed of a membrane-bound subcomplex (F0), a large extramembranous
complex (F1) that resides in the matrix space, and a stalk connecting the two. Protons from the intermembrane space are
allowed to enter complex V through F0, leading to subunit rotation, with the energy generated by the rotation being used to
generate ATP. Complex V deficiencies are associated with clinical findings of both Leigh syndrome and NARP (neuropathy,
ataxia, and retinitis pigmentosa), as well as a milder condition known as familial bilateral striatal necrosis (985). Almost
all of these disorders are associated with lactic acidosis and an elevated lactate/pyruvate ratio (985).
Disorders causing Leigh syndrome
Leigh syndrome (OMIM 256000) refers to a symptom complex with characteristic, but variable, clinical and pathologic
manifestations (379,989). It is the most common manifestation of mitochondrial disease, most often caused by mutations of
nuclear DNA that affect subunits of complex I (990), assembly factors of complex IV (991), or the pyruvate dehydrogenase
complex (PDHC), but can be a result of mitochondrial DNA point mutations (T8993 mtDNA mutation causing maternally
inherited Leigh syndrome, also called MILS (992,993)); indeed, mutations affecting nearly every mitochondrial complex and
more than 60 genes) can cause Leigh syndrome, which is thought to result from the effects of defective oxidative metabolism
upon the developing nervous system (10,974). Affected infants and children typically present between the ages of 3 and 12
months, but some patients may become symptomatic prenatally or as adults (994). Typical signs and symptoms at onset include
hypotonia and psychomotor deterioration, often triggered by metabolic challenges such as acute infections (977,994). Ataxia,
ophthalmoplegia, ptosis, dystonia, seizures, abnormal eye movements (such as nystagmus or slow saccades), breathing
irregularities (leading to respiratory failure), 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 (379,977,995).
Although it has been known for some time that several biochemical and genetic abnormalities cause Leigh syndrome, the
different genetic causes continue to be elucidated. The disorder seems to be the result of defective terminal oxidative
metabolism from any of a number of causes that are likely to impair energy production (996). Many disorders can result in
Leigh syndrome; indeed, mutations of both mitochondrial and nuclear DNA, involving genes coding for proteins in respiratory
chain complexes I, II, III, IV, and IV, mitochondrial transcription/translation, PDHC, thiamine transport, and coenzyme Q10,
have been implicated (Table 3-17) (3,55,994). A few groups (complex 1, complex IV, complex V, and PDHC) seem to account
for the large majority of cases (10,974,994); however, the means by which these different disorders impair mitochondrial
function are beyond the scope of this book. Interested readers are referred to an excellent discussion in the recent paper by
Gerards et al. (994).
Many years of studies exploring brain imaging of patients with Leigh syndrome, both in practice and in the literature, has
convinced the authors that no genotype–phenotype correlation exists in Leigh syndrome other than involvement of the
subthalamic nuclei, medulla (usually ventral in the olivary nuclei and nucleus of the solitary tract), central tegmental tract and
reticular formation in the dorsal pons, inferior cerebellar peduncles, cerebellar dentate nuclei, and (often) substantia nigra in
SURF1 (complex IV) mutations (Fig. 3-94) (997–1001). Of note, lactate elevation is rare in SURF1 mutations.
Another somewhat distinctive cause of Leigh syndrome is mutation of SLC19A3, encoding the second thiamine
transporter. Kevelam et al. (1002) reported seven patients who developed a severe encephalopathy within a few weeks after
birth, with rapid deterioration of neurologic functions, followed by respiratory failure and death. All patients had predicted
pathogenic mutations and deletions of the SLC19A3 gene, which encodes the second thiamine transporter. Ortigoza-Escobar et
al. (1003) found a profound deficiency of free thiamine in the CSF and fibroblasts of affected patients. Haack et al. (1004) and
Tabarki et al. (1005) both found substantial, very promising improvement in patients who received thiamine treatment; Tabarki
et al. (1005) found no significant improvement when biotin was added to the treatment. On examination of pathology of the
brain tissue, the presence of severe cerebral atrophy was noted, as well as histologic findings characterized by rarefaction and
vacuolar degeneration with some areas of cavitary necrosis, as well as prominent, dilated capillaries and reactive astrogliosis
in the cortex, white matter, basal nuclei, brain stem, and cerebellum. It was noted that these findings were very similar to those
in Leigh syndrome (1002), and SLC19A3 mutations are now considered a cause of the syndrome. Imaging findings are
characteristic, although severity varies among individuals (1006). Initially, edema (swelling and T2 hyperintensity) is seen in
the basal ganglia, thalami, cerebral and cerebellar white matter, cerebral cortex, central pons, midbrain, and, sometimes,
cerebral cortex (Fig. 3-95). Rarefaction, often with cavitation of the white matter and, sometimes, basal ganglia, rapidly
ensues, followed by atrophy. Patches of reduced diffusivity are present in affected areas. MRS shows elevation of lactate
levels and reduced NAA (Fig. 3-95) (1002).
Figure 3-94 Leigh syndrome secondary to SURF1 mutation in a 2-year-old child. A–C. Axial T2-weighted images through the brain stem
show involvement of the inferior olives (large black arrows in A), inferior cerebellar peduncles (small white arrows in A), central tegmental tracts
(small white arrows in B), nuclei of trigeminal nerves (white arrowheads in B), cerebellar nuclei (large white arrows in B), and subthalamic nuclei
(white arrows in C). D. Axial diffusion-weighted image (b = 1000) shows reduced diffusion (hyperintensity, white arrows) in the subthalamic
nuclei, which is commonly involved in SURF1 mutations.
Figure 3-95 Leigh syndrome in an infant due to mutation of SLC19A3 encoding the second thiamine transporter. A and B. Axial T2-weighted
images show abnormal mild hyperintensity throughout most of the cerebellum white matter (white arrows in A), central pons (white arrowhead in
A), most of the cerebral white matter (small white arrows in B), anterior thalami (small black arrows in B), and severe hyperintensity of the
putamina (large black arrows in B), indicating extensive injury throughout the brain. C. Axial ADC map at the level of the lateral ventricular
bodies shows areas of reduced diffusivity indicating acute injury (hypointensity, white arrows) and increased diffusivity indicating more chronic
injury (hyperintense, black arrow). D. Proton MRS (TE = 144 ms) at basal ganglia level shows low NAA and moderate lactate peak (Lac),
strongly suggestive of mitochondrial disease.
For the many other causes of Leigh syndrome (for a nearly exhaustive list, see Gerards et al. (994)) imaging appearances do
not appear to vary with gene or with specific mutation, although there may be some general correlations between the type of
mutation (mtDNA vs. nDNA mutation, complex I vs. complex IV mutation, etc.) and the pattern(s) of injury. In general, mtDNA
point mutations tend to result in more specific imaging and clinical features (MELAS, Kearns-Sayre syndrome, MERRF) (4),
while complex I mutations seem to result more commonly in cavitary white matter injury with callosal involvement and high-
lactate/low-NAA levels on MRS (Figs. 3-96 to 3-98) (986,990,1007–1009). More acute injury is associated with white matter
swelling and higher lactate (Fig. 3-97), while more chronic injury has more cavitation, volume loss, and lower lactate levels
(Fig. 3-98). Occasionally, cerebral dysgenesis may be seen, particularly when the E1 alpha subunit of pyruvate dehydrogenase
is deficient (PDHA1 at chromosome Xp22.12) resulting in callosal dysgenesis, subcortical heterotopia, absent medullary
pyramids, ectopic olivary nuclei, dysplasia of the cerebellar dentate nuclei, and polymicrogyria (1010). Rarely, succinate
dehydrogenase deficiency (OMIM 612848), resulting from a complex II mutation, can present with a Leigh syndrome
phenotype, usually at the end of the first year or in the first half of the second year of life (1011–1013). Patients typically
present with acute neuromotor deterioration, sometimes provoked by an illness, injury, or vaccination, late in the first year or
early in the second year of life. Clinical course is subsequently static or slowly progressive (1013). MRI shows extensive
T2/FLAIR hyperintensity of periventricular and deep cerebral white matter (with sparing of subcortical “U” fibers) together
with cerebellar white matter, transverse pontine fibers and middle cerebellar peduncles (50%), corticospinal tracts, and
central gray matter of the spinal cord (Fig. 3-99A–C). The corpus callosum is usually swollen and is bright on T2/FLAIR
imaging. The posterior thalamus/pulvinar region is commonly involved. Diffusivity is reduced in actively involved areas (Fig.
3-99D). Diagnosis can be confirmed by proton MRS, which shows a large singlet (succinate) at 2.4 ppm in white matter (Fig.
3-99E) but not in gray matter.
In summary, the patterns of injury in patients with Leigh syndrome vary considerably, depending on the precise mutations
that cause the syndrome; some reasonably well-established patterns are described in the previous paragraphs and summarized
in Table 3-18. Diffusion characteristics and proton spectroscopic characteristics 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 and lactate will be high/NAA low in the areas most affected. If no permanent damage ensues, these
imaging parameters may return to normal. However, if significant astrogliosis or necrosis ensues in the injured area, diffusivity
will be increased. MRS has shown decreased NAA and elevated lactate, with lactate elevation most pronounced in areas with
acute mitochondrial dysfunction (and consequent anaerobic glycolysis) and in those areas most severely affected on the
imaging studies (1019,1020). As other disorders that involve the basal ganglia may not have increased basal ganglia lactate
(1021), the presence of lactate in a patient with a characteristic imaging pattern supports the diagnosis of Leigh syndrome
(986,1001). 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, inflammation, and neoplasm can also cause elevated
lactate).
Figure 3-96 Leigh syndrome due to pyruvate dehydrogenase deficiency. Axial FLAIR images show abnormal high signal in the corpus
striatum (large white arrows in A), posteromedial thalami (white arrowheads in A), and several regions of cerebral cortex (small white arrows in
B).
Figure 3-97 Leigh syndrome due to complex 1 deficiency, acute/subacute phase. A. Axial T2 image shows homogenous hyperintensity of
white matter with compression of cortical sulci and a thick callosal genu (CC) due to extensive white matter edema. B. Axial FLAIR image at
the same level shows some cavitation (white arrows) in the affected peritrigonal white matter (small white arrows). The intermediate signal in
the frontal white matter (larger white arrows) may reflect extensive edema without frank cavitation. C. Proton MR spectroscopy shows an
enormous lactate peak (Lac) at 1.33 ppm.
Figure 3-98 Leigh syndrome due to complex 1 deficiency, more chronic injury. A. Sagittal T1-weighted image shows cavitation and atrophy of
the posterior body and splenium of the corpus 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 volume loss and more marked hypointensity,
suggesting cavitation posteriorly (white arrows). C. Coronal FLAIR image shows heterogeneous hyperintensity of cerebellar (arrow head) and
cerebral periventricular and deep white matter, with some central areas of hypointensity (white arrows) indicating complete cavitation. D. Single-
voxel proton MRS from frontal white matter showing a low NAA peak and markedly elevated lactate (Lac).
A diagnosis of mitochondrial disorder can be suggested by recognition of certain clinical features characteristic of many of
the mitochondrial disorders; these include seizures, hypotonia, peripheral neuropathy, ataxia, ophthalmoplegia, bulbar signs,
short stature, mental deterioration, muscle weakness, cardiomyopathy, cardiac arrhythmia, exercise intolerance, and
neurosensory hearing loss (4,973,974,981). These clinical findings may be supported by magnetic resonance studies showing
characteristic imaging and proton spectroscopy findings (5,990,1001,1008,1009,1022). When the classic symptom 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 authors (974) believe that certain clinical features are adequately clustered 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 and point out that many disorders of organic and
fatty acid metabolism cause abnormal mitochondrial function; they await a molecular/genetic classification (3,980,981).
Recent analyses show that signs/symptoms consistent with a diagnosis of Leigh syndrome can result from mutations affecting
any of the five molecular complexes of the respiratory chain and from mutations of both mitochondrial and nuclear DNA
(1023). However, it is not certain that all of these disorders will respond to the same therapy (if and when treatments are
developed); therefore, this section will approach mitochondrial disorders from the approach that certain clinical, imaging, and
proton spectroscopy phenotypes can suggest a diagnosis of mitochondrial disorder that will require molecular confirmation.
Figure 3-99 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 callosum (small white arrows, B),
and 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 arrowheads) 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 is courtesy of Dr. Vernon Byrd, Charlotte.)
Pyruvate dehydrogenase complex deficiency Involvement of corpus striatum and, in infants, thalami. White matter cavities. Sometimes
malformations
Cytochrome oxidase deficiency with SURF1 mutation Subthalamic nuclei, periaqueductal gray matter, central tegmental tract, cerebellar nuclei,
cerebellar peduncles, inferior olivary nuclei
Complex V deficiency with mtATPase6 mutation Anterior putamina, globi pallidi, dorsal mesencephalon and pons
(includes neuropathy, ataxia and retinitis pigmentosa
(NARP) (1014)).
Infantile thiamine deficiency Frontal cortex, mamillary bodies, putamina, periaqueductal gray matter, dorsal brain stem
Succinate dehydrogenase deficiency Periventricular and deep white matter in all cerebral lobes and cerebellum. Posterior thalami
affected. Corpus callosum is involved centrally and may cavitate. MRS shows large singlet at 2.4
ppm (succinate).
Biotinidase deficiency May have only white matter involvement at presentation: cerebrum, brain stem, or spinal cord
(1015–1017)
Complex I deficiency with MTND1 mutation Subthalamic nuclei, corpus striatum, dorsal brain stem (especially medulla) (1018)
SLC19A3 mutations encoding second thiamine Basal ganglia, thalami, cerebral and cerebellar white matter, central pons, midbrain; sometimes
transporter cerebral cortex (1002)
Other complex I deficiencies Callosal and white matter involvement with cavitation. May have cerebellar atrophy
Considering the considerable clinical and genetic overlap among mitochondrial disorders, it is not surprising that the
imaging findings are not distinctive. In our experience, some patients with a clinical diagnosis of Leigh syndrome have only
delayed myelination or a nonspecific T2 prolongation in the white matter, while others have white matter cavitation, still others
have injury confined to the brain stem or basal ganglia, and still others have isolated cerebellar atrophy. However, certain
imaging characteristics should cause mitochondrial disorders to be included in the differential diagnosis. Disorders of
mitochondrial function should be considered in any infant or child who has abnormalities of the deep cerebral gray matter
(including the subthalamic nuclei) or dorsal brain stem, 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 MRS also supports the
possibility of mitochondrial disease (1024) (please note, however, that mild elevation of lactate is common and nonspecific).
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 (1025).
Although, as has been discussed, it is difficult to precisely define mitochondrial disorders, I will discuss certain syndromes
that are reasonably distinct in the following pages based largely on their clinical manifestations (Table 3-19). Note that certain
mitochondrial disorders, such as MERRF (myoclonus, epilepsy, 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 stroke-like episodes
MELAS (OMIM 540000) refers to a heterogeneous group of disorders caused by point mutations of mitochondrial DNA.
Affected patients present at any age (most commonly second decade) with episodes of throbbing headache, nausea, seizures,
episodic vomiting, and permanent or reversible stroke-like events (hemianopsia and hemiparesis) in conjunction with some of
the signs and symptoms of generalized mitochondrial disease (1026,1027). Serum and CSF lactate are usually elevated at the
time of presentation. Affected patients may have any of more than a dozen mutations of mitochondrial DNA (1028), the most
common mutation being m.3243A→G tRNALeu(UUR) (1029). The cause of the stroke-like events is unknown, although there is
evidence that it is a mitochondrial angiopathy (1030,1031). Currently, the disorder is believed to result from derangements in
COX enzymatic function and consequent effects on neuronal ATP levels (1027).
Table 3-19 Clinical Classification of Mitochondrial Disorders
Imaging studies in the acute phase show swelling, with T1 hypointensity and T2/FLAIR hyperintensity in the affected areas
of the brain (Fig. 3-100), primarily the parietal and occipital cortex and subcortical white matter (1032) (but any cortical area
may be affected), and in the basal ganglia (1019). In some patients, the dorsal brain stem and spinal cord are involved (1033);
cerebellar atrophy may develop in late stages of the disease (1034). Sequential scans may show resolution and subsequent
reappearance of the abnormal areas or, more commonly, development of new lesions (Fig. 3-100). Eventually, T1
hyperintensity may appear in the affected cortex, indicative of permanent cortical damage, and atrophy then ensues (1035). The
lesions are not restricted to a specific arterial distribution (Fig. 3-100)—indeed, single lesions often cross vascular
boundaries and new lesions appear in completely different areas of brain—helping to distinguish MELAS from embolic or
thrombotic infarction. The size of the diffusion abnormality may increase over several weeks or new lesions may appear on
sequential studies (1035). This progression and the crossing of vascular boundaries may be useful in separating MELAS from
embolic or thrombotic infarcts. MRS shows high lactate in affected areas of brain (1019). However, as infarcts of any cause
seem to result in local increases in lactate (1036), the presence of lactate in the region of an acute cortical lesion is not specific
for MELAS; the presence of lactate in areas of the brain that are 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 (1037). Reports describing the findings of diffusion imaging in MELAS are conflicting. Some authors report reduced
diffusion in some affected areas (1038,1039), while others report increased diffusion (1040). This difference likely reflects 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. Perfusion studies show increased local blood flow but decreased local glucose
uptake and oxygen extraction fraction (1041) and decreased cerebrovascular reactivity in affected brain tissue in the acute
phase as assessed by MR arterial spin labeling (1042).
Myoclonic epilepsy with ragged red fibers
Myoclonic epilepsy with ragged red fibers (MERRF, OMIM 545000) is a severe neuromuscular disorder with onset in
childhood that is characterized by epilepsy (most commonly generalized epilepsy, but also myoclonic or focal seizures),
cerebellar ataxia, ptosis, intention tremor, myopathy, proximal renal tubule dysfunction, cardiomyopathy, peripheral
neuropathy, optic atrophy, deafness, multiple lipomatosis, and, ultimately, dementia (4,976,1027,1043). It is caused by
mitochondrial DNA point mutations, most commonly m.8344A→G tRNA or m.8356T→C tRNA (4). There may be significant
overlap of the clinical findings in MERRF with those in MELAS and other disorders caused by mitochondrial point mutations.
Figure 3-100 Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). This teenage girl with a history of short
stature and developmental delay presented with left-sided weakness and headaches at a sporting event. A–C. Axial diffusion (A) and FLAIR (B
and C) images show reduced Dav in the right posterior frontal lobe (arrows in A) with variable FLAIR hyperintensity of the posterior right cortex
(arrows in B and C). D–F. Diffusion (D) and FLAIR (E and F) images 1 month later when the patient developed new right-sided weakness. A
new area of reduced diffusivity is seen in the left frontal and parietal cortex (arrowheads in D). High signal is seen in that region on the FLAIR
images (arrowheads in E and F). Note that the prior right hemisphere injury is still seen on the FLAIR images but not on the diffusion imaging.
Proton MRS in the area of new edema showed lactate elevation, which is consistent with, but not diagnostic for, MELAS.
Imaging of affected patients shows generalized atrophy, which is seen in late adolescence and young adulthood as
T2/FLAIR prolongation and atrophy that is most severe in the dorsal midbrain (periaqueductal), cerebellum, and superior
cerebellar peduncles (1044). Atrophy of the cerebrum is more generalized, involving cortex, white matter, and basal ganglia,
with the globi pallidi undergoing premature calcification (1019).
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 characterized by progressive external
ophthalmoplegia with cardiac and retinal manifestations, although PEO usually has a later onset (in adulthood). To establish the
diagnosis of Kearns-Sayre syndrome, patients must have, as a minimum, external ophthalmoplegia, ptosis, retinitis pigmentosa,
and one of the following before the age of 20 years: complete heart block, CSF protein >100 mg/dL, or cerebellar ataxia
(1028,1029). Patients may also have dementia, short stature, sensorineural hearing loss, endocrine dysfunction, elevated serum
and CSF lactate, and cardiomyopathy (1045–1048). Partly deleted mtDNAs are present in all examined tissues, implying that
the deletion event occurred in the germ line or soon after fertilization in affected patients (4,55,1028). Progressive external
ophthalmoplegia patients have exercise-induced or permanent extraocular pareses with progressive external ophthalmoplegia;
partly deleted mtDNAs are present only in muscle (1028). The disorder is associated with mutations of the nuclear-encoded
DNA polymerase gamma gene (POLG) located at chromosome 15q25 and the thymidine phosphorylase (TYMP) gene at
22q13.33, although most reported patients have had deletions of mitochondrial DNA (1028). There appears to be some
overlaps of progressive external ophthalmoplegia with MNGIE (see following section).
The neuroimaging findings in Kearns-Sayre syndrome and ophthalmoplegia 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 (74,1049). It is not clear whether the calcification is the result of the
primary disorder or the associated hypoparathyroidism that often accompanies the syndrome (1050). Early MR scans (Fig. 3-
101A–D) show patchy T2 hyperintensity in the deep gray matter nuclei, particularly the dorsal midbrain, medial and posterior
thalami, and the globi pallidi, as well as the cerebral white matter, predominantly subcortical, with early involvement of the
subcortical U fibers and sparing of periventricular areas (1019,1051). All of the characteristic MR findings may not be present
early in the course of the disease (1052), but the amount of supratentorial white matter involvement gradually increases over
time as shown in Fig. 3-101. The affected white matter shows reduced diffusion (Fig. 3-101D and H) (39), which may persist
over several years (Fig. 3-101H) (1053). DTI in a single patient with Kearns-Sayre syndrome appeared to show low FA and
increased diffusivity compared to age-matched normals (1054). Proton MRS of affected regions shows increased lactate and
reduced NAA.
Figure 3-101 Kearns-Sayre syndrome, onset and evolution in child with sensorineural hearing loss, ophthalmoplegia, diabetes mellitus, and
short stature. A–D. First MR shows abnormal hyperintensity in the dorsal brain stem (arrow in A), globi pallidi (black arrows in B), and
subcortical white matter (white arrows in B and C). Notice that a fairly thick layer of normal white matter is still seen on the diffusion-weighted
image (arrows in D). E–H. MRI 4 years later shows similar findings in the dorsal brain stem (white arrow in E) and globi pallidi (white arrows in
F). However, the involvement of the white matter has progressed dramatically, spreading substantially medially toward the ventricles (black
arrows in E, F, and G). Note how much less medial white matter appears normal in (H) (compare with D).
Figure 3-102 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.
MRI establishes the diagnosis. On T2-weighted images, the disease starts as hyperintensity in the periventricular and deep
cerebral white matter; the posterior corpus callosum is involved earlier and more severely than the anterior portions; as the
disease advances, all cerebral white matter becomes involved (Fig. 3-103C and F). In the brain stem, the superior and inferior
cerebellar peduncles, pyramidal tracts, medial lemnisci, anterior spinocerebellar tracts, and intraparenchymal trajectories of
the trigeminal nerves (CN V) are affected (T2 hyperintense) early in the disease (Fig. 3-103) and remain abnormal, while the
middle cerebellar peduncles and transverse pontine fibers are affected later. Imaging of the spinal cord shows involvement of
the dorsal columns and the lateral corticospinal tracts (Fig. 3-103G) in essentially all patients. Reduced diffusivity may be
seen in early phases of the disease, but there is significant variability, which is most likely due to the extreme variability of the
timing of the MRI with respect to the onset of the disease. Proton MRS shows a significant decrease in NAA with increased
myo-inositol and lactate in the white matter in most patients; some mutations do not cause an elevation of lactate (1074). Less
remarkable increase in choline may be found if the metabolite peaks are quantified (1075,1076).
Complex I deficiency secondary to NUBPL mutation
In 2013, Kevelam et al. (986) reported a series of patients with delay of early motor development and signs of cerebellar
dysfunction during the late first year or early second year of life, followed by episodes of regression with partial recovery
superimposed upon continuing development. Spasticity and motor problems, secondary to ataxia, ensued with variable
cognitive progress. Plasma and CSF lactate were elevated. Assays of respiratory chain enzymes revealed complex 1
deficiency, and genetic analysis showed mutations of NUBPL at chromosome 14q12 (OMIM 613621), encoding a Fe/S protein
involved in complex I assembly (986).
MRI findings are quite consistent, with early involvement of the corpus callosum consisting of sharply defined lesions (on
sagittal images) that often expand the structure, multifocal (sometimes confluent) cerebral hemisphere lesions that are often
continuous with the callosal lesions but spare the subcortical U fibers, and extensive involvement of the cerebellar cortex, with
sparing of deep cerebellar white matter and the hilus of the dental nuclei (Fig. 3-104). Later imaging shows volume loss in the
corpus callosum and cerebral hemispheres, associated with disappearance of the high signal, as if the cavitated white matter
has collapsed (somewhat similar to what is seen in cavitary white matter injury of prematurity as shown in Chapter 4).
Cerebellar involvement continues to progress, however, expanding to involve the entire cerebellum, which then undergoes
severe atrophy associated with secondary pontine atrophy (986).
Figure 3-103 Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. A–C, and F. Axial T2-weighted images
show abnormal hyperintensity in the corticospinal tracts (white arrowheads) and spinothalamic tracts (black arrows) and extensive changes in
cerebral white matter (L). D and E. Axial DWI images show reduced diffusivity in the inferior cerebellar peduncles (arrows in D), trigeminal
nuclei (small arrows), and trigeminal tracts (large arrows). G. Sagittal T2 image of spinal cord shows involvement of central gray matter in
spinal cord (black arrows).
Figure 3-104 An 1-year-old boy with loss of motor skills and new cerebellar signs; NUBPL mutation. A and B. Sagittal and axial T1 images
show atrophy of the superior cerebellar vermis (small arrows), thinning and cavitation of the callosal splenium (large arrow), and edema within
the inferior cerebellar vermis (large arrowhead). Note also, small subacute subdural hematoma over left hemisphere due to recent fall. C.
Coronal FLAIR image shows extensive cavitation of the peritrigonal white matter (large arrows) as well as atrophy of the cerebellar
hemispheres (small white arrows) and the subdural collection along the tentorium (black arrows). D. Axial T1 image shows volume loss and
cavitation in the supratentorial periventricular white matter, with some ex vacuo ventricular enlargement (white arrows).
Figure 3-106 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 temporal opercula. D. Coronal FLAIR image shows germinolytic cysts (black arrows) in addition to the abnormally
hyperintense putamina (black arrowheads).
Figure 3-107 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
arrowheads). B. Axial T2-weighted image shows abnormal hyperintensity of the basal ganglia (black arrows) and the periventricular and deep
white matter (white arrows), classic findings when seen in conjunction with the enlarged sylvian fissures.
The few recently reported imaging studies describe variable cerebral white matter involvement and (in a single case
(1106)) hypoplastic opercula (1103,1107). Patients we have seen with glutaric aciduria type II mostly showed T2/FLAIR
prolongation in the white matter (cerebral hemispheres, corpus callosum, middle cerebellar peduncles), although one patient
had T2 prolongation in the caudate head and posterior putamen, as well. Others have reported abnormal hyperintensity of the
globi pallidi (1108), hypoplasia of the temporal lobes, and, in one instance, absence of the cerebellar vermis (1109). Proton
MRS reportedly shows elevated lactate and high Ch/Cr (indicating dysmyelination) (1102,1109).
Friedreich ataxia
Friedrich ataxia is discussed in the section of cerebellar disorders.
Ethylmalonic encephalopathy
Ethylmalonic encephalopathy (OMIM 602473) is an extremely rare autosomal recessive disorder, caused by genetic
abnormalities of sulfite metabolism (1110), and seen mostly in Mediterranean and Arab populations. The cause is mutations of
a gene called ETHE1, located at chromosome 19q13.32 (1111). The function of the ETHE1 protein is thought to be sulfide
detoxification (1110); the consequences of its malfunction include accumulation of hydrogen sulfide (H2S) in brain, muscle,
liver, and colonic mucosa up to levels that inhibit short-chain acyl-CoA dehydrogenase (SCAD) and COX activities (1112).
Affected patients usually present in early childhood with encephalopathy, petechial purpura from vasculopathy, and chronic
hemorrhagic diarrhea (1112). Known clinical phenotypes include neonatal onset with acute metabolic crisis and early or late
infantile onset with slowly progressive encephalopathy with or without metabolic decompensation. Patients with the slowly
progressive phenotype present with psychomotor regression, spastic tetraparesis, axial hypotonia, dystonia, and seizures
(1110). The most prominent systemic manifestation of the disease is vasculopathy (tortuous 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. Affected patients appear to have
patchy T2 and FLAIR hyperintensity in the basal ganglia, cerebral white matter, and sometimes brain stem, findings typical of
mitochondrial disorders (1111,1113). Progressive atrophy is seen on sequential studies (1114) and some reports have
suggested cerebral vasculopathy (1115). Another report found CNS malformations: tethered cord and Chiari I malformation
(1116).
Nonspecific mitochondrial disorders
Although they are becoming fewer, many mitochondrial disorders do not fit into any described syndromes and do not (yet) have
identified genetic causes. These nonspecific mitochondrial disorders can present in patients of any age, from neonates to senior
citizens (3,980,981,1117). Presenting signs and symptoms are variable, as in all mitochondrial disorders (3,980,981,1019),
with seizures, short stature, mental deterioration, muscle weakness, exercise intolerance, and neurosensory hearing loss being
the most common (1067,1118,1119).
Imaging findings are nonspecific with tissue damage (low attenuation on CT, T1 hypointensity and T2/FLAIR hyperintensity
on MR) in the brain stem, deep gray matter nuclei, cerebral/cerebellar white matter, and cerebral or cerebellar cortex (1052),
virtually 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 brain stem involvement (Fig. 3-108) (1120) to isolated
cerebellar atrophy (Fig. 3-109) (1121,1122) to isolated white matter involvement that may include small- to moderate-sized
white matter cysts (1007,1008,1123). As mentioned and illustrated many times in this section, diffusion imaging and
spectroscopy are often useful to differentiate acute metabolic injury from subacute or chronic injury.
Figure 3-108 Nonspecific mitochondrial disorder with isolated brain stem involvement. Axial T2-weighted images show abnormal
hyperintensity (black arrows) in the pons (A) and midbrain (B) with normal-appearing cerebellum.
Figure 3-109 Mitochondrial disorder resulting in isolated cerebellar atrophy. Sagittal (A) and coronal (B) T1-weighted images show shrunken
cerebellar cortex with widening of cerebellar sulci.
Citrullinemia types I (neonatal) and III ASS 9q34.11 Argininosuccinic acid synthetase High plasma citrulline, ammonia, alanine. High urinary
(infantile)/215700 orotic acid
Citrullinemia type II/605814 SLC25A13 Argininosuccinic acid synthetase High plasma citrulline, ammonia
7q21.3 in liver
Argininosuccinic aciduria/207900 ASL 7q11.21 Arginosuccinase High plasma argininosuccinate. Moderate citrulline in
plasma
OMIM, Online Mendelian Inheritance in Man; CPTD, carbamoyl phosphate synthetase deficiency; OCTD, ornithine carbamoyltransferase deficiency.
In our experience, similar patterns of injury are seen with OCTD, CPSD, and citrullinemia (1145), and possibly with
argininosuccinic aciduria and hyperargininemia. The CT pattern in affected patients is nonspecific, with a pattern of diffuse
edema (Fig. 3-110A), 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 MR, the appearance is somewhat more specific, as certain regions
of the cerebral cortex and deep gray matter show T1 hypointensity 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 swelling (Figs. 3-110 and 3-111). In affected neonates, T1 hyperintensity of affected deep gray and cortical
structures will appear within the first few days of life (Fig. 3-112). 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 of the cortex (Figs. 3-110 and 3-111) (1145); the
insulae and cingulate gyri are most commonly affected and, in general, the frontal lobes seems more affected than the parietal,
occipital, or temporal lobes. The perirolandic and occipital cortex seem to be specifically spared (1145). Bireley et al. (1146)
recently reported similar findings: with increasing severity of hyperammonemia, the peri-insular cortex is affected first,
extending progressively into the frontal, parietal, temporal, and, lastly, occipital lobes. One report found reduced Dav in the
midbrain tegmentum during acute hyperammonemia in neonatal citrullinemia (1147). If the hyperammonemia is not effectively
treated, the disease progresses and reduced diffusivity is found in the thalami (1146); ultimately, gray and white matter atrophy
develops, often severe and sometimes multicystic. The white matter injury can be quantified by DTI, with FA and Dav serving
as the most useful measurements (1143). Two characteristics of brain involvement are noteworthy: (a) the subcortical U fibers
are not spared—the subcortical white matter is involved severely and early (1148); (b) cerebral involvement is often slightly
asymmetric.
Proton MRS in both of these disorders in the acute or subacute phase shows elevation of lactate (a doublet centered at 1.33
ppm) and of glutamine/glutamate resonances (a broad peak at 2.1–2.4 ppm, just downfield from NAA, and at 3.75 ppm, also
attributable to glutamine (1149,1150)). Because of the short T2 relaxation times, the glutamine/glutamate peaks are best seen
with short echo time (20–30 ms) STEAM sequences (Fig. 3-111) (1149).
CT and MR reveal increased water (low attenuation and T1 hypointensity, T2/FLAIR hyperintensity), most commonly in
globi pallidi in methylmalonic acidemia (Fig. 3-113) (1156) and in the white matter, putamina, and caudate nuclei in propionic
acidemia (Fig. 3-114) (1157). CT often shows calcification of the basal ganglia in MMA (1157), while MRI typically shows
nearly symmetrical cystic changes of varying size in the globi pallidi on MR (Fig. 3-113B) (1156). Cysts have also been
described in the substantia nigra, but these are in locations where large perivascular spaces are commonly seen in normal
patients, so their significance is questionable. Abnormal hypodensity (CT) and T2 hyperintensity (MR) are sometimes
observed in the periventricular white matter (1157,1158); 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 diffusivity may be seen in
the affected regions, likely a result of mitochondrial dysfunction (1159).
Proton MRS in propionic reportedly shows decreased NAA and myo-inositol and increased glutamate/glutamine in the
basal ganglia (1160); reduced NAA is also reported in MMA (1159). Lactate elevation has been reported in a few cases of
both disorders (1159,1161). 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 (1162).
Figure 3-111 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.
Figure 3-113 Methylmalonic aciduria; 8-year-old boy, new onset of severe dystonia with recurrent vomiting. A. Axial T2 image shows
abnormal hyperintensity of the globi pallidi (white arrows). B. Axial FLAIR image shows heterogeneous hyperintensity in the globi pallidi (white
arrows). C. Axial Dav map shows high diffusivity (white arrows) compatible with cavitation.
Figure 3-114 Propionic acidemia 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.
Neuroimaging findings in infantile GM1 gangliosidosis, Tay-Sachs, and Sandhoff disease are nearly identical
(1166,1172–1174), although there are some subtle differences. CT studies show high attenuation in the thalami and low
attenuation in the white matter in early stages, with cerebral and cerebellar atrophy in later stages (1175). MR shows some T1
hyperintensity/T2 hypointensity in the thalami (1173,1174) and T1 hypointensity/T2 hyperintensity in the corpus striatum (Fig.
3-115) in Sandhoff disease (1176). T1 hypointensity/T2 hyperintensity is seen in the basal ganglia and posteromedial thalami
in Tay-Sachs disease, but some T1 and T2 shortening together with reduced Dav are seen in the anterior thalami (Fig. 3-116)
(1174). One report of MR in the late infantile form of GM1 gangliosidosis 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 (1177). The T2 hyperintensity in the basal
ganglia of GM2 gangliosidoses may render the basal ganglia isointense to surrounding white matter (Figs. 3-115 and 3-116), in
contrast to the dramatic high signal of the basal ganglia seen in organic acidemias and mitochondrial disorders. Diffuse,
progressive T2 hyperintensity in the white matter (Figs. 3-115B and 3-116D) is seen in both Tay-Sachs and Sandhoff diseases,
occasionally presenting a leukodystrophy-like or, in the opinion of some (54), a hypomyelinated appearance; however, the
corpus callosum usually remains well myelinated. Atrophy and T2 shortening of the thalami is seen in older patients with
Sandhoff disease (74,1173). Eventually, cerebral and cerebellar atrophy ensue.
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 (1178,1179). 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-acetylhexosamine are in white matter and
thalami (1180).
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 (1181). The gene encodes a putative mitochondrial protein, which the authors dubbed “duranin,” with
homology to FAD-dependent oxidoreductases (1181). 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 (1182). Mental
deficiency of variable severity typically becomes manifest during the second year (1183–1186), sometimes followed by
dystonia and pyramidal signs. Rarely, the disease may have a fulminant course resulting in infantile death (1187). Pathologic
analysis of affected brains shows spongiform degeneration of cerebral and cerebellar white matter with intense gliosis and
vacuolation of the neuropil. 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 (1183–1185,1187–1189).
The MR imaging findings are virtually pathognomonic for the disease. T1 and T2 prolongation are seen in the globi pallidi
and cerebellar nuclei (Fig. 3-117A, B, and E). Cerebral white matter exhibits a very characteristic centripetal and slightly
anteroposterior gradient; subcortical white matter is most severely affected with virtually total loss of normal signal intensity,
whereas periventricular white matter and in particular central corticospinal tracts and corpus callosum are spared (Fig. 3-
117B and C). 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 subtly abnormal (866,1183,1186,1190). The thalami are normal, but the cerebellar nuclei
are always abnormal and somewhat swollen (Fig. 3-117B and E) (866,1182,1183,1186,1190). Over time, more extensive
involvement of white matter is noted and affected structures tend to atrophy (866,1182,1186,1190). When patients present as
neonates, T2 images may show cerebellar hyperintensity in the first few days of life. 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 (39) and is increased in chronically affected subcortical white matter (1191). Short
echo time proton spectroscopy is reportedly normal other than slightly reduced NAA and increased myo-inositol (Fig. 3-117D)
(1191).
Figure 3-115 GM2 gangliosidosis (Sandhoff disease) in an 11-month-old boy. A. Sagittal T1-weighted image shows some hypointensity and
thinning (arrows) of the anterior body and genu of the corpus callosum. B. Axial T1-weighted image at the level of the corona radiata shows
hypomyelination with essentially no hyperintensity of the white matter pathways other than the corpus callosum. C and D. Axial T1-weighted
(C) and T2-weighted (D) images show hyper- (C) and hypointensity of the thalami but marked T1 hypointensity/T2 hyperintensity of the basal
ganglia (white arrows) as well as absence of any myelination in the subcortical or deep white matter.
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 (5%–10%) of brain tumors in patients with L-2-
hydroxyglutaric aciduria (1192,1193). 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 (1194).
Pathologic analysis of affected brains shows edema, causing necrosis of the neurons and glia, in the thalamus, brain stem
tegmentum, and cerebellar dentate nucleus. There is florid petechial hemorrhage around small caliber intraparenchymal
vessels. There may also be nonhemorrhagic white matter lesions in the cerebral and cerebellar parenchyma. An absence of
inflammatory cells, except a few extravasated leukocytes, differentiates this disorder from ADEM and acute hemorrhagic
encephalomyelitis (1195).
Neuroimaging studies in ANE show bilateral thalamic lesions (the imaging hallmark of the disease), which are continuous
with lesions in the lateral putamina and external/extreme capsules (Fig. 3-118). Ring enhancement around the hemorrhagic
areas develops after a few days, but diffuse thalamic enhancement has been identified during the first day, possibly due to
highly elevated levels of cytokines causing endothelial damage and blood–brain barrier breakdown (1213). The putamina tend
to be spared. Most studies also show low CT attenuation and T2/FLAIR hyperintensity in the brain stem (the tegmentum or the
entirety of the affected region; Fig. 3-119B) and, in some, the nuclei and deep white matter of the cerebellum (Fig. 3-119D).
Any of these areas may cavitate and become hemorrhagic, particularly in their central portions (Fig. 3-119F and G) (1214). In
about half of affected patients, the cerebral hemispheres are involved, usually by patchy hypodensity and T2 hyperintensity
(Figs. 3-118 and 3-119I); some cavitate, but hemorrhage seems to be much less common in these cerebral hemispheric lesions
(1195,1209). Reduced diffusivity may be seen in the affected regions of the brain stem, cerebellum, and thalami during the first
few days after onset of symptoms (Fig. 3-119F and G) (1207,1215), but the lesions appear to rapidly cavitate such that
diffusivity becomes increased (Fig. 3-118), likely because of the rapid tissue necrosis. Volume loss often ensues (Fig. 3-119H
and I).
Figure 3-118 Acute necrotizing encephalopathy (ANE). A 3-year-old with seizures after 1 day of fever, vomiting, and 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) from the thalamus shows low NAA and markedly elevated lactate (Lac).
3-Methylglutaconic Aciduria
3-Methylglutaconic aciduria (3-MGA-uria) is a fairly common biochemical abnormality that is found in many metabolic
disorders; however, a group of disorders with significantly and persistently increased urinary 3-MGA had been identified (41).
Previously, the disorders in significant elevation of 3-methylglutaconic acid in the urine were divided into five categories
based upon the order of discovery. Recently, Wortmann et al. (41) proposed a new classification based upon pathomechanism;
that classification will be used here. This classification distinguishes “primary 3-methylglutaconic aciduria (primary 3-MGA-
uria)” due to defective leucine metabolism (AUH defect, OMIM 250950) from three groups of “secondary 3-methylglutaconic
aciduria.” The latter are further classified and named by their defective protein: defective phospholipid remodeling (TAZ
defect, OMIM 302060), mitochondrial membrane–associated disorders (OP3, DNAJC19, or TMEM70 defect, OMIM
258501), and “not otherwise specified” 3-MGA-uria (41).
Figure 3-119 Acute necrotizing encephalopathy with necrosis and hemorrhage; two patients. In the first patient, axial T2-weighted image (A)
shows edema in both thalami (white arrows), while axial FLAIR image (B) at the pons shows diffuse edema (hyperintensity, arrows) with some
low signal intensity centrally. Axial gradient echo image through the pons (C) shows hypointensity hemorrhagic necrosis centrally (black
arrows). Early imaging of the second patient show extensive edema in the cerebellar nuclei (arrows in D), pons and internal capsules (large
black arrows in E), and periventricular white matter (white arrows in E). ADC maps acquired at the same time show reduced diffusivity in those
areas (white arrows in F and G). Follow-up images show significant volume loss and small areas of cavitation (white arrows in H and I).
Figures (D–I)) are courtesy of Dr. Ali Radmenesh, NYU.
Patients with primary 3-MGA-uria (OMIM 250950) typically present with early-onset dementia with progressive spasticity.
These patients have defective leucine metabolism due to mutations in the AUH gene, which encodes 3-methylglutaconyl-CoA
hydratase (1216). The phenotypic presentation varies, however, as some patients manifest delayed development of language
and hyperchloremic acidosis associated with gastroesophageal reflux, while others have a much more severe phenotype,
including seizures, and cerebellar findings (712). In early phases, MRI is reported to show mild T2/FLAIR hyperintensity of
the deep frontal white matter, while later stages show more diffuse white matter involvement and atrophy of the basal ganglia
(1217).
Patients with secondary 3-MGA-uria secondary to defective phospholipid remodeling from a TAZ defect (formerly type II
3-MGA-uria, or Barth syndrome, the most common cause of disease (1218)) most commonly present in the second decade but
can have onset anytime between birth and age 50 years (1217). Major manifestations are an X-linked cardiomyopathy, short
stature, neutropenia, defects of oxidative phosphorylation (OXPHOS), hypercholesterolemia, cognitive dysfunction, and mildly
dysmorphic features; brain MRI is normal. Those with a SERAC1 mutation as a cause for defective phospholipid remodeling
(formerly type IV 3-MGA-uria) have progressive spasticity, dystonia, deafness, severe psychomotor retardation, and defective
OXPHOS. Neonatal hypoglycemia and lactic acidosis have been noted in some cases (1162,1219), as has presentation as
Leigh syndrome (1220). Their MRI resembles Leigh syndrome with reduced diffusion and T2/FLAIR hyperintensity of the
basal ganglia, cerebral white matter, and midbrain (Fig. 3-120).
Patients with secondary 3-MGA-uria secondary to a mitochondrial membrane–associated disorder include those with OPA3
mutations (formerly type III 3-MGA-uria or Costeff syndrome (1221)) that affect the outer mitochondrial membrane, those with
DNAJC19 mutations (formerly type V) that affect mitochondrial protein import, and TMEM70 mutations (formerly type IV) that
are thought to affect the inner mitochondrial membrane and possibly mitochondrial complex V assembly. Patients with OPA3
mutations present with ataxia, extrapyramidal dysfunction, and optic atrophy; MRI findings are unremarkable. Those with
DNAJC19 mutations have dilated cardiomyopathy, nonprogressive cerebellar ataxia, testicular dysgenesis, growth failure,
anemia, and hepatic steatosis. Patients with TMEM70 mutations have variable phenotypes that may include ATPase deficiency,
myopathy, hypertrophic cardiomyopathy, cataracts, psychomotor retardation, lactic acidosis, and hyperammonemia (41,1221).
Imaging findings in these 3MGA variants are usually unremarkable, although occasionally, atrophy may be identified.
Figure 3-120 3-Methylglutaconic aciduria, type I. Axial T2-weighted image shows T2 prolongation in the caudate heads and the anterior halves
of the putamina.
Figure 3-121 Molybdenum cofactor deficiency in acute phase (age 5 days) and chronic phase (age 7 weeks). A and B. Acute phase T2-
weighted images show edema (manifest as T2 hyperintensity) of the cerebral cortex (which is isointense to white matter other than frontal
cortex), basal ganglia, and thalami (especially pulvinar). C. ADC map shows reduced diffusivity (hypointensity) in much of the cortex, in
subcortical white matter, and in the basal ganglia. Frontal cortex and thalami are less hypointense, possibly due to less injury. D. Proton MR
spectrum at basal ganglia level shows very high lactate peak (Lac), but NAA and Cho peaks have nearly normal size; this would be unusual in
hypoxic–ischemic injury where NAA and Cho would be low. E–G. Sagittal T1 image and axial T2-weighted images on follow-up MRI show
results of severe brain injury: markedly shrunken brain with extensive encephalomalacia (T2 hyperintensity), small deep gray nuclei, and
cortical thinning.
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 3-123 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 exposure should always be considered if
disease manifestations or disease onset is in any way atypical, particularly the acute onset of neurological signs and symptoms
in a previously healthy adolescent or teen.
A. Cerebellar Atrophy
1. With Ataxia as an Early Clinical Sign
a. Friedrich ataxia
b. Late-onset Tay-Sachs disease
c. Pontocerebellar hypoplasia
d. Mitochondrial disorders (particularly disorders of respiratory chain complex I and coenzyme Q)
e. Cerebrotendinous xanthomatosis
f. DNA polymerase gamma disorders (mitochondrial recessive ataxia syndrome)
g. Neuronal ceroid lipofuscinoses (all types, cerebellar findings most pronounced in late infantile form and progressive epilepsy/mental
retardation form)
h. Ataxia–telangiectasia (see Chapter 6)
i. Ataxia–telangiectasia–like disorder
j. Ataxia with oculomotor apraxia, types 1 and 2
k. Autosomal recessive ataxia of Charlevoix-Saguenay
l. Infantile-onset spinocerebellar ataxia
m. Mevalonic kinase deficiency
n. Marinesco-Sjögren syndrome
o. Spinocerebellar ataxias
p. Ataxia with selective vitamin E deficiency
q. Abetalipoproteinemia
r. Cayman ataxia
s. Dentatorubro-pallidoluysian atrophy
2. Without Ataxia as an Early Sign
a. Congenital disorder of glycosylation 1a
b. Infantile neuroaxonal dystrophy
c. Infantile olivopontocerebellar atrophy
d. Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome
e. Langerhans cell histiocytosis
f. Wolfram syndrome
g. Hypomyelination with atrophy of the basal ganglia and cerebellum (discussed in previous section)
h. 3-Methylglutaconic aciduria types I and IV
B. Cerebellar Hypoplasia
C. Marinesco-Sjögren syndrome
1. X-linked nonprogressive congenital cerebellar hypoplasia
2. Höyeraal-Hreidarsson syndrome
3. Revesz syndrome
Figure 3-124 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.
Cerebellar Ataxias
Many genetic disorders cause cerebellar ataxia as an early sign of neurologic disease. These can roughly be divided into two
major groups; those presenting in before the age of 20 years are traditionally classified 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 grouping is quite useful for the purposes of this book. Table 3-22 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.
Figure 3-125 Cerebellar hypoplasia. A. Moderate hypoplasia. The vermis (white arrows) is small, not extending superiorly to the intercollicular
sulcus or inferiorly to the obex. Fissures are not enlarged, however, 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. Note the pons (white
arrowheads) is extremely small.
Friedreich FXN 9q13 Mitoc hondrial Ataxia, nystagmus, weakness, amyotrophy, Normal Cb
ataxia iron metabolism unstable gaze fixation, Babinski, deafness, Spinal cord atrophy
cardiomyopathy, diabetes, scoliosis
Late-onset Tay- HEXA 15q23-24 Glycos phingo- Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy
Sachs lipid metabolism saccadic ocular pursuit, spasticity, hypotonia,
tremor, myoclonus, dystonia, impaired cognition,
epilepsy
Cerebro- CYP27 2q33-ter Bile acid Ataxia, weakness, amyotrophy, spasticity, Cb atrophy, cerebral atrophy, diffusely
tendinous synthesis myoclonus, dystonia, Parkinsonism, impaired increased FLAIR and T2 white matter
xanthomatosis cognition, epilepsy, cataracts, tendon xanthomas signal intensity
Mitoc hondrial COQ2 9p13.3 Many Hypotonia, motor delay, ataxia, or seizures Cb atrophy (vermis and hemispheres)
CoQ10 APTX 6q21
deficiency PDSS1 10p12.1
PDSS2 4q21-q22
CABC1 1q42.2
Mitoc hondrial POLG 15q22-26 Mitochondrial Ataxia, nystagmus, weakness, amyotrophy, Mild vermian atrophy, increased FLAIR
DNA DNA repair and ophthalmoplegia, saccadic ocular pursuit, and T2 white matter signal intensity in Cb
polymerase replication Babinski, tremor, myoclonus, choreoathetosis, white matter, thalami. In some variants,
gamma impaired cognition, epilepsy, impaired hearing, T2 hyperintensity in occipital lobes, brain
disorders hepatic failure stem.
Spinocerebellar Many Many Many Ataxia, weakness, amyotrophy Cb atrophy, spinal cord atrophy in some,
ataxias 1-36 pontine atrophy in some
Dentatorubro- ATN1 12p13.31 Unstable CAG Myoclonus, cerebellar ataxia, and mental Cb and midbrain atrophy, cerebral
pallidoluysian repeat retardation atrophy, white matter volume loss.
atrophy (anticipation)
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, choreoathetosis,
like disorder radiosensitivity, immunodeficiency
Ataxia with APTX 9p13 DNA repair, Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy, mostly in vermis
oculomotor possibly RNA oculomotor apraxia, ophthalmoplegia, gaze
apraxia type 1 processing fixation instability, hypotonia, tremor, dystonia,
choreoathetosis, impaired cognition, scoliosis,
optic atrophy
Ataxia with SETX 9q34 Unknown Ataxia, nystagmus, weakness, amyotrophy, Cb atrophy, mostly in vermis
oculomotor oculomotor apraxia, saccadic ocular pursuit,
apraxia type 2 strabismus, Babinski, tremor, myoclonus,
dystonia, choreoathetosis, impaired cognition,
scoliosis
Autosomal SACS 13q11 Protein folding Ataxia, nystagmus, weakness, amyotrophy, Cb vermian atrophy, spinal cord atrophy
recessive saccadic ocular pursuit, spasticity, Babinski,
ataxia of tremor, myoclonus, dystonia, choreoathetosis,
Charlevoix- impaired cognition
Saguenay
Infantile-onset C10orf2 10q24 DNA replication Ataxia, weakness, amyotrophy, ophthalmoplegia, Cb atrophy, spinal cord atrophy, brain
spinocerebellar hypotonia, choreoathetosis, impaired cognition, stem atrophy
ataxia 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, amyotrophy, Mild Cb atrophy
Sjögren strabismus, hypotonia, tremor, psychomotor
syndrome delay, impaired cognition, scoliosis, skeletal
deformities, cataracts, hypogonadism
Ataxia with vit E TTPA 8q13.1- Vit E Ataxia, amyotrophy, Babinski, tremor, RP, Normal or mild Cb atrophy
Deficiency 13.3 homeostasis cardiomyopathy
Refsum PHYH 10 pter- Fatty acid Ataxia, amyotrophy, RP, cardiomyopathy, skeletal Normal Cb
disease PEX7 p11.2 oxidation deformities, renal failure, elevated CSF protein
6q22-q24 Peroxisomal
protein
importation
Autosomal SYNE1 6q Not known Dysarthria, ataxia, dysmetria, hyperreflexia, Cb vermian and hemispheric atrophy
recessive Cb nystagmus
ataxia Type 1
S/Sx, signs and symptoms; Cb, cerebellum; RP, retinitis pigmentosa; vit, vitamin.
Cerebellar Atrophy
Friedreich ataxia
Friedreich ataxia (OMIM 229300) is the most common form of hereditary ataxia, with a prevalence of 2.1 × 10−5. This is an
autosomal recessive disorder; the genetic locus of the FXN gene has been mapped to chromosome 9q13, with no evidence of
genetic heterogeneity (1246). The function of the encoded protein (called frataxin) is unknown, but it is known that frataxin is
located at the inner mitochondrial membrane and its mutation seems to trigger deficiency of iron–sulfur cluster-containing
enzymes, such as mitochondrial respiratory chain complexes I to III (1029). Deficiency of frataxin is generally 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 1000 triplets (1247). The disease shows considerable variability in
age of onset, rate of progression, severity, and extent of disease involvement; although the disease can present at nearly any
age, onset is typically around age 10 (before the age of 10 years in 35%–40%) (1248). 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 and is
the main cause of death at an average age of 37 years (1249). A high incidence of diabetes mellitus (25%) is present in
childhood-onset cases (1246). The main pathologic features are early loss of large sensory neurons in the dorsal root ganglia,
followed by degeneration of the posterior columns of the spinal cord, spinocerebellar tracts, and pyramidal tracts (1250). MR
is most often normal but may show atrophy of the superior vermis (Fig. 3-126), inferior and superior cerebellar hemispheres,
spinal cord, and, occasionally, brain stem (Fig. 3-126) (1251,1252). DTI using tract-based spatial statistics has demonstrated
increased diffusivity in the cerebellum and decreased FA in the superior cerebellar peduncles (1252,1253).
Figure 3-126 Friedreich ataxia. A. Sagittal T1-weighted image shows a small cerebellar vermis with thick 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.
Ataxia–Telangiectasia
Ataxia-telangiectasia is a fairly common cause of ataxia and cerebellar 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.
Formerly known autosomal recessive spinocerebellar ataxia, AOA type 2 (OMIM 606002) is an autosomal recessive
disorder caused by mutations (missense, in frame deletion or splice mutations, or truncations) of the SETX gene at chromosome
9q34.13 (1263). Affected patients present later than those with AOA1, with onset usually between ages 10 and 22 years. They
are characterized by the onset of gait ataxia during the second decade, associated with oculomotor apraxia (~50%), peripheral
neuropathy (>95%), impaired smooth pursuit (100%), and gaze-evoked nystagmus (90%). Pyramidal signs are present in
approximately 20% and tremor and extrapyramidal signs in 10% to 15%, and cognitive changes are found in some populations
(1264,1265). Serum alpha-fetoprotein is elevated (1265). MRI is similar to that in type 1, with cerebellar atrophy that is
largely confined to the vermis (1264–1266).
Ataxia with oculomotor apraxia type 3 (AOA3, OMIM615217) is caused by mutations of the PIK3R5 gene on chromosome
17p; only a single family (from Saudi Arabia) has been reported (1267). All patients had onset during the teen years with
varying degrees of unsteadiness of the legs and frequent falls, followed by onset of arm dysmetria, slurred speech, and truncal
ataxia as well as ocular apraxia (1267).
Marinesco-Sjögren Syndrome
Marinesco-Sjögren syndrome (OMIM 248800) is an autosomal recessive disorder manifested mainly by congenital cataracts,
cerebellar ataxia, myopathy resulting in progressive muscle weakness, and psychomotor delay; less prominent features include
short stature, hypergonadotropic hypogonadism, and skeletal deformities (resulting from muscle weakness) (1268–1270). It is
caused by homozygous or compound heterozygous mutations in the SIL1 gene on chromosome 5q31 (1270) and (although rare)
appears to be the one of the five most common causes of autosomal recessive progressive cerebellar ataxia, after Friedreich
ataxia, ataxias with oculomotor apraxia (AOA1 and AOA2; see preceding section), and ataxia–telangiectasia (see Chapter 6)
(1271). Imaging findings are limited to diffuse cerebellar cortical atrophy (Fig. 3-128), which results from extensive Purkinje
and granule cell loss (1270); in the setting of congenital cataracts, short stature, and myopathy, the diagnosis of Marinesco-
Sjögren syndrome should be at the top of the differential diagnosis.
Figure 3-128 Marinesco-Sjögren syndrome; 17-year-old with congenital cataracts, long-standing incoordination, and mild intellectual disability.
A. Sagittal midline T1 image shows severe, diffuse vermian atrophy; otherwise normal appearance. B. Coronal T2-weighted image shows
diffuse thinning of cerebellar cortex and hyperintensity of subcortical white matter. Diffuse loss of deep cerebellar white matter and abnormal
hyperintensity of cerebellar nuclei are also seen. C. Axial T2-weighted image at level of fourth ventricle shows marked loss of cerebellar
parenchyma, showing prominent cortical fissures and marked fourth ventricular enlargement.
Figure 3-129 Cerebellar atrophy due to coenzyme Q10 deficiency. Sagittal T1-weighted (A) and axial T2-weighted (B) images show
holocerebellar atrophy, with prominent fissures (white arrows) and enlarged fourth ventricle (IV).
Pontocerebellar Hypoplasias
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 portion of the pons. As a
result, abnormal development of the pontine nuclei, cerebellar nuclei, or the cerebellar cortex or injury to these structures
during the developmental period (with subsequent degeneration of axons coursing through the middle cerebellar peduncles)
results 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 (1290). Fifteen separate clinical syndromes have been
defined in which the pons and cerebellum are hypoplastic in infancy; these are referred to as the pontocerebellar hypoplasia
types 1 to 10, with mutations of three separate genes causing PCH1 and five genes causing PCH2 (see Rudnik-Schöneborn et
al. (1290) and OMIM for more detailed information). These disorders are also included in Chapter 5 but are principally
discussed here, as their clinical courses are progressive. An important concept here, as in the remainder of this book, is that
the gene affected is less important than the specific mutation! Note that TSEN54 mutations cause PCH2A, PCH4, and PCH5.
This is because different mutations result in different alterations of the protein product and, consequently, different effects on
the function of the molecular pathway.
PCH type 1 is genetically heterogeneous, with three known genetic causes (see Table 3-23). Affected patients typically
present with progressive microcephaly, central hypotonia, visual impairment, abnormal eye movements, and delayed
psychomotor development (1290,1294). They are often myopathic from involvement of the anterior horn cells of the spinal
cord and may be born with contractures of the extremities (1295). Both the cerebellum and pons are small at birth and show
further atrophy on subsequent studies; 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. 3-130), which is different from most cerebellar
atrophies (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. (1296,1297), is inherited as an autosomal recessive trait. It
is genetically heterogeneous, with mutations of five genes known to cause this disorder at the time this chapter is being
composed. All have similar clinical characteristics, but of varying severity; the phenotype varies with both the gene mutated
and the specific mutation (1298). Affected patients are characterized by progressive microcephaly, epilepsy, and severe
neurological compromise, including early-onset chorea and extrapyramidal dyskinesias that are progressive (1290); in the
more severe genotypes, there is essentially no developmental progress (1296,1298). Pathologically, these brains are
characterized by a reduced number of folia in the cerebellum and an undersized 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 pontine neurons and
diminished number of myelinated axons within the basis pontis (1299). In addition, segmental focal lesions are seen in the
cerebellar cortex, dentate nuclei, and inferior olives (1300). On imaging, the pons may be quite small or have a slight ventral
bulge; the cerebellum is variable in size, ranging from mildly to severely hypoplastic (Fig. 3-131) (1298). As with type 1 PCH,
the vermis is relatively spared compared with the cerebellar hemispheres, giving a so-called “dragonfly” appearance on MRI.
Supratentorial structures are reported to be essentially normal, but the subarachnoid spaces may be enlarged and white matter
may have abnormal T1 hypointensity/T2 hyperintensity (Fig. 3-131).
A third form of PCH (PCH3, OMIM 608027) (1301), whose clinical, imaging, and genetic studies demonstrated a similar
disorder to PCH2 (cerebellar atrophy with progressive microcephaly) except for the absence of dyskinesias and the presence
of optic atrophy, has linkage to chromosome 7q11-q22. Distinct features are craniofacial dysmorphisms and optic atrophy
(1290). Unfortunately, no pathological information is available for this entity. Additional PCH types were proposed by Patel et
al. (1302), who suggested that PCH cases with severe olivary hypoplasia (“C-shaped” inferior 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. (1300) performed pathologic examinations on two patients with PCH4, finding
features nearly identical to those in PCH2, only of greater severity. In reviewing these 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 pathway (1303). Clearly, the understanding of these disorders is evolving.
PCH4 (OMIM 225753, originally known as olivopontocerebellar hypoplasia) also results from mutations of TSEN54
(mostly A307S); it is manifested as massive myoclonus, either prior to birth or in the neonatal period. Affected patients are
respirator dependent from birth and early death (often first postnatal week) is characteristic (1290). This is the most severe
end of the PCH spectrum from the imaging perspective, with very severe and rapidly progressive cerebral and cerebellar
atrophy (1298).
PCH1A VRK1 607596 Prenatal onset, congenital respiratory and feeding Atrophy-like appearance with large fissures in
14q32.2/AR impairment, arthrogryposis multiplex with anterior hemispheres and vermis. Reduced supratentorial white
horn cell degeneration matter without atrophy
PCH1C EXOSC8 616081 Single family. Failure to thrive at 2–4 mo, muscle Variable vermis hypoplasia, thin corpus callosum, cortical
13q13.3/AR weakness, spastic quadriparesis, psychomotor atrophy
delay
PCH2A TSEN54 277470 Progressive microcephaly, clonus, jitteriness, Pontine and cerebellar atrophy with “dragonfly” pattern on
17q25.1/AR extrapyramidal dyskinesias, dystonia, central coronal images caused by flat cerebellar hemispheres and
visual impairment, seizures relatively preserved vermis
PCH2B TSEN2 612389 Severe prenatal-onset microcephaly, epileptic Cerebellum and brain stem hypoplasia, thin corpus
3p25.2/AR encephalopathy callosum, enlarged ventricles
PCH2D SEPSECS 225753 Postnatal-onset microcephaly, severe cognitive Progressive cerebrocerebellar atrophy without pontine
4p15.2/AR disability, spasticity, variable seizures involvement
PCH2E VPS53 615851 Slow progression of hypotonia, psychomotor Progressive diffuse cerebellar > cerebral atrophy
17p13.3/AR retardation, microcephaly, motor impairment
PCH3 PCLO 608027 Hypotonia, hyperreflexia, microcephaly, optic Cerebellar atrophy with progressive microcephaly
7q21.11/AR atrophy, early seizures
PCH4 TSEN54 225753 Pre- or neonatal myoclonus, hypertonia, joint Severe olivopontocerebellar hypoplasia with very severe
17q25.1/AR contractures cerebral and cerebellar atrophy
PCH5 TSEN54 610204 Cerebellar hypoplasia in second trimester, fetal Severe pontine and cerebellar hypoplasia. Move to PCH2.
17q25.1/AR seizures, and myoclonus
PCH6 RARS2 611523 Mitochondrial respiratory chain defects; Cerebellar hypoplasia with progressive atrophy of pons,
6q15/AR hypotonia, poor sucking, intractable seizures, cerebellum, cerebrum
progressive microcephaly
PCH7 Not mapped 614969 Single patient. Apnea, generalized seizures, poor Severe PCH, enlarged ventricles, reduced white matter
movements at birth
PCH8 CHMP1A 614961 Hypotonia, psychomotor retardation, abnormal PCH, reduced white matter, thin corpus callosum
16q24.3/AR movements, ataxia, joint contractures
PCH9 AMPD2/AR 615809 Severely delayed psychomotor development, Small cerebellum, flattened pons, generalized cerebral
1p13/AR progressive microcephaly, spasticity, seizures atrophy with thin corpus callosum
PCH10 CLP1/AR 615803 Severe psychomotor delay, progressive Pontocerebellar hypoplasia, thin corpus callosum,
11p12.1/AR microcephaly, spasticity, seizures simplified gyral pattern
Patients with PCH5 (OMIM 610204) also have severe mutations of TSEN54; they present prenatally with myoclonus or
seizure-like activity. Imaging and pathological findings are similar to PCH2, but the cerebellar vermis is more severely
affected than the hemispheres. These patients will probably eventually be reclassified at PCH2 (1290).
PCH6 (OMIM 611523) is distinct from the other forms of PCH in that it is caused by a nuclear gene (RARS2) encoding a
protein that functions in mitochondrial translation (1304). This phenotype is rather distinctive on MRI, with vermis more
affected than hemispheres and the anterior vermis (anterior to the primary fissure) more affected than the posterior vermis in
early stages of the disease (1305). Eventually, the entirety of the cerebellar hemispheres and vermis are affected, as well as the
cerebrum with consequent diffuse thinning of the corpus callosum (1306). Clinically, affected neonates have severe
encephalopathy with generalized hypotonia, poor suck, intractable seizures, lactic acidosis, and progressive microcephaly
(1306).
PCH7 (OMIM 614969) has been proposed in a single male with a combination of primary hypogonadism and PCH (1307).
The patient developed irritability, seizures, apneic episodes, and reduced spontaneous movements during the first weeks of
life; autopsy revealed absent testes. No causative gene was identified. MRI shows severe PCH with enlarged
ventricles/reduced cerebral white matter (1307).
PCH8 (OMIM 614961) has been shown to result from loss of function mutations to human CHMP1A, a chromatin-modifying
protein that is a member of the ESCRT-III (endosomal sorting complex required for transport III) complex that is believed to
regulate chromatin structure. Affected patients show variable psychomotor retardation, abnormal movements, hypotonia with
limb spasticity, hyperreflexia, ataxic gait, and variable visual defects (1308). The presence of growth retardation and joint
contractions differentiated this group from other types of PCH. MRI showed PCH and diminished cerebral white matter with a
thin corpus callosum (1308).
Figure 3-130 Pontocerebellar hypoplasia type 1. Sagittal T1-weighted image (A) shows a small pons and slightly hypoplastic cerebellar
vermis. The callosal splenium is too small. Axial T2-weighted image (B) shows that the vermis (black arrows) is relatively spared compared
with cerebellar hemispheres.
PCH9 (OMIM 615809) is an autosomal recessive disorder caused by mutations of the AMPD2 gene. Affected patients have
severe microcephaly, profoundly delayed psychomotor development, and spasticity; seizures are present in nearly all, and
dysphagia, dystonia with clonus, and optic atrophy/visual impairment are common (1291). Imaging shows severe atrophy of the
cerebral white matter (with virtual disappearance of the corpus callosum in some patients), brain stem, and, to a lesser extent,
cerebellum; the authors make note of an “H-shaped” midbrain–pontine junction on axial images as a characteristic finding
(1291). Of significance, cell was prevented death in the laboratory by bypassing the block in de novo purine synthesis, making
this a potentially treatable condition (1291).
PCH10 (OMIM 615803) is an autosomal recessive disorder caused by mutations of the CLP1 gene that results in
destabilization of the tRNA endonuclease (TSEN) complex and consequent impaired pre-tRNA cleavage (1292). After an
unremarkable prenatal period, affected infants fail to develop motor skills or speech while developing progressive spasticity
and severe psychomotor delay and epilepsy (1292,1293). Dysmorphic facial features appear (high-arched eyebrows,
esotropia, long palpebral fissures, hypoplastic nasal alae). MRIs of the majority of cases published (1292,1293) show atrophy
in the cerebrum greater than cerebellum and brain stem. Overall, these patients have a heterogeneous and very different
imaging appearance than the other pontocerebellar hypoplasias; they are, perhaps, better characterized as generalized
neurodegenerative disorder.
Figure 3-131 Pontocerebellar hypoplasia type 2. Sagittal T1-weighted image (A) shows the cerebellar vermis (larger white arrows) and entire
brain stem to be abnormally small. The posterior corpus callosum (small, long arrows) is too thin. Coronal T2-weighted image (B) shows
prominent CSF spaces and “dragonfly” pattern of larger vermis (thick black arrow) with very small cerebellar hemispheres (long, thin black
arrows).
Figure 3-132 Congenital disorder of glycosylation, type 1a. Sagittal T1-weighted image shows a small, atrophic cerebellar vermis (white
arrow). This is thought to represent atrophy that begins before birth.
On pathology, cerebral and pronounced cerebellar atrophy are 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 preserved in number although reduced in size, deformed, and slightly misaligned (dendrites were
horizontally oriented). The molecular layer is reduced in volume. The optic nerves are atrophic. Myelination appears normal
(1330,1334).
Neuroimaging studies during the first year of life are often normal, other than thinning of the corpus callosum (1335).
Subsequent studies show reduced volume of cerebral white matter along with progressive cerebellar atrophy, involving the
entire cerebellum (Fig. 3-133) (1335). The reduced cerebral white matter volume results in progressive thinning of the corpus
callosum (Fig. 3-133D) (1330,1336). Serial neuroimaging studies showed that the disease process is operative during the
postnatal period, although a prenatal onset cannot be excluded (1334). Short echo proton MRS, not surprisingly, shows
progressive reduction of NAA throughout the brain, along with the presence of small amounts of lactate (1335).
Figure 3-135 Cerebellar and cerebral degeneration due to KIF1A mutation. A and B. Sagittal and coronal T1 images at age 2 years show
slight superior vermian atrophy (arrows), but an otherwise normal appearance. C and D. Repeat imaging at age 14 years, accompanying very
significant neurodevelopmental delay, shows development of significant atrophy of the cerebellar cortex in the hemispheres and vermis, with
resultant enlargement of fissures and fourth ventricle.
Spinocerebellar Ataxias
The spinocerebellar atrophies are a group of phenotypically and genotypically heterogeneous group of dominantly inherited
disorders. At the time of the writing of this book, at least 36 have been described (1275), including dentatorubro-
pallidoluysian atrophy (DRPLA) (1275). Most of these disorders have their onset in adults and differentiation is difficult,
depending on a combination of clinical features, radiologic features, and genetic testing (1275). 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 (1352). 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
(1275,1353,1354).
Cerebrotendinous Xanthomatosis
Cerebrotendinous xanthomatosis is a disorder of the hepatic bile acid synthesis pathway caused by mutations of the CYP27
gene on chromosome 2q33-qter (1261,1355). 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 extrapyramidal signs, sensorimotor peripheral neuropathy, and seizures (39,1355).
Psychiatric problems and early dementia may ensue. Associated findings 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 (Fig. 3-137) and cerebellar nuclei (39,1261,1355). Calcifications are often
present in the affected cerebellar white matter.
Wolfram Syndrome
Wolfram syndrome was originally described as a combination of diabetes mellitus and bilateral optic atrophy (1356). It was
later called DIDMOAD for prominence of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (1357). In more
than 90% of affected patients, the disorder (OMIM 222300) is caused by mutations of the WFS1 gene located at chromosome
4p16.1 (1358); a second form of the disease (WFS2, OMIM 604928) is associated with mutations of CISD2 at chromosome 4q
(1359). Affected patients can also have anosmia, 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 addition, there was widespread axonal dystrophy with
axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices, and the deep cerebral white
matter (1360). Two reports of MR in Wolfram syndrome noted striking brain stem and cerebellar atrophy in addition to atrophy
of the optic system and hypothalamus (1361,1362); both were adults at the time of the scan. However, another report described
normal cerebellum and brain stem other than T2 prolongation in the substantia nigra (1363). 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, perhaps) remains to be clarified.
Figure 3-136 Langerhans cell histiocytosis involving the cerebellum. Axial T2-weighted image (A) shows abnormal hyperintensity (white
arrows) pons in the region of the corticospinal and corticopontine tracts. Coronal T2-weighted image (B) shows abnormal 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 cerebral cortical atrophy.
Figure 3-137 Cerebellar atrophy associated with cerebrotendinous xanthomatosis; this young man had firm swellings on his Achilles
tendons. A. Sagittal T1-weighted image shows prominent fissures between narrow vermian folia, particularly superiorly (black arrow). B and C.
Axial images at the level of the medulla and cerebellar nuclei show hyperintensity of the white matter (large arrows) around the cerebellar
nuclei. In the medulla, arrows show flattening of the surface in the region where the inferior olives are usually prominent and abnormal
hyperintensity (small black arrows) in the region of the inferior olivary nuclei. (This figure is courtesy of Dr. Junichi Takanashi, Tokyo).
Cerebellar Hypoplasia
In cerebellar hypoplasias, and in many other disorders, disagreements abound regarding classification. Dr. Enrico Bertini from
Rome has suggested classifying X-linked disorders with cerebellar dysgenesis into a group, the hallmark of which is a
cerebellar defect, seen in MRI, that is caused by gene mutations or genomic imbalances on the X-chromosome. In this group, he
includes cerebellar hypoplasia from mutations of OPHN1 and CASK gene mutations, orofaciodigital syndrome type 1/Joubert
syndrome, fragile X syndrome, X-linked Opitz syndrome, X-linked lissencephaly with cerebellar hypoplasia and abnormal
genitalia due to ARX mutations, and Rett syndrome, among others (1364). Although this is an interesting concept, it will not be
followed in this book. This author does agree, however, that cerebellar hypoplasias, with or without dysgenesis, are nomadic
and seem to wander between metabolic and malformative classifications (e.g., tubulinopathies and the very wide range of
pontocerebellar atrophies with supratentorial anomalies).
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 that progresses to pancytopenia (1367–1369). It is caused by mutation of the DKC1 gene at chromosome
Xq28 (1370), the same gene that causes X-linked dyskeratosis congenita, and Höyeraal-Hreidarsson syndrome is now
considered a severe variant of that disorder in which the children die before they develop the skin and nail abnormalities
(1371). Neuropathological findings are of delayed myelination and hypoplasia of the cerebellar granule cell layer without loss
of Purkinje cells (1367,1368,1372). Fetal imaging may show cerebellar hypoplasia. Postnatal imaging shows a small
cerebellum (with slightly enlarged fissures but no progression on successive scans) and small pons, usually with reduced
cerebral white matter, a thin corpus callosum, and delayed myelination (1373,1374). Calcification of the basal ganglia, pons,
and subcortical white matter may be present (1375). Radiographs may show distal metaphyseal flaring of the long bones
(1374).
Revesz Syndrome
Revesz syndrome (OMIM 268130) is a variant of dyskeratosis congenita, a rare disorder characterized by bone marrow failure
and integument abnormalities, such as abnormal skin pigmentation, dystrophic nails, and leukoplakia (1376). It is caused by
mutations of the TINF2 gene at chromosome 14q12 (1377). In Revesz syndrome, patients present with leukocoria due to a
Coats disease–like retinopathy (1378). In addition, patients can have aplastic anemia, ataxia with cerebellar hypoplasia, and
multiple cerebral parenchymal abnormalities (1378,1379). Mental retardation is found in up to 25% of patients (1376).
Imaging 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 (1379).
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Brain and Spine Injuries in Infancy and Childhood
Erin Simon Schwartz and A. James Barkovich
Introduction
Basic Patterns of Brain Destruction
Porencephaly
Hydranencephaly
Encephalomalacia
Neonatal Hypoglycemia
Bilirubin Encephalopathy (Kernicterus)
Brain Injury Associated with Congenital Heart Disease
Hypernatremic Dehydration
CNS Trauma in Infancy and Childhood
Birth Trauma
Postnatal Trauma
Abusive Trauma (Child Abuse)
Mild Traumatic Brain Injury (Concussion)
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 resulting from physical, hypoxic–ischemic,
hypoglycemic, and hyperbilirubinemic 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.
Porencephaly
The term porencephaly has many different definitions. Pathologists use the term to describe focal cavities with smooth walls
and minimal 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 (4,5). Used in this sense, porencephaly is essentially synonymous with schizencephaly, 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 developing early in the second trimester as encephaloclastic
porencephalies, smooth-walled cavities without any surrounding gliosis, in order to differentiate them from agenetic
porencephalies and from cystic encephalomalacia (see discussion below), a condition characterized by shaggy-walled
cavities with considerable astroglial reaction and resulting from late gestational, perinatal, or postnatal injuries (2,6,7).
On imaging studies, (encephaloclastic) porencephalies appear as smooth-walled cavities that are isointense to
cerebrospinal fluid (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 differentiate
from ex vacuo enlargement of the lateral ventricles secondary to complete liquefaction and absorption of surrounding white
matter; indeed, the “cyst” may be completely integrated into the adjacent ventricle.
Figure 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 map at the same level shows very high diffusivity (white arrow), compatible with freely
moving water molecules in a cyst.
Hydranencephaly
Hydranencephaly is a condition in which most of the brain mantle (cortical plate and hemispheric white matter) has been
damaged, liquefied, and resorbed (8); it can be considered as porencephaly of nearly the entire cerebrum. The cerebral
hemispheres are largely replaced by thin-walled sacs containing CSF (2,5). In rare cases, the cerebellum may be similarly
involved. The membranes of the sacs are composed of an outer layer of leptomeningeal connective tissue and an inner layer of
remnants of the cortex 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 transfusion (9) and congenital infection (10,11) 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
hydranencephaly (2,4). Clinically, affected patients may be microcephalic, normocephalic, or macrocephalic, depending upon
the presence and degree of associated hydrocephalus (4). Because of the nearly complete lack of cortical tissue, the children
reach few developmental milestones (4). Note that, rarely, an appearance of hydranencephaly is caused by very severe
developmental hydrocephalus in which the ventricles herniate through the choroidal fissures to give the appearance of absence
of brain parenchyma in the posteromedial and anteromedial cerebral cortex, which has been called hydranencephaly with
abnormal genitalia (HYD/AG) but appears to be massive hydrocephalus with herniation of the lateral ventricles through the
choroidal fissures associated with agenesis of the corpus callosum and hypoplastic basal ganglia (12).
Imaging studies of patients with hydranencephaly show that the cerebral hemispheres are nearly completely replaced by
CSF (13,14). The thalami are usually preserved. The inferior medial aspects of the frontal lobes and the inferior medial
aspects of the temporal and occipital lobes may also be preserved (Fig. 4-3). The brain stem is usually atrophic; the
cerebellum is typically normal but may be affected similar to the cerebrum in exceptional cases. MR angiography shows abrupt
narrowing of the supraclinoid carotid arteries (and of the distal basilar artery if the cerebellum is affected); however, this does
not imply a vascular etiology of the injury, as blood vessels narrow in response to reduced demand.
The diagnosis can also be made in utero by sonography or MRI, both of which will show the thin rim of cerebral tissue
around dilated ventricles; MRI is probably best for fetal diagnosis, as it is not subject to shadowing or reverberation artifacts
(Fig. 4-4) (13). MRI has made it much easier to differentiate hydranencephaly from hydrocephalus in fetuses, even when the
condition is extremely severe and results in large ventricular diverticula through the choroidal fissures, because the thin rim of
tissue can be distinguished from the enlarged ventricles. This distinction is important because hydrocephalic children may
respond 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. Also,
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.
Figure 4-2 Porencephaly secondary to periventricular hemorrhagic infarction. A. Coronal transfontanelle sonogram in a 4-day-old 26-week
premature infant shows a large echogenic hemorrhage (small arrows) in the region of the left lateral ventricular germinal matrix. The slightly
less echogenic region superolaterally (larger arrows) is a focus of hemorrhagic infarction. B. Follow-up axial transfontanelle sonogram at age
10 weeks shows an enlarged, echo-free left lateral ventricle (arrows). This area of porencephaly is composed of the cyst created by the
infarction (and lack of astroglial response) joined with the adjacent lateral ventricle. C and D. Coronal FLAIR (C) and axial T2 (D) images show
the area of porencephaly caused by liquefaction and resorption of the damaged tissue and enlargement of the lateral ventricle (V) into the
damaged area. Some blood products (or calcification) persist as hypointensity (white arrows in D) in the lateral wall of the cyst. Note the
difficulty in differentiating this destructive lesion from ex vacuo enlargement of the ventricle.
Encephalomalacia
Encephalomalacia, in contradistinction to porencephaly and hydranencephaly, is characterized pathologically by astroglial
proliferation and, often, septations within the area of damaged brain. There is a “border zone” between porencephaly and
encephalomalacia, sometimes called macrocystic encephalomalacia (Fig. 4-5), a condition showing large cystic spaces of the
cerebral cortex and white matter, sparing only a small region of periventricular white matter. More commonly, MR 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. 4-6). In infants, images obtained in the subacute phase after injury will often show T1 hypointensity
and T2 hyperintensity of the injured cortex and white matter (Fig. 4-7). This is likely from the increased water content of the
damaged tissue, as newborns generate less than 10% of the astroglial response to injury seen in adults. The inherently poorer
contrast resolution of CT limits reliable differentiation of porencephaly from cystic, and even noncystic, encephalomalacia
(Fig. 4-6A). 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 (5).
Multiple cystic cavities of variable size, separated by glial septations, form in the necrotic area (Figs. 4-6 to 4-8) (5). The
location of the lesions varies with the nature of the insult. If caused by thrombotic or embolic infarction (Figs. 4-6 and 4-8), 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 intervascular boundary zones (see the section on ischemic injury in
neonates, later in this chapter) or, in some cases (incompletely understood), may affect virtually the entire cortex with sparing
of the basal ganglia (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 (15,16). Neonatal hypoglycemia causes damage in the parietal
and occipital lobes (17,18). 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, the imaging appearance does not characterize the cause.
Ultrasound will show increased echogenicity between the 2nd and 5th days after injury, with cystic degeneration developing
between the 7th and 30th day after injury in term infants (19). The variation in the time to cavitation 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. Septations are
often seen within the damaged region, and calcification may be present (2). On MR, 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. 4-6 to 4-8). Some
heterogeneity is often present, as a result of the combination of variably sized glial septa 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 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.
Figure 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.
Figure 4-4 Fetal hydranencephaly. Axial (A–C) and coronal (D–F) images. The appearance is that of liquefaction/resorption of both MCA
vascular territories with relative sparing of the ACA and PCA vascular territories. Fetal MRI is the best technique to make this diagnosis, as the
remnants of tissue in the anterior cerebral artery distribution (black arrowheads), posterior cerebral distribution (black arrows), and the deep
gray nuclei (white arrows) are sharply defined and easily distinguished from the fluid occupying the remainder of supratentorial space. (These
figures are courtesy of Dr. Sean Bryant, Denver, CO.)
Figure 4-5 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 septa.
Localized Infarctions
Stroke is being increasingly recognized as an important cause of morbidity and mortality in childhood (21,22). Indeed, it is one
of the top 10 causes of childhood death (23,24). Approximately 25% of all pediatric strokes occur in neonates, and
approximately 50% occur in children less than 1 year of age (23,24); fetal MRI has demonstrated that many infarcts
(hemorrhagic and nonhemorrhagic) occur before birth. The reason for this high incidence of strokes in fetuses and infants is not
established, although an increasing number of investigators suspect that inflammation plays an important role both in this group
and in older children (20,25,26). 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 (21,27–30).
Figure 4-6 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, tissue (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.
Figure 4-7 Severe, extensive encephalomalacia secondary to moderate hypotension. A and B. Axial T1- (A) and axial T2-weighted (B)
images show cortical thinning with abnormal T1 hypointensity and T2 hyperintensity involving virtually the entire cerebral cortex. Note the
relative sparing of the basal ganglia (BG) bilaterally. The thalami typically show more atrophy than do the basal ganglia in the chronic phase. C.
Proton MR spectroscopy from a voxel in the centrum semiovale of the left hemisphere shows markedly reduced NAA due to the severe,
widespread damage.
Figure 4-8 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 middle cerebral artery distribution. Thin septa (arrowheads) are present within the cavity.
A large number of focal brain infarctions in the pediatric population are still considered “idiopathic”; that is, the cause of
the stroke is never found; however, the increasing recognition of transient cerebral arteriopathy (TCA) secondary to prior
infections (see the following paragraph) (27–29) has lowered this number considerably. The number of idiopathic stokes
remains high in neonates (36). Childhood strokes may be associated with inflammation (27,28), metabolic disorders, anemia
(40), or disorders of coagulation (41). In patients with no underlying metabolic disorders, trauma and previous viral infection
are significantly more common (27,28,42,43). Lack of vaccinations has recently been shown to be associated with childhood
stroke, further promoting infection as a very common cause (27). Genetic or acquired conditions causing thrombophilia are
less common causes (44,45).
Maternal factors/conditions
Thrombotic disorders
Infertility and infertility treatment
Preeclampsia
Prolonged rupture of membrane (>24 h)
Chorioamnionitis
Maternal autoimmune conditions and autoantibodies (platelet alloantigen-1)
Antiphospholipid syndrome
Fetal/neonatal disorders
Complicated delivery
Mutations in COL4A1/COL4A2 (genes for procollagen IVa1)
Inherited thrombophilia
Twin-to-twin transfusion syndrome
Fetal/neonatal polycythemia
Congenital heart disease
Neonatal hypoglycemia (in preterm infants)
Persistent fetal circulation and extracorporeal membrane oxygenation therapy
Intrauterine growth restriction
Fetal/neonatal infections and meningitis
Nonspecific factors
Central venous catheter
Ethnicity and race (higher incidence in black infants compared with non-Hispanic white infants)
Infant gender (higher incidence in boys)
As noted in the prior paragraph, a number of recent studies have shown that transient cerebral arteriopathy (TCA) is an
important cause of childhood stroke (25–29,46). Defined by the presence of an in situ arterial abnormality (stenosis,
irregularity, occlusion, banding, pseudoaneurysm, or dissection flap) on imaging, arteriopathy was found in 36% of a group of
355 children, aged 29 days through 18 years, from 4 continents and Australia (29). This is an important diagnosis to establish
because prognosis can be improved by treatment of the inflammation. Several studies have shown that the affected blood
vessel, which may be irregular, narrowed, or enlarged when diagnosed by MRA, CTA, or catheter angiography, may change in
appearance over the short term (they may become narrower or wider or show more irregularities), but over the long term, they
usually normalize (~25%), stabilize after improvement (32%), or stabilize (45%) without further infarctions (29,46). Outcome
is much better in patients in whom the arteriopathy stabilizes or improves than in those in whom it progresses (46). The authors
postulate that the subset of arteriopathies that eventually stabilize result from an inflammatory process (indeed, many are seen
within a year of varicella infections) and are most accurately described as TCA (29,46). Increasing evidence suggests that
these arteriopathies are inflammatory in origin (20,28,46) and that vaccination may reduce their incidence (27).
In east Asian populations, the incidence of childhood brain infarction is similar to that in western populations, but the
underlying causes differ (30,47); congenital heart disease, CNS infection, vascular diseases (particularly moyamoya), and
hematologic disease (leukemia, thalassemia) are the most common predisposing causes (30,47), although metabolic causes are
seen in up to 20% (30).
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 (48). Poor motor outcome is associated with basal ganglia involvement and
with periventricular venous infarction (32). Seizures, poor cognition, and delayed development are associated with cortical
involvement (32,46). Patients with larger infarctions or infarctions involving eloquent regions of cortex obviously have larger
residual deficits than do those with smaller infarcts and those involving less eloquent regions (49,50). 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 (48). 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 the
brain will be taken over by other regions that have been spared (51). When epilepsy develops, however, cognitive recovery is
impaired (51). 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% (30,47). 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% (52). However, it appears that children (but not infants
(48)) have a higher incidence of persistent dystonia after basal ganglia infarction (50,53) and, possibly, a higher (25%–50%)
incidence of epilepsy after ischemic stroke (54) than do adults.
As alluded to earlier, disorders of coagulation may be identified in neonatal strokes (40,41,55,56), including deficiencies of
proteins C and S (56,57), G20210A prothrombin mutations (56), and factor V Leiden (55), as well as the presence of
anticardiolipin antibodies (58,59). Other causes are listed in Tables 4-2 and 4-3.
Table 4-2 Some Causes of Pediatric Stroke
Vasculitis (29,60,61)
Cardiac causes
Cyanotic congenital heart disease (62,63)
Cardiomyopathy (64)
Vascular dissection (64)
Mitral valve prolapse (64)
Cardiac tumors (65)
Thrombosis
Polycythemia (66)
Trauma (67)
Vasculopathies (sickle cell disease (68), moyamoya disease (69,70), Kawasaki disease (67), PHACE syndrome (71), COL4A1 mutations (39,72,73),
postinfectious/inflammatory (26–28,46,74,75), fibromuscular disease (67), neurofibromatosis type 1 (67), radiation induced (67), spontaneous
dissection (76,77))
Infection (viral (75,78–81), bacterial meningitis (82), aspergillus if immunosuppressed (83))
Coagulopathies (deficiencies of protein C or protein S (84–88), factor V Leiden (85,86), methylene tetrahydrofolate reductase (89,90), lipoprotein (a)
(89,90), or presence of antiphospholipid antibodies (59,87,91,92))
Maternal drug abuse (93,94)
Migraine (63,95)
Dissection (104–107)
Organic acidurias
Hyperhomocysteinemia
Propionic aciduria
Methylmalonic aciduria
Isovaleric acidemia
Glutaric aciduria type I
Glutaric aciduria type II
3-Methylcrotonyl-CoA carboxylase deficiency
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency
Mitochondrial disorders
Mitochondrial myopathies
Leigh disease
MELAS syndrome
Cytochrome oxidase deficiency
Other
Progeria
Sulfite oxidase deficiency
Hyperlipoproteinemia
Phosphoglycerate kinase deficiency
Congenital disorders of glycosylation
L-Carnitine deficiency
Disorders of cholesterol and triglyceride metabolism
CT is not recommended in children unless MRI is not available or the child is too unstable to be transported to MRI. If CT
is obtained, cerebral infarction in the neonate has a similar appearance to that in the older child or adult. Infarct of the cerebral
cortex has 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. Some caution must be used, however, as
certain areas in the posterior temporal and occipital cortices have low attenuation normally 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 enhancement of the infarcted region of the cortex starting about 5 days after the injury;
enhancement will slowly disappear starting 4 to 6 weeks after the injury, as the blood–brain barrier heals.
On MR, 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 and as hypointense signal on calculated diffusivity maps (also called average diffusivity [Dav] or apparent diffusion
coefficient [ADC] maps); these abnormalities are easily recognized and are identical to the appearance of acute infarction in
adults. Diffusivity decreases within hours (124) and remains reduced for about 6 days before pseudonormalization occurs
(125); diffusivity then increases to above normal by approximately day 12 (126). Note that none of these numbers are absolute;
they vary somewhat with the age of the patient, size of the stroke, and how quickly collateral blood flow is recruited.
Evaluation of white matter tracts during the acute phase may show early evidence of wallerian degeneration (manifested as
reduced diffusivity along white matter tracts originating in the area of infarction; Fig. 4-10D) (110,127), which may be
predictive of persistent neurologic impairment (110,128). Therefore, diffusion images should be obtained in children with an
acute onset of unexplained neurologic deficits or infants with unexplained seizures.
The imaging appearance of the infarction evolves over the first week. Standard imaging shows the cortex becoming
edematous and, therefore, isointense to underlying white matter, which changes little on T2-weighted and FLAIR sequences, an
appearance very different than in older children that can be quite subtle (Figs. 4-9 to 4-11). In newborns, the acutely
edematous, infarcted cortex becomes isointense with the underlying unmyelinated white matter on routine spin-echo sequences
(the “missing cortex sign,” showed nicely in Figs. 4-10 and 4-11). 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 infarction. The internal capsules should also be carefully examined, as high signal intensity or
reduced Dav of the posterior limb of the internal capsule on T2-weighted images is often associated with the development of
contralateral hemiplegia (110). It should be noted that infarcts may be difficult to see on FLAIR images in neonates/young
infants (bright signal upon bright signal) (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
calcification. 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.
Figure 4-11 Missing cortex sign, reduced diffusivity, and decreased susceptibility in area of acute neonatal PCA infarction. A. Axial T2 image
shows absence of the hypointense ribbon of cortex in the left occipital lobe (arrows). B. Axial Dav map shows the low signal of reduced
diffusivity in the same area (arrows). C. Susceptibility-weighted image shows a paucity of low intensity from feeding arteries and draining deep
medullary veins in the area of infarction (white arrows) as compared to other regions of the cerebrum.
Figure 4-12 Middle cerebral artery infarction secondary to embolus. A. Axial T1-weighted image shows hyperintensity in the right lentiform
nucleus (arrows) and poor differentiation of the cerebral cortex from the underlying white matter in the right middle cerebral artery distribution.
B. Axial T2-weighted image shows hyperintensity of the cortex in underlying white matter in the right middle cerebral artery distribution. 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 cerebral cortex in the middle cerebral artery distribution. E. Postcontrast T1-weighted
image from follow-up scan performed 1 week after event. Marked enhancement is seen in the injured regions of the brain. (This case is
courtesy of Dr. Chip Truwit, Minneapolis, MN.)
Infarction of the deep gray matter nuclei in neonates and young infants is seen on sonography as subtle hyperechogenicity
that is initially seen (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 section on “profound hypotension.” The point to be stressed is that ischemic injury to the
basal ganglia (particularly when bilateral) is easy to overlook on ultrasound or CT (of neonates or older children; Fig. 4-
13A) unless the radiologist carefully assesses the deep gray matter echogenicity or attenuation, respectively. On MR,
infarcted basal ganglia have a variable appearance, 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
diffusion-weighted images (Fig. 4-9C) or as a hypointense region on a Dav map (Fig. 4-13B). On spin-echo imaging, the
acutely infarcted basal ganglia will appear normal 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 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 (Fig. 4-12). By the end
of the first week, the injured basal ganglia may appear somewhat hypointense on T2-weighted images. As with cortical
infarctions, infarct detection is difficult if FLAIR is the only sequence used.
Evidence in adults suggests that perfusion imaging, preferably using magnetic resonance 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); extraction of the clot is done more in older children and teens than in infants and younger
children in whom vessels are smaller and more likely to spasm, while breakdown and resorption of the intravascular clot is
faster.
At UCSF, we routinely perform time-of-flight (TOF) MRA and perfusion imaging using ASL in children with suspected
infarction, after the Dav sequence has revealed the infarct. Both MRA and ASL can help to identify the cause of the infarction,
as well as aiding in differentiation of ischemic infarct from other causes of local brain injury and acute neurological deficit. In
particular, MRA and ASL are very useful in identifying reduced perfusion (causing stroke or stroke symptoms) in patients with
arteriopathy (Figs. 4-13 to 4-15) which, as noted earlier, is an important cause of infarction in children (28,29,111,129). If
arteriopathy is suspected (due to history of recent viral illness) and MRA is equivocal, arterial wall imaging (using 3DT1
acquisition that is reformatted with submillimeter image thickness in three planes) is performed (Figs. 4-13 to 4-15). In our
experience, the appearance of the abnormal blood vessels (see below) on MRA may vary from day to day, but enhancement of
the wall is consistently present; therefore, arterial wall imaging should be performed in children in whom vasculopathy is
suspected and special attention should be paid to the supraclinoid carotid artery and the proximal segments of the ACA and
MCA. Indeed, between 64% and 74% of arterial defects in pediatric ischemic infarctions are located in the supraclinoid
carotid artery or the proximal (M1 segment) middle cerebral artery (113). Contrast is administered, and the blood vessels are
carefully scrutinized, looking for enhancement of vessel walls, which indicates vasculopathy. The technique is described in
Chapter 1.
Figure 4-13 Posterior putamina infarction secondary to vasculopathy; 7-year-old boy with onset of hemiparesis after mild head blow. A. Axial
Dav map shows low signal intensity in the posterior left putamen (arrow), suggestive of lateral lenticulostriate infarction. B. Axial ASL map
shows patchy diminished perfusion to the posterior putamen (black arrows), a pattern suggesting reduced flow in many, but not all, vessels
perfusing the area. C. Arterial wall imaging shows enhancement (white arrow) of the left A1 segment of the anterior cerebral artery (ACA). D.
Reconstructed AP view of a 3D time-of-flight MRA shows irregular narrowing of the left supraclinoid carotid artery (arrowhead), A1 segment of
the ACA (large white arrows), and M1 segment of the middle cerebral artery (small white arrows).
Figure 4-14 Vasculopathy diagnosed by arterial wall imaging after normal MRA. A 13-year-old boy with new hemiparesis. A. Axial diffusion-
weighted image shows hyperintensity (arrow), indicating reduced Dav, in the left putamen. B. View of left ICA and its branches from time-of-
flight MRA is normal. C. Arterial wall imaging shows enhancement of the wall of the supraclinoid left carotid artery and proximal left MCA shows
enhancement (arrows) of the vessel walls, strongly suggesting an inflammatory vasculopathy.
Some genetic arteriopathies of childhood can cause pre- or post-natal hemorrhagic brain injury (39,130–132). If family
history is present, consider hemorrhage due to collagen IVA (COL4A1 or COL4A2) mutations (72), or JAM3 mutations
(133,134), which look identical to hemorrhagic venous infarction on MR (39,73). Hemorrhage due to COL4A1/COL4A2
mutations can range from mild (presenting with vasculopathy or a myelination disorder in teen years or early adulthood) to
very severe and, in the most severe fetal cases, can even resemble hydranencephaly (135). 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 (136). Imaging in older children with COL4A1/COL4A2 mutations
commonly shows leukoencephalopathy (132), presumably due to small-vessel ischemia. Patients with both COL4A and JAM3
mutations may have associated anomalies such as congenital cataracts (both), microcornea, and Axenfeld-Rieger anomaly
(134,137).
As of this writing, there is no evidence to support the routine use of proton MRS in children with acute localized infarction.
MRS is more useful in the evaluation of patients with diffuse ischemic injury, to be discussed later in this chapter.
Some pediatric arterial strokes can be treated intravascularly; these are discussed in Chapter 12.
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 (142) and, rarely, epidural (143). Parasagittal injuries, often hemorrhagic, are
seen most commonly in association with superior sagittal sinus thrombosis (Figs. 4-16 and 4-17), temporal lobe hematomas
are usually associated with transverse sinus (and consequent vein of Labbé) thrombosis (Fig. 4-18), and thalamic hemorrhage
is usually associated with vein of Galen/straight sinus thrombosis (Fig. 4-19). 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. 4-20).
Figure 4-16 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.
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 (factor V Leiden (85,86) or proteins C and S (84–88), high coagulation factor VIII (139), G20210A
prothrombin mutations (56)), thermolabile methylene tetrahydrofolate reductase polymorphism (89,90), increased lipoprotein
A (89,90), and the presence of anticardiolipin antibodies (87,91,92). The second is that venous thrombosis often resolves in
neonates without aggressive therapy and without neurologic residua (144–146). 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
(136,139). No large prospective trial of the efficacy of anticoagulation in this group of neonates has been reported. Therefore,
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 (136).
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, MR is the imaging modality of choice. Routine T1- and T2-weighted spin-echo images should be obtained (and
FLAIR in older infants and in children), in addition 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 ms) (147). If the thrombosis
is subacute, the sagittal T1-weighted images are diagnostic by themselves, as they show subacute clot (high signal intensity) in
the sagittal, straight, or transverse sinuses (Fig. 4-16); this appearance is diagnostic. CT venography, showing thrombi as
hypodense areas within the affected venous structure, is rarely needed anymore, as multiple MRI techniques have been
developed to detect venous thromboses. On CT, venous infarcts are usually poorly delimited, hypodense, or mixed-attenuation
areas involving the subcortical white matter and producing a slight mass effect (Fig. 4-17A). 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 overlies the hypodensity. The thrombosed vein may be seen
overlying the infarction as a curvilinear region of high attenuation. On MR, early venous infarcts may be identified by
visualization of prolonged T1 and T2 relaxation times in characteristic regions (most commonly frontoparietal parasagittal
[Figs. 4-16 and 4-17] and temporal [Fig. 4-18]). Another early imaging sign is visualization of thrombus in the deep medullary
veins (Fig. 4-19); this is best identified using susceptibility-weighted imaging (SWI) and 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 (148–150). 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, 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 infarction. The frequent presence
of blood (Fig. 4-20), the paramagnetic 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. 4-20) to petechial hemorrhages within edematous brain
parenchyma (Figs. 4-16 and 4-18) (136,151). The hemorrhages are generally subcortical and often multifocal with irregular
margins. They are occasionally linear in nature, indicating hematoma in and around the vein; this appearance is quite specific.
Figure 4-17 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 two-dimensional time-of-
flight 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.
Figure 4-18 Temporal lobe hemorrhagic venous infarct secondary 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).
Figure 4-19 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.
Finally, although CT venography is the most definitive method for establishing the diagnosis of venous thrombosis (152),
we use contrast-enhanced 3D MRV (153) as our first choice for making the diagnosis in infants because of the lack of ionizing
radiation and because it better evaluates areas where flow-related enhancement is diminished due to rapid flow or flow is
parallel to the imaging plane on 2D time-of-flight sequences. Venous sinus thrombosis is discussed further in the section on this
chapter on Ischemia Secondary to Venous Thrombosis and in Chapter 11, in the section on Complications of Meningitis.
The physiology of brain injury resulting from hypoxia and ischemia is rather complex and remains incompletely 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 blood pressure. The
hypercarbia and hypoxia cause a loss of the normal vascular autoregulation in the brain of the term neonate (164,165), resulting
in so-called pressure-passive flow. (In the noncompromised term neonate, blood vessels of the brain constrict when blood
pressure 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 (165).) The combination of decreased blood pressure and pressure-
passive flow results in decreased perfusion of the brain (166,167) and may result in ischemic injury in term infants (probably
mediated by excitotoxicity (168), discussed in subsequent sections) and in germinal matrix hemorrhage (GMH) or parenchymal
(usually white matter) injury in preterm infants (167,169–171). The newborn brain is quite resistant to hypoxia in the setting of
normal cerebral blood flow because energy substrates, such as glucose and ketone bodies, can be used as energy sources to
minimize or prevent brain damage (172). Thus, most hypoxic–ischemic brain injury in neonates is a result of cerebral
hypoperfusion.
The duration of the hypoperfusion is a critical factor in determining whether brain damage results from an episode of
hypoperfusion (16). 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 no abnormalities on their subsequent imaging studies and developmental exams.
Animal models support this, as well. In asphyxiated neonatal sheep, selective neuronal necrosis is seen only after 10 minutes
of perfusion arrest (173,174), and in monkeys, damage is detected only after 7 minutes of perfusion arrest (175), with basal
ganglia injury seen after 8 to 12 minutes and severe injury of the entire brain after 20 minutes (176,177). 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 (178).
Although hypoperfusion is the primary cause of neonatal brain injury in these situations, hypoxia does have a role. In
addition to its effect on autoregulation, hypoxia reduces cardiac contractility/cardiac output and alters capillary permeability.
Reperfusion of the weakened capillaries (particularly those within the germinal matrices of premature infants, which are
structurally weaker than are the capillaries in the remainder of the premature brain (179)) can cause rupture of cerebral blood
vessels and result in intracranial or intraventricular hemorrhage (IVH) (171,180). Inflammation also plays a role, as hypoxia–
ischemia induces rapid activation of microglia and mast cells, resulting in perivascular accumulation of inflammatory cells
(neutrophils, myeloid cells, T cells, and natural killer cells) that peaks about 24 hours after the event (20,181,182).
Secondary energy failure
A useful concept in understanding imaging results after hypoxic–ischemic injury is that of secondary energy failure (Fig. 4-21).
During moderate hypoxia–ischemia, significant changes occur in the brain on magnetic resonance studies. P-31 spectroscopy
shows depletion of phosphocreatine or NTP (nucleotide triphosphates, including ATP) (183), proton spectroscopy shows
elevated lactate (184), and diffusion-weighted imaging shows reduced diffusivity (185,186). 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 (184). It is postulated to be the result of accumulation of reactive
oxygen/nitrosative species and intracellular calcium during postischemic reperfusion, triggering mitochondrial structural
damage and reduction of high-energy phosphate reserves; this structural damage accumulates during the “early recovery
period,” and its accumulation results in deterioration of cellular metabolism and ultimately cell death (187,188).
Figure 4-22 Intervascular boundary zones. Axial SE 600/16 images (A and B) show the intervascular boundary zones between the anterior
cerebral artery (ACA) distribution and middle cerebral artery (MCA) distribution anteriorly and between the posterior cerebral artery (PCA)
distribution and the MCA posteriorly.
In profound hypotension, the location of injury is initially to the posterior brain stem, deep cerebral nuclei (thalami and
basal ganglia) and internal capsules, and the most active regions of the cerebral cortex (the sensorimotor region). Damage to
the remainder of the cortex and white matter occurs only later in the course of the hypotensive episode (15,193,197,200,201).
The location of injury seems related to energy demand, which is related to the state of maturity of the various structures that
compose the brain (16,168,202). Positron emission tomography studies of glucose uptake in the developing brain (203), which
reflect metabolic activity; SPECT studies, which show relative regional perfusion (204,205); and proton spectroscopy (206),
which reflects biochemical maturation, all show excellent temporal and topological correlation with one another and with
myelin development (207) (Fig. 4-23). In addition, the regions affected in profound hypotension are connected by circuits that
use glutamate as their neurotransmitter (208). Immature NMDA receptors have heightened excitability and can be opened in
hypoxia–ischemia. This, combined with impaired removal of glutamate by energy-dependent transporters, is an important
cause of cell injury in severe hypoxia–ischemia (168). 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
that have suffered profound hypotension corresponds quite closely to the patterns of myelination, perfusion, and glucose uptake
at the time of injury (15,16,193,202,203,209). 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 postconceptional age of the child.
Premature infants who suffer mild to moderate hypotension typically sustain injury to the periventricular and deep white
matter with sparing of the subcortical white matter and cerebral cortex (these lesions can have other causes, including
microglial activation from infection, inflammation, excitotoxicity, and oligodendrocyte injury (20)). In contrast, term infants
who suffer similar degrees of hypotension sustain injury in the watershed portions of the cerebral cortex and in the underlying
subcortical and periventricular white matter. The probable reasons for this evolution have recently been elucidated. 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 exacerbates 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
maturation and proliferation (in preparation for myelination). The developing cerebral white matter in this region responds to
oxygen deprivation by utilizing anaerobic glycolysis, an inefficient mechanism of glycogen metabolism that results in depletion
of high-energy phosphates and in localized lactic acidosis. Late oligodendrocyte progenitor cells (OPCs) are very susceptible
to lactic acidosis from hypoxia–ischemia (210), probably because their AMPA glutamate receptors lack GluR2 subunits,
allowing them to flux high amounts of calcium (toxic to the cells (211,212)); in addition, they do not have proper enzymes to
detoxify nitric oxide and other oxygen free radicals (213).
Perhaps most importantly, inflammation can affect brain development (20). Inflammation is known to be a cause of
premature birth; it also causes damage to oligodendrocyte precursors, resulting in impaired myelination, and is associated with
gray matter dysmaturation (20). In addition, when microglia are activated by proinflammatory stimuli, they release substantial
amounts of glutamate, which can be toxic to OPCs (211). The time at which OPCs are present in the brain coincides with the
period of vulnerability of periventricular and deep white matter injury in the fetal brain (214). Thus, the combination of
immaturity of the premature brain and its vascular supply together with abnormal microglial activation due to inflammation
puts the developing neurons and white matter areas at high risk in prematurely born neonates, and this seems exacerbated when
autoregulation is compromised. Although its gross anatomic severity has diminished (it is now rare to see large areas of cystic
necrosis within the cerebral white matter), white matter damage of prematurity (sometimes called periventricular
leukomalacia) remains a fairly common brain injury in prematurely born children. Three different types of white matter injury
are described by Volpe (167): 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 MR imaging and are described in the next section, on imaging of brain injury
in premature neonates. White matter injury of prematurity is probably multifactorial in origin, as a result of ischemia or
inflammation, which both impair maturation of oligodendrocyte precursors. Some of these inflammatory substances, such as
those belonging to the toll-like receptor family, are thought to enter the brain via the choroid plexus where they induce
transcription of the tumor necrosis factor gene and increase leukocyte diapedesis into the brain (20). In contrast to the
premature brain, the term neonate (38–42 postconceptional weeks) and postterm neonate (43–46 postconceptional weeks) have
normal GluR2 expression in the oligodendrocytes, but reduced GluR2 expression in the neocortex (212); thus, the cortex
becomes selectively vulnerable to mild–moderate ischemia as the neonate approaches term. Thus, due to maturation 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 boundary zones; note that white matter involvement frequently still occurs and this can be seen on good
quality imaging studies (199). These so-called watershed areas are almost always involved if mild to moderate hypotension of
sufficient duration takes place after 36 weeks (215), but injury to these locations is virtually never seen at 34 weeks or earlier.
In some patients, the damage extends medially and laterally from the boundary zones to involve larger areas of the cerebrum.
Figure 4-23 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 (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.)
Pontosubicular necrosis, in which the subiculum and fascia dentata of the hippocampus and ventral pontine nuclei are
selectively involved (5,216), is seen almost exclusively in premature infants, typically in the setting of hypocarbia and
hyperoxemia (217,218). Although the precise causes/mechanisms are not known, the fact that pontosubicular necrosis is almost
always seen in the setting of periventricular leukomalacia added to the fact that the fascia dentata seems to undergo apoptotic
cell death suggests that the combined hypocarbia and hyperoxemia exacerbate cellular injury from hypoxia–ischemia in the
pons and hippocampus in the premature infant (216).
Although most brain injury in premature babies involves perturbations of in the maturation and function of interneuronas,
oligodendrocytes, and astrocytes (219), the pattern of injury from profound hypotension evolves as brain regions mature,
because the increased metabolic demand combines with the stage of maturity of the glutamate receptors to change the patterns
of vulnerability of the brain (15). The process of maturity involves changes in (a) neurotransmitters, (b) the maturity of the
receptors (168,212), (c) local glucose uptake (203), (d) relative regional blood flow (204,205), (e) levels of metabolites
(206), (f) myelination (193,202), and probably other factors. The thalami and dorsal brain stem have the highest metabolic
activity in the early third trimester; from the middle of the third trimester through 40 postconceptional weeks, the brain stem,
thalami, basal ganglia, and perirolandic region have the highest metabolic activity (15,16,203,220). By the end of the first
postnatal month (44 postconceptional weeks), the visual cortex becomes more metabolically active (Fig. 4-23) (203). After the
third or fourth postnatal month, the remainder of the cerebral cortex and the basal ganglia become increasingly metabolically
active and the regions more likely to be damaged shift from the thalami and perirolandic cortex to the basal ganglia and the
remainder of the cerebral cortex (193). These remain the areas most commonly affected in an arrest of blood flow to the brain
in childhood and adulthood. Of note, the perirolandic cortex is relatively spared in diffuse hypoxia–ischemia of the mature
brain.
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 delivery. 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 hypotension do not
seem to cause brain injury; this has been found in animal models, as well (173–175). 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.
Cerebral germinal Walls of lateral ventricles (may extend into Hemorrhage secondary to rupture of thin-walled capillaries in germinal
matrix hemorrhage ventricle and cause hydrocephalus) matrix
White matter injury Deep cerebral white matter (may be multifocal or Focal/multifocal inflammation, which impairs oligodendrocyte production.
diffuse) Rarely cavitates. Associated with long-term volume loss
Venous infarction Thalami, deep and periventricular white matter Infarction often hemorrhages. May liquefy, leading to porencephaly
Cerebellar Most common in biventer lobules and tonsils. May Probably in external granular layer
hemorrhage occur in gracile or semilunar lobules
Figure 4-24 Papile grade 1 hemorrhage with cerebellar hemorrhages. 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
arrow) in the wall of the body of the right lateral ventricle. C. Axial T2-weighted image through the lower cerebellum shows several foci of
hypointensity (black arrows), representing cerebellar germinal matrix hemorrhages.
Ventricular enlargement in grade III hemorrhages is often associated with damage (usually cavitation) of white matter;
therefore, it is an excellent 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 hemorrhage survived
(300). Improved imaging has revealed that the prognosis is less dire; patients with mild hemorrhage and normal ventricular
size have less than a 10% incidence of long-term neurological sequelae (301), and no abnormalities of white matter
microstructure are seen in extremely premature babies in the absence of hemorrhages (302). However, patients with enlarged
ventricles associated with IVH have approximately a 50% incidence of neurological sequelae, with the outcome becoming
worse with increasing diminution of white matter (303). Not surprisingly, bilateral PVHI and large unilateral PVHI have the
poorest prognoses (304). In summary, extensive white matter injury from both cavitary WMI of prematurity and from PVHI is
associated with significant permanent brain injury; 50% to 90% of affected patients have serious neurological sequelae that are
related to the location and extent of the parenchymal injury (171,241,276,300,303,305).
Figure 4-25 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.
Several groups have studied the white matter of prematurely born infants with DTI (251,313,321–327). Results have shown
that the corticospinal tracts and the optic radiations seem to be particularly commonly affected (327); in general, increased
radial diffusivity, decreased fractional anisotropy, and, in some cases, increased mean diffusivity (all of which suggest
structural injury and, possibly, cavitation) are associated with poorer neurodevelopmental outcome; however, patients with
a few small white matter injuries may develop normally (327). Some caution should be observed in interpreting diffusion
tensor studies of prematures, however, as the methods of acquisition and processing of the data vary considerably and often
“do not meet the highest standards” (328). Hemorrhagic lesions are more likely to have clinical consequences, but are felt to
have a different pathogenesis (329) and are therefore considered separately by many authors (327,329).
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 shortening in the white matter, (b) reduced white
matter volume, (c) ventriculomegaly, (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 adding the individual
scores (330). Using this method, they found that motor and cognitive outcome at age 2 years are strongly associated with the
severity of white matter injury (331). Sie et al. (332) 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 6 lesions or less; grade 4—more than
6 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.
In terms of effects upon networks within the developing brain, microstructural development of the cerebral cortex and
white matter pathways of the brain is reduced by premature birth, likely as a result of longer exposure to the extrauterine
environment; as a result, prematurely born infants have a less mature cerebral cortex and altered white matter connectivity, as
assessed by parameters of water diffusion using graph theory methodology, than do infants of the same postconceptual age who
are born at term (221,222). Although a core of key connections in the deep gray matter is not affected, alterations (manifested
by reduction of neurite density index) of local connectivity involving the thalami, cerebellum, superior frontal lobe, cingulate
gyri, and short-range corticocortical connections were detected and found to be related to the degree of prematurity; these
contributed to an alteration of global connectivity (221). This delay in microstructural maturation is predictive of lower
neurodevelopmental scores at 2 years of age. This suggests that the rapidly developing microstructure of the cerebral cortex
may be impacted by early birth, possibly secondary to disturbances of neuronal arborization (223), with potential effects upon
cortical development.
Cerebellar injury
It has recently been discovered that late cerebellar growth is impeded in many 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 (333). In prematurely born neonates, mean cerebellar volume at term
equivalent age is significantly smaller than that of infants born at term; importantly, cerebellar volume and cerebellar NAA/Ch
ratios at term equivalent age are associated with cognitive scores at age 24 months (296). Although this cerebellar growth
impairment is strongly correlated with associated cerebral and cerebellar injury, it is more strongly associated with IVH, even
in the absence of direct cerebellar injury (263–265,290,333,334). The mechanisms by which subarachnoid blood impair
cerebellar growth are unclear; possibilities include disturbance of granule cell proliferation in the external granular layer,
possibly from disturbed WNT signaling (335), impaired SHH release by the leading processes of migrating Purkinje cells
(336), and impaired signaling between SDF1α in the overlying leptomeninges and CXCR4 (a target of FOXC1) in the
developing cerebellum (SDF1α activation is crucial to proliferation of radial glia and Purkinje cells in the embryonic
cerebellar ventricular zone and consequent development of the cerebellum (285)). It is possible that all of these mechanisms
contribute to cerebellar hypoplasia. Most of the volume loss in children with IVH is in the dorsorostral cerebellar hemispheres
(265), which are areas characterized by late arrival of granule cells.
Cerebellar hypoplasia can also result from intracerebellar hemorrhages, a finding being discovered with increasing
frequency in prematurely born infants, particularly those born at weights less than 750 g (287), with early MRI studies (at 1.5
T) reporting an incidence of about 10% (337,338). Our more recent studies using SWI at 3 T have found close to a 50%
incidence of cerebellar hemorrhages (265), with the location most common in the caudomedial aspect of the cerebellum, in the
tonsils, biventer, paramedian, and inferior semilunar lobules; antenatal magnesium sulfate exposure reduces the incidence of
hemorrhage (339). Most of these hemorrhages are small, but larger hemorrhages (more than 5 mm) are often associated with
focal volume loss in the cerebellar cortex at the site of the hemorrhage (see next section) and in the underlying white matter,
with the amount of volume loss proportional to the size of the hemorrhage (265). Studies suggest that the most commonly
affected areas have functional connectivity with the cerebral association cortex (340). A high association of cerebellar growth
impairment and diminished regional cerebral cortical volumes has been documented, suggesting that cognitive and behavioral
disabilities in prematurely born infants may be related to these cerebellar injuries (264,289,290).
Imaging findings and clinical correlations in premature neonates
Except in very rare instances, CT is not used in the assessment of neonatal brain injury because it has low sensitivity and
because the neonatal brain is sensitive to radiation. Sonography is the primary tool, and MRI is used if sonography does not
account for the clinical condition. It is apparent from the above discussion that much of the brain injury in premature infants is
manifested in the deep areas of the cerebrum and in the cerebellum. For example, GMH occurs mostly at the “caudothalamic
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. 4-24 to 4-27).
Moreover, sonography can be performed in the neonatal intensive care unit (NICU), using the anterior and posterolateral
fontanels as sonographic windows. Maintenance of body temperature is vital in these infants, and it is difficult to provide
adequate warmth and monitoring outside of the neonatal ICU unless an MR compatible incubator is used (341). Therefore,
initial imaging evaluation of these infants in the NICU by sonography is appropriate despite the known superior sensitivity and
added information provided by MRI (121,253,309,320,331,342–344). However, it is important to remember that much
cerebellar injury and noncavitary cerebral injury occurs in premature children (265,290,338), and these are poorly assessed by
sonography; therefore, MRI is an important part of the imaging evaluation of premature neonates.
Periventricular and intraventricular hemorrhage
Sonograms show germinal matrix hemorrhage as a region of increased echogenicity. Images acquired in the coronal plane
show a well-defined area of increased echogenicity adjacent to the ventricular wall. The most common location is the
“caudothalamic notch” at the ganglionic eminence, inferior to the floor of the posterior part of the frontal horn (Figs. 4-24 and
4-25), but the hemorrhages can occur nearly anywhere in the ventricular wall. The sagittal plane is often very useful in
differentiating GMH 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 hemorrhages lie immediately anterior to the foramen.
MR of infants born at less than 32 weeks commonly show small hemorrhages, mostly small and located in, or immediately
adjacent to, the wall of the lateral ventricle. These presumed GMHs are round to ovoid lesions that are hypointense on T2- or
susceptibility-weighted images (SWI); they are much more easily identified at higher field strength and with SWI (see below).
Susceptibility changes commonly extend along the wall of the ipsilateral lateral ventricle, particularly in the trigone or
occipital horn. When subacute, GMH are hyperintense on T1-weighted images (Fig. 4-24C). When isolated and not
accompanied by significant IVH, they are rarely of clinical significance (345,346). As described above, MR also frequently
shows hemorrhages of variable size in the cerebellar cortex (large ones are also seen by ultrasound), most often in the tonsils
and biventer lobules, less commonly in the gracile and semilunar lobules (Fig. 4-28). It is postulated that these result from
bleeding within the transient external granular layer, a germinal zone for glutamatergic neurons of the cerebellar cortex (286).
Limperopoulos et al. (289) found such hemorrhages unilaterally in the cerebellar hemisphere in 71%, isolated to the vermis in
20%, and involving both vermis and hemisphere in 9%; they were isolated to the cerebellum in 23%, with the rest being
associated with supratentorial lesions (289). Imaging at 3 T, a study at UCSF found them in nearly 40% of patients studied, but
in nearly 50% of those in whom susceptibility-weighted imaged was performed (265). These cerebellar hemorrhages have the
same appearance as do supratentorial GMHs, but because they are not intraventricular, they do not result in hydrocephalus.
When cerebellar hemorrhages are large and occur in the late second or early third trimester, significant atrophy may ensue (Fig.
4-28).
Intraventricular hemorrhage results in filling of a portion or, sometimes, the entire ventricular system. When acute, the
IVH is extremely echogenic (Figs. 4-24 and 4-25) and may be difficult to differentiate from the normally echogenic choroid
plexus. Power Doppler sonography, which shows vascularity within the choroid but not within clot, may be useful to make this
differentiation (347). Over the first few weeks after the acute event, the intraventricular 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, with the clot less echogenic than the choroid plexus situated posteromedial to the thalamus. Conventional
spin-echo and gradient echo or susceptibility-weighted MR sequences are the methods of choice to look for hemorrhage in the
neonate. Neonatal intraparenchymal hematomas are iso- 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. 4-25 and 4-26) (348). Between 7 and 14 days, the hematoma 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. 4-27) (348). If residual iron remains, the area will remain hypointense on SWI
indefinitely.
Figure 4-28 Cerebellar germinal matrix hemorrhages with volume loss. A–C. Axial (A, B) and coronal (C) T2-weighted images at age 3
weeks in an infant born at 27 weeks shows multiple hypointense hemorrhages (white arrows) in the inferior vermis, tonsils, and biventer lobules
of the cerebellum, with the left hemisphere more extensively affected. D. Coronal T2-weighted image at adjusted age 6 months shows
significant volume loss of the left inferomedial cerebellar hemisphere (arrows).
In the acute phase after IVH, ventricular dilation 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 cisterns, but can also occur in the aqueduct or in the fourth
ventricular outflow foramina of Luschka and Magendie. The arachnoidal adhesions block the normal flow of CSF and
necessitate permanent CSF diversion. Superimposed upon this secondary hydrocephalus is the fact that patients with
posthemorrhagic ventricular enlargement have an increased incidence of periventricular white matter injury, pontosubicular
injury, and olivocerebellar injury (349). Tissue loss secondary to cavitary white matter injury results in ventricular
enlargement that usually appears toward 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 (244). Such ventricular dilation is well demonstrated by
transfontanelle sonography or MRI (Figs. 4-26 and 4-27); the patient should be scanned approximately 1 week after initial
documentation of the hemorrhage in order to exclude subsequent ventricular enlargement.
Periventricular hemorrhagic infarctions
Periventricular hemorrhagic infarctions (PVHIs) are ischemic parenchymal injuries with associated hemorrhage that typically
occur in the periventricular white matter adjacent to the lateral ventricle. These lesions result from germinal matrix bleeds that
compress veins that drain into the lateral ventricles (most commonly the thalamostriate vein that drains into the ventricle near
the foramen of Monro (350)); as a result, they are usually periventricular. They rarely extend peripherally beyond the territory
of the deep medullary veins, so the subplate zone and cortex are rarely, if ever, affected (329). 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; hemorrhage 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 (Fig. 4-29),
while hemorrhage adjacent to the trigone implies occlusion of the lateral atrial vein (more superior injury) or the inferior
ventricular vein (more inferior injury) (351). PVHIs are seen on sonography as globular, crescentic, or fan-shaped areas of
mixed hyper- and hypoechogenicity (Fig. 4-27A); they become less echogenic over time as the infarcted tissue cavitates and
the blood products are resorbed. It is difficult to determine how much hemorrhage is present based solely on the sonogram;
MRI is best for evaluating the extent of injury. Acutely, MRI shows regions of hemorrhage (dark on T2-weighted images), often
surrounded by nonhemorrhagic venous infarct (hyperintense on T2-weighted images) (276). As the lesion evolves, the blood
oxidizes to methemoglobin (Fig. 4-27B) and the infarcted tissue is slowly resorbed, resulting in liquefaction of the infarcted
area (Fig. 4-27C and D), which may then shrink, resulting in either expansion (ex vacuo) of the adjacent ventricle into the
infarcted region of the hemisphere or the cyst remains, usually in communication with the adjacent ventricle (Fig. 4-27E and
F). “Cysts” associated with PVHI are, in fact, cavities of variable size; they are unlike the cysts in white matter injury of
prematurity, which are typically multiple and small. Color Doppler ultrasound studies of these hemorrhages show that the vein
draining the 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 (352)) is nearly always completely occluded (350,352),
adding to the accumulating evidence that these are venous infarctions. DTI studies show increased diffusivity, delayed
development of white matter anisotropy, and delayed loss of anisotropy in the cortex of affected brain regions. SWI shows high
susceptibility for as long as the blood products remain, usually months (353).
White matter injury of prematurity
A very important concept in the imaging of white matter injury of prematurity is that white matter lesions evolve over time.
The injury may remain noncystic over a time period of days to weeks before cavitation, and the cavities will eventually shrink
and disappear over more weeks. It is important to recognize that the cyst is the result of liquefaction of brain tissue (not a cure)
and its disappearance is, in effect, the end stage of a process of white matter disintegration; a careful analysis of subsequent
imaging will show that the white matter volume is significantly reduced and that the ventricle in the affected area is mildly to
moderately enlarged and has irregular walls due to tissue loss (354). Therefore, it is important to perform imaging (usually
ultrasound) at multiple time points in prematurely born infants; if only a single MRI is obtained, it is important to look for
reduction of white matter volume, irregular ventricular margins, and white matter hyperintensity on T1-weighted MR
images (particularly in the immediate periventricular areas) as signs of prior cavitary injury (354).
Figure 4-29 Small periventricular hemorrhagic infarction secondary to germinal matrix hemorrhage near the drainage of the thalamostriate
vein. A and B. Axial T1- and T2-weighted images show a subacute periventricular/deep white matter hemorrhage (white arrow) in the left frontal
lobe. C. Axial susceptibility-weighted image (SWI) shows a hematoma (black arrow) in the lateral wall of the lateral ventricle at the level of the
foramen of Monro. D. Axial SWI at the level of the fourth ventricle shows multiple small hemorrhages (black arrows) on the periphery of the
cerebellar hemispheres, likely originating in the external granular layer of the cerebellar cortex.
When the cerebral white matter is investigated by cranial ultrasound, high-frequency transducers (up to 10 MHz) should be
used for optimal evaluation, and multiple sequential exams should be obtained, as abnormalities may be transient (355). White
matter injury of prematurity may be suspected on ultrasound studies when increased echogenicity is present in the
periventricular regions (356); however, edema also causes increased echogenicity and can resolve without any subsequent
brain damage. In addition, increased echogenicity can be seen in this region in the absence of either injury or edema,
probably due to specular reflections from the normal bundles of axons. 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
architecture); instead, the damaged tissue has an indistinct, “globular” appearance (Fig. 4-30A). In addition to the loss of
normal tissue architecture, 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 (355); 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 tetraplegia is 50% (357). However, flares have a low
sensitivity and positive predictive value for the presence of white matter injury (309) and for long-term outcome (358,359).
Definitive diagnosis of white matter injury by sonography requires demonstration of heterogeneity (called heterogeneous flares
(332) 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. 4-30) (121). The timing of cavitation
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 (310,360). 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) (121,354).
White matter injury can be graded by the characteristics of the periventricular white matter on sonography (361). Grade I is
defined as periventricular and deep white matter areas of increased echogenicity present for 7 days or more (prolonged
periventricular flare). Grade II has areas of increased echogenicity that evolve into small, localized frontoparietal cysts (Fig.
4-30C). In grade III, periventricular areas of increased echogenicity evolve into extensive periventricular cystic lesions
involving occipital and frontoparietal white matter (Fig. 4-30D). Dammann has suggested that grade I white matter injury can
be further divided into “brief flares” that resolve within 6 days, “intermediate flares” that last for 6 to 13 days before
resolution, and “prolonged flares” that resolve after 14 days (362). Sie et al. have suggested that “heterogeneous flares” (Fig.
4-30A and B) have a worse prognosis and that they should be classified as grade 1b (with grade 1a being applied to
homogeneous flares) (332). 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 is noncavitary white matter injury and seems to be becoming
progressively less common (309,320,331). 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
(309,319,320). At most institutions, MR does not currently play a major role in the early diagnosis of white matter injury of
prematurity because of the difficulty involved in transporting and caring for sick premature neonates. However, the institutions
that use MR have found many signal abnormalities in the white matter early in the course of the injury. No sonographic
abnormalities are seen that consistently correspond to these MR findings in the majority of reports (309,320); although Leijser
et al. have reported heterogeneous hyperechogenicity in affected regions, they found MR to be much more reliable than
ultrasound in the detection of mildly and moderately abnormal (i.e., noncavitated) white matter (355). In our experience, MRI
is more sensitive and more specific for parenchymal injury. Punctate areas of T1 hyperintensity are seen as early as 3 to 4 days
after birth (Fig. 4-31A and B); mild T2 hypointensity can usually be seen, as well, if the voxel size is small enough and the
signal-to-noise high enough. Reduced diffusivity may be seen if imaging is performed in the first week, but such early MRI is
uncommon in our practice as sonography will usually show large brain injuries that require intervention. The T1 and T2
abnormalities may represent reactive astrogliosis (363), possibly due to microglial activation (20,364). These lesions
typically remain visible in the white matter on T1 and T2 images for several weeks to months after injury (365); although some
have been reported to disappear after a few weeks (319,320), those were small lesions and could have been missed due to
motion. They should be differentiated from hemorrhage, which has much shorter T2 relaxation time, lower signal intensity on
T2-weighted images, and high susceptibility on SWI (see, e.g., Fig. 4-31D). When extensive (involving more than one lobe),
these white matter lesions are associated with reduced FA, higher radial diffusivity, and higher average diffusivity (Dav) in
much of the cerebral white matter (366). FA may be reduced at term equivalent age, even in the absence of white matter
hyperintensities at that time (367) (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 neurodevelopmental outcome at age 2 years (367).
Larger areas of white matter hyperintensity may undergo necrosis, resulting in the development of T1 hypointensity either
within or adjacent to the areas of T1 hyperintensity and sometimes T2 hyperintensity within the areas of T2 hypointensity (Fig.
4-32). If the area of damage is large, small foci of cavitation may coalesce into larger ones, resulting in the presence of frank
cavities within the white matter (Figs. 4-30D–F and 4-31C–E). The process of cavitation decreases the area of T1
hyperintensity. This process, combined with evolution of the reactive astrogliosis and subsequent increasing T1 hyperintensity
caused by myelination, causes these lesions to disappear on MR imaging 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. 4-30H–J),
characteristic of what has been called “end-stage periventricular leukomalacia” (318).
Figure 4-30 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 spaced, 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. D. Coronal transfontanelle sonogram at age 25 days shows increasing bilateral cavitation of the damaged white matter. E
and F. Coronal (E) and sagittal (F) T1-weighted MR images obtained a few days after (D) 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 callosum (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.
Figure 4-31 Varying severities of white matter injury of prematurity. A and B. Sagittal and coronal T1-weighted images shows small, punctate
foci of T1 hyperintensity (small white arrows) in the deep white matter. The lesions, which typically appear during the first week to 10 days, are
of uniform intensity, with no regions of hypointensity to suggest cavitation. Incidental note is made of a small, subacute germinal matrix
hemorrhage (larger white arrow) in the lateral wall of the right temporal horn. C. Axial T1-weighted image in a very young baby born at 26 weeks
shows multiple moderate-sized hyperintensities (white arrows) in the deep white matter above the trigones. Low-intensity areas (black arrows)
are present in the frontal white matter, likely the result of some cavitation. D. Axial T2-weighted shows hypointensities (white arrows) in the deep
white matter bilaterally, representing WMIP. Areas of cavitation (black arrows) are seen between the hypointensities and the ventricle walls.
Note that the low-intensity lesions do not represent blood, which is more hypointense (as in the ependyma of both lateral ventricles, designated
by small black arrows). E. Cystic white matter injury (black arrows) in the periventricular and deep white matter bilaterally is the result of severe
white matter injury. The dilated temporal horns (T) suggest that the dilated lateral ventricular bodies result from hydrocephalus as well as loss
of white matter tissue. The punctate hyperintensities in the walls of the cysts (white arrows) likely represent injured tissue, but some component
of blood cannot be excluded.
Figure 4-32 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. Solid
black arrow in A and B points to small germinal matrix hemorrhage. 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.
Sie et al. have looked at the MR evolution of white matter lesions on sequential MR studies of premature neonates (368).
They report that the small white matter T1 hyperintensities become small areas of astrogliosis (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 also tend to shrink into small foci of astrogliosis. Therefore, when
cavitation of the white matter in the premature neonate is mild, mild ex vacuo ventricular dilation will develop along with
focal gliosis and focal thinning of the corpus callosum; this constitutes end-stage white matter injury of prematurity.
Extensive white matter injury often cavitates; the MR appearance evolves into diffuse white matter gliosis with thinning of the
entire corpus callosum and moderately to markedly dilated lateral ventricles (Fig. 4-30H–J). The white matter changes vary in
severity; extensive lesions throughout the white matter (periventricular, deep, and subcortical) result in almost total white
matter loss, often with severe ventricular dilation, irregular ventricular margins, and diffuse callosal thinning and shortening; a
shorter corpus callosum (Fig. 4-30H) is associated with poorer neurodevelopmental outcome (369).
Correlations have been shown between the severity of white matter injury and clinical outcome at ages 18 (368) and 24
months (250,331). Of interest, clinical outcome correlated more with the extent and location of injury than the type (cystic,
noncystic, hemorrhagic) of injury (250,355,368). Early MRI shows most injuries and gives accurate prediction of outcomes
(370). Early ultrasound is not useful, while sequential ultrasounds give some prediction of outcomes, but less accurately than
MRI (371). MRI is much more useful in showing small to moderate-sized cerebellar hemorrhages, which appear to be
associated with abnormal short- and long-term neurodevelopmental outcomes (269,290,338,372). Neonates with a few
scattered supratentorial 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 (368).
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. 4-33), before ultrasound or conventional MR sequences show any abnormality (373), but the
diffusivity changes normalize quickly (usually within 6 days) in infants (125,127). An important point is that it is crucial to
look at calculated average diffusivity (Dav, also called ADC) values in all scans of neonates, as the diffusion-weighted
images may be falsely negative due to the very long T2 values of the neonatal brain (remember that diffusion-weighted
images have contribution from both diffusion and T2). In the premature neonate without brain injury, Dav of white matter
decreases by 0.021 mm3/s per week (302); therefore, sequential studies can detect abnormal white matter development even
if imaging is not obtained immediately after injury. Fractional anisotropy, determined by diffusion tensor imaging, 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 (342) (also unpublished 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
decreased FA later in infancy (at term equivalent age) seems to be associated with impaired neurodevelopment (367,374),
suggesting that the earlier microstructural changes may be a harbinger of impaired development, as well. Reduced FA in the
corticospinal tracts prior to term equivalent age correlates with impaired motor outcome (375); reduced FA in the optic
radiations, both prior to (251,252) and at term equivalent age (376), correlates with impaired visual function. Volumetric
analyses show that increasing prematurity is associated with reduced volume of the thalami, the hippocampi, and the cerebral
cortex in the orbitofrontal and posterior cingulum; reduced thalamic volume was associated with decreased cerebral cortical
volume (377). In addition, connectivity of the thalamus with the frontal cortex, supplementary motor cortex, occipital cortex,
and temporal cortex are diminished (378). Spectroscopy may also prove useful in early evaluation of white matter injury, as
decreased NAA/Cho in combination with increased Cho/Cr in the posterior periventricular white matter at term equivalent age
is associated with impaired motor outcome at a corrected age of 1 year (379).
MR and CT are both useful (but MR is preferable) for the diagnosis of end-stage white matter injury (“end-stage
periventricular leukomalacia”) in later infancy and childhood after the fontanels have closed. MR is also useful in making a
diagnosis in mild cases of white matter injury where nonspecific ventriculomegaly is the only detectable abnormality on
sonography. Imaging findings of end-stage white matter injury are (a) irregular outline of the body and trigone of the lateral
ventricles; (b) reduced volume of white matter, always at the trigones but in severe cases involving the whole centrum ovale;
(c) deep, prominent sulci that abut or nearly abut the ventricles with little or no interposed white matter; (d) increased signal
intensity in the periventricular white matter on FLAIR and T2-weighted images, most commonly observed in the peritrigonal
regions bilaterally (Fig. 4-30H–J) (215,318,380,381); and (e) delayed myelination (382,383). In general, lower birth age
correlates with more severe myelin deficit (384). The midline, sagittal MR image will show thinning of the corpus callosum,
most commonly the posterior body and splenium, resulting from degeneration of transcallosal axons (Fig. 4-30H)
(215,385,386). MR volumetry has shown that the white matter volume is reduced (387) and ventricles enlarged (388) in end-
stage white matter injury. DTI studies have shown increased Dav (389), smaller size of the retrolenticular internal capsule and
the posterior thalamic radiations (390,391), and reduced FA in the corticospinal tracts (389,392). Although these findings seem
to be useful for predicting the severity of neurodevelopmental deficits in affected patients (251,367,376,393), these
sophisticated techniques are not necessary to make the diagnosis of end-stage white matter injury.
The signal abnormalities of end-stage white matter injury have a superficial resemblance to the normal areas of slow
myelination dorsal and superior to the trigones (see Chapter 2 and Fig. 4-34). These normal regions of unmyelinated white
matter, however, are separated from the ventricular wall by a thin band of myelinated white matter from the splenium of the
corpus callosum and tapetum, whereas the abnormal signal attributable to injured white matter directly abuts the ventricular
wall. The differentiation is best seen on coronal, T2-weighted sequences; axial views may not depict this finding (381).
Moreover, loss of volume of the cerebral white matter is not present on normal scans (394), and the ventricular contour in
normal patients is smooth, not irregular.
One final comment should be made regarding abnormal periventricular signal in infants and children. A finding of abnormal
periventricular hyperintensity and volume loss on FLAIR or T2-weighted images is not specific for white matter injury of
prematurity or any sort of perinatal injury. 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 (395,396). The cause cannot be established without a thorough past medical
history (and sometimes not even then).
Figure 4-33 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 are courtesy of Dr. Joel Cure.)
Cerebellar injury in premature neonates
Studies have shown that a significant number of premature neonates (in the range of 8%–20%) suffer either focal or diffuse
cerebellar injury (271,288,334,397–399). Focal cerebellar injury is usually due to 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 (286,288,399); detection sensitivity seems to be increased
by use of the mastoid fontanelle (288). Only half of these hemorrhages are associated with supratentorial hemorrhage (Figs. 4-
28 and 4-29), and nearly all of the isolated smaller ones are clinically silent (286). MR shows a higher incidence of
hemorrhage (~20% when imaged at 1.5 T, ~30% when imaged using T2-weighted images at 3 T, and up to 50% when using
susceptibility-weighted images at 3 T (265)), seen as marked hypointensity on heavily T2 or SWI in the cerebellum, often
multifocal (Fig. 4-29D) (288). In our experience, the most common location is in caudal cerebellum, particularly the tonsils
and biventer lobules, although small hemorrhages can occur more rostrally (265). In those patients with moderate to large
hemorrhages in whom subsequent MR scans were obtained, focal or diffuse (Figs. 4-28 and 4-35) frank cerebellar atrophy is
found (286), and smaller distortions can often be detected at sites of smaller bleeds (265). 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, although Volpe suggests that it is a form a selective neuronal necrosis (167). Other
possibilities include diaschisis due to cerebral white matter injury or interference with trophic influences from surrounding
posterior fossa leptomeninges (263,264,285,400). The clinical consequences of the localized cerebellar volume loss are not
clear, but several studies have suggested that development is impaired (264,290,295,296,338).
Figure 4-34 Normal immature peritrigonal white matter. Axial (A–C) and coronal (D) T2-weighted images show a normal area of
hyperintensity (arrows) in the peritrigonal white matter. This is an area of slower myelination superimposed with slightly large perivascular
spaces giving the appearance of slight hyperintensity throughout the first decade (and sometimes more). It should not be mistaken for injury.
Figure 4-35 Large cerebellar hemorrhage in premature neonate. A. Coronal reformation of SPGR image shows large hemorrhage (white
arrows) involving nearly the entire right cerebellar hemisphere and 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.
Figure 4-36 Sonogram of profound hypoxic–ischemic basal ganglia injury in a 3-day-old infant (A) shows markedly echogenic thalami
(smaller white arrows) and putamina (larger white arrows). Compare with normal neonatal sonogram (B).
Figure 4-37 MR of profound hypotensive injury in a 2-day-old 28-week–gestational age infant. A to 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). E. Proton MR spectrum (288 ms) 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 calcification. 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 arrowheads).
An important concept is that both hypoxia–ischemia and anoxia/arrest can occur in utero (Table 4-5 and Fig. 4-40A). 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. 4-40B and C) (15,215).
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 NICU without moving the neonate and is, therefore, the initial imaging study of choice in all
premature neonates with definite or suspected neurologic impairment. Techniques such as color Doppler, quantitative
sonographic feature analysis (403), examination through posterolateral fontanelles (286), and use of high-frequency transducers
(404) may ultimately result in such dramatically improved sonographic detection of parenchymal injury that utilization of other
techniques will become unnecessary. At present, however, sonography is not very sensitive to the detection of nonhemorrhagic,
noncavitary parenchymal injury (309,320,405) or to brain stem or cerebellar injury. Therefore, if the neurologic status of a
child is worse than can be explained by ultrasound findings, another imaging study is usually necessary. CT, even low dose CT,
is not an option because the information obtained is far inferior to that obtained by MR, and it is best to avoid the use of
ionizing radiation in imaging children (image gently and wisely) and in neonates in particular. Therefore, MR is the
neuroimaging study of choice after ultrasound. Anatomic MR imaging has much higher contrast resolution and can detect blood
almost immediately and brain injury (manifest as T1 shortening of affected brain parenchyma) within 2 to 3 days of injury.
Proton spectroscopy shows metabolic disturbances within hours of injury (406). 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
(125,127,406,407), but is highly sensitive from 2 to 5 days after injury (125,127). In addition, DTI can be used to assess the
size and integrity of white matter pathways (251,321,375,376,408), and ASL can now reliably demonstrate perfusion in the
neonatal brain (112,409). Moreover, small, neonatal MR scanners that can be located in the NICU will soon be commercially
available. Even without them, MR can be performed safely if blankets or MR compatible incubators (now commercially
available) are used to keep the neonate warm, appropriate ear covering and/or quiet sequences reduce noise, and nonmagnetic
or properly shielded life support and monitoring equipment is used (see Chapter 1). If therapeutic hypothermia (TH) is used
after the asphyxic event, mild to moderately injured regions will show normal or slightly elevated diffusivity (410), but
diffusion imaging of severely injured regions will show changes similar to severe hypoxic–ischemic injury in more mature
newborns (410,411).
Figure 4-38 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 prolongation in the lateral thalami, globi pallidi, and lateral
putamina.
Figure 4-39 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.
Figure 4-40 MR of prenatal profound hypoxic–ischemic injury. A. Axial SSFSE image of a 27-week fetus whose mother had suffered an arrest
at 25 weeks of gestational age. Thalami are small, and abnormal hypointensity is seen in the lateral thalami (white arrows). Posterolateral 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 basal ganglia and thalami, with abnormal hyperintensity in the ventrolateral thalami
(white arrows) and posterior putamen (small white arrowhead). The lateral thalamus is abnormally hypointense (large arrowhead), indicating
injury to that structure, as well.
Table 4-5 Some Causes of Fetal Brain Injury
Maternal origin
Maternal shock
Maternal hypoxia
Maternal thrombophlebitis
Maternal abdominal trauma
Maternal hypo-/hypertension
Fetomaternal transfusion
Fetal origin
Fetal infection (arteritis, hypotension)
Fetal arteriopathy (COL4A1 mutations)
Hydrops fetalis
Fetal embolism (placenta, other)
Fetofetal transfusion
Placental origin
Premature placental separation
Excessive placental infarction
Patients with parasagittal injuries tend to present with seizures and/or hypotension. Eventually, the neurological exam
evolves to proximal extremity weakness and spasticity (244). Cognitive outcome is variable, but seems worse when the frontal
watershed zones are involved (420,436); data indicate that this cognitive impairment becomes more apparent as the child
matures (420,422,437). Disproportionate disturbances in development of language or visuospatial abilities may also be noted
(244,421).
Detection of watershed ischemic injury is difficult by ultrasonography (122) because the affected areas of the brain lie close
to the inner table of the skull near to the midline and angling the transducer to visualize these regions can be difficult. Using
state of the art techniques with high-frequency transducers, the affected areas can be seen and will show increased echogenicity
of the parasagittal white matter, reflecting edema in the subcortical watershed regions (Fig. 4-42A) (404). In severe cases, the
cortex will also become edematous; the resulting increase in cortical echogenicity results in blurring of the cortical–white
matter junction and effacement of sulci with consequent inability to see the extremely echogenic leptomeninges. CT of the brain
is not recommended in neonates as ultrasound shows most of the brain well, and if an additional study is necessary, MR shows
much more detail without ionizing radiation.
If it is possible to obtain MR imaging during the first 24 to 48 hours of life, average diffusivity (Dav) images and proton
spectroscopy are the most sensitive MR techniques for the identification of brain injury; Dav images are 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. 4-42D and E), but sometimes, the area of
reduced diffusivity is confined to subcortical white matter and the cortex appears normal, while other times, the entirety of the
cerebral cortex is involved, well beyond the intervascular boundary zones (Fig. 4-43); the basal ganglia and posterior fossa
structures are relatively spared (Fig. 4-43). Sometimes (usually in patients who are born before 40 gestational weeks), the
white matter injury is isolated (197,199), 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 (438)) and
inflammation (20). Diffusion imaging can give false-negative results if performed in the first few hours after injury (prior to
secondary energy failure (125,185,186,406,407,439)) and may underestimate the extent of injury if performed in the first 24
hours (127,406), but this depends upon the timing of the injury with respect to the time of birth. Increased sensitivity is gained
by assessing calculated Dav images or the Dav values themselves (127,440), rather than the diffusion-weighted images, to
compensate for the very long T2 values of the neonatal brain (remember that signal intensity on diffusion-weighted images 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 (127,406,441,442) in the cerebral cortex (most notably in the watershed zones) and subcortical white matter,
more so than in the deep gray matter (Figs. 4-42F and G and 4-43F and G).
Figure 4-42 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 boundary 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/mm 2) show reduced diffusion (low signal intensity, white arrows) in the
intervascular boundary zones; note that both cortex and subcortical white matter are affected. F. Proton MR spectrum (TE = 288 ms) in the
basal ganglia is essentially normal. G. Proton MR spectrum (TE = 288 ms) 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 1,3-propanediol.
Between 24 hours and 8 days, the use of diffusion imaging and proton spectroscopy improves assessment of brain injury,
with significantly better association with outcome (443). On diffusion imaging, the pattern of injury seen on the Dav maps
evolves, with diffusivity normalizing in some regions and becoming abnormal in others (127). The reason for this is not
certain, but it is likely either wallerian degeneration along white matter tracts or spreading excitotoxic injury. Proton MRS
remains abnormal, with lactate levels peaking at 3 to 5 days after injury and then slowly declining, while NAA levels start to
decline about 3 days after injury (127). On T2-weighted images, the affected cortex will be hyperintense compared with
adjacent normal cortex beginning within 24 hours of injury; it may become isointense with edematous white matter (Figs. 4-
42C and 4-43A, B). On T1-weighted images, the edematous brain will appear as areas of low signal intensity in the cortex and
subjacent white matter when compared with normal white matter (444,445); the most obvious finding of cortical injury, when
present, is loss of gray matter–white matter distinction (Fig. 4-43A and B), but this is mainly seen in very severe injury. The
multiplanar imaging capacity of MR also aids detection of ischemic brain damage; the coronal and sagittal planes are best for
assessing high convexity regions, while the anterior and posterior poles of the cerebrum are better assessed in the axial and
sagittal planes. FLAIR imaging can be tricky in neonates, as the injured tissue may be hypo- or hyperintense compared with
normal tissue depending upon the field strength of the scanner and the precise parameters used. We recommend spin-echo T2-
weighted images, as discussed in Chapter 1, for evaluation of the neonatal brain rather than FLAIR.
As the injury evolves, spectroscopy and diffusion images undergo pseudonormalization (from about 6 to 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 (125,127,440). On anatomic images, cortical thinning and cystic degeneration of the underlying white matter are seen in
the parasagittal vascular boundary zones. After 3 to 4 weeks, the cavitary areas shrink into astroglial scars (hyperintense on T1
images; Fig. 4-44). Ex vacuo dilation of the adjacent lateral ventricles can be seen, particularly in the trigones and occipital
horns. The parasagittal white matter shows abnormal T2 and FLAIR hyperintensity, although the abnormal signal intensity of
the white matter may not be apparent until the end of the first year when T2 hypointensity, secondary to myelination, appears
(446).
Figure 4-43 Severe cortical–subcortical injury in a 4-day-old neonate who had severe meconium aspiration. A. Axial T2-weighted image
shows edema in the frontal cortex (white arrows) and much subgaleal fluid. Basal ganglia appear normal. The normal dot of low signal in the
posterior limb of the internal capsule is not seen. B. Axial T2 image at a slightly higher level shows that the cortex is very edematous in the
frontal and posterior temporal–occipital lobes (white arrows). C. Dav map at the level of the basal ganglia shows hypointensity (reduced
diffusivity) in the deep frontal cortex and in the occipital cortex (gray arrows). The low diffusivity in the lateral thalami (small white arrows) may
be wallerian change due to cortical injury. D and E. Dav maps at the level of the ventricular bodies (D) and centrum semiovale (E) show
reduced diffusivity (hypointensity, some of which is marked by gray arrows) in many of the cerebral cortical sulci, indicating extensive cortical
injury. F and G. Proton MR spectra (TE = 288 ms) from the basal ganglia (F) and frontal lobe (G) show very elevated lactate throughout the
brain. NAA is normal level in basal ganglia, implying lack of serious injury; however, the low NAA in the frontal white matter confirms injury seen
in the images.
Figure 4-44 Chronic watershed injury at age 5 months. A. Sagittal T1-weighted image shows an abnormally thin corpus callosum (white
arrows) secondary to white matter injury in the cerebral hemispheres. B. Axial T1-weighted image shows abnormal 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) immature 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.
Figure 4-45 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.
A correlation has been shown between the severity of the cortical damage and the severity of the subsequent spastic paresis
(189,447,448) and cognition (420–422,436) of the patient. The shrunken cortex has a peculiar pattern in which the deep
portions of the gyri are more affected than are 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. In the newborn,
perfusion is greater to the apical cortex of the gyri than to the cortex at the depths of sulci (449). Therefore, when a hypoxic–
ischemic event occurs, the tissue loss is greater in the depths of the sulci, resulting in the characteristic “mushroom” shape.
Good quality MR can identify ulegyria because of the characteristic gyral pattern and the underlying tissue loss and gliosis
(Fig. 4-45). Probably the most important reason to identify this entity is to differentiate it from polymicrogyria, which results
from preterm (second trimester) injury to deep cortical layers and is seen in a number of inherited syndromes. In the
myelinated brain, polymicrogyria (see Chapter 5) may appear on MR as an area of thickened cortex with irregularity of the
inner or outer cortical surface (or both). It is probably a result of an early to mid-second trimester injury, 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 cardiocirculatory arrest, as compared to mild or moderate hypoxia/hypotension (see Table 4-6)
(5,16,127,176,193,424,450). This group of patients shows injury primarily in the lateral thalami, posterior putamina,
subthalamic nuclei, hippocampi, and corticospinal tracts on MR studies (193,202,209,440,451), locations corresponding to
those regions of the brain most metabolically active (203), with the highest blood flow (205), and highest degree of synapse
construction (208,452) at the time of birth. Some patients will, in addition, show injury in the lateral geniculate nucleus and
optic radiations; the reasons for the variations are not completely known, but probably relate to metabolic demand in the
various parts of the brain at the time of birth. The cortex is relatively spared, other than the perirolandic gyri (most
metabolically active) (193,202,209,424). The most severely injured patients in this group have injury to brain stem nuclei
(especially nuclei of the inferior colliculi) (127,424,453); the majority of these brain stem–injured patients likely die before
they are imaged and, therefore, are represented more in pathology (5,200,202,209,402,454) than in radiology literature.
Table 4-6 Patterns of Injury in Diffuse Hypoxic–Ischemic Injury
Premature Periventricular/deep white matter injury Thalamic, basal ganglia, and brain stem injury
neonate (up to 32
postconceptional
weeks)
Term neonate Cortex and white matter injury (white matter exclusively in mild injury; Dorsal brain stem, anterior cerebellar vermis, thalamus,
(~34 to ~56 parasagittal watershed cortex and white matter in moderate injury; basal ganglia, corticospinal tracts, and perirolandic cortex
postconceptional entire cortex and underlying white matter in severe injury) injury. In severe injury, all supratentorial structures affected
weeks)
Older child (more Parasagittal watershed injury (cortex and white matter) Basal ganglia and diffuse cortical injury; perirolandic and
than 4–6 postnatal thalamic sparing
months)
Patients with the profound hypotension pattern appear to have different neonatal courses and different subsequent neurologic
deficits than do those with the moderate hypoxia/hypotension pattern. They have very low 1 minute Apgar scores, usually 3 or
below (450,455), or a postnatal cardiocirculatory arrest (424,456). Clinical manifestations depend upon the severity of the
injury. Patients with very severe brain injury often die in infancy (424,450,455) or develop choreoathetosis in addition to
quadriparesis, severe seizure disorders, microcephaly, and mental retardation (420,450,451,456,457). Patients with moderate
injury almost always have spastic and dyskinetic motor impairment (451,455,456). Patients with mild injury may initially
develop normally after mild neonatal encephalopathy or may be mildly delayed (196,453,455,458,459). It is important to
remember that many children who develop choreoathetosis may not manifest extrapyramidal signs until after the first year of
life (244,456), with the large majority developing choreoathetosis between the ages of 1 and 4 years (460,461). However,
some patients do not develop abnormal movement until as late as 7 to 14 years (244,460–462). Moreover, nearly half of the
patients with late onset of choreoathetosis have a history of normal neurologic development until the extrapyramidal signs and
symptoms develop (460–462) (of interest, such children seem to have injury to the subthalamic nuclei (451)). Finally, many
children who appear normal at age 1 or 2 years go on to have cognitive delay (420) and learning difficulty when they reach
school age (459). Therefore, even mild imaging abnormalities may have significant consequences upon long-term outcome.
On pathologic studies, affected patients have been found to have moderate to severe destruction in the hippocampi,
putamina, inferior colliculi, central gray matter of the midbrain, other brain stem nuclei, and the ventrolateral nuclei of the
thalami (176,402,454,463). Positron emission tomographic studies of patients with athetoid cerebral palsy showed normal
cortical activity, but diminished metabolism in the thalami and lentiform nuclei (464), 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 injuries may be seen only
on perfusion or diffusion-weighted MR imaging for several days. The imaging findings evolve continuously for many weeks, so
it is important to either image the neonates at a consistent 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. 4-46 and 4-47). Sonograms will show hyperechogenicity of the affected structures, CT (not recommended)
will show reduced attenuation of affected structures, anatomic MRI will show T1 hypo- and T2 hyperintensity, diffusion-
weighted MR will show reduced diffusivity, proton MR spectroscopy will show elevated lactate and abnormally small NAA
peaks (127), and perfusion using ASL will show increased perfusion of injured areas (466). Note that the timing of this
evolution changes with treatment by hypothermia (410,432) (see the following section).
In the first 2 to 3 days after profound hypotension, ultrasound may show hyperechogenicity in the thalami, globi pallidi,
putamina, periventricular white matter, and perirolandic cortex (Figs. 4-36, 4-46, 4-47). This hyperechogenicity can easily be
overlooked if the sonographer is not actively searching for it (404,467); the finding of thalamic hyperechogenicity portends a
poor neurologic outcome (196,468). With very severe injury, increased echogenicity is seen diffusely throughout the cerebrum
(Fig. 4-47). Initially it will be more apparent in the white matter, and the differentiation between hyperechoic white matter and
hypoechoic cortex becomes more pronounced 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. 4-47A and B).
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 velocity 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 (469).) Fluctuations
in RI have also been reported, likely reflecting impaired autoregulation (404).
Table 4-7 Findings and Effective Times for Imaging Techniques in Mild to Moderate Perinatal Hypoxic–Ischemic Injury
Ultrasound Increased echogenicity 2–10 d Poor assessment of deep structures and of cerebral convexities
X-ray computed tomography (CT) Low attenuation 1–7 d Temporal lobes difficult to assess. Ionizing radiation
Proton MRS Increased lactate 1–15 d Relatively mild elevation until secondary energy failure (>24 h)
Decreased NAA Day 3 or later
CT, X-ray computed tomography; MRS, proton magnetic resonance spectroscopy; DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging.
CT is not recommended, but it shows hypoattenuation of the thalami and basal ganglia (Fig. 4-46G); these gray matter
structures become isodense with surrounding white matter (193), a symmetrical finding that can be easily overlooked (it is
more difficult to appreciate what is NOT there), as can the hypointensity of the cerebral cortex (particularly perirolandic) and
superior cerebellar vermis. It is, therefore, essential to specifically assess gray matter structures (cortex, thalami, and basal
ganglia) to be sure that the attenuation values are similar to other gray matter structures. The presence of low attenuation
in the thalami on postnatal days 2 to 4 is highly predictive of poor neurological outcome (450). In very severe brain injury, the
CT shows diffuse hypodensity on the first day of life, involving the basal ganglia, white matter, and cortex (Fig. 4-48A); the
cerebellum is often spared.
MRI findings vary with the severity of the injury. Findings on diffusion imaging and proton spectroscopy vary with the
severity of the injury. With very severe injury (presumably from prolonged >15–20 minutes without blood flow), the
appearance of abnormality appears early and remains. T1- and T2-weighted images show diffuse edema, with the T1-weighted
images nearly uniformly hypointense and T2-weighted images nearly uniformly hyperintense due to the diffuse edema; cerebral
ventricles and subarachnoid spaces are compressed. Dav maps are nearly uniformly hypointense (gray and white matter) 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. 4-48) (406,441,442). Within 48 hours, the cortex and basal ganglia become abnormally hypointense on T1 images and
abnormally hyperintense on T2 images. By 4 days, blurring of the cortical–white matter junction may be seen. Frank tissue
breakdown may be seen by day 10, manifested as small foci of hyperintensity on T2 images and increasing diffusivity.
With mild to moderate brain injury, the amount of injured tissue varies with the severity of the hypoxic–ischemic insult.
Anatomic MR imaging will typically be normal if performed on the first days after birth. Dav is reduced and lactate level
elevated on MRS during the birth process but normalizes after birth and remains normal for 20 or more hours (although the
duration of this delay varies) before rising again at the time of secondary energy failure. In this situation, NAA levels typically
remain normal for the first 2 to 3 days. Diffusion imaging will typically show mildly reduced diffusion in the lateral thalamic
nuclei within the first 24 hours of life (Fig. 4-46C) (127,406,407). However, diffusion imaging may yield false-negative results
in the early hours after birth (185,406,407) and will nearly always underestimate the amount of damage if performed in the first
24 hours of life (before the onset of secondary energy failure) (125,127,406). Dav values of less than 0.8 × 10−3 mm2/s in the
thalami or posterior limb of the internal 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 (440,470). It should be noted that metabolite ratios (on MRS) and Dav values (on DTI)
change continuously over the first week of life (see Fig. 4-46) and pseudonormalize in neonates by the fifth or sixth day
(125,127). By day 3 after injury, T1- and T2-weighted images become definitely abnormal, although findings are subtle
(127,192). T2-weighted sequences show that the basal nuclei, particularly the posterior thalami, are isointense with white
matter (instead of normal hypointensity); this relative hyperintensity is best seen on the first (60 ms) echo but will be seen with
longer echoes, as well (Fig. 4-46I). During days 3 to 5, diffusion abnormalities will be at their maximum; diffusion-
weighted/Dav images showing reduced Dav (Fig. 4-46J1) and T1-weighted images showing abnormal hyperintensity in the
lateral thalami and posterior putamina (Fig. 4-46H) and along the corticospinal tracts up to the perirolandic cortex (127). If
perfusion is studied using pulsed arterial spin labeling (pCASL), diminished perfusion will be seen on day 1, but
hyperperfusion will be seen on days 2 and afterward in injured areas (Fig. 4-46J2) (471). If the brain stem is injured, reduced
diffusivity is seen in the dorsal midbrain (typically at the level of the inferior colliculi) or pons (Fig. 4-37 and 4-38). 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 (127). Reduction of Dav by more than 25% to 35% is
associated with poor long-term outcome (127,374,440,470,472) (for normal neonatal Dav values see Bartha et al. (473)).
Extensive cortical injury, if seen (Figs. 4-47E, F and 4-48D, E), portends a very poor neurologic outcome (424,448). T2-
weighted images may be normal or show symmetric absence of the normal spot of hypointensity in the posterior limb of the
internal capsule (Fig. 4-47D), as well as T2 hyperintensity of the basal ganglia, which become isointense with white matter on
T2-weighted images (Figs. 4-46M and 4-48C). 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 (127,472). Limited experience with perfusion imaging in the subacute phase
shows hyperperfusion of injured regions (Fig. 4-49) in the early subacute phase (up to 7 days after birth). 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
calcification, in the affected gray matter nuclei (193,201). On MR, Dav has nearly normalized at this phase in the thalami,
basal ganglia, and corticospinal tracts (Fig. 4-46N), although it may be reduced in locations that were initially normal (127);
the new areas of reduced diffusion may represent wallerian 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. 4-46O) (127).
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, in the ventrolateral thalami, and in the posterior putamina (Fig. 4-
46L). Heterogeneous high and low signal is seen in the basal nuclei on the T2-weighted images, probably the result of
astrogliosis and mineralization (363).
The extent of injury is variable and probably is related to the severity and duration of reduced supply of energy substrate to
the tissues, possibly superimposed upon genetic predisposition. In the least severely injured patients, injury is limited to the
lateral thalami and posterior putamina. Progressively more severe injury involves the perirolandic cortex, hippocampi,
superior cerebellar vermis, the remainder of the deep cerebral nuclei, the central mesencephalon, and the remainder of the
cerebral cortex. In the most severely injured patients, the entire cerebral cortex, all the deep cerebral nuclei, the cerebellar
vermis, and many brain stem nuclei are injured (Figs. 4-47 and 4-48) (189,192,193,448). The T1 hyperintensity and T2
hypointensity slowly fade (Fig. 4-47) as atrophy of the injured tissues develops and myelination progresses.
Figure 4-46 Profound neonatal hypotension of moderate severity; evolution at ages 17 hours, 4 days, 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. C. Axial Dav map
at age 17 hours shows minimal reduced diffusivity in the ventrolateral thalami (white arrows). D. Proton MRS (TE = 288 ms) 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. 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 (small arrows) and the ventral thalami show
faint, diffuse hyperintensity. I. Axial T2-weighted image at age 4 days shows diffusely hyperintense white matter (nearly as bright as CSF) and
slightly bright posterior thalami. The hypointensity in the ventrolateral thalami (white arrowheads) is normal. J1. Axial Dav map at age 4 days
shows hypointensity (reduced Dav, white arrowheads) in the ventral thalami and posterior putamina. J2. Axial PCASL perfusion study at age 4
days shows increased blood flow (perfusion) to the ventral thalami (white arrowheads) and posterior putamina (white arrows). K. Proton MRS
(TE = 288 ms) 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 ventrolateral thalami (white arrowheads), posterolateral putamina (white arrows), and medial putamina (black arrowheads). M.
Axial T2-weighted image at age 8 days shows persistently hyperintense thalami (black arrows) and basal ganglia, 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
diffusivity in the ventrolateral thalami (white arrowheads) has nearly completely disappeared. O. Proton MRS (TE = 288 ms) 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.
Figure 4-47 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 ganglia 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 hyperintensity 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. 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 matter
(W). The extent of reduced diffusivity suggests a severe injury. G. Proton MRS (288 ms) 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. 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.
Figure 4-48 Extremely severe profound hypotensive injury; images obtained 1 day after birth. A. Axial noncontrast CT shows extensive brain
swelling with hypoattenuation of the basal ganglia, 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 ganglia. The ventrolateral thalami (white arrows) stand out as relatively hyperintense, possibly because they are more cellular and
myelinated than are 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 diffusivity) of nearly all parts of the brain with the exception
of the frontal white matter (F) and cerebellum (C). F. Proton MRS (TE = 288 ms) from basal ganglia/thalami shows enormous lactate peaks
(Lac). Note that the NAA peak is already lowered.
In the chronic phase, weeks to months after the injury, the affected areas of the brain may undergo cavitation (Fig. 4-47H–
K); or they become shrunken and show T2 hyperintensity compared to normal myelinated brain tissue (Fig. 4-50). In mild–
moderately affected patients, mild volume loss, T1 hypointensity, T2 hyperintensity, and increased Dav are most commonly
seen (>90%) in the ventrolateral thalami, posterior putamina, and corticospinal tracts from the internal capsule up through the
perirolandic cortex (Fig. 4-47J and K); in 50% to 60% of patients, the anterior cerebellar vermis is affected (474,475).
Involvement of the subthalamic nuclei may be seen in children with dyskinesia (451). Callosal axons are often affected in the
region of the central sulcus, so the corpus callosum may become thin, particularly so in the posterior callosal body and isthmus
(476). In some of the more severely affected patients, multicystic encephalomalacia may develop in most of the brain (Fig. 4-
51). Damage to the white matter pathways may not become evident in the cerebral white matter until myelination is well under
way at the end of the first year (446) or during the early second year, depending on the location of the injury and the degree of
associated myelination delay (Fig. 4-52). MR is much more sensitive than is CT to the damage in the deep cerebral nuclei and
corticospinal tracts (193,477) and to the myelination delay that almost invariably accompanies diffuse ischemic brain injury
(215,382).
Effects of therapeutic hypothermia (brain cooling)
In the past decade, therapeutic hypothermia (TH, consisting of lowering body temperature to 33.5°C for 72 hours) has been
increasingly used as an immediate treatment for neonatal hypoxic–ischemic brain injury. Results showed a significant reduction
in neurodevelopmental disability in early (425,478–484) and 18 month follow-up exams (431) of children treated with mild to
moderate hypothermia. Of note, TH has required recalibration of many commonly used “outcome predictors,” clinical,
biochemical, and imaging tests that are used to predict outcome in asphyxiated newborns (485). In addition, along with other
techniques such as amplitude-integrated electroencephalography, TH has had significant effects upon decision-making in the
neonatal ICU (433); all of these reasons have resulted in establishing TH as the standard of care. Our experience is similar to
that of others; TH seems to reduce the amount of injury in mild or moderate brain injury due to profound hypotension. It reduces
brain stem, thalamic, and corticospinal tract injury but does not seem to significantly reduce watershed injury (cortical or white
matter) or very severe (total brain) injury (410,432). However, we have seen injury that appeared to affect the whole cortex
reduced to damage resembling mild watershed injury (Fig. 4-53). It is likely that TH ameliorates secondary energy failure, but
the mechanisms by which this occurs are unknown.
Figure 4-49 Value of arterial spin labeling (ASL) in early detection of neonatal brain injury. Images A–E are acquired at age 24 hours, while F–J
are acquired at 4 days. A and B. Axial T1 and T2 images shows no definite abnormality. C. Axial ASL image, performed using
pseudocontinuous ASL, shows increased blood flow to the ventrolateral thalami and basal ganglia (white arrows). D. Axial Dav map shows
reduced Dav (hypointensity, white arrows) in the lateral thalami. E. Proton MRS acquired in the basal ganglia shows markedly elevated lactate
(Lac) and low NAA for age. F and G. Axial T1- and T2-weighted images at age 4 days show extensive T1 hypo- and T2 hyperintensity of most
gray matter structures (white and black arrows), related to edema. H. Axial ASL image shows persistent hyperperfusion of the basal ganglia,
now localized more to the posterolateral putamina, and ventrolateral thalami. I. Axial Dav map shows markedly reduced diffusion throughout the
cortex and basal nuclei, indicating injury to much of the brain despite treatment with hypothermia. J. Proton MRS shows diminution of choline
(Cho) and NAA peaks with increasing lactate (Lac).
Several other aspects of therapeutic hypothermia are important for imagers interpreting brain MRI in neonates. First, the
evolution of diffusivity changes is prolonged. Without hypothermia, Dav normalizes after 6 to 7 days; after TH, Dav normalizes
after about 11 days (465). Second, in the first 1 to 2 days after TH, Dav is about 10% higher than normal; the reasons for this
elevation of Dav are unknown (410). Third, there is about a 10% incidence of small IVHs in neonates treated with TH (486);
there is no known clinical consequence of these hemorrhages. Most important, treatment with TH does not diminish the
usefulness of MR techniques in the evaluation of encephalopathic neonates. The presence of elevated Lac/NAA or significant
reduced diffusivity during TH suggests that severe injury has occurred that is not responsive to the therapy. The value of
arterial spin labeling (pCASL) in distinguishing responders to hypothermia from nonresponders is not yet established at the
time of this writing (466). In patients who do respond, evaluation of the brain with DTI and tract-based spatial statistics
(TBSS) and other advanced methods appears to be useful in assessing minor injury and, potentially, directing therapies
(487–489).
Timing of studies
The subject of optimal timing of imaging studies after neonatal hypoxic–ischemic brain injury warrants has become far less
important since the use of TH has become standard of care (490). Although not yet proven, it appears that three groups do not
respond well to TH: (a) catastrophic injury, where injury appears quickly and affects nearly the entire brain; (b) injury
acquired over several days prior to delivery, often associated with decreased fetal movements; and (c) injury from other
causes such as infection, metabolic diseases, or other hereditary disorders. The first group is suggested by the profound
clinical presentation, the second by the history; identification of both can be strengthened by imaging, which shows early,
severe injury of the entire cerebrum in the first group and watershed injury in the second. The last group is identified by signs
and symptoms (and lab tests or MRIs, as discussed in Chapters 3, 5, and 11) that identify the cause as one caused by a problem
other than the birth process.
Figure 4-50 Detection of small injury by ASL. A and B. Axial T1-weighted images at age 4 days show low intensity of the normal hyperintense
corticospinal tract in the posterior limb of the internal capsule (black arrows in A). C. Axial ASL image shows increased perfusion in the
posterior putamina (large white arrows) to a greater degree than in the ventrolateral thalami (small white arrows). D and E. Axial T2-weighted
images at age 6 months show abnormal hyperintensity (black arrows) of the posterior putamina, confirming the injury detected by ASL. F. Axial
Dav image shows very high diffusivity (black arrows) in the posterior putamina, confirming significant injury.
Metabolic disorders, partial list (see Chapter 3) Isolated sulfite oxidase deficiency
Molybdenim cofactor deficiency
Maple syrup urine disease
Urea cycle disorders (hyperammonemia)
Glycine encephalopathy
Biotinidase deficiency
Phenylketonuria
Congenital hypoglycemia
Mitochondrial disorders
Disorders of peroxisome formation
Figure 4-54 Intraventricular, bilateral thalamic and periventricular hemorrhage in a neonate secondary to extensive venous thrombosis. A.
Sagittal T1-weighted image shows abnormal hyperintensity, representing clotted blood, in the internal cerebral veins (arrowhead), straight sinus
(large arrows), and third and fourth ventricles (small arrows). B and C. Axial T2 images show blood in the third ventricle (H) and frontal horn
(small arrow). The thalami are edematous and hemorrhagic (large arrows). Small hemorrhages are seen at the tips of the frontal horns
(smallest arrows in B and arrows in C). D. Susceptibility-weighted image shows extensive low intensity (arrows) in the ventricles, thalami, and
periventricular white matter due to venous dilation and parenchymal hemorrhages from increased venous pressure. E. Anteroposterior view of
MR venogram shows that the only patent dural venous sinuses are the anterior portion of the superior sagittal sinus (arrow) and the right
transverse sinus (arrowhead) The internal cerebral veins, vein of Galen, straight sinus, posterior portion of the superior sagittal sinus and left
transverse sinus are occluded, resulting in the massive venous dilation and hemorrhages in the cerebral hemispheres.
Another disorder to consider when large parenchymal hemorrhages are seen in fetuses or neonates is neonatal alloimmune
thrombocytopenia. In this disorder, which occurs in about 1/1000 births, 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
maternal antibodies cross the placenta and enter the fetal circulation, fetal platelets are destroyed and their function impaired
(494,499). 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 (500,501). The diagnosis is
made by demonstrating maternal alloantibodies directed against a paternal platelet antigen. The rate of recurrence in
subsequent pregnancies is quite high (499). 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 macrocystic encephalomalacia are
present, usually with ex vacuo enlargement of the adjacent ventricle (502).
Figure 4-55 Hemorrhagic left frontal infarct secondary to sagittal sinus thrombosis. A. Sagittal T1-weighted image shows complex hematoma
in left frontal lobe. Note hyperintense methemoglobin (black arrows) and isointense deoxyhemoglobin (black arrowheads) within the hematoma.
B. Axial T2-weighted image shows the markedly hypointense hematoma (black arrows). Note the enlarged superior sagittal sinus (black
arrowheads), suggesting thrombosis. C. Sagittal maximum intensity projection from 2D time-of-flight angiogram shows absence of flow-related
enhancement along the course of the superior sagittal sinus (black arrows).
Figure 4-56 Acute occipital lobe hemorrhage in a neonate. 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 time-of-flight venogram shows lack of flow-related enhancement in
the right transverse sinus (white arrows), consistent with acute thrombosis.
Figure 4-57 Multiple cerebral hemorrhages due to vasculopathy from COL4A mutation. A. Coronal transfontanelle sonogram in a young infant
shows multiple cysts (asterisks) in the left cerebral hemisphere, displacing the left lateral ventricle (LV). The right lateral ventricle has an
irregular lateral margin, suggesting prior injuries. B. Parasagittal view of the right lateral ventricle shows hemorrhagic debris (white arrows)
layering in the occipital horn. C. Axial T2-weighted image shows a large area of porencephaly in the left frontal horn (black asterisk) and a
smaller one in the right basal ganglia (black arrow), both likely secondary to prior hemorrhages. Note the hypointense signal of hemosiderin,
from prior intraventricular bleeds, lining the walls of both occipital horns (white arrows).
The imaging appearance of intraventricular blood was described in the section on premature infants.
Figure 4-58 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 MR image 10 days later shows abnormal hyperintensity of the basal
ganglia, posterior thalami, and cerebral white matter diffusely.
If MRI is not quickly available or if adequate monitoring/support cannot be performed on the MR scanner, CT perfusion can
be performed, as the unstable child is easily monitored within the CT scanner; this is less desirable than is MR, but expeditious
evaluation is of great importance. Initial CT images (<24 hours) will show subtle hypoattenuation of the basal ganglia and
insular cortex; sometimes, the cisterns around the midbrain are effaced. Subsequent scans (24–72 hours) will show diffuse
cerebral edema, with decreased gray matter–white matter differentiation, effacement of sulci and cisterns, and decreased
attenuation of the basal ganglia and cortex (Fig. 4-57A) (508,509). 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 cerebral hemispheric
white matter becomes hyperdense compared to the cortex (Fig. 4-61A) (510,511). 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 (510,511).
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. 4-23) (203–206).
Beyond the age of 1 year, however, patterns of injury are similar in all age groups.
CNS Injury in Multiple Pregnancies
Ischemic brain injury in twin gestation is an important subject and deserving of some discussion (512). Twin pregnancies
represent 1.2% of spontaneously conceived pregnancies (513). 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 monochorionic), or may each have their own amniotic sac and placenta (diamniotic dichorionic; these
fetuses are in the same situation as dizygotic twins). When two or more ova are 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.
Figure 4-59 Drowning injury in a 4-year-old boy. A. Axial T1-weighted image shows blurring of the cortical–white matter junction in the
occipital lobes. B. Axial T2-weighted image, somewhat degraded by motion, shows hyperintensity of the frontal and parietooccipital cortex. C
and D. Axial diffusion-weighted images (b = 1000 s/mm 2) 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). E and F. Axial T2 image (E)
and coronal FLAIR image (F) acquired 2 months later show profound atrophy of the hippocampi, basal ganglia, and white matter with ex vacuo
ventricular enlargement and persistent T2/FLAIR hyperintensity of the cortex.
Figure 4-60 Watershed injury in a 4-month-old infant. A and B. Axial T2-weighted (SE 3000/120) image 5 days after injury shows abnormal
hyperintensity (white arrows) of the cerebral cortex and subcortical white matter in the intervascular boundary zones. C. Dav map shows
hypointensity (reduced diffusivity, white arrows) in intervascular boundary zones.
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 IVH, localized cerebral infarctions (single or multiple), porencephaly,
hydranencephaly, multicystic encephalomalacia, periventricular leukomalacia, and polymicrogyria (5,167,513,517).
Biomorphic analyses have shown subtle changes of brain morphology, perhaps resulting from regional ischemia (527), while
diffusion imaging has revealed subtle strokes seen better in the subacute phase (due to reduced diffusivity) than in more chronic
phases (where the abnormality is local atrophy) (528). 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 (e)
venous hypertension (167,513,529). The fourth mechanism (placental circulatory stasis and impaired umbilical cord blood
flow) is currently believed to be the most common (522). Norman et al. (530) make the point that monoamniotic twins are
particularly prone to umbilical cord entanglement.
Figure 4-62 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 junction 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.
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 (513,528,531). In particular,
one should look for hemorrhage, infarctions (acute or chronic), polymicrogyria, porencephaly, hydranencephaly, multicystic
encephalomalacia, and cavitary white matter injury (Fig. 4-63). 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 postconceptional ages; all have been discussed
and illustrated in earlier sections of this chapter.
Figure 4-63 Fetal MRI manifestations of injuries from twin–twin transfusion syndrome. A. Sagittal SSFSE image shows periventricular
hemorrhage (white arrows) in a 22-week fetus due to presumed hypotension/ischemia. B. Axial SSFSE image shows a large germinal matrix
bleed (white arrows) in the region of the ganglionic eminence. Hydrocephalus is present, and blood–CSF levels (black arrows) are present in
the ventricles. C and D. Coronal (C) and sagittal (D) SSFSE images show parenchymal loss and irregularity of the cerebral cortex (black
arrows) in a 22-week fetus who was a donor in twin–twin transfusion. Postnatal scan showed polymicrogyria. E. SSFSE image shows a
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. F and G. SSFSE images show marked ventriculomegaly and marked hyperintensity (arrows) in both
cerebral hemispheres in this donor of twin–twin transfusion. Lesions progressed to hydranencephaly. H. SSFSE image shows
hydranencephaly of surviving co-twin. (This case is courtesy of Dr. Joel Cure.)
Neonatal Hypoglycemia
Neonatal hypoglycemia is probably underrecognized, 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 (532).
The definition of hypoglycemia in infants varies with the maturational state of the infant, as less mature infants tolerate lower
glucose levels than do more mature ones and mature infants tolerate lower levels than do older children and adults (533). The
suggested blood glucose operational threshold concentrations at which clinicians should consider intervention are as follows:
a single measurement of blood glucose less than 1 mmol/L (18 mg/dL); blood glucose level less than 2 mmol/L (36 mg/dL),
which remains below the same value at the next measurement; or a single measurement of less than 2.5 mmol/L (45 mg/dL) in a
newborn with abnormal clinical signs (534). Others still suggest using a value below 30 to 35 mg/dL in the first 24 hours and
below 40 to 45 mg/dL after 24 hours in term infants (532). 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, hyperbilirubinemia) all impact on whether or not brain injury will occur (532,534,535).
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 (536). These low glucose levels can exacerbate brain injury due to the birth process or complications
thereof (537). However, many authors point out that there is “no evidence that asymptomatic hypoglycemic infants will benefit
from therapy” (533).
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 (538,539), (b) low energy requirements of the immature neurons resulting from the low level of neuronal
activity (532), (c) the relatively minor effect of hypoglycemia upon cardiovascular function of the newborn (540), and (d)
marked increase in cerebral blood flow provided by even moderate hypoglycemia (532). 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 (438,532).
Volpe (532) describes four major causes of neonatal hypoglycemia. 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 diabetic mothers, infants with
erythroblastosis, and preterm infants who suffer hypoxia–ischemia. Infants in this group are rarely symptomatic. Secondary-
associated hypoglycemia describes infants with hypoglycemia secondary to associated illnesses, such as hypoxia–ischemia,
intracranial hemorrhage, sepsis, and congenital anomalies. Affected neonates typically present at the end of the first day of life,
duration of hypoglycemia is brief, degree is fairly mild, and response to glucose therapy is prompt. About half of infants in this
category exhibit neurologic symptoms. 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 disorders 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 UCSF, the most common cause of neuroimaging-apparent
brain damage secondary to neonatal hypoglycemia is hyperinsulinism secondary to congenital tumors or hyperplasia of
pancreatic beta cells. Three principles appear to be 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 hypoglycemia combined with mild hypoxia causes injury, whereas either of
the two conditions in isolation does not (438,537).
Imaging studies of patients who have suffered damage from perinatal hypoglycemia reflect the pathological findings
(541–543) of diffuse brain damage, with the most severe injury localized primarily to the parietal and occipital cortex of the
brain and the underlying white matter (17,18,544); 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.
4-64), including the callosal splenium; T1 hypointensity and T2 hyperintensity in the affected cortex result in lack of distinction
between the cortex and subcortical white matter on T1- and T2-weighted images (Fig. 4-64). MR 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 hyperintensity 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. 4-65). In the chronic phase (Fig. 4-
64D and E), the cortex and underlying cerebral white matter initially show cystic encephalomalacia and, ultimately, become
shrunken and atrophic. When hypoglycemia is associated with perinatal brain injury, however, the pattern is similar to
normoglycemic perinatal injury with the exception of some increased injury in the corticospinal tracts (537). The cause of this
specific location is not understood.
Figure 4-64 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 SE 3000/120 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/mm 2) shows reduced diffusivity
(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.
Figure 4-65 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.
The only reported proton MRS studies were performed with a short echo time of 30 ms. Large peaks were seen from 0.9 to
1.6 ppm (545). 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 macromolecular lipids. Although it is not unreasonable to suppose that some lactate was
present, verification will require further MRS studies.
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;
motor impairment seems to correlate with peak bilirubin levels (546). Delayed development 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 (463,547).
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 (547). A group of transporter molecules in neurons, glia,
and capillary endothelial cells usually export the bilirubin from brain cells to the extracellular space and then across capillary
walls into the blood. Disturbance in the action of these transporters, either due to genetic causes or due to depletion of energy
sources, may play an additional role in neuronal injury by bilirubin (547). 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 demonstrated damage to the globus pallidus, subthalamic nucleus, and the CA2 and CA3 regions
of the hippocampus (5,463). Of interest, sick, acidotic, and edematous preterm infants with low serum albumin levels can
develop pallidal injury and hearing loss from bilirubin encephalopathy, even in the setting of clinically acceptable serum
bilirubin levels, possibly because they have a less mature blood–brain barrier or because their low albumin level results in
higher free bilirubin levels (547,549,550).
No specific CT or ultrasound findings have been described in bilirubin encephalopathy. In our experience, transfontanelle
sonograms inconsistently show hyperechogenicity of the globi pallidi (Fig. 4-66A) (550,551). On MR, neonates with acute
bilirubin encephalopathy show increased T1 shortening of the globi pallidi compared to controls (but this is not seen
consistently (546,552,553)) and, rarely, T2 prolongation in the affected regions (Fig. 4-66B and C) (550,552–554). Proton
MRS with TE of 144 ms in the acute phase shows elevated myo-inositol/Cr and Glx/Cr (555) and significantly elevated
NAA/Cr (553) but no lactate. In the chronic phase, T2 prolongation and atrophy can be seen in the globi pallidi, subthalamic
nuclei, hippocampi, and cerebral white matter (Fig. 4-66D and E). At this time, it is probably accurate to say that a qualitative
increase in T1 shortening of the globi pallidi and elevation of NAA/Cr is very suggestive of basal ganglia injury from
hyperbilirubin injury.
Hypernatremic Dehydration
Young infants and, especially, premature infants are susceptible to hypernatremia resulting from their relatively large surface
area compared to body weight (and thus increased insensible water loss through the skin) and the inefficiency of water
conservation secondary to their renal immaturity (566). The most common cause of hypernatremia dehydration is severe
diarrhea (566,567). Affected infants typically are extremely lethargic, yet hyperirritable to stimuli. Other signs and symptoms
include muscle rigidity, hyperreflexia, and, occasionally, seizures (566,567). Brain damage is common, often with significant
neurologic sequelae (567). Other causes are rare and include salt wasting due to mutations of the carbonic anhydrase XII
(CA12) gene at chromosome 15q22.2 (568) and cystic fibrosis (569,570).
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 tearing 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 (571). Finally, dural venous sinus thrombosis can develop, with associated
venous infarctions (572).
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 structure than normal brain
tissue; as the hemorrhages coagulate, they become hyperechoic. On CT and MR, the interstitial edema is seen as decreased
attenuation and prolonged T1 and T2 relaxation times, respectively, in the cerebral and cerebellar white matter. Reduced
diffusion is seen acutely in the lateral thalami and globi pallidi (573). Focal, well-defined hemorrhages are seen in the
cerebrum and cerebellum in the cortex and the cortical–white matter junctions (574).
Figure 4-67 Brain injuries associated with congenital heart disease include infarction, ischemic cerebral white matter injury, and, in the
chronic phase, atrophy. A. Axial diffusion-weighted image 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 ventricular trigones, indicating reduced diffusivity and acute injury. C. Axial inversion recovery 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 or infiltration of microglial cells.
Birth Trauma
Ultrasound is the initial imaging modality of choice for the evaluation of birth trauma because the scans can be obtained in a
rapid fashion 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 choice if available. MR
better demonstrates acute cerebral ischemia than does 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
MR, hyperacute hematomas are seen by MR as space-occupying masses; their hemorrhagic nature can be confirmed by the very
low signal intensity on T2 gradient echo or susceptibility-weighted sequences. It may be difficult to detect acute subarachnoid
hemorrhage by MR, although some studies indicate that FLAIR and/or SWI sequences can be more sensitive than CT (576) and
3D double inversion recovery is even more sensitive in the subacute period (577); however, the identification of subarachnoid
hemorrhage is rarely critical in the neonate, and skull fractures are less readily detected with MR (576). Similarly, the
difficulty of distinguishing the signal void of intracranial air (pneumocephalus) from that of overlying 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, although the
widespread availability of MRI-compatible incubators is increasing the speed and safety of MRI in the critically ill neonate
(578,579). When CT is obtained in this patient population, 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 hematomas
(particularly along the tentorium and at the falcotentorial junction) are common after vaginal deliveries and are of no clinical
significance (580,581). 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.
MR has been proven to be more sensitive than CT in the detection of small extra-axial fluid collections, white matter injuries,
and cortical injury (576,582–585). Brain stem injuries, important for determining prognosis, are better detected by MR
(586,587). Birth-related carotid artery injury may present as large arterial territory infarction (588,589). 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.
Figure 4-68 Birth trauma secondary to difficult breech delivery; sequential scans. A. Sagittal T2-weighted image shows abnormal
hyperintensity (white arrow) of the spinal cord at the C2 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
C2 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.
Figure 4-69 Birth trauma with spinal injury. A. Sagittal T2-weighted imaging shows the fracture dislocation (large white arrow) through the C5
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 (arrow).
Figure 4-70 Birth trauma. Spinal and intracranial extraparenchymal hematomas. Sagittal T1-weighted image shows hyperintense
extraparenchymal blood in the dorsal spine, posterior fossa subdural space (black arrows), and interhemispheric subdural space (white
arrows).
Head Trauma
Extracranial birth trauma
Caput succedaneum is one of the three major varieties of extracranial hemorrhage, the other two being subgaleal hemorrhage
and cephalohematoma. 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. Radiography is neither diagnostic nor necessary (624).
Subgaleal hemorrhage refers to hemorrhage subjacent to the aponeurosis 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 secondary to blood loss (and a
small percentage may be fatal), the lesion usually resolves over 2 to 3 weeks. Therefore, imaging of asymptomatic subgaleal
hematomas is not typically necessary (624); however, those that are symptomatic have a higher association with intracranial
hemorrhage, encephalopathy, and skull fracture, so imaging should be considered (625,626).
The term cephalohematoma refers to a traumatic subperiosteal hemorrhage; because the blood is beneath the outer layer of
the periosteum, it is confined by the cranial sutures (Fig. 4-74). Cephalohematomas occur in approximately 1% of live births;
the incidence increases markedly with the use of forceps and even more significantly with vacuum-assisted deliveries (627).
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 (624). When seen on CT or
MR, 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 MR when imaged in the subacute stage (Fig. 4-74). 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. CT at this stage will show both an inner rim (calvarium) and an outer rim (calcified elevated
periosteum) of calcification (Fig. 4-74D). 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.
Figure 4-71 Spinal extra-axial hematoma from birth trauma. A. Sagittal T1-weighted image shows abnormal heterogeneous hyperintensity
within the spinal subarachnoid 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 is courtesy of Dr. Erik Gaensler, San Francisco, CA.)
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 (628,629) and some authors reporting that skull
fractures may actually diminish injury to the underlying brain (by dispersing the force from the trauma) (630), more recent,
larger studies indicate that the presence of a skull fracture increases the likelihood that the child has suffered a clinically
significant traumatic brain injury (631). Certainly, the absence of a skull fracture by no means excludes brain damage.
Documentation of fractures may be useful in the overall documentation of trauma, however (especially abusive trauma in older
infants; see section later in this Chapter). When documentation is desired, reformations in the coronal plane and 3D
reformations using bone algorithms are valuable to detect fractures in the horizontal plane, which are difficult to detect on
(routine) axial CT scans. For children less than 2 years old, adding 3D reformations to 2D CT scans has been shown to
increase sensitivity and specificity for the diagnosis of linear skull fractures (632,633). Additionally, fractures can be
confirmed by obtaining close examination of the lateral “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.
Figure 4-72 Neurogram of brachial plexus injury due to shoulder dystocia. A and B. Coronal STIR images show edematous right C7 and T1
nerve roots (bright and enlarged roots, white arrows). C. Axial STIR image shows the edematous roots/trunks (arrows) as they course through
the neck.
Figure 4-73 Nerve root avulsion in a neonate. A. Coronal fat-suppressed T2-weighted image shows a pseudomeningocele (arrow) 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 C7 to T1 neural foramen.
Figure 4-74 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 the 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.
The most common skull fractures are linear and are most often localized to the parietal or frontal bones. When the bone is
not displaced, the fracture heals spontaneously and no treatment is indicated. In infants, skull fractures may heal in less than 6
months. In older children, 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 (634).
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 concerned about a developing epidural hematoma
when an infant sustains a linear fracture of the squamous temporal bone (52).
Depressed skull fractures may result from pressure of the head against the pelvis during the birth process or may be induced
by application of forceps (635,636). Whereas plain films may visualize 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. 4-75), whereas plain radiography does not. Depressed skull
fractures may be elevated percutaneously or noninvasively (637,638).
Occasionally, skull fractures are associated with tears of the underlying dura. When dural tears occur, meninges and brain
tissue can herniate 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 (634,639,640). Leptomeningeal cysts are seen in 0.6% of all fractures, with 90%
occurring in patients less than 3 years old (639,640). On imaging studies, leptomeningeal cysts have distinct bony margins at
the fracture site (634,641), simulating a lytic calvarial lesion if the associated abnormalities of the subarachnoid space and
underlying brain are not appreciated (642). Intracranial tissue or CSF may be seen extending between the edges of the bone at
the fracture site (Figs. 4-76 and 4-77); this finding may be useful to make the diagnosis early in the course of the injury, before
the fracture begins to progressively enlarge (643). Encephalomalacia of the underlying brain is usually present, in our
experience, appearing as an area of low attenuation on CT (Fig. 4-76) and as an area of prolonged T1 and T2 relaxation time
on MR (Fig. 4-77). Early diagnosis and treatment may improve outcome (644).
Figure 4-75 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 hemorrhage are also present. B. Axial proton density image shows left medial parietal lobe contusion (black arrow) and
periventricular injury. C. Axial diffusion-weighted image shows reduced diffusion, manifest as hyperintensity in the affected cortex.
Figure 4-76 Leptomeningeal cyst. A. Plain film shows a well-marginated lucency (arrows) 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 (black arrow).
Encephalomalacia (white arrow) is present in the underlying brain.
Subdural hemorrhage is common in vaginally delivered neonates and is probably caused by lacerations of subdural veins
near the falcotentorial junction that result from molding of the head. MR has greatly increased the knowledge concerning the
frequency and severity 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. 4-78), reported in 26% to 63% of uncomplicated vaginal deliveries
(580,581,647). They are usually small (<3 mm) and are rarely of clinical importance (580,581). 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 brain stem function; in the latter cases, they are surgical emergencies (648,649). There are four major
categories of neonatal subdural hemorrhage: (a) tentorial laceration, (b) occipital osteodiastasis, (c) falx laceration, and (d)
rupture of bridging superficial cerebral veins.
Tentorial laceration and occipital osteodiastasis
These two injuries are discussed together because both result in posterior 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 (648). Lesser
degrees of infratentorial subdural hemorrhage may result from smaller tentorial tears or rupture of smaller infratentorial veins
without tentorial tears (Fig. 4-78). As stated above, these small subdural collections are being recognized more frequently as a
result of the increased sensitivity of MR 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. 4-78)
(580,649,650).
Figure 4-77 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 (curved arrows) at the fracture site. (This case is
courtesy of Dr. Chip Truwit, Minneapolis, MN.)
Figure 4-78 Small posterior subdural hematomas in neonates. 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 posterior to the cerebellum (curved arrows) and along the tentorium cerebelli
(small solid arrows) and posterior falx cerebri (open arrow).
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 supraoccipital–exoccipital synchondrosis) during birth.
This can be seen on lateral radiographs or on CT with bone windows (651). In severe cases, the dura and occipital sinuses are
torn; the result is cerebellar laceration and a massive posterior fossa subdural hemorrhage (616,652). The posterior fossa
subdural hematoma lies under the tentorium and extends laterally between the dura and arachnoid overlying the cerebellar
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. 4-79A and B). Both the fluid collection lying beneath the tentorium and the hydrocephalus
resulting from compression of the fourth ventricle and aqueduct can be detected (Fig. 4-79). 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. 4-79C and D). These lesions are usually seen well on coronal and
sagittal reformations; the high-density hematoma is seen immediately beneath the tentorium (634,653). 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 subdural hematoma may be isodense or even hypodense to the 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 iso- to slightly hyperintense compared with CSF on T1-weighted images, isointense or mixed iso-
/hypointense compared to CSF on T2-weighted images, hyperintense on diffusion-weighted images (DWI), and hypointense on
calculated ADC images. An acute subdural hematoma is isointense to the brain on T1-weighted spin-echo sequences,
hypointense to the brain on T2-weighted spin-echo and gradient echo sequences (Figs. 4-79 and 4-80), and hypointense on both
DWI and ADC images; this appearance results from the presence of deoxyhemoglobin in the red blood cells (654–657). Fast
spin-echo and volumetric T2 sequences are less sensitive to the presence of blood products, but they will usually be
hypointense (Fig. 4-79G). FLAIR sequences are not sensitive to acute blood and are not used in infants with acute trauma at
our institutions. 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 conversion of deoxyhemoglobin
to methemoglobin. The hematoma remains largely hypointense on DWI and ADC images at this stage (657). 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) (658). Finally, as the blood breakdown 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 conjunction with brain injury (Fig. 4-80). 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 neurologic 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, laceration 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 frontooccipital elongation. When laceration of
the falx occurs, the subdural hematoma is usually located in the inferior aspect of the interhemispheric fissure over the corpus
callosum (624).
Figure 4-79 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. C and D. Noncontrast CT images show interhemispheric subdural hematoma (arrows). Axial CT image at the level of the fourth
ventricle (C) shows the high attenuation of the subdural hematoma in the left side of the posterior 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 brain stem.
Rupture of superficial cortical veins that bridge the dura results in hemorrhage over the cerebral convexity. In
contradistinction, an 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 hematomas in the
newborn are usually unilateral and accompanied by subarachnoid blood. An underlying cerebral contusion may be present
(659).
The ultrasound, CT, and MR appearances and evolution of supratentorial subdural hematomas (Fig. 4-81) 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 subdural collections can be seen
relatively easily on sonography, convexity hematomas are more difficult to visualize because of the difficulty involved in
angling the transducer to see the convexity region. While sonography can be performed in the neonatal ICU and, therefore, does
not necessitate transporting very ill patients, the advent of commercially available MRI-compatible incubators has facilitated
the safe acquisition of MRI in critically ill neonates.
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,
abusive head trauma is 10 to 15 times more common than is accidental head trauma in infants less than 1 year of age (660,661),
and abusive head trauma is the leading cause of subdural hemorrhage at autopsy in children less than 1 year of age (662). Thus,
when findings of severe head trauma are found on imaging studies of infants, the suspicion of abusive head trauma should
always be raised. The imaging findings of trauma in adults are described in a number of publications (641); 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.
Although some institutions are considering MR for initial assessment (663), CT currently remains the initial imaging study
of choice for acute head injury, in most centers, 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 C3), an area that is
highly susceptible to injury in young infants (664). After the patient has stabilized, MR is the imaging modality preferred for
assessing the full extent of damage to the brain. MR has been proven to be more sensitive than CT in the detection of small
extra-axial fluid collections white matter shearing injuries and cortical injury (576,582,583,585,641,665). Brain stem injuries,
which have important prognostic significance, are better detected by MR (586,587). Moreover, MR is extremely sensitive to
the presence of hemosiderin from old hemorrhage (585) and the number and volume of lesions seen with SWI has been shown
to correlate with patient outcome following traumatic brain injury (666); the presence of old CNS injuries in association with
newer ones may be important evidence in the diagnosis of abusive trauma. In order to detect hemorrhage with maximal
sensitivity, T2 gradient echo images or susceptibility-weighted images (585,666,667) should be obtained in all trauma or
suspected trauma cases.
Figure 4-80 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
show 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 midlevel cervical spine (large white arrow) with prevertebral edema (small white
arrows). Note the hypointense hemorrhage (black arrowheads) at the falcotentorial junction.
Figure 4-81 Birth trauma. A and B. Axial noncontrast CT images show subdural hemorrhage along the left leaf of the tentorium (large white
arrow), in the interhemispheric fissure near the falcotentorial junction (small white arrow), along the left cerebral convexity subdural space, and
in the subcutaneous and subgaleal spaces. Note the severity of the cerebral cortical involvement, which was not detected by the sonogram.
Spinal Trauma
Vertebral column fractures and spinal cord injuries in children are less common than in other age groups; however, they are not
rare and have received increasing attention in the medical literature since the advent of modern imaging techniques. As
discussed in the section on birth trauma, the pediatric spinal column has anatomic characteristics that create different patterns
of susceptibility to injury among children, as compared with adults. These include increased elasticity of ligaments and soft
tissues, open epiphyses, lack of development of ossification centers, and changes in osseous strength, shape, and size
(598,668,669). For example, epiphysial plates are still open in the vertebral bodies of younger children; they start to fuse at
many levels by age 8 years. Facet joints are relatively horizontal in infancy, becoming more vertical with ossification between
ages 7 and 10 years. Another factor concerns the large head size and the relatively poorly developed paraspinous muscles in
infants. This combination, coupled with the increased elasticity of ligaments, creates a relative hypermobility that leads to a
predisposition for cervical spinal cord injury without plain film radiographic abnormality (592,593). The greatest amount of
motion in the cervical spine is at C2-C3 in infants and young children; thus, injury is most common at and above this level. The
fulcrum of movement moves to C3-C4 by the age of 5 to 6 years and to C5-C6, the same as in mature adults, by about age 15
years (592,598,670,671). Taking children as a whole, approximately 30% of injuries involve the upper cervical spine, 15%
involve the lower cervical spine, 30% involve the thoracic spine, and 20% to 25% involve the lumbar spine (670,672–674).
Younger children are more likely to sustain ligamentous injuries and have a significantly higher mortality rate following spinal
trauma than do older children (675).
The causes of spinal injury also vary with age. Cervical injuries in infants and toddlers usually result from falls, motor
vehicle accidents, abusive trauma, and falls; those in children aged 3 to 10 years result most often from falls, bicycle accidents,
and auto–pedestrian accidents; and those after age 10 years are most commonly the result of sports and automobile accidents
(671). As populations spend more time in motor vehicles, the causes and location of cervical spine injuries change. In the
United States in 2000, the majority of spinal cord injuries in the pediatric population were found in unrestrained children
involved in motor vehicles accidents (676). In such groups, more fractures and cervical spinal cord injuries in young children
were found in the lower cervical spine (C5-C7) than expected (677); however, the occiput–C2 remains the most common site
of injury for children less than 7 years of age (678).
As infants and young children have a propensity for spinal cord injury, an MR 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 referring
to up to 4 mm of anterior motion of C2 on C3 and C3 on C4 in up to 40% of children under the age of 8 years (679). 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 C2 (598,679), although this can be
greatly affected by the phase of inspiration and patient positioning. In adults, the prevertebral thickness measured on
radiographs is normally 5 to 6 mm at the C3 level (598), while evaluation with multidetector CT determined 7 mm as the upper
limit of normal at the C3 level in adults, with 18 mm the limit at C6 and C7 (680). Edema can be seen ventrally (usually a
result of fracture) or dorsally (as a result of ligamentous injury), and in either location, local soft tissue swelling (focal mass
effect) is most worrisome.
With the increase in use of multidetector CT as the primary imaging modality for pediatric cervical spine injuries, upper
limits of normal for prevertebral soft tissue thickness have been established. As expected, they vary with age and level. At
C2, maximum thickness is 7.6 mm (0–2 years), 8.4 mm (3–6 years), and 6.8 mm (7–15 years); at C6, thickness changes from
9.0 mm, (0–2 years) to 9.8 mm (3–6 years), 12.1 mm (7–10 years), and 14.5 mm (11–15 years). The upper limit of normal had
the highest variability at the C3 and C4 levels for all ages, ranging from 7.6 mm (C3, 3–6 years) up to 16.3 mm (C4, 11–15
years) (681).
Although neurological function at presentation remains the single best predictor of long-term neurological outcome
(682,683), children have a significantly greater recovery of function after spinal cord injury than do adults (684,685). MR is a
useful adjunct in the evaluation of spinal trauma, especially in children who have abnormal findings on radiographs or CT,
unexplained instability after normal studies in the acute phase, persistent or delayed symptoms, disturbances of consciousness,
or distracting injuries (686–689). In addition to demonstrating spinal cord injury or extramedullary hematomas, MR may show
swelling of prevertebral soft tissues, injury (seen as abnormal T2 prolongation) to interspinous soft tissues (Fig. 4-82) or the
posterior longitudinal ligament, or traumatic disc herniations, in addition to cord injury (690). These findings may affect
management in patients, although surgical stabilization is less commonly necessary in children (683,686). In addition, as
discussed in the section on neonatal spinal injury, MR findings are a sensitive indicator of the severity of spinal cord injury.
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. The worst prognosis for subsequent spinal cord function is in patients
who have intramedullary hemorrhage (610,612); therefore, it is recommended that sagittal or axial T2 gradient echo images be
obtained (see Figs. 4-68 and 4-69 in neonatal spine injury section). The next most severe MR imaging sign is the presence of
edema extending over more than one segment; this is best identified on sagittal T2-weighted images. Prognosis is best in those
patients without hemorrhage or edema and in those with edema involving one segment or less (610–613). 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 (691).
Figure 4-82 Interspinous ligament injury. Sagittal STIR through the midline in an infant shows T2 prolongation in the interspinous ligaments of
the midcervical spine (arrowheads). Focal subcutaneous edema and epidural fluid are also present posteriorly.
A great deal of literature has been concerned with the concept of spinal cord injury without radiologic abnormality
(SCIWORA) in children (592,593). However, it is not necessary to justify classification of SCIWORA as a separate entity, as
long as the radiologist and treating physician 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. Despite a recent paper noting that sports injuries
are currently the most common cause of SCIWORA in children (692), 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 avulsions, subluxation without fracture, growth
plate injuries, and epiphysial separations are common. Most spinal injuries in this age group involve the cervical spine.
Injuries, including fatalities caused by automobile air bags, fall into this category, particularly when children are improperly
restrained (693,694). Upper cervical injuries include atlantooccipital dislocations, which were frequently fatal in the past
(695); however, with improvements in on-scene resuscitation, immobilization, and transportation techniques, rates of survival
have increased (696), particularly in atlantoaxial dislocations, which tend to be less serious because of the more capacious
spinal canal at C1 (695). A combination of atlantooccipital dislocation and atlantoaxial dislocations can also be encountered.
It is important to remember that the synchondrosis between the dens and the body of C2 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 fracture through the bony dens,
but in a disruption of this synchondrosis, resulting in separation of the ossification center of the odontoid from that of the body
of C2 (697,698). Plain radiographs in active (not passive!) flexion and extension (performed carefully under physician
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 atlantooccipital injuries in children (Figs. 4-83 and 4-84) (699,700). A condylar–C1 interval at the point of greatest
separation in the midjoint in the sagittal plane measuring more than 2.5 mm unilaterally or the sum of the right- and left-sided
measurements greater than 5.0 mm indicates atlantooccipital dislocation (700). As discussed in Chapter 1, newer CT
technologies (such as automated dose modulation algorithms) allow spine CT to be performed at doses lower than previous
standards (701). It is also important to remember that only MR will reliably show an associated spinal cord or brain stem
injury (Figs. 4-83 and 4-84) (591,611,702,703). As discussed in the section on neonatal injury, the MR may show edema,
hemorrhage, or atrophy, depending upon the severity and chronicity of the injury (606). Long segments of edema, extensive
intramedullary hemorrhages, and persistent compression of the spinal cord all are predictive of poor neurologic outcome
(610,613,682,700). MR findings are highly correlated with chronic neurologic sequelae and may be a useful adjunct for
determining the neurologic level in children who are unable to cognitively engage in the International Standards for Neurologic
Classification of Spinal Cord Injury examination (704). Diffusion-weighted imaging and/or DTI in the acute setting may be
valuable in the evaluation of traumatic spinal cord injury (Fig. 4-84C and D) (705–707).
Figure 4-83 Upper cervical spinal injury. A. Sagittal reformation of C2 fracture shows fracture (large white arrow) at the synchondrosis
between the dens and body of C2. Note also the anterior position of the posterior arch of C1 (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.
Traumatic rotatory subluxations accompany rupture of the transverse ligaments and can become fixed. Diagnosis of fixed
rotatory subluxations is made by performing CT scans from the skull base to C2 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 C1-C2). 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 T11 to L2 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 (708). Soft tissue injuries, involving the
ligaments, cartilage, or growth plates, are more common. Soft tissue injuries can be most reliably identified with MR using
sagittal T2-weighted images with fat saturation and STIR; on the MR sequences, soft tissue damage is seen as areas of high
signal on T2-weighted images (709). Spinal cord injury is, of course, best seen on MR (Figs. 4-85 and 4-86). Seat belt
injuries, secondary to flexion–distraction (fortunately uncommon in the current era of shoulder and lap belt systems for all
passengers), tend to occur at the L2 to L4 levels (Fig. 4-85), lower than in older patients (710). The increased risk of serious
spinal injury in children under age 12 may be reduced by the use of age- and size-appropriate restraint systems, including
booster seats or similar positioning devices to improve seat belt fit in older children (711). Thirty to fifty percent of patients
are reported to have associated visceral injury (710,712). These primarily horizontal injuries may be difficult to identify on
axial CT images alone (713,714); routine reformations in the sagittal and coronal planes will increase detection, and 3D
reformations may be valuable for surgical planning. Burst fractures are uncommon in the pediatric population, with thoracic
level lesions having a higher incidence of neurologic injury than lumbar lesions (715). The combination of flexion–extension
radiographs and MR remains a useful combination in the diagnosis of spinal trauma.
Figure 4-84 Atlantoaxial 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 interspinous ligament at C1 to C2 (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 cervical spinal cord, with a more superior curvilinear hyperintense artifact. D. Sagittal ADC
map shows low intensity in same location to confirm the abnormally reduced diffusion in the spinal cord.
Adolescent injuries
Adolescents from ages 9 to 16 years sustain spinal injuries at a rate 10 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 (716). As children get older, they more often injure bone rather than exclusively soft tissues; these injuries
tend to be fairly evenly distributed through the cervical levels. Multilevel injury is more common in children 8 years and older
(717), while the C5-C7 levels are most frequently injured in adolescents (716,717). 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 in those with radiograph
abnormalities (598). Noncontiguous second level injuries have been reported to occur in the adolescent population at a higher
rate (~12%) than that of adults (~6%) (718,719).
Figure 4-85 Spinal injury secondary to motor vehicle accident. Sagittal T2-weighted image shows flexion–distraction injury centered at the L2
level causing an acute kyphosis, fracture (white arrow), and retropulsion, which narrows the spinal canal. Abnormal hyperintensity is present in
and between the spinous processes of L1 and L2 (black arrows), indicating ligamentous and osseous injury at those sites. Note also the
extensive subcutaneous edema. (This case is courtesy of Dr. Adam Flanders, Philadelphia, PA.)
Figure 4-86 Spinal cord injury secondary to motor vehicle accident. Radiographs were normal. Sagittal T2-weighted image shows focal
hyperintensity (arrow) of the lower spinal cord, indicating a contusion. No osseous or ligamentous injury was present.
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 consider flexion–extension radiographs, especially in younger adolescents. Sagittal T2-weighted MR 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 (641,709). 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 MR than on radiographs (720). This finding is important in surgical planning
(721). Although radiographs and CT are adequate for evaluation of bone injuries, MR is essential to determine the presence
and extent of spinal cord injury (Fig. 4-86) and, thus, to establish a prognosis (722,723). 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 (610,611,613).
Another syndrome that is relatively unique to children and adolescents (and reported in only one infant to date) is
posttraumatic spinal cord infarction (724–726). The putative mechanism is fibrocartilaginous embolism from the nucleus
pulposus (726). Typically, patients have onset of neurological signs several hours to several days after the injury, and
infarction may become evident after only minor trauma. Para- or quadriparesis and dissociated sensory loss then ensue;
prognosis is variable. Radiographs, CT, and myelography are normal (724,725). MR will show anterior spinal artery
infarction, manifested as T2 prolongation in the anterior half to two-thirds of the spinal cord (Fig. 4-87A and B) or as
hyperintensity in the ventral gray matter of the cord with a varying degree of disc desiccation or T2 hypointensity at adjacent
level(s). Diffusivity will be reduced in the acute/subacute phase (Fig. 4-87C). Imaging in the subacute phase may show
enhancement of the infarcted region.
Patients with certain genetic abnormalities are predisposed to spinal cord injury as a result of ligamentous laxity, osseous
defects, spinal stenosis, spinal kyphosis, or stenosis of the foramen magnum. Included in this group are patients with Down
syndrome (see Chapter 5), mucopolysaccharidoses (especially Morquio syndrome; see Chapter 3), achondroplasia (see
Chapter 8), Klippel-Feil syndrome (see Chapter 9), 22q11.2 deletion syndrome, and spondyloepiphyseal dysplasia. These
patients should be observed for neurologic dysfunction and neck pain in a longitudinal fashion and should be carefully
examined after even minor neck trauma (604,727,728).
Torticollis/rotational deformities of C1-C2
Torticollis is a common problem of childhood. Most cases have no radiologic abnormalities and resolve spontaneously when
treated conservatively. Rarely, the deformity persists, due to anatomic derangements 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 sternocleidomastoid, 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 (729,730). This condition is discussed further
in Chapter 7. Benign paroxysmal torticollis of infancy is a disorder of uncertain etiology (possibly migraine related) that is
likely underdiagnosed and consists of brief, repeated episodes of unusual sustained posture of the head and neck. It is self-
limited and episodes are often accompanied by autonomic features, crying, agitation, ataxia, and drowsiness (731). Affected
infants have a strong family history of migraine headache, possibly associated with CACNA1A mutations (732) and have
shown a high incidence of gross and fine motor delays (733). Locally painful neck conditions that cause torticollis include
lymphadenitis and other cervical inflammatory processes, cerebellar tonsillar ectopia (Chiari I malformations), and tumors of
the cervical spine and posterior fossa (674).
The other major cause of torticollis in childhood is rotatory subluxation of the atlantoaxial joint, which can progress to
fixation. Rotation of the head largely relies on motion at the atlantoaxial joint; indeed, 50% of total neck rotation occurs at this
level (734,735). In rotatory subluxation or fixation of C1-C2, the normal rotation becomes limited, possibly due to
inflammation of the synovium or spasm of the sternocleidomastoid muscle. Most cases occur in children below the age of 13
years (735). Patients typically present with sudden onset of torticollis, often with a history of minor trauma, otitis media, upper
respiratory infection, or a recent procedure of the head or neck (736).
Diagnosis is made by CT (737,738). Plain films are difficult and confusing because of the inability of the patient to
straighten the neck (674). 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 subluxation or fixation is present, there will be no significant motion of C1 on C2 in one direction. If the torticollis is
due to other causes, some rotation will be present. Sedation may be valuable, as muscle spasm may preclude significant
motion, and the muscle is relaxed by the sedation. If rotatory subluxation or fixation is found, the patient is treated with
reduction and immobilization; surgery may be necessary if the deformity persists, or if neurological deficits are present (739).
Figure 4-87 Spinal cord infarction; subacute 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.
Fielding and Hawkins have divided rotatory fixation into four categories for the purposes of prognostication (740). Type I is
the most common and has the lowest incidence of neurological impairment. Rotatory fixation is present without displacement
of C1. In type II, rotatory fixation is associated with anterior displacement of 3 to 5 mm of C1. In type III, anterior
displacement of C1 is more than 5 mm. In type IV, posterior displacement of C1 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 problem. 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 spondylolisthesis, intervertebral disc herniation, intervertebral disc degeneration, and Scheuermann disease.
Spondylolysis and spondylolisthesis are identical in children and adults and will not be discussed here, other than to note the
increasing use of MRI rather than CT in pediatric patients due to radiation concerns (741,742). Scheuermann disease is a
poorly understood phenomenon that is discussed in both pediatric radiology and bone radiology texts and, similarly, will not
be discussed here.
Intervertebral disc herniations in children are similar to those in adults with four exceptions. (a) The size of disc
herniations is larger in children than in adults (743–745). (b) Lumbar disc herniation in children is more commonly associated
with structural malformations, such as elongated L5 transverse processes or transitional vertebrae (746). (c) 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 MR than on plain radiographs (720). This finding is important in surgical planning (721).
(d) Pediatric disc herniations may be calcified (747–749), possibly because of accompanying discitis (748); the true incidence
is likely underestimated (750). The presence of a calcified disc does not change treatment, which is almost always
conservative. It is important to remember two facts when a disc herniation is seen in children: first, most children with disc
herniations are asymptomatic (750,751), and 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 (751,752). MR 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 (752). Although the incidence 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 multidetector CT is
extremely fast and easily obtained; it is sensitive in detection of intra- 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 sitting as the head scan.
As of this writing, the ACR appropriateness criteria for head trauma (child) rate CT higher than MRI (753). We obtain 2.5- to
3-mm thick sections from the vertex to the C3 vertebral body in most pediatric trauma patients. The reason for obtaining images
in the upper cervical spine is the high propensity for injury in this region in younger children (594,664,697,698). Given the
theoretical 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 (631,754,755). While the US (PECARN) trial has been validated, the Canadian (CATCH)
and UK (CHALICE) trials have not yet been validated at the time of this writing. One direct comparison study indicated that
the PECARN clinical decision rule was 100% sensitive for “clinically important traumatic brain injury” in children,
CHALICE was more specific but only 84% sensitive, while CATCH was 91% sensitive but not very specific (756). The
reader is reminded that the PECARN prediction rules rely on accurate patient history and, as a result, do not apply in the
setting of suspected abusive head trauma (757). Much work is also being done to identify a biomarker, such as GFAP or
S100β, for pediatric brain injury; however, a sensitive and specific marker or panel of markers has yet to be validated
(758–762).
In the interest of reducing radiation exposure, some centers advocate rapid MR screening sequences, such as multiplanar
FSE and T2* acquisitions, as first-line imaging for the acutely traumatized child; however, the sensitivity and specificity of
these techniques are variable, and skull fracture detection rate is low (576,663,763,764). Implementation of this approach
requires that screening for the presence of metal and contraindications to the MR environment does not result in unacceptable
delays in imaging, diagnosis, and treatment.
As with neonates, MR (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 (606,703,709). Indeed, magnetic resonance more
sensitively assesses the full extent of damage to the brain (765). MR has been proven to be more sensitive than CT in the
detection of small extra-axial fluid collections and white matter shearing injuries (576,585,641). Brain stem injuries, which
have important prognostic significance, are better detected by MR (586,587,766). Moreover, MR is extremely sensitive to the
presence of both acute hemorrhage and hemosiderin from old hemorrhage (585,654,667), particularly with the use of SWI
(585); the presence of older CNS injuries in association with newer ones presents important evidence in the diagnosis of
abusive head trauma. In order to detect hemorrhage with maximal sensitivity, T2 gradient echo images or, preferably,
susceptibility-weighted images (585,666,667,767) should be obtained in all trauma or suspected trauma cases; SWI has been
shown to be superior to T2 gradient echo imaging for hemorrhage detection, even in the setting of mild traumatic brain
injury (768). DTI shows reduced water diffusivity in the acute and subacute phase and increased water diffusivity with
reduced FA of white matter pathways in the chronic phase. Performing DTI should always be considered when MR is
performed in trauma cases (769–772). When performed with many (more than 25) diffusion-encoding directions, DTI finds
many more injuries than does FLAIR or susceptibility-weighted images (769) and may contain important prognostic
information (773–775); DTI may also be valuable for cognitive outcome prediction (776,777). Additional advanced imaging
techniques, including high angular resolution DWI, arterial spin-labeled perfusion, and resting-state functional MR for the
assessment of acute and chronic traumatic brain injury, suggest alterations in structural integrity, perfusion, and functional
connectivity, respectively, but remain largely experimental at this time (778–783). Proton MR spectroscopy can aid in
determining the severity of parenchymal injury in the subacute and chronic phases to determine the severity of parenchymal
injury (771,784). 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 (785–787).
Extraparenchymal hematomas
Epidural hematomas are uncommon in infants and increase slowly in incidence throughout childhood to reach peak incidence
in adults (604). 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 (788,789) and in younger children than in
adolescents (790). In young children, epidural hematomas 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 (143)); in older children and
adolescents, arterial causes are far more common (604). The difference in clinical presentation results from two factors: (a)
the pediatric skull is more pliable than is the adult’s and can expand as a posttraumatic hematoma accumulates (791); and (b)
intradural injury is uncommon (790). As a result, the clinical presentation does not evolve as rapidly. Moreover, in
contradistinction to adults, in whom the head injury characteristically induces a loss of consciousness, children more
commonly are only stunned by the injury. This necessitates consideration of early imaging 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 historically high, the outcome and prognosis following epidural hematoma are
generally very good after rapid radiological identification and surgical decompression (788). In a large pediatric series,
patients with epidural hematomas of less than 15 mL on initial CT scan, no mass effect, and no neurological deficit were not
immediately surgically decompressed; patients were found to be at low risk for progressing during observation (792).
The findings of epidural hematomas in children on CT and MR are identical to those of adults. CT will usually reveal a
lentiform hyperdense extraparenchymal collection that does not cross cranial sutures, other than in the uncommon instance
when the suture is violated by a fracture or traumatic diastasis (Figs. 4-88 and 4-89) (793). Skull fractures and soft tissue
swelling are often present overlying the hematoma. Contusions may be present in the subjacent brain parenchyma or in a
contralateral location (contrecoup injury). If the fracture extends into the mastoid air cells or a paranasal sinus,
pneumocephalus may be seen (Fig. 4-89). If the fracture is in the frontal bone and extends into the orbital roof, a subperiosteal
orbital hematoma may develop, sometimes resulting in acute proptosis; loss of vision may ensue unless the hematoma is
expediently decompressed. On MR, the hyperacute hematoma is typically dark on T1-weighted images and bright on T2-
weighted images. The acute hematoma is generally bright on T1-weighted images and dark on T2-weighted 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 the brain on T1-weighted images and dark on T2-
weighted images (658). Retroclival hematoma (typically epidural), with or without tectorial membrane injury, is more
commonly seen in children than adults, both in the setting of accidental and abusive head trauma (794,795).
Figure 4-88 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).
Subdural hematomas are most common in infants and elderly adults and are less common in older children and adolescents
(796). They result from tears of cortical veins bridging the subdural space on their way to the dural sinuses. The soft
consistency of the unmyelinated brain results in increased brain distortion during trauma and puts increased stress upon these
veins (604). 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 (604,791,797–800). Other factors predisposing to hematomas include blood dyscrasias and
prematurity (801). Infants with benign enlargement of the subarachnoid spaces have been reported to be at increased risk for
subdural hematoma; however, this remains controversial, and an evaluation to assess for abusive trauma should be undertaken
when encountered without appropriate clinical history (802–805). In a more recent series, children less than 2 years old with
benign enlargement of the subarachnoid spaces and an accidental fall of less than 6 ft. were more likely to have
subarachnoid/subpial or multicompartment hemorrhage than were controls, but not isolated subdural hemorrhage (806).
Figure 4-89 Epidural hematoma with pneumocephalus secondary to mastoid 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.
Infants with subdural hematomas have been reported to present with seizures, vomiting, hyperirritability, lethargy, or
progressive head enlargement (799,807,808). 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 (807,809,810). If children 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 (811).
Imaging appearances of subdural hematomas in children are identical to those in adults. In the acute phase, CT will typically
show a high attenuation extraparenchymal crescentic fluid collection over the frontoparietal convexity that typically crosses
cranial sutures (Fig. 4-90). Within 1 to 3 weeks after the hemorrhage, the blood generally becomes isodense with brain tissue.
At this stage, compression of the ventricles and medial displacement of the gray–white junction with compression of the white
matter will indicate presence of the extra-axial fluid collection (Fig. 4-91A). If intravenous contrast is given, the inner and
outer membranes of the subdural hematoma will enhance (Fig. 4-91B) (641). It is essential to recognize shift of the ventricles,
medial displacement of the corticomedullary junction, and medial displacement of the cortical sulci at this state (634,812).
Patients with visible subarachnoid spaces on the side of the subdural hematoma may have a better prognosis (813). After 2 to 3
weeks, the density of the hematoma will typically be lower than that of the 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 (634). On MR, the signal intensity of the extra-axial fluid collection has been generally
understood to evolve as those described for the epidural hematoma in the previous section (Figs. 4-88 and 4-90), although a
systematic review of the imaging characteristics of subdural hematomas in children and adults demonstrated broad and
overlapping time intervals for the various MRI signal intensities (814). While they also found the evolution of subdural
collection density on CT to be fairly broad and overlapping, there was a significant difference between children and adults,
with children having shorter durations of each stage of density (hyper-, iso-, and hypodense); however, all densities were seen
in children from the time of injury (time 0). Fluid–fluid layers are often present as a result of layering of the blood cells in the
dependent portion of the subdural collection (see Fig. 4-75A). MR is also useful in the identification of injury to the underlying
parenchyma (such as axonal shearing injuries, contusions, and infarctions; see subsequent section) that commonly accompanies
traumatic subdural hematomas (Figs. 4-90 and 4-92) (576,582–586,665).
Figure 4-90 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 collection,
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.
Diffusion-weighted image (b = 1000 s/mm 2) shows reduced diffusivity, manifested as high intensity (black arrows) in the left lateral frontal lobe
and left posteromedial parietal lobe.
Figure 4-91 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.
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 (641,654). 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.
Subarachnoid hemorrhage
Subarachnoid hemorrhage often accompanies intraparenchymal damage in both the child and the adult. In the acutely injured
child, CT remains the imaging study of choice to detect the hyperdense subarachnoid blood, although the use of MR in the acute
trauma setting is increasing, as discussed above. In the acute phase after injury, when nonhemorrhagic parenchymal lesions are
difficult to identify by CT, subarachnoid hemorrhage may be the harbinger of more severe underlying brain damage, having
been shown to correlate with higher injury severity (812,815,816). Routine T1- and T2-weighted MR sequences are not
sensitive for the diagnosis of acute subarachnoid hemorrhage, probably because the hemoglobin is less concentrated than in
clotted blood and the high oxygen tension of CSF inhibits the conversion of hemoglobin to deoxyhemoglobin and
methemoglobin (654,817,818). FLAIR and susceptibility-weighted sequences are more sensitive to both acute and subacute
hemorrhage (585,819,820) and should be utilized to search for subarachnoid blood if an MR is obtained; T2 gradient echo
imaging should be performed if SWI is not available or if a more rapid sequence is needed. 3D double inversion recovery
sequence has been reported to have even higher sensitivity for subacute subarachnoid hemorrhage (577). 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 SWI, subarachnoid hemorrhage will appear hypointense, in comparison with the hyperintense CSF (819).
It is important to remember, however, that rapidly flowing CSF (such as that around the foramina of Monro, the aqueduct of
Sylvius, and the prepontine cistern) will commonly 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 subarachnoid space. Traumatic subarachnoid
hemorrhage is most commonly seen in the posterior interhemispheric fissure, adjacent to the falx cerebri (Fig. 4-92), or
layering along the tentorium cerebelli. Blood along the tentorium is best demonstrated in the coronal plane; sometimes, this
increased attenuation is the only abnormality seen on the CT scan. 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 (821) (Figs. 4-93 and 4-94). 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 itself can have a high attenuation on CT. The falx, however, should be thin and regular in contour, and no extension of
the high attenuation into the cortical sulci should be seen.
Figure 4-92 Subdural hemorrhage and cerebral infarction secondary to abusive head trauma. A and B. Axial CT image shows the high
attenuation of blood (black arrow) in the right frontal lobe secondary to hemorrhagic contusion. The putamina and the posterior portions of the
middle cerebral artery distributions of the cerebral hemispheres are hypodense bilaterally (white arrows) secondary to infarction. Mixed-density
subdural hematomas are present over both cerebral convexities (arrowheads). Note also the linear, hyperdense subdural blood along the left
side of the posterior interhemispheric fissure and the tentorium bilaterally.
Figure 4-93 MR of severe head trauma; brain CT was normal. A. Coronal fat-suppressed FLAIR image shows two right frontal cortical
contusions (white arrows) and bilateral deep white matter axonal shearing injuries (white arrowheads). B. Axial GRE T2 image shows low-
intensity foci (arrows) in the bifrontal regions of white matter injury. These regions also demonstrated reduced diffusion and are likely foci of
hemorrhage. C. Axial Dav map shows marked hypointensity (white arrow), indicating reduced diffusivity, in a contusion of the splenium of the
corpus callosum.
Figure 4-94 Traumatic injury with subarachnoid hemorrhage and parenchymal injury. A. Axial CT image shows subarachnoid blood in the
ambient cisterns (large solid black arrows) and 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.
Figure 4-95 Trauma in an infant; 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 cerebellopontine 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 peripheral 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).
Parenchymal lesions resulting from head trauma include cerebral contusions and white matter shearing injuries (639,828).
Cerebral contusions are bruises of the brain most commonly caused by deceleration injuries in which the brain forcibly
contacts the rough edges of the skull in the anterior temporal and orbitofrontal regions (Fig. 4-96) (630,829). They may also
result from direct impact transmitted through the skull (Figs. 4-93 and 4-95); they are less common in children than in adults
(830,831). 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 (641). Because the unmyelinated brain is less rigid than is the
mature brain (and consequently more susceptible to distortion) and because the subarachnoid spaces are more capacious,
shearing injuries are a more common consequence of rotational injury in infants and young children. Indeed, as compared to
frontal impact, lateral impact, with a greater rotational component, has been reported to have an 11-fold increase in the
incidence of diffuse axonal injury (832).
Shearing injuries most commonly occur at the junction of the gray and white matter, in the deep white matter of the centrum
semiovale, in the corpus callosum, in the internal capsule, in the basal ganglia, and in the brain stem (Figs. 4-93 and 4-96)
(630,639,665,828,833). IVH on CT at presentation is a strong predictor of the presence of severe diffuse axonal injury (834).
Many of the brain stem lesions will be missed unless MR is obtained (586,766); as the presence of brain stem injuries strongly
correlates with outcome, as indicated by the Glasgow Coma Scale, MR should be considered in all children with severe head
injury or coma (587,766). Diffusion-weighted imaging should be utilized in the acute to subacute stages, primarily for
subjective evaluation. Quantitative assessment of diffusion metrics is not as widely used clinically; however, mean ADCs from
regions of normal-appearing white matter on T2 and FLAIR images may be predictive of long-term outcome in children with
traumatic brain injury (835). Findings should be interpreted cautiously, as they vary over time: increases in FA seen with DTI
within 3 days of mild traumatic brain injury can normalize by 1 month postinjury (836), while small decreases in cortical
volume and increases in ventricular volume develop simultaneously, without evidence of microhemorrhages, on SWI (836). As
discussed below, DTI might be the best way to assess for shearing injuries in the chronic phases, as the microstructural
changes alter both mean diffusivity and FA (769,771,825,837,838). 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 (769,839).
CT is sensitive in the diagnosis of hemorrhagic cerebral contusion in the acute phase and during the early hemorrhagic
conversion of bland cerebral contusions because it is sensitive to the presence of large areas of acute blood within the brain
(Figs. 4-90 and 4-94) (829,833) and to the accompanying extra-axial hematomas (Figs. 4-88 and 4-90) or air
(pneumocephalus) that may be present (Fig. 4-89); moreover, the patient is easily monitored and assessed during a CT scan.
Thus, as stated earlier, CT 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 is MR in the detection of contusions (hemorrhagic or nonhemorrhagic; Figs.
4-93, 4-95, and 4-96) and axonal shearing injuries, particularly in the subacute and chronic phases of injury (576,585).
Therefore, MR 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. 4-93 and 4-95) (825,826). Hyperacute
hemorrhage (in the first hours after injury, when blood largely remains in the oxyhemoglobin configuration) will appear on
diffusion-weighted 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 (657). In the subacute and chronic
phases, a combination of T2-weighted scans, FLAIR, and susceptibility-weighted images is most sensitive to both the
nonhemorrhagic and hemorrhagic injuries that are present at the site of prior contusions and shear injuries (576,585).
Susceptibility-weighted images (585,667,767,840) are the most sensitive sequences for detecting products of hemorrhage
(Figs. 4-96 and 4-97) and, therefore, are an essential adjunct in the MR examination of trauma victims. Fewer lesions on
susceptibility-weighted images seem to correlate well with better neurological outcome (666,771). Fast/turbo spin-echo and
FLAIR sequences are relatively insensitive to the presence of intraparenchymal blood (Fig. 4-89) at 1.5 T and should not
relied upon to exclude parenchymal hemorrhage in the setting of trauma; 3 T MRI is far superior and should be used if
available. FLAIR is useful to assess the full extent of white matter injury in older children, but in neonates and young infants,
FLAIR may be insensitive to parenchymal injuries of all kinds (Figs. 4-83 and 4-90). If the MR is performed at 3 T, acute and
subacute blood may be seen as hypointense on RARE and FLAIR sequences (841); however, the addition of SWI at 3 T
increases sensitivity for microhemorrhage (see Fig. 4-96G–I) (840). 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 does normal brain), low signal intensity (residual blood breakdown
products from previous hemorrhage: Fig. 4-96B and C), or both. Both subacute and chronic hemorrhagic injuries have low
signal intensity on gradient echo scans with long echo times (Fig. 4-90) and on susceptibility-weighted images (Figs. 4-96 and
4-97) (667); however, blood products may show heterogeneity and/or high signal on SWI, particularly if substantial
hyperintensity is seen on T1-weighted imaging (842). The presence of lesions in characteristic locations (e.g., orbitofrontal
surface of the frontal lobes and anterior temporal lobes) is strongly suggestive of prior trauma. Moreover, the location and
number of injuries within the brain may be of prognostic value in terms of how much recovery of normal brain function can be
expected. Prognosis is probably predicted best by the use of advanced imaging methods, as described below.
Severe swelling of the brain or midline shift suggests a guarded prognosis (822,843,844) as does the presence of the
“reversal sign” in which cerebral white matter has a higher attenuation than does cerebral gray matter (Fig. 4-54) (510,511). It
is difficult in this acute phase to detect axonal shearing injuries by CT. Therefore, one cannot determine whether diffuse
cerebral swelling is the result of increased blood volume or axonal shearing injuries (604,845). Perfusion imaging, proton MR
spectroscopy 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 be visible, even with CT, if the brain has suffered significant injury, but the
swollen brain may return to a “normal” appearance if neuronal damage has not occurred; be aware, however, that quantitative
measures may reveal subtle volume loss (836). Follow-up standard MR scans of children with mild head injury will appear
normal at 3 months after the injury. Of children with moderate to severe closed head injury and, therefore, an overall poorer
prognosis, children with bilateral frontal lobe lesions at follow-up were found to be more frequently neurologically and
psychologically disabled than those with diffuse injury (846). Children with unilateral frontal lobe lesions (independent of
side) had impaired behavioral functions, as well as a higher frequency of maladaptive behavior, but no impact on cognitive
function was found (847). When imaged in the chronic phase, 3 months after injury, the finding of brain stem injury (T2
prolongation from astrogliosis or evidence of hemosiderin accumulation) portends a poorer prognosis (848). Cerebellar
damage, frequently underappreciated in the setting of major supratentorial injury, has been associated with overall lower
cognitive performance, dyscalculia, and lower visual recognition memory scores (849).
As indicated in the previous paragraphs, more recent evidence suggests that MR diffusion tensor imaging (DTI), MR
spectroscopy (MRS), and susceptibility-weighted imaging have a role in the acute phase to differentiate swelling from acute
axonal shear injury (850,851). Indeed, in the chronic phase, DTI and MRS correlate better with clinical outcome than do any
anatomic imaging sequences, although results have been inconsistent (769,837,851,852). Diffusion-weighted imaging (DWI;
Figs. 4-90 and 4-95) demonstrates reduced microscopic water motion (average diffusivity or Dav) in injured regions of the
brain (increased signal 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 diffusivity (decreased intensity on diffusion-weighted
images and increased intensity on Dav images). DWI may detect abnormalities (manifested as reduced Dav) more than 2 weeks
after injury (772). In addition, studies suggest that reduced fractional anisotropy, as assessed by DTI, may be an early and
more sensitive method of detecting axonal injury (769,825,837,851–853). In the chronic phase of injury, the presence of
reduced anisotropy in specific white matter tracts correlates with the Glasgow Coma Scale (837,851,852) and measures of
learning and cognitive performance (769,838). Proton MR spectroscopy (MRS) may be useful in differentiating swelling
secondary to increased blood volume from swelling secondary to shearing injury; the spectrum is nearly normal in the absence
of parenchymal injury but shows decreased NAA and increased choline, lactate, and glutamate/glutamine within the first 2 to 4
days after injury if significant neuronal injury has occurred (854–857). Indeed, animal studies indicate that NAA is reduced as
early as 1 hour after injury (858,859). NAA/Ch levels seem to correlate well with cognitive outcome, particularly when the
frontal lobes are sampled (860) and lower NAA/Ch ratios, higher Ch/Cr ratios, and the presence of lactate all correlate with
poor outcome (771,855,861,862). Indeed, proton MRS shows reduced area under the NAA peak (indicating impaired
intracellular metabolism in the voxel) even in patients with mild brain injury and normal MR imaging studies (784). SWI, a
high spatial resolution, three-dimensional gradient echo technique in which alterations of phase are amplified (863) (see Figs.
4-96 and 4-97), is even more sensitive to blood products than are standard gradient echo images, showing tenfold more
hemorrhagic lesions in one study (667,767) and studies in small groups that show correlations between the number of lesions
detected by SWI and the location of lesions, with clinical outcome (585,767,771,864). SWI has become a highly valuable
sequence for initial assessment of shearing injuries, and follow-up high-resolution SWI studies performed at ultrahigh field
strengths (3 T and 7 T) can show over 40% more lesions than seen with routine sequences (865). Cerebral perfusion, as
assessed by arterial spin labeling (ASL) perfusion imaging, has not been studied in children with acute traumatic brain injuries,
as of this writing. Findings regarding the utility of CT perfusion in adults with severe traumatic brain injury may be cautiously
extrapolated to a pediatric population; perfusion imaging in the acute phase shows significantly reduced local perfusion in
cerebral contusions, and lower rCBV values accurately predicted poorer outcome at 3 months follow-up (866).
Figure 4-96 Trauma; value of SWI and diffusion imaging in detecting hemorrhagic injury. A–D are images from a 3-year-old boy who was in
an auto accident without being properly secured in the car. F–G are from a teenager with a similar story. A. Axial CT shows areas of low
attenuation (white arrows) along the orbital surface of the right frontal lobe. Blood is present in the anterior right temporal lobe (arrowhead). B.
Axial FLAIR image shows more contusions and blood (low intensity, white arrow) in the large injury above the right orbit. C. Axial T2-weighted
image shows many more foci of high and low attenuation hemorrhage (white arrows) bilaterally in the frontal lobes. D. Axial ADC map shows
high diffusivity (high signal intensity), suggesting that this injury is subacute or chronic. E. Axial T2-weighted image in an older (teen) patient
shows a large contusion in the splenium of the corpus callosum (black arrow). A thin subdural hematoma is present over the right posterior
cerebrum (white arrows). A small injury is present in the left frontal white matter. Note the right parietal scalp hematoma. F. Axial diffusivity (Dav)
image shows the splenial contusion more conspicuously (black arrow) and additional sites of shearing injury in the left perisylvian region
(arrowheads). G–I. Axial SWI shows many more foci of low attenuation hemorrhage bilaterally in the frontal lobes, right temporal and occipital
lobes, the cerebellar vermis, and both parietal lobes. The hemorrhagic contusion in the splenium of the corpus callosum is well seen (black
arrow), but the subdural hemorrhage (white arrows) is more difficult to discern adjacent to the hypointense calvarium.
Figure 4-97 Abusive trauma; value of SWI and diffusion imaging. A. Axial Dav image shows two foci of contusion in the splenium of the
corpus callosum (arrowheads). B–D. Axial SWI images show multifocal regions of hemorrhage not seen with other sequences, including in the
right frontal white matter and left thalamus (arrowheads) as well as the body of the corpus callosum and the left posterior frontal lobe.
Associated injuries
Although injury to the brain is the primary concern after head trauma, it is important to assess the facial bones, orbits, temporal
bones, and, as already mentioned, craniocervical junction in all affected children. Orbital injury is of particular consequence,
as it may result in transient, or permanent, loss of vision, particularly if CT discloses the presence of intraorbital hematomas
(highest risk for intraconal or posterior globe hematomas), intraconal air, or fracture of the optic canal (867). Injury to the
petrous bone may result in longitudinal > transverse > mixed fractures or in ossicular dislocations. These may result in
sensorineural or conductive hearing loss, loss of balance, vertigo, facial nerve paralysis, or, rarely, other cranial nerve injuries
(868). CT is optimal for evaluation of the petrous bones, while MRI is useful to assess for orbital trauma in children, as
injuries are well seen and it spares irradiation of the globes.
Sequelae of trauma
The sequelae of trauma include infarction from severe brain edema and vascular injury, infections, leptomeningeal cyst
formation, inflammation, and hydrocephalus (869–871). 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 subarachnoid blood. In children, it is sometimes impossible to differentiate communicating hydrocephalus from
cerebral atrophy, which can also result from trauma, by imaging. Both can appear as dilation of the cerebral ventricles and
sulci on imaging studies, and both can result from severe cerebral injury (872). Differentiation can sometimes be made by
careful analysis of the contours of the third ventricle (see Chapter 8). Alternatively, diagnosis can be made by monitoring
intracranial pressure or by a radionuclide flow study. The radiolabeled compound is injected into the spinal subarachnoid
space via lumbar puncture. If flow of the radionuclide upward over the cerebral convexities is not seen by 24 hours after its
injection or if the radionuclide is seen within the lateral ventricles at 24 hours after injection, there is very likely a block to
CSF flow and hydrocephalus (873–875). Of course, the most important features are clinical: an enlarging head size and sutural
splitting indicate hydrocephalus, whereas a decreasing 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 (791). Hydrocephalus can also be a
complication of traumatic cervical spine or skull base injury. Survivors of atlantooccipital dislocation are at high risk for
postoperative hydrocephalus; brain imaging should be considered if the patient experiences a neurological decline following
spinal fixation (876).
Vascular complications of head injury include carotid–cavernous fistulas, arterial dissections, and venous sinus occlusions.
Signs and symptoms of carotid–cavernous fistulas include pulsating exophthalmos, deficient ocular motility from multiple
cranial nerve palsies, and, sometimes, blindness or subarachnoid hemorrhage. Catheter angiography is necessary for both
diagnosis and treatment (see Chapter 12). Arterial dissections can present with obtundation, mono- or hemiparesis, dysphasia,
or Horner syndrome (see Chapter 12). T1-weighted MR of the skull base/neck with fat saturation is very sensitive in
establishing the diagnosis of dissection. A crescentic rim of hyperintensity, presumably methemoglobin, will be seen in the
vessel wall. MRA or CTA may show intimal irregularities that allow the diagnosis to be established. Diagnosis of dissection
on cross-sectional imaging typically obviates the need for catheter angiography. CT or MR is essential to diagnose associated
cerebral infarction. Venous sinus occlusion can be diagnosed by MRV, CT venography, or intravenous digital subtraction
angiography, as described in Chapter 1 on techniques and Chapter 11 (“Complications of Meningitis” section).
Infection is an uncommon complication of brain injury. When infection does occur, it is usually in the form of meningitis,
secondary to bacterial seeding from basilar skull fracture, or cerebritis/abscess from penetrating injuries. The latter is
extremely rare in children and is diagnosed from postcontrast CT or MR examinations (see Chapter 11). To diagnose a CSF
leak from a basilar skull fracture, CT cisternography following intrathecal contrast administration can be performed, acquiring
direct coronal, thin (<2 mm) sections from the frontal sinuses through the temporal bones. If the patient is actively leaking,
contrast can usually 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 MR imaging (CISS, FIESTA) and intrathecal contrast-enhanced MR
cisternography, are less established 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 (877–879).
The role of inflammation in contributing to the neurologic sequelae of traumatic brain injury is not well understood.
Evidence suggests that inflammation can have both detrimental and beneficial effects following 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
(870,880). In the future, targeted anti-inflammatory agents may aid in the prevention of secondary insults following traumatic
brain injury, but to date, neuroprotective trials have failed due to widespread immune suppression (880).
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. Even when the CT is normal and the child is without neurological signs or symptoms, many suggest that the high
sensitivity of MRI with diffusion imaging can detect clinically significant injury when CT findings are subtle
(585,587,768,864,896,922,923). The utilization of brain and spine MRI for medical–legal documentation purposes should not
be discounted, potentially including aiding in the timing of hemorrhages (920,924). Follow-up CT scanning has been reported
to be most valuable in children with new alterations in neurological status, positive findings on prior imaging, moderate to
severe initial injury severity, or coagulopathy; although about 30% of repeat CT scans show new or worsening findings,
however, neurosurgical intervention following repeat imaging is rare (925). If the early MR showed brain parenchymal injury
or if neurologic abnormality persists, then some authors recommend follow-up MR after 2 to 3 months to look for enlarging
subdural collections, hydrocephalus, or a developing leptomeningeal cyst (920).
Imaging Findings
In children aged 6 years and under, subdural hemorrhage, cerebral ischemia, retinal hemorrhage, and skull fracture with
intracranial injury are the intracranial imaging findings significantly associated with abusive head trauma (903). Epidural
hemorrhage(s), scalp swelling, and isolated skull fracture(s) are more significantly associated with accidental injury, while
subarachnoid hemorrhage(s), diffuse axonal injury, and cerebral edema are not significantly more associated with intentional
or accidental trauma (903,926). Unilateral hypoxic–ischemic injury has also been reported in young children with abusive
head trauma, even in the absence of vascular or spinal cord injury (927); the mechanism for this is unclear and may be related
to cervical vascular compression, due to either direct strangulation or hyperflexion/hyperextension.
Figure 4-99 Use of 3D CT reformation in head trauma. A and B. Axial noncontrast CT bone images demonstrate a linear fracture extending
into the parietal bone from the temporosquamosal suture (arrowheads). C. 3D surface rendered reformation in bone algorithm unequivocally
shows the oblique linear fracture (arrows) through the right parietal bone and the junction with the temporosquamosal suture (arrowhead).
Subdural hemorrhage is one of the most common intracranial manifestations of abuse, and its presence in any young child
without an appropriate history is strongly suggestive of abusive head trauma. Subdural hematomas are particularly suggestive if
seen in conjunction with intraparenchymal hemorrhages of varying ages (such as acute subdural and chronic intraparenchymal
hemorrhage) because the presence of injuries of different ages suggests repeated trauma. Other findings suspicious for abuse
include multiloculated hematomas, presence of a fluid–fluid layer in the acute phase (suggesting hemorrhage into a preexisting
subdural hematoma; Fig. 4-98), and subdural hematomas in association with severe retinal hemorrhage, particularly absent
signs of impact; these have been reported to be highly specific, albeit not very sensitive, for abusive head trauma
(864,903,928). The “tadpole” or “lollipop” sign on CT, MR, and/or MRV (Fig. 4-100), indicative of direct bridging vein
injury and thrombosis in association with a subdural hematoma or hygroma, has recently been reported as a strong indicator of
abusive head trauma in the absence of an appropriate accidental trauma history (922,929,930). The oval- to round-shaped
“body” of the tadpole represents thrombotic material within the subarachnoid or subdural space, and the bent “tail” reflects the
torn bridging vein expanded by clotted blood; typically, the “tadpole” appears hyper- to isodense on CT, hyperintense on T1-
weighted MRI, and iso- to hypointense on T2-weighted MRI (929). A series of children 3 years of age and younger with
abusive head trauma has recently revealed retroclival fluid collections (subdural and/or epidural) to be common; these were
previously thought to predominately be seen following major accidental trauma, such as motor vehicle accidents (794).
Retroclival epidural hematoma and tectorial membrane injury, however, remain associated with major accidental trauma
(795).
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 diagnosis of trauma (but not
necessarily abusive head trauma) can confidently 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. 4-98, 4-101, 4-
102).
Figure 4-100 Abusive trauma; tadpole sign of bridging vein injury and parenchymal lacerations. A. Axial noncontrast CT reveals the
thrombosed bridging vein (tadpole head) as a rounded region of hyperdensity in the prominent left frontal subdural space (black arrow). Two
areas of right frontal lobe hypodensity reflect sites of parenchymal laceration (white arrows). Note also the bulging anterior fontanelle. B and C.
Coronal T2-weighted images depict the torn, thrombosed left frontal cortical vein (tadpole tail in B, arrowhead; tadpole head in C, black arrow).
Right frontal subcortical parenchymal lacerations (white arrows) have been more highly correlated with abusive than accidental head trauma. D.
Axial SWI at the vertex shows numerous thrombosed, enlarged cortical veins and adjacent hemorrhage. E. Coronal FLAIR imaging with fat
suppression demonstrates extensive, bilateral, mildly hyperintense subdural hemorrhage (white arrowhead), parenchymal lacerations (white
arrow), and the hyperintense tadpole sign (black arrow).
Subdural hematomas, subarachnoid hemorrhage, and acute cerebral contusions can be visualized by CT (Fig. 4-103).
Contusions may be seen as ovoid areas of low attenuation or as accumulations of intraparenchymal blood (high attenuation)
with surrounding edema (Fig. 4-104). 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 axial CT images but may
be more readily appreciated with coronal and sagittal reformations. As mentioned earlier in the chapter, hemorrhage becomes
more difficult to detect by CT subacutely, as the blood becomes progressively isodense with the brain (Table 4-9).
Figure 4-101 Abusive trauma in an infant. A. Noncontrast CT shows hyperdense small left frontal subdural hemorrhage (black arrow), with
hypodense contusion (white arrow) in the right frontal lobe. B. Axial T2-weighted image shows a left gyrus rectus laceration (black arrow) and
blood in the bilateral occipital horns of the lateral ventricles (black arrowheads). C. Axial T2-weighted image shows left superior frontal gyrus
and left posterior parietal subcortical white matter lacerations (arrowheads).
MR is much more sensitive than is CT in diagnosing subacute hematomas, both subdural and intraparenchymal, at the vertex
(Fig. 4-105) and in transversely oriented locations (subfrontal, along the tentorium) in the middle and posterior cranial fossae
(833). The MR appearance of hematomas varies with location, size, and stage of degradation; moreover, the rate of
degradation varies with size and location of the blood collection (Table 4-10) (798,928,933). It remains to be determined if
this general evolution scheme developed from 1.5 T imaging is equally applicable for 3.0 T imaging.
As discussed, subdural hematomas resulting from abusive head trauma are often of mixed density on CT (933–935). 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-density collection (933). Indeed, the only CT features that seem to support a combination of
two temporally distinct traumatic events are (a) membranes within a collection, (b) large low-density collections associated
with expanded underlying subarachnoid spaces (impaired absorption of CSF due to old blood products obstructing immature
arachnoid granulations), and (c) a history of slowly enlarging head circumference (895).
Although abusive head trauma is, by far, the most common cause of subdural hematomas in infants, it is important to keep in
mind that metabolic diseases can also cause bilateral subdural hematomas. In particular, Menkes disease, glutaric aciduria type
1, and Hermansky-Pudlak syndrome can cause both subdural hematomas and retinal hemorrhages (936). These diseases,
although very rare, should be kept in mind when evaluating infants with such imaging findings. It has also been reported that
infants with benign enlargement of the subarachnoid spaces (see Chapter 8) may develop subdural hematomas after relatively
minor trauma; however, this remains controversial, and an evaluation to assess for abusive trauma should be undertaken when
they are encountered without appropriate clinical history (802–805). Indeed, all infants and children with subdural
hematomas and no satisfactory explanation should be referred to pediatricians subspecializing in child abuse, when
available, or child protective services, for thorough evaluation, as a traumatic cause will commonly be found (937,938).
Radiologists should be aware that all 50 United States have mandatory reporting statutes for suspected child abuse and neglect.
Figure 4-102 Abusive trauma. A. Axial noncontrast CT image shows hypodensity of the posterior cerebral hemispheres bilaterally (arrows).
Note also the linear, hyperdense subdural hemorrhage along the posterior interhemispheric fissure. B. Axial ADC map demonstrates the
hypointense regions of cytotoxic edema in the posterior cerebral hemispheres (arrows). C. 3D surface-rendered CT reformation in bone
algorithm shows large, complex fractures of the left parietal bone. D. Axial noncontrast CT image through the orbits detects hyperdense
hemorrhage along the posterior aspects of the retinas in both globes (arrowheads).
Edema and parenchymal injury of the cortex and white matter are commonly present and more sensitively detected by MR
than by CT; in the early phase of injury, diffusion images make the lesions more conspicuous (585,587,864,896,922,923,939),
and the size and location of the abnormalities are associated with neurodevelopmental outcomes (835,940). Common locations
for the contusions include the anterior temporal and anterior frontal lobes (Figs. 4-103 and 4-104). Brain parenchymal
laceration has been reported as a predictor of abusive head trauma (896), as lacerations were seen in 13% of patients in their
abusive head trauma cohort, but not seen at all in their accidental head trauma cohort. Similarly, noncontusional cerebral
cortical/subcortical injury has been reported in child abuse, sometimes associated with ipsilateral subdural hemorrhage,
although the precise mechanism is not always elucidated (883,939,941). These lesions are typically not in classic vascular
territories (they often cross vascular territories); therefore, it is not certain that they represent infarcts. The presence of these
lesions is associated with poor clinical outcome (864,939). Single large areas or multiple noncontiguous areas may be
involved (Figs. 4-103 and 4-105). When large areas of cortical injury are seen in conjunction with subdural or
subarachnoid hemorrhage in an infant, the possibility of abusive head trauma should be raised (913,942). If the MR study
is performed soon after the event (during the first day), the injured tissue may be difficult to detect by routine sequences.
Performing diffusion imaging is invaluable in this setting, as the injured areas will show reduced diffusivity (Figs. 4-103 and
4-105), often in areas that appear normal on standard sequences (943,944). 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 the 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 signal intensity, first on T1-weighted
and then on T2-weighted sequences. Old hemorrhage within the brain can be identified by the presence of blood degradation
products, predominantly hemosiderin and ferritin, which appear as ill-defined areas of very low signal intensity on T2-
weighted spin-echo, gradient echo (GE), or susceptibility-weighted (SWI) sequences (see Fig. 4-98). GE or SWI is especially
useful in suspected abusive head trauma cases because of their sensitivity to regions of different magnetic susceptibilities,
especially when long (>30 ms) echo times are used for GE (Figs. 4-98 and 4-105C); SWI is more sensitive but requires longer
imaging time. The finding of acute or subacute microhemorrhages is associated with worse neurological outcome (864). Areas
of old hemorrhage can be seen on GE and SWI 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, fast spin-echo, or FLAIR images, and
significant parenchymal injury may be missed when GE or SWI sequences are employed exclusively. The reverse is also true:
fast/turbo spin-echo and FLAIR sequences, which are relatively insensitive to paramagnetic substances (Figs. 4-96, 4-98,
4-105), should not be the only sequences utilized at 1.5 T static field strength in trauma cases, as the presence of old and
new hemorrhage is of critical importance. As 3 T scanners have become more common, acute and early subacute blood may
be more easily detected as low signal intensity on FLAIR and FSE sequences at 3 T (841) (but GE and SWI remain more
sensitive).
Figure 4-103 Abusive trauma; use of diffusion imaging and spectroscopy. MR 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. C. Axial ADC image (b = 1000 s/mm 2) shows reduced diffusion (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 encephalomalacia in the injured brain regions.
Figure 4-104 CT and MR of abusive trauma. A. Noncontrast CT shows hypodense chronic bilateral subdural hematomas with superimposed
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. Perimesencephalic cisterns are effaced. B. Noncontrast CT near the vertex shows the more acute, hyperdense
bilateral subdural hematomas (a) and the more hypodense chronic subdural hematomas (c) containing posteriorly layer blood products
(arrows). Scalp tissue is swollen over the left parietal bone fracture. Note the severe parenchymal edema. C. Axial T2-weighted image shows
the bilateral subdural fluid collections, hemorrhagic right anterior frontal contusion and nonhemorrhagic left posterior deep white matter injury.
Subacute Isodense 1½ to 3 wk
N.B.: Several authors have found that hypodense components can be seen within previously uniformly hyperdense subdural hematomas within several
hours of injury and that mixed-density hematomas are more common than uniformly hyperdense hematomas, likely related to prior injuries or an
admixture of serum, clotted and unclotted blood, and CSF (814,931).
Adapted from Vinchon M, de Foort-Dhellemmes S, Desurmont M, et al. Confessed abuse versus witnessed accidents in infants: comparison of clinical,
radiological, and ophthalmological data in corroborated cases. Childs Nerv Syst 2010;26(5):637–645; Vezina G. Assessment of the nature and age of
subdural collections in nonaccidental head injury with CT and MRI. Pediatr Radiol 2009;39:586–590.
Figure 4-105 Abusive 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 the subdural blood along the tentorium (white
arrowheads) is significantly more hyperintense than parenchyma, likely more acute. B. Coronal T2-weighted image shows the heterogeneity of
the subdural hemorrhage, with hypointense blood over the medial right parietal cortex (black arrowheads) and hyperintense blood over both
convexities. Note the membrane in the left-sided subdural hematoma (black arrow), confirming chronicity. C. SWI 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 hyperintense 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.
Chronic (subdural membrane) Iso Hypo Unproven, likely iso Few weeks to years
Chronic (subdural contents) Hypo but brighter than CSF Hyper Unproven, likely hypo but brighter than CSF Few weeks to years
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. Refs. (928,932).
Adapted from Vinchon M, de Foort-Dhellemmes S, Desurmont M, Delestret I. Confessed abuse versus witnessed accidents in infants: comparison of
clinical, radiological, and ophthalmological data in corroborated cases. Childs Nerv Syst 2010;26(5):637–645; Vezina G. Assessment of the nature and
age of subdural collections in nonaccidental head injury with CT and MRI. Pediatr Radiol 2009;39:586–590.
Injury to the spine and spinal cord is commonly seen in pathologic examinations of abused children (Fig. 4-106). The
cervical spine is particularly affected by shaking injury and should always be examined if other evidence 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, MR is the examination of choice for imaging of the spine. Both sagittal and axial T1-
and T2-weighted images, as well as T2 gradient echo and STIR, should be obtained to look for spinal cord injury (even cord
transection), subdural and epidural hematomas, injuries to the vertebral bodies, ligamentous injury, soft tissue injuries, and
paraspinous hemorrhage due to the vertebral body injuries (899,900,945).
Proton MRS obtained in the subacute phase may be useful to assess prognosis in shaken babies (Fig. 4-103). In particular,
the presence of elevated lactate or the reduction of NAA on MRS studies obtained 5 to 7 days after the injury indicates
significant damage; preliminary studies suggest that these patients will have a poor prognosis (946). 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 (861).
Figure 4-107 MEG scan following a concussion. A. MEG whole head sensor array depiction of abnormally slow activity (~4 Hz, delta
frequency band waves, circled) arising from the left temporal sensors, as viewed from the vertex. B. The red dots indicate the cluster of slow
wave generators detected with MEG and coregistered to volumetric axial T1 gradient echo, which allows localization to the midportion of the
lateral aspect of the left temporal lobe. (This case is courtesy of Dr. Roland Lee, San Diego, CA.)
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Congenital Malformations of the Brain and Skull
A. James Barkovich and Charles Raybaud
Chromosomal Anomalies
Trisomy 21
Trisomy 18
Trisomy 13
Fragile X Syndrome
Inversion Duplication of Short Arm of Chromosome 8
Wolf-Hirschhorn Syndrome
Abnormal brain development, leading to dysplasia or malformation, is a common finding in the neuroimaging studies of
children with developmental delay, mental retardation, or epilepsy (1–3). This chapter will begin with a discussion of
essential embryology of the brain and then will proceed to discuss brain malformations and the disturbance(s) that likely
resulted in malformations, including the causative genes and (when known) molecular pathways disrupted to cause the
malformation, the clinical presentations, the optimal imaging techniques to aid in diagnosis, and imaging findings. This
information should allow the reader to diagnose most disorders of brain development.
This chapter has been organized to help the reader locate the discussion of the malformation; it is only necessary to figure
out what part of the brain or skull is affected. If the malformation involves the cerebral hemispheres or the commissures
connecting them (corpus callosum, anterior commissure, hippocampal commissure), it will be found in Anomalies of Dorsal
Prosencephalon Development. If it primarily involves the basal ganglia, the hypothalamic–pituitary axis (HPA), the olfactory
structures, or the orbits, it will be found in Anomalies of Ventral Prosencephalon Development. If it mainly involves the
brainstem or cerebellum, look in Anomalies of Midbrain–Hindbrain development. The Chiari malformations are discussed in
Anomalies of the Craniocervical Junction. Anomalies of the calvarium, skull base, subarachnoid space (lipomas and cysts),
and leptomeninges are discussed in Anomalies of the Mesenchyme. Hopefully, this organization will facilitate navigating the
chapter. Before discussing the anomalies themselves, it is important to understand the fundamentals of brain development. This
knowledge will help the reader to recognize malformations and to distinguish them from distortion of normal brain.
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 telencephalon develops, the cerebral hemispheres grow posteriorly to cover the diencephalon,
mesencephalon, and portions of the rhombencephalon (Fig. 5-1); accompanying this growth of the hemispheres, the corpus
callosum seems to grow from anterior to posterior (see section on cerebral commissures). Further details of the development
of the telencephalon will be discussed in the section on anomalies of neuronal migration and that on holoprosencephalies.
The rhombencephalon will eventually divide into the myelencephalon, which will form the pons and cerebellum (a dorsal
extension of the pons), and the metencephalon, which will form the medulla oblongata. This process of development will be
discussed further in the section on anomalies of the hindbrain.
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 fibers that cross through the isthmus connects the
pre- 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
contains 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 pellucidum is bounded superiorly by the callosal body, anteroinferiorly by the lamina rostralis,
and posteroinferiorly by the body of the fornix (Fig. 5-2) (44).
In order to understand commissural anomalies, it is essential to understand the basics of commissural development (45–47).
At approximately the seventh week of gestation in humans, glial cells from a specialized population of fetal astroglia, known as
midline zipper glia (MZG), migrate from the midline neuroependyma into the interhemispheric fissure near the junction of the
diencephalon (the ventral part of the forebrain) and the telencephalon (the dorsal part of the forebrain). Under the influence of
FGF8-induced NFIA and NFIB signaling, the bipolar MZG cells transition into multipolar MZG cells that position on either
side of the interhemispheric fissure and extend multiple processes that intercalate with one another across the midline through
the leptomeninges (45). As this mesh-like structure is formed and the leptomeningeal tissue is degraded, the interhemispheric
fissure is remodeled as the axons from the two cerebral hemispheres cross (Figs. 5-4 and 5-5) in what has been called a “glial
sling” or “midline glial zipper” (45,48–51). The cells that compose the sling/zipper presumably express surface molecules and
secrete chemicals into the extracellular space that help to guide axons across the midline (52–54). The midline crossing of
these callosal axons seems to occur coincidently with the extension of glial fibers from the medial surface of the cerebrum
across the midline; the key regulatory step in the interhemispheric remodeling is the transformation of radial glia from the
cingulum into these specialized astroglia, initiated by FGF8 signaling to downstream NFI transcription factors (45).
The first callosal axons to cross along the glial sling arise from the developing cingulate gyri (Fig. 5-5C) (52,55,56). 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–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 callosum 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 eventually meet in what will become the posterior body of the corpus callosum. Therefore,
the anterior and the posterior callosum originally are separated (57), 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
reuniens, is pushed posteriorly (stretching the forniceal columns) and becomes located under the splenium (41). This apparent
front-to-back progression is generally interpreted as a front-to-back growth of the corpus callosum, but is probably 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
(44). Therefore, while the initial pioneer axons are beginning to cross in the region of the interventricular foramina of Monro
(41), the glial “sling” is just beginning to form in the anterior body, while the sulcus medianus telencephali medii is forming in
the posterior body (58,59). The genu, lamina rostralis, and body appear to form in rapid succession, and all are present at
week 15 (Fig. 5-6) (54,60); the hippocampal commissure develops earlier, but the splenium (using hippocampal commissure
axons as guides for fasciculation to cross the midline) does not become prominent until weeks 18 to 19 (54). So although the
anterior corpus callosum (including the lamina rostralis) appears after the hippocampal commissure, it enlarges and becomes
grossly visible first; the splenium forms over the hippocampal commissure during the formation of the anterior corpus callosum
and it enlarges later (41,60,61).
Figure 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 sensorimotor commissural
axons). This example illustrates that the rostrum, genu, and body contain frontal commissural fibers, while the splenium contains parietal,
occipital, and temporal fibers.
Figure 5-4 Development of the lamina reuniens and of the corpus callosum, sagittal midline. A. During week 7, the upper portion of the lamina
terminalis (LT), which connects the hemispheres across the midline, thickens and forms the lamina reuniens (LR) of His. B. In the following
week, olfactory commissural fibers cross the midline through the ventral aspect of the lamina reuniens to form the anterior commissure (AC).
C. In the following weeks, fibers develop 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 the lamina reuniens and form the
hippocampal commissure (HC). 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 commissure, and glial sling. Depending on their origins, early neocortical commissural fibers cross the midline
along the anterior commissure (temporo-occipital fibers), the glial sling (frontal fibers), or the hippocampal commissure (parieto-occipito-
temporal fibers). F. The corpus callosum grows by addition of further commissural fibers and forms a single continuous structure stretched
between the anterior commissure and the hippocampal commissure; it circumscribes the 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 backward above the velum interpositum (roof above the third ventricle), stretching the body of the fornix.
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 hippocampal commissure (week 11). The fibers that connect the
medial septal nucleus with the ipsilateral cingulate 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 callosum along the way. Because the septum pellucidum develops in
the walls of the sulcus medianus telencephali medii, 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) (41,62); when the cavum extends posteriorly between the corpus callosum and the hippocampal commissure, this extension
is called the cavum vergae. The cavum becomes apparent about 20 weeks and usually disappears within 3 months after birth,
its lumen becoming progressively effaced from the back to the front (63,64).
Figure 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 indusium griseum glia and the glial wedge form
above and below the corticoseptal boundary. C. The pioneer commissural fibers are channeled from the cingulate 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 pellucidum) 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.
Figure 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.
After crossing the midline, the growth cones of the callosal axons follow cues (neuropilins, netrins) to the homotopic
contralateral hemisphere (the same area from which it originated, only in the other cerebral hemisphere). In mouse models, the
axon “loses its way” if it enters the wrong part of the corpus callosum and ends up in the wrong (heterotopic) area of the
contralateral hemisphere (65). These ectopic axons are seem to be eliminated by “pruning” (65), although the precise time
when this occurs has not been determined.
Figure 5-7 Schematic representations of various commissural and septal disorders. A. With complete absence of commissures, the leaves
of the septum pellucidum (s) border the medial edge of the limbic lobe. 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. 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
commissure (hc, violet line between fornices) is present. E. In isolated agenesis of the hippocampal commissure, the corpus callosum (cc) is
present but fornices are not connected. F. In septooptic dysplasia, both callosal and hippocampal commissures are present, but the leaves of
the septum pellucidum are missing.
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 (66,68). In the middle interhemispheric
variant of holoprosencephaly, the genu and splenium may be present without a normal callosal body (69). Examples are
shown in the holoprosencephaly section 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
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 ventricle, forniceal fibers are present,
allowing development of a hippocampal 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 (67,70). 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, normal anterior callosum; the posterior body does not form because the interhemispheric continuity has
impaired formation of the corticoseptal boundary and prevented the eventual fusion of the anterior and posterior callosal
segments (44).
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 (71) or transcallosal surgical approaches to the lateral or third ventricles (72) have callosal defects that may mimic
congenital callosal defects if the surgical history is not known.
As stated above, the anterior commissure and hippocampal commissure are typically affected when the corpus callosum
develops abnormally (73). Most commonly, the anterior commissure will be small and the hippocampal commissure absent in
the setting of callosal agenesis (67,73). Occasionally, however, the hippocampal commissure will be enlarged in patients with
hypogenesis or agenesis of the corpus callosum (59): the enlarged commissure may mimic a section of callosum on midline
sagittal images; analysis of coronal images will show that this commissure connects the fornices, not the cerebral hemispheres
(Fig. 5-13). An enlarged anterior commissure may be seen in callosal agenesis, but this was rarely observed in large reported
series (67,74,75) and appears to be quite unusual.
Figure 5-8 Complete (tricommissural) agenesis in a child and a fetus. A–D. Eight-year-old child. 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 parahippocampal gyri (black arrows)
where the white matter tract (ventral cingulum) is hypoplastic or absent. 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. E–G. A 22-week fetus. E. Sagittal SSFSE image shows extensive hyperintensity from enlarged interhemispheric fissure.
No commissures are seen. Axial image (F) shows slightly enlarged ventricular trigones and expanded interhemispheric fissure (f). Hypointense
germinal zone is seen at the lateral walls of the ventricles (black arrows). G. Coronal image shows a large interhemispheric fissure (f) with no
interhemispheric commissures.
Figure 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.
Figure 5-12 Callosal tapering, with mild posterior callosal hypogenesis. On this midline sagittal T1-weighted image, the anterior commissure
and anterior callosum look normal, with a normal junction of the fornix suggesting a normal hippocampal commissure. The splenium is less
well developed suggesting a posterior callosal commissural defect. As is commonly seen with splenium hypoplasia, the rostrum is absent.
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
characteristic facial and neurologic features (97). Patients with severe facial anomalies, such as midline craniofacial
dysgenesis (see section on large midline clefts) have a high incidence of callosal anomalies.
Figure 5-13 Callosal agenesis with hippocampal commissure mimicking a splenium. A. Midline sagittal T1-weighted image shows apparent
formation of the splenium (white open arrows) in the absence of the anterior callosum. B. Coronal T1-weighted image shows that the
commissure (white open arrow) connects the fornices (white arrows) at the lower margins of the Probst’s bundles (black arrows) and, therefore,
is a hippocampal commissure, not a splenium. (Reprinted with permission from Barkovich AJ. Apparent atypical callosal dysgenesis: analysis
of MR findings in six cases and their relationship to holoprosencephaly. AJNR Am J Neuroradiol 1990;11:333–340.)
Figure 5-14 Medial hemispheric clefts resulting in large callosal remnant and unusual hippocampal commissure. A. Midline sagittal image
shows a large anterior callosal remnant (large white arrow), anterior commissure (small white arrow), and hippocampal commissure (black
arrow). Neither an inverted cingulate gyrus nor cingulate sulcus is seen in most of the hemisphere. B. Coronal T2 image shows gray matter–
lined clefts (technically schizencephalies, white arrows) coursing superomedially from the tops of the ventricular trigones to the
interhemispheric fissure. C. Parasagittal T1 image just off the midline shows the body of a fornix (black arrows) coursing anteriorly from the
hippocampal commissure and then extending inferiorly as a forniceal column toward the mammillary bodies. D. Parasagittal T1 image lateral to
(C) shows the gray matter–lined cleft shown in (B) coursing superior and parallel to the ventricular body and trigone.
Figure 5-15 Commissural agenesis with cortex abnormally covering superomedial surfaces of lateral ventricles. A. Sagittal T1-weighted
image shows absent corpus callosum and anterior commissure. Linear structure near the top of the third ventricle (white arrows) may be
venous or, possibly, hippocampal commissure. Note dysmorphic-appearing pons (P) and cerebellar vermis. B. Coronal T2-weighted image
shows cortex (black arrows) extending abnormally from the medial wall of the cingulate gyrus laterally above the superior walls of the
ventricles, potentially inhibiting cells from migrating to form the glial sling and wedge and, thereby, inhibiting callosal development.
Figure 5-16 Commissural agenesis with small, rotated vermis and enlarged fourth ventricle. Midline sagittal T2-weighted image shows that
the anterior commissure (black arrow) is present, but not the hippocampal or the callosal commissures. The posterior fossa is large with high
insertion of the tentorium, hypoplastic rotated vermis, and a small pons. The CSF flow void that is continuous within the enlarged fourth
ventricle strongly suggests absence of associated cyst.
Other commissural abnormalities seen on neuroimaging studies include ventriculomegaly and cavae septi pellucidi et
vergae (98). The septum pellucidum may also be too small (surface area disproportionately 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 matter fascicle in the midline, or the persistence of residual cellular material,
possibly glial or neuronal, in the lumen of the cavum. This finding has not been associated with any clinical condition (98).
Figure 5-17 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.
Figure 5-18 Posterior tapering of the corpus callosum with hypothalamic hamartoma, pituitary stalk agenesis, and posterior pituitary ectopia.
The corpus callosum is short with posterior tapering (large white arrows), but the junction 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).
Figure 5-19 Agenesis of the corpus callosum with midline brainstem cleft secondary to AMPD2 mutation. A. Sagittal T2-weighted image
shows callosal agenesis. Note also rostrocaudal elongation of the ventral midbrain (m) and tectum (black arrows) and small cerebellum
(arrowheads) with small pons (P). B. Axial T2 image at the level of the midbrain shows midline cleft (black arrows) and abnormal CSF-filled
spaces in the cerebellar parenchyma. C. Axial T2 image at the basal ganglia level shows large massa intermedia and enlarged trigones and
occipital horns of the lateral ventricles (colpocephaly). D. Coronal T2-weighted images shows hypoplastic ventral and dorsal cingula (c) and
small Probst bundles (white arrows). E. Axial color fractional anisotropy map shows absence of red (crossing) axons in the midbrain (white
arrows).
Figure 5-20 Aicardi syndrome. A. Midline sagittal T1-weighted image shows absent corpus callosum with two interhemispheric cyst (C1 and
C2) and upwardly rotated, hypoplastic cerebellar vermian. B. Axial T2-weighted image shows bilateral ocular colobomas (black arrows) and
multiple nodular heterotopia (large black arrowheads) in the walls of the temporal horns. C. Axial T2 image at the upper level of lateral ventricles
shows the two interhemispheric cysts (C1 and C2) in addition to extensive polymicrogyria in the left hemisphere (black arrows) in both
hemispheres. D. Coronal T2 image shows extensive polymicrogyria in the left hemisphere, small areas of polymicrogyria in the right
hemisphere (large arrows), and heterotopia in the wall of the left lateral ventricle (small arrows).
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.
Table 5-1 A Partial List of Syndromes Commonly Associated with Commissural Anomalies
Aicardi syndrome
Apert syndrome
Chiari II malformation
Dandy-Walker malformation
Oro–facial–digital syndromes
Walker-Warburg syndrome
Figure 5-21 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. (After Rakic and Yakovlev Bedeschi MF, Bonaglia MC, Grasso R, et al.
Agenesis of the corpus callosum: clinical and genetic study in 63 young patients. Pediatr Neurol 2006;34:186–193.)
Figure 5-22 Schematic drawing illustrating the findings in callosal agenesis (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 holoprosencephaly. AJNR Am J Neuroradiol 1990;11:333–
340, with permission.)
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, especially 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, the white matter that
surrounds the ventricles is more loosely organized when the callosal splenium is absent. Moreover, multiple white matter
tracts (including the dorsal cingulum, within the cingulate sulcus, and the ventral cingulum, within the parahippocampal gyrus)
are often hypoplastic or absent when the corpus is hypogenetic, including those coursing around the ventricular trigone and
temporal horn (44,105). In callosal hypogenesis, therefore, the temporal horns, trigones, and occipital horns of the lateral
ventricles often 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) (106,107). 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. MR, 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 MR are much
superior to those of other modalities. In addition, diffusion tensor imaging (DTI) and tractography may allow a better
understanding of the abnormal intra- and interhemispheric connectivity (Fig. 5-10K and L). The severity of callosal
hypogenesis or dysgenesis is assessed well on the midline sagittal images (Figs. 5-8 to 5-12). As mentioned earlier, a
hypogenetic corpus callosum is defined as one that is abnormally short, with small or absent inferior genu and rostrum.
Therefore, a hypogenetic corpus callosum appears as a short and thin corpus; the appearance is that of posterior genu and
anterior body; genu and entire body; or entire genu, body, and hypoplastic splenium. Keep in mind, however, that it is
impossible to know where the commissural fibers originate without using tractography; the axons of what appears to be the
“genu” of a hypogenetic corpus may come from the parietal (or even occipital) lobes, and one cannot confidently differentiate a
hypogenetic corpus callosum from a hypoplastic one or a disproportionately small or absent splenium from a hypoplastic
hippocampal commissure without tractography (Figs. 5-10 and 5-23) (105). Other MR findings in the absence of a corpus
callosum include lack of inward folding of the cingulate gyri (with the medial hemispheric sulci extending all the way 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 ventral cingulum (106)), and
extension of the roof of the third ventricle into the interhemispheric fissure (Figs. 5-9 to 5-11, 5-20).
As mentioned above, 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 bundles connect anterior
regions of the hemisphere with more posterior regions, with the axons exhibiting a topographic organization (104). 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 connectivity) and asymmetrically (heterotopic connectivity) via
so-called sigmoid bundles (Fig. 5-10) (104,105). Tractography is also useful for detecting other midline crossing defects (Fig.
5-19).
Adapted from Baker LL, Barkovich AJ. The large temporal horn: MR analysis in developmental brain anomalies versus hydrocephalus. AJNR Am J
Neuroradiol 1992;13:115–122; Barkovich AJ, Simon EM, Walsh CA. Callosal agenesis with cyst: a better understanding and new classification.
Neurology 2001;56:220–227.
Type 2 cysts are often multiloculated. Under these circumstances, it is important to establish which of the loculations
communicate with one another and which, if any, communicate with the ventricles, in order to properly plan which
compartments should be shunted and in what order. If MR or sonography do not give sufficient information, a CT cystogram or
ventriculogram maybe 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
(usually from hydrocephalus). Patients with type 1a and type 2d cysts have the best prognosis in our experience, 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 (67,114); however, this has not been
verified in a prospective 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 ultimately have normal
neurologic exams and normal school performance (67,73), although epilepsy may become a problem.
MR imaging is the optimal modality to assess the fetal brain parenchyma after 18 to 20 weeks of 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 easily 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 sagittal and axial images. Other commonly associated abnormalities better shown by MR
include delayed sulcation and/or shallow sylvian fissure, gray matter heterotopia, polymicrogyria, lissencephaly (with thick
cortex), schizencephaly, and choroid plexus cysts (Figs. 5-28 to 5-31) (36,115–118). The remainder of the fetus should be
examined, if possible, for extraneural abnormalities of the skeleton, heart, and trunk.
Figure 5-25 Callosal agenesis with type 2a interhemispheric cyst. A. Sagittal T1-weighted image shows absence of the corpus callosum with
very little midline tissue; mass effect from an oblong cyst (c, large white arrows) compresses the quadrigeminal plate (white arrowheads). The
anterior commissure (small arrow) is large. B. Axial T2-weighted image shows the cyst (c) posterior to the right thalamus (white t), displacing
the right posterior temporal and occipital lobes (black arrows); thalamus; and, to a lesser extent, left thalamus and posterior temporal lobe
(black arrowheads). C. Coronal T2-weighted image shows the interhemispheric cyst extending on both sides of the falx cerebri, displacing the
right lateral ventricle (large white arrow) and third ventricle (black arrows). Note inferomedial extension of the temporal horns (small white
arrows) due to hypoplasia of the inferior cingula.
Figure 5-26 Callosal agenesis with type 2b interhemispheric cyst. A. Sagittal T1-weighted image shows absence of the corpus callosum and
a mass that is hyperintense to CSF in the midline where the corpus callosum should be. Note the absence of a dorsal cingulum above the third
ventricle. B. Axial T2 image shows the cyst (c) in the interhemispheric fissure and extending into the anterior left trigone via a small connection
(white arrow). Note the abnormal “steerhorn” shape of the frontal horns. C. Coronal FLAIR image shows the cyst in the left paramedian
interhemispheric cistern and continuing into the left lateral ventricle (c). Both components are hyperintense (compare to hypointensity of the
temporal horns), likely due to increased protein content.
RGCs tend to be grouped in fascicles that consist of 4 to 10 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 (139). Neuronal 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 channels or blocking N-methyl-D-
aspartate receptors inhibits cell migration (140,141). 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
(5,32,33,138,142–148). As migration nears completion, many of the RGCs begin to produce astrocytes, while others may
transform into astrocytes (30).
Figure 5-27 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.
In contrast to the generation of glutamatergic neurons in the dorsal ventricular zones, the vast majority of GABAergic
neurons that will ultimately migrate to the basal ganglia and cerebral cortex seem to be generated predominantly in the
subpallium ventricular zones (the medial [MGE], lateral [LGE], and caudal [CGE] ganglionic eminences and the preoptic area
[POA], Fig. 5-32) (133,134,149). These zones have been divided based on the expression patterns of several transcription
factors, suggesting that specific features of the interneurons may be programmed very early during the developmental process
(31,150–153). 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, CGE progenitors produce primarily cortical interneurons, and the POA progenitors
produce neurons that migrate to the POA, amygdala, globus pallidus, and cortex (134,154–159). It appears that the subtype
identity of the interneuron can be predicted by its time and place of origin (150,152,155,157,160). POA-derived neurons
destined for the cerebral cortex initially migrate to the developing cortical layer 1 and then migrate inward to deeper cortical
layers (157,161,162), whereas cortical interneurons from the MGE migrate tangentially to the SVZ of the dorsal pallium
germinal zone (149,163–169) from where they attach to a RGC, along which they migrate radially outward to the developing
cortex (30,136,170). Although some have postulated that GABAergic cells are generated in the SVZ of the dorsal pallium
(5,166), recent work suggests that most of these interneurons are produced in the ganglionic eminences and subsequently
migrate to the SVZ (171).
Figure 5-28 Commissural agenesis in a 24-week-GA fetus. A. Coronal image shows the characteristic appearance of commissural
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.
Figure 5-29 Commissural hypogenesis in a 24-week-GA fetus. A. Coronal image shows a rudiment of corpus callosum bridging the
hemispheres, but the general morphology is similar to that in Figure 5-24A. B. On this sagittal image, only the posterior genu/anterior corpus
callosum body (black arrow) is seen. 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.
Figure 5-30 Type 1 ACC/IHC in a 22-week fetus. A. Sagittal SSFSE image shows the presence of an anterior callosal remnant (white arrows).
CSF seems to fill most of the cranium. The cerebellum (black arrow) appears pushed caudally. B. Axial image shows absence of the right
ocular globe and herniation of the right lateral ventricle through the choroidal fissure (white arrows), displacing the occipital cortex posteriorly
and laterally. C. Coronal image shows herniation of the ependyma of the lateral ventricle superiorly and laterally, displacing the parietal/occipital
cortex laterally (black arrow) and expanding the calvarium (white arrows) due to mass effect.
The cortical layer in which a neuron will eventually reside can be predicted by the known sequence of neuronal
development and migration (143,172). The level at which the migrating neuron disengages from the RGC seems to be
determined by short-range interactions with other cells during the last mitotic cycle while the neuron is still in the germinal
zone (173,174). This disengagement requires secretion of a glycoprotein (called reelin) by neurons in cortex layer 1 (175).
Reelin seems to be involved in the final stages of neuronal migration, as well as disengagement of the migrating neurons from
the RGCs (176,177) (and may also be involved in initiating migration by participating in the “notch” pathway, in the
ventricular zone) through radial glia (178). 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” (179–183)) 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 (137,184,185). After their arrival in the cortex, neurons become arranged in discrete horizontal layers and establish
synaptic contacts with local and distant neurons in a process known as cortical organization (186–188). The subplate
(transient layer 7 of the cortex, which forms by 15 weeks and nearly disappears by term) is believed to play a large role in this
organizational process, providing a “waiting area” where neurons remain for a variable period before migrating to their final
cortical location to function as thalamocortical afferent, basal forebrain cholinergic afferent, and callosal or ipsilateral
corticocortical afferent axons (179–181,189,190).
Figure 5-31 Commissural agenesis with type 2a interhemispheric cyst in a 29-week-GA fetus. A. Midline sagittal image shows that 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 foramina 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.
Regional specification of the cerebral cortex (remember that different regions of the cortex have different layering patterns
and different functions) is likely determined by a combination of genetic factors and connections with other portions of the
nervous system (5,191). It appears that early specification is the result of a cascade of genetic effects: morphogens and growth
factors secreted by signaling centers in the embryonic forebrain regulate expression of transcription factor gradients across the
developing cerebrum, in many cases by promoting specific factors while repressing others (191,192). 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 (5,148,191,192).
Figure 5-32 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 begin their migration. 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) and the striatum (Str) and migrate tangentially to become
GABAergic interneurons in the cerebral cortex (CTX). Neurons generated in the preoptic area (POA) contribute to the preoptic area, the
amygdala, and the globus pallidus, as well as some cortical interneurons. Also labeled is the thinner dorsal portion (the pallium), which will
become the cerebral mantle.
Figure 5-33 This schematic demonstrates the dorsal (pallial) germinal zone, where glutamatergic cerebral cortical neurons (those that
secrete glutamate as a neurotransmitter) are generated, and the migration of those neurons. Some of the cells generated in the ventricular
zone become ventricular radial glial fibers (vRGCs); others become neurons that either undergo mitosis or attach to a vRGC and migrate
apically (toward the pial limiting membrane). More cellular proliferation/mitosis occurs in the outer subventricular zone; again, some daughter
cells become outer radial glial cells (oRGCs, which later become migrating neurons), while others become neurons that will migrate along
oRGCs to the developing cerebral cortical plate. Note that the migrating neurons may move to an adjacent RGC several times during migration.
As the neurons enter the cortical plate, they pass cells that have previously migrated (aided by reelin). Neurons generated in the oSVC,
therefore, form the outer cortical layers (layers 2, 3, and 4). (This figure is modified from Lui JH, Hansen DV, Kriegstein AR. Development and
evolution of the human neocortex. Cell 2011;146:18–36, with permission of the authors.)
Some evidence has been presented that proton MR spectroscopic imaging (MRSI) (221–223) and diffusion tensor imaging
(DTI) (207,224) may be useful in localization of epileptogenic foci. MRSI is most useful in the temporal lobe, particularly in
hippocampal sclerosis. Woermann et al. have shown abnormal metabolite levels in nearly 90% of patients with malformations
of cortical development; however, the abnormalities were inconsistent, with the metabolite levels varying among patients
(223). In addition, the spectroscopic abnormalities have been far more widespread than the lesion (225,226), suggesting that
the MRS findings reflect secondary changes rather than the primary epileptogenic focus. Li et al. 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 polymicrogyria (in which the neurons are mature) (227). This suggests that the
low NAA values present in some cortical malformations result from dysplastic or immature neurons in the malformation;
however, these results have not been reproduced. In our experience, MR spectroscopy has only been useful in hippocampal
sclerosis, but modern neuroimaging (especially using 3 Tesla MRI) shows the temporal lobe abnormalities very well,
rendering MRSI unnecessary. We have found DTI even less useful; although the white matter underlying a cortical
malformation often has increased diffusivity (increased in the apparent diffusion coefficient) and decreased anisotropy
compared with the same area of the brain in age-matched controls (228), it is equally likely that these findings are a result of
the seizures as opposed to a reflection of the changes in the brain that cause of seizures. 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 (207). 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 MR imaging might better locate the lesion.
Overall, MR imaging remains the cornerstone of the imaging evaluation of malformations of cortical development
(202,229–231), with PET, SPECT, and MEG as the main imaging adjuncts (204,209,210,217). Even if the epileptogenic focus
is identified by another technique, the focus is always coregistered with an MR image before any intervention is planned.
Therefore, this section will deal primarily with MR imaging.
Malformations secondary to abnormal stem cell proliferation or apoptosis
Microcephalies
Microcephalies are divided into primary microcephalies (also called microcephaly vera), which are autosomal recessive
disorders that result in intellectual disability without other neurological disabilities (232), and secondary microcephalies,
which are the result of an in utero event that results in diminished brain and head growth. Patients with this disorder usually
have a mutation in genes encoding proteins that play fundamental roles in various processes that collectively enable
chromosome segregation and mitotic division; these include centrosome and spindle microtubule defects, mitotic spindle
orientation, premature chromosomal condensation, defects in proteins that respond to and repair DNA, microtubule dynamics,
transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by
neuronal precursor cells, and defects in the origin recognition complex core and associated components (involved in DNA
replication and cilia function) (232–247). Although many causative genes have already been identified (247), it is likely that
many others will be found soon, as the interest in this process is rapidly increasing. Other forms of microcephaly are
associated with abnormal brain structure, such as lissencephaly, callosal anomalies, heterotopia, abnormal sulcation, and
cerebellar anomalies; these have mutations in genes that are important in neuronal migration and axon navigation, in addition to
cell proliferation; these are discussed separately, later in this section.
Figure 5-35 Use of 18FDG (18-Fluorodeoxyglucose) positron emission tomography (PET) in imaging of focal cortical dysplasia. Note the
diminished myelination in the left hemisphere (white arrows) on both the T1- (A) and T2-weighted (B and C) images. The PET image (D)
shows reduced uptake in the left frontal lobe (white arrows in D) indicating decreased uptake of 18FDG in the epileptogenic lesions on this
interictal study. PET is most useful when coregistered with MRI. Histology after resection showed focal cortical dysplasia type Ia.
Too many genes associated with microcephalies have been discovered to list them all with their specific characteristics; the
reader is referred to review papers on the subject (232,246–249). Clinical features can sometimes be used, but they do not
often help the imager; some authors separate microcephalic primordial dwarfism into categories of Seckel syndrome,
microcephalic osteodysplastic primordial dwarfism, and Meier-Gorlin syndrome (250), but there have been no imaging
characteristics described to reliably differentiate them. Although the child’s stature is useful for classifying the microcephaly
(Table 5-4), that information is not available to the neuroradiologist. Therefore, other brain characteristics are more useful.
Using purely morphologic characteristics, microcephalies can be segregated by seven major categories: severity of
microcephaly (251), gyral patterns (252–254), cortical thickness (244,252), presence or absence of heterotopia (255), callosal
anomalies (244,256), and relative size of the forebrain, hindbrain, and ocular structures (249). The gyral pattern can be
normal, simplified (sulci are too few and too shallow, but cortical thickness is normal, Fig. 5-36), microgyric (Fig. 5-37), or
pachygyric (sulci are too few and too shallow with thick cortex, Fig. 5-38). Heterotopia may be present (Fig. 5-36) or absent.
The corpus callosum can be absent, hypoplastic, or hypogenetic (see earlier section on callosal anomalies and Figs. 5-36 and
5-38). The forebrain can be large compared with the hindbrain (Fig. 5-38), commensurate in size with the hindbrain, or small
compared with the hindbrain (Fig. 5-37). Similarly, the ocular globes can be commensurate with cerebral size or large. It is
important to note that most of these characteristics can be identified on MRIs of the fetus (Fig. 5-37), as well as on postnatal
studies. Specific findings may help to make a diagnosis: wrapping of the frontal horns around the outside of the basal ganglia
and absence of the anterior limb of the internal capsule (Fig. 5-38) or profound microcephaly with lissencephaly, absent or
very small corpus callosum (Figs. 5-39 and 5-40), and marked cerebellar hypoplasia with a large tectum (Fig. 5-39) suggest a
tubulinopathy, particularly mutations of TUBA1A. Profound microcephaly with a very simplified gyral pattern, periventricular
nodular heterotopia (PVNH), and very small brainstem and cerebellum should raise the possibility of an NDE1 mutation (Fig.
5-41). Although the work of classifying microcephalies is in its infancy, ultimately, the imaging analysis of them will depend on
these characteristics. Significant progress has been made since the prior edition of this book, but a great deal of work remains
(Fig. 5-42).
Table 5-4 Some Genetic Causes of Microcephaly with Known Imaging Findings
CDK5RAP2 9q34 608201 CDK5 regulatory subunit-associated protein 2 AR Simplified gyral pattern
SLC25A19 17q25.3 607196 Mitochondrial deoxy-2-ketoglutaric aciduria AR Simplified sulcation, early death
nucleotide carrier
FOXG1 14q12 164874 QIN protein, a transcription repressor IC Progressive frontal lobe atrophy
ASNS 7q21.3 108370 Asparagine synthetase; transfers ammonia AR Progressive microcephaly and encephalopathy
from a glutamine to aspartic acid Cortical and cerebellar deficiency
NDE1 16p13.11 609449 Role in mitosis and neuron migration AR Profound microcephaly
Simplified gyration
Periventricular heterotopia
TUBA1A 12q13.12 602529 Roles in mitosis, neuron migration, axon AD Variable microcephaly, neuron migration abnl,
pathfinding axon navigation abnl, microlissencephaly
AR, autosomal recessive; AD, autosomal dominant; PVNH, periventricular nodular heterotopia; HCC, hypogenesis of the corpus callosum; WM, white
matter; Abnl, abnormality.
Actin- or tubulinopathies
An important cause of malformations of cortical development associated with microcephaly is mutations of (a) genes encoding
portions of F-actin, a structure that navigates through the developing brain and forms the infrastructure for microtubule
polymerization (257,258); (b) tubulin genes, which encode the proteins that are the building blocks of microtubules (259–262);
(c) genes encoding microtubule-associated proteins (MAPs), which are involved in intracellular transport along microtubules
(259,260,263–265); or (d) genes encoding proteins involved in epigenetic modification of proteins involved in tubulin function
(266–268). Microtubules are of great importance in many aspects of brain development. In proliferating cells, they attach to
microtubule organizing centers (also called centrosomes) and aid in the assembly and organization of the mitotic spindle (259).
Because of the importance of microtubules in cell division, patients with mutations of tubulin genes often have microcephaly
(269,270). Together with actin, microtubule polymerization (attraction) and depolymerization (repulsion) in leading processes
aid in pathfinding of axons and migrating neurons, extending from a centrosome to the leading process, where they interact with
interstitial molecules that induce polymerization in the direction of attractive signals or depolymerization to retract from
repulsive signals. They also complex with so-called microtubule-associated proteins (such as LIS1, cytoplasmic dynein, NDE-
1, and DCX) in pulling the nuclei of migrating neurons forward to follow the leading process during migration, a process
called nucleokinesis; in the absence of nucleokinesis, neuronal migration does not take place. Mutations of tubulin genes cause
many types of cortical malformations in addition to microcephaly; these include lissencephaly and heterotopia (Figs. 5-38, 5-
39, and 5-43), as well as abnormal sulcation and absence or hypoplasia of white matter tracts (Figs. 5-38 and 5-43), wrapping
of the frontal horn around the caudate head (Fig. 5-43), or abnormal sulcation (Fig. 5-43). However, no strict gene–phenotype
relationship has been established because the phenotype depends upon which functions of the microtubules are affected during
the development. This is an important concept, that phenotype resulting from any genetic mutation is determined by the
timing of the mutation, the specific pathway(s) affected by the mutation, and how severely the function of the pathway is
affected.
Figure 5-36 Microcephaly with simplified gyral pattern, moderate and severe. A and B. Moderately simplified gyral pattern. Sagittal T1-
weighted (A) and axial T2-weighted (B) images show too few gyri, shallow sulci (about 1/2 of normal), normal myelination, and a normal
thickness of cerebral cortex. C–E. Extremely simplified gyral pattern with hypoplastic corpus callosum, proportional cerebellum, and
heterotopic gray matter. Sagittal T1-weighted image (C) shows extreme microcephaly with a very thin corpus callosum (white arrows).
Cerebellum and brainstem are proportionate 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 periventricular nodular heterotopia (white arrows) protruding into the ventricular
trigones.
Figure 5-37 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).
Figure 5-38 Microcephaly with absent corpus callosum, frontal pachygyria, and pontocerebellar hypoplasia due to TUBA1A mutation. 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) and absent anterior limb of the internal capsules. Note the abnormal enlargement and shape of
the lateral ventricles wrapping around the basal ganglia (white arrows).
Figure 5-39 Severe microcephaly with lissencephaly (microlissencephaly), absent corpus callosum, abnormal tectal plate (white arrow), and
severe cerebellar hypoplasia (white arrowhead) due to TUBA1A mutation.
One last, important, comment about tubulinopathies is that microtubules are very important in many aspects of brain
formation and, depending upon the gene mutated and the precise mutation, the phenotype of the resulting brain can show
lissencephaly, dysgyria, polymicrogyria, brainstem dysgenesis, cerebellar hypoplasia, cerebellar dysgenesis, white matter
pathway dysgenesis, and (likely) many other brain anomalies.
Cortical dysgenesis with abnormal proliferation (too many cells/abnormal cell types) but without neoplasia
This group of disorders is characterized by abnormalities of cell proliferation due to mutations affecting the mammalian target
of rapamycin (mTOR) pathway (271–273). This pathway transmutes information from amino acids, neurotransmitters, growth
factors, and guidance molecules to the mTOR protein groups (mTORC1 and mTORC2), which are then further transmuted into
the processes of DNA transcription, mRNA translation, and cell growth/proliferation/differentiation (Fig. 5-44). The PI3K,
PTEN, AKT, TSC1, TSC2, DEPDC5, RHEB, and mTOR genes must all be functioning properly for mTOR to be suppressed at
the proper stage of development. When mutations of this pathway disturb the function of mTOR (or, more precisely, of
mTORC1) during developmental processes, the result is overgrowth, which may involve the architecture of the cells
themselves, the size of the cells, the proliferation of the cells, or the differentiation of the cells. (Of note, proper function of
mTOR is also critical for normal aging and disturbances can result in premature neurodegeneration.) The reason the histology
of several disorders in this group (tuberous sclerosis complex, FCD type II, and HME) is nearly identical is that the mutations
all affect the ability of the TSC gene products (hamartin and tuberin) to repress the function of mTOR, resulting in the same
kind of cellular dyplasias and (in the case of HME and TSC) localized overgrowth. (Equally important, abnormalities of
mTOR are found in nonlesional focal epilepsies, and therapies are now being aimed at this pathway (274,275), usually in
association with abnormalities of the GATOR1 complex of mTORC1 (276) (see Fig. 5-44); this discussion is, however,
beyond the scope of this book). In addition to FCD II, TSC, and HME, abnormalities of the mTOR pathway have been
identified in megaloencephaly–capillary malformation (MCAP) syndrome and megaloencephaly–polymicrogyria–polydactyly–
hydrocephalus (MPPH) syndrome (130,271,277,278). Subsequent studies showed that mosaic mutations of a single gene,
PIK3CA, can result in bilateral megaloencephaly with dysplasia (also called dysplastic megaloencephaly or DMEG),
hemimegaloencephaly, or FCD IIa (131). Moreover, increased PI3K/AKT/mTOR signaling was found in all specimens of FCD
IIa and IIb by Jansen et al., even in the absence of detected mutations, strongly implicating other causative mechanisms leading
to a common pathophysiology (131). Therefore, TSC, FCD II, HME, and DMEG will be considered a part of the same family
of diseases in this book. For imaging purposes, they will be divided into dysplasias with normocephaly (FCD types IIa and
IIb) and those with megaloencephaly (HME and DMEG).
Figure 5-40 Less severe microlissencephaly. Sagittal (A) and coronal (B) images show a profoundly microcephalic brain (compare size of
brain to size of face) that is completely smooth, with a thick cortex that has a central cell-sparse zone (S in B). The corpus callosum is
hypogenetic (small splenium, absent inferior genu, and rostrum seen in A) (black arrows) and the ventral pons is extremely small (white arrow
in A).
Figure 5-41 Sagittal image shows profound microcephaly with absent corpus callosum, periventricular nodular heterotopia in right lateral
ventricle (white arrows in B and C), large interhemispheric fissure (F in C and D), tiny pons (white arrow in A), and small vermis. These are
classic findings of an NDE mutation.
Figure 5-42 Leukodysplasia, microcephaly, and cerebral malformation. 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 cortical thickness, very large
subarachnoid spaces, reduced white matter, ventriculomegaly, and lack of operculation. The disproportion between calvarial size and brain
size suggests brain atrophy late in gestation.
Figure 5-43 Multiple anomalies in patient with TUBB2B mutation. A. Sagittal T1 image shows short, thick corpus callosum; small anterior lobe
of the vermis (large white arrow); and small pons (P). B. Coronal T1 image shows normal olfactory sulcus on the right (black arrow) but no
olfactory sulcus or bulb on the left. C–E. Axial T1 (C) and T2 images show the left frontal horn (arrowheads) wrapping around the caudate head,
absence of the anterior limbs of the internal capsules (they should be at the location of the black arrows in C and D), nodular area of
heterotopic gray matter in the right temporal lobe (white arrows), and disorganized sulcation, which is seen on all images.
Dysplasias with abnormal lamination but normal-appearing neurons (FCD 1a and 1b)
Focal cortical dysplasias type 1 are much less common than type II, and FCD Ib are much less common than FCD 1a. On MRI,
FCD 1a (abnormal vertical lamination of cortex) typically looks like an absence or marked reduction of myelination (Figs. 5-
35 and 5-45). In the young infant, the cortex has normal thickness and sulcation, but the underlying white matter has the signal
of completely unmyelinated white matter (Fig. 5-35). This usually contrasts considerable with the contralateral hemisphere,
even during the middle portion of the first year of life when some signal change of myelination has been seen, but may not be
obvious when the contralateral hemisphere has shown a similar change. Older children in their second or third year will have
an appearance of hypomyelination deep to the affected cortex, but the cortex may be less well seen because it is isointense to
the hypomyelinated white matter (Fig. 5-45). PET studies will show markedly decreased uptake of 18F-fluorodeoxyglucose in
the affected area (Figs. 5-35 and 5-45). In contrast, the author’s experience is that FCD Ib (abnormal horizontal lamination of
the cortex, with loss of layers) appears on MRI as cortical thinning, often in a vascular territory (Fig. 5-46). This appearance,
in combination with the common location in the sylvian/perisylvian region, has led some to postulate that FCD Ib results from
prenatal ischemic stroke.
Figure 5-44 Schematic of the mTOR pathway, which is important for transmuting information from amino acids, neurotransmitters, growth
factors, and guidance molecules into the processes of DNA transcription, mRNA translation, and cell growth/proliferation/differentiation, as well
as many other processes still being studied. Understanding of pathways is critical for development of treatments.
Dysplasias with dysplastic neurons (also called focal transmantle cortical dysplasia, bottom of sulcus dysplasia, focal cortical dysplasia types IIa, IIb)
FCD type II is an important cause of epilepsy, both in children and in adults (131,132,202,231,283,288). This malformation is
referred to by many names, including Taylor type of FCD, focal transmantle cortical dysplasia (289), bottom of sulcus
dysplasia (290), and forme fruste tuberous sclerosis (because many FCD II lesions are histologically and radiologically
identical to cortical hamartomas of patients with tuberous sclerosis (71,291), and some show a loss of heterozygosity at the
TSC1 (292) or the TSC2 gene locus (293,294)). In the presence of other manifestations of TSC, the term cortical tuber can be
used. However, FCD type II is preferred and should be used in the absence of other signs of TSC; reports should describe the
transmantle sign or the bottom of sulcus sign to support the diagnosis. 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, kidneys, heart, etc.) for tuberous sclerosis (291).
Patients with FCD type II come to medical attention because of the onset of seizures during the first two years of life,
sometimes as early as the first few weeks (122,202,231,289). They have high seizure frequencies (up to 50 or more per day);
seizures are typically extratemporal in location and outcome after surgery is generally (1) better for FCD II than in FCD I and
(2) better for FCD IIb than for FCD IIa (202,231,283). The seizure type seems to vary with patient’s age (122,295). The
epilepsy of most patients is highly refractory to medication secondary to the high intrinsic epileptogenicity of these lesions,
which may be related to the high levels of glutamate production and release (204,295). Therefore, many of these patients are
helped by surgical resection of the dysplasia if the epileptogenic focus can be identified. 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 (202,204,283,295). EEG
is characterized by total absence of background activity and a distinctive pattern of repetitive, high amplitude, fast spikes
followed by high amplitude slow waves interspersed with relatively flat periods (204).
Figure 5-45 FCD Ia in a 2-year-old boy with refractory epilepsy. A and B. Axial images show a area in the right posterior temporal and right
occipital lobe with increased signal of the white matter (white arrows). Note that the remainder of the white matter has low signal, as expected in
a 2-year-old due to the process of myelination (see Chapter 2). C. Similarly, the white matter of the right posterior temporal lobe/inferior
occipital lobe (white arrows) lacks the normal hyperintensity of myelinated white matter (compare with normal left hemisphere). D. Axial black
and white image from FDG-PET scan shows reduced glucose uptake (black arrows) in the area. Surgical resection revealed histology of FCD
Ia.
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 (124,287). Glial proliferation 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 (296,297). 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 and excessive activation of mTOR, probably
explaining the intrinsic epileptogenicity of the affected cortex (298–301). Developmental lineage studies suggest that the
abnormal cells derive from the neocortical (dorsal) ventricular and SVZs, possibly from RGCs, and are likely glutamatergic
(excitatory transmitters) (302).
Publications describing neuroimaging studies of patients FCD types I and II are confusing, largely because the distinction
between FCD Ib and FCD IIa was unclear in the classifications that preceded the current one (287,303). The experience of this
author suggests that MRI findings in FCD type IIa are most commonly those of blurring of the cortical–white matter junction
(Figs. 5-47 and 5-48), while those of FCD type IIb have a more variable appearance, often with associated T2 hyperintensity
of the subcortical white matter. In some, the T2 hyperintensity extends through the entire cerebral mantle (“transmantle sign”
from cortex to the superolateral border of the lateral ventricle, Figs. 5-49, 5-50, and 5-52), but sometimes it is limited to the
bottom of a sulcus (“bottom of sulcus” sign), and sometimes it extends only partially from the bottom of the sulcus toward the
ventricle; in the latter cases, it is likely that the tract has coursed out of the imaging plane. Still other times, the FCD IIb is
situated entirely within an expanded gyrus (appearing identical to a cortical tuber, Fig. 5-51).
Figure 5-46 FCD 1b in a 3-year-old boy with right body seizures starting in the shoulder and arm. A and B are FLAIR images showing
marked thinning (white arrows) of the insular cortex and some areas of operculum. FCD Ib histologically shows loss of cortical layers; some
(including this author) believe that it is a sequela of prenatal infarction.
In all patients with suspected FCD, thin-section, high-resolution imaging with good signal to noise is essential. We image
the patients at 3T if at all possible, optimizing contrast between gray and white matter on T1, T2, and FLAIR sequences, using
volumetric acquisition with high signal to noise, and reformatting the data at 1 mm slice thickness in the three orthogonal
planes. Suspicious regions are often viewed in multiple oblique planes in real time and (when available) correlated with
results from EEG, MEG, PET or SPECT. When the involved region of brain is large, the cortical gyral pattern may be
abnormal, with expanded gyri and, occasionally, irregular sulci (Fig. 5-52). When 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 (Figs. 5-51 and 5-52) but is often indistinct on FLAIR images
(202,231).
Figure 5-47 FCD IIa in a 3-year-old with left body seizures; he had history of infantile spasms. A–C. Parasagittal (A), axial (B), and coronal
(C) T1-weighted images show a deep right parietal lobe sulcus with blurring (black arrows) of the cortical–white matter junction; this type of
blurring is seen in many FCD IIa lesions. D. Axial T2-weighted image shows a portion of the abnormal sulcus; the signal of the affected sulcus
(white arrows) is hypointense compared to the remainder of the cortex; the deep part of the cortex is more severely affected.
One important feature of FCD IIb is that the detectability of this focus varies with the age of the patient. In (unmyelinated)
neonates and young infants, the affected area is bright on T1-weighted images and somewhat dark on T2-weighted images (Fig.
5-50), similar to what is found in newborns with tuberous sclerosis (see Chapter 6); this is most likely caused by intrinsically
abnormal tissue although some have suggested that it is caused by stimulation of myelination by the electrical activity of the
seizures (304). Between the ages of about 12 and 30 months, while the brain is incompletely myelinated, FCD IIb’s may be
difficult to detect by MR using any standard sequences if it is located in a region that is only partly myelinated. If EEG studies
continue to show focal epileptogenesis in this age range, the T1 hyperintensity of myelinated white matter can be suppressed
with a magnetization transfer pulse (305) to facilitate detection of the hyperintense lesion and correlate its location with PET
or ictal SPECT. If magnetization transfer and PET or SPECT are used, it should not be necessary wait for complete
myelination to confirm the diagnosis. After the white matter myelinates, the transmantle tract, if present, appears hyperintense
on T2-weighted and, especially, FLAIR images, particularly when the image obtained within the plane the tract (Fig. 5-49)
(306), which correlates well with the location of the balloon cells (306,307); however, the abnormal signal is more likely due
to the associated gliosis and hypomyelination of the white matter. The T1 hyperintensity of the tract is difficult to see after
myelination has begun unless the above-mentioned magnetization transfer pulse is used to suppress the hyperintensity of the
white matter (305). Uncommonly, long-standing dysplasias may erode the inner table of the calvarium (Fig. 5-51) like cortical
tubers of tuberous sclerosis (see Chapter 6). On occasion, T2 hyperintensity is seen extending for several millimeters 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.
Figure 5-48 FCD IIa in an 8-year-old boy with long history of seizures, localized to the right frontal lobe by EEG. A. Coronal T1-weighted
image shows blurring of the cortical–white matter junction (black arrows) in the right orbitofrontal cortex. B. Axial FLAIR image shows extensive
cortical–white matter blurring (white arrows) in the right orbitofrontal region (compare to normal left side).
Figure 5-49 Axial (A) and coronal (B) T2-weighted images in a child with medially refractory partial epilepsy shows a hyperintense
“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.
A group of patients with calcified FCD type II lesions have been reported (294). These look like calcified cortical tubers of
tuberous sclerosis (see Chapter 6), with subcortical calcification (very hyperattenuating in CT, hypointense on T2-weighted
MR images, variable, depending upon the density of the calcium, on T1-weighted images) and volume 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 (207). 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. We have not found diffusion
imaging or diffusion tensor imaging to be helpful.
We do not use proton MR spectroscopy for the evaluation of possible FCD. 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 (221,227). The choline peak is normal to slightly increased. On short echo spectra (TE = 20–30 ms),
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.
Figure 5-50 FCD IIb in young infant. Coronal T1-weighted (A) and T2-weighted (B) 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.
Figure 5-51 FCD IIb resembling a tuber of tuberous sclerosis. Axial T1 (A) and FLAIR (B) images and coronal T2 image (C) show a focally
expanded gyrus (arrows) in the left temporal lobe, causing remodeling of the overlying calvarium. The dysplasia (cortex and underlying white
matter) is hypointense in (A) and hyperintense in (B) and (C). The cortical–white matter junction is more indistinct in (A) and (B) than in (C).
Figure 5-52 FCD IIb with transmantle sign resembling cortical tuber. Note that, on all sequences (A–D), the dysplasia in the subcortical region
(D) has signal intensity of water but is expanding the gyrus and has a transmantle sign (arrow).
Pathologically, HME and dysplastic megalencephaly are disorders reflecting abnormalities in proliferation, migration,
maturation, and differentiation of neurons (327). Affected hemispheres contain areas of pachygyria, polymicrogyria, and
neuronal heterotopia, as well as dyslamination, dysplastic neurons, immature neurons, balloon cells, hypomyelination, and
astrogliosis of the hemispheric white matter (312,313,318,327,328).
On CT and MR, part or all of a single hemisphere or bilateral hemispheres may be affected; when bilateral, involvement is
usually fairly symmetrical. When asymmetrical, the asymmetry is usually mild. When involvement is unilateral and localized,
the frontal and occipital lobes are involved in nearly equal frequency (Fig. 5-53) (329). An important concept in unilateral
megalencephaly is that, because of the mosaicism, no two hemispheres look exactly the same; each seems to have its own
unique topology and pattern of involvement. The involved region may be moderately to markedly enlarged. Although the
appearance of the affected hemisphere(s) 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 cortical thickening
(Figs. 5-53 and 5-54); however, the gyral pattern may appear grossly normal or may be frankly polymicrogyric (Fig. 5-55) or
agyric (Fig. 5-56) (310,311). The white matter is of abnormally low signal on CT and often shows heterogeneous signal
intensity (some T2 hyperintense [Fig. 5-55] and some nearly isointense to myelinated white matter) on MR studies,
representing heterotopia and dysplastic neurons and glia. The configuration of the lateral ventricle in affected HME hemisphere
is usually characteristic; it is enlarged, usually in proportion to the enlargement of the affected hemisphere, with the frontal
horn being abnormally straight and pointing superiorly and anteriorly (Figs. 5-54 and 5-55) (310). In occasional patients,
however, the ipsilateral ventricle is small (330). Rarely, the affected area of the HME brain has a bizarre, hamartomatous
appearance (right hemisphere in Fig. 5-56) (310,311); in this situation, the characteristic enlargement of the affected
hemisphere and ventricle allows diagnosis. In a minority of HME cases, the cerebellar hemisphere and brainstem ipsilateral to
the affected cerebral hemisphere are enlarged (331).
Figure 5-53 Localized megaloencephaly in an 8-year-old with developmental delay and seizures. Axial T1 (A) and coronal T2 (B) images
show enlargement of the left posterior temporal and occipital lobe (white arrows) with broad gyri, shallow sulci, and blurred differentiation of
cortex and underlying white matter. The axial T1 image better shows abnormal white matter signal intensity, and both show poor cortical–white
matter differentiation in the megaloencephalic region (arrows).
In dysplastic megalencephaly, the location(s) of the dysplasia varies, but the region around the insula seems commonly
involved. Occasionally, the diagnosis is made in utero by identification of polydactyly combined with early development of
abnormally small gyri and sulci (332). More commonly, affected patients present in infancy with macrocephaly, sometimes
with hypotonia, seizures, or hypoglycemia (333). Genetic analysis may show germline mutations of AKT3, PIK3R2, PIK3CA,
or other genes in the mTOR pathway (131,277,314,319,333,334). Mutations of PTEN can cause dysplastic megalencephaly
associated with Cowden syndrome: malignancy risk, intestinal polyposis and other mucocutaneous lesions with malignancy
risk (breast, endometrium, thyroid) or Bannayan-Riley-Ruvalcaba syndrome with dysplastic megalencephaly (unilateral or
bilateral), lipomas, penile pigmented macules and malignancy risk similar to Cowden syndrome (314). When dysplastic-
appearing cortex is seen in these areas in babies with relative macrocephaly (Fig. 5-57), the baby should be closely watched
as the head may grow precipitously and CSF diversion may become necessary; cerebellar tonsillar herniation and
hydrosyringomyelia (see Chapter 9) may ensue (333,335). (Remember that congenital CMV [see Chapter 11] often has
bilateral perisylvian PMG, but they have normal to small heads, in contrast to dysplastic megalencephaly.) Evidence of other
signs of overgrowth syndromes (vascular, cutaneous, patterning, mesenchymal masses) should be sought.
Figure 5-54 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 positron emission tomography (PET) study (D) shows reduced uptake of 18-F fluorodeoxyglucose in the affected left
hemisphere, most notably in the posterior hemisphere (white arrows).
It is important to recognize that the radiologic appearance of the HME brain may change over time. Wolpert et al.
reported a patient in whom the affected hemisphere atrophied during the first year of life and was smaller than the contralateral
(normal) hemisphere when imaged at age 1 year (336). An analogous change was seen on SPECT imaging, where the tracer
uptake in the affected hemisphere diminished over time (337). We have seen reduction in hemispheric size of affected patients
after episodes of status epilepticus. Salamon et al. reported that the “normal” hemisphere is often smaller than in age-matched
controls and suggest that it is not normal at all (318); indeed, they report that children with small “normal” hemispheres have
poorer neurodevelopmental outcomes after hemispherectomy.
Proton MR spectroscopy in dysplastic megalencephaly syndromes shows reduction of the glutamate and NAA peaks and
higher choline 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 (221,227) 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. 5-54) (338). Anatomic hemispherectomy, anatomical hemispherotomy, functional
hemispherectomy, or hemidecortication may, therefore, be indicated if the seizure disorder is intractable and the contralateral
hemisphere is normal (339,340). However, hemispherectomy is contraindicated if the contralateral hemisphere has cortical
malformations; therefore, careful assessment of the contralateral hemisphere is crucial in affected patients.
Localized dysgenesis without mTOR involvement
The only disorder currently known in which cortical dysgenesis is localized and is not associated (as far as we know) with
mTOR involvement is sublobar dysplasia. This is an uncommon malformation of cortical development; only two reports have
been published (341,342). The largest series was of five unrelated patients with a localized region of dysplastic-appearing
brain that was separated from the remainder of the affected lobe or hemisphere by a deep infolding of cortex (Fig. 5-58). It was
called sublobar dysplasia because of the location and the imaging appearance, which showed characteristics of dysplastic
brain (341). Four of five patients presented with seizures; the fifth presented with a calvarial anomaly but developed epilepsy
within the first few years. All were neurologically and developmentally normal. MRI showed that the areas of sublobar
dysplasia were frontal in two patients and temporal, parietal, and occipital in one patient each. The cortex in the affected
region of brain was thickened with shallow sulci and an abnormal sulcal pattern in all affected patients. In three patients, the
cortical–white matter junction was irregular. The ipsilateral lateral ventricle was dysmorphic in all patients. Associated
anomalies included callosal anomalies (five patients), cerebellar vermian hypoplasia (three patients), and venous
malformation (one patient). A second report described a single patient born with facial anomalies (hypertelorism and a
proboscis) to nonconsanguineous parents of German descent after an uneventful pregnancy (342). Medically, refractory focal
seizures began during the second year of life. Subsequent MRI showed dysmorphic brain lateral to the insula, posterior to the
frontal operculum and anterior the temporal operculum, separated from the adjacent brain by subarachnoid space. The lesion
was resected (after congruent findings suggested focal, well-circumscribed epileptogenesis from the malformation) and
became seizure free. Histology showed cortical dyslamination with many heterotopic neurons and dysplastic neurons
surrounded by a strong reactive astrogliosis but no evidence of inflammatory or neoplastic components. Sublobar dysplasia
appears to be a distinct cortical malformation of unknown etiology that causes no neurologic deficits but ultimately results in
epilepsy. Histologic findings suggest an abnormality of neuronal proliferation.
Cortical dysgenesis with abnormal cell proliferation and neoplasia, including dysembryoplastic
neuroepithelial tumor (DNET), ganglioglioma, and gangliocytoma
These disorders are generally considered neoplastic (although it is likely that there is a dysplastic component). They are
discussed in Chapter 7.
Figure 5-55 Hemimegalencephaly with more severe anomaly. Axial T1-weighted (A and B) and T2-weighted (C and D) images of a 3-month-
old infant with macrocephaly and seizures show irregular cortex that appears polymicrogyric in the right frontal lobe (small white arrows) and
left frontalcortex (large white arrows) with extensive white matter anomaly (gliosis?) in the deep white matter (asterisks). The ipsilateral
ventricle is large with a straight frontal horn (small black arrows in A).
Figure 5-56 Hemimegalencephaly with bizarre, lissencephalic enlargement of the entire right hemisphere. The cortex is thick and
lissencephalic in the posterior temporal and occipital lobes and pachygyric in the frontal lobe. The small size of the midbrain in A and C gives
indication of the massive degree of brain enlargement. The periventricular regions of hyperintensity in B and hypointensity in D (white arrows)
represent calcifications.
Although heterotopia likely have many causes, one intriguing hypothesis is that many (most?) PNH are caused by loss of
integrity of the neuroependyma at the ventricular wall, due to either physical trauma or mutations that inhibit the ability to
repair the ependyma after migration of cells from the periventricular zone (344,345). The loss of integrity of the
neuroependyma may disrupt the attachment of RGCs, thus impairing migration of neurons to the radial glia from the ventricular
zone (345,346). This is an attractive hypothesis, as it explains the high incidence of PNH in patients with congenital
hydrocephalus (such as patients with myelomeningoceles) or other disturbances of CSF flow (cephaloceles).
Patients with PVNH can be separated into three large groups: anterior predominant or diffuse PNH, posterior predominant
(temporal–trigonal or infrasylvian) PNH, and linear or band-like PNH (distinguished from so-called band heterotopia or
double cortex in which the layer of gray matter is situated in the white matter, separated from the ependyma). Most patients
have heterotopia that are asymmetric and single or few in number; they may be found anywhere in the periventricular region
(126) but are most common in the trigones (Fig. 5-59); these may be isolated or associated with a wide range of other CNS or
systemic anomalies (126,343). A second group has multiple heterotopia that are largely posteriorly located (trigones,
occipital horns, temporal horns, Fig. 5-60); associated anomalies of the cerebellum (typically dysmorphic, Fig. 5-60) and
corpus callosum (hypoplastic), diminished white matter volume, and underrotation of the hippocampi are common (347–349).
The third group has PNH located either anteriorly (in the frontal horns and bodies) or diffusely throughout the ventricular
system; these are sometimes associated with mega cisterna magna (Fig. 5-61) or corpus callosum anomalies (often agenesis)
(126,348). A smaller number of patients in the third group have a large number of heterotopic nodules that completely or nearly
completely line the walls of the lateral ventricles (Fig. 5-72). PNH are uncommonly familial but are often associated with
other brain anomalies such as the Chiari II malformation, cerebellar hypoplasia, cephaloceles, ectopic posterior pituitary
gland, polymicrogyria, frontonasal dysplasia, Ehlers-Danlos syndrome, Donnai-Barrow syndrome, fragile X syndrome, and
agenesis of the corpus callosum (126,350–354). PNH may be familial, with both X-linked and autosomal recessive patterns of
inheritance (355–357). A number of causative genes have been identified (355), including the filamin-A (FLNA) gene at
chromosome Xq28 (358–360) and the ARFGEF2 gene at chromosome 20q13 (associated with microcephaly (357)). Other loci
associated with PNH include 1p36 (361), 5q14.3-15 (129), and 7q11.23 (362).
Figure 5-57 Dysplastic megaloencephaly in infant with severe macrocephaly (>3 SD above mean) and infantile spasms. A. Sagittal T1-
weighted image shows infant has abnormal midline sulcation (note absence of cingulate gyrus and sulcus) and abnormally shaped corpus
callosum. B and C. Axial T2-weighted images show enlarged ventricles and extensive polymicrogyria in the frontal, temporal, and occipital
lobes. Basal ganglia (arrows) are dysmorphic and small. Germinolytic cysts (c) are present at the foramina of Monro in (C). D. Coronal T2-
weighted image shows the size discrepancy between the markedly enlarged cerebral hemispheres and the cerebellum. Note the abnormal
gyration throughout the cerebral hemispheres.
Whether sporadic or familial, children with isolated heterotopia (i.e., no other brain or visceral anomalies) usually manifest
mild clinical 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 (8,126). Microscopic FCD 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 (363). Girls with X-linked PNH often have a large cisterna magna and may have a small cerebellar
vermis (Fig. 5-61) (358,359,364), while 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
(126,365). Children with ARFGEF2 mutations typically have microcephaly (366,367). Boys with syndromic subependymal
heterotopia may have associated cortical malformations, syndactyly, ear abnormalities, and severe mental retardation (358).
Girls or boys with periventricular heterotopia and other malformations (callosal agenesis, schizencephaly, polymicrogyria,
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 (8,368).
Figure 5-58 Sublobar dysplasia in an infant with seizures. A. Sagittal T1 image shows a gray matter–intensity mass (arrows) in the midline,
extending from the midbrain into the cerebrum. No plane of separation from the midbrain can be seen. B and C. Axial T2 images show that the
dysplasia appears clearly distinct from normal tissue in some areas (black arrows in B) but less so in others (white arrows in B). Two parts of
the lesion are seen in C (white arrows). D. Coronal T2 image shows the large size of the dysplastic mass (white arrows); in this plane, it
appears heterogeneous with components of both gray matter and unmyelinated white matter, separating the cerebral hemispheres.
On imaging studies, PVNH are smooth, round, or ovoid masses (Figs. 5-59 to 5-61), often found in clusters, that are
isointense with gray matter on all imaging sequences. When ovoid, the long axis is parallel to the adjacent ventricular wall.
They may appear exophytic, protruding into the adjacent lateral ventricle (Fig. 5-59A) and sometimes causing the ventricle to
appear compressed, or they may extend into adjacent white matter (Fig. 5-61D); occasionally, particularly anterolateral to the
frontal horns, the heterotopia are entirely extraventricular with 1 to 2 mm of white matter separating them from the ependyma.
Some of the clusters of nodules have recently been found to have small clusters of axons within them, which may explain how
seizures are transmitted from these nodules to the cerebral cortex (369). PNH due to FLNA mutations vary in configuration
depending on what part of the filamin-a protein the mutation affects and how severely protein function is impaired
(355,365,370). Although most patients with mutation of this gene show diffuse PNH lining the walls of the bodies of the lateral
ventricles, some with (presumably mosaic) missense mutations may show only a few bilateral peritrigonal PNH (365). Patients
with PNH associated with FLNA mutations also have an increased incidence of associated mega cisterna magna (Fig. 5-61)
(365,371,372).
Figure 5-59 Postnatal and fetal periventricular nodular posterior heterotopia confined to the walls of the trigones and occipital horns of the
lateral ventricles. A and B. Adult images. Axial T1-weighted image (A) and coronal T2-weighted image (B) show nodules of heterotopic gray
matter (white arrows) protruding into the ventricular trigones. When confined to temporal horns and trigones, PVNH can be difficult to identify on
axial images. C and D. Fetal images. Large black arrows show PVNH as hypointense nodules in the walls of both ventricular trigones. Note a
small schizencephalic cleft (smaller black arrow in C) between the superior right occipital horn and the subarachnoid space.
Periventricular heterotopia can be 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 (373–375)), (b) their signal intensity (subependymal hamartomas of tuberous sclerosis are
usually iso- to hypointense compared to mature white matter (376), not isointense with gray matter), and (c) the fact that they
do not enhance after intravenous infusion of paramagnetic contrast (373,376).
PNH can be identified by fetal MR imaging and fetal brain sonography (377,378), appearing as nodules of gray matter
intensity in the wall of the lateral ventricle (Fig. 5-59C and D). As in the postnatal diagnosis, they are often associated with
other anomalies such as mega cisterna magna, cephalocele, schizencephaly 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 PNH (Fig. 5-59), are likely to be heterotopia. If uncertain, a follow-up MR examination in 2 to 3 weeks
may be useful.
Figure 5-60 Heterotopia in the temporal horns, occipital horns, and trigones associated with cerebellar vermian hypo/dysgenesis. A and B.
Axial T1-weighted images show gray matter nodules in the trigones (black arrows in A and B) and occipital and temporal horns (black arrows in
B). C and D. Note anteroposterior elongation of the fourth ventricle (4) and the funny shape and small size of the vermis (white arrow). D shows
heterotopia around occipital horns and extending upward into the centra semiovale (white arrows).
PNH 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 MR imaging to look for the cause of the ventricular
enlargement (377). 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 PNH.
Rarely, periventricular heterotopia are smooth and linear, conforming to the contour of the wall of the lateral ventricle (Fig.
5-62). The significance of these heterotopia and the relationship to PVNH (or to band heterotopia) are unclear.
Figure 5-61 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 heterotopia (white
arrows) along the ventricular bodies, while coronal T2-weighted image (C) shows heterotopia (white arrows) extending into white matter lateral
to ventricular bodies and temporal horns.
Malformations due to localized or generalized abnormal transmantle migration (radial and nonradial)
Focal subcortical heterotopia
Focal subcortical heterotopia is the name given to large, swirling, curvilinear masses of mixed gray matter and white matter,
extending from cortex to ventricle and often containing blood vessels and CSF (possibly from subarachnoid space) (379,380).
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 typically have 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 (379,380). Almost all affected patients eventually develop epilepsy, usually during the first or second
decades (379,380). Some early reports suggested that surgical resection may be useful in patients with subcortical heterotopia
and medically refractory epilepsy (381), but some cases are controlled by medication alone (382). The cause is unknown, but
one pathologic study reported the presence of small reelin-positive cells (reelin is a compound secreted by Cajal-Retzius cells
in layer 1 of the cerebral cortex that signals neurons to detach from the RGC and terminate its migration) within the heterotopia,
suggesting that ectopic neurons or malprogrammed neurons may be signaling neurons to stop their migration (383). If verified,
this may also explain why affected hemispheres are small and why ectopic blood vessels and subarachnoid space are
sometimes seen within these lesions (see below). Another recent study showed that mutation of the tubulin-associated protein
gene EML1 causes ribbon-like subcortical heterotopia; the mechanism here does not appear to be a problem with migration of
neurons but with abnormalities of maintenance and organization of neuronal progenitors in the ventricular zone (384).
Combined with the work of Sheen et al. (see previous section), this supports the concepts that some periventricular,
subcortical, and subpial heterotopia (at least) result more from disruption of radial glia than of the migrating neurons
themselves (345,346,385).
Figure 5-62 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.
On neuroimaging, focal subcortical heterotopia appear as large, somewhat heterogeneous masses that are isointense to
cortical gray matter on all sequences. Some appear as deeply infolded cortex, often crossing the entire cerebral mantle from
cortex to ventricle (Fig. 5-63), and others as multinodular gray matter masses (Fig. 5-64), and still others appear to be
composed of swirling, curvilinear bands of gray matter (Fig. 5-65). When the heterotopia are localized, the portion of the
hemisphere that is affected is almost always small compared with the contralateral side, and the overlying cortex is thin with
shallow sulci, somewhat resembling polymicrogyria (Figs. 5-63B and 5-64). Subcortical heterotopia may appear to exert mass
effect on the adjacent ventricle or the interhemispheric fissure (Fig. 5-64) 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
administration of contrast agents (380). Associated brain anomalies are common; callosal agenesis or hypogenesis is present in
up to 70%, and the ipsilateral basal ganglia are dysmorphic in greater than 70% (379). As noted above, subcortical heterotopia
will sometimes appear to contain blood vessels or fluid (Fig. 5-65); on superficial examination, these might be mistaken for
tumor vascularity or cysts. Closer examination in these cases will show that the vessels and fluid are cerebrospinal fluid and
vessels coursing inward from the surface of the cerebral cortex and are in communication with the subarachnoid space
(379,380,386). The embryological mechanism by which the CSF and vessels get into the center of the cerebral hemisphere is
unclear, but the aforementioned discovery of excessive reelin in these lesions suggests the possibility of a premature “stop”
sign for the migrating neurons.
Figure 5-63 Focal transmantle subcortical heterotopia in a 7-year-old with new onset of seizures. A. Parasagittal T1 image shows continuous
irregular gray matter (black arrows) along the superior surface of the trigone and occipital horn of the left lateral ventricle. Note that the overlying
sulci are abnormally deep, adding to the transmantle-like character of the malformation. B. Coronal T1 image at the posterior thalamus level
shows that the curvilinear heterotopic mass (large white arrows) curves laterally from the posterior temporal horn and then inferomedially to the
bottom of the collateral sulcus. Another focus of heterotopia (black arrow: this was continuous with the more caudal heterotopia when viewed
on sagittal and coronal images) is seen indenting the body of the ventricle. Note that the affected occipital lobe is smaller than the (normal)
contralateral occipital lobe; the overlying cortex (small white arrows) is thin and undersulcated. C. Axial T1 image shows the heterotopia
coursing posteriorly along the collapsed occipital horn (white arrow) to reach the lateral occipital sulcus. The more anterior nodule (black arrow)
was continuous on other images.
Figure 5-64 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 arrowheads). The affected hemisphere is small. (These images are courtesy
of Dr. Gilbert Vezina, Washington, DC.)
Occasionally, regions of heterotopia course radially through the cerebral mantle from the cortex to the ventricular surface
(Fig. 5-66). These patients almost always come to medical attention because of epilepsy; occasionally, they have fixed
neurological deficits as well, with the type of deficit depending on the location of the lesion. These transmantle 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 schizencephalic cleft. The relationship of transmantle heterotopia to
schizencephaly is unclear; the morphology is quite different from transmantle dysplasias (a subset of FCD IIb, discussed in the
previous section).
No fetal diagnoses of subcortical heterotopia have been reported.
Marsh et al. (387) reported that proton spectroscopy of heterotopia shows elevated creatine and choline with normal NAA.
Li et al. found that the NAA/Cr ratio is variable, ranging from normal to low compared with age-matched normal controls
(227). In our limited experience, perfusion of heterotopia is similar to that of cerebral cortex.
Malformations with too few or too shallow sulci
Anterior predominant, posterior predominant, or diffuse classic (four-layered) lissencephaly (LIS) and subcortical band heterotopia (SBH), associated with
mutations of tubulin or microtubule-associated protein mutations
Smooth brains can result from many causes, including congenital infection (especially cytomegalovirus, see Chapter 11) and
diminished cell proliferation (“microcephaly with simplified gyral pattern,” see Malformations Secondary to Abnormal Stem
Cell Proliferation in this chapter), in addition to abnormal neuronal migration. Careful attention to factors such as brain size
(three or more standard deviations below normal at birth suggest microlissencephaly, which is often associated with TUBA1A
or ARX mutations (269,388,389)), cortical thickness (diminished thickness should suggest insufficient neuron proliferation or
in utero infection, whereas increased thickness suggests mutations in genes for F-actin, alpha or beta tubulin or microtubule-
associated proteins (244,269,270)), and smoothness of the cortical–white matter junction (irregularity of this junction indicates
either polymicrogyria from mutation or midgestational injury or cobblestone cortex from disturbances of late migration due to
gaps in the pial limiting membrane) 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, discussed in the next section on Malformations due to Abnormal
Cortical Organization or Late Migration) and those due to diffuse arrest of neuronal migration (lissencephalies).
Lissencephaly (the agyria-pachygyria complex)
The term lissencephaly 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 pachygyria is defined as the presence of a few broad, flat gyri with thickened cortex
and is used interchangeably with the term “incomplete lissencephaly.” 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 migration (390). A finding of broad gyri and shallow sulci in the absence of thickened cortex should be
considered a simplified gyral pattern, resulting from either deficient cell production or impaired white matter development in
utero (390). Of importance in distinguishing pachygyria from polymicrogyria (see section below on Malformations Secondary
to Abnormal Late Neuronal Migration and Cortical Organization) is the observation that the sulci seen in pachygyria (and in
simplified gyral patterns) is the finding of normal, early forming sulci that can be identified and named by those with
knowledge of neuroanatomy; the sulci in polymicrogyria 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 polymicrogyria,
with high-resolution imaging, will be seen to have irregularities due to the microgyri and microsulci (391).
Figure 5-65 Extensive bilateral curvilinear SCH in an infant with early-onset epilepsy. Images through the cerebrum show curvilinear cortex
swirling inward from the brain surface. CSF and blood vessels are seen in some areas (white arrows), suggesting that this is cortical infolding
in continuity with the subarachnoid spaces.
Both agyria and pachygyria are likely caused by abnormal regulation of neuron migration. One important component of
neuron migration is microtubule activity, as actins and microtubules, with the help of microtubule-associated proteins (called
MAPs), are essential for navigation of the leading process of the migrating neuron through the developing brain and for and
for nucleokinesis, the process of perinuclear and nuclear translocation following the leading process (259,392,393). Actins
and microtubules are involved in many key intracellular processes, such as mitotic spindle orientation, intracellular protein
transport, and nuclear migration; their dysfunction causes impaired neuron proliferation, impaired neuronal migration, and
impaired axon pathfinding (259–261,392,394–396). Therefore, it is not surprising that most genes that cause classic
lissencephaly code for actins (which precede tubulins in pathfinding through the developing brain (257,260,392,397)), tubulins
(the building blocks of microtubules), or MAPs (244,270,389) (fewer mutations of the actin family have been found, possibly
because actins are even more fundamental than microtubules and their mutations may be less compatible with fetal survival).
Lissencephaly is, therefore, caused by undermigration of neurons and is distinct from cobblestone malformations due to
abnormal pial basement membrane formation (sometimes called lissencephaly type II), which are caused by overmigration of
neurons through gaps in the pial limiting membrane (discussed in the following section on Malformations Secondary to
Abnormal Cortical Organization and Late Migration) (Table 5-5).
Figure 5-66 Transmantle heterotopia. Coronal 3D GRE image shows a linear focus of gray matter extending from the cortex to the ventricular
surface. No dimple is seen at the ventricular surface to suggest the presence of a cleft (which would be indicative of closed-lip
schizencephaly).
Lissencephaly due to mutations of actins, tubulins, and microtubule-associated proteins
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 cortical layer, and (d) the thickest part of the cortex located deep (medial) to the cell-
sparse zone (Fig. 5-67, keep in mind that all four layers are not usually seen on MRI). Considerable work over the past
several years has shown that most lissencephalies and band heterotopia (slightly thick cortex with shallow sulci overlying
a layer of incompletely migrated cortical neurons) are the result of mutations of tubulins (proteins that compose
microtubules), actins (proteins that do pathfinding before the microtubules follow them (392,398,399)), and microtubule-
associated proteins (MAPs, proteins that link to microtubules for intracellular transport). Some of the most commonly
affected MAPs involved in neuronal migration include doublecortin (DCX), LIS1, NDE1, dyneins (particularly DYNC1H1),
and kinesins (particularly KIF2A) (244,251,270,389). It has been postulated that about 50% of patients with lissencephaly
have LIS1 mutations, including a subset that also has mutation of the adjacent YWHAE gene, resulting in characteristic 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 (400,401). Another approximately
10% of patients with classic lissencephaly have mutations of the DCX gene at chromosome Xq22.3-q23 (X-linked
lissencephaly (402)); these patients are typically hemizygous boys whose mothers have band heterotopia (403–405) (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 (406); the diagnosis can be suggested if the patient has
significant microcephaly (often called microlissencephaly, with OFC more than 3SD below the mean), an anomalous corpus
callosum (absent rostrum, abnormally curved body, or vertical splenium), small cerebellum, rounded hippocampi, absent
anterior limb of internal capsule or thin/dysmorphic brainstem are identified (270,389). The percentage caused by mutations of
other tubulin genes, dynein genes, and kinesin genes (Table 5-6) is unknown at this time. It should be noted that WDR62
mutations are considered microlissencephaly by some authors (407), but close examination of many MRIs shows multiple
small gyri and sulci, more suggestive of polymicrogyria, as well as variable corpus callosum morphology; it is not clear
whether these differences reflect different mutations or mutations of additional genes (408).
Other than those with severe microcephaly, which suggests mutation of tubulin or actin genes, children with classic
lissencephaly have similar neurological syndromes, although the age of onset and severity of the clinical syndrome may vary
depending upon the precise mutation and consequent severity of the cortical malformation (270,409,410); indeed, Bahi-
Buisson et al. found several “hot spot” mutations that represent 40% of all TUBA1A mutations. Those with complete classic
lissencephaly typically come to medical attention during the first few months life due to early neurologic deficits (mild
hypotonia, poor feeding, and opisthotonos), delayed motor milestones later in the first year, or onset of seizures (most common)
(411); less severe involvement results in less severe early feeding difficulties, but worsening often occurs around age 3 years
(411). 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 (411).
Macroscopic examination of the brain shows that most patients in this group have areas of both agyria and pachygyria, that
is, incomplete lissencephaly; especially in mutations of tubulins, regions of band heterotopia may be present, as well
(270,410). The severity of the gyral pattern is related to the number of neurons that are mutated and to the severity of the
mutation (405,412–418). Fewer mutated neurons (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) (389,418). In patients with LIS1, TUBA1A, DYNC1H1, and TUBBG mutations, the areas of agyria are most
frequently parieto-occipital in location, while the pachygyric areas are more common in the frontal and temporal regions
(244,270,419); indeed, about two-thirds of patients with posterior predominant lissencephaly and normal or nearly normal
head size have mutations of LIS1 (409). 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 (420), although those with
severe microcephaly should be tested for F-actin mutations (Baraitser-Winter syndrome) (392). 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 containing 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. 5-67) (421). The inner layer of
neurons is thought to represent neurons that were prematurely stopped during their migration to the cortex. The presence of
radial or horizontal organization is variable in the cortex of patients with TUBA1A mutations; a cell-sparse zone may or may
not (128,389,422) be identified, depending upon the location of the mutation and, perhaps, other factors.
Table 5-6 Genes that Cause Classic Lissencephaly
Gene Gene Location Head Size Gyrus Gradient Corpus Callosum Cerebellum
LIS1 17p13.3 Low normal P>A Vertical Mild anterior vermis hypoplasia
splenium
DYNC1H1 14q32.31 Low normal P>A Vertical Mild anterior vermis hypoplasia
splenium
Imaging studies of patients with complete classic lissencephaly (agyria) reveal a smooth brain surface with diminished
white matter and shallow, vertically oriented, sylvian fissures (Figs. 5-68 and 5-69) (401,419,423–425). In patients with
mutations of MAPs, a thin outer cortical layer is separated from a thick deeper cortical layer by a zone of white matter (the
cell-sparse zone, shown by arrows in Fig. 5-69) that seems to myelinate normally as the child matures. The LIS1 cerebrum has
been described as having a figure-of-eight appearance on axial images as a result of the shallow, vertical sylvian fissures, and
this same appearance can be found in severe TUBA1A mutations (Fig. 5-70). The ventricular trigones and occipital horns are
enlarged, mostly because of underdevelopment of the calcarine sulci (Fig. 5-58) (419). The brainstem often appears small,
probably because many of the corticospinal and corticobulbar tracts do not form. Absence or severe hypoplasia or hypogenesis
of the corpus callosum, other axonal pathfinding anomalies (such as absence of the anterior limb of the internal capsule), or
severe pontine/cerebellar hypoplasia (Fig. 5-70) should suggest a TUBA1A mutation (244,269,270,389). However, the reader
should be aware that TUBA1A mutations can result in a wide range of brain phenotypes (244,269,270,389), depending upon the
molecular pathways affected during development; microlissencephaly is the most severe. A vertical callosal splenium (Fig. 5-
69) or small anterior vermis should suggest a MAP mutation (269). 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. 5-71), 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 lissencephalic patient has a shallow, rounded sylvian fissure (426)).
Figure 5-68 Complete and nearly complete agyria. A. Sagittal T1-weighted image in a neonate shows no medial hemispheric sulci other than
the parieto-occipital sulcus. B and C. Axial (B) and coronal (C) T2-weighted images in the same patient shown in (A) show a smooth cerebral
surface and the typical cortical pattern with thin (dark) outer cortical layer, relatively thick (bright) cell-sparse zone, and thick (dark) inner
cortical layer (black arrows). Sulci are present in frontal (B) and temporal (C) lobes. Note relative enlargement of the ventricular trigones. D and
E. T1- and T2-weighted images of complete agyria.
Figure 5-69 Agyria in a 6-month-old with a LIS1 mutation. A. Sagittal T1-weighted image shows a 90° angle of the corpus callosum (white
arrows), common in lissencephalies associated with MAP proteins. B and C. Axial T2-weighted images show a nearly completely smooth, thin
outer cortex (a few small gyri, especially in prefrontal cortex), the cell-sparse zone (white arrows), and a band (B) of incompletely myelinated
neurons. Note that the cell-sparse zone is more clearly seen in the more severely affected posterior frontal, parietal, and occipital cortices. D.
Coronal T1 image does not show the band (B) or the cell-sparse zone (arrows) as clearly. E. In a different patient, a second, inner band is seen
adjacent to the right trigone, separated from the outer band by an inner cell-sparse zone.
Figure 5-70 Agyria in a neonate secondary to TUBA1A mutation. A. Sagittal T1 image shows smooth cerebrum with small craniofacial ratio
diagnostic of microcephaly. Note the very small pons and cerebellum that is very characteristic of tubulin mutations. B. Axial T2-weighted
image shows fused basal ganglia (BG) due to absence of anterior limb of the internal capsule, which is very common in tubulin mutations. Note
the relatively small band of heterotopic gray matter (B) and large cell-sparse zone (CS).
Incomplete lissencephaly, in which the brain is pachygyric (Fig. 5-72), or areas of pachygyria are present together with
areas of agyria or areas of normal brain (Fig. 5-73), is much more common than complete lissencephaly. Areas of pachygyria
also have a thickened cortex, but broad gyri and shallow sulci (Figs. 5-72 and 5-73) are present. Pachygyria can be
distinguished from polymicrogyria (discussed later in this chapter) by obtaining thin section, high-resolution, high-contrast
images to optimally assess the malformation whenever possible (201,391). 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. 5-72 and 5-73). In
polymicrogyria, the cortical–white matter junction is always irregular (201,427,428) (see Fig. 5-74 and subsequent section on
polymicrogyria under “Malformations Secondary to Abnormal Cortical Organization”). Pachygyria can be focal or diffuse.
When focal (Fig. 5-73), it is almost always bilateral and typically posterior in patients with MAP mutations (269,270). When
diffuse (Fig. 5-60), it is often associated with regions of agyria and is typically more severe in the parieto-occipital region of
the brain (and least severe in the frontal and temporal lobes) in LIS1, TUBA1A, DYNC1H1, and KIF2A mutations (420).
Diffuse pachygyria without an underlying band heterotopia is often associated with mutations of F-actin and is called the
Baraitser-Winter syndrome (Fig. 5-72) (392,429). The midfrontal lobes are most severely affected in pachygyria secondary to
DCX mutations (Fig. 5-75) (244,269,270,420), and the sylvian/perisylvian cortex may be exclusively affected in some
TUBA1A mutations (270); as with other patients with TUBA1A mutations, these will usually have callosal anomalies, absence
of the anterior limb of the internal capsule, and some degree of cerebellar hypoplasia (270). When patients have classic
lissencephaly 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.
5-75D).
Band heterotopia/double cortex
The double cortex, or band heterotopia, seen in women with DCX mutations constitutes a distinct type of MAP-associated
malformation because only about half of the neurons are affected (the others have one normally functioning X chromosome)
(430). A wide range of severity is found in affected women, which appears to depend upon the effects of the mutation upon
stability of protein structure and, in turn, upon the substituted amino acid (410). In general, the severity of the clinical syndrome
is associated with the thickness of the band (thicker band is associated with more severe outcome in female patients) and
family history (sporadic band heterotopia more severe than familial band heterotopia) (410). Some women with familial band
heterotopia have normal intelligence with epilepsy and sometimes completely normal MRIs (410,431). Males with DCX
mutations have lissencephaly and are very severely affected (432). Imaging findings (Fig. 5-76) vary and typically correlate
fairly well with clinical phenotypes: thick bands with thin cortex and relatively few, shallow sulci have significantly worse
prognoses than thin bands with normal cortex and normal/nearly normal sulcation. Keep in mind that not all band heterotopia
are caused by DCX mutations; mosaic mutations of other tubulin or MAP genes can result in a similar imaging phenotype
(413,432,433).
Lissencephaly with central predominance
In some patients with lissencephaly, the most severe gyral anomalies are in the posterior frontal region (434). This pattern has
been described to occur in patients with TUBA1A mutations (where the pachygyria is most pronounced in the insular and peri-
insular regions and the remainder of the cortex normal or slightly dysgyric (270)) and in the Baraitser-Winter syndrome (where
pachygyria is diffuse but most severe in the posterior frontal and anterior parietal cortex (392) and appears histologically
similar to that of lissencephaly from DCX mutations (421), see Fig. 5-72). Baraitser-Winter syndrome (435) is caused by
mutations of actin genes ACTB and ACTG1 and characterized by microcephaly, ocular anomalies (iris and retinal colobomas,
ptosis, hypertelorism, epicanthic folds), ptosis, mental retardation, dysmorphic features, and short stature (392,429). A similar
pattern can be seen with some DCX mutations, with imaging showing abnormal sulcation with simplified gyral pattern (too few
sulci) and frank pachygyria (with cortical thickening) in the suprasylvian/paracentral cortex but normal cortex in the frontal and
occipital poles.
Figure 5-71 Agyria in a 32-week fetus. Sagittal image (A) shows a mature posterior fossa with large pons and cerebellar 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;
normally, “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).
Figure 5-73 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).
Figure 5-74 Polymicrogyria. Note the irregular cortical–white matter junction (black arrows). Contrast with Figures 5-60 and 5-61.
Figure 5-75 Members of family with X-linked lissencephaly (DCX mutation). 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 brain is diffusely abnormal, with some gyrification (white arrows) in
the posterior regions of the brain, and agyria with a cell-sparse zone (white arrowheads) is present in the frontal lobes anterior. D. Isolated
unilateral, thin band heterotopia (black arrows) was found in the mother of the patient shown in (A and B).
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 composed 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 (421,445,448). Mouse knockout models shows that germline loss of Arx results in a thin,
disorganized cortex, malformed thalami, major defects of white matter tracts, and mislocalization/loss of cortical and striatal
interneurons (439), while selective removal of Arx from interneurons results in normal cortical thickness, but fewer
interneurons in the cerebral cortex and hippocampus, resulting in severe epilepsy (449).
Imaging studies show anterior pachygyria, with only a few, shallow sulci, and posterior agyria (Fig. 5-77); no cell-sparse
zone is present. 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 tubulin or microtubule-associated protein (LIS1 or DCX or DYNC1H1)
mutations (which are usually about 10–15 mm thick) (439). The corpus callosum is always completely absent and the basal
ganglia are either small and dysplastic (often cystic, Fig. 5-77) or completely absent. Hydrocephalus may be present, which (in
severe cases) causes the ventricles (and their ependymal border) to herniate into the interhemispheric fissure, separating the
cerebral hemispheres and giving the appearance of hydranencephaly (Fig. 5-78); in fact, this is better considered as
lissencephaly with agenesis of the corpus callosum and interhemispheric cyst. The brainstem and cerebellum appear normal.
Figure 5-76 Typical appearance of band heterotopia with moderate thickness. A and B. Parasagittal T1-weighted image shows the gray
matter–intensity band of moderate thickness (b) separated from the cortex with rather shallow sulci by a layer of partially myelinated white
matter (m). Note that the cortex has normal thickness (seen equally well in B) but shallow sulci, the latter indicating a band of moderate to
severe thickness. B and C. Axial T2-weighted image (B) and coronal T1-weighted image (C) show ventriculomegaly, moderately thick band
(b), and incomplete subcortical myelination (m).
Figure 5-77 Neonate with X-linked lissencephaly with agenesis of the corpus callosum and ambiguous genitalia (XLAG) due to ARX mutation.
A. Sagittal T1-weighted image shows absence of the corpus callosum and abnormal sulcation of the medial cerebral hemisphere. B. Axial T1-
weighted image 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 due to diminished interneuron
production in the ganglionic eminences, with enlarged perivascular spaces (white arrows) in their place.
Imaging studies of children with RELN mutations shows a thickened cerebral cortex (measuring up to 1 cm in thickness)
with too few sulci (Fig. 5-79); no cell-sparse zone is identified. Hippocampi are incompletely rotated. The brainstem and
cerebellum are extremely small. The cerebellum is nearly or completely smooth, with no foliation (Fig. 5-79), because of the
arrest of Purkinje cell migration mentioned in the previous paragraph. The appearance is extremely characteristic and is
sometimes referred to as the Norman-Roberts type of lissencephaly (450). Patients with VLDLR and DAB1 mutations have the
same findings but less severe (Fig. 5-80) (452).
Malformations secondary to abnormal cortical organization and late migration
Malformations due to abnormal pial basement membrane formation: polymicrogyria, cobblestone malformations, tubulinopathies, and Zika-associated cortical
malformations
Recent studies of autopsy material of fetuses, children, and adults have shown that the cortical malformations that we know as
polymicrogyria (PMG), cobblestone malformations, and some called lissencephaly or pachygyria are the result from abnormal
development of the pial limiting membrane (also called the glia limitans) of the brain with consequent overmigration of
neurons through gaps in the membrane and early abnormal folding of the cortex (389,465). The cause can be genetic or
acquired, but the pial surface is abnormal in more than 90% of affected patients (465). The importance of the fetal meninges in
the maintenance of the pial limiting membrane (PLM, which is necessary for basal attachment of radial glia), regulation of
cortex neurogenesis, and the migration and positioning of neurons and glia is well established (466). The importance of the
PLM has been known for many years (467–470), as has its defects in the causation of cobblestone malformations (471–473),
but the concept of its dysfunction as a cause of cortical malformations in patients with tubulinopathies (389) and nearly all
cases of PMG (465) is new and sheds a new light on many aspects of brain development, both normal and abnormal.
In both classic polymicrogyria (PMG) and in cobblestone cortex (the form of PMG associated with congenital muscular
dystrophies [CMDs]), the process of normal cortical development is interrupted during the late stages of neuronal migration
and during the stages of cortical organization, resulting in dyslamination of the cerebral cortex and the formation of multiple
small gyri. Thus, it is classified as a disorder of cortical organization (3,9). We will divide the polymicrogyrias into several
sections, with the largest one dividing patients who have CMD from those who do not.
Figure 5-78 Newborn with severe macrocephaly due to X-linked lissencephaly with agenesis of the corpus callosum and ambiguous genitalia
(XLAG) with hydrocephalus. A. Sagittal T1 image shows an enlarged craniofacial ratio (indicated a large head). A large supratentorial fluid
collection is seen pushing down the brainstem and cerebellum. No corpus callosum or other midline supratentorial structures are seen. B.
Coronal T2-weighted image shows CSF extending upward from the bottoms of the ventricles to the calvarium, probably secondary to dilated
lateral and third ventricles expanding upwards in the absence of a corpus callosum. Cerebral cortex is moderately thick, and minimal sulcation
is seen. High signal (black arrows) in the basal ganglia regions likely represent perivascular spaces at the site where basal ganglia would be. C
and D. Axial T2 images show the herniated ventricular system pushing the posterior temporal and occipital lobes anterolaterally (arrows in D).
Again, cerebral cortex is moderately thick with severe undersulcation. (This case is courtesy of Dr. Gonca Koc, Kayseri, Turkey.)
Figure 5-79 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.
A number of studies have shown that several of the four major phenotypes of CMD with malformations of cortical
development—WWS, FCMD, MEB, or frontoparietal PMG (FPPMG)—can be produced by mutations of many of the genes
involved in the linkage of the RGCs to the pial basement membrane (125,481–486,489,507,508) with those mutations having
the most severe effect on function causing WWS and those with the least severe effect causing classic FCMD, limb-girdle
muscular dystrophy, or FPPMG. This concept (that the effect of the specific mutation upon function of the protein (formed by
gene transcription and epigenetic modifications) in the pathway is more important that the gene itself) should be kept in
mind as these major phenotypes and their imaging findings are described below.
Figure 5-80 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 cerebellum 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.)
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 abnormalities (retinal
dysplasia, colobomas, persistent hypoplastic primary vitreous, congenital glaucoma or microphthalmos, optic nerve hypoplasia
(509)) and progressive macrocephaly due to congenital hydrocephalus; they may have posterior cephaloceles and testicular
defects as well (478,479,510,511). Most patients have severe lack of psychomotor development and die in the first year of life
secondary to recurrent aspiration and respiratory illnesses. Affected patients appear to have absence of both alpha and beta
dystroglycan, which markedly impairs linkage between radial glia and the pial limiting membrane with resultant gaps in the
membrane (512). While the WWP is seen in all ethnic groups, a striking difference has been observed 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), hydrocephalus, callosal hypoplasia, and profound
hypomyelination (Fig. 5-81) (513,514). An occipital cephalocele is present in about 10% (Fig. 5-82). The cerebral cortex
(Fig. 5-81) 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 (186); this appearance has been called a
cobblestone cortex (515). Small nodules of gray matter may be seen a few millimeters deep to the projections from the inner
cortical margin (Fig. 5-81). The bundles of neurons are separated by fibroglial vascular tissue 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 cerebral mantle is compressed by the enlarged ventricular system (Fig. 5-81); therefore,
careful observation 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 superior and inferior colliculi, and a
distinctive “kink” in the dorsal pons; a second “kink” may be present at the ventral cervicomedullary junction (Figs. 5-81 and
5-82). The cerebellum is small and dysmorphic with abnormal foliation; the vermis is more severely affected than the
hemispheres (Figs. 5-81 and 5-82, often referred to—incorrectly—as “cerebellar polymicrogyria”). Orbital imaging findings
include ocular asymmetry, secondary to congenital microphthalmos or congenital glaucoma, with vitreal and subretinal
hemorrhages due to retinal dysplasia or sublenticular hemorrhage due to persistent hyperplastic primary vitreous (PHPV) (Fig.
5-83). See the section on “Anomalies of the Eye” in this chapter for a discussion and descriptions of ocular anomalies. Rarely,
a coloboma is identified. No correlation has been noted between the MR appearance of the brain or orbits and the mutated
gene (125).
Figure 5-81 Walker-Warburg phenotype in a neonate. 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.
Figure 5-82 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.
The Walker-Warburg phenotype can be detected by fetal MRI during the mid second trimester (Fig. 5-84) by observation of
the very small cerebellum, the characteristic “kinked” 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) (516), the
absence of normal cerebral lamination. The ocular findings (microphthalmia, colobomas) are confirmatory, if detected.
Fukuyama congenital muscular dystrophy phenotype
FCMD is the most common CMD in Japan (474,475). It is an autosomal recessive disorder, with the vast majority of Japanese
cases (with the classic phenotype) being caused by an ancient retrotransposon insertion in the 3′ noncoding region of the FKTN
gene at chromosome 9q31-33 (517,518). However, other mutations of FKTN can cause the very severe WWP (508,519) and
the milder limb-girdle muscular dystrophy phenotype (520); 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 (484). Patients with FCMD phenotype present with hypotonia and severe developmental delay; seizures develop
during the first year of life in about half of affected individuals. Analysis of serum shows elevated creatine kinase level; this
elevation typically leads to a muscle biopsy, which shows changes consistent with muscular dystrophy (474,475,521,522).
Patients with FCMD may have ocular abnormalities (in particular dysplasias of the retina that lead to myopia, nystagmus,
chorioretinal degeneration (523)), but they are less clinically severe than those in muscle–eye–brain and Walker-Warburg
phenotypes. 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 (521,522,524–526). Within the cerebral cortex, three types of
abnormality are seen pathologically (524). Of these, two are detected by imaging: unlayered polymicrogyria, which is seen
primarily in the frontal lobes, and cobblestone cortex, which is largely temporo–occipital (522). The frontal unlayered
polymicrogyria is seen as irregularity of the cortical surface and cortical–white matter junction (Fig. 5-85C and D). The
temporo-occipital cobblestone cortex is thick with a smooth outer surface (Fig. 5-85) but a slightly irregular 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. 5-85D). Most patients with Fukuyama CMD have dysmorphic cerebellar cortex, which is manifest on imaging studies as
dysmorphic folia with subcortical cysts. These cysts tend to be located in the dorsal midportion of the cerebellar hemisphere,
particularly in the superior semilunar lobule (Fig. 5-85B, E–G) (521). On histology, the cysts are found to have leptomeningeal
tissue within them and a molecular layer of nearly normal cerebellar tissue lining their walls, suggesting that they may have
formed from subarachnoid spaces that were engulfed by fusion of neurons and glia that migrated beyond the cerebellar pial
limiting membrane (521,526). The other major finding on imaging studies of Fukuyama CMD is delayed myelination. The
abnormal white matter is hypodense on CT and shows abnormal T1 hypointensity and T2 hyperintensity on MR. Of interest,
when myelination does occur, it begins in the subcortical white matter (Fig. 5-85E–G) and extends centrally (522) 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).
Figure 5-83 Ocular anomalies in Walker-Warburg phenotype include intravitreal hemorrhage (A), subretinal hemorrhage (B), and persistent
hyperplastic primary vitreous (C and D).
Fukuyama CMD is difficult to detect by fetal MR. 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 muscle–eye–brain phenotype (MEB) was originally thought to be a specific disorder (476,477), found predominantly in
Finland, and caused by mutations of POMGnT1 (527), 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, including POMGnT1 (c.1814 G > A (p.R605H) is the most common mutation in Finland and Turkey) (528,529),
POMT1 (483), LARGE (530), and FKRP (481). Affected patients are hypotonic from birth (eventually followed by spasticity
and hyperreflexia) and have impaired vision (manifest as impaired visual fixation) from birth; epilepsy is common and mental
retardation is usually severe (477,529).
On pathologic examination, the cerebral cortex of patients with MEB shows abnormal convolutions with a granular
(cobblestone) surface to the cerebral cortex. A limited area of agyria may be seen over the occipital convexity. Light
microscopy shows resemblance to the cortex in WWP and Fukuyama CMD 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 (515). No horizontal lamination or vertical 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 (515). Examination of the ocular globes typically shows cataracts and retinal detachments (529).
Neuroimaging of patients with muscle–eye–brain phenotype reveals diffuse cobblestone cerebral cortex, which resembles
polymicrogyria on MRI; it is thickened with decreased number and depth of sulci, with most severe involvement in the frontal
lobes (Figs. 5-86 and 5-87). Myelination is delayed, and, as in FCMD, it involves the subcortical, instead of deep, white
matter (Fig. 5-86C and D). Patches of T2 hyperintensity may remain within the cerebral hemispheres (Fig. 5-87B) even after
myelination is completed. The brainstem is characterized by a very hypoplastic pons with a vertical anterior midline cleft
(Figs. 5-86A and 5-87A) and a large, abnormally rounded midbrain tectum (Fig. 5-86A). The ventricles are typically large, the
sylvian fissures are wide, and the cerebellum is hypoplastic with dysmorphic folial pattern and cortical/subcortical cysts
(Figs. 5-86B, C and 5-87A) (531). Hydrocephalus may be present and require shunting, the septum pellucidum may be absent,
and the corpus 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 Walker-Warburg and Fukuyama
CMD phenotypes.
Figure 5-84 Fetal MRI of Walker-Warburg phenotype. A. Sagittal image at 22 weeks of gestation shows extreme ventriculomegaly, large
tectum (black arrows), pontine kink (black arrowhead), and cervicomedullary kink (small white arrow). The cerebellar vermis (larger white arrow)
is very small. B and C. Axial (B) and coronal (C) images show marked ventriculomegaly with a thin cerebral mantle and small cerebellum.
The diagnosis of MEB phenotype can be suggested on fetal MR if a fetus is found to have a large tectum and small pons
with ventral cleft in association with delayed or abnormal sulcation (Fig. 5-88). A finding of ocular anomalies (colobomas,
microphthalmia) or small cerebellum with cysts confirms the diagnosis.
GPR56-related cobblestone malformation (bilateral frontoparietal polymicrogyria)
The syndrome called bilateral 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 hemisphere, as
well (532). It has been well described and the causative gene (GPR56) has been identified at 16q12.2-21 (532,533). In the
cerebrum, the gene product (GPR56) appears to be important for attachment of the distal end of RGCs to the laminin III in the
pial limiting membrane; when the gene is knocked out in animal models, gaps appear in the membrane, allowing overmigration
of neurons (480,534). Of note the frontoparietal location of the malformation matches expression pattern of GPR56 in the
cerebral cortex at the preplate stage (535). 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 (536). These
pathophysiologic mechanisms are very similar to those described in the other (cobblestone) disorders described in this
section; thus, it is not surprising that a cobblestone malformation develops (489). 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 polymicrogyria;
therefore, we will refer to this disorder as a GPR56-related cobblestone malformation. Affected patients show a characteristic
syndrome of developmental delay in both cognitive and motor spheres, disconjugate gaze (typically esotropia), refractory
seizures (most commonly symptomatic generalized epilepsy, with onset in childhood and EEG finding of low amplitude
anterior bursts of α-like (489)), and ataxia (537).
Figure 5-85 Fukuyama congenital muscular dystrophy in an 11-month-old girl. A. Sagittal T1-weighted image shows hypoplastic 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 myelination (arrows) beginning in the subcortical white matter with the deep and
periventricular white matter still unmyelinated.
Figure 5-86 Myelinating muscle–eye–brain phenotype in a 2-year-old boy. A. Sagittal T2 steady-state image shows hypoplastic pons (P),
small, dysmorphic cerebellar vermis (v), and fused midbrain colliculi (small black arrows). Note the large fenestration of the septum pellucidum
(black arrowheads) and the thin posterior corpus callosum (white arrows). B. Axial T1 image through the pons and cerebellum shows midline
pontine cleft (white arrow) and irregular cerebellar cortex with subcortical/cortical cysts (white arrowheads), which are characteristic of all
cobblestone malformations. C and D. Axial T2-weighted images show ventriculomegaly with abnormally shallow sulci and thick, dysmorphic
gyri in the frontal/parietal lobes and incomplete myelination. Note that the subcortical U fibers are affected in some areas of the frontal lobes but
spared in the parietal and occipital lobes. (These images are courtesy of Dr. Jorge Velez, San Antonio.)
Figure 5-87 Muscle–Eye–Brain phenotype. Axial T2-weighted images show midline pontine cleft (white arrowheads in A), cerebellar cysts
(white arrows in A), abnormal frontal gyri (white arrows in B), and foci of abnormal myelination (white arrowheads in B).
Figure 5-88 A 32-week fetus with MEB phenotype. A. Sagittal image shows ventriculomegaly with large tectum (black arrow), small pons, and
small cerebellum. Pontine kink is similar to that in WWS phenotype. B. Axial image shows small cerebellar hemispheres and small pons with
midline cleft (white arrow). C. Axial image shows marked ventriculomegaly and abnormal cortex with multiple small gyri.
Figure 5-89 Maturational changes in GPR56 mutation. A. Sagittal T1 image at age 18 months shows unusual corpus callosum: thick with
vertical splenium (white arrows). Also note the small pons and cerebellar vermis. B. Axial T2 image at 18 months shows ventriculomegaly and
diminished white matter volume with ventriculomegaly. The patchy deep white matter hyperintensities (white arrows) are common in
cobblestone malformations. C. Follow-up axial T2 image at age 5 years shows that the cortex remains somewhat thick, especially in the frontal
and parietal lobes, but the hyperintense (presumed unmyelinated) foci have disappeared and the lateral ventricles have diminished in size.
MR imaging shows thickened, irregular frontal cortex; the medial aspects of the frontal lobes are often involved, which
helps differentiation from true polymicrogyria (Fig. 5-89). Abnormal foci of T2 prolongation are commonly seen in the white
matter immediately subjacent to the cortex, predominantly in the frontal lobes (Fig. 5-89B); these mostly disappear with
advancing age. The corpus callosum is large and shows abnormal contour (Fig. 5-89A). The cerebellum is small and
dysmorphic, with an appearance similar to those of patients with CMDs, but only a few, small cysts are seen, usually in the
superior vermis; we have seen cerebellar cysts only occasionally, but Bahi-Buisson reported them in 11/13 patients (489). The
pons is typically small (Fig. 5-89A) (532), but not as small as in MEB (Fig. 5-86).
Occipital cobblestone malformations: laminin mutations
A number of patients have been reported with varying occipital and cerebellar malformations associated with mutations of
laminin proteins, specifically laminins α, β, and γ. These results, combined with animal experiments showing fracture of the
pial basement membrane (to which radial glia and Cajal-Retzius cells attach) and alteration of dystroglycan (a laminin
receptor) (493), strongly suggest that the laminins play an important role in the formation of the occipital cortex and the
cerebellar cortex. Patients with mutations of the genes encoding these proteins, specifically LAMA1, LAMA2, LAMB1, and
LAMC3, have been found in patients with occipital cobblestone malformations and, in the case of LAMA1, with cerebellar
dysgenesis with cysts and retinal dystrophy (488,491,494,496,538), findings commonly seen in the spectrum of cobblestone
malformations with CMD described in the previous sections. Specifically, the occipital cortex appears slightly thick with little
or no sulcation, with a thin band of cortex just central to it, separated by a thin cell-sparse zone (Fig. 5-90). Variable degrees
of white matter disease are seen. Although investigations of these disorders are still in early stages, the finding of occipital
cobblestone malformations, especially when associated with cerebellar dysplasia with cysts, muscular disease or ocular
malformations, should raise suspicion for mutations of laminins genes.
In the opinion of the authors, patients with so-called CMD with occipital agyria (502) probably belong in this group.
Figure 5-90 Occipital cobblestone malformations associated with LAMC3 mutation. A. Sagittal paramedian image shows slightly thickened
agyric cortex (black arrows) in the occipital lobe. B. Axial T1 image shows the agyric cortex (black arrows) over the posterior temporal and
occipital convexities. Note the very thin, deeper cortical layer (small black arrows) that was seen in the same linear form in Fukuyama CMD
(Fig. 5-85) and as nodules in the Walker-Warburg phenotype (Figs. 5-81 and 5-82). C. Occipital agyria (white arrows) in a different patient with a
LAMC3 mutation.
Figure 5-91 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.
Figure 5-92 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).
Patients with polymicrogyria, but without CMD, may present with developmental delay, focal neurologic signs and
symptoms, or epilepsy, depending upon the portion(s) of the brain involved (428). No differences in neurologic manifestations
have been detected in patients who have polymicrogyria due to different causes (551,552). Affected patients may present at any
age. The severity of the clinical presentation depends upon the extent of cortical involvement; bilateral involvement and
involvement of more than half of a single hemisphere are poor prognostic indicators, portending moderate to severe
developmental delay and significant motor dysfunction (551). The malformation may be focal, multifocal, or diffuse; it may be
unilateral, bilateral, and asymmetrical or bilateral and symmetrical; it is most commonly asymmetrical (465). The sylvian
fissure is affected in 60% to 80% of cases (428,553); however, any area, including the frontal, occipital, and temporal lobes,
can be involved (428,551,554–557). Associated brain malformations are common and include corpus callosum agenesis and
hypogenesis, cerebellar hypoplasia (10), PVNH (352), and subcortical heterotopia (386). Affected patients may be
microcephalic, normocephalic, or macrocephalic (552). Those with macrocephaly may have one of the
polymicrogyria/macrocephaly syndromes such as macrocephaly with polymicrogyria, polydactyly, and hydrocephalus (MPPH)
or macrocephaly with capillary malformations (MCAP) (333,335,546,558–560).
Imaging of polymicrogyria without congenital muscular dystrophy
Polymicrogyria (PMG) has a variable appearance on MR imaging studies (427,561,562). The pattern that is seen depends
partially upon the plane of imaging, the thickness of the slices, the stage of myelination of the brain at the time of the imaging
study, the imaging sequence utilized, and the field strength of the MRI (201), but the variability also reflects the many different
morphologies (which probably constitute a continuum) within the spectrum of polymicrogyria (427). The most common
appearance is a slightly thick cortex with an irregularly bumpy outer and inner surface; high-resolution images can sometimes
resolve many small individual gyri in these cases (Fig. 5-92) (201). However, the outer surface may appear paradoxically
smooth because the outer cortical (molecular) layer fuses over the microsulci (Fig. 5-92A). The affected cortex may range
from thick and coarse (Fig. 5-92) to fine and delicate (Fig. 5-93). Sometimes the gyri look thin and long, between sulci deep; if
careful examination shows that the thin, long gyri are composed of multiple small gyri, it is probably true PMG. Such small
microgyri are often 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 1.0 mm partition size) are obtained. Evaluation in three planes is often necessary to detect
irregularities of the gray matter–white matter junction, which may be the only evidence of dysmorphic brain (Fig. 5-93)
(391). The volume acquisitions can be displayed as three-dimensional 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 unmyelinated regions,
the polymicrogyric cortex looks thin (2–3 mm) and bumpy, while in myelinated areas, it looks thicker (5–8 mm) and relatively
smooth (Figs. 5-94 and 5-95) (561). The reason proposed for this is that a thin layer of gliotic white matter runs through the
polymicrogyric cortex, blending in with white matter in the unmyelinated brain and blending in with cortex after myelination
(Fig. 5-94) (561). Whatever the reason, it is important to realize that both of these cortical appearances can be seen in patients
with polymicrogyria and that polymicrogyria has a different appearance and may be more difficult to detect after
myelination (Figs. 5-94 and 5-95).
Because of the overmigration of neurons through the pial limiting membrane, portions of the brain surface of polymicrogyria
may appear flat and congruent to the arc of normal cortex on imaging (Fig. 5-92) or may extend centripetally, with the cortex
appearing as if it were buckled or folded inward (Fig. 5-94). 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 polymicrogyria, with bumpy, irregular inner and outer
cortical surfaces.
Figure 5-93 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 irregularity of the individual gyri (white arrows) over the
left frontal convexity. D and E. Delicate focal PMG in a different patient. Coronal T1-weighted images in the posterior right sylvian region show
slight irregular (microgyri) of the superior temporal sulci and posterior right sylvian fissure (black arrows) that correlated with the seizure focus.
Note that the PMG is bilateral (black arrows in E).
Figure 5-94 Evolution of MR appearance of polymicrogyria. A. Axial T2-weighted image at age 2 months. Polymicrogyria is seen in much of
the right hemisphere. 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. Note the large vessel in the deep sulcus.
Polymicrogyria may be unilateral (~40%) or bilateral (~60%). As stated above, the cortex surrounding 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 (428,556). The striate cortex, cingulate gyrus, hippocampus, and gyrus
rectus are typically spared (556). Rarely, in less than 5% of affected patients, polymicrogyric 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 venous drainage from polymicrogyric cortex is anomalous (563) in up to 50% of patients (556). Large
vessels are especially common in regions where there is a large infolding of thickened cortex (Fig. 5-94C). Such large vessels,
when seen in association with abnormal, thickened cortex, should not be mistaken for vascular malformations; AV shunting
does not occur and angiography is not indicated.
On fetal MRI, polymicrogyria can be detected late in the second trimester or early in the third trimester by the appearance of
shallow sulci earlier than expected and in locations where early sulci do not normally develop (465) (Fig. 5-96A, and see list
of timing of normal sulcal development in Chapter 2). These early-appearing microgyri often appear in cortex that was
previously injured by infarction or infection, as is twin–twin transfusion situations (564). Later in development, many small
gyri and sulci may be seen (Fig. 5-96B). In bilateral polymicrogyria 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 polymicrogyria.
Syndromes (other than congenital muscular dystrophy) associated with polymicrogyria
Bilateral Perisylvian Polymicrogyria
Several specific clinical/imaging syndromes are associated with cerebral polymicrogyria. The syndrome of bilateral
perisylvian polymicrogyria (also called congenital bilateral perisylvian syndrome (565)) is the most common polymicrogyria
syndrome (428). It seems to be mainly sporadic, but some cases are familial (566,567), with the literature suggesting that
mutations of Xq21.33-q23 (SRPX2), 22q11.2 (a region associated with DiGeorge syndrome), and Xq28 are sometimes
associated with this syndrome (552,567–570); cases associated with 22q11.2 mutations are often asymmetrical, with a
predisposition for the right hemisphere (569). Bilateral perisylvian PMG can also be seen associated with mutations of genes
involved in the mTOR pathway, as discussed in the following section (546,558).
Sporadic cases, thought to be caused by in utero infection (most likely cytomegalovirus) or ischemia (571), seem to be more
common; patients with severe involvement may present with a syndrome of developmental pseudobulbar palsy (oropharyngeal
dysfunction and dysarthria, 100%), epilepsy (80%–90%), mental retardation (50%–80%), and, sometimes, congenital
arthrogryposis (565,572–574). Less severely affected patients present in infancy or early childhood with developmental delay
(60%), poor palatal function (40%), hypotonia (30%), arthrogryposis (30%), or motor deficits (25%) (573,575); seizures
(many clinical types) are present in 40% to 60% (573,575). Studies of familial cases of congenital bilateral perisylvian
polymicrogyria show a lower incidence of these clinical manifestations (567,576), 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 (577).
MRI of bilateral perisylvian PMG typically has a coarse PMG appearance, but the appearance of this malformation varies
considerably with severity. Bilateral perisylvian polymicrogyria can be graded according to severity (with grade 1 the most
severe and grade 4 the mildest) (576):
Grade 1, with perisylvian polymicrogyria extending to the frontal or occipital pole (Fig. 5-97)
Grade 2, with polymicrogyria extending beyond the perisylvian region but not to either pole (Fig. 5-98)
Grade 3, with polymicrogyria of the perisylvian region only (Fig. 5-99)
Grade 4, with polymicrogyria restricted to the posterior perisylvian regions
Figure 5-95 A two-year-old child with seizures since infancy: difficulty in detection of PMG after myelination. A and B. Axial T2-weighted 3-mm
images at age 5 months show polymicrogyria in the anterior sylvian fissure (small arrows) and adjacent frontal cortex (larger arrows in A). C
and D. Axial T2-weighted 3-mm images at the same levels at age 2 years shows only a little blurring at the anterior insular cortex (white
arrows).
Figure 5-96 Fetal MRI of polymicrogyria. Coronal image (A) at 23 gestational weeks shows small gyri (black arrows) in the right frontal lobe;
the anterior frontal lobe should be agyric at this age. Axial image of another fetus at 31 weeks (B) shows microgyri (white arrows) over the left
frontal convexity. Compare to normal gyri in the contralateral hemisphere.
Figure 5-97 Grade 1 bilateral perisylvian polymicrogyria. Sagittal (A) and axial (B) images show course polymicrogyria centered in both
sylvian fissures and extending to the occipital poles.
Figure 5-98 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.
Figure 5-99 Grade 3 bilateral perisylvian polymicrogyria. Axial T1-weighted images show the polymicrogyria restricted to the sylvian fissures
and immediate suprasylvian areas.
Microcephaly-Polymicrogyria Syndromes
Some patients with microcephaly syndromes have polymicrogyria; the best known of these are those associated with ASPM
mutations (personal communication, Dr. Christopher Walsh), RAB3GAP2 mutations (associated with microphthalmia and
congenital cataracts as part of Warburg Micro syndrome (579,580)), and WDR62 (236,581).
Other Bilateral Polymicrogyria Syndromes
Other syndromes of bilateral symmetrical polymicrogyria have been described (562). In addition to the bilateral perisylvian
PMG, already discussed, several groups have described bilateral symmetrical frontal polymicrogyria (Fig. 5-101) (582).
These patients typically present with spastic quadriparesis and epilepsy. Guerrini et al. have described patients with bilateral
medial parietal-occipital polymicrogyria (Fig. 5-102) (554,583). The authors have seen cases of bilateral lateral parietal
polymicrogyria and many with combinations of the abovementioned patterns; thus, it appears that nearly any region of cortex
may be involved by bilateral, symmetrical polymicrogyria (562). A syndrome of congenital hemiplegia and epilepsy has been
described in patients with large areas of unilateral polymicrogyria (584). These patients typically present in infancy with
delayed motor development. A familial syndrome of unilateral polymicrogyria has also been described (127). In
contradistinction to the coarse pattern of PMG in bilateral perisylvian PMG, bilateral frontal PMG and bilateral parasagittal
parieto-occipital PMG have more delicate PMG patterns. A different imaging appearance is seen in bilateral frontoparietal
polymicrogyria secondary to GPR56 mutations, which is better classified as a cobblestone malformation (i.e., secondary to
abnormal pial basement membrane formation (480)) and has been discussed in that section.
Epilepsy Syndromes Associated with Polymicrogyria
Epilepsy syndromes can also be associated with polymicrogyria (551,554,555,572,585,586), including Aicardi syndrome,
which was discussed in the section on callosal anomalies, oculo–cerebral–cutaneous syndrome (Delleman syndrome
(587,588), which has frontal predominant polymicrogyria, PVNH, enlarged lateral ventricles or hydrocephalus, agenesis of the
corpus callosum sometimes associated 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
genes are deleted resulting in cardiac, renal, and parathyroid anomalies as well as right > left polymicrogyria (569)), and
Warburg Micro syndrome (microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and
hypogenitalism with hypotonia, callosal hypo- or agenesis, and frontoparietal polymicrogyria (589–591)). 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 paramicrogyral zone (592). Studies in laboratory animals show increases in postsynaptic glutamate (excitatory)
receptors and decreases in GABAA (inhibitory) receptors in the paramicrogyric cortex (592), factors that likely promote
epileptogenesis. In addition, the polymicrogyric cortex appears to have fewer axonal connections with the rest of the brain
(592). This lack of connections may be the reason why PMG cortex does not function normally and why seizures emanate from
the paramicrogyral zone instead of the dysplastic cortex itself.
Schizencephaly
Schizencephaly, sometimes called agenetic porencephaly, 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
(593,594). It is classified as a malformation due to abnormal cortical organization (3) because it is known to be associated
with vascular disruptions and because so many cases seem to be associated with polymicrogyria. Schizencephaly is a rare
malformation, with a population prevalence of approximately 1.5 per 100,000 population (595). It is associated with young
parental age, lack of prenatal care, and alcohol use (595,596). One-third of affected patients have a non-CNS abnormality,
more than half of which may be classified as secondary to vascular disruption, including gastroschisis, bowel atresias, and
amniotic band syndrome. Some reported cases were associated with prenatal infection, others with thrombophilia (597) or
disorders of blood vessel wall integrity (598); still others had chromosomal aneuploidy or were familial, suggesting possible
genetic causes, but no genetic locus was identified (599–602). Finally, MRI studies commonly see evidence of prior
hemorrhage in and around the cleft when schizencephalies are studied in utero (603). Taken together, these observations
suggest that schizencephaly has heterogeneous causes, many of which include prenatal vascular disruption (595,596,598);
genetic causes seem uncommon.
Figure 5-100 Megalencephaly with capillary malformation: Neonate with macrocephaly and hypotonia. A. Sagittal T1-weighted image shows
an enlarged head with a stretched and thin corpus callosum; the craniofacial ratio was abnormally high. B and C. Axial T2- and T1-weighted
images show ventriculomegaly with subependymal heterotopia in the wall of the left anterior horn (white arrowhead). Sylvian fissures are
enlarged and deep, with the posterior sylvian cortex (white arrows) close to the ventricular walls. Too many gyri and sulci are seen, particularly
in the frontal lobes. D. Axial T2-weighted image shows far too many small gyri (white arrows) over the frontal and parietal convexities. This
patient had a mutation of PI3KCA.
On clinical examination, patients with schizencephaly typically have seizures, hemiparesis, or variable developmental
delay. The severity of the patients’ symptoms is related to the amount of involved brain (604–607). Those patients with a single
cleft with fused lips generally have epilepsy and, perhaps, a mild hemiparesis but are otherwise developmentally normal or
mildly affected (604,608). Patients with unilateral clefts with separated lips usually present with 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 (604,605,608). Patients with bilateral clefts tend to be severely retarded with early onset
of epilepsy, severe motor anomalies, and, frequently, blindness (604,605). The blindness probably results from optic nerve
hypoplasia, which is seen in up to one-third of patients with schizencephaly (424,609,610). 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 (609). Some authors have noted that epilepsy is less common in bilateral than in unilateral
schizencephaly (611) and speculate that the bilateral clefts may impair spread of the epileptic discharges. However, most
reports suggest that seizures begin earlier and have worse outcome when clefts are bilateral (604,607).
Figure 5-101 A and B. Bilateral frontal polymicrogyria. Axial T1-weighted images show delicate polymicrogyria (white arrows) extending
through the entirety of the frontal lobes.
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 (604,605,608,612). In the clefts with fused lips, the walls appose
one another directly, obliterating the CSF space within the cleft at that point (Fig. 5-103A). When the lips are separated, CSF
fills the cleft all the way from the lateral ventricle to the subarachnoid spaces surrounding the hemispheres; these may be
narrow (Figs. 5-103B and 5-104) or wide (Figs. 5-105 and 5-106) (605).
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 pre- and postcentral gyri (6); in
fact, the locations in which they occur are nearly identical to those in which polymicrogyria occurs (551,605), supporting the
increasingly accepted theory that both lesions are most often disruptive.
Imaging studies of schizencephaly show a full-thickness CSF-filled cleft through the affected hemisphere; gray matter,
typically characterized by a bumpy outer surface and an irregular gray matter–white matter junction (Fig. 5-104B), lines the
cleft (424,605). Closed-lip schizencephalies may look like transmantle heterotopia if the walls of the cleft are fused through
the entire cortical mantle; indeed, some cases of transmantle heterotopia (Fig. 5-66) may 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 (612). When schizencephaly is bilateral (40%–50%), clefts are nearly (but not exactly)
symmetrical in about 80% (Fig. 5-104), but the size may vary (Fig. 5-105); their location 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%
(604,605,612). When schizencephaly is unilateral (50%–60%), the lips are open in approximately 65% and closed in
approximately 35%; the location is mid to posterior frontal or parietal in approximately 80%, temporal in approximately 10%,
and occipital in approximately 10% (604,605). 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. 5-104), which may also accompany schizencephalies, separate from the cleft, supporting the concept that some PNH are
caused by disruption of the neuroependyma (345). 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. 5-103). 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 differentiate schizencephaly from transmantle
heterotopia or deep infoldings of polymicrogyria. Of note, clefts with fused lips might be missed if section thickness is large
(>3 mm) and the imaging plane 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 cerebral
cortex, most likely polymicrogyria, may be present in a “mirror-image” location in the hemisphere contralateral to a unilateral
schizencephaly, particularly when the schizencephaly is large and open-lipped (Fig. 5-106) (551,605); 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. 5-106) rather than closed-lipped (613).
Figure 5-102 Parasagittal parieto-occipital polymicrogyria. Parasagittal (A) and axial (B) T1-weighted images show polymicrogyria (black
arrows) coursing through the parasagittal parietal white matter.
Figure 5-103 Closed- and open-lip unilateral schizencephaly. A. 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. B. Coronal T2 image shows a
moderate-sized, gray matter–lined open-lip cleft (white arrows) into the right sylvian fissure.
Figure 5-104 Bilateral open-lip schizencephaly with small clefts. A. Coronal image of a 22-week fetus shows bilateral gray matter–lined clefts
(arrows) and absence of the septum 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 heterotopia when they extend into the ventricle (black arrowhead). 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 extent of the cleft (white
arrows).
Figure 5-105 Coronal T2-weighted image shows bilateral schizencephaly with large open clefts (white arrows). The black arrowhead points to
a ventriculostomy catheter from a shunt.
Figure 5-106 Axial T2-weighted image shows a large open-lip right hemisphere schizencephaly (S) with expansion (black arrowheads) of the
overlying calvarium. Note an infolding of polymicrogyria (white arrows) in the contralateral hemisphere.
The calvarium is often expanded over the opening of an open-lip schizencephaly (Figs. 5-104 and 5-106). 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 (612); 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 ventriculoperitoneal shunt may help to dampen the pulsations and
partially reverse the cranial asymmetry.
The appearance of schizencephaly on fetal MRI may be identical to that on postnatal MRI (Fig. 5-104A), but the amount of
fluid in cleft may be rather small, and the associated polymicrogyria and optic nerve hypoplasia may be difficult to appreciate,
even when extra time is taken to acquire additional sequences (603); fetal MRIs with transmantle pathology should be
closely monitored and extra sequences obtained in order to appreciate the full extent of CNS anomalies. Keep in mind that
visualization of the cerebrum in three planes is especially important when imaging the small fetal brain.
Dysgyria associated with tubulin mutations
Malformations associated with mutations of genes encoding proteins that form microtubules and MAPs have already been
discussed in the section on lissencephaly. However, as discussed earlier in this chapter in the section on microcephalies,
lissencephalies are also commonly a result of mutations of TUBA1A or TUBG1; mutations of other tubulin genes (such as
TUBB2B, TUBB3, and TUBB) are more likely to show disrupted axonal pathways (absence of the cerebral commissures and
the anterior limbs of the internal capsules being the most common supratentorially and asymmetry of the brainstem inferiorly)
and an abnormal gyral pattern that has been called “polymicrogyria” but does not really look like PMG or any other type of
dysmorphic gyral pattern; the author suspects that the gyral pattern reflects the pattern of defects in the pial limiting membrane
(glia limitans) often found with tubulin mutations, as described earlier. The sulci in these patients tend to have a very uniform
appearance and are very often of one or two similar depths (in contrast to normal gyri which vary considerably in depth); they
tend to point toward the center of the brain. Until a better term is coined, we have chosen to call this pattern “dysgyria” (Fig. 5-
43). Many of the TUBB2B and TUBB3 cases in Bahi-Buisson et al. (270) have this appearance. Any patient with microcephaly
and abnormal cortical gyral pattern consistent with dysgyria, a small cerebellum (most prominently the anterior lobe), and
abnormal white matter pathways (especially the corpus callosum and anterior limb or the internal capsule) (269,270) should
be suspected of having a tubulinopathy. The reason for the abnormal sulcation is not understood.
Holoprosencephaly
The holoprosencephalies are a group of disorders that are characterized by a failure of differentiation and midline cleavage of
the prosencephalon. 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 prosencephalon show the
multiple morphogens and their signaling networks in the regions, with both positive and inhibitory feedback that directs the
formation of 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 (614). Those structures that will normally form the most rostral
medial portions of the (ventral or dorsal) brain fail to form in holoprosencephaly (614,615). 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), midline apoptosis
fails to occur, resulting in a failure of the interhemispheric fissure to form, and, as a result, the cerebrum fails to divide into
distinct cerebral hemispheres; in addition, the medial structures of the hemispheres fail to form so the structures that are
normally positioned more laterally are located in the midline, continuous with identical 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 environmental (teratogens) and genetic factors, and, most likely, the wide variation of
HPE phenotypes is explained by a combination of these factors (616). Holoprosencephaly is reported in 1% to 2% of infants of
diabetic mothers (diabetic embryopathy) (6). Because cholesterol is important for SHH processing and signaling, marked
reduction in cholesterol levels in mice can produce HPE (617). HPE can be seen in congenital anomaly syndromes (Smith-
Lemli-Opitz (OMIM 270400), Pallister-Hall (OMIM 146510), and Rubinstein-Taybi (OMIM 180849) syndromes are among
the best known); up to 45% of affected patients have clear cytogenetic abnormalities such as the Patau syndrome (trisomy 13),
Edwards syndrome (trisomy 18, less common), and triploidy (618). Facial dysmorphism, particularly hypotelorism and
midline facial clefts, is frequently seen in the more severe forms (619–622). The embryogenesis of holoprosencephaly has not
been clearly elucidated. Mutations of at least 13 different genetic loci have been implicated in the development of familial
holoprosencephaly in humans; of note, some of these (such as DISP1 mutations) have facial features consistent with HPE-
spectrum anomalies but may not have corresponding brain anomalies (623). Currently recognized HPE-related mutations
include HPE1 (TRAPPC10) on chromosome 21q22.3 (624); HPE2 (SIX3) on 2p21 (625); HPE3 (SHH) on 7q36 (626); HPE4
(TGIF) on 18p (627); and HPE5 (ZIC2) on 13q32.3 (628), HPE7 (PTCH1) at 9q22.3 (629), HPE8 at 14q13 (630), HPE9
(GLI12) at 2q14 (631), HPE11 (CDON, an SHH coreceptor) at 11q24.2, DISP1 at 1q42, NODAL at 10q22.1, and FOXH1 at
8q24.3 (632). All of these genes seem to be involved in dorsal or ventral induction and patterning of the developing
prosencephalon (633). Additional chromosomal regions (on chromosomes 1, 3, 5, 6, and 20) continue to be identified, as well,
by high-resolution cytogenetic techniques such as microarray-based comparative genomic hybridization (array CHG) and
subtelomeric multiplex ligation-dependent probe amplification (MLPA) (634), supporting the genetic heterogeneity of this
disorder. Mutations are found far less commonly in sporadic cases of HPE (627,635); overall, mutations are found in
approximately 25% of HPE cases (632). 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 (636).
Mutations of human sonic hedgehog gene (SHH) at the HPE3 locus (637), which cause an autosomal dominant form of
holoprosencephaly (638), have been studied most extensively (627,639,640). Sonic hedgehog is a protein that has a role in
maintenance of the notochord; the SHH pathway is involved as well in production of prechordal mesenchyme (the prechordal
plate) and patterning/induction of the ventral forebrain (for review, see (641)), supporting the concept that defects of
dorsoventral induction can cause holoprosencephaly. Also well studied are mutations of additional genes in the human SHH
signaling pathway: the SHH receptor PTCH1, the ligant transporter DISP1, the transcription factor GLI2, and SIX3, which
regulates SHH in the ventral forebrain (632). Abnormal expression of dorsalizing factors (chemicals that induce development
of the dorsal midline, such as the interhemispheric fissure and choroid plexuses), such as bone morphogenic proteins (BMPs)
and ZIC2 (628,642–644), also causes HPE. Of note, both overexpression of ventralizing factors and underexpression of
dorsalizing factors have been shown to impair dorsal induction (645). Indeed, various mutations of ZIC2 are associated with
all types of HPE: disturbances of the BMP pathway and ZIC2 mutations that impair roof plate development cause the MIH
variant of HPE (70) (a disturbance of dorsal induction), while classic HPE is caused by different mutations of ZIC2 that result
in impaired formation of the prechordal plate (646) (a disturbance of ventral induction). Thus, normal face and brain
development results from a balance of normal dorsalizing and ventralizing factors; HPE results from disturbances of this
balance in the developing prosencephalon.
Clinical presentation depends upon the severity of the malformation. 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, movement disorder, or developmental delay.
DeMyer has divided holoprosencephaly into three subcategories in which the most severe malformation affects the ventral
prosencephalon: alobar, semilobar, and lobar (621,622). These categories are useful for classifying holoprosencephalies of
different severities (although the divisions among these categories are far from distinct (see below (615)). MIH, also called
syntelencephaly, is a variant in which the dorsal prosencephalon is more severely affected (69,647). The reader should be
aware, however, that the holoprosencephalies represent a continuum of forebrain malformations, that no clear distinctions
among the different categories exist (so don’t spend too much time agonizing about whether the MRI shows severe alobar
versus mild semilobar HPE—it should not change management or outcome), and that other classification systems have been
suggested (69,609,615,619,621,622,647). Indeed, the authors have seen a lack of cerebral hemispheric separation at nearly
every location in the telencephalon, as well as some include a lack of separation of the cerebellar hemispheres
(rhombencephalosynapsis, in the section on hindbrain malformation) 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 holoprosencephaly diagnosed by prenatal imaging (648,649),
affected patients are rarely imaged postnatally because most affected infants are stillborn and others have a very short life span
(650). Alobar holoprosencephaly is the most severe form of holoprosencephaly. Most affected children have 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 (651,652).
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, vomer) never form. As a result, the hypothalami and basal ganglia are fused and reduced in volume and the
third ventricle is absent (Fig. 5-107) (615). No interhemispheric fissure, falx cerebri, or corpus callosum can be identified.
Most commonly, the cerebrum is composed of a pancake-like mass of tissue in the rostral-most portion of the calvarium. No
sylvian fissures can be identified in most cases, and, when present, these fissures lie in the most anterior portion of the brain
close to the midline (653). 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. 5-107). Alobar HPE is easily recognized
on fetal MRI or sonography by the absence of the septum pellucidum and absent interhemispheric fissure (Fig. 5-107A and B).
The vascular supply to the cerebrum consists of multiple small vessels arising 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. On
fetal MRI, it is important to look for facial and orbital anomalies such as ocular colobomas and midline facial clefts (Fig. 5-
108). Milder cases of alobar HPE can be difficult to distinguish from severe semilobar cases, especially if the cerebral mantle
is relatively thick (Fig. 5-109). Closer examination, however, shows no corpus callosum, no interhemispheric fissure, no basal
ganglia, and no separation of the lateral ventricles other than the temporal horns (Fig. 5-109A–D).
Semilobar holoprosencephaly
In the semilobar form of holoprosencephaly, the brain is more developed 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 abnormalities typically consist of upper extremity choreoathetosis and lower extremity spasticity
(654,655).
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. 5-110 to 5-112).
Rudimentary temporal horn formation is seen, although the hippocampus is incompletely formed (Fig. 5-110). 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. 5-111 and 5-112) (653). The callosal splenium is present without a
callosal body or genu in many patients with semilobar holoprosencephaly (Fig. 5-112E) (59,66,619). Holoprosencephaly is
the only brain anomaly described in which the posterior corpus callosum forms in the absence of any anterior callosal
formation. As the spectrum of holoprosencephaly is observed from the most poorly differentiated 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 formation
(68). Because the severity of classic holoprosencephaly is related to how completely the ventral/anterior (hypothalamus and
low frontal) regions of the brain are developed, the anterior extent of callosal formation, which reflects the anterior extent of
cerebral development, 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.
5-111 and 5-112). In the most severe cases, the central gray matter may be significantly reduced in volume and fused into a
mass (Fig. 5-110) (615).
Figure 5-107 Severe fetal alobar holoprosencephaly. Sagittal (A) and axial (B) fetal MRI at 22 weeks of gestational age show a small crescent
of the brain (white arrows) in the anterior calvarium, containing a large monoventricle (v) and continuous (black arrows) with a large dorsal cyst
(c). Sagittal and coronal postnatal MR images (C and D) 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). An axial image (E) shows the continuity of the cyst
with the monventricle.
On fetal MR, 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. 5-112A–C). Ocular abnormalities are
detected, as well, if an attempt is made to evaluate the orbits (Figs. 5-108 and 5-112). 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-
110 and 5-111) (656). In all likelihood, a combination of thalamic fusion and aqueductal 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 may take on the appearance of a ball (Fig. 5-110) (619–622,657). Myelination is
typically delayed (658).
Figure 5-108 Alobar holoprosencephaly with ocular and facial anomalies. A. Midline sagittal image shows absence of corpus callosum and
upper lip (arrow). B. Axial T2 image at the level of the tongue shows a large cleft (arrow) of the palate. C. Axial T2 image at the level of the orbits
shows a retrobulbar cyst most compatible with an ocular coloboma. D. Axial T2 image at the level of the thalami shows a thick cortex with a
blurred cortical–white matter junction, thick cerebral cortex, and nearly complete agyria (lissencephaly). No basal ganglia have formed, and the
thalami are small.
Lobar holoprosencephaly
Patients with lobar holoprosencephaly have less severe clinical manifestations than do patients with alobar or semilobar
holoprosencephaly. Affected patients typically present with mild or moderate developmental delay, hypothalamic–pituitary
dysfunction, or visual problems (654,655). 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 holoprosencephaly; 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 (653). The deep cerebral nuclei are nearly
completely formed (Fig. 5-113) (615). In these patients, the interhemispheric 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-
114). The hippocampi are normal or nearly normal and the temporal horns and third ventricles are better defined than in the
semilobar brains (619–622,657). Thus, as a general rule, if the third ventricle is fully formed, some frontal 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. 5-114).
Figure 5-109 Alobar holoprosencephaly; fetal MRI at 22 weeks. A. Sagittal image shows a very short (rostrocaudal) telencephalon. No visible
corpus callosum or third ventricle is identified. B and C. Lower axial image (B) shows the presence of temporal horns but no evidence of basal
ganglia or third ventricle; moderate hypotelorism is present. More dorsal image (C) shows continuity of lateral ventricles across the midline. It is
not clear whether the cleft posteriorly represents a very rudimentary interhemispheric fissure of a folded holoprosencephalon. A very
rudimentary falx cerebri is present dorsocaudally (black arrow). D. Coronal image shows no internal structure nor interhemispheric fissure.
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 cerebrum 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 hypothalamus (Fig. 5-113).
Imaging in MIH shows normal-appearing basal forebrain with normal basal ganglia and olfactory sulci and normal-
appearing 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 are dysplastic or absent when the two hemispheres
become continuous across the midline (Fig. 5-115). Sometimes sulci (typically extensions of the sylvian fissures) are
continuous or nearly continuous across the midline, as well (Fig. 5-115D). Heterotopic gray matter is often present of the
dorsal surface of the ventricles at the levels of the interhemispheric fusion (Fig. 5-116). MIH may be associated with an
occipital cephalocele, and we have seen several cases associated with rhombencephalosynapsis (another malformation
secondary to abnormal dorsoventral patterning; see section on cerebellar malformations). 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. 5-117) (661). 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 on Callosal Anomalies earlier in this chapter and Fig.
5-115A).
Arrhinia/Arrhinencephaly
Absence of the olfactory lobe of the brain, a condition known as arrhinencephaly, 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, also
spelled arhinia) (6). 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 to 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 MR by about the 30th gestational week (Fig. 5-118A and B) (662). The olfactory bulbs lie
just above the cribriform plates, through which they receive olfactory nerves from the nasal cavities. They lead into the thinner
olfactory tracts, which conduct the axons of the secondary olfactory neurons in the lateral, intermediate, and medial olfactory
striae to their specific terminations within the olfactory cortex. Although the olfactory bulbs can be first identified by histology
at Carnegie stage 18 (44th day of development), they cannot be identified by fetal MR until around 30 weeks because of their
small size and the current limits of technology (662). They are best identified postnatally by thin section (3 mm or less) coronal
T2-weighted images (Fig. 5-118C), where they are seen to undergo a characteristic maturation pattern (663).
Figure 5-112 Relatively mild semilobar holoprosencephaly with ocular coloboma. A. Somewhat oblique sagittal image from fetal MRI shows a
rudimentary corpus callosum (white arrows). B. Coronal image shows the corpus callosum (black arrow) crossing the midline. Neither discrete
basal ganglia nor a third ventricle is seen. C. Sylvian fissures (small white arrows) seem positioned anteriorly because of the small frontal
lobes. No discrete basal ganglia are seen (large arrows) although thalami (t) are present. D. Axial image through ocular gloves shows
microphthalmia (arrow) with colobomatous cyst (C). E and F. Sagittal T1-weighted (E) and axial T2-weighted (F) postnatal images show small
posterior callosal remnant (black arrows in E) and larger, better separated basal ganglia with a tiny remnant of anterior third ventricle (white
arrowhead in F). Sylvian fissures (white arrows in F) are abnormally anterior and medially rotated.
Figure 5-113 Pre- and postnatal MR images of a patient with severe lobar holoprosencephaly. A. Coronal image of a 30-week fetus
immediately anterior to 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.
Figure 5-114 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 putamina
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).
Figure 5-115 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 characteristic 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).
Arrhinencephaly is typically associated with multiple congenital anomalies; cleft lip, cleft palate, hypoplasia/absence of the
nose and nasal cavity, and holoprosencephaly are the most common (664). 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 (665) and small olfactory bulbs with shallow olfactory sulci
were seen in all 10 patients in a series studied by MRI (666). (See the later section on Ocular Anomalies/Syndromes with
Microphthalmia for more on the CHARGE association). Ocular anomalies (hypertelorism, microphthalmia, and iris
colobomas) (667) and other developmental anomalies of the nose and paranasal sinuses (668) may be associated with
arrhinencephaly, as well. Bosma syndrome is a rare disorder in which arrhinia, with absence of essentially the entire nasal
cavity, is associated with microphthalmos, palatal abnormalities, impaired taste and smell, inguinal hernias, and hypogonadism
with cryptorchidism (669,670); the pathways involved are unknown. 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.
Figure 5-116 Middle interhemispheric variant of holoprosencephaly: neonatal MRI. A. Sagittal FSE image shows that the genu of the corpus
callosum (large white arrow) is present, but not the remainder. Note how the ventricular system herniates upward (black arrow) in the parietal
region, with adjacent nodules of (heterotopic) gray matter (small white arrows). B. Axial FSE T2 image shows absent septum pellucidum and
germinolytic cysts (G). No corpus callosal axons are seen posteriorly. C. Axial image at a higher level shows continuity between the left and
right cerebral hemispheres across the midline (white arrows), diagnostic of the middle hemispheric variety of holoprosencephaly. D. Coronal
FSE image shows continuity of the two cerebral hemispheres across the midline in the parietal lobe, with a large nodule of (heterotopic) gray
matter (white arrow) lying on top of the ventricle. (These images are courtesy of Prof. Rick Leventer, Melbourne, Australia.)
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 diagnosis. Indeed, neuroimaging studies are usually performed in patients with facial anomalies primarily
to assess associated anomalies of the brain; therefore, MR 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. 5-119) (671). In
milder cases, congenital nasal pyriform aperture stenosis or choanal atresia may be present, just as they may be present in
holoprosencephaly (672,673). MR typically shows arrhinencephaly as absence of the olfactory sulci, olfactory bulbs, and
olfactory tracts (Fig. 5-119A) (674). Anomalies of the HPA, corpus callosum, and ventral forebrain are the most common
associated findings. When anosmia or hyposmia is associated with hypogonadotropic hypogonadism, the diagnosis of
Kallmann syndrome should be considered (see section on Anomalies of the Hypothalamic–Pituitary Axis later in this chapter).
Figure 5-117 Middle interhemispheric variant of holoprosencephaly: fetal MRI. A. Sagittal image shows extension of the lateral ventricles
dorsally into the interhemispheric fissure (black arrow). Note the presence of an occipital cephalocele (white arrow; this is an unusual finding in
MIH). B. Axial image superiorly shows continuity of the cerebral hemispheres across the midline (white arrow), diagnostic of HPE. C. Coronal
image confirms continuity of the cerebral hemispheres across the midline, and absence of the septum pellucidum establishes diagnosis of
holoprosencephaly. The presence of an interhemispheric fissure more rostrally confirms a diagnosis of MIH.
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 (675). 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 (676); a wide range of associated anomalies has been reported (677). In all probability, the “syndrome” of
septooptic dysplasia is the end result of many different acquired and, possibly, genetic abnormalities (primarily abnormal
expression of genes in the ventral and rostral prosencephalon) (609,678,679). A large review of reports on optic nerve
hypoplasia notes a paucity of genetic findings and a striking preponderance of young mothers and primiparity among the cases;
they note that research suggests a potential role for prenatal nutrition, weight gain, and factors of deprivation in this disorder
(680). In contrast, Dattani and colleagues report a family with septooptic dysplasia and several individuals with a sporadic
form of the syndrome 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 (676,681,682). This location suggests that proper induction of
the prosencephalic midline depends upon HESX1 expression, supporting the concept of an overlap of these patients with those
manifesting holoprosencephaly. HESX1 is also produced (at a later stage of development) by Rathke pouch primordium, a fact
that possibly explains the observed hypopituitarism of many affected patients (683). More recently, duplications of SOX3 and
mutations of SOX2 and SOX3, transcription factors involved in pituitary development, have been implicated in the etiology of
SOD (684). In summary, many different genes and a variety of phenotypes have been found in association with the clinical and
imaging findings of SOD, and many associated findings have been reported on MRI: SOD appears to be a very heterogeneous
disorder (685).
Figure 5-118 Normal olfactory apparatus on MRI. Axial (A) and coronal (B) scans of a 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
cribriform plate) and olfactory sulci (white arrowheads) are easily seen on coronal T2-weighted images.
Approximately two-thirds of patients with SOD have hypothalamic–pituitary dysfunction (686–690); indeed, some authors
(particularly endocrinologists) consider it an essential part of the syndrome. The clinical presentation is variable, as expected
from a heterogeneous disorder. Visual symptoms may include nystagmus and diminished visual acuity; however, patients can
have normal vision (687). 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
(686,689,690). The diagnosis of septooptic dysplasia is made by ophthalmological examination in 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-
120) (609,620,691,692). Patients with complete septal absence have a higher incidence of hypothalamic–pituitary dysfunction
and worse neurological and developmental outcome than those with partial septal absence (693). The absence of the septum
can often be identified on the sagittal image by the low position of the fornices (Fig. 5-120A). High-quality, thin section
coronal MR images allow confirmation of the absent septum and facilitate the diagnosis of hypoplasia of the optic nerves in
severe cases, best seen on T2-weighted images (Fig. 5-120C). However, determining mild hypoplasia of the optic nerves,
chiasm, and tracts by neuroimaging is extremely difficult; in fact, optic nerve hypoplasia is recognized on neuroimaging studies
in only about 50% of affected patients (609). Severe optic 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. 5-120) (693). Brodsky and Glasier (678) showed that patients with neuroradiologic findings limited
to isolated optic nerve hypoplasia or optic nerve hypoplasia in conjunction with partial or complete absence of the septum
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 (694). Patients with 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 abnormal 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 (694).
Figure 5-119 Arrhinia with arrhinencephaly. 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 reformation (C) shows absence of the nasal bones. (This case is courtesy of
Clark Carroll, MD.)
Several distinct MR subgroups have been identified in patients with septooptic dysplasia (609,678). One group shows a
high incidence of malformations of cortical development (especially schizencephaly, polymicrogyria, and gray matter
heterotopia (609,678,693)) and partial absence of the septum pellucidum (Fig. 5-121); these patients are often found to have
incomplete rotation of the hippocampi, as well (693). The finding of hippocampal anomalies is strongly associated with
callosal anomalies and neurologic/developmental difficulties (693). 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 cerebri
or the genu of the corpus callosum (Fig. 5-122), 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 pituitary ectopia (Fig. 5-120) (678,695), and a fourth subset likely includes those in the family
described by Dattani et al., who have hypogenesis of the corpus callosum (676,681). Severino et al. (696) have recently
reported anomalies of the brainstem and cerebellar vermis, including a small pons, reduced anteroposterior diameter of the
medulla, and a short anteroposterior measurement of the cerebellar vermis; 30% of their patients also had a thick
quadrigeminal plate. The authors suggest that the midbrain–hindbrain structures be closely evaluated in all patients with ONH
and absent septum.
Figure 5-120 Septooptic dysplasia with ectopic posterior pituitary lobe. Sagittal T1-weighted image (A) shows hyperintense posterior pituitary
lobe (white arrow) at the median eminence of the hypothalamus instead of in the sella turcica. The anterior pituitary (in the sella) is small. 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).
Figure 5-121 Septooptic dysplasia with schizencephaly. Coronal SPGR T1-weighted images show hypoplasia of the left intracranial optic
nerve (black arrow in A) and, more posteriorly, bilateral schizencephalies (white arrows in B).
Embryology
To briefly summarize, 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 evidence supports origin from neuroectoderm, along the anterior neural ridge
(699). 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. 5-123). The connection of Rathke pouch with the
buccal cavity then undergoes obliteration, although portions of it may persist as the craniopharyngeal canal or as nests of
ectopic pituitary tissue in the nasopharynx or sphenoid sinus. After its connection to the buccal cavity is obliterated between 42
and 44 days of gestational age, Rathke pouch becomes known as the adenohypophysis or anterior pituitary lobe (700,701). The
molecular biology of this transition has been elucidated and is nicely reviewed in several publications (702,703).
Between 37 and 42 days of gestational age, lateral lobes form in the developing adenohypophysis. These lobes, known as
the tuberal processes, will differentiate into the pars tuberalis. Between 42 and 44 days, the tuberal processes surround the
infundibulum and developing 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 hypothalamic–pituitary axis are now in place by day
49 and will slowly evolve into the mature system (700,701).
Figure 5-122 Septooptic dysplasia with dysgenesis of the corpus callosum. Sagittal T1-weighted image (A) shows lack of 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).
Figure 5-123 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 neurohypophysis or posterior pituitary lobe (nh). B. The connection of Rathke pouch with the buccal cavity
undergoes obliteration between 42 and 44 days of 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 hypothalamic–pituitary axis are
now in place and will slowly evolve into the mature system.
Functional specialization of the pituitary gland involves the formation of the portal circulatory system and differentiation of
hormone-secreting cells. It is postulated that this differentiation requires directed contact of the gland with the hypothalamus
(704). The genetic basis of pituitary cell differentiation is being established and seems to involve formation of an organizing
center (the ZLI organizer), which expresses multiple signaling molecules including SHH and members of the WNT and FGF
families (705). Different concentrations of SHH induce differential expression of proteins in the developing cells and
interstitium, supporting the notion that SHH acts as a morphogen to control pattern formation and forming transient signaling
gradients that induce nuclear genes to produce mediators that lead to cell specification (705–708). This primary organogenesis
is a complex, tightly regulated process that is not yet well understood (708,709). It depends upon several transcription factors,
such as PROP1, POU1F1, HESX1, LHX3, and LHX4, to execute temporally and spatially organized expression and
interactions; mutations of these genes are postulated to result in different combinations of hypopituitarism that are sometimes
associated with structural alterations (706). The transcription factor SOX2 appears to have many functions in pituitary
development: absence of SOX2 results in severe anterior lobe hypoplasia with drastically reduced expression of the pituitary
specific transcription factor POU1F1 and severe disruption of somatotroph and thyrotroph differentiation, as well as presence
of insufficient precursors to produce the cell lineages of the anterior lobe (710). Indeed, Jayakody et al. (710) found that the
number of differentiated cells produced was very reduced and insufficiently stimulated to by tropin-releasing hormones to
perform their normal functions. The normal mediators of cell specification include numerous transcription factors acting as
repressors or activators, and associated coregulators that arise from the adenohypophysis and neighboring structures
(702,703,711). Details of these processes are beyond the scope of this book. Suffice it to say that mutations of certain genes
that are important in pituitary development cause widely ranging impaired development, while others show fairly specific
deficiencies in anterior and posterior pituitary development as well as development of other brain and visceral structures
(710,711). For a discussion in greater depth, interested readers are referred to the chapter by Drouin (712).
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’s node, then move rostrally under the influence of the
prechordal plate and its secreted proteins such as sonic hedgehog (614). Therefore, disorders that result from abnormal
induction of the ventral midline forebrain, such as holoprosencephaly, nearly always result in abnormalities of the
hypothalamus and abnormal hypothalamic function (713). In addition, some hypothalamic cells migrate to the hypothalamus
from other regions of the developing embryo (714). 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.
Figure 5-124 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.
Very rarely, the hypothalamus and pituitary gland may be duplicated (Fig. 5-125), or even triplicated (717); other anomalies
of the face and brain are nearly always present (718–720). 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 (particularly partial fenestration of the basilar artery (721)), and anomalies of the olfactory
bulbs and tracts (719,722). Delayed or precocious puberty may be found in affected patients (723).
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 maturation. 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; therefore, it is important to look for deficiencies of other hypothalamic
hormones in children presenting with dwarfism (724). Controversies remain on the cause, diagnosis and management of
isolated growth hormone deficiency (IGHD) in children. The most common genes implicated in IGHD are those encoding
growth hormone (GH1 at chromosome 17q22-24) and the receptor for growth hormone releasing factor (GHRHR at
chromosome 7p14) (724). Recent data suggest that growth hormone deficiency may have a wider impact on the health and
neurological development of affected children than previously recognized; it is unknown how much this can be avoided by
treatment with recombinant human growth hormone (724). The 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 (725). A number of familial and genetic causes of IGHD and combined pituitary
hormone deficiencies have been described (711,726), but these are rarely found in clinical practice (711,727).
Imaging studies show a range of features, including a small sella turcica and anterior pituitary lobe with normal
neurohypophysis (Fig. 5-124) and hypoplasia or absence of the anterior lobe and pituitary stalk; the high signal intensity
neurohypophysis (posterior lobe) may be in the infundibulum or at the median eminence of the hypothalamus (“ectopic bright
spot”) (Fig. 5-126) (728–731). 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 deficiencies
(combined pituitary hormone deficiencies, or CPHD) and lower levels of growth hormone (729,730,732). MR scans of
patients with IGHD are more likely to have a more normal sized adenohypophysis and a visible infundibulum than those with
multiple hormonal deficiencies (731,733); the ectopic posterior pituitary gland will typically be found along the pituitary stalk
(Fig. 5-127). This less severe anomaly is sometimes called “partial” pituitary ectopia (731). When complete posterior
pituitary ectopia (posterior pituitary located within the median eminence of the hypothalamus) is present, patients have a higher
incidence of CPHD (49%), breech delivery (32%) and associated brain and skull base anomalies (12%), including callosal
anomalies (Fig. 5-126), optic nerve hypoplasia, and PVNH (350,711,716,732).
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
(725,734). PROP1 is a transcription 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 hormone. Mutations of PROP1 seem to account for about 40% of
cases of CPHD (735–737). 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 (738,739).
Figure 5-125 Pituitary duplication. Sagittal T1-weighted image (A) shows an abnormally thick floor of the third ventricle (open white arrows).
Coronal T1-weighted images show a thick bar of gray matter at the floor of the third ventricle with two pituitary stalks (small white arrows in B)
exiting from it; these terminate in two separate pituitary glands (black arrows in C).
Figure 5-126 Anterior pituitary hypoplasia with ectopic posterior pituitary lobe. Sagittal (A) and coronal (B) 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).
Figure 5-127 Posterior pituitary ectopia in infundibulum. 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.
Recently, several authors have described hypothalamic adhesions, small areas of gray matter intensity and variable cross-
sectional area coursing from one wall of the hypothalamus to the other (Fig. 5-129) (751–753). Many of the patients have had
other abnormalities of the brain; however, the indications for MRI have rarely been referable to the hypothalamus. At UCSF
Benioff Children’s Hospital, we have identified several of these each year since we began doing thin section imaging at 3T in
our patients. Not surprisingly, they are seen more frequently when we focus our study upon the hypothalamus. Following the
lesions over time, however, we have not seen them grow. We have mostly seen them in patients with other anomalies, but we
image a highly selected group of patients and we have seen a number of them in patients without any neurodevelopmental
disabilities. Moreover, those patients with neurodevelopmental disorders do not have signs/symptoms associated with
hypothalamic function. Therefore, we consider them to be minor anomalies that are rarely, if ever, the cause of neurological
signs or symptoms. Because of their location, they should be considered “don’t touch” lesions unless they grow
(disproportionally compared to the rest of the diencephalon) or enhance and cause symptoms.
Ocular Malformations
As the genetic basis of ocular malformations remains unclear at this time, these malformations are most easily classified by
differentiating them into microphthalmic, anophthalmic, and macrophthalmic malformations. Ocular anomalies associated with
specific syndromes, such as Trisomy 13, septooptic dysplasia, WWS, muscle–eye–brain disease, and the phakomatoses, are
discussed in the sections and chapters on those specific disorders.
Microphthalmia, anophthalmia, and colobomas
Microphthalmia, anophthalmia, and colobomas are frequently grouped together as the so-called MAC spectrum of disorders
(754) because they are characterized by a smaller or absent eye or a missing portion of the eye structure that can be limited to
one or involve multiple tissues. The overall incidence of MAC disorders has been estimated at 6 to 13 per 100,000 births
(anophthalmia 0.6–4.2/100,000, microphthalmia 2–17/100,000 and coloboma 2–14/100,000) (758,759). About 30% of MAC
patients are syndromic; these include craniofacial, brain, genital, skeletal, renal, and cardiac anomalies. Brain anomalies are
more commonly associated with anophthalmia, while urologic/genital anomalies are most frequent in patients with coloboma
(758,759). More than 80 genes are known to be associated with MAC anomalies (760), with transcription factors being the
largest group (754). Among known MAC associated genes, transcription factors represent the largest group (HMG-box
domain-containing gene SOX2; homeodomain-containing factors OTX2, PAX6, VSX2, PITX3, RAX, and SIX6; paired domain
gene PAX6; forkhead family member FOXE3; zinc-finger gene SALL2; and basic helix-loop-helix gene ATHO7), followed by
TGFβ/BMP signaling molecules (BMP4, BMP7, GDF6, GDF3), retinoic acid (RA) pathway genes (ALDH1A3, STRA6,
RARB), and other with variably known functions in ocular development (SHH, ABCB6, MAB21L2, C12orf57, TENM3 (ODZ3),
PXDN, YAP1, HMGB3, and CRIM1) (754).
The term anophthalmia refers to congenital absence of one or both eyes. Some authors contend that true primary
anophthalmia is incompatible with life and that the condition seen in live newborns is best termed extreme microphthalmia or
clinical anophthalmia (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 20% to 40%
of severe bilateral anophthalmia/microphthalmia (762,763). Anophthalmia of at least one eye was found in 73% and the
majority of the remaining cases had microphthalmia (759); in addition, affected infants commonly have associated esophageal
atresia, vertebral segmentation anomalies, facial dysmorphisms, and anomalies of male genitalia (761,764). Mutations of
OTX2 on chromosome 14q22 and RAX on chromosome 18q21.3 have also been associated with primary anophthalmia, with
43% having absence of at least one eye, with the other eye typically microphthalmic (759,765). With either cause, the brain
(and in particular the “visual cortex”) appears normal (766). Secondary anophthalmia is more common and is generally
related to infection (such as rubella), trauma, vascular events, toxic/metabolic events (hyper- or hypovitaminosis A), or
exposure to toxins occurring during the early part of the fourth gestational week (764); however, evidence for environmental
factors in causing anopthalmia/microphthalmia is more circumstantial and accounts for a smaller proportion of cases so less
information is available. In true anophthalmia (primary or secondary), imaging shows that neither the optic nerves nor the
globes are present (Fig. 5-131). Extraocular muscles, the lachrymal apparatus, and blood vessels may be identified.
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. Some patients have anophthalmia of one eye and microphthalmia of the other, with the
consequence that many authors consider them part of a continuum, with anophthalmia being at the more severe end (754).
Primary microphthalmia is a finding in many syndromes (767); it can be the result of primary ocular hypoplasia, ocular
coloboma, PHPV, congenital infections (most commonly rubella, see Chapter 11), chromosomal disorders (listed in previous
paragraphs) (754,759,764,768), and inborn errors of metabolism (most commonly Lowe syndrome, see Chapter 3). In children,
secondary microphthalmia is most commonly the result of retinopathy of prematurity (ROP), ocular infection, or prenatal toxin
exposure (767,769); 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.
Figure 5-131 Anophthalmia. A and B. Axial and coronal SSFSE images of an early third trimester fetus shows neither optic nerves nor
globes. Hyperintense extraocular muscles are identified on the coronal image (B). C and D. Axial T1- and coronal T1-weighted images in a
neonate show the presence of extraocular muscles and very rudimentary structures (white arrows) resembling immature globes.
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 (770); as a result of the failure of closure, the globe itself is almost always
small. Mutations of many genes have been implicated in their formation, the best characterized being PAX6 (771), GDF6 (772),
ALDH1A3, (773), and STRA6 (774). 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 (775,776). They are associated with many brain malformation syndromes, including
Joubert syndrome, Aicardi syndrome, Walker-Warburg syndrome (776), and the CHARGE association (see below). 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 syndrome is commonly associated
with brain anomalies such as callosal agenesis and basilar encephaloceles (777). Imaging studies have a characteristic
appearance in which a section of retina at the site of the optic nerve head is displaced posteriorly (Fig. 5-132). The displaced
portion may be rectangular or cone-shaped. Contiguous (Fig. 5-132B) or bilateral (especially in Aicardi syndrome, Fig. 5-
132C) retrobulbar cysts may be present (777). Coloboma with cyst (also called microphthalmia with cyst) is a malformation
caused by extensive proliferation of the embryonic retina with consequent separation of the inner and outer retinal layers
(770,778). 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. 5-132B); large cysts, therefore, may be associated with extrusion of vitreous humor into the cyst and consequent
diminished size and displacement of the globe (Fig. 5-133). Indeed, large cysts may be larger than the globe itself (Figs. 5-
132B and 5-133) and may cause proptosis (Fig. 5-133). The globe can be differentiated from the cyst by the presence of a lens.
Imaging studies will often demonstrate continuity of the globe and the retrobulbar cyst, confirming the diagnosis and aiding
differentiation from other conditions (775).
Figure 5-132 Colobomas. A. Axial T2-weighted image shows a small left coloboma (white arrow) with the posterior midline wall of the globe
being posteriorly displaced. B. Axial T1-weighted image 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. C. Axial T2-
weighted image in a patient with Aicardi syndrome shows bilateral colobomas (white arrows). Note also heterotopia in lateral walls of temporal
horns (black arrows) and abnormal temporal lobe sulcation.
Figure 5-133 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.
The term CHARGE association refers to a fairly common association of anomalies, affecting 0.1 to 1.2/10,000 live births,
that arises from maldevelopment of multiple organs during early fetal development (779). The name comes from the first letter
of some of the more common features identified in these children: coloboma (usually retinochoroidal) and cranial nerve
defects (80%–90%); heart defects in 75% to 80%, especially tetralogy of Fallot; atresia of the choanae (blocking nasal
breathing passages) in 50% to 60%; retardation of growth (70%–80%) and development; genital hypodevelopment due to
hypogonadotropic hypogonadism; and ear abnormalities associated with sensorineural hearing loss (>90%) (780). The cause
is usually a new mutation of the CHD7 gene at chromosome 8q12.1-q12.2, which is essential for the activation of genes
involved in transcription and, possibly, in the migration of multipotent migratory neural crest. The neural crest, in turn, forms
the affected structures (781). Mutations of the SEMA3E gene at 7q21.11 have also been implicated (782).
Diagnostic criteria for CHARGE association require at least two of the three major criteria (ocular coloboma, choanal
atresia/stenosis, hypoplasia or aplasia of the semicircular canals in the temporal bone) and two minor criteria (cranial
neuropathies, hypothalamo/hypophyseal dysfunction, ear malformation, malformation of the heart or esophagus, and intellectual
disability) (783). Ocular colobomas are described above. The most common cranial nerve anomalies involve cranial nerve
VIII, and the children are often noted to have hearing loss of variable severity, often necessitating cochlear implants. Temporal
bone imaging (MR or CT) shows a hypoplastic cochlea with absence of hypoplasia of the semicircular canals in most cases,
often accompanied by characteristic external ears that are short and wide, protrude, and lack earlobes. Other common cranial
nerve anomalies include swallowing (CN IX/X), asymmetric facial palsy (CN VII), and absent/reduced smell (CN I).
Anomalies of CN I are often associated with hypogonadotropic hypogonadism (Kallmann syndrome). Choanal atresia is found
in about half of all children with CHARGE, resulting in an inability to breathe through the nose, which necessitates surgery
(779).
Persistent hyperplastic primary vitreous
Persistent hyperplastic primary vitreous (PHPV), also called persistent fetal vasculature of the eye, is a malformation that is
caused by a failure of regression of the fibrovascular tissue of the primary vitreous and of the hyaloid artery, which delivers
blood to the primary vitreous and the developing lens (770,784). The embryonic intraocular vascular system is composed of
two components: an anterior system near the iris and a posterior retrolental system within the vitreous. Persistence of these
vessels often results in vascular proliferation, which can cause PHPV in the anterior or posterior segment of 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 (769,784). PHPV is the second most common cause of leukocoria (after retinoblastoma, see Chapter 7),
accounting for 20% to 25% of cases (785). Most cases of PHPV are sporadic, but both autosomal dominant (OMIM 611308)
and recessive (OMIM 611311) forms have been described (one paper suggests a gene in the chromosome10q11-q21 region
(786), but no candidate gene has been isolated). Most cases are unilateral, although bilateral PHPV is much more common
when associated with Norrie disease, WWS, and other neurologic and systemic abnormalities (787).
Pathologically, patients with anterior PHPV have a shallow anterior 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 (787,788).
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 show 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 vitvreous (789). 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 (immediately behind the lens) (Fig. 5-134) (784,790). A generalized
increase in attenuation of the vitreous is sometimes present. It is also important 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). MR 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. 5-83 and 5-134 ) (789–791). Moreover, MR 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.
Retinopathy of prematurity
ROP is caused by the vasoconstrictive effect of high blood levels of oxygen in immature neonates (fortunately, the use of
antenatal steroids has significantly reduced the incidence of lung disease associated with prematurity). The vasoconstriction
results in chronic retinal ischemia, which, in turn, causes neovascularization. The neovascularization and its subsequent
regression cause subretinal exudation, hemorrhage, and scarring; both the scarring and the subretinal exudate may result in
chronic retinal detachment and, eventually, microphthalmia. In countries with high-quality neonatal care, sight-threatening ROP
is largely confined to babies with birth weight less than 1000 g (792); available evidence suggests that greater than 50% of
babies with birth weight less than 1000 g develop some degree of acute ROP (793). Most of these resolve, but a small
proportion progress to become severe, requiring laser therapy (794).
Figure 5-134 Persistent hyperplastic primary vitreous. Axial contrast-enhanced CT (A); contrast-enhanced, fat-suppressed T1-weighted MR
(B); and axial fat-suppressed T2-weighted MR (C) show a small right globe with abnormal vitreal signal, an abnormally shaped lens, and
abnormal structure 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 MR).
Imaging studies of affected patients show changes that are nearly always bilateral but often asymmetrical. Microphthalmia is
always bilateral and, therefore, may be difficult to appreciate. The shape of the globe is affected, resulting in refractive errors
(most commonly myopia). 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. Calcification is rare and is seen only in long-
standing disease (795). MR will show high signal intensity on T1-weighted images and low signal intensity on T2- and T2*-
weighted images. More chronic detachment will show intermediate to low signal intensity on T1-weighted MR images and
variable intensity on T2 and gradient echo images depending upon the amount of deoxyhemoglobin remaining (see (796) and
Chapter 4). Scarring in the posterior vitreous may be difficult to separate from retinoblastoma by MRI. Ocular ultrasound is the
study of choice to differentiate the noncalcified 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
bilaterality 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 (797). 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 (798). 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
(799). Congenital glaucoma may be an isolated finding (autosomal recessive primary congenital glaucoma, OMIM 231300,
is caused by mutation of cytochrome P450 1B1 [CYP1B1], an important modulator of oxidative homeostasis (800,801)), or it
may be seen in association with systemic disorders such as the Marfan syndrome and Smith-Lemli-Opitz syndrome, some of the
phakomatoses (particularly neurofibromatosis type 1 and Sturge-Weber syndrome, see Chapter 6), some metabolic disorders
(particularly Lowe syndrome and homocystinuria, see Chapter 3), and congenital infections (rubella, syphilis) (798,802). It is
bilateral in up to 80% of affected patients (769). 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 enlargement is in the anterior chamber and (b) the
medial and lateral orbital walls restrict medial–lateral enlargement (Fig. 5-135).
Other congenital ocular anomalies
Coats disease is a congenital, nonhereditary, usually (75%) unilateral ocular anomaly, seen in males more than females (3:1)
caused by a vascular disorder of the retina in which lipoproteinaceous exudate accumulates in the subretinal space, leading to
retinal detachment (789,803). 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. Affected children typically present with diminished
vision in the affected eye or strabismus and are found on examination to have leukocoria; therefore, differentiation from
retinoblastoma (see Chapter 7) is essential and is aided by the normal to small size of the affected globe (803). Another
important disease to exclude is infection by Toxocara canis (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 (789). Hemorrhage is common in the vitreous and subretinal space. The CT
features of Coats disease (Fig. 5-136A) are nonspecific, 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 (790,804). 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). MR may be useful in that the proteinaceous exudate in Coats disease is of uniform signal intensity, intermediate
between brain tissue and vitreous, on T2-weighted images and does not enhance on postcontrast images (Fig. 5-136B–D)
(790), 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) (805).
Figure 5-135 Congenital glaucoma (buphthalmos). Axial (A) and sagittal (B) T2-weighted images in a patient with bilateral congenital
glaucoma shows bilateral ocular enlargement. Enlargement is greater from front to back because much of the enlargement is in the anterior
chamber and the orbital walls restrict mediolateral enlargement.
Figure 5-136 Coats disease. A. Axial noncontrast CT image shows that the globes are of equal size. A hyperdense proteinaceous exudate
(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
(white arrowheads in C) to be nonenhancing, homogeneous, and of intensity similar to that of brain tissue.
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 myelencephalon). This
differentiation along the anteroposterior (AP) axis (also called the rostral–caudal axis) is the result of secretion of numerous
transcription factors from the surrounding tissues (the notochord and prechordal plate ventrally and the roof plate dorsally) that
in turn stimulate the release of other transcription factors within the neural tube; this process is called patterning
(191,813,814). The mechanisms that result in early AP patterning are currently poorly understood and, other than the formation
of the diencephalic–mesencephalic boundary (DMB) and the midbrain–hindbrain boundary (MHB), are beyond the scope of
this book. The region of the midbrain and hindbrain is established by the expression of a cascade of transcription factors,
including WNT1, GBX2, OTX2, EN1/2, PAX2, LMX1b, and FGF8, with FGF8 appearing to be the most critical organizing
molecule (807). 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 mesencephalon (807,815) (Fig. 5-137). 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; this expression is regulated by FGF8 (816), the expression domain of which is, in turn,
regulated by the relative concentrations of Otx2 and Gbx2 (817), indicating the presence of a feedback loop. 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 (818). The interaction of Otx2 and Gbx2 also specifies the location of the isthmus organizer (IsO, Fig. 5-137), a
critical structure that organizes gene expression and directs specification of cell type (807,819) and the normal development of
the cerebellum (807). Once the midbrain (Otx2+) and hindbrain (Gbx1+) territories are established, cells from those
respective territories do not intermix (807).
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 bone morphogenic protein—BMP—
family, which are produced by nonneural ectoderm) and ventralizing factors (members of the sonic hedgehog—SHH—family,
which emanate from the notochord and floor plate) (614,807). Along the DV axis, the mesencephalon is divided into the
tegmentum (ventral region) and tectum (dorsal region), while the metencephalon is divided into the pons (ventral region) and
the cerebellum (dorsal region). The subtype of the neurons in these regions is specified by expression of local HOX genes
(820), the influence of local organizers (such as the IsO (Fig. 5-137 (807)), and on the presence of graded doses of signaling
molecules, such as the SHH and BMP, from the floor plate and roof plate (821), all influenced by local organizers especially
the IsO (822–824).
Figure 5-137 Anteroposterior patterning and the isthmus organizer. Patterning of the brain starts with the formation of patterning centers that
secrete signaling molecules such as the nodal and sonic hedgehog (SHH) in the ventral forebrain and the fibroblast growth factors (FGFs),
such as Fgf8 and FgF17, which are important signaling molecules at both the anterior forebrain and the midbrain–hindbrain junction. In the
forebrain, FGFs help to direct formation of the prefrontal 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 isthmus organizer (IsO) is induced to secrete Fgf8 and Fgf17 by
the interaction of transcription factor Gbx2 from the rhombencephalon and Otx2 from the caudal mesencephalon, as well as homeobox genes
Pax2 and Irxs. 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.
Figure 5-138 Embryology of the cerebellar cortex. The cells that form the cerebellum are generated in germinal zones lining the walls of the
fourth ventricle. The cerebellar ventricular zone in the rostral–dorsal rhombencephalon generates 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 laterally to
form a transitory external granular layer (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).
The cerebellum contains five main classes of neurons, of which two (Purkinje cells and inhibitory interneurons) produce
GABA (gamma-aminobutyric acid) as a neurotransmitter (these are called GABAergic neurons) and three (deep cerebellar
nuclear projection neurons, granule neurons, and unipolar brush cells) use glutamate as a neurotransmitter (glutamatergic
neurons). Morphological and genetic approaches both suggest that all GABAergic types are produced from the cerebellar
ventricular zone (Fig. 5-138) (807). Among glutamatergic types, deep cerebellar nuclear projection neurons come from the
rhombic lip (807). Granule cells are produced from the EGL, which is a rhombic lip derivative (807,828). The origins of
unipolar brush cells have been difficult to discern (829), but new data suggest that they are likewise produced from the
rhombic lip (830). Together, these findings suggest that most or all glutamatergic neurons in the cerebellum originate from the
rhombic lip (Fig. 5-138) (807). Thus, cerebellar neurogenesis seems divided according to the type of neurotransmitters 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).
Between 9 and 13 postconceptional weeks, the GABAergic neurons of the cerebellar cortex and the deep cerebellar nuclei
migrate radially outward from the ventricular zone along RGCs similar to those in the cerebrum (Fig. 5-138) (831), under the
influence of SDF1α, CXCR4 and other molecules (826). In contrast, the glutamatergic neurons have more complex migration
routes along the surface of the developing cerebellum that are guided by BMP2,4, and probable adhesion molecules,
neurotrophins, and repulsive molecules that may be on the surface of cells or in the interstitium (Fig. 5-138) (826,832–835).
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, an important facilitator of the terminal steps of Purkinje cell migrations. In later stages of development, the
subpial stream is replaced by the EGL, which is itself a germinal zone, where progenitor cells, driven by SHH secreted by
extensions of migrating Purkinje cells, transform into granule cell precursors (828,836,837). The same Purkinje cell processes
receive Reelin from the GABAergic granule cells that aid in the migration of that cell into the developing cortex (838). The
NTZ organizes into distinct deep cerebellar nuclei (Fig. 5-138) (839). The EGL forms between the 10th and 11th
postconceptional weeks and persists until about 15 postnatal months. At the end of their migration through the EGL, the granule
cell neuroblasts migrate inward between clusters of Purkinje cells with the presumed aid of glial (Bergman) fibers, to form the
definitive internal granular layer (Fig. 5-138) (828). Also formed at this time are the stellate and basket cells of the cerebellar
cortex (28,825,840–842). 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 (843,844). Malexpression of these genes likely
causes cerebellar malformations.
Figure 5-139 Brainstem embryology. Many of the neurons 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 brainstem (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 stopping 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.
While cells produced in the rostral rhombic lips form the cerebellum, 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, these neurons, along with the other neurons that form other brainstem nuclei, also migrate to their final location
(Fig. 5-139). Their migration pathway consists of an initial tangential migration along the periphery of the brainstem (some
also migrate longitudinally along the rostrocaudal axis of the brainstem), followed by radial migration inward. During or at the
end of the radial migration, axons are extended to connect 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
neuronal precursors: fourth nerve from rhombomere 1, fifth nerve from rhombomeres 2 to 3, sixth nerve from rhombomeres 5
to 6, and seventh nerve from rhombomeres 4 to 5 (845), with an important role of Shh signaling as a suppressor of Wnt (846).
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 function is determined by its position along the DV axis. Graded expression of
specific chemicals (sonic hedgehog, Pax6, and Nkx.2.2) along the DV axis appears to generate domains conducive to either
motor (ventral) or sensory (dorsal) neuron development (845). Another chemical, the paired-like homeodomain protein
Phox2b, is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain (847).
Figure 5-140 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 the 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 expand posteriorly, creating the appearance of a fourth
ventricular–cisterna magna cyst (E), identical to what is seen in the Dandy-Walker malformation.
Figure 5-141 Normal midline sagittal anatomy of the midbrain–hindbrain. The midline sagittal image is important for assessing proportions of
the structures. The rostrocaudal length of the vermis in the midline should be approximately equal to the distance from the intercollicular sulcus
to the obex. In the midline, the primary fissure (large black arrow) and the prepyramidal fissure (large white arrow) should divide the vermis
approximately into thirds, but the middle third is usually smallest, while the anterior third is the largest. On this midline sagittal image, the
distance from the top of the midbrain to the bottom of the angle (small black arrow) where the midbrain intersects the pons ventrally is
considered one unit. The distance from that same angle point (small black arrow) to where the pons meets the medulla (small white arrow)
should measure approximately two units. The distance from that small white angle to the obex should be about one unit (0.8–1.2 units). Finally,
the midpoint of the 4th ventricle (arrowhead) should be located just below the mid pons.
Midbrain–Hindbrain Malformations
As the embryology of the structures in the brainstem and cerebellum is intertwined (the junction of the midbrain and hindbrain
induces the isthmus organizer, which is important for differentiation of the brainstem and induction of the cerebellum),
malformations of the midbrain and hindbrain must necessarily be discussed together (807,819).
Figure 5-142 Appearance of vermian folia/fissures and cerebellar peduncles. The locations and sizes of normal superior (SCP), middle
(MCP), and inferior (ICP) cerebellar peduncles are demonstrated. Note also that on coronal images (A–B), the fissures of the cerebellar
hemispheres should point to the location of the cerebellar nuclei and the sides of the fourth ventricle (N in A). In the axial plane (C–E), the
fissures should be oriented approximately parallel to the calvarium. Note that P denotes pons, and M denoted medulla.
Disconnection syndromes
Brainstem disconnection syndromes (861–865) are disorders in which the connection of the superior portion of the brainstem
the inferior portion is disturbed, often connected only by a thin cord of tissue (Fig. 5-144A and B). Affected infants are
profoundly affected from birth, with mildly dysmorphic features (downward slanting eyes, low-set ears, mild micrognathia,
and widely spaced nipples) (861). Neurologic examination reveals weak suck, diminished corneal, gag, and oculocephalic
reflexes, pronounced flexor tone, and hyperactive deep tendon reflexes with minimal ocular motility and disturbed respirations
that require mechanical ventilation (864–866); some affected patients were known to have fetal alcohol syndrome (866). In
three reported patients, the disconnection was in the lower midbrain/upper pons, and in five, it was in the lower pons/upper
medulla. Neuropathological analysis of two cases by Sarnat et al. 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 neurons 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 (861). In contrast, Barth et al. (865) found central cavitation that they interpreted a syrinx and postulated a vascular
cause.
Diagnosis is established by MR imaging in the fetus or the newborn (862,863,866–868) and shows a relatively normal
upper brainstem that abruptly tapers into a thin band of tissue (usually visible on imaging) that connects to the lower segment of
normal-appearing brainstem. The cerebellum is typically small (Fig. 5-144A–C). The vertebrobasilar vasculature is abnormal,
with vessels of the posterior circulation typically very narrow or even absent; fetal posterior cerebral arteries are usually
present. One reported case revealed absent cervical vertebral arteries with reconstitution via persistent segmental arteries and
PVNH (869), while another showed an associated syrinx in the brainstem (865).
Figure 5-143 Anteroposterior patterning defects. A. Sagittal T1-weighted image shows an abnormally long midbrain (white arrows) and short
pons, suggesting a defect in AP patterning. B. Abnormally long midbrain and short medulla, with bulbous rostral midbrain component (white
arrow; this was not a tumor) and very think caudal midbrain (white arrowhead). Note that the midbrain is twice as long as the pons, which is the
opposite ratio of the normal situation, and the cerebellum (especially anterior vermis) is short. C. Abnormally short midbrain and long pons.
Note the large vermis (coming from rostral R1), especially the anterior lobe.
Rhombencephalosynapsis
Rhombencephalosynapsis (889) is an anomaly characterized by lack of separation of the cerebellar hemispheres, with absence
or severe hypoplasia of the cerebellar vermis and midline continuity 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 (890,891). The cause is unknown, but one of the authors has seen two cases associated with holoprosencephaly,
suggesting a defect in dorsoventral patterning. Rhombencephalosynapsis is a part of the cerebellotrigeminal 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, midface hypoplasia,
oxycephaly due to bilateral lambdoid suture synostosis, low set ears, and fifth finger clinodactyly (892–894). It has also been
described in conjunction with the VACTERL-H association (vertebral anal, cardiac, tracheoesophageal, renal, and limb
anomalies with hydrocephalus) (895) and autosomal dominant polycystic kidney disease type 1 (896). Affected fetuses may
sometimes be identified by ventriculomegaly with absent septum pellucidum; high-quality imaging will show midline
continuity of the cerebellar hemispheres (Fig. 5-147) (895,897,898). 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 deficits and
hyperactivity (899,900). Motor milestones are often delayed and physical exam will typically show a cerebellar syndrome
with dysmetria, dysdiadochokinesis, and dysrhythmokinesis.
Figure 5-147 Pre- (A–C) and postnatal (D–F) images of rhombencephalosynapsis. A. Sagittal fetal image show massive hydrocephalus,
which depresses the tentorium cerebelli and the cerebellar hemispheres (black arrows). B. Axial image shows the midline continuity of the
cerebellar hemispheres (black arrows). C. Coronal image shows the depression of the tentorium and the marked compression of the
cerebellum by the enlarged, hydrocephalic cerebral hemispheres. D. Midline sagittal image shows that the tentorium and cerebellum have been
pushed even further caudally and the hydrocephalus has increased. E. Axial T2-weighted postnatal image confirms absence of the septum
pellucidum. F. Axial T2-weighted image at the fourth ventricle confirms continuity of the cerebellar folia and the deep cerebellar nuclei (white
arrows) across the midline, confirming the diagnosis.
In addition to partial (20% of affected patients) or complete (80%) absence of the cerebellar vermis, autopsy studies show
the most common brain anomalies to be midline continuity of the deep cerebellar nuclei, superior cerebellar peduncles, and
thalami; absence of the septum pellucidum; olivary hypoplasia; anomalies of the limbic system; callosal agenesis or
hypogenesis; and aqueductal narrowing with resultant hydrocephalus (543,895). However, many patients do not have all of
these findings, and a wide range of other associated supratentorial, infratentorial, and nonneurologic anomalies have been
reported in association with the cerebellar deformity, most commonly absent olfactory bulbs, callosal dysgenesis, and absent
septum pellucidum (543,698,895,901,902).
As affected patients may be initially detected due to a finding of fetal ventriculomegaly (Fig. 5-147), an effort should be
made to identify a normal vermis in fetuses with severe ventriculomegaly and absent septum pellucidum; if the midline sagittal
image shows abnormal vermian foliation or coronal/axial images show continuation of the cerebellar hemispheres across the
midline (Fig. 5-147), a diagnosis of rhombencephalosynapsis should be strongly suggested. In affected neonates, imaging
studies often show severe hydrocephalus (often depressing the tentorium and causing marked cerebellar compression) with
absent septum pellucidum and apparent aqueductal stenosis (Fig. 5-147D). The cerebellum should be scrutinized in such cases
for evidence of a show a characteristic appearance of absence of the vermis with dorsal midline continuity of the cerebellar
hemispheres, cerebellar nuclei (Fig. 5-147F), and superior cerebellar peduncles, in addition to the ventriculomegaly (Fig. 5-
147E). The cerebellar anomaly may be difficult to detect on CT but may be suggested if dorsal pointing of the fourth ventricle
(Fig. 5-148D) is detected in a patient with large lateral ventricles and absence of the septum pellucidum (present in >50%).
The diagnosis is most easily established on MR 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. 5-148). 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 (903).
It is noteworthy that about 20% of patients with rhombencephalosynapsis may have a small, dysplastic vermis (Fig. 5-149);
this is referred to as incomplete or partial rhombencephalosynapsis (895). In such patients, the diagnosis can still be made by
observation of continuous folia across the midline in other regions. Once the diagnosis is established, the cerebral cortex,
ventricles, and limbic system should be carefully evaluated. In addition to the previously discussed hydrocephalus, callosal
anomalies, olfactory dysgenesis, and absent septum pellucidum, associated anomalies include cortical malformations, bilateral
lambdoid suture synostoses, and, rarely, holoprosencephaly involving the dorsocaudal cerebrum (899).
Finally, patients with the Gomez-Lopez-Hernandez syndrome have a very different appearance, with midface hypoplasia,
turricephaly, and frontal bossing. Imaging shows ventriculomegaly and a large posterior fossa but only a rather round and,
sometimes, small cerebellum (lacking vermis) and small pons, often associated with a very large cisterna magna (904).
Malformations Associated with Generalized Developmental Disorders that Significantly Affect the Brain
Stem and Cerebellum
Mesenchymal–neuroepithelial signaling defects associated with mid-hindbrain malformations: the Dandy-
Walker complex
The Dandy-Walker complex is a group of disorders that have generated considerable confusion and controversy (905–907).
The Dandy-Walker malformation (DWM) has been defined for many years as a malformation complex composed of an
enlarged posterior fossa with a high position of the tentorium (and, consequently, the confluence of venous sinuses, commonly
called the torcular Herophili), hypoplasia or agenesis of the cerebellar vermis, and a dilated, cystic-appearing fourth ventricle
that fills nearly the entire posterior fossa (Fig. 5-150) (906,908). However, there is a wide variation in the severity of the
vermian hypoplasia, the size of the fourth ventricle, the elevation of the tentorium, and the association with hydrocephalus.
Since the advent of fetal MRI, it has become apparent that prenatal cerebellar injury can cause DWM (Fig. 5-151). In addition,
although mutations of several genes have been shown to be associated with DWM, wide variation can be seen in families with
the same genetic mutation, ranging from normal brain structures to mild vermian hypoplasia to mega cisterna magna to varying
severities of true Dandy-Walker malformation (852,909). Of interest, one of the few genes known to cause familial DWM,
FOXC1 (at chromosome 6p25.3), is not expressed in the cerebellum, only in the mesenchyme (developing leptomeninges)
surrounding the cerebellum (826,852). Further analysis of the function of FOXC1 in the developing posterior fossa showed that
it controls the expression of several secreted factors such as SDF1α (which induces Purkinje cell proliferation in the
cerebellar ventricular zone, maintains RGCs and their processes, functions as a chemoattractant to neurons migrating away
from the ventricular zone, and attracts granule cell progenitors from the rhombic lip to form the EGL) and BMP2,4, which
maintain the rhombic lip progenitor pool (826). Therefore, when FOXC1 is deleted or its function impaired by alteration of the
developing posterior fossa leptomeninges, there is a marked down-regulation of cerebellar neuron production as well as
altered development of the choroid plexus and the posterior fossa subarachnoid space; the Dandy-Walker malformation is
the result. These observations suggest that events that alter the mesenchyme around the developing hindbrain (known as the
meninx primitiva), such as blood from intraventricular hemorrhage or mutations within the mesenchyme, can cause cerebellar
hypoplasia, posterior fossa cysts, or both (with the latter being a true Dandy-Walker malformation). This concept that abnormal
substances in the subarachnoid space can impair cerebellar growth is supported by the observation that prematurely born
babies with large intraventricular hemorrhage (that will circulate into the pericerebellar subarachnoid space) have smaller
cerebella (910). In contrast, retrocerebellar CSF collections such as arachnoid cysts and enlarged cisternae magnae (Fig. 5-
152) are not associated with cerebellar dysgenesis and seem to be of little, if any, clinical significance in the absence of mass
effect (causing hydrocephalus) or associated cerebral/cerebellar dysgenesis. If a brain malformation or hydrocephalus is
present, patients often have developmental delay (911–913), with the degree of developmental delay related to the level of
control of hydrocephalus and the severity of associated supratentorial anomalies (911,914) 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 associated with poor intellectual outcome (913,915). Seizures, hearing or
visual difficulties, systemic abnormalities, and other CNS abnormalities 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 (911).
Figure 5-148 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.
On imaging studies, the classic Dandy-Walker malformation is identified by hypoplasia or absence of the cerebellar vermis,
hypoplasia of the cerebellar hemispheres, a large-to-enormous fluid-filled fourth ventricle, and a large posterior fossa with
high tentorium and elevation of the torcular Herophili (Fig. 5-150) (916). The brainstem is often compressed against the clivus.
The cerebellum may be markedly, moderately, or mildly hypoplastic, typically with the vermis being more severely affected,
and the vermis markedly variably rotated (Figs. 5-150 to 5-153). The brainstem may be normal or thin. Associated anomalies
are common: hydrocephalus in 70% to 90%, callosal anomalies in as about 20%, and polymicrogyria or gray matter
heterotopia in 5% to 10% (911,912). (Occipital cephaloceles should NOT be included in the Dandy-Walker spectrum, as the
cause of the small vermis is completely different, with a portion of it undergoing ischemic degeneration after herniating through
the cranial defect with resultant reduction of blood flow.) Syringohydromyelia may be present (rarely) if the cyst obstructs CSF
circulation through the foramen magnum (917). 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. 5-154). Axial or coronal images will show the cerebellar hemispheres in apposition without an
intervening vermis. Dandy-Walker malformation has been reported in association with neurocutaneous melanosis (918)
(probably related to the abnormality of the leptomeninges during fetal development) and PHACE syndrome (919) (see Chapter
6), but most of the reports describe mislabeled cerebellar hypoplasia.
Mega cisterna magna may be differentiated from DWM by the presence of a normal (in size, lobulation, and orientation)
vermis. Both of these should be differentiated from the Blake’s pouch cyst, in which the inferior aspect of the fourth ventricle
herniates through the foramen of Magendie into the vallecula and retrovermian cistern (854,855,857,907) with resulting
counterclockwise rotation of the vermis. Blake pouch is normal in the fetus and may persist after birth; it should also be
identifiable by acquisition of a thin section sagittal balanced steady-state free precession sequence (bSSFP, FIESTA), which
allows the wall of the cyst to be identified. However, identification of the wall is unnecessary if there is no mass effect and
hindbrain structures and no hydrocephalus. To avoid confusion in dealing with these many cystic hindbrain malformations, one
should keep in mind the following concepts: (a) Blake’s pouch is a normal structure (NOT a malformation) with the only
imaging finding being mild counterclockwise rotation of a normal vermis (Fig. 5-155); (b) all malformations in this group are
associated with abnormal development of the posterior fossa mesenchyme; and (c) abnormal neurodevelopment of the affected
patient appears related more to parenchymal anomalies (dysmorphic or hypoplastic vermis, supratentorial anomalies) than to
the cyst or hydrocephalus.
Figure 5-149 Partial rhombencephalosynapsis. Axial (A) and coronal (B) T2 images show a small remnant of vermis (white arrows), but most
of the cerebellar tissue is continuous across the midline.
Figure 5-150 Pre- and postnatal images of a classic Dandy-Walker malformation. A–C. Sagittal (A), axial (B), and coronal (C) images from a
fetal MRI show a counterclockwise rotation of the cerebellar vermis (black arrow in A) and widely separated cerebellar hemispheres (H in B, C)
without a vermis covering the fourth ventricle (black 4 in B, C). D and E. Sagittal (D) and axial (E) MR images show a high tentorium and
straight sinus (black arrows), high torcular herophili (large white arrow), hypoplastic and rotated cerebellum (small white arrow), and large
cisterna magna (C) that expands the posterior fossa large white arrowheads.
Malformations of neuronal and glial proliferation that prominently affect the brain stem and cerebellum
This group of disorders consists of patients with nearly normal cerebral hemispheres, both in size and morphology, associated
with significant cerebellar anomalies.
Lhermitte-Duclos disease/Cowden syndrome (dysplastic cerebellar gangliocytoma)
Also known as diffuse hypertrophy of the cerebellar cortex, dysplastic cerebellar gangliocytoma was first reported by
Lhermitte and Duclos in 1920 (920). As discussed in the section on dysplastic megalencephalies, this disorder is associated
with mutations of genes involved in the mTOR pathway (most commonly PTEN, but also MTOR, PI3K, and AKT)
(277,314,319). Patients may become symptomatic at any age as a result of mass effect from the lesion with resultant
intracranial hypertension (921–923); most common presenting symptoms are headache (from hydrocephalus), visual
disturbances, ataxia, cranial neuropathies, or ataxia; however, cerebellar signs are usually mild or absent (924) and the
anomaly may be discovered incidentally at autopsy or during imaging for an unrelated condition (921–923). Associated
anomalies may include megalencephaly, heterotopia, microgyria, polydactyly, partial gigantism, macroglossia, and multiple
visceral hamartomas and neoplasms (924,925). Associated visceral lesions often include multiple hamartomas, including
mucocutaneous manifestations of tricholemmomas, related follicular malformations, and distinctive hyalinizing, mucinous
fibromas and oral papillomas (926). Because PTEN also functions as a tumor suppressor gene (927), patients have an
increased frequency of malignancies and hamartomas of the breast, thyroid, colon, and pelvic adnexa (928).
Figure 5-151 Fetal injury resulting in DWM. A–C. Fetal images at 23 weeks. Sagittal image (A) shows a normal-appearing vermis. Axial
images (B and C), however, show geographical areas of abnormal hyperintensity and irregular margins (black arrows) of the cerebellar
hemispheres. D and E. Early postnatal image shows hydrocephalus. Sagittal image (D) shows enlarged inferior recess of third ventricle
(arrowhead in D) and compression of superior vermis (white arrow in D). Axial image (E) shows both cerebellar hemispheres being
compressed (white arrows). F. After shunting, a small cerebellar vermis (V) is rotated counterclockwise but is no longer compressed and the
size of the posterior fossa cyst has decreased. This is the appearance of a classic Dandy-Walker malformation, and it was the result of a fetal
injury.
Figure 5-152 Mega cisterna magna. A. Sagittal T1-weighted image shows a large posterior fossa (white arrows). B. Axial T2 image shows
enlargement, but no displacement, of leaves of the falx cerebelli (black arrows) and normally formed cerebellum, indicating that this is not an
arachnoid cyst or a Dandy-Walker malformation.
Figure 5-153 Malformations included the Dandy-Walker spectrum. A. Sagittal T1-weighted image shows a moderate Dandy-Walker
malformation with a combination of hydrocephalus, moderate vermian rotation/hypoplasia, and moderate posterior fossa enlargement. B.
Sagittal T1-weighted image shows a malformation in the Dandy-Walker spectrum with mild vermian hypoplasia combined with severe cisternal
enlargement. The corpus callosum is anomalous, which has been described in up to 20% of patients with DW spectrum.
Pathologically, Lhermitte-Duclos disease consists of a sharply marginated region of enlarged cerebellar cortex. Typically, a
portion of one cerebellar hemisphere is involved; the process may extend into the vermis or, rarely, the contralateral
hemisphere (543). 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 (543).
CT scans show the presence of a nonspecific hypodense cerebellar mass (929). MR shows a sharply marginated cerebellar
mass with T1 and T2 prolongation; coursing through the mass are curvilinear structures of gray matter intensity that appear to
be the cerebellar cortex (Fig. 5-156). The cortical ribbon appears of normal or slightly less than normal thickness (930).
Enhancement has been reported after intravenous administration of paramagnetic contrast (Fig. 5-157) (931), but it is
uncommon. Mass effect from the lesion can cause cerebellar tonsillar herniation, often described as a Chiari I malformation,
and associated syringomyelia (932). Diffusion-weighted imaging (Fig. 5-156D) shows diffusivity similar to cerebellar cortex
(933–935), while perfusion imaging reportedly shows increase in relative cerebral blood volume, relative cerebral blood
flow, and mean transit time (932). Proton MR spectroscopy with intermediate (135 ms) 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%) compared to unaffected cerebellar tissue (932,934–936). MRS, therefore, is a very useful technique to help distinguish
this localized 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 useful tests for this distinction (934).
Figure 5-154 Dandy-Walker malformation after shunting of the posterior fossa cyst. Sagittal T1-weighted image (A) shows the corpus
callosum is hypogenetic with only the middle and posterior 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 hemispheres in apposition (arrows)
without an intervening vermis.
Figure 5-155 Probable Blake pouch cyst. Sagittal T2-weighted image in a neonate shows the inferior aspect of the cerebellar vermis being
posteriorly displaced (black arrow). The cisterna magna caudal to the vermis is enlarged, suggesting the presence of an ependyma-lined sac.
As Blake pouch cysts are a persistent fetal structure without harmful effects, no further investigation was performed in this patient.
Joubert syndrome and related disorders with “molar tooth” malformation caused by mutation of ciliary
proteins
The concept of Joubert syndrome has evolved from that of a rare cerebellar malformation presenting in children with episodic
hyperpnea, abnormal eye movements, ataxia, and mental retardation (943–946) to a much more complicated entity
encompassing multiple syndromes (947) and back again to the simple term Joubert syndrome because the many syndromes do
not segregate distinctly, but overlap as part of a wide phenotypic range (948,949). The genetic basis of Joubert syndrome and
related disorders appears to be highly heterogeneous, with more than 27 causative genes identified; however five genes
(C5ORF42, CC2D2A, CEP290, AHI1, and TMEM67) were found to account for the majority of affected individuals and 10
genes (adding CSPP1, TMEM216, INPP5E, RPGRIP1L, and MKS1) accounted for 86% in one large study (949). Most of the
related syndromes seem to be the result of mutations to genes involved in the function of the primary cilium, an immotile
organelle that protrudes from the surface of nearly all cell types, or the basal body, a cylindrical cytoplasmic organelle that
forms the base of a flagellum or cilium (949). Although once thought to be a vestigial remnant without a relevant function, the
primary cilium has recently become the focus of intensive research that has drawn attention to its many key roles in embryonic
development, inherited human diseases, and even tumorigenesis; it is important in a wide range of functions, including
ciliogenesis, body axis formation, renal function, brain development, and ocular development (948,950–957). The result is a
wide range of pathologic findings, as listed in Table 5-8.
Figure 5-158 Cerebellar hypoplasia secondary to mutation of CASK. Sagittal T1-weighted image (A) and coronal T2-weighted image (B)
show moderate cerebellar and pontine hypoplasia. The cerebrum has mildly diminished white matter and some blurring of the cortical–white
matter junction. A small periventricular nodular heterotopion is present (white arrow) in the left trigone.
Table 5-7 Classification Scheme for Midbrain–Hindbrain Malformations
I. Malformations secondary to early anteroposterior and dorsoventral patterning defects or to misspecification of mid-hindbrain germinal zones
A. Anteroposterior 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. Dorsoventral patterning defects
1. Defects of alar and basal ventricular zones germinal matrix (VZ)
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 prominently affect the brainstem and cerebellum
1. Cerebellar tubers (tuberous sclerosis)
2. Lhermitte-Duclos disease/Cowden syndrome
3. Microcephaly with disproportionate brainstem/cerebellar hypoplasia
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 involvement 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 (PCH)
B. Mid-hindbrain malformations with congenital disorders of glycosylation (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)
Modified from Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain–hindbrain malformations. Brain
2009;132:3199–3230.
In addition to the core diagnostic features of Joubert syndrome (molar tooth sign on MRI, ataxia, hypotonia, hypo- and
hyperpnea, cognitive dysfunction, and oculomotor apraxia), several extra-CNS findings are common including retinal
dystrophy, cystic kidney disease, liver fibrosis, oro–digital–facial features, tongue tumors, strabismus, oral frenulae, epilepsy,
and scoliosis (949).
Few neuropathology studies of affected individuals have been reported. Friede reported a small, dysplastic cerebellar
vermis with midline clefting, dysplasias and heterotopia of cerebellar nuclei, near-total absence of the pyramidal decussation,
and anomalies in the structure of the inferior olivary nuclei, descending trigeminal tract, solitary fascicle, and dorsal column
nuclei (543). Yachnis and Rorke (958) reported absence of decussation of the superior cerebellar peduncles and central
pontine tracts, as well. Saito et al. (959) found that “the midline structures of the brainstem are disordered both structurally and
functionally” in Joubert syndrome.
The imaging features of the molar tooth malformation are characteristic, facilitating the diagnosis (960,961). Sagittal images
show a small, abnormally foliated vermis that is situated abnormally high such that the fastigium of the fourth ventricle is at the
upper pons or at the pontomesencephalic junction (Fig. 5-159), rather than its normal position at the middle or low-middle
pons. In severe cases (Fig. 5-160A), the vermis may be at the level of the tectum. Thin sagittal images will often show that the
midbrain–pons junction (the “isthmus”) is abnormally thin (Fig. 5-159A). Coronal images typically show a cleft (Fig. 5-159B)
in the superior vermian midline. The small size of the dysmorphic vermis results in a triangular-shaped mid-fourth ventricle
(Fig. 5-159C) 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. 5-159C). 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
cerebellum, surrounded by CSF (Figs. 5-159B, D, F and 5-160C). The isthmus (midbrain–pons junction) is small in its
anteroposterior diameter, particularly in the midline (Fig. 5-159A and D), probably because of the absence of the decussation
of the superior cerebellar peduncles. Occasionally, a small nodule of tissue is seen in the interpeduncular cistern (Figs. 5-
159A and 5-160A); this nodule has been described as “interpeduncular heterotopia” (962), although its precise nature is not
known. 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. 5-159D). Some patients have excess
tissue over the dorsal medulla and upper dorsal spinal cord (Fig. 5-160A) that represents a heterotopia containing neurons and
astrocytes (954). Diffusion tensor tractography confirms the absence of decussation of the superior cerebellar peduncles,
manifested as absence of the red (horizontally oriented) “dot” between green (A-P oriented) pathways (903).
Primary Criteria
Developmental delay
Oculomotor apraxia
Nystagmus
Strabismus
Mild retinopathy
Extra-CNS Findings
Mild nephropathy
Hepatic fibrosis
Renal cysts
Nephronophthisis
Renal failure
Cleft lip/palate
Tongue tumors
Bifid digits
Zaki MS, Abdel-Aleem A, Abdel-Salam GMH, et al. The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system
tested in Egyptian families. Neurology 2008;70:556–565; Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar ataxia with the
molar tooth. Lancet Neurol 2013;12:894–905.
From the imaging perspective, it is important to remember that in order to properly assess all patients with the molar tooth
malformation, they should be screened for supratentorial anomalies (callosal anomalies (Fig. 5-160), hypothalamic hamartoma,
polymicrogyria (Fig. 5-160D), or other malformations of cortical development), ocular, hepatic, and renal disease (947), in
addition to the brainstem and cerebellar anomalies. The polydactyly is usually apparent on physical exam.
In addition, fetuses with large retrovermian CSF collections (“large cisterna magna”) are often referred for fetal MRI.
These patients should be carefully scrutinized for a small, dysmorphic vermis (Fig. 5-161A; the midline cleft is difficult to see
in the fetus), a narrow midbrain–pons junction and the presence of a molar tooth sign on axial images (Fig. 5-161B), and the
presence of large, horizontal superior cerebellar peduncles on coronal (Fig. 5-160) or parasagittal images (963). 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 (HGPPS)
In the early 1970s, Dretakis and Konodoyannis (964,965) and Crisfield (966) reported a group of patients with congenital
scoliosis associated with horizontal gaze palsy. The disorder is autosomal recessive, and most reports describe mutations of
the ROBO3 gene, located at chromosome 11q23-q25 (967,968), although one report described a similar phenotype without
ROBO3 mutations (969), likely due to mutation of the DCC gene (88). Both DCC and ROBO3 proteins have been shown to be
important for midline crossing of axons in the brainstem and spinal cord (968), while DCC is known to be involved in the
midline crossing of callosal axons (46). Affected patients have congenital horizontal gaze palsy: no horizontal smooth pursuit,
saccades, optokinetic nystagmus, or vestibuloocular responses but vertical motions are normal; convergence movements may
be markedly reduced. These abnormalities are often not detected until medical examination is initiated for the progressive
scoliosis (970), which develops during childhood and has variable severity (971). Diagnosis of midline crossing
abnormalities can be made by MR, which shows characteristic anomalies of the brainstem (ROBO3 and DCC) and cerebrum
(DCC). Midline sagittal images of DCC mutations show a small pons, but the diagnosis is established from axial images,
which show a dorsal midline pontine cleft and both dorsal and ventral midline clefts of the medulla (Fig. 5-162). The
appearance of the medulla has been described as looking like a butterfly (Fig. 5-162C) (972). The cerebellum and midbrain
appear normal, while spine images show progressive scoliosis with no underlying spinal cord lesion. Diffusion tensor
tractography shows no decussation of rostrocaudally directed axonal bundles (ventral or dorsal), including the decussating
pontocerebellar axons and the superior cerebellar peduncles (973,974). These findings are concordant with
neurophysiological studies (973,975). 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 neuromuscular diseases that are
currently called congenital cranial dysinnervation disorders. They include congenital, nonprogressive sporadic or familial
abnormalities of cranial musculature that result from developmental abnormalities of one or more cranial nerve with primary
or secondary muscle dysinnervation (976). 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 (845,977). 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 (978). Diagnosis is confirmed by MR imaging, which shows a normal-appearing
brainstem, but very small or absent oculomotor nerves (979). 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.
Figure 5-159 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, but the ventral midline above it is abnormally convex, possibly a small interpeduncular heterotopia. Coronal T1-weighted
image (B) shows the large superior cerebellar peduncles (small white arrows) and the vermian cleft (large 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 (large white arrows).
CFOEM can also be a part of the TUBB3 E410K syndrome (980), characterized by facial weakness, intellectual and social
disabilities, and Kallmann syndrome (anosmia with hypogonadotropic hypogonadism), in addition to CFOEM. This syndrome
can be sporadic or inherited (981); it is caused by de novo c.1228G>A mutations in the TUBB3 gene that disturb axon guidance
(982). Imaging findings are small olfactory sulci and olfactory nerves (980).
Midbrain malformations
Tectal enlargement
Two groups of patients have been described in which striking enlargement of the midbrain tectum was identified (10). 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 (predominantly located near the orbit), and cerebral
malformations consisting of unilateral frontal polymicrogyria with PVNH, agenesis of the corpus callosum (sometimes with
interhemispheric cyst), large dysmorphic tectum, absent cerebellar vermis, and small cerebellar hemispheres (587,588,983).
Milder cases of OCCS may have normal orbits and cerebral hemispheres; they are identified by enlarged inferior colliculi and
absent cerebellar vermis (Fig. 5-163). Another group of patients with tectal enlargement was characterized by an enormously
enlarged quadrigeminal plate, but no other brain anomalies (10). The mechanism by which these tectal anomalies develop is
not known (10).
Figure 5-160 Neonate with hypotonia, polydactyly, dysmorphic features (These images are courtesy of Dr. Hussein Kamel, Doha.) A. Sagittal
T2-weighted image shows agenesis of the corpus callosum, an elongated midbrain with a ventral rostral convexity (“interpeduncular
hamartoma,” black arrowhead), a small, dysmorphic counterclockwise-rotated vermis (small arrow), and an elongated nodule of heterotopic
tissue (large black arrow) covering the dorsal medulla and upper cervical spinal cord. B and C. Coronal T2-weighted (B) and axial T1-weighted
(C) image shows absent corpus callosum, heterotopic nodules (white arrows in B) in the walls of the lateral ventricles, large isolated superior
cerebellar peduncles (small black arrows in B, white arrows in C), small dysmorphic cerebellar hemispheres (C) without a vermis, and a cyst
(large black arrow in B) in the interhemispheric fissure adjacent to the falx. D. Axial T2-weighted image shows widely separated cerebral
hemispheres due to absent corpus callosum, multiple periventricular nodular heterotopia (black arrows), and dysmorphic-appearing cerebral
gyri with several small areas of polymicrogyria (small white arrowheads).
Figure 5-165 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 are courtesy of Dr. Guido Gonzales, Santiago, Chile.)
Focal hemispheric dysgenesis is usually identified by either abnormal sulcation (Fig. 5-166) or abnormal contour and
foliation of the affected hemisphere (Fig. 5-167A–C) or by lack of the normal arborization of the cerebellar white matter (Fig.
5-167A, D, and E). (Normally, the cerebellar fissures are radially oriented from the deep cerebellar nuclei on coronal images
and the white matter bundles follow that same orientation; see Fig. 5-142.) Abnormal fissure orientation (Fig. 5-167C) should
raise suspicion for focal dysgenesis; loss of volume or a frank cleft may accompany the abnormal fissuration (Fig. 5-167D and
E) (875). 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. 5-141); an inability to identify them (Fig. 5-166) should suggest a malformation.
Occasionally, diffuse (Fig. 5-168) malformations of the cerebellar cortex are encountered without associated supratentorial
dysplasias (991), but focal cerebral cortical dysplasia commonly accompanies focal cerebellar cortical dysplasia (Fig. 5-
167C) and supratentorial cortical clefts (schizencephaly) often accompany cerebellar clefts (Fig. 5-167F). Diffuse cerebellar
cortical dysgenesis is more commonly associated with malformations of cerebral cortical development, typically
polymicrogyria or cobblestone cortex (see section in this chapter on Malformations of Cortical Development) (6,543). When
the dysgenesis is unilateral and the entire 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 three cases of duplication of the cerebellar hemisphere, one of which was associated with
ipsilateral internal, middle, and external ear duplication (992). In two patients, no cerebellar signs or symptoms were reported,
while the third had a calvarial protuberance in the occipital region, generalized hypotonia, depressed deep tendon reflexes, and
mild truncal ataxia. MR imaging in the sagittal and coronal planes makes the diagnosis if the supernumerary hemisphere and its
peduncles can be identified (Fig. 5-169). The embryologic cause of this malformation is not known.
Figure 5-166 Abnormal vermian foliation. Sagittal T1-weighted image shows abnormal foliation of the vermis, diagnostic of vermian
dysgenesis. Note that no normal primary fissure or prepyramidal fissure can be identified. Compare with normal vermis in Figure 5-141.
Figure 5-167 Examples of focal cerebellar dysgenesis. A. Coronal T2-weighted image shows ectopic gray matter deep (white arrows) within
the small left cerebellar hemisphere along with areas of abnormal foliation (black arrows). B. Coronal T2 image in an infant shows nodular
ectopic gray matter (black arrow) and loss of cortical volume (white arrow) in affected left hemisphere. C. Coronal T1 image shows dysmorphic
cortex in the inferior right cerebellar hemisphere (black arrows). Note the dysmorphic areas of cerebral cortex (white arrows) suggesting diffuse
or multifocal prenatal injury. D and E. Cerebellar hemispheric clefts (arrows), likely due to prenatal injury (hemorrhage or infarction or infection).
F. Parasagittal T2 image shows cerebellar cleft (white arrow) associated with cerebral schizencephaly (black arrows).
Pons malformations
Pontine tegmental cap dysplasia
Patients with this pontine tegmental cap dysplasia present with cranial neuropathies; the eighth cranial 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 (993,994). Cerebellar signs, pyramidal signs, seizures, skeletal anomalies, and cardiovascular anomalies have been
reported in association with these findings (995). The diagnosis is made by MR imaging, which shows a small ventral pons in
association with a round or “beak-shaped” dorsal pontine protuberance (the tegmental cap, Fig. 5-170). 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. 5-170F), and that the
normal ventral transverse pontine fibers in the ventral and middle pons are absent. Jissendi-Tchofo et al. (994) propose three
potential mechanisms, including abnormal axonal navigation, abnormal neuronal migration, and a combination of the two. Thin
section, steady-state imaging techniques (CISS, FIESTA) can be used to demonstrate hypoplasia of the affected cranial nerves
(996).
Figure 5-168 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.
Figure 5-169 Cerebellar hemisphere duplication. Parasagittal and coronal images (A and B) show two completely separate components (1
and 2) of an enlarged right cerebellum. This was an incidental finding in a patient who was imaged for an unrelated cause. (These images are
courtesy of Dr. Junichi Takanashi, Tokyo, Japan.)
Medulla malformations
Medullary tegmental caps with callosal agenesis/hypogenesis
Rarely, dorsal medullary protuberances are identified on MR imaging in infants being imaged for multiple anomalies of the
musculoskeletal (clinodactyly, rocker bottom feet), genitourinary, or gastrointestinal systems. (The reader must keep in mind,
however, that if no other brain anomalies are present, dorsally exophytic glioma will be a more likely diagnosis!) 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. 5-171). The nature, degree of heterogeneity, and cause(s) of the “cap” are not clear at present.
Chiari I Deformity
The Chiari I deformity is defined as caudal cerebellar tonsillar ectopia, that is, caudal extension of the cerebellar tonsils
below the foramen magnum. However, the cerebellar tonsils of a majority of asymptomatic people younger than age 20 years
extend below the foramen magnum. More important, among asymptomatic patients less than 10 years old, more than 5% have
tonsils that extend 8 mm or more below the foramen and 30% have tonsils extending 4 mm or more below (998). In addition,
30% of patients with tonsil descent between 5 and 10 mm below the foramen magnum are asymptomatic (999). Moreover,
patients who are discovered to have tonsillar ectopia and do not have symptoms referable to foramen magnum obstruction are
very unlikely to develop them (1000). To summarize, 5 to 10 mm of cerebellar ectopia is seen in a very substantial
percentage of normal children and may be an incidental finding (998,1001); in the absence of other neurologic or imaging
signs (syrinx or presyrinx), all other sources of headache need to be excluded before surgery is contemplated.
Children with symptomatic Chiari I deformities typically present clinically with occipital or posterior cervical headaches
(especially when straining or coughing), lower cranial nerve palsies, otoneurologic disturbances (such as disequilibrium,
tinnitus, or vertigo), or dissociated anesthesia of the extremities secondary to syringohydromyelia (1002,1003). In infants and
nonverbal children, headaches may be manifested as irritability or crying, often associated with arching (hyperextension) of the
neck (1004). Nystagmus, particularly downbeat nystagmus, is reported to be strongly associated with lesions of the foramen
magnum, particularly with brainstem compression (1005).
Syringomyelia is present in about 10% at the time of diagnosis (1006). Impaired oropharyngeal function has been reported
in children who are less than 3 years old at presentation (1007), and sleep apnea was attributed to the deformity in several
cases (1008–1010). Older age at time of diagnosis is associated with increased risk of headache and significant neurologic
symptoms (1006).
Cerebellar ectopia is likely the result of several different processes. The most common type of Chiari I deformity 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. 5-172 and 5-173) (1011,1012), (b) the straight sinus is more vertical than normal (Fig. 5-174), (c) a strong
correlation exists between posterior fossa volume and degree of cerebellar ectopia (1013), and (d) a high incidence of osseous
craniovertebral anomalies has been noted (1012,1014,1015) in affected patients: up to 90% of affected patients have median
basilar invagination (Fig. 5-173), with 20% showing additional paramedian invagination. Many of the patients with basilar
invagination and shortened clivus also have C1 assimilation (1015) with remodeling of the inferior surface of the foramen
magnum that leads to bony indentation between the assimilated C1 and the superior facets of C2. The foramen magnum is, thus,
in an abnormal position that results in an irreducible posterior odontoid invagination (Fig. 5-173) (1016). The odontoid
invagination in combination with the abnormal clivus, compounded by the tonsillar herniation and the abnormal position of the
inferior medulla, leads to progressive neural compromise (1015).
Figure 5-170 Pontine tegmental cap dysplasia. Sagittal T1-weighted (A) and T2-weighted (B) images show ventral pontine hypoplasia and the
appearance of a rounded (white arrows in A) or beak-like (black 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 fractional anisotropy (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 longitudinal tracts (black arrows), and green middle
cerebellar peduncles (m). FA map of pontine tegmental cap dysplasia (F) shows absence of the ventral decussation 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, superoinferior; green, anteroposterior.
Figure 5-171 Dorsal medullary cap malformation in a patient with multiple congenital anomalies. (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 (white arrow) is 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 are courtesy of Dr. Susan Blaser, Toronto.)
Figure 5-172 Chiari I malformation with associated presyrinx. A. The cerebellar tonsil (white arrows) is enlarged, compressed (pointed), and
extends more than 1 cm below the bottom of the foramen magnum. Notice that the upper cervical spinal cord is compressed (white arrowhead)
between the odontoid and the cerebellar tonsil. A “presyrinx” (the term used for increased edema within the spinal cord, but not a frank fluid
collection, labeled S) is present. B. Sagittal image from the cardiac systole portion of a CSF flow study shows that the compressed and
inferiorly displaced cerebellar tonsil (large white arrows) is moving inferiorly, superior to the CSF (large arrowheads, also white and therefore
moving from superior to inferior). The medulla (small white arrows is moving little).
Figure 5-173 Chiari I malformation with horizontal clivus/basilar invagination. Sagittal T1-weighted image shows platybasia and shortened
clivus (large white arrows). Note the long odontoid process pointing posteriorly and compressing the medulla/cervicomedullary junction. The
cerebellar tonsil (T ) is pointed (small white arrows). This chronic process has caused tissue from the posterior spinal cord to form a small
nodule just below the tonsil.
Figure 5-174 Chiari I malformation. Sagittal T2-weighted image shows compressed, low-lying cerebellar tonsils (small white arrows). The
clivus is normal, but the posterior fossa is small because of a steep tentorium cerebelli, manifested by the nearly vertical straight sinus (large
white arrows).
However, this theory of causation applies only to part of the group that has been identified by some imaging studies as
having the Chiari I deformity. A number of other subgroups of patients can be identified with tonsillar extension through the
foramen magnum and resultant compression of the neural structures and CSF spaces that have no osseous deformities
whatsoever. Importantly, many of these so-called malformations result from either increased intracranial pressure
(intracranial hypertension or masses, treated CSF shunt or mass resection) or decreased spinal pressure (resulting from
CSF leaks, treated by stopping the leak, usually with a blood patch (1017)). The first group (with increased pressure) may
have 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 tonsillar herniation (1018). They
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. The second group is composed of patients with intracranial
hypotension secondary to chronic CSF leaks (the “sagging brain”) (1019,1020). These patients can be identified by the
character of their headache (made worse by standing up, better by lying down), associated clinical signs and symptoms
(nausea, vomiting, cranial neuropathies, vertigo, hyperacusis, neck pain/stiffness) (1021–1023) and certain specific imaging
characteristics (Fig. 5-175): the brainstem and third ventricle “sag” inferiorly; the pituitary gland is enlarged and upwardly
convex; the dura is thickened and shows marked enhancement after administration of intravenous contrast; and the dural venous
sinuses are enlarged (1019,1020,1023). In very severe, longstanding cases, the midbrain may appear swollen and flattened
(1023). In these patients, the hindbrain malformation will resolve after the site of the CSF leak (often a spinal arachnoidal
diverticulum) is identified and treated (1021,1022). The CSF leak can be diagnosed by administration of subarachnoid contrast
material and subsequently finding extrathecal CSF on spinal imaging (MR first with myelogram to follow if MR is equivocal);
initial treatment of choice is epidural blood patch (1021,1022). Tonsillar ectopia can also develop as a consequence of lumbar
to peritoneal shunting of cerebrospinal fluid (1024,1025); the tonsillar herniation in this situation, which has similar
pathophysiology to spontaneous intracranial hypotension, may reverse after removal of the shunt. Both of these groups of
patients can present with headaches that are made worse by activity and, hence, may be considered as candidates for
foramen magnum decompression, which is precisely the wrong therapy.
Another cause of tonsillar ectopia belonging to this group may be effects ventriculoperitoneal shunts that are placed for
treatment of infantile hydrocephalus (1002,1026). It is likely that some of these patients have premature closure of their cranial
sutures because shunting of CSF reduces the volume of their brain; as a result, the forces required to keep the sutures open
disappear. When the brain subsequently grows enough to fill the cranial vault, the calvarium cannot expand enough to keep up
with brain growth; as a result, the brain grows downward with the tonsils ultimately protruding through the foramen magnum.
Tonsillar ectopia can result from calvarial thickening in dysplasias of bone (1027) and as a result of premature closure of
multiple cranial and facial sutures due to genetic causes, such as Crouzon syndrome and Pfeiffer syndrome, in which premature
suture closure results in a small posterior fossa and skull base and increased venous sinus pressure, and consequent tonsillar
herniation (often called Chiari I deformities) (1028–1030). Other syndromes that result in a small skull base (primarily
chondrodystrophies) can also result in tonsillar ectopia/Chiari I deformities (1031,1032).
Figure 5-175 Tonsillar ectopia secondary to intracranial hypotension. Sagittal T1-weighted image (A) shows low-lying cerebellar tissue (T),
flattening of the ventral pons (white arrows) against the clivus and dens against the medulla (white arrowhead), an enlarged pituitary gland (black
arrow), and sagging floor of the third ventricle. Coronal T1-weighted image (B) shows smooth, uniform enhancement (white arrows) of all dural
surfaces from venous engorgement.
Another group of patients with tonsillar ectopia are those with acquired deformities of the foramen magnum that lead to
basilar invagination (1033). These patients, nearly always adults, also present with headaches, cranial neuropathies, or
syringohydromyelia. Still another subgroup, mislabeled as having Chiari I deformities, is composed of patients with
myelomeningoceles with mild hindbrain anomalies consisting primarily of tonsillar ectopia (2% of myelomeningocele patients
in Emery’s series of 100 autopsies of patients with myelomeningoceles had tonsillar ectopia as their only hindbrain anomaly
(1034)). The patients in this subgroup have myelomeningoceles at birth but mild brain anomalies (e.g., hypogenesis of the
corpus callosum, mild tectal beaking, and fenestrations of the falx), presumably because the CSF leak at the myelomeningocele
was slow. This group is better classified as having Chiari II malformations with mild hindbrain manifestations.
In general, tonsillar ectopia of less than 10 mm should not be considered pathologic in an asymptomatic child unless the
tonsils are compressed (pointed), the CSF spaces at the foramen magnum and C1 are effaced, CSF flow studies show that
the cerebellum and brainstem pulsate abnormally through the foramen magnum instead of the CSF around brainstem and
tonsils, and there is no deformity of the brainstem or intracranial dural enhancement (998,1035,1036). In adults, mild
cerebellar tonsillar ectopia (<6 mm below a line from the basion to the opisthion on a sagittal midline image and with no
compression of the cervicomedullary junction or the subarachnoid space at that level) appears to be of no clinical significance
in most patients (999,1036,1037). 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 (1038).
Chiari II Malformation
The Chiari II malformation is part of a complex malformation involving the hindbrain, spine, and mesoderm of the skull base
and spinal column (997). By definition, all patients with Chiari II malformations have spinal CSF egress in utero secondary to
myelomeningoceles (indeed, all the patients with Chiari II hindbrain deformity as initially described by Chiari (997) and
Cleland (1039) had myelomeningoceles). Craniospinal pressure differential, with lower spinal pressures due to loss of CSF
through the open spinal defect, seems to cause the hindbrain malformation; fetal repair results in near normalization of the
hindbrain and bony posterior fossa (1040,1041). Often, the myelomeningocele is discovered in utero as a result of prenatal
sonography or elevation of alpha-fetoprotein on amniocentesis; prenatal closure of the myelomeningocele is rapidly becoming
the standard of care for this patient group (1040). If the closure of the myelomeningocele is postnatal (usually within the first
48 hours of life), more than 80% of affected patients develop hydrocephalus (1042); radiologist is most often exposed to these
patients in the postnatal period for evaluation of the hydrocephalus (although imaging is increasingly performed prenatally by
fetal sonography and fetal MRI). Less commonly, the infant develops swallowing difficulties, stridor, apneic spells, weak cry,
or arm weakness and is imaged to look for compression of the brainstem at the foramen magnum or C1 level (1043). Patients
with brainstem dysfunction have a significantly greater mortality than those without, even if decompressive surgery is
performed (1044). Epilepsy occurs in 17% of patients born with myelomeningoceles, almost always a result of CNS pathology
beyond the manifestations of the Chiari II malformation: encephalomalacia/stroke, PVNH, or calcifications (1045).
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 (NTDs) in mice; however, the pattern of occurrence in humans suggests a
multifactorial polygenic or oligogenic etiology (1046), 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 NTDs (1046). In addition, many transcriptional regulators and proteins that affect chromatin
structure are necessary for neural tube closure (1046). Although the downstream molecular pathways regulated by these
proteins are unknown, it has been known for some time that folate supplementation during pregnancy reduces NTDs and
inositol supplementation has recently been shown to reduce NTDs in animal models (1047). Some key signaling pathways
involved in the formation of myelomeningoceles have been identified, including overactivation of sonic hedgehog signaling and
loss of function in the planar cell polarity pathway, retinoid signaling, and inositol signaling (1046). Epigenetic processes,
such as DNA methylation, histone modifications, and nucleosome positioning, are also being investigated (1048). 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 (1048). If the posterior 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
pressure) spaces. The pressure gradient causes posterior fossa structures to stretch and herniate downward. This theory,
proposed by McLone and his colleagues (1049), is supported by fetal MRI, which shows mild hindbrain malformations in
fetuses with small/intact myelomeningocele (MMC) sacs but more severe hindbrain malformations in fetuses with large or
ruptured MMC sacs (Fig. 5-176). The concept is supported by results of fetal myelomeningocele repair, which show
improvement of the posterior fossa malformation, in addition to improvement of hydrocephalus (Fig. 5-177) and normalization
of the size of the posterior fossa after repair (1040,1041,1050–1052). Already, the number of Chiari II malformations is
diminishing in large urban areas due to the effects of fetal repair.
The McLone theory (1049) also explains the characteristics of the hindbrain findings in fetuses who do not benefit from in
utero MMC repair. These 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 CSF pressure gradient. The result is
that the cerebellum is “sucked” out of the posterior fossa by CSF gradient as it grows and it becomes abnormally small
caudally displaced, indented superiorly by the low tentorium and inferiorly by the foramen magnum or, more commonly, the
posterior arch of C1. The pons and fourth ventricle are stretched inferiorly and narrowed in their anteroposterior diameters
(Figs. 5-178 and 5-179). 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. 5-178 and 5-179). This kink is seen in approximately 70% of
patients with the Chiari II malformation (1034,1053). The cerebellum sometimes extends anterolaterally into the
cerebellopontine and cerebellomedullary angles, wrapping around the brainstem (Fig. 5-179). The fourth ventricle is low in
position (typically below the pons), vertically oriented, and narrowed in its anteroposterior diameter (Figs. 5-178 and 5-179).
The cerebellar vermis is usually partially herniated into the cervical spinal canal (Figs. 5-178 and 5-179). The herniated
cerebellum often degenerates; when this degeneration is severe, virtually no cerebellum may be present (Fig. 5-180) (1053);
this is becoming very uncommon. Occasionally, the fourth ventricle can herniate posteriorly and inferiorly, behind the medulla
and beneath the vermis; this condition is known as “an encysted fourth ventricle” (1053). The fourth ventricle may also be
isolated or “trapped” (see Chapter 8) as a result of a combination of aqueductal narrowing (or scarring) and diminished CSF
flow through the fourth ventricular outflow foramina or the basilar cisterns (Fig. 5-181).
Figure 5-176 Variation of hindbrain malformation with size and integrity of myelomeningocele (MMC) sac. A and B. Sagittal image of spine (A)
shows an intact MMC sac (white arrows). Sagittal image of the brain (B) shows normal-sized, but slightly low cerebellar vermis (black arrows)
in a slightly enlarged posterior fossa. C and D. Sagittal image showing MMC (white arrow in C) shows a small opening but no sac, suggesting
open communication of CSF with amniotic fluid. Sagittal image at the upper cervical spine (D) shows cerebellum compressed by small
posterior fossa and extending down to the C2-C3 level (black arrow), likely due to a strong rostrocaudal CSF pressure gradient. E. Sagittal
image shows a small sac at the lumbar level (black arrows), but the dorsocaudal aspect of the sac (large black arrowhead) shows a defect,
indicating communication between the CSF and the amniotic fluid. The posterior fossa is small and crowded (white arrows), and the
cerebellum extends down to C3/4 (white arrowhead). F–H. Oblique sagittal (F) and axial (G) images shows a large, but apparently intact, MMC
sac (black arrows) with CSF in the sac communicating with subarachnoid space through spina bifida. Sagittal image of the brain (H) shows the
cerebellum lying somewhat low but much less compressed than in images (D and E).
Figure 5-177 Chiari II malformation before (at 22 postconceptual 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. 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 quadrigeminal 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 (E) 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.
The fourth ventricle may be very small in patients with Chiari II malformations (Figs. 5-178 and 5-182); 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 othe signs of hydrocephalus. When affected patients have
hydrocephalus or an isolated fourth ventricle or component of the fourth ventricle, the spine should be examined because of a
high incidence of associated syringohydromyelia (Figs. 5-181 and 5-182). 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 rostrocaudal pressure gradient; the result is that the tectum
is stretched posteriorly and inferiorly (“beaked” tectum, Figs. 5-178 and 5-180) (1054). Another finding that may be present is
a posterior concavity of the petrous bones and, less commonly, clivus (Fig. 5-180A), probably resulting from pressure effects
of the cerebellum and brainstem in the small posterior fossa (1055). This “scalloping” of the petrous bones may be difficult to
appreciate on MR.
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 hypogenesis (absence of the splenium and absence
of the rostrum) (Figs. 5-177 and 5-179) (59); callosal hypogenesis may, however, be more severe (Fig. 5-181). PVNH are
present in 15% to 20% of affected children (Fig. 5-178) (1056), with some studies finding them in as many as 30% (1057).
Pathological studies have reported higher numbers (1058), likely from more severe malformation complexes. The heterotopia
result from disruption of the neuroependyma in the ventricular wall from the altered CSF dynamic, resulting in (a) impaired
linkage of the radial glia to the ependyma and (b) consequent inability of the immature neurons to attach to the radial glia and
begin their migration (344). Enlargement of the caudate heads and massa intermedia is common (1059). 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 dysgenesis. Prominence of the occipital horns and of the posterior third ventricle is
common and can remain even after shunting (Fig. 5-178) (1059–1061), 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-containing 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. 5-178 and 5-181). This pattern is not polymicrogyria, because the cortex is
of normal thickness, but may be secondary to decompression 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 (543,1062).
Figure 5-178 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, and 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.
Figure 5-179 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.
Figure 5-180 Chiari II malformations with near absence of the cerebellum. Sagittal T1-weighted MRI images (A and B) show callosal
hypogenesis, 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.
Analysis with DTI and fiber tracking shows abnormalities of the fornices and cingula, which were reported as
discontinuous or dysplastic in 69% to 77% of patients (1063). (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) (1063).
Figure 5-181 Chiari II malformation with isolated fourth ventricle. Sagittal 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 callosum is hypogenetic. The clivus is very thin, presumably due to pressure erosion. Note the cervical syringohydromyelia (white
arrowheads).
In the past, irregularity of the surfaces of the inner and outer table of the skull was used to diagnose patients with
myelomeningocele. 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 disorganization of the collagenous outer meninges from which
the membranous calvarium forms (1049). It is of no diagnostic significance in the era of CT and MR, and it seems to normalize
by age 6 months.
The multiple findings described above are present in a variable proportion of patients (Table 5-9), with the variation likely
due to the volume of CSF egress from the MMC. It was always unusual to see all of the cerebral and cerebellar manifestations
of the Chiari II malformation in a single patient, and, in the era of fetal MMC repair, it is rare. In the absence of fetal repair, 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 deformities are often classified as having the Chiari I
malformation; however, the presence of supratentorial anomalies and myelomeningocele suggests that these patients belong in
the Chiari II classification. It should be noted that the term “Arnold-Chiari malformation” is only properly applied to the Chiari
II malformation.
Table 5-9 Frequency of Brain and Spine Anomalies in Patients with Chiari II Malformations
Anomaly Frequency
Myelomeningocele Always
Syringohydromyelia ~50%
Affected patients usually present with difficulty in breathing and swallowing as well as with long tract signs (that may be
secondary to the disorganization of brainstem nuclei), seizures, and developmental delay (1065). Definitive diagnosis is
established by MR imaging, which shows the cerebellum, brainstem, or cervical spinal cord herniating through a high cervical
spina bifida (Fig. 5-183). Treatment is surgical repair; outcome is guarded (1065).
Figure 5-183 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.
Other terms are often used in discussing cephaloceles. Meningoencephaloceles are herniations of CSF, brain tissue, and
meninges through the skull defect. Meningocele refers to herniation of the meninges and CSF only. Atretic cephaloceles are
formes fruste of cephaloceles consisting of dura, fibrous tissue, and degenerated brain tissue; they are most common in the
parieto-occipital area. Glioceles consist of a glial-lined cyst containing CSF. In all of these conditions, the skull defect and
herniation most commonly occur in the midline. Occasionally, cephaloceles may develop in adults, due to gradual thinning of
bone, most commonly in the walls of the sphenoid sinus or mastoid air cells. Ultimately, dura, leptomeninges, and sometimes
brain may herniate through the thinned bone causing an acquired cephalocele. These can become symptomatic (usually hearing
loss or recurrent otitis and otorrhea) and require repair (1072). However, acquired cephaloceles will not be a topic of this
section.
Causation and classification of cephaloceles
Both genetic and nongenetic factors are known to be involved in the causation of cephaloceles (and of all NTDs (1073)), but
current data suggests that genetic causes predominate, with the wingless (WNT), sonic hedgehog (SHH), bone morphogenic
protein (BMP), and retinoic acid (RA) pathways playing important roles (1073). It is likely that there are many more.
Cephaloceles are named for the location of the bone defects through which they course. The categories of cephaloceles
include (a) occipitocervical (involving the occipital bone, foramen magnum, and posterior arches of upper cervical vertebrae
and often called Chiari III malformations as discussed in the previous section), (b) occipital, (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 pterygopalatine fossa), (h) sphenoorbital (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) (1074).
A complete discussion 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 frontoethmoidal cephaloceles, as the clinical presentation can be very similar;
moreover, dermoids and cephaloceles may have a common etiology (1075,1076). Finally, this section includes a discussion of
calvarial dermoids and other lesions that present as calvarial masses in childhood, as well as congenital calvarial defects,
both of which can mimic cephaloceles.
Imaging goals
As fetal imaging has become more prevalent, many cephaloceles are diagnosed in utero (1077), and their characteristics will
be illustrated and discussed with those of postnatal ones. If possible, fetal imaging should be used to determine the amount of
brain tissue and blood vessels within the cephalocele and to look for other, associated malformations in the nervous system and
in the other organ systems. This assessment will aid in genetic testing, and also in guiding management. Fetal sonography and
MRI are essentially complementary, and the combination of the two studies, in experienced hands, will give a comprehensive
analysis, both functional and anatomic, of organ system development and maldevelopment (1077–1083).
Occipital cephaloceles
The occipital bone is the most common location for defects leading to cephalocele formation 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 (1084). As with all cephaloceles, neurodevelopmental outcome is related to the size of the
cephalocele, the amount of tissue present in the sac, and the presence of associated anomalies (up to 50%) (1077,1084,1085).
Supratentorial and infratentorial structures may be involved with equal frequency; indeed, it is not uncommon to see
supratentorial structures, infratentorial structures, and the tentorium all included within the cephalocele. The tentorium
cerebelli may be dysplastic (1086).
The diagnosis is usually obvious clinically and is often known before birth, as the diagnosis can be made by fetal imaging
(Fig. 5-184); in addition, it is important to assess the hands for polydactyly and the kidneys for cysts, as these indicated a
diagnosis of Meckel Gruber syndrome (MKS, see discussion in next paragraph), which is uniformly lethal. Postnatal imaging
studies are ordered to answer two major questions: (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? MR is the modality of
choice to answer these questions (Figs. 5-184 to 5-186). CT better depicts the bony changes (Fig. 5-185A), but routine MR
imaging studies (Fig. 5-185) will show the amount of brain tissue versus CSF in the cephalocele in addition to demonstrating
associated cerebellar cortical dysgenesis, gray matter heterotopia (Fig. 5-184E), callosal anomalies, venous sinus anomalies,
dorsal interhemispheric cysts, tonsillar and brainstem ectopia, or Dandy-Walker malformations, all of which have higher
frequencies in patients with cephaloceles (1087–1090). The integrity and the course of the dural venous sinuses are best
demonstrated by the use of 3D MR venography (1091) acquired at the time of the MR imaging study (Fig. 5-186).
Among the many syndromes associated with occipital cephaloceles, Meckel-Gruber syndrome (MKS, a variant of Joubert
syndrome) (1092) and Knobloch syndrome (1093) are the best understood from a genetic/developmental perspective. MKS is
a lethal disorder caused by autosomal recessive mutations that lead to defective function of the primary cilium (many patients
with this syndrome are allelic to those with Joubert syndrome, discussed in the section on midbrain–hindbrain malformations
affecting the cerebellum). As noted above, it is characterized by occipital cephaloceles (often with other brain anomalies),
polycystic kidneys and postaxial polydactyly (1094), which should be actively searched for on prenatal imaging. Knobloch
syndrome is a rare autosomal recessive disorder caused by mutations of COL18A1 and characterized by ocular abnormalities
(high myopia, lens subluxation retinal detachment and degeneration and early cataracts) and occipital skull abnormalities
(cephaloceles, osseous defects) and, in some patients, malformations of cortical development, epilepsy, and midface
hypoplasia (1093).
Repaired cephaloceles
After surgical repair of a cephalocele, an imaging study always shows a calvarial defect, with diminution of remaining brain
tissue in the area, and stretching of that remaining brain (along with a tract of CSF) toward the defect (Fig. 5-184H). A small
amount of subcutaneous tissue resembling brain may be present. The stretching of the brain and accompanying CSF tract are
very helpful in identifying patients who have had prior repairs of encephaloceles. The stretching of the brain tissues toward the
site of the encephalocele probably results from in utero extrusion of nonmyelinated brain tissue through the calvarial defect.
Unmyelinated brain tissue is extremely soft and is easily deformed. The brain tissue tends to retain 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
(1034).
Figure 5-184 Occipital cephaloceles. A. Sagittal image from a fetal MRI shows a large low occipital CSF-filled sac (white arrows) with some
brain tissue (black arrow) within it, connected to the cerebellum via a bone defect. B. Axial fetal image shows brain tissue from the cerebellum
(black arrow) extruding through the defect (white arrows) in the occipital bone. C. Sagittal T1-weighted image shows a small posterior fossa
with brainstem and cerebellum stretched posteriorly toward an occipital bone defect. A mostly cystic mass (white arrows) extends through the
defect. D. Axial T2-weighted image shows the vermis stretched posteriorly through the calvarial defect. A small amount of vermis extends
through the calvarial defect. E. Axial T1-weighted image shows multiple subependymal nodules (white arrowheads) of gray matter in the walls
of the lateral ventricles. F. Sagittal T1-weighted image of a different patient shows a large occipital cephalocele. Both supra- and infratentorial
brain tissues are distorted as they enter the sac along with CSF from cisterns and the fourth ventricle. G. Axial T2-weighted image (same
patient as F) shows the supra- and infratentorial structures stretching into the cephalocele sac. H. Repaired occipital cephalocele, different
patient. Note the adjacent brain (cerebellum) is diminished in size, distorted (small white arrows), and stretched toward the calvarial defect
(large white arrow); this is strong evidence that the patient had an encephalocele repair, probably in infancy.
Figure 5-185 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.
Figure 5-187 Embryology of the frontoethmoidal region. Nasal dermoids, frontoethmoidal cephaloceles, and nasal gliomas all are believed to
have similar embryologic derivations. Frontal cephaloceles presumably result from lack of closure of the fonticulus frontalis (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, et al. Congenital nasal masses: CT
and MR imaging features in 16 cases. AJNR Am J Neuroradiol 1991;12:105–116, with permission.)
Figure 5-188 Formation of nasal dermal sinuses. If the dural projection (Fig. 5-187B) 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, et al. Congenital nasal masses: CT and MR imaging features in 16
cases. AJNR Am J Neuroradiol 1991;12:105–116, with permission.)
Figure 5-189 Formation of frontoethmoidal cephaloceles. Cephaloceles presumably result from herniation of intracranial tissues into the dural
projection through the fonticulus frontalis (A) or foramen cecum (B). (Reprinted from Barkovich AJ, Vandermarck P, Edwards MB, et al.
Congenital nasal masses: CT and MR imaging features in 16 cases. AJNR Am J Neuroradiol 1991;12:105–116, with permission.)
Figure 5-190 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. 5-187B) with subsequent regression
of the more superior portion of the projection. (Reprinted from Barkovich AJ, Vandermarck P, Edwards MB, et al. Congenital nasal masses: CT
and MR imaging features in 16 cases. AJNR Am J Neuroradiol 1991;12:105–116, with permission.)
MR is the modality of choice for imaging these malformations, particularly if thin section (≤2 mm, with 1 mm being best),
contiguous images can be obtained. Although CT better shows the relationship of the dermal sinus to specific bones as it
courses through the nasal septum, volumetric T2 and steady-state (CISS, FIESTA) sequences do an excellent job without
artifact from the differing suspectibilities of air, bone, and brain. MRI also better shows associated nasal, paranasal sinus, and
intracranial (epi)dermoid cysts (Figs. 5-191 to 5-193) and does not use ionizing radiation; moreover, intrathecal contrast is not
necessary for MR evaluation. If MR is not available or is contraindicated, CT should be performed using no more than1.0 mm
slice thickness; subarachnoid infusion of iodinated contrast helps to detect intracranial masses. (Epi)dermal cysts have
variable signal intensity due to differences in protein/fluid balances (Figs. 5-192 to 5-194) (1102). Care should be taken not to
mistake normal marrow in the crista galli or the nasal process of the frontal bone (see Chapter 2) 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. For optimal assessment of CSF spaces and their relationship to solid structures, steady-state
sequences (CISS, FIESTA) with ≤1 mm slices are necessary. Finally, the administration of a gadolinium-compound
intravenously may demonstrate the enhancement associated with infection/inflammation (Fig. 5-191D and 5-193B). 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.
MR is also the study of choice in the evaluation of cephaloceles and nasal gliomas because it directly shows the extension
of brain tissue through the bone defect (Figs. 5-194 to 5-196) in cephaloceles and the lack thereof in nasal gliomas (Fig. 5-197)
(1103). 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 tissue (1103); therefore, anatomic factors are more important than signal characteristics in
making a distinction between these malformations. In difficult cases, acquisition of (MR or CT) images through the defect after
intrathecal (paramagnetic or iodinated, respectively) 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. MR is also superior to CT
in showing the presence or absence of associated brain anomalies (Fig. 5-196F), the presence of which has profound
prognostic implications. Anomalies of the corpus callosum are the most common associated brain malformations;
interhemispheric lipomas and malformations of cerebral cortical development also frequently accompany nasofrontal
encephaloceles (1078). Frontoethmoidal encephaloceles are commonly associated with craniofacial anomalies, callosal
dysgenesis, or lipomas, often in the form of midline craniofacial dysraphisms (also known as frontonasal dysplasia, see Fig.
5-198) (1088,1104,1105). Hypertelorism is common in all cephaloceles in this group and in nasal gliomas because of
separation of midline structures by the herniating brain tissue.
Figure 5-192 Nasal dermal sinus/dermoid with intracranial dermoid in a 1-year-old boy. A. Sagittal T1 image shows two hyperintense nodules
on the surface of the nose (small white arrows); these were visible on clinical exam and palpable on clinical exam, and the MR confirmed that
they were nasal dermoids. The crista galli (black arrow) appears normal for age. B. Axial T1 image shows an area of hyperintense dermoids
(white arrow) slightly higher in the nose, slightly displacing the nasal septum. C. Postcontrast fat-suppressed T1 image shows that the
dermoids are hypointense (small white arrows). The crista galli (black arrow) has normal appearance. Abnormal hyperintensity is extending
upward through the enlarged foramen cecum (large white arrow), suggestive of intracranial dermoid extension.
Figure 5-193 Dermal sinus with large intracranial dermoid. A. Axial T2 image shows hyperintense lesion (small white arrows) in the midline,
anterior to the crista galli (white arrowhead) at the location of the foramen cecum. A small area of intermediate signal (large white arrow) is seen
just behind the nasal bone. B. Sagittal postcontrast fat-suppressed T1 image shows the area (asterisk) to be of intermediate signal intensity
with surrounding enhancement likely representing sinus mucosa. A linear area of hyperintensity (small white arrows) extends through the bone
and subcutaneous tissues to the skin (large white arrow). C. Axial postcontrast fat-suppressed image shows the enhancement around the fluid
collection (small white arrows) and tubelike ring enhancement (large white arrow) in the linear structure in the subcutaneous tissue seen in (A
and B). D. Axial T2 image shows that the tube in the subcutaneous tissues opens through a cutaneous defect (white arrow). This was the
opening of a dermal sinus.
If MRI is not available, CT can be used; however, as discussed many times in this book, ionizing radiation should not be
used if safer techniques are available. In addition, CT evaluation of the nasofrontal region is often difficult in the neonate, as
the anterior skull base is largely cartilaginous at birth. Therefore, 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, but not the anterior midline of the anterior cranial fossa. 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 completely 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 (1106). If a cephalocele is suspected, an
MR should be obtained.
Parietal and atretic cephaloceles
Parietal cephaloceles are uncommon, comprising approximately 10% to 20% of cephaloceles (1082). When large, they are
often 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
holoprosencephaly (1074,1087,1107,1108). However, the large majority of parietal cephaloceles are so-called atretic
cephaloceles in which little, if any, brain herniates; therefore, brain and brain function remain largely intact, without obvious
neurological deficits; mild motor delay is sometimes reported (1108,1109). Uncommonly, some cephaloceles include both
frontal and parietal lobes; these can be large and, therefore, are easily recognized on fetal sonography. They are also difficult
to manage and, because the sensorimotor cortices are included in the extruded tissue (Fig. 5-199), prognosis is generally poor.
It is particularly important to locate the position of the dural venous sinuses with respect to the cephalocele in these patients
(Fig. 5-200); the sinus may be displaced or fenestrated, with the cephalocele ascending through the fenestration (1082).
Neurosurgical repair is much more difficult when the sinus is located within the cephalocele. Equally important, the straight
sinus may be vertically position and the vein of Galen elongated or a falcine sinus persistent (Fig. 5-201); less common venous
anomalies include vertical internal cerebral veins, ascending inferior sagittal sinus, and sinus pericranii (1110). Other
associated anomalies may include callosal agenesis, intracranial cysts, tentorial malformations, cerebellar vermis agenesis,
hydrocephalus, and gray matter heterotopia (1082).
Figure 5-194 Dermal sinus/dermoid with intracranial extension. A. 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. B–D. Sagittal T1-weighted (B) and T2-weighted (C) 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 (D) shows the
heterogeneous mass extending posteriorly (white arrows) along the sinus tract.
Figure 5-195 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.
Figure 5-196 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. 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 frontoethmoidal 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 heterotopia (black arrows).
Figure 5-197 Nasal glioma. T1 (A) and T2 (B) off-midline images show a mass (m) in the nose that is of the same signal as the brain. Axial
T1-weighted image (C) with contrast again shows a similar appearance to the brain. No communication is seen between the mass and the
intracranial cavity (in contrast to Fig. 5-178).
Figure 5-198 Midline craniofacial dysraphism. A. Sagittal T1-weighted image shows the interhemispheric lipoma (large black arrows) situated
dorsal to the thin, shortened corpus callosum (small black arrows) and extending from the posterior frontal region down through the frontal
bone (small white arrow) into the thickened subcutaneous fat that is continuous with the upper lip. The midline features of the face/nose (large
white arrow) are not seen. B. Axial T1 image of the face at the mid orbital level shows marked hypertelorism with the orbits widely separated.
The nasal cavity (black arrows) is widened and dysmorphic. Excessive subcutaneous fat is present over the dysmorphic, widened nose.
Figure 5-199 Fetal and postnatal images of a large frontoparietal encephalocele discovered in utero. A. Fetal MR image acquired in the fetal
coronal plane shows the brain on the reader’s left. The smaller hemisphere (in the center of the image) extends through a calvarial defect
(white arrow) into the cephalocele sac (S, on the reader’s right). B. Fetal MR image acquired in the fetal axial plane in the middle of the
cerebrum shows the very large cephalocele sac (S) on the reader’s right. The brain shows a small left hemisphere with curvilinear
hypointensities that represent heterotopic gray matter. The interhemispheric fissure (white arrows) is displaced to the reader’s right due to loss
of tissue into the cephalocele sac. C. Fetal MR image in the axial plane near the vertex shows brain tissue (B) extending through the calvarial
defect into the cephalocele sac (S). D. Postnatal sagittal T1 MRI image near the midline shows a dysmorphic-appearing hemisphere, with
multiple linear areas of abnormal appearing cortex, exiting the calvarium through a defect in the calvarial bone (white arrows) and entering the
cephalocele sac (S) above it. Some dysmorphic brain (B) is in the sac, along with a few blood vessels (white arrowhead). E. Axial T1 image
through the middle of the brain shows the interhemispheric fissure (white arrows) displaced from right to left. Note the extensive intermediate-
intensity heterotopic gray matter throughout both hemispheres. F. Time-of-flight MRI angiogram shows extensive vasculature (large white
arrows) running through the cephalocele defect into the dysmorphic brain (small white arrows), adding to the difficulty of surgical treatment.
A high percentage of parietal cephaloceles, and indeed of all cephaloceles, fall into the category of atretic cephaloceles
(1107,1108), 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 induction of ectoderm and mesoderm (1111,1112). Atretic parietal cephaloceles usually present as
small (5–15 mm), hairless midline masses near the vertex (1108). A sharply marginated calvarial defect is present below the
skin lesion, through which the cephalocele communicates with the intracranial cavity via a strand of connective tissue (Fig. 5-
201). The calvarial defect may be small (Fig. 5-201B), sometimes too small to see on standard spin echo MR images; thin
section (1–2 mm) volumetric T1-weighted images or T2 steady-state images such as CISS/FIESTA (1109) should be acquired
to establish the communication. Because of the proximity of parietal cephaloceles to the superior sagittal sinus, venous
anomalies, particularly fenestration of the superior sagittal sinus and persistence of an embryonic falcine sinus (sometimes
associated with absence of the vein of Galen and straight sinus) are seen in many affected patients (Fig. 5-201)
(1109,1113,1114).
Atretic parieto-occipital or occipital cephaloceles (Fig. 5-201B) usually present as nodular, small (less than 15 mm)
masses just above the external occipital protuberance (1108). They enter the calvarium through a 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
incidence of associated anomalies and a good prognosis for normal development (1108).
Nasopharyngeal cephaloceles
Nasopharyngeal cephaloceles (also called transsphenoidal cephaloceles) are very uncommon. They are important, however, as
they are occult cephaloceles; they are not obvious on clinical examination. In contrast to cephaloceles in other locations, which
are often detected by fetal sonography and usually obvious on initial postnatal physical examination, nasopharyngeal
cephaloceles are most often discovered toward the end of the first decade of life. The usual clinical presentation may be
persistent nasal stuffiness or excessive “mouth-breathing” by the child secondary to obstruction of the nasopharynx
(1090,1101) or spontaneous CSF rhinorrhea (1115). Clinical examination will reveal a nasal or pharyngeal mass that increases
in size with Valsalva maneuver. Associated intracranial and ocular anomalies are common. Agenesis of the corpus callosum is
seen in approximately 80% of reported patients (Fig. 5-202). Hypoplasia of the optic discs is seen on ophthalmologic exam;
retinal dysplasia and colobomas may be apparent on imaging studies, as well (Fig. 5-202B), sometimes associated with the
“morning glory syndrome” (1116). 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. 5-202A and C)
(1090,1101).
Large nasopharyngeal cephaloceles can be diagnosed 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.
MRI demonstrates a deep sella turcica with CSF extending through this bone defect into the soft tissues of the nasopharynx. In
large encephaloceles, erosive changes will be seen in the hard palate (Fig. 5-202A); in smaller or less advanced ones, fluid
will accumulate between the hard and soft palates (Fig. 5-202C and D), eventually becoming the source of a CSF leak. 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. 5-202A) (1090,1101). 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.
Figure 5-200 Parietal cephalocele. A. Midsagittal T2-weighted image 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 is correspondingly elevated. The superior colliculi and superior vermis
appear “pulled” toward the defect. The corpus callosum is abnormally thin. B. Midline sagittal image of postcontrast T1-weighted MR
demonstrates a persistent falcine sinus and the presence of venous structures (white arrows) within the cephalocele. C. Sagittal view of an MR
time-of-flight venogram demonstrates the persistent falcine sinus but fails to show the venous content of the cephalocele.
Figure 5-201 Atretic parietal cephaloceles. A. Sagittal T2-weighted image shows a small subcutaneous mass (white arrows) in the parietal
region. No continuity is seen of the brain tissue with the mass. B. Midsagittal T2 image of another patient shows a tract of hyperintense CSF
extending from the quadrigeminal plate cistern midline bony defect. Some hypointensity from a persistent falcine vein (small white arrows) is
seen along the ventral surface of the CSF channel at the location of the parieto-occipital sulcus. In the scalp, just external to the defect, some
fluid is present in the small cephalocele (larger white arrow).
Figure 5-202 Nasopharyngeal (sphenoidal) cephaloceles. A. Sagittal T1-weighted image reveals the encephalocele extending down through
the sphenoid bone into the nasopharynx and impression upon the posterior hard palate with erosive changes (small arrows). The dorsum sella
(curved arrow) remains intact. The optic chiasm (open white arrow) runs through the encephalocele. The corpus callosum is absent. B. Axial
T1-weighted image shows the cephalocele defect (white arrows) and a small left globe (black arrows) with retinal detachment. C. Sagittal T2-
weighted image shows a low optic chiasm (small C), enlarged sella turcica (black S) with the pituitary gland displaced anteriorly and inferiorly,
and extending into the craniopharyngeal canal (black arrows). Fluid (large white arrows) has leaked through the canal and is accumulating in the
submucosal spaces above the soft palate. Some fluid (white arrowhead) has leaked inferiorly between the soft palate and the adenoids (white
A) and may be leaking. D. Coronal T2 image at the level of the sella turcica shows the optic chiasm (C) pulled inferiorly and the pituitary gland
(P) being pulled into the craniopharyngeal canal (white arrows). A small collection of fluid (black arrows) is trapped above the adenoids (A).
Figure 5-203 Dermoids of the anterior fontanelle. A. Sagittal T1-weighted image shows a low intensity mass (large arrow) overlying the
anterior fontanelle, separated from intracranial contents by intact calvarium. Note the hypogenetic corpus callosum (small white arrow), which is
unrelated. B and C. Sagittal (B) and axial (C) SSFSE images from an MRI of a 22-week fetus shows a well-demarcated, hyperintense rounded
mass (black arrow) in the scalp at the level of the anterior fontanelle.
Martinez-Lage et al. (1117) and Yoon and Park (1122) reported the frequency of various pathologic entities that presented
as masses on the head in childhood and adolescence. They found that the incidence varies depending upon the age of the patient
at the time of presentation (see Table 5-10). They found that MR 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 fontanelle or other sutures (1123).
Solitary infantile myofibromatomas of the skull are benign tumors that are composed of fascicles, whorls, and nodules of
spindle-shaped cells with myofibroblastic features (1124). Radiologically, they appear as solitary lytic lesions of calvarium
that show increased uptake on Tc 99m-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 contrast. On
MR, they exhibit long T1 and T2 relaxation times compared with gray matter and otherwise show similar features to those seen
on CT (1125,1126). Prognosis is excellent after excision (1127).
Table 5-10 Calvarial Masses in Childhood (by Age)
Hemangiomas
Metastatic neuroblastoma
Ewing sarcoma
Leukemic masses
Infantile myofibromatosis
Sinus pericranii
Atretic cephaloceles
Ages 1–7 y
Epidermal cysts
Malignant tumors
Angiomas
Atretic cephaloceles
Sinus pericranii
Ages 8–17 y
Fibrous dysplasia
Osteomas
Sinus pericranii
Angiomas
Martinez-Lage JF, Capel A, Costa TR, et al. The child with a mass on its head: diagnostic and surgical strategies. Childs Nerv Syst 1992;8:247–252; Yoon
SH, Park S-H. A study of 77 cases of surgically excised scalp and skull masses in pediatric patients. Childs Nerv Syst 2008;24:459–465.
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 (1128). Rarely, they occur in lateral frontal and temporal
locations (1129). Diagnosis is made clinically (the lesions are soft and spontaneously reduce when intracranial pressure is
reduced) and patients usually require no treatment (1128); they may have an increased incidence in craniosynostosis (1130).
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 (1131); intracranial vascular anomalies, in particular developmental venous anomalies, are frequently present
(1132). The calvarial defect can sometimes be seen on a thin section CT or MR image; sagittal images may show the
relationship to the underlying dural venous sinus (Fig. 5-204A) (1117,1131). 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. 204B). Angiographic analysis is not 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
arteriovenous fistula (1132).
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 aplasia cutis congenita.
Parietal Foramina and Enlarged Parietal Foramina
Parietal foramina are oval, usually paired defects that are parasagittally located in the mid to posterior parietal bones (1133).
Parietal foramina may appear unilateral, or as a continuous defect crossing the midline, in early infancy, but the bilaterality
only becomes apparent with development of the ridge of bone along the sagittal suture (Fig. 5-205A) (1134). The overlying
skin and hair are normal. Normal bone growth never occurs within the defects (1133). 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
enlarged parietal foramina or foramina parietalia 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)
(1135–1137). 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 (1135). 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 (1138). Another report associates
craniosynostosis, delayed fontanelle closure, parietal foramina, imperforate anus, and skin eruption; it is known as CDAGS
(1139).
In addition to these syndromes, giant parietal foramina are worthy of note in this neuroimaging text because they may be
mistaken for cephaloceles on fetal imaging and because they are associated with rather characteristic intracranial anomalies.
Fetal sonography and fetal MR may show focal bulging of cerebrospinal fluid beyond the margins of the calvarium in the
parasagittal parietal bone (1140). This should not be mistaken for a cephalocele, as it will resolve over time. Recognition 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 occipital gyri herniate inferiorly into the tentorial
incisura, giving a characteristic appearance on MR studies (Fig. 5-205B). Finally, the straight sinus is underdeveloped,
resulting often in the presence of persistent embryonic venous structures such as falcine sinuses (Fig. 5-205B) and persistent
median prosencephalic veins (1136,1137). Coronal or sagittal images may show the parietal cortex appearing to protrude into
the calvarium (Fig. 5-205C). Associated malformations may include craniosynostosis, vertebral anomalies, digital anomalies,
clavicular hypoplasia, and absence of the acromion process.
Figure 5-204 Sinus pericranii. A. Sagittal postcontrast T1-weighted image 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. B.
Doppler sonogram through the lesion shows that the mass communicates with the superior sagittal sinus (SS) through an emissary vein (e).
Figure 5-205 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 sagittal 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.
Figure 5-206 Calvarial defect associated with aplasia cutis congenital. Axial postcontrast CT image (A) shows parietal calvarial defect
(arrows) with abnormal thinning of the overlying skin and irregular bone, better seen on the bone window (white arrow) (B). This is not a location
for cranial sutures.
Differential diagnosis includes Potocki-Shaffer syndrome (proximal 11p deletion syndrome), ALX4-related frontonasal
dysplasia, MSX2-related craniosynostosis, and mutations of distal portions of chromosome 5q (1141).
Calvarial Defects Associated with Aplasia Cutis
Aplasia cutis congenita is the name given to the absence of a portion of skin at birth, in a localized or widespread area (1142)
that occurs in about 0.01% of uncomplicated births (1143). It most commonly (60%–70%) presents as a solitary defect on the
scalp, but multiple lesions sometimes occur (1143). 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 (1142). 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 10% to 20% of cases involving the scalp have
associated calvarial defects (Fig. 5-206), probably due to the same forces that caused the cutaneous lesion (1143,1144); the
skull lesions do not heal by spontaneous regeneration (1145).
Isolated congenital defects of the calvarium with intact brain, scalp, and meninges are rare (1145). These defects usually
occur in the midline and are of variable size (ranging from 1 to 10 cm (1134)). They probably represent either a fusion defect
or a congenital failure of ossification 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 (1135). Bone regeneration rarely
occurs without surgical intervention (1134,1145). Perlyn et al. (1135) 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 (1146); 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 imperfecta, cleidocranial dysostosis), endocrine disorders (athyrotic
hypothyroidism), chromosomal abnormalities (trisomy 13, 18, or 21), and drug or toxin exposure (fetal hydantoin syndrome)
(1147). Rarely, no cause is found (1148).
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 (1149,1150). Lipomas are malformations; they are believed to result from abnormal differentiation of the
meninx primitiva, the undifferentiated mesenchyme that surrounds the developing brain (1151–1153). Normally, the meninx
primitiva differentiates into the leptomeninges, the stroma of the choroid plexuses, and the subarachnoid space. For some, as
yet unknown, reason, the areas of meninx that evolve into subarachnoid space the latest differentiate into fat in some patients,
forming intracranial lipomas (1151,1153). As a result of their formation from the meninx, intracranial lipomas are almost
always located in the subarachnoid space. As they are malformations, 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 adjacent structures. Moreover, because lipomas are, essentially, maldifferentiated 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 (almost always originating
from the tuber cinereum of the hypothalamus, 10%–20%), the cerebellopontine angle cisterns (~10%), and the Sylvian cisterns
(~5%) (1150,1153). Occasionally, lipomas are found on the surface of the cerebral cortex (1149). 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 lamina, prominent astrocytosis, and abnormal synaptic profiles (1149).
Figure 5-207 Large, lobular interhemispheric lipoma. Axial CT scan (A) through the lipoma shows a lucent area (large white arrows) in the
interhemispheric 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 (B) shows a large bulky interhemispheric lipoma (large white arrows). Note that the corpus
callosum (white arrowheads) is hypogenetic with no anterior genu, rostrum, or splenium. Coronal T1-weighted image (C) shows the lipoma
extending into the velum interpositum and then through the choroidal fissures into the choroid plexuses of the lateral ventricles.
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 agenesis 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 associated, as well, usually in the frontal region. In fact, several midline
developmental disorders appear to have lipomas of the interhemispheric 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 frontonasal dysplasia (see Fig. 5-198 in the section of this chapter on frontonasal cephaloceles) (99). When
interhemispheric lipomas and callosal anomalies are associated with median cleft lip or palate and cutaneous polyps of the
face, a diagnosis of Pai syndrome can be made (1154,1155).
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 (78). On CT, lipomas are sharply
demarcated areas of marked hypodensity in affected cisterns (Fig. 5-207). Lobulated interhemispheric lipomas may extend (a)
inferiorly through the choroidal fissures into the choroid plexus of the ventricles, (b) anteriorly in front of the callosal genu, (c)
posteriorly behind the hypoplastic body or splenium, or (d) dorsally into the interhemispheric fissure. Calcification is often
present in lobulated interhemispheric lipomas, most commonly within a fibrous capsule surrounding the lipoma (1156). The
calcification may be curvilinear, located at the periphery of the lipoma (Fig. 5-207A) or, less commonly, nodular and within
the center of the lipoma. Calcification is less common in lipomas located elsewhere. The full extent of the lipoma and
associated callosal hypogenesis can only be fully appreciated on MR.
Figure 5-208 Fetal and postnatal MR 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. C. Postnatal sagittal T1-weighted
image shows the lipoma (white arrows) immediately dorsal to the hypogenetic corpus callosum (white arrowheads).
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. 5-207 to 5-209) and when fat suppression is applied.
Loss of signal with fat suppression confirms the diagnosis; use of other sequences is not productive unless the initial sequences
reveal areas of tissue other than calcium or fat. On fetal MR, lipomas are iso- to slightly hypointense compared with
surrounding brain (Fig. 5-208). Smaller lipomas may have no adjacent brain malformations, but dysplastic brain tissue often
accompanies large ones; for example, the cerebellar vermis is sometimes small and dysmorphic when adjacent to a large
supravermian/collicular lipoma (1150). When lipomas are large, it is common to see significant associated chemical shift
artifact (areas of hypo- and hyperintensity on opposite sides of the lipoma in the frequency encoding direction), particularly
when conventional T2-weighted images are acquired with a short bandwidth, resulting from the different chemical shifts of
water and fat protons (Fig. 5-210). The presence of the chemical shift artifact should alert the reader that the lesion is fat, and
not blood. This is rarely a problem with modern 3D acquisitions and acquisition techniques, but if question remains,
application of a fat suppression sequence will make the lipoma hypointense to gray matter (Fig. 5-210), which eliminates the
artifact and confirms the diagnosis. Fat suppression is useful to differentiate small hypothalamic lipomas from ectopic
posterior pituitary glands (Fig. 5-211, also see section on Anomalies of the Hypothalamic–Pituitary Axis). Other common
locations for intracranial lipomas are the quadrigeminal plate/supravermian cisterns (Fig. 5-212) and cerebellopontine angle
cisterns (Fig. 5-213), both of which may be quite large. Occasionally, sylvian fissure lipomas are associated with aneurysms of
the middle cerebral arteries and their branches (1157); again, thin section 3D acquisition or fat suppression can be useful to
obtain the proper diagnosis.
Lipomas can be considered to arise from misprogrammed mesenchyme (meninx primitiva), as is the stroma of the choroid
plexus; therefore, sometimes lipomas extend through the choroidal fissure and into the stroma of the choroid plexuses of the
lateral ventricles (Fig. 5-207). Curvilinear lipomas are thin and typically extend posteriorly behind the corpus (Fig. 5-209),
sometimes wrapping around the posterior callosum and coursing into the velum interpositum. In these cases, the posterior
corpus callosum is essentially always shortened (Fig. 5-209); no callosal fibers are seen dorsal or posterior to the lipoma
(Figs. 5-207 to 5-209) (1153).
Figure 5-209 Montage of pericallosal lipomas. Note that in all of these cases, the corpus is shortened without a normal genu or rostrum and
without a full-sized splenium. The lipoma (arrows) in (A) initially appears to be only beneath the splenium but on close observation is seen
extending around the splenium, along the top of the body all the way to the genu. In (B), the lipoma is rather thick over the posterior body (black
arrows), leading to a large chemical shift artifact dorsally (white arrows). The lipoma in (C) is thick posteriorly, resulting in a shortened posterior
body and absent splenium. The lipoma in (D) is similar to the one in (A), extending around most of the callosum, but is thicker; splenium and
genu (white arrows) are shortened.
Arachnoid Cysts
Pathologic Characteristics
Arachnoid cysts are congenital lesions of the arachnoid membrane that expand by CSF secretion. Light and electron
microscopic studies 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 (1158–1161). 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 (1159,1161). Ultrastructural studies have shown that the cells lining
true arachnoid cysts contain specialized membranes and enzymes for secretory activity (1162). When true arachnoid cysts
expand, therefore, the mechanism appears to be an accumulation of CSF secreted by cells in the cyst wall rather than by
osmotically induced filtration or a ball–valve mechanism. The precise differences between arachnoid cysts that expand over
time and those that remain stable in size have yet to be worked out (1161,1163,1164), although a recent study by Rabiei et al.
(1165) suggests that the cysts have considerable differences in wall thickness, cellularity, connective tissue elements, and
vascularization. Their variable growth may reflect the differences in morphology.
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%) (1164,1166).
Clinical Characteristics
Arachnoid cysts usually occur sporadically. They have a higher incidence in individuals with autosomal dominant polycystic
kidney disease, being reported in as many as 8.1% of patients with this disorder (1167), and in Aicardi syndrome (93). Most
cysts, if not associated with other anomalies, remain clinically silent and are only detected incidentally (1168), although some
series show that some (~20%) grow, most (50%–70%) remain stable in size and some (~20%) decrease in size (110). 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 almost
always asymptomatic and their discovery is incidental. When middle cranial fossa cysts are large, they are often discovered as
a result of cranial asymmetry (Fig. 5-202); occasionally middle cranial fossa cysts may be associated with seizures,
headaches, or, rarely, hemiparesis (1159), but the actual relationship of these symptoms to the cyst is questionable (1164). The
incidence of hydrocephalus associated with arachnoid cysts is low, and current estimates of less than 10% (1168) are much
higher than the authors’ experience would suggest. When hydrocephalus develops, it is usually associated with large
supratentorial 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 syndrome (1159,1160,1169). When hydrocephalus is present, it may be
communicating or noncommunicating and may result from either defective CSF resorption or mechanical obstruction to egress
of CSF from the ventricles (1170). After treatment of the cyst, cognitive and neurological outcome are excellent (1171).
Figure 5-210 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 heterogeneity (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.
Figure 5-211 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.
Ectopic posterior pituitary glands do not suppress.
Figure 5-212 Quadrigeminal plate/supravermian lipomas. Sagittal T1-weighted images show a small (white arrow in A) and a large (white
arrows in B) lipoma located between the inferior colliculus and the superior cerebellar vermis.
Imaging Characteristics
Arachnoid cysts appear on CT and MR as sharply marginated, homogeneous, unilocular masses that have signal identical to
CSF on both CT and MR (Fig. 5-214). The use of FLAIR and diffusion sequences (Fig. 5-214C and D) can help to confirm the
diagnosis of cyst. On transfontanelle sonography, they are sharply marginated, sonolucent masses with a well-defined posterior
border and enhanced through transmission. Fetal MR will show most arachnoid cysts as a CSF-intensity mass that displaces
adjacent parenchyma with a very sharp margin between the parenchyma and the cyst (Fig. 5-215).
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 interpeduncular 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. 5-216). 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 foramina of Monro, causing hydrocephalus; it may even bulge further superiorly between the
leaves of the septum pellucidum (Fig. 5-216). 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. MR usually easily makes diagnosis, with the midline sagittal image showing the cyst displacing the floor of the
third ventricle superiorly (Fig. 5-216).
Figure 5-213 Cerebellopontine angle lipoma enveloping cranial nerve. Axial CT scan (A) shows a hypodense mass (white arrows) in the right
cerebellopontine 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.
Figure 5-214 Large middle cranial fossa arachnoid cyst in a neurologically asymptomatic 2-year-old child presenting with plagiocephaly
(normal development). 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 (interhemispheric fissure, septum
pellucidum) is shifted from left to right. Axial FLAIR (C) and average diffusivity (D) images show contents isointense with ventricular CSF,
confirming that the mass is a cyst.
The major differential diagnoses of suprasellar arachnoid cysts are epidermoids and cystic astrocytomas. By standard MR
and CT techniques, epidermoids are usually less sharply marginated than arachnoid cysts and are more heterogeneous, with
highly lobulated rather than smooth walls; however, there are cases in which differentiation by standard spin echo MR imaging
is impossible. As discussed in the section on epidermoids in Chapter 7, differentiation is straightforward using diffusion
imaging, FLAIR, or magnetization transfer imaging. Cystic astrocytomas are more easily differentiated. Intravenous
administration of paramagnetic contrast will show an enhancing solid tumor component in cystic astrocytomas; arachnoid cysts
do not enhance and do not have mural nodules.
The middle cranial fossa is the most common location for arachnoid systs, with 60% to 65% developing in that area; their
appearances may differ somewhat, depending upon size. Approximately 20% are small, biconvex or semicircular lesions with
little mass effect and no expansion of bone (1160). These small cysts can be missed on CT because of bone artifact and volume
averaging; of note, 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 generally considered to be of clinical significance.
Approximately 50% of middle cranial fossa cysts are of moderate size. They occupy the anterior and middle portions of the
temporal fossa and frequently displace the tip of the temporal lobe posteriorly, superiorly, and medially (Fig. 5-217). They
cause a characteristic flat medial border of the sylvian fissure and open the lips of the fissure laterally. The temporal fossa is
usually mildly expanded by these lesions.
Approximately 30% of middle cranial fossa cysts are large, occupying nearly the whole temporal fossa, sometimes
extending to the frontal fossa and over the cerebral convexity (Fig. 5-214). These large cysts cause substantial mass effect and
may expand the hemicranium, compress adjacent brain, and result in midline shift (Fig. 5-214). In neonates, they cause
macrocephaly and plagiocephaly, which is often the reason the children are imaged; of interest, many of the affected patients
are asymptomatic. 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
(1172). The bleeding is probably caused by the disruption of cortical veins, which frequently traverse the cyst near its
periphery. These veins bleed readily with slight manipulation at the time of surgery. 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 hemorrhage. 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 (1160). Middle
cranial fossa arachnoid cysts may rupture into the subdural space spontaneously, or after trauma as a result of pre-existing or
traumatic communication (Fig. 5-218) (1173,1174); this may result in formation of a subdural hygroma or, in some patients,
persistent headaches or intracranial hypertension (1175) that may persist. Rarely, spontaneous disappearance of arachnoid
cysts has been reported; this presumably results from spontaneous decompression of the cyst into the subdural space, perhaps
through a weak portion of the cyst wall (1176).
Figure 5-215 Fetal MRs of arachnoid cysts. Note that the walls of the cyst cannot be seen on SSFSE images. A and B. Parasagittal (A) and
axial (B) images show the sharply marginated, 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. C and D. Axial (C) and coronal
(D) images show expansion of the right posterior fossa (white arrows). The impression of the cyst upon the posterior aspect of the right
cerebellar hemisphere can be seen in C (black arrow). Note the expansion of the right side of the posterior fossa (white arrows in C, black
arrows in D). E and F. Left ambient cistern cyst displaces posteromedial tempo-occipital tissue laterally (black arrows in E) and superiorly
(larger black arrows in F). Smaller black arrow in (F) shows displacement of the superomedial aspect of the tentorium.
Figure 5-216 Suprasellar arachnoid cyst. Sagittal T1-weighted image (A) shows the large suprasellar cyst extending upward to compress 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 reformatted 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. Small arrows in (D) point to the cyst walls at the foramina.
Figure 5-217 Moderate-sized middle cranial fossa arachnoid cyst. A. Parasagittal T1-weighted image shows the hypointense cyst (C)
displacing the anterior portions of the frontal and temporal lobes posteriorly. B. Axial T2-weighted image shows only moderate mass effect from
the cyst (C) with minimal midline shift when compared to the large cyst in Figure 5-214.
Approximately 25% of arachnoid cysts occur in the posterior fossa (Figs. 5-215A, B, and 5-219). These lesions are usually
large (>5 cm) before they cause clinical symptoms (1160,1170,1177). Although the cysts can occur anywhere in the posterior
fossa, the cerebellopontine angle and inferior or dorsal midline (Fig. 5-219) are the most common locations. The importance of
these lesions is twofold: (a) they may compress the fourth ventricular outflow foramina and cause hydrocephalus, and (b) when
dorsal and midline, they must be differentiated from mega cistera magna and enlarged fourth ventricles (Dandy-Walker
complex) or Blake pouch cysts. If the patient is asymptomatic (the cyst is an incidental finding, which is the case in the vast
majority), the differentiation is not important, even if there appears to be a small amount of mass effect upon the cerebellum.
Clinically, in the uncommon situation when cysts 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 complex usually present in infancy either with hydrocephalus or developmental delay (905). Radiologically,
differentiation is made by determining whether the cyst is an enlarged fourth ventricle (Dandy-Walker malformation or
persistent Blake pouch cyst) or whether it is isolated from the surrounding subarachnoid space (arachnoid cyst). Magnetic
resonance cisternography with 3D steady-state imaging such as constructive interference in steady state (CISS) or fast imaging
employing steady-state acquisition (FIESTA) can depict thin membranes such as the walls of cysts (1178). 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 communication between the cyst and the fourth ventricle; however, flow can be complex and such studies
may be misleading. The most reliable methodologies, 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) and the ventricular system (the cyst fills after injection of iso-osmolar nonionic contrast into the lateral ventricle and
tilting the head up) or is an isolated arachnoid cyst or loculation (cyst doesn’t fill or fills only after a long delay after either
injection). Large retrocerebellar cysts may be associated with anomalies of the dural venous sinuses (Fig. 5-219).
Figure 5-218 Spontaneous rupture of a middle cranial fossa arachnoid cyst into the subdural space. Axial T2 MR shows an enlarged left
sylvian fissure with scalloping of overlying bone (arrows) from a middle cranial fossa arachnoid cyst (C). Note the enlarged ipsilateral subdural
space (SD) and the left-to-right midline shift.
Craniosynostosis
Embyrology of the Bones of the Face and Skull
The head is an amazingly complex structure. The calvarium is composed of bones that enclose and protect the brain; it also
functions as a scaffold for the face and thereby, in combination with the muscles, blood vessels, connective tissues and nerves,
supports the functions of feeding and breathing (1179). The skull itself is formed from both mesoderm and neural crest-derived
mesenchyme (1070,1071). Cranial neural crest cells originate at the lateral edges of the neural plate; some then migrate to the
developing face and anterior skull. Precursors of the mesenchymal stem cells arise at the mesencephalon/diencephalon
boundary (in response to sonic hedgehog signaling from the adjacent notochord) and migrate to the supraorbital regulatory
center, located above the developing eye at the base of the developing coronal suture (1180), where they are situated between
cephalic mesodermal cells (which will become parietal bone) and cranial neural crest cells (which will become the frontal
bone). This arrangement is maintained during skull growth so that the developing coronal suture is composed of only
mesodermal derivatives and cranial neural crest cells never cross that suture (1180). Alterations of this process leads to
premature closure of the frontal sutures and disrupts development of the skull, while disruption of the migration of the cranial
neural crest cells from the diencephalon and mesencephalon results in abnormal development of the five facial primordia (the
frontonasal prominence and the paired maxillary and mandibular processes), which surround the oral cavity (1179) (see
http://www.indiana.edu/~anat550/hnanim/face/face.html (open access) for more detail on this developmental anatomy of the
face). Many recent studies have shown that mutations of genes involved in these processes can result in premature fusion of
sutures, both in the calvarium and in the face (1071,1179–1182).
Figure 5-219 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 venogram (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.
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 error of development. The cause is thought to be a primary genetic problem that leads to a anomalous
development of the skull base. Secondary synostosis refers to premature sutural closure resulting from external 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 individuals and as a part of syndromes associated with other developmental anomalies (1183–1185).
Overall, about 15% of cases are syndromic, 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
(1186).
The precise cause of premature sutural closure has not been fully clarified. As discussed above, it appears that suture
patency is dependent upon the presence of a population of mesenchymal stem cells, which are critical for skull growth, within
the suture (1181). These cells form the supraorbital regulatory center (SRC), where they lie between cephalic mesodermal
cells (which will form the parietal bone) and the cranial neural crest cells (which will form the frontal bone) (1180). Multiple
transcription factors, including MSX2 and TWIST1, are expressed in this region and are involved in the commitment of cells to
an osteogenic fate. Mutations of TWIST1 and TCF12 (the latter codes for a partner protein of TWIST1 in skull formation)
cause coronal synostosis (1187). Craniosynostosis can also be caused by mutations of genes with important roles in cell
division, such as CDC45 (1188). Thus, it is likely that most craniosynostoses, including the nonsyndromic synostoses, are
the result of mutations of genes important in the development, maintenance, and balance of the cranial neural crest cells
and mesodermal cells at the SRC and coronal suture. These include the fibroblast growth factors (FGFs) and their receptors
(FGFRs), which also influence the balance between the proliferation of osteoprogenitor cells and the differentiation of new
bone in the membranous bones of the calvarium, processes that take place at the sutures (1185). When the balance is shifted
from proliferation of progenitors to production of bone, the sutures close. All of the genes that have been found to be causative
in craniosynostosis syndromes (FGFR1, FGFR2, FGFR3, TWIST1, and MSX2) seem to participate in the molecular pathways
involved in this process (1071,1179,1180).
When isolated to a single suture, craniosynostosis is usually sporadic; the affected child is typically referred for evaluation
of an abnormally shaped head. Isolated sagittal synostosis accounts for about 60% of simple nonsyndromic craniosynostosis
(NSC) cases (1189) and causes a long, narrow head shape with variable frontal bossing (scaphocephaly or dolichocephaly,
Fig. 5-220); this disorder is easy to diagnose clinically and probably does not need radiologic evaluation unless it is atypical
(1190,1191). Of note, affected patients may have speech and language deficits (1192). Isolated metopic synostosis accounts for
18% of simple NSC cases (1186) and causes a prominent, wedge-shaped forehead with compensatory widening posteriorly
(trigonocephaly, Fig. 5-221); underlying syndromes, such as 11q23 deletion, 9p deletion, Opitz C syndrome, and various
aneuploidies, are seen in up to 30% of affected patients (1193). Isolated unilateral coronal (20%–30% of NSC, with 60%–
75% of those affected being female, Fig. 5-222) or lambdoid (<5% of NSC, Fig. 5-223) synostosis causes cranial asymmetry
(plagiocephaly). In coronal synostosis, the ipsilateral forehead is flattened with elevation of the superior orbital rim, while
frontal bossing occurs on the contralateral side (1191), whereas lambdoid synostosis causes flattening and reduction of
posterior skull height with posterior malpositioning of the ear on the side of the fusion and contralateral posterior bossing
(1191). Considering only craniosynostosis in which a molecular diagnosis is made, the most common form is Muenke
syndrome, followed by Saethre-Chotzen syndrome (1185). It is important to remember that the most common cause of
plagiocephaly is not synostosis, but “positional flattening” resulting from (a) the neonate being positioned almost
exclusively in the supine position with the head usually tilted to the same side, (b) only bottle-feeding with the bottle on the
same side, or (c) slow motor development (1194).
Figure 5-220 Scaphocephaly secondary to sagittal suture synostosis. Axial CT image (A) shows an elongated, narrow head secondary to
sagittal synostosis. Note the ridge of bone (black arrows) 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.
Figure 5-221 Trigonocephaly. A. Axial CT shows a pointed frontal region (large white arrow) secondary to premature closure of the metopic
suture. The coronal sutures (small white arrows) are patent. B and C. 3D surface reformations of the calvarium obliquely (B) and from a
superior aspect (C) show a ridge of bone (black arrows) along the prematurely closed suture. The remaining sutures and the anterior fontanelle
(black f in image C) are open.
Multiple suture involvement is seen in about 5% of patients with NSC (1195). Clinically, they are divided into two groups:
those with premature fusion of two sutures and those with complex craniosynostosis due to involvement of more than two
sutures (1195). Patients with two-suture fusion have similar clinical courses to those with monosutural fusion (normal
development, normal intelligence, normal intracranial pressure) other than a higher rate of reoperation (25% vs. 5%)
(1186,1196). In contrast, those with complex craniosynostosis have a high incidence of increased intracranial pressure,
cerebellar tonsillar herniation and developmental delay; the rate of reoperation is 37% (1186). Of NSC patients with multiple
suture involvement, 40% to 50% have oxycephaly secondary to bilateral coronal and lambdoid synostosis, 30% to 40% have
brachycephaly secondary to bilateral coronal synostosis, and about 20% are “unclassified” secondary to multiple assorted
sutural synostoses. It is important to remember that cases of single or dual suture synostosis may be genetic. This is
particularly true for coronal synostoses; the recurrence risk for bilateral coronal synostosis is 5% to 7% (1197). Bilateral
lambdoid synostosis should raise suspicion for rhombencephalosynapsis (see section in this chapter on cerebellar
malformations). Syndromes with craniosynostosis are discussed in the following section.
Figure 5-222 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 reformation 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.
Radiology of synostosis
Isolated sagittal, metopic, unilateral coronal synostosis, or positional plagiocephaly is diagnosed clinically and confirmed by
plain films of the skull; cross-sectional imaging studies are not indicated to assess the sutures (1198). The characteristic
findings on CT are available in any standard text on pediatric radiology. Briefly, premature sagittal synostosis causes
scaphocephaly and ridging along the sagittal suture (Fig. 5-220), premature metopic synostosis causes trigonocephaly and
ridging along the metopic suture (Fig. 5-221), and premature coronal synostosis shows plagiocephaly and an uplifting of the
lateral orbital roof (Fig. 5-222), giving the “Harlequin eye” appearance.
Figure 5-223 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. Posteroinferior 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.
Although experienced surgeons may treat single suture synostosis without the assistance of imaging studies (1191), many
surgeons now request 3D reconstructions of the calvarium (derived from CT scans, see Figs. 5-220 to 5-223) in order to plan
their surgery. Neuroimaging is also performed to look for underlying brain anomalies; therefore, images are archived using
both soft tissue CT windows to look at the brain and bone windows to look at the calvarium. Infants with trigonocephaly may
have anterior midline anomalies and should be evaluated for Opitz C syndrome, Jacobsen syndrome, holoprosencephaly, and
others (1195,1199).
Unilateral posterior plagiocephaly (unilateral occipital flattening) is most commonly caused by persistent supine positioning
of the child during early infancy; this is most commonly done to reduce the possibility of sudden infant death (1200) but can
also result from torticollis, prematurity, developmental delay, (1201) or benign enlargement of the subarachnoid spaces (see
Chapter 8) (1202). Less commonly, patients may exhibit reduced movement as a result of an underlying brain anomaly or brain
damage (either anatomic or secondary to metabolic disease), which can cause reduced infant mobility. This secondary
flattening, resulting from lack of infant movement, is usually not associated with synostosis. This benign flattening is most
easily differentiated from lambdoid synostosis by the head shape and location of the ipsilateral ear: head shape is trapezoidal
with the ipsilateral ear located posteriorly in synostosis but the head has a parallelogram shape with ipsilateral ear located
anteriorly in positional flattening (1203). In the absence of underlying neurologic abnormality, the vast majority of cases of
occipital plagiocephaly are nonsynostotic and improve once the children no longer lay on the same side of their head all the
time (1201,1204). If necessary, the child may wear a helmet during sleep (1204,1205).
The radiologic evaluation of children with unilateral occipital plagiocephaly is evolving. In most cases, when the children
are developing 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 (1206). Plain skull
films are not helpful in either ruling out underlying brain abnormality or in diagnosing lambdoid synostosis. If the children
exhibit developmental or neurologic abnormalities, an MR should probably be obtained, as MR is the most sensitive method
for detecting brain abnormalities. MR can also provide information regarding the position of the ipsilateral ear (important in
posterior plagiocephaly, see previous paragraph). If CT is obtained for surgical planning, it should be acquired with as low a
dose of radiation as possible while performing a technically adequate study, and three-dimensional reformations should be
constructed (Figs. 5-220, 5-222, and 5-223).
Certain compensatory changes in calvarial shape are seen with occipital plagiocephaly of any etiology. The anterior portion
of the ipsilateral middle cranial fossa is enlarged. The orbit is elevated and there is increased lateral convexity of the
squamous portion of the ipsilateral temporal bone. Additional abnormalities found in isolated coronal synostosis include
expansion of the ipsilateral inferior occiput (below the suture), narrowing of the sphenopetrosal angle, decreased size of the
ipsilateral frontal fossa, flattening and posterior displacement of the ipsilateral frontal calvarium, compression of the
ipsilateral anterior cranial hemifossa, and medial, posterior, and superior displacement of the orbital roof (1207).
Anomalies of venous drainage can occur with multisutural synostosis of both syndromic and nonsyndromic causes
(1208,1209). If surgical 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) (1210). Abnormal venous
pressure may be associated with increased intracranial pressure (or frank hydrocephalus), and consequences of this elevated
pressure should be contemplated and addressed in advance (1029,1208). Moreover, in the setting of increased intracranial
venous pressure, transcalvarial emissary veins may enlarge around the cranial sutures (1029); 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 fontanelle 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, comptomelic 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, 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 associated anomalies involving mainly the face and limbs and are considered to be
syndromic (1186,1199). 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). The
essentials of facial and skull growth were discussed at the beginning of this section on synostosis and will not be repeated
here.
Although several different syndromes are defined on the basis of clinical features, a precise classification of affected
patients is difficult because of considerable overlap (1199). In addition, patients with mutations of the same gene can have
different phenotypic manifestations and vice versa (1211). FGFR2 mutations have been found in patients carrying the diagnosis
of Apert, Crouzon, Pfeiffer, and Beare-Stevenson craniosynostosis syndromes, in addition to the so-called bent bone syndrome,
suggesting that these entities may represent a clinical spectrum of the same disorder, with the differences resulting from
epigenetic effects (1195,1211,1212). Moreover, the same phenotype can be caused by mutations in different genes, as in cases
of Pfeiffer syndrome due to FGFR1 and FGFR2 mutations (1213) and Carpenter syndrome from MEGF8 and RAB23 mutations
(although the latter have somewhat different phenotypes (1211). Thus, as in many genetic disorders, the precise phenotype of
the affected patient is mostly likely related to the effects of specific mutations upon the function of the protein product in the
different pathways, of effects from intersecting pathways (proteins involved in more than one), and to epigenetic modifications
of the protein; many craniosynostosis syndromes are allelic and have overlapping features. Nonetheless, it is useful to have
some method to classify these disorders, and Table 5-11 is included for this purpose. For a more detailed table, refer to Online
Mendelian Inheritance in Man (OMIM) or to the recent review of Twigg and Wilkie (1211).
Apert, Apert- FGFR2 Acrocephalosyndactyly I, II Cranios ynostosis (esp. coronal), midface hypoplasia, Autosomal
Crouzon/101200 severe syndactyly hands and feet, down-turned dominant
mouth, hypertelorism
Nonsegmentations of C-spine
Venous anomalies
Chiari I malformations
Callosal septal ageneses
Limbic anomalies
Saethre-Chotzen/101400 TWIST1 Acrocephalosyndactyly III Craniosynostosis, facial asymmetry, low hair line, Autosomal
ptosis, deviated nasal septum, syndactyly of second, dominant
third fingers
Normal cognition
Muenke/602849 FGFR3 Nonsyndromic coronal craniosynostosis Craniosynostosis, thimble-like middle phalanges, Autosomal
coned epiphyses, carpal and tarsal fusions dominant,
Most common syndromic cause of craniosynostosis, usually
usually unilateral or bilateral coronal paternal
Pfeiffer, Noack/101600 FGFR2 Acrocephalopolys yndactyly I, V Craniosynostosis, malformed enlarged thumb and Autosomal
70% great toe; soft tissue syndactyly of second, third dominant
FGFR1 digits; polydactyly; stenosis/atresia of external
8% auditory canal; normal intelligence
FGFR3
3%
Carpenter, Summitt, RAB23 Acrocephalopolys yndactyly II, III, IV Craniosynostosis, preaxial polydactyly, soft tissue Autosomal
Goodman, Sakati-Nyhan/ MEGF8 syndactyly, malformed ears, obesity, hypogenitalism, recessive
201000 variable mental retardation
Crouzon, craniofacial FGFR2 Craniosynostosis with other somatic Craniosynostosis, maxillary hypoplasia, shallow Autosomal
dysostosis/123500 abnormalities orbits with proptosis, bifid uvula or cleft palate dominant
Craniosynostosis, fibular Unknown Craniosynostosis with other somatic Craniosynostosis fibular aplasia Autosomal
aplasia, Lowry/218550 abnormalities recessive
Craniosynostosis, FGFR2 Craniosynostosis with other somatic Craniosynostosis, varus deformity of great toes, Autosomal
midface hypoplasia, foot FGFR1 abnormalities tarsal fusion dominant
defects, Jackson-
Weiss/123150
Craniosynostosis, mental Unknown Craniosynostosis with other somatic Craniosynostosis, cleft lip and palate, choroidal Autosomal
retardation clefting/218650 abnormalities coloboma, mental retardation recessive
Craniosynostosis, radial RECQL4 Craniosynostosis with other somatic Synostosis of one or more sutures, bilateral radial Autosomal
aplasia, Baller- abnormalities aplasia recessive
Gerold/218600
Craniosynostosis, FBN1 Craniosynostosis with other somatic Synostosis of multiple sutures, mandibular and Autosomal
arachnodactyly hernia, abnormalities maxillary hypoplasia, multiple abdominal hernias, dominant
Shprintzen- exophthalmos, mental retardation
Goldberg/182212
Craniosynostosis Type 2 MSX2 Craniosynostosis (variable) with digital Synostosis ranges from metopic ridging to cloverleaf Autosomal
(Boston Type abnormalities (short metatarsals) skull dominant
Craniosynostosis)/604757
Craniosynostosis with FGFR2 Craniosynostosis and ear defects, Most have cloverleaf skull. De novo
Cutis Gyrata Beare- Cutis gyrata Sudden, unexpected death is common. mutations
Stevenson/123790 Acanthosis nigricans
Anogenital anomalies, skin tags
Tracheal cartilaginous sleeves
X-linked PHEX Sagittal synostosis with growth Sagittal synostosis, dolichocephaly. Autosomal
hypophosphatemic retardation, rachitic/osteomalacic bone Occasionally multiple sutures recessive
rickets/307800 disease, hypophosphatemia, and renal
defects in phosphate resorption
Of the many types of suture synostosis patterns, bilateral coronal synostosis (Fig. 5-224) is the most common combination,
but combined 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 configuration known as cloverleaf skull or Kleeblattshädel (Fig. 5-225). Multiple
synostosis syndromes may be isolated or associated with syndactactyly, polydactyly, fusion of cervical vertebrae, anomalies of
the middle ear, or other somatic anomalies (Table 5-11) (1183,1184,1199,1214–1216).
Imaging of craniosynostosis syndromes
As stated above, considerable overlap exists among the craniofacial manifestations of the different syndromes; therefore, a
general description of the imaging findings will be given (for a summary, see Table 5-12). The shape of the head, as viewed on
sagittal MR images, is quite characteristic in most patients with multiple sutural synostosis syndromes. Because the coronal,
sagittal, and lambdoid sutures close early, the brain grows upward and anteriorly through a very enlarged anterior fontanelle
(Figs. 5-224 to 5-226), resulting in disproportionate enlargement of the frontal horns. This combination of forces results in an
appearance of turricephaly (tower head, Figs. 5-224 to 5-226). In addition, because of the premature sutural fusion, the skull
base and posterior fossa are abnormally small. This characteristic skull shape can be detected prenatally with fetal MRI (Fig.
5-227) (1217) and should allow prenatal diagnosis of a multiple suture synostosis syndrome, although the details to diagnose
the precise syndrome may not be visible. Sometimes, when multiple sutures fuse early, the midline sagittal image may look a
saddle to expansion of the anterior fossa (frontal bossing and expansion through the fontanelle), the parietal region, and
expansion of the temporal squamosal (Figs. 5-228 and 5-229).
Anomalies of the underlying brain are present in a significant number of affected patients (1179,1211,1218) and their
identification is the primary reason for obtaining MR studies. Although polymicrogyria is not described in these disorders, we
have seen several cases (Fig. 5-229). This finding is not altogether unexpected in view of the known interactions of the
cerebral cortex and overlying meninges (often abnormal in craniosynostosis syndromes) during development (493,1219,1220).
Ventriculomegaly (Figs. 5-225 and 5-226) is very common, probably as a result of the small skull base (resulting in mechanical
resistance to CSF outflow) and small jugular foramina (resulting in increased resistance to venous outflow); this situation
results in increased venous pressure, venous engorgement, cephalocranial disproportion, and increased CSF pressure
(1028,1221,1222) (Figs. 5-225 and 5-226). Frank hydrocephalus is present in approximately 12% of affected patients (Fig. 5-
225) (1223) and is most common in Crouzon and Pfeiffer syndromes (as high as 60% in some series (1221)). If nearly all
sutures are closed, the ventricles may remain small in spite of increased intracranial pressure, enlarging only after craniofacial
surgery has opened the calvarium (1223) (see discussion in Chapter 8). The differentiation of benign ventriculomegaly from
hydrocephalus can be difficult, as discussed in Chapter 8, and is dependent upon assessment of subtle features such as the
degree of enlargement of the anterior recesses of the third ventricle. Of note, enlargement of the temporal horns is not a good
sign of hydrocephalus in this group of patients, as the temporal horn enlargement is merely a consequence of the (common)
expansion of the middle cranial fossa (Fig. 5-230).
Venous anomalies are common and likely result from impairment of venous outflow through the small skull base foramina
(1210,1224) and consequent venous drainage through enlarged emissary veins (emissary veins carry the venous blood from
intracranial to extracranial veins through enlarged emissary foramina in the calvarium) (1209,1223,1225). Increased
intracranial pressure typically appears during the second year of life, as the cranial sutures begin to close (1222), but may
normalize as the emissary veins enlarge (1225). Preoperative identification of venous anomalies is important for surgical
planning; therefore, venography should be a part of the pre-operative evaluation of these patients (Figs. 5-224 and 5-226)
(1210,1226). 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).
Figure 5-224 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 calvarium (D) shows complete closure
of coronal suture, while superior view (E) shows the persistently open fontanelle (black arrows).
Figure 5-225 Kleeblattschädel with venous anomaly and hemorrhage in a neonate with no identified craniofacial 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 magnum. 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.
The small skull base, in conjunction with high intracranial pressure, is the probable cause of the high incidence of
cerebellar herniation through the foramen magnum, often (incorrectly) called Chiari I deformities (Figs. 5-224 and 5-230), in
these syndromes (1028,1223,1227). This phenomenon seems to be particularly common in Crouzon syndrome, in which
lambdoid sutures close particularly early and tentorial attachment to the calvarium is particularly low (1028), in Pfeiffer
syndrome (Fig. 5-230), and in patients with cloverleaf skulls (the Kleeblattschädel deformity) (Fig. 5-225) (1029). Other
common brain anomalies in craniosynostosis syndromes include PMG-like cortex, PVNH, callosal agenesis or hypogenesis,
agenesis or hypogenesis of the septum pellucidum, distortions or malformations of the hippocampus, and cephaloceles (Fig. 5-
230) (1209,1228–1230); these all seem to be most common in Apert syndrome.
Common
Ventriculomegaly/hydrocephalus
Less common
Dysmorphic hippocampi
CT with bone windows or good quality T2 images on MR often shows a dysmorphic-appearing calvarium with a thin,
irregular inner table (Figs. 5-226 and 5-230) that surgeons find 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. 5-226 and 5-230)
(1209). Patients with synostoses of multiple sutures have hypertelorism and shallow orbits with marked proptosis (Figs. 5-
225, 5-226, and 5-230). 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
(1183,1231).
Chromosomal Anomalies
Chromosomal anomalies have only recently been systematically catalogued and characterized with respect to their pathologic
and neuroradiologic findings (1232). An amazing website, called Online Mendelian Inheritance in Man (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 questions arise concerning
specific disorders. I have tried to include the chromosomal mutations associated with malformations in the appropriate
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 identical dysmorphic features and brain
anomalies that still fit no known genetic syndrome. As genetic evaluations become more common and more precise, the
chromosomal abnormalities that cause these disorders 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 anomalies that are seen in genetic disorders are described in this chapter, this imaging information, combined
with the lists of chromosomal disorders 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 1000 live births (1233). The disorder is a leading cause of cognitive impairment, with eighty percent of affected patients
being severely impaired (IQ < 50). Although examination of the brain at autopsy shows many abnormalities, including senile
plaques and neurofibrillary tangles at an early age, reduced brain weight, a narrow superior temporal gyrus, and hypoplastic
inferior frontal gyrus, imaging studies are not dramatic. Patients are brachycephalic with a short, round brain, reduced
anteroposterior diameter of the frontal lobes, a narrow superior temporal gyrus, small cerebellum and pons, and forward
kinking of the brainstem (1234). Premature cerebral atrophy and senile calcifications of the globus pallidus may be seen.
Figure 5-226 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. 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. G. MR venogram shows
hypoplasia of the left transverse sinus and abrupt termination (black arrow) of 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.
Cervical spine abnormalities are common in Down syndrome. The most common anomaly is atlantoaxial subluxation,
presumably as a result of ligamentous laxity, which has a prevalence of 10% to 22% (1235,1236). Ligamentous laxity may also
contribute to the increased incidence of atlantooccipital subluxation in affected patients (1237,1238). 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 dysplasia of the
odontoid and os odontoideum, have been described (1239,1240). Patients may also have hypoplasia of the posterior arch of C1
(1235) and they can develop progressive basilar invagination (1239). The craniocervical junction should always be closely
scrutinized 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 MR imaging 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.
Figure 5-227 Fetal MR images of craniosynostosis syndromes. A and B. Apert syndrome at 23 weeks of 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 weeks of 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.
Figure 5-228 Apert syndrome with calvarial expansion at multiple sites. A. Sagittal T1 image shows frontal expansion (medium white arrows)
with anterior frontal bossing (horizontal arrow) and expansion through the fontanelle (vertical arrow). A small saddle (large white arrow) is then
present anterior to another expansion (arrowhead) due to expansion of the parietal squamosae. Note the low-lying tentorium (small arrows). B.
Coronal T2 image shows expanded middle cranial fossae (black arrows) and midfrontal lobes (white arrows) expanding upward toward the
anterior fontanelle. C. Axial T2 image at the level of the midbrain shows the expanded middle cranial fossae and the shallow orbits (orbits
shown better in Fig. 5-226E). D. High axial T2 image shows irregular spicules of bone (white arrows) on the inner surface of the calvarium,
compressing brain tissue.
Figure 5-229 Apert syndrome with polymicrogyria. Sagittal T1-weighted image (A) shows marked turricephaly (white arrows) and an enlarged
proximal aqueduct (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.
Figure 5-230 Infant with severe craniofacial anomaly from Pfeiffer syndrome. A. Sagittal T1 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 image shows enlarged middle cranial fossae
and resultant temporal horn enlargement. C. Axial T2 image shows bilateral proptosis, enlarged temporal horns, and markedly compressed
posterior fossa structures. The cerebellum (black arrowheads) wraps around the brainstem. D. Axial T1 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 and posterior views of 3D reformation of the skull show the enormous anterior fontanelle (black arrows in E
and F), 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.
Trisomy 18
Trisomy 18, also known as Edwards syndrome, is the second most common trisomy encountered in newborns, previously
occurring in about 1 in 5000 live births, but is being seen less frequently. Patients are dolichocephalic with malformed low set
ears, micrognathia, short upper lip, short palpebral fissures, epicanthal folds, midline facial clefts, ptosis, corneal opacities,
and microphthalmos. Characteristic hand and foot anomalies, where the fingers flex and override (most commonly, the index
finger overlaps the long finger 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 (543,1233,1241).
The most consistently identified neuropathologic findings are anomalies of the cerebral gyral pattern, hypoplasia of the
cerebellum and basis pontis, hypogenesis or agenesis of the corpus callosum, and dysplasia of the hippocampus, lateral
geniculate body, and inferior olivary nucleus (543). CT may show dolichocephaly and cerebellar hypoplasia, but is not as
useful as MR in demonstrating the gyral anomalies, callosal hypogenesis, and hippocampal dysplasia (Fig. 5-231)
(1233,1234).
Trisomy 13
Trisomy 13, also known as Patau syndrome, occurs in about 1 in 6000 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 anomalies include callosal agenesis, olfactory hypoplasia, cerebellar
cortical dysplasias, and inferior vermian hypoplasia (Fig. 5-232) (1233,1241).
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 1/1500 live born boys (1242). The disorder is caused by an unstable sequence of DNA in the FMR1 gene
located at chromosome Xq27.3; the sequence codes for a trinuceotide repeat that is greatly amplified in affected individuals
(1243,1244). Affected males have a prominent forehead and mandible, narrow midface, large ears, and macroorchidism; they
may show autistic behavior, perseverative speech, and tactile defensiveness (1245). Pathologic findings include subependymal
and subpial heterotopia, siderosis of the globus pallidus with myelin loss, and hypoplasia of the cerebellar vermis (6). 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 (1246).
Wolf-Hirschhorn Syndrome
The Wolf-Hirschhorn syndrome, caused by partial deletion of the short arm of chromosome 4, is characterized by severe
growth retardation 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 (1249,1250). Diagnosis is made
by characteristic facies and the associated anomalies. Little neuropathology information is available. MR of the brain is
characterized by marked reduction of white matter, callosal hypoplasia, and, in some cases, characteristic cysts in the
periventricular white matter adjacent to the tips of the frontal horns.
Figure 5-231 Trisomy 18. Sagittal T1-weighted image (A) shows callosal agenesis, a simplified cerebral cortical gyral pattern, pontine
hypoplasia, 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.
Figure 5-232 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.
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1228. Cohen MM Jr. Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am J Med Genet
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1229. Taravath S, Tonsgard JH. Cerebral malformations in Carpenter syndrome. Pediatr Neurol 1993;9:230–234.
1230. Khonsari RH, Delezoide A-L, Kang W, et al. Central nervous system malformations and deformations in FGFR2-related
craniosynostosis. Am J Med Genet A 2012;158A:2797–2806.
1231. Cohen MM Jr. Craniosynostosis: Diagnosis, Evaluation, and Management. New York: Raven, 1986.
1232. Schinzel A. Catalogue of Unbalanced Chromosome Alterations in Man. Berlin, Germany: Walter de Gruyter, 1984.
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1234. Tamraz JC, Retmore MO, Iba-zizen MT, et al. Contributions of MRI to the knowledge of CNS malformations related to
chromosomal aberrations. Hum Genet 1987;76:265–273.
1235. Martich V, Ben-Ami T, Yousefzadeh DK, et al. Hypoplastic posterior arch of C-1 in children with Down syndrome: a
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1236. Peuschel SM, Scola FH. Atlantoaxial instability in individuals with Down syndrome: epidemiologic, radiographic and
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1237. El-Khoury GY, Clark CR, Dietz FR, et al. Posterior atlantooccipital subluxation in Down syndrome. Radiology
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1238. Martel W, Tishler JM. Observations on the spine in mongoloidism. Am J Roentgenol Radium Ther Nucl Med
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Neurocutaneous Disorders
Gilbert Vézina and A. James Barkovich
Neurofibromatosis Type 1
Clinical Manifestations
Cranial and Intracranial Manifestations
Spinal Manifestations
Malignant Peripheral Nerve Sheath Tumor
Neurofibromatosis Type 2
Clinical Manifestations
Imaging of Intracranial Manifestations
Imaging of Spinal Manifestations
Sturge-Weber Syndrome
Clinical Manifestations
Intracranial Pathology
Neuroimaging Manifestations
Extra-CNS Manifestations
Ataxia–Telangiectasia
Clinical Manifestations
Pathological and Neuroimaging Manifestations
Nijmegen Breakage Syndrome
Neurocutaneous Melanosis
Clinical Manifestations
Pathological Manifestations
Neuroimaging Manifestations
Incontinentia Pigmenti
Clinical Manifestations
Pathological and Neuroimaging Manifestations
Hypomelanosis of Ito
Clinical Manifestations
Neurological Manifestations
Neuropathological and Neuroimaging Manifestations
PHACE (Posterior fossa malformations, facial Hemangiomas, Arterial anomalies, Cardiac anomalies and
aortic coarctation, Eye anomalies) Syndrome
Clinical Manifestations
Neuroimaging Manifestations
Neurocutaneous disorders (also known as phakomatoses) are characterized by multiple 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’s neurofibromatosis, tuberous sclerosis (Bourneville disease), retinocerebellar angiomatosis
(von Hippel-Lindau disease), and encephalotrigeminal angiomatosis (Sturge-Weber disease). However, many other hereditary
diseases (over 60) have subsequently been classified under the heading of neurocutaneous syndromes (1). A discussion of all
of the neurocutaneous disorders that have been described is beyond the scope of this book. Instead, we will describe those that
are most commonly seen in practice and likely to be seen in moderate- to large-sized outpatient and inpatient practices.
Many of the neurocutaneous disorders may be attributed to defective development of the neural crest, a multipotent cell
population located between the neural and nonneural ectoderms at the lateral margins of the neural placode. Disorders that
result from abnormal expression, migration, differentiation, or death of neural crest cells (NCCs) during embryonic
development are termed neurocristopathies. NCCs migrate to nearly all tissues of the embryo; they form the neurons and glial
cells of the peripheral nervous system, melanocytes of the skin, chromaffin tissue (adrenal gland, the carotid body), smooth
muscle of the alimentary tract and of blood vessels, endothelial cells, adipocytes, fibroblasts, the sclera of the eye, cartilage,
and membranous bone (2,3). Five categories of NCCs have been identified, based on their shared paths of migration and
contribution to organs: cardiac, vagal, trunk, sacral, and cranial. Cranial NCCs give rise to a wide range of derivatives,
including the cranial meninges, most of the facial tissues, cartilage and bone of the skull and face (including the dentin, dental
pulp, and alveolar bone of the head), melanocytes, Schwann cells, smooth muscle cells/pericytes of the forebrain, and the
intracranial vessels (2).
Several phakomatoses (and other inherited cancer predisposition syndromes) carry an increased genetic susceptibility to
multiple primary malignancies, which is enhanced by sensitivity to ionizing radiation (4). The more common syndromes with
radiation sensitivity that are relevant to diagnostic radiation exposure are listed in Table 6-1; care should be used to minimize
exposure of patients with these disorders to radiation during diagnosis, treatment, and follow-up; MRI should be the favored
imaging modality.
Table 6-1 Inherited Cancer Predisposition Syndromes in Which Exposure to Ionizing Radiation Should Be Minimized
Modified from Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol 2009;39(Suppl 1):S27–S31.
Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF1), initially described by von Recklinghausen in 1882, is one of the most common autosomal
dominant central nervous system (CNS) disorders; its worldwide incidence is approximately 1 per 2500 to 3000 individuals,
without preference for race or sex (4–8). The genetic locus has been mapped to chromosome 17q11.2 (7). The NF1 gene
produces a cytoplasmic protein called neurofibromin, which is enormous and appears to have functions in multiple
intracellular processes. Neurofibromin is a negative regulator of the Rat sarcoma (RAS)/mitogen-activated protein kinase
(MAPK) pathway (or Ras/MAKP pathway; also known as the RAS/RAF/MEK/ERK pathway). The Ras/MAKP pathway leads
to expression of genes that encode proteins that regulate cell proliferation and survival, cell morphology determination, and
organogenesis. Germ-line mutations in the RAS/RAF/MEK/ERK pathway give rise to a group of conditions now termed
RASopathies (9), which are listed in Table 6-2.
In the CNS, neurofibromin is expressed primarily in neurons, Schwann cells, oligodendrocytes, and astrocytes (5,6).
Understanding of the molecular pathogenesis of NF1 and the functions of the NF1 gene helps to explain the extensive clinical
and imaging features of this syndrome and allows for the development of targeted therapies to improve the management of
clinical problems associated with NF1 (10,11). The many functions of neurofibromin include the following:
1. It acts as a tumor suppressor gene that functions in part as a negative regulator of the RAS protooncogene
(12) and of the mammalian target of rapamycin (mTOR) pathway (13).
2. It acts as a regulator of neural stem cell proliferation, survival, and astroglial differentiation, in addition to
regulating neuroglial progenitor function (14,15). Neurofibromin is required for regulation of 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) (16).
4. It is involved in the maintenance of the vascular wall. Neurofibromin is expressed in the vascular endothelium
and in vascular smooth muscle cells; loss of neurofibromin likely causes smooth muscle proliferation, possibly
in response to nonspecific injury to the vascular wall (15), which can lead to vasculopathy (17).
5. It is involved in bone formation and remodeling. Neurofibromin is expressed in osteoblasts; it inhibits collagen
synthesis, promotes mineralization, and regulates osteoclastogenesis (18).
6. It seems to be required for normal myelination by Schwann cells (18). In addition, the gene for
oligodendrocyte myelin glycoprotein, a major myelin protein, is embedded within intron 27b of the NF1 gene
(19). Therefore, it is not surprising that abnormalities of myelin/white matter are seen in patients with NF1.
NF1
Noonan syndrome (NS)
Costello syndrome
Capillary malformation–arteriovenous malformation syndrome
Cardiofaciocutaneous syndrome
Legius syndrome
NS with multiple lentigines (LEOPARD syndrome)
Phenotypic expression of the disease is extremely variable, both clinically and radiologically; this variation has resulted in
attempts to correlate phenotypes with underlying genetic factors (20). Overall, no genotype–phenotype relationships have been
identified by mutational analyses of NF1 patients (21). Regulatory and epigenomic modifiers, possibly including environmental
modifiers (at the level of the cellular milieu), unlinked to the NF1 locus, likely contribute to the variable expressivity of the
disease (22,23). Diagnostic criteria are listed in Table 6-3.
Clinical Manifestations
Café 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 (11). Freckling within the axilla will develop later in about two-thirds of patients (24–26) (Tables 6-3 and 6-4).
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
(24–26). 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 (27,28), 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% (29). 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 (30). About 4% to 7% of patients have epilepsy,
primarily related to intracranial masses and cytoarchitectural abnormalities (31).
Feature Incidence
Other systems 3%
Pseudarthrosis of long bones 1%
Sphenoid wing dysplasia 1%
Renal artery stenosis up to 50%
Osteoporosis
Adapted from North K. Neurofibromatosis type 1. Am J Med Genet 2000; 97:119–127; North K, Joy P, Yuille D, et al. Cognitive function and academic
performance in children with neurofibromatosis type 1. Dev Med Child Neurol 1995;37:427–436.
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 academic achievement) (24,25,32–34). The
most common neuropsychological manifestation of NF1 in childhood is a specific learning disability, defined as a major
discrepancy between ability (intellect or aptitude) and achievement (performance) in patients with IQ scores in the normal
range. Specific learning disability has been estimated to occur in 30% to 45% of children with NF1, which is more than three
times the prevalence in the general population (33,34). The occurrence of cognitive deficits does not seem to be associated
with the severity of other clinical features of the disease (33). In fact, a bimodal distribution of full-scale IQ scores is seen in
children with NF1, suggesting that there are two populations of NF1 patients, those with and those without a degree of
cognitive impairment. Multiple studies have attempted (with variable success) to establish a correlation between the presence
of the characteristic T2 bright white matter/basal ganglia foci seen in NF1 children and the cognitive deficits evident in
psychometric testing (33,35–38). The methodologies of these studies are complicated by the peculiar temporal evolution of the
T2 bright foci: they are absent at birth; they appear in early childhood, and reach peak numbers around ages 7 to 12; and they
essentially disappear by the end of the second decade of life. One of the most consistent markers of cognitive deficits between
ages 8 and 18 years appears to be the presence of T2 bright foci in the thalami (33,35–39). Interestingly, long-term assessment
of cognition in children with NF1 suggests that children with discrete hyperintense NF1 lesions show an increase in general
cognitive function between childhood and adulthood, while the NF1 children without characteristic T2 lesions exhibit a stable
cognitive profile (40); one wonders whether this suggests that the T2 hyperintensities are a result of impaired myelination.
Although learning disabilities are common in NF1, intellectual disability affects a much smaller proportion of patients.
Some intellectually affected NF1 patients have been found to have deletions of the entire NF1 gene, leading to a distinctive
phenotype that includes the development of a large number of neurofibromas and a distinctive facial appearance (41,42).
Affected patients also appear to have a greater number of structural anomalies detected in their brains by MR studies. It is
unclear whether this phenotype is the result of haploinsufficiency for the NF1 gene or whether a deletion of portions of
contiguous genes contributes to the clinical picture (41,42).
Neurofibromas are found in the majority of NF1 individuals. They are benign perineural nerve sheath tumors that also
involve the nerves themselves and are composed of Schwann cells, fibroblasts, perineural cells, and mast cells. NF1-deficient
Schwann cells are considered to be the primary neoplastic cell in the tumor (43). Neurofibromas can be classified according to
their appearance and location into four groups: cutaneous, subcutaneous, spinal, and plexiform (11). Cutaneous neurofibromas
develop particularly during childhood and early adulthood and may number several thousand per patient in extreme cases.
Subcutaneous neurofibromas present as palpable lesions with no risk of malignant transformation. Spinal neurofibromas can
involve an individual or multiple nerve roots at any vertebral level; they often grow in a bilateral symmetric fashion.
Plexiform neurofibromas (PNs) are locally aggressive congenital lesions found in up to 50% of individuals with NF1 and are
usually present at birth. They arise from multiple nerve fascicles or plexi and tend to grow along the length of a nerve; they can
be nodular or diffuse in appearance. Their growth rate is unpredictable; they grow most rapidly in early childhood, with a
median growth rate of approximately 20% volume per year in children less than 8 years (11,44,45), and do no accelerate due
to hormonal changes of puberty (46). Facial PNs causing disfigurement usually manifest early, within the first few years of life
(46). PNs can be a source of neuropathic pain and neurologic dysfunction ranging from minor sensory alteration to complete
myelopathy, and can undergo malignant transformation into a malignant peripheral nerve sheath tumor (MPNST). The
lifetime risk of developing MPNST in NF1 patients is 8% to 13% (11,47–49); the risk of malignancy increases with age.
MPNST usually present with localized motor deficits or pain and dysesthesias with or without evidence of a rapidly enlarging
mass.
Because PNs have complex geometric forms, three-dimensional volumetric measurements are preferred for size evaluation;
a 20% change in volume is the threshold criterion recommended to indicate a decrease or increase in tumor size (50). This
20% volume threshold is lower than what is used in the majority of brain tumor protocols (in which a 40% volume threshold,
or 25% surface area, is usually used). Biologic agents have shown activity in PNs, causing delay in time to progression.
Sirolimus (an inhibitor of the mammalian target of rapamycin (mTOR) pathway) (51), imatinib mesylate (Gleevec, a cMET
blocking agent) (52), and MEK inhibitors (53) have shown demonstrable activity in their treatment.
Of note, patients with Legius syndrome, one of the RASopathies, have been mistakenly diagnosed in the past as having NF1.
Patients with Legius syndrome present with café au lait spots and skin-fold freckling that are indistinguishable from NF1;
however, they have no Lisch nodules, optic pathway gliomas (OPGs), neurofibromas, or MPNST (54).
Although tumors of the intraorbital optic nerves can be evaluated with CT, MR is the preferred imaging modality for
evaluating the entire CNS in NF1 due to the increased information and lack of exposure of the child to ionizing radiation.
Assessment 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, but use of fat-suppression techniques eliminates the chemical shift artifact and
allows the nerve to be excellently evaluated, along with the intracranial optic nerves, optic chiasm, optic tract, and optic
radiations. T1 and fat-suppressed T2-weighted axial and coronal sequences, using less than or equal to 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 the
brain. Fluid-attenuated inversion recovery (FLAIR) and T2-weighted images show involvement of the optic tracts as high
signal intensity extending posteriorly, often to the level of the lateral geniculate bodies; the internal capsules and adjacent basal
ganglia are commonly infiltrated (Figs. 6-1 and 6-2). Further extension beyond the optic pathways can also be identified in
some patients: superiorly into the hypothalamus, fornices, and septum pellucidum; laterally into the temporal lobes; posteriorly
into the optic radiations; and inferiorly into the cerebral peduncles and the brainstem (Fig. 6-2). Rarely, tumor can extend into
the lateral ventricles.
Figure 6-3 Optic nerve tumor with infiltration of the optic nerve sheath. A. Postcontrast axial T1-weighted image with fat suppression shows
enlarged, enhancing 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 hyperintense signal (white arrows).
Figure 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. Significant
Ch:Cr elevation is also evident in the thalami bilaterally (yellow color). C. MR spectra from four different ROIs (numbered 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 thalami (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.
Figure 6-5 Spontaneous partial involution of a diencephalic tumor. A and B. Axial T2 FLAIR (A) and contrast-enhanced T1 (B) images of a 5-
year-old reveals a mass in the inferior left diencephalon with intense enhancement (long arrows, A, B); nonenhancing, presumed vacuolation is
evident in the right globus pallidus (short arrow, A). C. Axial FLAIR image 3 years later (without intervening treatment) shows only a small T2
bright residual abnormality, immediately behind the anterior commissure (arrow), which could represent vacuolation or residual tumor (lesion
did not enhance). T2 abnormality previously evident in the right globus pallidus shows near-complete resolution.
Care should be taken not to mistake enlarged subarachnoid spaces within the optic nerve sheaths (the result of ectasia of the
dura surrounding the optic nerves) for optic nerve tumors. The enlarged perioptic spaces have signal intensity identical to
cerebrospinal fluid (CSF) and do not enhance after contrast administration. 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). Differentiation of the two pathologies can be very difficult; features of OPG infiltration include contiguity, mass
effect, low T1 signal on precontrast images, enhancement after contrast administration, and significant elevations of choline (at
MR spectroscopy) (Fig. 6-4) (69).
Figure 6-6 Development of a pilocytic astrocytoma in an area of extensive myelin vacuolation. A. Axial T2-weighted image of a 5-year-old
child reveals multiple characteristic foci of T2 hyperintensity (arrows) in the deep cerebellar white matter and middle cerebellar peduncles. B
and C. Axial T2-weighted (B) and postcontrast sagittal T1-weighted image (C) obtained 4 years later. A large rim-enhancing T2 hyperintense
mass (arrows) has developed within the deep right cerebellar white matter, with surrounding edema.
Figure 6-7 Midbrain juvenile pilocytic astrocytoma in a 14-year-old 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-circumscribed 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, the likely diagnosis in this patient. 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 surrounding (normal) brain tissue
as the voxel (2 × 2 × 2 cm size) is slightly larger than the tumor.
Figure 6-8 Grade 2 (fibrillary) glioma in the left temporal lobe of a 10-year-old with NF1. A. Axial T2-weighted image shows a tiny, hyperintense
lesion (white arrow) in the white matter of the posterior 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.
Hamartomatous enlargement of the hypothalamus is occasionally seen in children with NF1 (Fig. 6-10), usually not
associated with precocious puberty or gelastic seizures (79). The lesion typically lies within the walls of the hypothalamus in
the lower third ventricle (intrathalamic/sessile configuration). Like hypothalamic hamartomas in children without NF1, they are
nearly isointense to gray matter on T1- and T2-weighted images and do not enhance (80); they should not be confused for a
chiasmatic or hypothalamic glioma.
In a small but significant number of patients with NF1, hydrocephalus is present (81–83). 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 hamartomas) of the adjacent tectum or tegmentum
of the mesencephalon. The diagnosis of a tectal glioma is relatively simple using MR. In contrast to benign aqueductal stenosis
(in which the proximal aqueduct is dilated and the tectum displaced superiorly and thinned, see Chapter 8), gliomas enlarge the
tectum and narrow (or 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 ventricular decompression.
Figure 6-9 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).
Figure 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 of 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.
Figure 6-11 Sagittal T1-weighted image shows an abnormally thick corpus callosum (white arrows). The ventral pons (black arrows) is
prominent.
MR imaging often reveals characteristic hyperintense T2 lesions in pediatric patients with NF1, located in the brainstem,
cerebellar white matter, basal ganglia (especially the globus pallidus), thalamus, internal capsule, corpus callosum, and,
occasionally, corona radiata (Figs. 6-12 and 6-13) (36,89,90) but not in the centrum semiovale or the subcortical white matter.
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. 6-9) and do not elicit vasogenic edema; their T1 signal appears iso- or
slightly hypointense compared to uninvolved white matter; and they do not enhance after intravenous administration of
paramagnetic contrast. Intermediate echo (TE = 144 ms) proton MR spectroscopy shows nearly normal N-acetylaspartate
(NAA)/creatine (Cr) and moderately increased Cho/Cr (69). These lesions are rarely identified in the first 2 years of life but
develop/become visible from late infancy to about age 12 years (Fig. 6-12) (89); new lesions almost never develop after age
15 years. The lesions start to regress starting late in the first decade of life (90,91) and slowly disappear; they are almost never
seen in patients over the age of 20 years (Fig. 6-13). In the peak age group (6–12 years), they are seen in up to 90% of NF1
children (39,92,93). A pathologic analysis has shown that these regions contain areas of myelin vacuolation, where the layers
of myelin become separated as they spiral around the axon (94). 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 (95); anisotropy is normal, but transverse
eigenvalues are increased (96). Multishell diffusion MRI studies have shown that the water contained in the T2 hyperintense
lesions behaves as intracellular water that has obtained extracellular-like properties, thus supporting the intramyelinic edema
appearance of vacuolation (97).
The discoveries that the oligodendrocyte myelin glycoprotein gene is imbedded within the NF1 gene (19) and that its
protein product (neurofibromin) is required for Schwann cell myelination (18) further support dysgenesis of myelin as the
cause of the white matter abnormalities in NF1. The vacuolization appears to 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 (98). The increased diffusivity of white matter (even normal-appearing white matter) in NF1 (99,100) further
supports the concept of abnormal myelin as an underlying cause.
Figure 6-12 Evolution of characteristic T2 bright signal abnormalities in pediatric NF1. A. Axial T2-weighted images through the posterior
fossa of a 14-month-old reveals a few ill-defined foci of increased T2 signal within the deep cerebellar white matter in the middle cerebellar
peduncles (arrows). B. Corresponding axial T2-weighted image in the same patient at age 3 years. There are now extensive foci of T2
abnormality within the deep cerebellar white matter, the middle cerebellar peduncles, and the pons (arrows). The volume of the involved tissue
is mildly increased, resulting in mild distortion of the fourth ventricle.
In view of the frequency with which the characteristic T2 hyperintense foci are encountered in children with NF1, neither
close imaging follow-up nor biopsy is indicated when they occur in the characteristic locations, are not significantly
hypointense on T1-weighted images, and lack associated mass effect, edema, and enhancement. However, a growing
astrocytoma of the basal ganglia, pons, or cerebellum, when small, may be indistinguishable from one of these lesions on
noncontrast MR—especially in cases when there are numerous, confluent T2 hyperintense foci in expected locations. If a
lesion has any suspicious characteristics, it is recommended that the patients have a follow-up contrast-enhanced MR scan,
including diffusion-weighted imaging (DWI), perfusion imaging, or proton MR spectroscopy, 6 months to a year after the first
study. A tumor will typically show progressive enlargement and mass effect on adjacent structures and often enhances (Fig. 6-
6); it may also have locally reduced diffusion in its solid portion (95), have increased blood volume (101), and show elevated
choline with decreased creatine and NAA on proton spectroscopy (69,102–105).
T1 hyperintensity is observed in the globi pallidi of patients with NF1, with a different radiologic appearance than the
characteristic T2 hyperintense foci: the hyperintensity on 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 (Fig. 6-14) (86,90,98,106). The distribution of the T1 bright signal can be diffuse within the T2
abnormality or be located along its periphery/rim. (Calculation of T1 values shows that the frontal white matter, caudate
nuclei, putamina, and thalami also have some T1 shortening (86), but it is not apparent to visual inspection in these other
areas.) In some patients, the T1 shortening is observed at the time of a first MRI, prior to exposure to gadolinium-based
contract agents. However, many of the NF patients with appreciable T1 bright signal changes in the globus pallidus also have
bright T1 signal in their dentate nuclei and have undergone multiple contrast-enhanced MRI exams; the T1 bright signal changes
in some of these cases, therefore, may be a reflection of gadolinium deposition in the brain (107), rather than a reflection of an
intrinsic abnormality of the myelin.
Figure 6-13 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 internal capsules. B. Axial T2-weighted image 4 years later shows significant
regression of the abnormalities.
Figure 6-14 T1 and T2 prolongation in the basal ganglia in NF1 of an 18-year-old. A and B. Noncontrast sagittal T1- (A) and axial T2 (B)-
weighted images show a lesion in the left globus pallidus with hyperintensity on both T1 and T2 images (arrows). There was no associated
mineralization or calcification on susceptibility-weighted images or CT images (not shown).
The overwhelming majority of these characteristic T2 bright lesions resolve over time. 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 (108), and
neoplastic-looking lesions can shrink or disappear (63–65). Also remember that focal lesions developing in the cerebral
cortex or in the subcortical or deep white matter do not represent characteristic T2 bright lesions of pediatric NF1 (Fig. 6-
8) (93); 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-weighted images,
often with increased volume (Fig. 6-15); this finding can be unilateral or bilateral and is not progressive; it persists throughout
childhood and adolescence (93), in contrast to the characteristic T2 lesions described above that regress during later
childhood and adolescence. The nature of the hippocampal abnormality is not known. NF1-related hippocampal T2 changes
should not be confused with hippocampal sclerosis (in which case the hippocampal volume is decreased) or with neoplastic
infiltration.
Vascular Dysplasia
Dysplasia of the cerebral vasculature is increasingly recognized in children with NF1; it develops at a young age, with
prevalence of up to 6% (109–111). The incidence in the symptomatic NF population appears to be higher, with a predicted
range of 7% to 15% (112). 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 hydrocephalus.
However, clinically, a majority of NF1 patients with vascular dysplasia do not have focal deficits as a result of their
arteriopathy by the time the dysplasia is diagnosed with MRI. Intracranial vascular dysplasias can result as a complication of
irradiation for optic nerve or optic chiasm gliomas (presumably radiation arteritis in these cases; see discussion in Chapter 3).
Common vascular abnormalities include stenoses, occlusions, ectasia, moyamoya disease, and fusiform aneurysm
formation. Most commonly, the dysplasia results from intimal and smooth muscle proliferation, with resultant stenosis or
occlusion; they can progress overtime (Fig. 6-16) and may require revascularization surgery (109,111). The carotid (common
or internal) artery, proximal middle cerebral artery, or proximal anterior cerebral artery is the most common site of
involvement (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 (113). (Moyamoya is discussed further in Chapter 12.) Fusiform
arterial dilation, cerebral aneurysms, and arteriovenous fistulas are also described, although less commonly (109,113,114).
Figure 6-15 High-resolution coronal FSE T2-weighted image reveals hyperintense T2 signal of both hippocampal formations (white arrows)
(compare signal to that of adjacent temporal cortex). The right hippocampus is brighter and larger than the left.
Figure 6-16 Progressive NF1-related vasculopathy. A. Axial T2-weighted image at age 18 months shows normal-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), consistent with an acquired complete occlusion (or very severe stenosis).
Vascular dysplasias can be difficult to detect on standard CT or MR images; with MR, close inspection of the arterial signal
voids (Figs. 6-16 and 6-17), 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 and
inspection of T2-weighted spin-echo images is strongly encouraged when imaging children with NF1, particularly those
with declining function. As many vascular lesions are subtle and easily overlooked, some authors promote the routine use of
MR angiography to better delineate intracranial vasculopathy (17). If vascular dysplasia is suspected, MR (or CT) angiography
should be performed; conventional, catheter angiography is usually reserved for a presurgical workup. Angiography generally
shows either severe stenosis or occlusion of the involved cerebral vessels (Fig. 6-17); arterial dysplastic lesions are also
demonstrated.
Figure 6-17 Vascular dysplasia in NF1. A. Axial T2-weighted image shows asymmetric appearance of the internal carotid arteries with absent
flow void within the right posterior cavernous sinus (short arrow). The left optic nerve sheath is enlarged (long arrow). B. Lateral view of catheter
angiography of the right common carotid artery shows dysplasia of the horizontal segment of the cavernous segment of the internal carotid
artery with three focal areas of aneurysm formation (arrows); focal stenosis is evident next to the most distal aneurysm.
Figure 6-19 Rapid progression of orbital plexiform neurofibroma. A. Axial fat-suppressed T2-weighted image of an 8-month-old reveals a
dysplasia of the left greater wing of the sphenoid with resultant enlargement of the left middle cranial fossa. Mild soft tissue thickening is evident
in the left cavernous sinus (black arrow) and in the lateral left orbital extraconal soft tissue (white arrows) indicative of a V1 distribution plexiform
neurofibroma. The left globe is mildly proptotic. B and C. Corresponding axial fat-suppressed T2 (B) and contrast-enhanced T1 (C) images 2
years later show marked progression in the size of the plexiform neurofibroma within the cavernous sinus (black arrows) and in the pre- and
postseptal soft tissues of the left orbit (white arrows). Left globe proptosis has significantly worsened.
Solitary neurofibromas have slightly greater signal intensity than does skeletal 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 intensity (121–124); this has
been referred to as the “target sign” (Figs. 6-20 and 6-21) (125). The central area of decreased T2 intensity is probably related
to the known dense central core of collagen within these lesions (122,123). Collagen has a low mobile proton density and
therefore is of low signal intensity on T2-weighted images. Enhancement after administration of paramagnetic contrast is
variable, although at least a portion of the tumor usually enhances (usually the central aspect, corresponding to the central T2
hypointense (“target”) components (see Fig. 6-24).
PNs tend to be of low attenuation on CT and generally show little enhancement after administration of intravenous contrast.
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 (126). The abnormal
curvature is usually minimal or mild in degree and can resemble idiopathic adolescent scoliosis. It can be severe, in which
case dystrophic curves are commonly encountered, with potential for rapid progression (Fig. 6-22) (127). Dystrophic curves
are associated with a high incidence of paraspinal or other internal neurofibroma next to the vertebra. Patients with paraspinal
PNs have sixfold higher odds of developing spinal curvature abnormalities compared to patients without PNs (128). Dysplasia
of the vertebral bodies is common, as are hypoplasia of the pedicles, transverse processes, and spinous processes; scalloping
of the posterior aspects of the vertebral bodies; and hyperplastic bone changes (120,129). 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 demonstrate the scoliosis optimally. CT is the optimal modality for demonstrating 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.
Figure 6-20 Slow progression of an extensive plexiform neurofibroma. A. Coronal inversion recovery fat-suppressed T2 image at age 5 years
reveals several infiltrative T2 hyperintense masses (numbered 1 to 3, seen to connect on other images) in the paravertebral, deep cervical, and
upper thoracic soft tissues typical of a plexiform neurofibroma. B. Corresponding coronal fat-suppressed T2 image 12 years later shows
marked enlargement of the plexiform neurofibroma. The largest component measures approximately 40 mm in diameter. It has preserved
central T2 dark/target characteristic (evident in all components of the mass); findings are not suggestive of a malignant transformation.
Figure 6-21 Malignant nerve sheath tumor developing within a plexiform neurofibroma in a 15-year-old who recently experienced lower neck
pain. A and B. Axial (A) and coronal (B) T2-weighted images with fat suppression reveals 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 confluent area (white arrows) without target sign is evident. Malignant nerve sheath tumor was confirmed by needle biopsy of
this area.
Figure 6-22 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 mid cervical 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, infiltrating
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 lateral 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.
When abnormal spinal curvature is present, the question often arises as to whether it results from the dysplastic bone of
neurofibromatosis or from an intrinsic spinal cord lesion such as a tethered cord, syringomyelia, or a tumor. If an intrinsic
spinal cord tumor is present in a patient with NF1, it is likely to be an astrocytoma (130). 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 symptoms, 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 rapidly
progressive, associated with pain, or associated with neurologic deficits, have a significantly higher incidence of underlying
spinal cord abnormalities (131). Imaging of scoliosis is discussed further in Chapter 9.
Figure 6-23 Dural ectasia in NF1. A and B. Sagittal (A) and axial (B) T2-weighted images demonstrate scalloping of the posterior vertebral
bodies at the lumbosacral junction (arrows, A). Bilateral anterior sacral meningoceles are evident (arrows, B). The largest on the left extends
out of the spinal canal through a widened neural foramen (*).
Figure 6-24 Extensive plexiform and spinal neurofibromas with cord compression 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 arrow). 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 intradural component of the right-sided
neurofibroma displaces the thecal sac to the left (white arrow). Extensive plexiform neurofibromas infiltrate the retroperitoneum.
Most nerve sheath tumors in NF1 appear to be neurofibromas (121), with schwannomas uncommon. Although isolated
spinal neurofibromas can be seen in patients unaffected by NF1, patients with von Recklinghausen disease can have
neurofibromas of varying sizes at several levels throughout the spinal canal (55,122). However, in general, patients with NF1
have only a few (5,6) nerve sheath tumors, in contradistinction to patients with NF2, who typically have many (more than 10)
spinal nerve schwannomas (see section on NF2 below).
The MR appearance of neurofibromas is that of masses that may be entirely within the spinal canal. When small, intradural
neurofibromas appear as nodules of soft tissue along the nerves roots, most commonly identified along the cauda equina (Fig.
6-25). Larger intraspinal neurofibromas (which can be intra- or extrathecal) may displace the spinal cord or nerve roots of the
cauda equina to the contralateral side of the canal (Fig. 6-24) and can cause canal enlargement. 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. 6-26). Furthermore, the lesions can extend outward from the spinal canal through neural foramina
(Fig. 6-24) that are usually of enlarged secondary to pressure erosion of the bone (121,122).
Outside the spinal canal, neurofibromas show a slightly greater signal intensity than skeletal muscle on T1-weighted
sequences and high intensity periphery with variable intensity center on T2-weighted sequences (121–123), sometimes
resulting in the aforementioned “target sign” (Fig. 6-24) (125). On CT, the paraspinal neurofibromas have low attenuation
when compared to muscle.
Figure 6-25 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.
Figure 6-26 Bilateral C1-C2 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 arrowheads). An intradural neurofibroma component is evident on the right
(large white arrowhead). (* denotes odontoid process of C2).
Currently, 18F-fluorodeoxyglucose (FDG) PET imaging seems to be the best way to differentiate benign from malignant
nerve sheath tumors; malignant tumors show significantly higher uptake of FDG than do benign tumors (143). A SUV max
greater than 3.5 is indicative of malignant transformation in a PN (140,141).
Neurofibromatosis Type 2
Clinical Manifestations
Neurofibromatosis type 2 (NF2) has also been called neurofibromatosis with bilateral acoustic schwannomas. NF2 is a
separate disease altogether from NF1. NF2 is associated with mutations of chromosome 22 (critical region in about 6
megabases within 22q12.2 (144)). The product of the NF2 gene is called merlin (Meosin-ersin-raxidin-like protein, also
called schwannomin); it is a tumor suppressor gene that is believed to control interactions between affected cells and
surrounding structures in the extracellular matrix, largely by regulating essential signal transcription pathways, including
growth stimuli to cell cycle progression (145). Mutated merlin inhibits cell adhesion, which is important for regulating cell
growth, and is more soluble than normal protein, making its interaction with the cytoskeleton unstable (146,147). 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 (148,149).
NF2 is autosomal dominant, with an estimated incidence of 1 in 25,000 to 33,000 births (47). About 50% of cases represent
new mutations, and as many as one-third are mosaic for the underlying disease causing mutation (150). The major feature of
NF2 is the presence in nearly all affected individuals of bilateral vestibular schwannomas (Figs. 6-27 and 6-28). When
detected very early, before the age of 1 year, bilateral vestibular schwannomas have a propensity to remain asymptomatic until
the second decade of life (151). Other tumors of the central nervous system, particularly meningiomas and other schwannomas
(Figs. 6-29 and 6-30), may be present as well. (Most children with meningiomas do not have NF2; however, 72% of pediatric
meningiomas harbor deletions of the NF2 gene (152).) Although tumors begin to develop in children, symptoms are often
delayed until early adulthood (late teens or 20s) when the tumors become large enough to cause symptoms. 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 presenting symptoms, as are neurologic symptoms related to brainstem and/or spinal cord tumors
(150,153,154). Tumor load tends to be extensive when presentation is during childhood; cranial meningiomas are seen in 60%
of cases, cranial schwannomas (other than vestibular) in 36%, and spinal schwannomas and meningiomas each in 80% (154).
NF2-associated intracranial tumors show substantial variability in growth rate and pattern. The most common growth pattern is
saltatory, characterized by periods of growth and quiescence; linear growth and exponential growth are less common (155).
Figure 6-27 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 interval auditory canals by the hypointense schwannomas
(arrows) and a filling defect in the right vestibule (arrowhead) from intralabyrinthine tumor extension.
Cutaneous manifestations are much less frequent than in NF1: only about 25% of affected patients will have café au lait
spots, and, when present, the spots are pale and few in number (<5) (137,156); only 1% will meet NIH criteria for NF1 (157).
Cutaneous nerve sheath tumors (predominantly schwannomas) are seen in about 65% of affected patients but are minimal in
size and few in number (137). 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 (156,158,159).
Subcapsular cataracts are present in more than half of patients and may be present during childhood (137,160). Therefore, skin
tumors and cataracts are valuable clues in the early detection of children with NF2 (156,158,159). The established
diagnostic criteria for NF2 are listed in Table 6-5 (47). It should be noted that these criteria do not work well in children or in
patients without a family history of NF2 (as many as 50% of affected patients (150,161)). Indeed, less than 20% of patients
with NF2 are diagnosed during childhood (159). 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 management
(162).
Some authors have noted that NF2 can be subdivided into two large groups (163). 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 (meningioma 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 schwannomas,
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 do those with type 1 NF2 (137). 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.
Figure 6-28 Bilateral acoustic schwannomas and cerebellar hamartomas in an adolescent with NF2. A and B. Postcontrast axial T1 (A) and
axial fat-suppressed fast spin-echo T2 (B) images demonstrate bilateral nerve VIII schwannomas (arrows, A); the larger left-sided lesion
expands the internal auditory canal and extends into the cerebellopontine angle cistern, compressing the middle cerebellar peduncle. Multiple
nonenhancing T2 bright lesions are evident in the cerebellar hemispheres (arrows, B), with associated retraction deformities; appearance is
consistent with that of hamartomas.
Figure 6-29 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 (black 5) 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 schwannoma (white arrows) extending through and
expanding the right foramen ovale.
The mainstay of management of NF2 is surgical removal of symptomatic cranial and spinal tumors. However, there are
recent reports of slowing of the growth of vestibular schwannomas with therapies targeted to the intracellular signaling
pathways involved in NF2 tumorigenesis (47,164). The antiangiogenic agent bevacizumab, an inhibitor of the VEGF-pathway,
is highly efficacious in shrinking the lesions, with resulting improvement of hearing (138,165).
Two-thirds of the NF2 patients harbor meningiomas. The tumors are most frequently located at the convexity and along the
falx cerebri, followed by the skull base and the lateral ventricles. Growth of meningioma tends to be faster in younger
individuals (under 30 years of age) and when the meningioma elicits adjacent brain edema (166).
Definite:
1. Bilateral vestibular schwannomas.
2. A parent, first-degree relative, or offspring with NF2 and a unilateral eighth nerve tumor at less than age 30 y or two of the following:
•• Neurofibroma
•• Meningioma
•• Glioma
•• Schwannoma
•• Juvenile posterior subcapsular lenticular opacities/juvenile posterior cortical cataract
Presumptive or probable:
1. A unilateral vestibular schwannoma diagnosed before the age of 30 y, plus at least one of the following:
•• Meningioma
•• Glioma
•• Schwannoma
•• Juvenile posterior subcapsular lenticular opacities/juvenile posterior cortical cataract
2. Two or more meningiomas and a unilateral vestibular schwannoma and age <30 y or one of the following:
•• Glioma
•• Neurofibroma
•• Schwannoma
•• Juvenile posterior subcapsular lenticular opacities/juvenile posterior cortical cataract
Adapted from Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis.
Neuro Oncol 2016;18(5):624–638.
The imaging characteristics of schwannomas and meningiomas are described in Chapter 7. If bilateral acoustic tumors are
present or a diagnosis of NF2 is suspected for other reasons, the imaging procedure of choice should be contrast-enhanced MR
of the entire brain and spine, with thin (≤3 mm) postcontrast T1 sections and high-resolution, submillimeter heavily T2-
weighted sequences (FIESTA/CISS) through the posterior fossa. Schwannomas and meningiomas both enhance brightly after
the infusion of intravenous contrast; smaller lesions may not be apparent on precontrast scans (90,137).
An important point is that schwannomas and meningiomas are unusual tumors in children and young adults (under age 30
years). If a meningioma or schwannoma is seen in a young patient, a contrast-enhanced MR scan should be obtained
through the brain to look for other asymptomatic schwannomas or meningiomas that may aid in establishing the diagnosis
of NF2. Regularly repeated contrast-enhanced MR scans are recommended for patients in whom the disease is established, as
new tumors continue to develop throughout life and surgical or gamma knife therapy is necessary when they grow large enough
to cause hydrocephalus or symptoms. Repeated exams or genetic testing may also be useful when isolated meningiomas or
schwannomas are detected in young children. The authors have seen multiple children with “isolated” meningiomas who have
bilateral acoustic schwannomas 5 to 8 years later.
Malformative cerebral and cerebellar parenchymal lesions are commonly identified in NF2 patients. In the cerebrum,
nonspecific T2 hyperintense lesions in the cortex and white matter, cortical dysplasias (presenting as T2 hyperintensities, often
wedge shaped), transmantle sign, abnormal cortical mineralization (T2 hypointense), and focal enlargement of Virchow-Robin
spaces are observed. Cerebellar dysplasias are also seen (Fig. 6-28B). Most of the observed parenchymal lesions appear to be
manifestations of an underlying disorder of neuronal migration, including glioma hamartomas (167).
Meningiomas are common in the intraspinal as well as intracranial compartment in NF2 (48). As in patients without
neurofibromatosis (see Chapter 10), spinal meningiomas are most common in the thoracic region. They are intradural,
extramedullary masses that displace the spinal cord as they grow. These dural-based masses will sometimes cause pressure
erosion of the adjacent bone. They can be identified as extramedullary, intradural masses on CT with intrathecal or IV contrast.
MR is the preferred diagnostic modality; sagittal and coronal images are essential to visualize the extent of the tumor and its
relationship to the spinal cord and neural foramina. These lesions are usually isointense with cord on both T1- and T2-
weighted images. They uniformly enhance after contrast infusion (169–171).
Syringohydromyelia has been described in association with NF1 and NF2. The syrinx is almost always a secondary
phenomenon, resulting from either a primary tumor of the spinal cord or an intradural, extramedullary mass, such as a
meningioma or neurofibroma, that alters the CSF dynamics of the surrounding spinal subarachnoid space (see Chapter 9)
(172,173). The syrinx will often disappear after removal of the tumor (173,174). The cause of the syrinx cavity resulting from
primary spinal cord lesions is less clear. The syrinx most likely results from altered CSF dynamics; however, in some patients,
the syrinx may be caused by fluid secreted into the spinal cord and central canal by the tumor (175). If syringohydromyelia is
seen in neurofibromatosis (either NF1 or NF2) and no extramedullary mass can be seen, a thin section, contrast-enhanced MR
of the spinal cord should be performed to rule out an intramedullary lesion. Syringohydromyelia is discussed in more detail in
Chapter 9.
Schwannomatosis
Schwannomatosis is the third major form of neurofibromatosis. It is a rare disorder with an incidence of 0.58 per 1,000,000
persons and a reported peak incidence between the ages of 30 and 60 years; very few pediatric cases have been reported
(176,177). It is characterized by a predisposition for the development of multiple schwannomas in the absence of bilateral
vestibular schwannomas; meningiomas are less common (5%). Schwannomas commonly affect the spine and peripheral nerves;
large cranial nerve schwannomas are uncommon. Anatomically limited disease, presumably due to genetic mosaicism, is seen
in approximately 30% of patients. Unilateral vestibular schwannomas have been reported (47).
The genetics of schwannomatosis is complex and incompletely understood; more than 90% of sporadic cases and
approximately 50% of familial cases have no currently identifiable genetic mutation (176,178). Most cases are sporadic, likely
representing new mutations. The inherited form constitutes 15% to 25% of cases and is of autosomal dominant transmission.
Germ-line involvement of the SMARCB1 gene plays a role in tumorigenesis of schwannomatosis; in addition to schwannomas,
patients with SMARCB1 germ-line mutations are at a higher risk for specific malignancies including MPNST, rhabdoid-type
tumors of the kidneys, and atypical teratoid rhabdoid tumors (176,178).
Schwannomas arise from schwann cells and grow eccentrically with respect to the underlying nerve. This is in sharp
contrast with neurofibromas, which are located centrally within the affected nerve. Schwannomas reveal a single cell type with
two distinct histologic patterns termed “Antony A” and “Antony B” regions; compared to Antony A regions, Antony B regions
are less cellular and show more disorganized matrix and common cystic degeneration.
Imaging findings include multiple discrete, well-defined, rounded to oval lesions situated in the spinal canal
(extramedullary) or along the course of peripheral nerves, paraspinous nerve roots, or cranial nerves. Spinal tumors are seen
in about 75% of cases, most frequent in the lumbar spine, followed by the thoracic spine and the cervical spine (Fig. 6-31).
Peripheral schwannomas are present in about 90% of cases (177). Lesions tend to be slightly hypo- to isodense to skeletal
muscle on CT, with varying contrast enhancement. On MR, lesions are typically low to intermediate signal on unenhanced T1-
weighted sequences and T2 hyperintense; they show heterogeneous, often intense enhancement after IV contrast administration.
Heterogeneous appearance may result from cystic degeneration, hyalinization, and calcification. The target sign identified in
PNs is usually absent (178).
Clinical Manifestations
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that is characterized by the presence of tumor-like
lesions (hamartomas) in multiple organ systems. Two separate genes have been identified that are mutated or deleted in
patients with tuberous sclerosis. The TSC1 gene is localized to chromosome 9q34 (179,180) and codes for a protein called
hamartin; the TSC2 gene has been localized to chromosome 16p13.3 (181,182) and codes for a protein called tuberin.
Mutations can be identified in 75% to 85% of TSC patients (21,183–186). Hamartin and tuberin interact physically in vivo, a
fact that clarifies how mutations in two different genes result in the common phenotype (187,188). These proteins form a
heterodimer that functions as a suppressor of factors of cell growth by inhibiting the mammalian target of rapamicin (mTOR)
kinase cascade. MTOR is active in transduction of factors such as amino acids, neurotransmitters, glucose, and growth factors
into normal growth and homeostasis. Overactivation of mTOR, however, may result in organized or disorganized cellular
overgrowth and differentiation, resulting on overgrowth syndromes or neoplasia (186,189–192); mutation of either protein
seems to lead to both increased protein translation and cell size enlargement (193). Overall, about 75% of TSC mutations are
spontaneous (186); however, before concluding that an affected child has a new mutation, it is necessary to examine both
parents thoroughly, including Wood light examination, neuroimaging, and, if possible, chromosomal analysis from multiple
tissues including germ cells (194). A 2% to 3% risk of recurrence in future pregnancies remains even if both parents seem
unaffected (194).
TSC2 mutations are about five times more common than are mutations of TSC1 (186). TSC1 mutations are slightly less
common in sporadic TSC cases (those with no family history, about two-thirds of all patients) and are somewhat more common
(15%–50%) in familial cases (21). It is of interest that the TSC2 gene is located only 48 base pairs of DNA from the gene for
adult-onset polycystic kidney disease (PKD1). When patients have a continuous deletion of both TSC2 and PKD1, they have a
particularly severe phenotype with very early onset of PKD and early renal failure (195).
Overall, compared to those with TSC1 mutations, the TSC2 group is associated with more and larger tubers, more radial
migration lines (RML), more subependymal nodules (SENs), higher risk of intellectual impairment, and higher frequency of
seizures, renal disease, and facial angiofibromas (166,185,196,197). However, as with all disorders, the outcome depends
upon the effect of the mutation upon the function of the protein product in affected pathways (in this case, mTOR); therefore,
some TSC2 mutations have relatively mild phenotypes, likely due to small effects upon tuberin function (192).
Classically, TSC has been characterized by the clinical triad of mental retardation, epilepsy, and characteristic skin lesions
known as adenomata sebaceum (198). The term adenoma sebaceum is used to describe a nodular rash of brownish red color
that is disseminated over the face, typically originating in the nasolabial folds and eventually spreading to cover the nose and
the middle of the cheeks in the infraorbital region. Epilepsy is the leading cause of morbidity in children with TSC and arises
in 75% to 90% of children (199). Half of affected patients have normal intelligence.
Almost any organ of the body can be affected (200). As a result, more sophisticated criteria for clinical diagnosis of the
disorder have been established and are listed in Table 6-6 (201). Increasing awareness of the condition has resulted in a
revision of the estimated incidence from approximately 1 in 100,000 patients (198,202,203) to 1 in 6000 live births (204,205).
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 neuroprogenitor cells of the developing brain (206,207). As a consequence,
these stem cells do not differentiate, develop, or migrate properly (208). The result is the presence of dysplastic, disorganized
cells in the ventricular zone, subventricular zones, the cortex, and along the radial glia coursing between them (19,206,209).
Approximately half of TSC patients develop intractable epilepsy (199). 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 presenting with infantile spasms have tuberous sclerosis (210). 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%) (211). The seizures often decrease in frequency with increasing age (212),
particularly when the epilepsy is partial (213). Patients with TSC can have nearly any type of seizure; therefore, the diagnosis
of tuberous sclerosis should be considered in any child with epilepsy. The incidence of intellectual disability is about 50%
(214); approximately two-thirds will be moderately to severely disabled, and one-third only mildly to moderately affected.
Cognitive impairment in TSC is a multifactorial condition; a link exists between cognitive disabilities and lesion load (based
on the proportion of brain volume occupied by tubers and on the number of RML (215)), age at seizure onset, and history of
infantile spasms (216); however, these factors explain only part of the intelligence quotient variability (186).
Table 6-6 Diagnostic Criteria for Tuberous Sclerosis Complex (Revised 1998)
Major Features
Facial angiofibromas or forehead plaque
Nontraumatic ungual or periungual fibromas
Hypomelanotic macules (more than three)
Shagreen patch (connective tissue nevus)
Multiple retinal nodular hamartomas
Cortical tubera
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Lymphangioleiomyomatosis b
Renal angiomyolipomab
Minor Features
Multiple randomly distributed enamel pits in dental enamel
Hamartomatous rectal polyps c
Bone cysts d
Affected first-degree relative
Cerebral white matter radial migration lines a,d
Gingival fibromas
Nonrenal hamartomac
Retinal achromic patch
“Confetti” skin lesions
Multiple renal cysts c
Definite TSC: Either two major features or one major plus two minor features
Possible TSC: Either one major feature or two or more minor features
aWhen cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of
tuberous sclerosis.
bWhen both lymphangioleiomyomatosis and renal angiomyolipomas are present, other features of tuberous sclerosis should be present before a definite
diagnosis is assigned.
cHistological confirmation is suggested.
dRadiologic confirmation is sufficient.
TSC, tuberous sclerosis complex.
From Roach E, Gomez M, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol
1998;13:624–628.
Neuroimaging often plays an important role in making the diagnosis of TSC (217,218); characteristic abnormalities are
present on neuroimaging studies in more than 95% of affected patients (218). These CNS abnormalities are present from before
the time of birth (Fig. 6-32), whereas the cutaneous malformations, such as adenomata sebaceum, may not develop until much
later in childhood. Current recommendations are for cranial imaging every 1 to 3 years until the age of 25 years (and every 3–6
months if a giant cell tumor is present) and renal ultrasound every 1 to 3 years at all ages (because renal angiomyolipomas may
enlarge at a concerning rate) (219,220).
Cutaneous Manifestations
Although not radiologically apparent, cutaneous adenomata sebaceum are a characteristic component of tuberous sclerosis,
and the imager should have a general knowledge of their clinical characteristics, which were described in the previous section.
These lesions, which are histologically classified as angiofibromas, usually develop between ages 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 years) and may continue to develop throughout life (221). Depigmented nevi
in the form of oval areas with irregular margins (ash-leaf spots) occur on the trunk and extremities 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 (222). 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 phakomatosis (223). Rarely, patients may develop lesions of the scalp that induce
hyperostosis of the underlying calvarium; histologically, these seem to be epidermal inclusion cysts. The other common
cutaneous lesions of tuberous sclerosis, shagreen patches and subungual fibromas, do not usually appear until after puberty
and will not be discussed here.
Figure 6-32 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 superolateral surface of the right
lateral ventricle. A subependymal hamartoma (black arrow) 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).
Ocular Manifestations
Ocular findings are common in tuberous sclerosis. The most common of these is the retinal hamartoma, an astrocytic
proliferation that is seen on or near the optic disc in 15% of affected patients (198,202). Retinal hamartomas are usually
present in both eyes and are often multiple (212). They may not be present at birth, developing over the first few months to
years of life (224,225); the affected globe may be small (224) 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 (226). Retinal hamartomas are seen on CT as nodular masses originating from the
retina (Fig. 6-33); when hamartomas calcify, they can be seen as small, calcified retinal masses that may be difficult to
differentiate from a retinoblastoma (224,227). The presence of calcified SENs in the brain will help to make the
differentiation. On MR, retinal hamartomas appear as solid retinal nodules that show moderate uniform enhancement after
administration of paramagnetic contrast (Figs. 6-33 and 6-34). A subretinal exudate may be present, leading the
ophthalmologist toward a presumptive diagnosis of Coats disease (see Chapter 5) (228); again, the observation of SENs in the
brain will lead to the proper diagnosis. The reader should be aware that, although they are most common in tuberous sclerosis
(they are seen in over half of the cases), retinal hamartomas are seen occasionally in the other phakomatoses as well (227).
Figure 6-33 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.
Intracranial Manifestations
Subependymal Nodules
SENs are benign collections of swollen glia and unusual multinucleated cells that are mainly 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 (202,229). Less commonly, the nodules may be detected along the frontal and temporal horns, the lateral ventricular
bodies, the third ventricle, or the fourth ventricle. SEN are hamartomas that differ histologically from the cortical hamartomas
(tubers) and therefore behave differently on imaging studies.
In neonates, subependymal hamartomas can be detected by transfontanelle sonography, on which they appear as echogenic
subependymal masses (Fig. 6-35A). 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 (217). Thus, they may be difficult to detect on CT scans of infants (Fig. 6-36C) but become progressively
easier to identify as they calcify (Fig. 6-37, also Fig. 6-40B). On MR scans, subependymal hamartomas appear as irregular
SENs that protrude into the adjacent ventricle. Their appearance changes as the signal of the surrounding white matter changes
(209,230). In fetuses and infants, who have unmyelinated white matter, the hamartomas are relatively hyperintense on T1-
weighted images and hypointense on T2-weighted images (Figs. 6-35 and 6-36) (231); in fetuses and newborn (especially
premature) infants, these may be mistaken for subependymal hemorrhages unless other lesions of tuberous sclerosis are
identified. As the brain myelinates, the SENs 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. Larger SENs manifest variably low signal intensity on the T2-weighted images, depending upon the
extent of calcification (209,232,233). T2*-weighted gradient echo or susceptibility-weighted images are optimal for showing
the calcification because of the magnetic susceptibility differences of calcium and brain (see Fig. 6-41). After intravenous
administration of paramagnetic contrast, SENs show variable enhancement; some will enhance markedly, some mildly, and
some not at all (209,234,235). The presence or absence of enhancement has no clinical significance. SENs have increased
diffusivity and reduced FA compared to surrounding white matter (236).
Figure 6-34 Hamartoma in TSC. Axial T2-weighted (A) and postcontrast T1-weighted (B) image reveals a retinal hamartoma presenting as a
small nodule along the posterior left retinal layer (black arrow), near the optic nerve head.
Figure 6-37 Axial noncontrast CT scan shows multiple calcified subependymal hamartomas (white arrows) along the walls of the lateral
ventricles. A hypodense right frontal tuber can also be identified (black arrow).
SEGAs tend to grow into the ventricle and uncommonly invade brain parenchyma. Rarely, they degenerate into higher-
grade, or infiltrating, neoplasms (237,238). Such degeneration should be suspected radiologically if the tumor is seen to invade
the brain parenchyma (interstitial edema will typically be seen in the adjacent parenchyma) or if rapid enlargement is seen. The
treatment of benign giant cell tumors is either pharmacological or surgical. A 60% to 70% response rate after 5 years of
treatment with everolimus, an mTOR pathway inhibitor, has been reported for patients SEGA associated with TSC (239,240).
Treatment of SEGAs prior to the development of symptomatic hydrocephalus is advisable, as patients who present with acute
obstructive hydrocephalus have a poorer outcome (220). 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 (49); these tumors have a
worse prognosis for disease-free survival than the giant cell tumors of TSC (241). 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.
Figure 6-39 Large SEGA in a patient with TSC. A. Coronal contrast-enhanced T1-weighted image shows a large, heterogenously 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.
In infants, tubers can be seen on transfontanelle ultrasound where they appear as foci of cortical hyperechogenicity (Fig. 6-
35A). As a result of fears of radiation effects, CT is rarely used in infants anymore, but neonatal and infantile cortical
hamartomas appear on CT as lucencies 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
hardening by the overlying calvarium, making identification of cortical tubers quite difficult unless they are calcified (Fig. 6-
40) (198), even with helical scanners. The calcification can be demonstrated on MR when susceptibility sequences are
obtained (Fig. 6-41). The MR appearances of cortical tubers also change with age but are quite characteristic. 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. 6-32, 6-35, 6-36); about 20% of affected gyri are
enlarged (209,246,247). The T1 hyperintensity/T2 hypointensity may extend from the tuber through the cerebral mantle to the
ventricle (see next section) (231,246,247).
Figure 6-40 Cortical tuber in TSC. A. Axial T2-weighted image of a 4-month-old 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 deepest part of the sulcus. A small calcification (long white arrow), probably a small subependymal hamartoma, is
noted in the right temporal horn.
Figure 6-41 Susceptibility-weighted imaging in TSC. A. Axial T2-weighted image shows a prominent U-shaped tuber in the right frontal lobe
with a T2 hypointense focus of mineralization within the white matter (long arrow). Additional, smaller tubers are identified (short arrows).
Multiple subependymal nodules are present. B. Phase-reconstructed image of the susceptibility-weighted acquisition reveals hyperintense
signal (consistent with calcification) associated with the frontal tuber (long arrow). Calcification is also evident in the multiple subependymal
nodules (short arrows).
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, unless they calcify (in this situation, they may appear bright on T1-weighted
images, presumably because of T1 shortening caused by the crystals of calcium (248)). Those tubers with inherent T1
shortening that are hidden as myelination ensues may be detected in older children and adults by the use of magnetization
transfer techniques: after suppression of the high intensity signal of the myelin within cerebral tissue by application of a
magnetization transfer pulse, parenchymal lesions may be more apparent than on standard T1-weighted images (Fig. 6-42C)
(249–251). On T2-weighted images, tubers become hyperintense on the T2-weighted images in the mature brain (Fig. 6-42)
(209,232–234); in the presence of calcification, low T2 signal is appreciated (Fig. 6-41). Degenerated, calcified cortical
tubers will sometimes enhance after contrast administration and display low signal and T2- and susceptibility-weighted
images. On diffusion-weighted studies, cortical tubers have increased diffusivity and decreased anisotropy compared to
normal white matter (236). On MR perfusion imaging, most (>90%) cortical tubers are hypoperfused relative to mean gray
matter (Fig. 6-43); presence of hyperperfused tubers is associated with increased seizure frequency (252).
T1 images with magnetization transfer and FLAIR images are the most sensitive sequences in detection of parenchymal
lesions in children and adults with TSC (253,254). The efficacy of FLAIR in the imaging of unmyelinated neonates and infants
has not been demonstrated. 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 (253). However, unless 3D volumetric FLAIR is acquired, artifacts
around the foramina of Monro (secondary to CSF flow) make SENs in that region difficult to identify. Whatever sequence is
used, the tubers themselves seem predominantly subcortical, separate from the overlying cortex (Figs. 6-36, 6-37, 6-41, 6-42).
Figure 6-42 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 hypo 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.
The inner (medial) margins of the tubers are poorly defined on all imaging sequences. 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. 6-42B]) are seen more
commonly in younger patients than in older children and adults (255); patients with cyst-like tubers appear to have a more
aggressive seizure phenotype (256).
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, dysplastic or neoplastic. Proton MR spectroscopy or perfusion MR imaging may be
useful to detect neoplasia. Proton spectra of tubers show normal to slightly elevated choline and slightly diminished NAA
(257,258). The myoinositol peak is increased on short TE (20–30 ms) spectra. In contrast, most childhood neoplasms have
marked elevation of choline and marked diminution of NAA (see Chapter 7) (105,259). 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 similar to that of normal white matter, but tubers are quite hypovascular (Fig. 6-43) (252). Cortical tubers are
virtually identical to type II FCDs, and, as both are benign and (often) epileptogenic, treatment decisions are not based on their
differentiation.
When children with TSC have medically refractory seizures, identification of the epileptogenic zone may allow for a
resection of the dysplastic tissue (a “tuberectomy”); surgery can be curative of epilepsy in up to 60% of patients. Studies have
suggested a marked reduction in seizure frequency if most seizures can be localized to a single lesion (260,261). Defining the
epileptogenic zone is a major challenge in TSC patients. It has been hypothesized that malformed tissue surrounding cortical
tubers rather than the tuber itself is the primary epileptogenic zone (199). Further, the normal-appearing cerebral tissue
surrounding tubers histologically contains many abnormal cell types, including giant cells and cytomegalic neurons, which form
characteristic “microtubers”(262). On MRI, cerebral tissue that has FCD-like features appears highly associated with the
epileptogenic zone—specifically, tissue characterized by large regions of perituberal increased cortical thickness, abnormal
gyral patterns, and calcification (Fig. 6-43) (199). These features are best appreciated on T2-weighted images.
Epileptogenic tubers are associated with a larger volume of hypometabolism relative to tuber size (based on FDG-PET
coregistered to MRI) and higher ADC values in the underlying white matter (263). PET scanning, using alpha 11-C-methyl-L-
tryptophan (AMT), has proven helpful in the identification of epileptic foci in TSC (264). Epileptogenic tubers show increased
interictal tracer uptake compared to nonepileptogenic tubers; a value of 0.98 in the PET uptake ratio between tuber and normal
cortex reliably differentiates between epileptogenic and nonepileptogenic tubers (265). BOLD imaging (260), magnetic source
imaging (266), and videotelemetry (261) may also be useful. Finally, the medial temporal lobe should be carefully evaluated
with MR imaging as mesial temporal sclerosis may occur in patients with TSC (267).
Figure 6-43 Perfusion imaging in TSC. A. Axial T2-weighted image shows a small cortical tuber (short white arrow) in the right frontal lobe and
a larger tuber with distorted cortex in the left frontal lobe (long white arrow) of a 15-month-old. A prominent subependymal nodule projects in the
right lateral ventricle (black arrow). B. Preoperative arterial spin labeling perfusion shows reduced blood flow in the left frontal tuber (arrow). C.
Postoperative ASL image following left frontal tuberectomy reveals an area of absent perfusion in the left frontal lobe. Focal increased perfusion
is however evident in the right frontal tuber (arrow), following a recent seizure.
Figure 6-44 Value of magnetization transfer imaging in TSC. A. Axial T2 image shows no definite abnormality other than a subcortical tuber
(white arrow). B. Corresponding axial T1-weighted image with magnetization transfer shows the subcortical tuber in the left parietal lobe (long
arrow) and the multiple radial linear white matter lesions primarily in the left hemisphere (short arrows point to some of these lesions).
Larger white matter lesions have a variable appearance that depends upon the amount of calcification within them. These
lesions have histologic and imaging characteristics identical to cortical tubers and to FCD type IIb (243) (see Chapter 5). On
CT, these regions appear as low-attenuation, well-defined regions within the cerebral white matter that do not enhance after
intravenous contrast 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
extremely high attenuation because of the calcification (198,217). If the lesion is calcified, the calcification may appear as low
or high signal intensity on T1-weighted images, depending upon the density of the calcium crystals, which determines how
much free water is hydrogen bound to the crystals (248). Also, as with cortical tubers, these white matter lesions have short T1
and T2 relaxation times in fetuses, neonates, and young infants (Figs. 6-35 and 6-36) (231,246,247). As with cortical tubers,
enhancement is only seen if the lesion has degenerated; under these conditions, calcification is usually present.
Cystic Lesions
Cyst-like structures are demonstrated in the cerebral hemispheric white matter of patients with TSC (274), with a reported
incidence of about 10% to 15% (253,275). 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. 6-45). Their clinical significance is uncertain
(274). They may grow slowly, but none are known to exhibit malignant degeneration or to show enough mass effect to
necessitate intervention.
Arachnoid cysts are found in approximately 5% of TSC patients (vs. approximately 0.5% in the general population). A
contiguous deletion of the TSC2-PKD1 gene significantly increases the probability of development of arachnoid cyst (276).
Cerebellar Lesions
Cerebellar lesions are more common than once thought; they are identified in up to 24% to 44% of TSC patients (277,278).
Patients with cerebellar lesions have overall higher autistic symptomatology than patients without cerebellar lesions (279).
The posterior fossa lesions are histologically similar to those of the cerebral hemispheres, consisting of cortical tubers,
heterotopic clusters in the white matter, and, occasionally, subependymal hamartomas (55,202,209). Cerebellar tubers are
usually wedge shaped and nodular or demonstrate distorted folia; they are not epileptogenic. They are difficult to see by CT
unless they are calcified (30%–50%) because of the beam-hardening artifact that occurs in the posterior fossa. On MR, the
majority show low T1, bright T2 signal; 30% to 50% enhance (277). Calcified lesions can be T2 hypointense (Fig. 6-34). The
majority have associated retraction deformities of the cerebellar tissue (Fig. 6-46). Unlike the majority of tubers in the
cerebrum, cerebellar tubers tend to change in appearance over time (Fig. 6-47). These changes include change (increase or
decrease) in lesion size, T2 signal and enhancement, progressive calcification, and new or increased associated retraction
deformity (277). Increases in size and enhancement occur mostly in the first decade of life and should not be misdiagnosed as a
developing tumor (278).
Vascular Lesions
Intracranial arteriopathy is approximately twice as common in the TSC population versus the general population and is
probably related to the dysfunction of smooth muscle cells; defects in the media due to deficiency and fragmentation of elastic
fibers have been postulated as a cause (280). Aneurysms can appear at a very young age; compared to sporadic aneurysms,
TSC-related aneurysms appear to be more frequently fusiform, giant, and multiple (281). Angiographic studies have
demonstrated arterial aneurysms in the kidney, liver, aorta, iliac arteries, and distal extremities in affected patients
(280,282,283). Therefore, radiologists should look for vascular manifestations in TSC.
Figure 6-45 Subcortical cysts in tuberous sclerosis. 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).
Non-CNS Manifestations
Although brain, ocular, and cutaneous lesions are the hallmarks of TSC, lesions also occur in the heart, kidneys, liver, lungs,
and spleen (198). Renal hamartomas occur in 40% to 80% of patients with tuberous sclerosis (202,284). Histologically, these
lesions are angiomyolipomas; 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. 6-32) are less common than the renal hamartomas but are important because they can
present as a congenital cardiomyopathy (202). These tumors are always subendocardial and may be either circumscribed or
diffuse. Because of their serious consequences, some authors feel that all patients with TSC should have screening
echocardiography.
Figure 6-46 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.
Pulmonary involvement is the next most common type of visceral abnormality in patients with tuberous sclerosis (198). The
characteristic pulmonary lesion is called lymphangioleiomyomatosis. In this condition, the lung parenchyma undergoes cystic
changes with a myomatous proliferation of tissue and chronic fibrosis occurring in the septa between the cysts. Other types of
visceral lesions include adenomas and lipomyomas of the liver, adenomas of the pancreas, and tumors of the spleen (198).
Bone lesions consist of multiple dense lesions in the cranium and cystic changes in the metacarpals and phalanges of the hands
(55,198,202).
Sturge-Weber Syndrome
Clinical Manifestations
Sturge-Weber syndrome (SWS), also known as encephalotrigeminal angiomatosis or meningofacial angiomatosis, is a
developmental disorder that is marked by angiomatosis involving the face, the choroid of the eye, and the leptomeninges. Other
clinical components of the syndrome are seizures, hemiparesis, hemianopsia, and mental retardation. Both sexes are equally
affected (285).
The facial nevus flammeus (or port-wine stain) is a capillary malformation that is found in approximately 1 in 300 people,
usually as an isolated finding; however, when associated with cerebral and ocular vascular malformations, it forms part of the
classical triad of SWS, with an incidence between 1 in 20,000 and 1 in 50,000 (286). The disorder is caused by a somatic
mosaic activation mutation of the gene for guanine nucleotide binding protein (GNAQ, OMIM 600998) (287). It is postulated
that GNAQ defects cause a dysregulation of endothelin (a peptide secreted by endothelial cells), resulting in vascular
endothelial dysgenesis, cortical venous capillary hypogenesis, and small vessel thromboses with resulting venous congestion
and development of collateral flow (such as dilated medullary veins in the cerebral white matter) (287). Thus, SWS is caused
by a primary venous dysplasia that produces focal venous hypertension and its attendant tissue responses (288).
Figure 6-47 Enlarging cerebellar hamartoma. A. Axial T2-weighted image at 1 year of age reveals an ill-defined architectural distortion of the
left lateral cerebellar hemisphere, with mild T2 hyperintensity, consistent with presence of a subtle hamartoma. B and C. Axial T2-weighted
image (B) and postcontrast T1 image (C) 4 years later reveal significant increase in the size and conspicuity of the hamartoma (arrow, B),
which shows heterogeneous enhancement (arrow, C). This should not be mistaken for a neoplastic lesion.
The facial nevus flammeus can involve part or all of the face. Ocular and facial involvement without cerebral involvement
(289) and ocular and cerebral involvement without facial involvement (290) have been described and are considered part of
the syndrome. A child with a port-wine stain on the face has approximately 6% chance of having SW, with the risk increasing
to 26% when the port-wine stain is located in the distribution of the first division of the trigeminal nerve (287). Traditionally,
the terminology stipulated that the ophthalmic division of trigeminal nerve territory was involved in SWS; a new classification
of port-wine stains based on the embryological vascular distribution of the face, and not the (trigeminal) innervation of the
face, has been proposed. Using this classification, a port-wine stain involving any part of the forehead is the strongest
predictor of SWS (286,291). The facial nevus is composed of an overabundance of thin-walled vessels that most closely
resemble capillaries. It is present at birth, usually unilateral (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. However, more and more
cases are being reported of SWS involving the brain without a facial nevus (292–294).
Patients with the SWS generally develop normally 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 (285,295). With time the seizures become progressively refractory to medication. They are accompanied
by an increasing hemiparesis in about 30% of patients and, often, by homonymous hemianopsia. The majority of affected
patients are mentally retarded (285,295). Prognosis is poor when both cerebral hemispheres or the majority of a single
hemisphere is affected (295).
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; approximately 15% of patients with SWS have bilateral intracranial
involvement (296). This pathologic process consists of multiple capillaries and small venous channels that are matted together
on the surface of the brain. The arteries are involved to a lesser extent and tend to undergo fibrosis. The combination of the
frontonasal cutaneous angiomas, the ocular lesions, and the cerebral pial angiomas has been postulated to derive from the
migration of abnormal neural crest cell (NCC) derivatives from the developing prosencephalon (forebrain) and anterior
mesencephalon (midbrain). Normal NCC derivatives from these two regions lead to the formation of the frontonasal
prominence, plus of the skin in the optic vesicle area (286,291). An early somatic mutation of this craniofacial complex likely
accounts for the abnormal vasculature responsible for SWS, whereas a later somatic mutation likely results in cutaneous
nonsyndromic port-wine stains (291).
Cortical calcifications are another pathological finding in SWS (Fig. 6-48E). The calcifications occur exclusively in areas
of the brain subjacent to the angioma. They begin in the subcortical white matter and later develop in the cortex, predominantly
in cortical layers two and three (285). They are found most frequently in the temporoparietooccipital region of the brain but
can be located anywhere in the cerebrum (55,285,297). Cortical calcifications can be bilateral in up to 20% of patients (297).
Although their cause is not confidently established, they are most likely dystrophic changes caused by the chronic ischemia that
results from impaired venous drainage (124).
Polymicrogyria is occasionally observed with SWS; its presence suggests that the impairment in cerebral circulation
occurred an early stage (during the second trimester of pregnancy) and resulted in disruption of the glia limitans (see Chapter
5) (298). In addition to polymicrogyria, pathologic specimens of many cortical resections/hemispherectomies in SWS reveal
varied degrees of cortical morphologic anomalies (including FCD), which are not detected on MRI examination due to their
subtle microscopic nature (299).
Neuroimaging Manifestations
Brain
Contrast-enhanced MR is the most accurate single imaging study for showing the extent of the pial angioma (300,301); contrast-
enhanced T2-weighted FLAIR images improve detection of leptomeningeal disease compared to postcontrast T1-weighted
images (302). Enhancement can sometimes be seen on CT if the patient is imaged in infancy, prior to the appearance of cortical
calcifications (297). However, calcifications mask the enhancement as determined by CT; moreover, MR is more sensitive to
the extent of enhancement than CT (303). After intravenous administration of contrast, the angioma appears on MR as an area
of enhancement that seems to fill the subarachnoid space, covering the surfaces of the gyri and filling the cortical sulci (Figs. 6-
48 and 6-49). 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 (Figs. 6-48D and 6-50) (304). 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 MR
imaging should be performed in all patients for whom surgery for seizure control is planned (301). It is important to note,
however, that “burned-out” cases of SWS, in which the affected hemisphere is markedly shrunken and heavily calcified, may
not show enhancement (305). The reason for this lack of enhancement is not clear, but it may relate to thrombosis of the vessels
composing the angioma. Optimal timing of the first MRI is debatable, some authors recommend screening within the first 3
months of life; others, cognizant of the common false-negative results, recommend waiting until 1 year of age unless there are
symptoms (306).
Figure 6-48 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
present 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 septal vein (white arrow) is present on the left. C. Postcontrast axial T1 image at age 7 years shows interval progression of the bilateral
leptomeningeal angiomas. Multiple abnormal 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).
Figure 6-49 Progressive cerebral atrophy in SWS. A and B. Patient at 2 months of age. Axial T2-weighted image (A) shows mild decrease in
the size of the right cerebral hemisphere and mild decrease in signal intensity of the right cerebral white matter, most evident in the frontal lobe.
Minimal increased T2 signal of the right skull diploe is evident (arrow). Postcontrast axial SE T1-weighted image (B) shows enlarged right
choroid plexus (arrow) and mild asymmetric increased leptomeningeal enhancement of the right hemisphere compared to the left. C and D.
Same patient at age 10 years of age. Axial T2 (C) and postcontrast axial SE T1 (D) reveal severe right hemispheric atrophy. The overlying
calvarium has thickened (white arrows). The conspicuity of the enhancing diffuse angiomatosis surrounding the right cerebral hemisphere has
increased (D); the right choroid plexus has further enlarged (black arrow, D).
The effects of the pial “angioma” (and the associated restricted cortical 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. 6-48E) (297,307). 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 MR imaging studies. It is more readily identified on T2-weighted images and,
especially, on susceptibility-weighted imaging (SWI) or on T2*-weighted gradient echo images, which are more sensitive to
the difference in magnetic susceptibility between the normal brain and calcium (Fig. 6-50) (304). 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 (304);
these areas seem to correlate with reduced fluorodeoxyglucose uptake on PET studies (304). Contrast-enhanced T1-weighted
sequences demonstrate 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. 6-50) (308).
Dynamic MR perfusion-weighted imaging reveals decreased perfusion value in patients with more severe atrophy and
longer duration of epilepsy and more frequent seizures. Increased perfusion is also observed, which may indicate an early
stage of SWS without severe brain atrophy (309). Proton MR spectroscopy of the 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
(310); similarly, increased diffusivity has been documented in normal-appearing white matter (311).
Figure 6-50 Child with Sturge-Weber syndrome and right hemispheric atrophy. Axial SWI shows the diffuse, hypointense cortical and
subcortical 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.)
The choroid plexus is frequently enlarged in patients with SWS (312), probably because blood is shunted to the deep
medullary veins, which drain into the lateral ventricles. Therefore, the degree of plexal enlargement in young children shows a
positive correlation with the extent of the leptomeningeal angioma; that is, the more extensive the parenchymal involvement, the
larger the choroid plexus (313). The enlarged choroid plexus is best demonstrated on contrast-enhanced T1-weighted images
as abnormally prominent enhancement of the choroid ipsilateral to the angioma (Figs. 6-48, 6-49, 6-51) (312). On T2-weighted
images, the affected choroid plexuses are enlarged and are hyperintense to brain parenchyma (312). This phenomenon is most
commonly a result of hyperplasia of the choroid plexus, possibly related to increased 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” (314).
In the infant with SWS, the white matter underlying the angioma typically shows accentuated T2 shortening compared to the
remainder of the brain (Fig. 6-49A) (315). 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 (DTI) (316). The
increased myelination may result from abnormal venous congestion or from repeated seizures (317). 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 (318).
The ipsilateral cerebral hemisphere ultimately becomes atrophic in most, but not all, patients with Sturge-Weber disease
(Figs. 6-48 to 6-50); atrophy is uncommon at the time of seizure onset. As might be expected, atrophy is bilateral in those
patients with bilateral angiomas (319). 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 (320). DTI shows increased diffusivity and
reduced FA in the affected white matter (304). These imaging characteristics most likely represent atrophy and astrogliosis in
the ischemic underlying brain.
Infratentorial involvement (presenting as leptomeningeal enhancement, atrophy and developmental venous anomaly) may be
more frequent than previously thought and has been reported in 10% to 40% of cases (321).
Figure 6-51 Early findings of SWS in a 15-month-old with a left facial port wine stain. A. Postcontrast coronal T1 image reveals minimal
asymmetric increase in size of the left choroid plexus (double short arrows). No angiomatosis is demonstrated at the periphery of the left
cerebral hemisphere. The diploic space of the left parietal calvarium (long arrow) is slightly thicker than on the right. B. Coronal fat-suppressed
T2-weighted image reveals asymmetric increased thickness and T2 hyperintensity in the diploic space of the skull on the left (arrow).
Skull and facial abnormalities are also observed. Hyperintense T2 signal in the marrow of the skull and/or marrow
enhancement is observed in the majority of SWS cases ipsilateral to the PWS. If the facial bones are involved, the majority of
patients have ipsilateral choroidal angiomas. In younger patients, marrow abnormalities are often observed without
leptomeningeal angiomatosis (Fig. 6-51). As the bone marrow signal abnormality may represent the only abnormality evident
on cranial MRI, it may reflect a milder phenotype or early disease manifestation. Therefore bone marrow signal changes in
the face and skull can provide an additional early diagnostic clue (322). With progressive 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 MR as a widening 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 secondary to the cerebral atrophy (323).
Enlarged vessels are commonly seen on CT and MR studies in the subependymal and periventricular region of the brain
(Figs. 6-48D and 6-50). Although venous malformations, arteriovenous malformations, and dural arteriovenous fistulae may be
seen in association with SWS (324), the cause for these enlarged deep hemispheric vessels in most patients is enlargement of
the deep venous system of the brain (318,325). When such enlargement occurs, it is a result of the maldeveloped superficial
venous system of the brain. The superficial pial angioma is associated with the maldevelopment of, and diminished outflow
through, the superficial venous system. Therefore, venous blood is shunted through the aforementioned deep medullary veins
and into the deep venous system of the brain (318,325). 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 (318,325).
Positron emission tomography (PET) using FDG has been used to study cerebral metabolism in children with SWS. In the
early stages of the disease, the affected area is typically hypermetabolic. However, hypometabolism soon ensues (326). In
general there is good correlation between susceptibility-weighted perfusion MRI and FDG-PET metabolic studies; however, a
perfusion/metabolic mismatch with increased white matter perfusion and preserved cortical metabolism in the overlying cortex
can be observed, possibly representing a disease stage where cortical function is preserved while increased white matter
perfusion provides collateral drainage of the cortex via the deep vein system (327). PET may be useful in surgical planning
when cortical resection is contemplated for treatment of intractable seizures and failure to attain developmental milestones
(326). Fusion of PET with MRI is more useful still (304).
Eye Anomalies
Abnormalities of the globe are seen in about 30% of patients with Sturge-Weber disease (285,328). 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 MR imaging 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 crescentic enhancement in the posterior globe on contrast-enhanced MR imaging of the orbit using a
fat-suppression pulse (Fig. 6-52) (329). The presence of choroidal angioma correlates with the presence of disease laterality
and with the extent of facial involvement; it does not correlate with the size of the intracranial pial angioma (329). 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.
Figure 6-52 Angioma of the choroid, infant with bilateral form of Sturge-Weber syndrome. Postcontrast axial T1 images show marked
enhancement of the choroid of the globes (arrows), slightly more intense on the right than on the left side, indicating the presence of choroidal
angiomas.
Extra-CNS Manifestations
Patients with SWS do not typically have abnormalities of the thoracic or abdominal viscera. However, some patients will have
angiomas of the viscera and extremities in conjunction with typical findings of SWS (285,330,331). The angiomas can be
localized or diffuse; they can be located in the intestine, kidneys, spleen, ovaries, thyroid gland, pancreas, or lungs (285). This
combination of SWS with involvement of the viscera and extremities is called Klippel-Trenaunay-Weber syndrome by some
authors (332), while others consider the entire complex to be a part of the SWS (330), and still others consider it an overlap
syndrome (333).
Clinical Manifestations
Also known as CNS angiomatosis, von Hippel-Lindau disease is an autosomal dominant disorder with incomplete penetrance
characterized by retinal angiomas, cerebellar and spinal cord hemangioblastomas, renal cell carcinomas, endolymphatic sac
tumors, pheochromocytomas, papillary cystadenoma of the epididymis, angiomas of the liver and kidney, and cysts of the
pancreas, kidney, liver, and epididymis (334–336). von Hippel-Lindau disease affects approximately 1 in 40,000 individuals;
both sexes are affected equally (336–338). 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 (338). The disease is caused by a germ-line mutation of a tumor suppressor gene, called VHL, at chromosome
3p25.3 (339); its gene product, pVHL, is involved in cell cycle regulation and angiogenesis. Inactivation of pVHL results in
overexpression of hypoxia-inducible factors (HIFs) which results in overexpression of several genes implicated in
angiogenesis, proliferation, apoptosis, and metabolism (including VGEF [vascular endothelial growth factor]) (340,341).
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 (334,337,338). Symptoms from the retinal angiomas typically antedate cerebellar complaints, but this
order of events is by no means constant; moreover, the ocular findings are nonspecific and often do not establish a definite
diagnosis. The usual sequence of events is reactive retinal 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. Headache, vertigo, and vomiting result from the
cerebellar tumor and associated increased intracranial pressure, when present. Other cerebellar findings such as
dysdiadochokinesis, dysmetria, and Romberg sign are common (337). 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 (338). Rarely, patients present with hearing
loss resulting from tumors of the endolymphatic sac. Cutaneous manifestations of VHL syndrome are infrequent and
nonspecific, including primarily hemangiomas and café au lait spots (338).
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 (338). 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% (337,338,342).
Although CT and MR can detect the secondary retinal detachment, the retinal angiomas themselves are usually quite small and
are rarely detected by imaging studies.
Figure 6-53 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.
Figure 6-54 Cerebellar and spinal 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 L4. Multiple other hemangioblastomas are difficult to see. D. Sagittal postcontrast T1-
weighted image of the spine shows the large L4 mass (white arrows) with some internal flow voids (black arrowheads) and innumerable other
enhancing hemangioblastomas (white arrowheads).
Cerebellar hemangioblastomas are present in more than half of patients with von Hippel-Lindau disease (338,342). They
are the second most frequent source of initial symptoms and frequently recur after surgical resection. 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, MR imaging and autopsy data demonstrate a considerably
larger number and higher incidence of spinal cord hemangioblastomas than were previously believed to exist (Figs. 6-54 to 6-
56) (55,337,338,347). 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. Differentiation of syringomyelia from tumor cysts and from
cord edema can be difficult, but T2-weighted images can often help to differentiate cyst from edema, as the cysts are typically
of higher signal intensity and have sharp margins, whereas edema is less hyperintense and has indistinct margins (Fig. 6-55). It
is difficult to differentiate idiopathic syringomyelia 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 (346,352). 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 (346,349). For more
definite delineation of the feeding arteries, digital subtraction angiography has traditionally been performed; however, 3D CT
angiography using modern CT scanners is a promising technology (353).
Hemangioblastomas also occur within the brainstem (Fig. 6-55) or the cerebral hemispheres (297). The radiologic
appearance of these lesions is identical to that of the cerebellar or spinal cord 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 facilitated by knowledge of the diagnosis of von Hippel-Lindau syndrome or the presence of other
hemangioblastomas.
Figure 6-55 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 cervicomedullary 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.
Figure 6-56 Hemangioblastoma of the conus medullaris in von Hippel-Lindau syndrome. A. Postcontrast sagittal T1-weighted image
demonstrates a cyst in the conus medullaris of the spinal cord containing an intensely enhancing nodule posteriorly (arrow). B. Sagittal fast
spin-echo T2 image shows the cyst (arrow) within the conus medullaris, but the nodule is difficult to detect.
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 (337). They occur later in life than most of the neurologic manifestations,
with the average presentation during the fifth decade of life (338). 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 (338,345). Thus, affected patients must be evaluated with
abdominal and pelvic imaging studies as well as neural axis imaging.
Ataxia–Telangiectasia
Clinical Manifestations
Ataxia–telangiectasia (AT) is an autosomal recessive multisystem disorder characterized by a complex set of clinical features
that include cerebellar degeneration, dilation of blood vessels, severe immune deficiencies, premature aging, predisposition to
cancer, acute radiation sensitivity, and elevated serum alpha-fetoprotein levels (359–364). AT is the prototype for an
overarching family of disorders characterized by X-ray irradiation sensitivity, cancer susceptibility, immunodeficiency,
neurological abnormality, and double-strand DNA breakage (so-called XCIND syndrome). Other entities in the XCIND
syndrome disorders include the Nijmegen breakage syndrome (NBS), severe combined immunodeficiency (SCID) variants,
and Fanconi anemias (365). Because of the DNA repair defects, these children are particularly sensitive to ionizing radiation;
exposure to X-rays should be avoided.
Figure 6-57 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 heterogeneous 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.
The incidence of AT is approximately 1 per 40,000 to 1 per 88,000 live births (359,364). The gene (called ATM for ataxia–
telangiectasia mutated) codes for the protein kinase ATM, which is located on chromosome 11q22-23 (366) and 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 (363). 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 (359,360,367).
Characteristic skin changes (mucocutaneous telangiectasias) manifest 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 (360,361). Patients with AT often have a dysfunctional immune
system, with resultant recurrent bacterial and viral sinopulmonary infections in most patients; these lead to bronchiectasis and
pulmonary failure, the most common causes of death. Malignancies develop in 10% to 15% of affected patients (368);
lymphomas and leukemia predominate in younger patients, whereas epithelial malignancies occur much more frequently in
adults (368,369).
Once the genotype of AT was defined, it became evident that phenotypic manifestations vary widely in age (childhood and
adult onset), severity (mild and severe forms), and clinical presentations (some patients lack oculocutaneous telangiectasia). A
new designation, ATM syndrome, has been proposed to reflect this expanded phenotype: a neurodegenerative disorder with
multisystem involvement due to the absence or reduced levels of ATM protein and kinase activity. Patients without ATM kinase
activity show the classical phenotype of AT; presence of residual ATM kinase activity results in a milder and atypical
phenotype (364).
Figure 6-58 Ataxia telangiectasia in an 11-year-old child. Sagittal T1-weighted (A) and coronal T2 (B) images show moderate to severe
diffuse atrophy of the cerebellar vermis (A) and hemispheric (B) cortex.
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 discussion of other causes of cerebellar
atrophy in childhood, see the last portion of Chapter 3.
Neurocutaneous Melanosis
Clinical Manifestations
Neurocutaneous melanosis (NCM), a neuroectodermal dysplasia, is characterized by the presence of congenital melanocytic
cutanteous nevi, a relatively rare birthmark occurring in approximately 1 in 20,000 to 50,000 live births, and melanotic
deposits in the meninges or the brain parenchyma (385,386). Congenital melanotic nevi (CNM) can be single or multiple at
birth and may be small (a few cm in diameter) or large; they may be isolated or associated with melanosis in the brain or
leptomeninges. Approximately 10% to 30% of children with multiple CNM have abnormal MRI of the central nervous system
(387); when these birthmarks are associated with melanosis of the leptomeninges or brain, a diagnosis of NCM can be made.
The underlying cause of multiple CNM was recently found to be a mosaicism for heterozygous activating mutations in codon
61 of NRAS, a developmental gene and oncogene involved in the control of key cell signaling pathways that is located on
chromosome 1p13.2 (388). As there are many nonmelanotic CNS lesions evident in patients with NCM and since a causative
single gene defect for the cutaneous and neurological findings has been discovered, an alternate terminology, termed “CMN
syndrome,” has been proposed, for patients with CMN and extracutaneous features (387).
With few exceptions, individuals with NCM have congenital pigmented nevi on the head and neck or trunk (usually dorsal
spine area), commonly with presence of multiple satellite nevi (389). The risk of congenital neurological abnormalities
increases with total number of nevi and the size of the largest one (387).
The majority (more than two-thirds) of patients have asymptomatic, isolated intraparenchymal lesions, with a low
incidence of malignancy or early deaths, including a low risk of CNS melanoma (387). Of 43 children with giant cutaneous
melanotic nevi over their head and neck or spine reported by Frieden et al. (390), 23% (10/43) had focal areas of T1
shortening strongly suggestive of melanotic deposits in one or multiple areas of the brain, particularly the anteromedial
temporal lobes (amygdalae), cerebellum, pons, and/or medulla. 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 (391). This result suggests that in patients with this asymptomatic form of NCM, the
brain MR findings 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 (391) but may not need routine repeat MRI examinations (387).
Patients with the symptomatic form of NCM typically develop central nervous disease at less than 2 years of age, while a
smaller, second peak of onset of symptomatic disease 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.
Hydrocephalus is seen in two-thirds of cases and is thought result from extensive leptomeningeal infiltration with melanosis or
with development of intracranial melanoma (392,393). Spinal involvement occurs in approximately 20% of cases and may
result in myelopathy, radiculopathy, and bowel or bladder dysfunction (394). The prognosis of symptomatic neurocutaneous
melanosis 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 (386). Patients with leptomeningeal disease need
monitoring by MRI; when the progression is documented, a biopsy may be necessary (387).
The following criteria have been proposed to define the population at risk (394,395): (a) large or multiple (three 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 histologically benign. Those
cases with histologic confirmation are considered definite; all others are considered provisional diagnoses.
Pathological Manifestations
Normal melanocytes originate from the ectodermal cells of the neural crest and are found in the reticular formation of the
medulla and pons, substantia nigra, and the leptomeninges (396–399). Patients with NCM, however, have orders of magnitude
more melanotic cells, located in the leptomeninges at the base of the brain, as well as in the parenchymal perivascular spaces
of the anterior temporal lobes, thalami, basal ganglia, cerebellum, pons, and medulla (386,395,399). A number of potential
explanations for the abnormal accumulation of melanotic cells in the meninges have been proposed, including abnormal
migration of melanocyte precursors (400); abnormal expression of melanin-producing genes within the leptomeningeal cells
(401); or rapid proliferation of “normal” melanin-producing leptomeningeal cells. The abnormal melanin-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 (395,402).
The anterior temporal lobes and cerebellum appear to be the most common locations for accumulation of melanotic cells in
NCM (395,403–408). In the anterior temporal lobe, the amygdala seems particularly commonly affected (395,403,407–409).
Other common locations include the thalami, pons, cerebellum, and the base of the frontal lobe (394,395,403,409). It is likely
that the preferential spread to these locations is a result of their close proximity to the basilar meninges, although there is also
evidence that melanin is produced within the neurons and glia rather than in melanocytes (387).
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 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. MR shows melanotic foci as areas of T1 hyperintensity, and
sometimes T2 hypointensity, in the brain parenchyma or meninges (Figs. 6-60 to 6-62), signal 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 make the melanin less conspicuous (391).
Thus, MR screening for melanotic deposits is best performed early in infancy, within the first 4 to 6 months of life (387).
FLAIR images show both parenchymal and leptomeningeal melanosis as hyperintense compared to normal parenchyma (410).
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. 6-60 to 6-62) (409,411). 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) (412,413).
The unpaired electrons in free radicals interact with water protons via dipole–dipole interactions with subsequent shortening
of both T1 and T2 relaxation times (414,415). When extensive leptomeningeal lesions are present, affected children typically
have hydrocephalus (Fig. 6-62) (416). Degeneration of the melanocytic accumulation into melanoma can be determined by the
identification of new nodularity or progressive growth of the lesion, by the presence of surrounding edema or mass effect, or
by the presence of central necrosis (409). Some authors have identified abnormal meningeal enhancement on MR studies of
patients with NCM (417,418); when seen in patients with increased intracranial pressure, this finding likely represents diffuse
leptomeningeal spread of tumor (418). However, enhancement is almost never seen until the melanotic deposits have
undergone malignant degeneration with disruption of the blood–brain barrier and spread throughout the subarachnoid spaces
(418).
Figure 6-60 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 leptomeningeal melanosis or changes of the relative signal intensities of the melanotic deposits and the brain parenchyma.
Figure 6-61 Neurocutaneous melanosis variations. A. Coronal T1 image shows large areas of melanosis anterior to the temporal horns of the
lateral ventricles (arrows); this is the most common location for melanosis. B. Coronal T1 image shows marked hyperintensity of the cerebellar
cortex, greater on the left than right. Note the cerebellar hypoplasia of the left greater than right hemisphere. C. Oblique coronal T1-weighted
image of a different patient shows multiple foci of hyperintense melanin: in the right amygdala (long arrow); in the pons, especially on the left
(double arrow); and multiple small hyperintense deposits in the right cerebellar cortex (short arrows).
Figure 6-62 Neurocutaneous melanosis with hydrocephalus. A. Sagittal T1-weighted image shows severe hydrocephalus. The cerebellum
appears slightly small and the cisterna magna is enlarged. B. Axial T1-weighted image shows multiple hyperintense deposits of melanin in the
cerebellar hemispheres and middle cerebellar peduncles. C. Axial T1-weighted image at the level of the midbrain shows bilateral melanin
deposits (white arrows) anterior to the temporal horns of the lateral ventricles.
Cerebellar (primarily vermian) and brainstem hypoplasia (Fig. 6-60) are typically seen when melanosis is present around
the cerebellum and pons, respectively (409,411). Over time, the melanotic deposits in the leptomeninges may become cryptic
to imaging detection (Fig. 6-60C); when imaged at this stage, patients may be mistakenly 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
is often made (394,419–421). Less frequent reported findings include tethered spinal cord (391,422), syringomyelia, spinal
lipomas (usually subpial), and arachnoid cysts (both intracranial and intraspinal) (390,416).
Incontinentia Pigmenti
Clinical Manifestations
Incontinentia pigmenti (IP, also called Bloch-Sulzberger syndrome) is a rare disorder characterized by congenital skin lesions,
dental and skeletal dysplasia, ocular abnormalities, and central nervous system involvement (423,424). Its estimated
prevalence is less than 1/100,000 (424,425). The name is derived from an apparent dislocation of melanin from the basal cell
layer of the epidermis to the upper dermis (426). The disorder is almost exclusively seen in females, with mutations of the
IKBKG (inhibitor of kappa B kinase gamma) gene, located at chromosome Xq28 (this gene was previously named NEMO)
(424); the most common mutation in IP is a genomic rearrangement that results in deletion of exons 4 to 10 (424). The mutation
appears to be lethal in males; in the few reported male cases, postzygotic mosaicism for IKBKG is evident (427). IKBKG gene
products activates NF-kB (nuclear factor-kappa B), which is important in the CNS for immune responses and protection
against neuronal damage and apoptosis caused by brain injury, hypoxia, and excitotoxicity induced by seizures (428).
The characteristic cutaneous lesions are vesicular or bullous eruptions that begin in the first 6 months of life; the
inflammatory vesicles often follow a linear pattern (V-shaped pattern on the back and S-shaped pattern on the anterior trunk)
corresponding to the migration of embryonic cells during fetal development (the lines of Blaschko) (429,430). Four stages of
cutaneous lesions are described: stage 1 is characterized by erythema, vesicles, and pustules; stage 2 by papules, verrucous
lesions, and hyperkeratosis; stage 3 by hyperpigmentation; and stage 4 by pallor, atrophy, and scarring (431). The major ocular
abnormalities are retinal vascular anomalies that cause retinal fibrosis (432); microphthalmia may be seen in conjunction with
persistent hyperplastic primary vitreous. The central nervous system is affected in 30% to 50% of affected patients, with
resultant epilepsy (about 25%), intellectual deficit (<10%), spastic or flaccid quadriplegia, and ataxia (433,434). Symptoms
may begin any time in childhood, sometimes as early as the first week of life; neonatal encephalopathy has been described
(435,436). Affected patients become progressively microcephalic.
Hypomelanosis of Ito
Clinical Manifestations
Hypomelanosis of Ito (formerly referred to as IP achromians (442)) is a common, but poorly known, neurocutaneous disorder
characterized by hypopigmentation of the skin along the Blaschko’s lines and extracutaneous involvement; it is reported as the
fourth most common neurocutaneous disorder, after neurofibromatosis, TSC, and SWS (443). The pathogenesis of the disorder
is unknown and is likely multifactorial. Autosomal dominant inheritance has been seen in some (but not all) cases; frequency is
equal among males and females (444). Karyotype analysis reveals a variety of chromosomal rearrangements, generally
associated with mosaicisms. Therefore, most experts now believe that hypomelanosis of Ito is not a distinct entity but is
rather of manifestation of many different genetic disorders and that the chromosomal abnormalities disrupt expression or
function of pigmentary genes (445,446).
The most characteristic clinical feature of hypomelanosis of Ito is the presence of cutaneous hypopigmented zones with
irregular borders, streaks, whorls, and patches (447,448). Other skin alterations are seen in up to 40% of affected patients and
include café au lait spots, angiomatous nevi, nevus marmorata, nevus of Ota, Mongolian blue spot, heterochromia of the iris or
hair, diffuse alopecia, grayish-white trichorrhexis, and mottled hair (449). Musculoskeletal abnormalities include
hemihypertrophy, kyphosis, scoliosis, hyperlordosis, rudimentary ribs, genu recurvatum, pes valgus, and pes cavus (448).
Genital and cardiac anomalies are found in 10% or less of affected patients (448,449).
Figure 6-63 Incontinentia pigmenti in an infant. A. Axial T2-weighted image at 10 months of age reveals striking bithalamic T2 hyperintensity
and swelling (long arrows). There is also a small T2 abnormality in the external and extreme capsules on the left (short arrow). B–D. Follow-up
study 6 months later. The axial T2 image (B) reveals progression of the bilateral thalamic abnormalities, along with development of extensive
T2 hyperintense abnormalities in the subinsular white matter bilaterally, in the bilateral occipital lobes, and in the right frontal and parietal lobes.
Postcontrast T1 image (C) shows mild leptomeningeal enhancement over the posterior cerebral convexities, more prominent on the right than
on the left. Diffusion image (D) reveals abnormal signal in the posterior cerebral cortex (long arrows), along with multiple punctate hyperintense
lesions in the thalami and the subcortical and deep cerebral white matter.
Neurological Manifestations
Most clinical interest in hypomelanosis of Ito derives from the frequency and importance of the neurological complications.
These consist primarily of seizures and mental retardation, both of which are present in more than half of affected patients
(443,448,449). Seizures usually develop during the first year of life and consist of infantile spasms, major motor seizures,
partial motor seizures, and other forms of myoclonic epilepsy (448,449). While some patients suffer from generalized seizures
that are well controlled with anticonvulsant therapy, many have severe, pharmacoresistant focal seizures (450). Developmental
delay is reported in 75% of affected patients and moderate to severe mental retardation (IQ < 70) in 57%; only 20% of patients
have an IQ above 85 (449). Other reported neurologic manifestations include macrocephaly, microcephaly, and hypotonia
(449).
Clinical Manifestations
The basal cell nevus syndrome (BCNS), also known as nevoid basal cell carcinoma syndrome and as Gorlin syndrome, is an
autosomal dominant 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 (456–458). Macrocephaly, often pronounced, is evident in 50% of cases (459). Prevalence of this syndrome
is approximately 1 in 60,000 (range: 1/57,000–1/256,000) (460). First described in 1960 by Gorlin and Goltz, BCNS most
commonly (70%) results from a heterozygous germ-line mutation in PTCH1, which is located on chromosome 9q22–31.
PTCH1 encodes a transmembrane glycoprotein that serves as a tumor suppressor in the hedgehog signaling pathway, a pro-
oncogenic pathway that controls proliferation, differentiation, and apoptosis (461,462). Less commonly, patients with BCNS
have a mutation of the fused (SUFU) gene; SUFU-associated genotype is characterized by the absence of keratocystic
odontogenic tumors (KOTs) and the presence of medulloblastoma before 5 years of age (462). The risk of development of
medulloblastoma is much higher in SUFU mutation–positive individuals (about 33%) than in PTCH1 mutation–positive
individuals (<2%) (463). Patients most commonly are initially seen due to development of basal cell carcinomas, which may
appear as early as age 2 years (464). 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 syndrome
(457,465). As this is a neuroradiology text, only manifestations in the face, spine, and CNS will be covered.
Neuroimaging Manifestations
The most common manifestations seen on neuroimaging are odontogenic keratocysts and calcifications of the intracranial dura
(Figs. 6-64 and 6-65). Odontogenic keratocysts (renamed KOT in the 2005 WHO classification) are typically multiple
(average, 3–6; range, 1–30) and involve both the mandible and maxilla (458,466–468). They appear after the seventh year of
life and are present in 80% of affected patients over the age of 20 years (466). 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 asymptomatic
(466). The cysts tend to recur after surgery. Rarely, ameloblastoma or squamous cell carcinoma may arise from a keratocyst
(457). The radiologic appearance is that of a sharply marginated lesion that seems to originate from the root of a tooth (Fig. 6-
64). 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 overlying cortical bone is expanded and thinned.
Early calcification of the dura mater is a common radiologic manifestation of the BCNS (457). The falx cerebri is the dural
structure most commonly affected (in 65%–90%), with the diaphragma sella (60%–80%), tentorium cerebelli (20%–40%),
and petroclinoid ligaments (20%) all commonly involved in this process. Osseous bridging of the sella turcica is an uncommon
finding in the general population but represents an important imaging clue for the diagnosis of BCNS (Fig. 6-64B) (460). Dural
calcification can be appreciated as increased attenuation and irregular thickening of these structures on CT (Fig. 6-65A and B)
and as hypointensity with irregular thickening on MR. MR demonstrates dysgenesis or agenesis of the corpus callosum in
approximately 10% of cases (467).
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 (457). Anomalies of the spinal cord have not been reported.
Figure 6-64 An 11-year-old with basal cell nevus syndrome. A. Sagittal noncontrast CT scan of the face reveals a mass occupying the inferior
aspect of the maxillary sinus and the destroying part of the adjacent alveolar process of the mandible (black arrows). The crowns of two
unerupted teeth (white arrows) are evident along the superior edge of the mass. Appearance is typical of an odontogenic keratocyst. B. Axial CT
image through the base of the skull reveals characteristic osseous bridging of the sella turcica (arrows).
Figure 6-65 BCNS and multiple radiation-induced tumors in a teenager previously treated for a childhood medulloblastoma. A and B. Axial
noncontrast CT scans at age 16 years show extensive calcification (black arrows) of the tentorium 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 earlier 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 meningioma (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 posterior ethmoidal region, surrounded
by T2 bright sinonasal 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 ethmoid air cells; it erodes the floor of the anterior cranial fossa (white arrowhead).
Biopsy revealed a rhabdomyosarcoma.
Figure 6-66 Early diagnosis of BCNS in a 3-year-old child. A. Axial T2-weighted image shows a heterogeneous, low signal intensity
medulloblastoma (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.
Patients with BCNS have an increased incidence of medulloblastoma, especially those who carry the SUFU mutation (Fig.
6-66); the overall frequency of medulloblastoma in patients with the syndrome is approximately 5%, whereas the frequency of
BCNS among patients with medulloblastoma is 1% to 2% (463,469,470). Indeed, symptoms related to medulloblastoma may
be initial presentation of the BCNS, particularly in patients with the SUFU mutation. BCNS patients with medulloblastoma
characteristically present during the first 2 years of life (465), in contrast to the usual presentation between ages of 5 and 9
years in the general population. Therefore, children who are diagnosed with medulloblastoma before the age of 4 years
should be carefully examined for other signs of the BCNS; in this situation, the presence of dural calcification, even small
areas (Fig. 6-66B), is highly indicative of the BCNS (471,472). At pathology, there is a preponderance of two histological
variants: medulloblastoma with extensive nodularity and desmoplastic medulloblastoma (473); although no analysis has been
published at the time this chapter was composed, these appear to be SHH group medulloblastomas, as SUFU is a downstream
component of the SHH pathway (474). The radiologic appearance of medulloblastoma in this group of patients does not differ
in any way from that of nonsyndromic patients (discussed in Chapter 7). It should be noted that because of the abnormality of a
tumor suppressor gene, it is best to avoid radiation therapy for medulloblastoma 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. 6-65) (471,472,475). Multiple
meningiomas and basal cell carcinomas in the radiation field are the most frequently reported radiation-induced neoplasms
(460). Basal cell carcinomas may be quite invasive and have a predilection for perineural spread. Therefore, contrast-
enhanced MR scans should be obtained and the cranial nerves should be particularly scrutinized in a search for
enhancement. Schwannomas, sarcomas, and osteochondromas have also been reported (475).
Other tumors of the central nervous system are much less common. Meningiomas (Fig. 6-65) appear to have an increased
incidence (465), and astrocytomas, craniopharyngiomas, and oligodendrogliomas have been reported in patients with the
syndrome (457). These tumors all appear to have a similar radiologic appearance and clinical behavior to those occurring in
the general population (see Chapter 7).
Neuroimaging Manifestations
Hemangiomas can be identified throughout the head and neck; intracranially, the cerebellopontine angle is a common location
(Figs. 6-67 and 6-68). Hemangiomas can be of various sizes and have either well-defined or infiltrative borders; they are
hypointense on T1-weighted images and T2 hyperintense and show intense enhancement. The most common vascular anomalies
include anomalous course or origin of the anterior cerebral arteries, persistence of the embryonic carotid-vertebrobasilar
arterial connections (persistent trigeminal artery is most common), absence or hypoplasia of the internal carotid artery (Fig. 6-
67), absence of the external carotid artery, and absence or hypoplasia of the vertebral, basilar, and posterior inferior cerebellar
arteries (489). Large, dysmorphic/dysplastic or hypoplastic vessels are frequently seen (Fig. 6-67C) (489), as are occlusive
vasculopathies that may result in the moyamoya syndrome (498). 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 unilateral or diffuse cerebellar hypoplasia (including the Dandy-Walker
malformation, see Chapter 5), and vermian hypoplasia (Fig. 6-68) (478). Several patients have been reported to have
polymicrogyria, periventricular nodular heterotopia, and intracranial hemangiomas The major importance of recognizing the
existence of this syndrome is to recognize that when PHACE syndrome is suspected, patients should have imaging studies
that evaluate both the brain (with particular attention to the posterior fossa) and the arterial vasculature of the aortic arch,
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 (476,489,499).
Figure 6-67 PHACE syndrome in a 4-month-old. A. Coronal contrast-enhanced fat-suppressed T1-weighted image reveals a large irregular
enhancing mass in the deep right facial soft tissues consistent with a hemangioma (black arrows). Additional enhancing masses are evident in
the right scalp (triple arrows), the superior right pinna (double arrows), and the right internal auditory canal (single white arrow) and also
consistent with hemangiomas. B. Coronal maximum intensity projection image from a 3D time-of-flight MR angiogram shows absent flow in
the expected distribution of the right internal carotid artery except for the very distal aspect (black arrow). A prominent left internal carotid artery
is evident (white arrows). C. AP view of a right subclavian arteriogram confirms absence of the right ICA; only branches of the right ECA are
opacified. The proximal right subclavian artery (arrows) is hypoplastic and dysplastic.
Figure 6-68 PHACE 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 interhemispheric fissure of the cerebellum (white arrowheads in B) is too prominent,
indicating hypoplasia of the vermis.
Chédiak-Higashi Syndrome
The Chédiak-Higashi syndrome is a rare, autosomal recessive syndrome characterized by variable degrees of oculocutaneous
albinism, recurrent pyogenic infections, a tendency for mild bleeding, and late neurologic dysfunction (506). Some patients
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 lymphadenopathy (507). The diagnosis is established by
examination of the blood, which demonstrates the presence of characteristic large peroxidase-positive panleukocytic granules,
and by identification of mutations of the CHS1 gene, located on chromosome 1q42-44 (508–511). Large, abnormal lysosome-
related organelles are identified in the melanosomes, which leads to the hypopigmentation.
Affected patients may come to attention because of recurrent infection, bleeding disorders, or neurologic signs and
symptoms (512). Alternatively, they 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
lymphadenopathy (507). The neurologic signs and symptoms generally reflect brainstem and cerebellar involvement and
include motor incoordination, horizontal nystagmus, intention tremor, and dysmetria. Seizures, peripheral neuropathies, and
mental retardation may also be present (513). Neuropathology shows perivascular cellular infiltrations by lymphocytes and
histiocytes in the leptomeninges; with more severe involvement, the cerebellum, brainstem, spinal cord, and peripheral nerves
are involved (508,514). Treatment is bone marrow transplantation, which is effective in treating the hematologic and immune
deficits (515).
Reports of neuroimaging studies in Chédiak-Higashi syndrome are few, reporting white matter lesions (delayed
myelination) and atrophy (516). In the accelerated phase of the syndrome, both supra- and infratentorial perivascular lesions
have been observed, with predominant involvement of the brainstem and cerebellum (508).
Overgrowth Syndromes
Overgrowth syndromes represent a group of conditions characterized by global, regional, or localized areas of excess growth
compared to an equivalent body part of age-related peer groups. Overgrowth syndromes with neurocutaneous manifestations
include neurofibromatosis type I (already discussed in this chapter), epidermal nevus syndrome (ENS),
encephalocraniocutaneous lipomatosis (ECCL), Proteus syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba (BRR)
syndrome.
The true incidence of ENS is unknown, but it is estimated that 8% to 18% of affected patients have systemic disorders
(529). Nevi involving the face or scalp are generally associated with cognitive deficits, mental retardation, and seizures (535).
Primary
Malformations of cortical development (hemimegalencephaly, polymicrogyria)
Gliomatosis
Hemiatrophy with and without parenchymal cysts
Vascular malformations
Intracranial/intraspinal lipomas
Secondary
Porencephaly
Infarctions
Atrophy
Figure 6-70 Periventricular white matter injury in epidermal nevus syndrome. Axial T1-weighted image shows multiple foci of T1
hyperintensity (open black arrows) in the periventricular white matter.
Encephalocraniocutaneous lipomatosis
Clinical Manifestations
Encephalocraniocutaneous lipomatosis (ECCL) (also known as Haberland syndrome) is a sporadic overgrowth
neurocutaneous syndrome characterized by the presence of cutaneous lesions (e.g., lipomas, connective tissue nevi, and
alopecia) along with ocular and CNS anomalies. The etiology of the disorder is unknown; some postulate an autosomal
mutation that survives only in a mosaic state (544). Dysgenesis of the cephalic neural crest and of the anterior neural tube is the
most widely accepted explanation of its pathogenesis (544). The two most common clinical markers of the disorder are ocular
choristomas (including epibulbar and limbal dermoids) and the nevus psiloliporus (a smooth, hairless fatty tissue of the scalp)
(545). Other skin lesions encountered include nonscarring alopecia, subcutaneous fatty masses, and aplastic scalp defects. Jaw
tumors, bone cysts and aortic coarctation are seen rarely. About two-thirds of patients develop normally or have mild
intellectual disabilities; the other third has severe intellectual dysfunction. Seizures are present in about half of patients. ECCL
has been considered as a localized form of Proteus syndrome but more recently has been postulated to be related to
oculoectodermal syndrome (545).
Neuroimaging Manifestations
Intracranial or spinal lipomas are the most common feature; these are often cryptic at first, with later progression leading to
neurologic manifestations (544). Intracranial lipomas are encountered in the majority of the patients; the cerebellopontine angle
is commonly affected (536,537). Spinal lipomas are found in most patients and can extend over long segments; spinal MRI is
recommended when ECCL is suspected, as progressive leptomeningeal lipomatosis has also been reported (546). Congenital
abnormalities of the meninges are also commonly seen, in particular arachnoid cysts (Fig. 6-71). Vascular dysplasias
(leptomeningeal angiomatosis (Fig. 6-71) and abnormal or excessive vessels) and ischemic lesions (atrophy, porencephaly,
hemispheric calcifications) can also develop (547–549). Therefore, the clinical and radiologic 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 that change over time (545).
Proteus Syndrome
Proteus syndrome is a complex hamartomatous disorder named after the Greek god Proteus, who could change his form at
will. It has multiple, diverse somatic manifestations that develop gradually during childhood and involve the skeletal system,
soft tissues, skin, and vascular systems (550). Cerebriform connective tissue nevi, abnormal asymmetric disproportionate
overgrowth, and hemihypertrophy are the typical clinical manifestations (551). This is another syndrome caused by mutations
involving components of the mTOR pathway (see Chapter 5), in this case a mosaic activating mutation of AKT1; the protein
product is an oncogene kinase involved in many processes including cell proliferation (552). Overgrowth of long bones,
macrodactyly, bony exostoses, and soft tissue tumors (hemangioma, lymphangioma, lipoma) are commonly found (Fig. 6-72);
skull manifestations include asymmetric macrocephaly (caused by focal calvarial thickening, hyperostosis, craniosynostosis)
(Fig. 6-72). Hemimegalencephaly, 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
(553,554).
Figure 6-71 Encephalocraniocutaneous lipomatosis in a 3-month-old. A. Coronal noncontrast 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 postcontrast T1-weighted image with fat suppression demonstrates abnormal thickening 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).
Figure 6-72 Proteus syndrome in a 12-year-old. A. Coronal CT image reveals marked enlargement of the left mandible (*); thickening and
fatty infiltration of the left hemitongue, submandibular, and cheek regions (short arrows); and hyperostosis of the left frontal bone (long arrow).
B. Coronal fat-suppressed T2 image demonstrates the thickened frontal bone (arrow), with enlarged left facial soft tissues and left mandible (*).
Cowden Syndrome
Cowden syndrome is an autosomal dominant multisystem disorder involving hamartomatous overgrowth of tissues of all three
embryonic origins—including mucocutaneous lesions (trichilemmomas, facial acral keratoses, papillomatous lesions),
hamartomas, macrocephaly—and an increased predisposition to cancers of the breast, thyroid, and endometrium. Seizures and
intellectual disabilities can be observed. Cowden syndrome is rarely diagnosed before adolescence. Approximately 30% to
35% of patients have an identifiable germ-line mutation of the PTEN (558). Within the CNS, the pathognomonic feature is the
presence of Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum, see Chapter 5) (559,560). Other
associations include macrocephaly, gray matter heterotopia, enlarged perivascular spaces with multifocal periventricular white
matter abnormalities (Fig. 6-73), and vascular abnormalities (venous and cavernous angiomas) (555,561).
Bannayan-Riley-Ruvalcaba Syndrome
Bannayan-Riley-Ruvalcaba (BRR) syndrome is an autosomal dominant syndrome associated with extreme macrocephaly and
subtle cutaneous features (including lipomas and hemangiomata). Mutations in the PTEN gene are found in approximately 55%
of patients (558). BRR syndrome is generally reported with a childhood onset, often with delayed motor and intellectual
development. The imaging findings include marked enlargement of the brain (megalencephaly); CSF signal white matter cysts,
located primarily in the parietal and frontal lobes; normal size ventricles; and extra-axial spaces (in keeping with
megalencephaly, given the marked macrocephaly) (562). BRR and Cowden syndrome likely represent age-related
manifestations of the same condition (562,563).
Figure 6-73 Three-year-old child with pronounced macrocephaly and Cowden syndrome. Axial T2-weighted FLAIR image at the atrial level
shows multifocal periventricular white matter abnormalities, with multiple rounded/linear hypointense foci consistent with enlarged perivascular
spaces.
Similar findings of enlarged perivascular spaces and multifocal periventricular white matter abnormalities have been
described in children with mutations in PTEN presenting with significant macrocephaly (on average >4 standard deviation
above the mean) and developmental delay with or without autism spectrum disorder as main symptoms (555).
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Intracranial, Orbital, and Neck Masses
Charles Raybaud, Zoltan Patay, and A. James Barkovich
Introduction
Incidence and Severity of Brain Tumors in Children
Changing Concepts on the Biology of Brain Tumors
Clinical Features of Brain Tumors
Ventricular Tumors
Subependymal Giant Cell Astrocytoma
Choroid Plexus Tumors
Extra-Axial Tumors
Pediatric CNS Tumors in Specific Contexts
Brain Tumors in the First Year of Life
Radiation-Induced Tumors of the Central Nervous System
Introduction
Table 7-1 Histological Types of Tumors Involving the CNS at Hospital for Sick Children (3)
Astrocytoma 39.4
Low grade (WHO I–II) 32.3
High grade (WHO III–IV) 7.1
Embryonal 15.4
Medulloblastoma 10.6
PNET 3.9
ATRT 0.9
Ependymoma 7.0
Classic (WHO II) 4.9
Anaplastic (WHO III) 1.7
Myxopapillary (WHO I) 0.3
Craniopharyngioma 6.8
Pineal 0.5
Pituitary 1.0
Mesodermal 9.7
Nonmeningothelial 5.0
Meningioma 1.7
Langerhans cell histiocytosis 3.0
Radiculoneural 3.1
Schwannoma 1.8
Neurofibroma 1.3
Miscellaneous: subependymoma, ganglioneuroma, hemangiopericytoma, hemangioblastoma, primary CNS lymphoma, primary CNS melanoma, etc.
The risk of untimely death is highest in survivors of embryonal tumors. In addition, neurological, neurocognitive, and
endocrine functions are commonly altered in those who have received surgery, radiotherapy, and chemotherapy, especially in
the survivors of embryonal tumors (8,9).
When a CT scan is performed, the most important images are precontrast images, which show whether the tumor has a high
attenuation (meaning high cellularity) or a low attenuation. Precontrast images also show if the lesion contains blood and
calcification, which is helpful for differentiating sellar/suprasellar tumors. Multiplanar reformats are useful; but even though
modern CTs provide much better definition and fewer artifacts than do older scanners, the anatomic resolution is still inferior
to that of MRI. Iodinated contrast media are usually administered, but this is not crucial if MR imaging is to be performed
shortly afterward or if CT imaging is done shortly after the MRI examination. The recommended contrast dose in these patients
is 3 mL/kg of contrast (concentration, 270–300 mg I/mL), up to a maximum dose of 120 mL. Contrast is usually given in a
single bolus immediately before the scan.
Imaging Characteristics Used to Identify Brain Tumors
Imaging evaluation of brain tumors must proceed by steps. In successive order, a lesion must be recognized and then
recognized to be a mass, precisely located, and identified as a tumor. Location, together with robust conventional and advanced
MRI features (including vascularity, vascular permeability, cellular density, and metabolic profile), often helps to recognize the
neoplastic nature of the lesion and suggest the tumor type, which is basic to the development of subsequent management
strategies. High-quality multiplanar and multiparametric imaging is also needed to (a) determine how much the tumor is
demarcated from, infiltrates, or invades the surrounding tissue; (b) evaluate the mass effect locally and globally; and (c)
consider possible surgical approach options. Later, imaging is used to appreciate the effects (and side effects) of therapy,
typically as part of a protocol.
Detecting a mass lesion is usually not a problem with modern imaging, especially with MR. Masses are typically
recognized on CT on the basis of density or MR as signal intensity differences from normal brain; other features include mass
effect causing distortion of normal brain structures and abnormal enhancement after the intravenous administration of contrast.
(In the normal central nervous system, contrast enhancement is only seen in the pituitary gland, pituitary stalk, tuber cinereum of
the hypothalamus, pineal gland, vessels, and the choroid plexuses.) Almost all brain tumors are either hypo- 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 matter on T2-weighted or FLAIR 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 will be discussed more thoroughly later in this
chapter. All tumors exhibit mass effect. In relatively slow-growing, peripherally located tumors, the mass effect results in
expansion or erosion of the cranial vault. In more rapidly growing, more centrally located tumors, growth of the mass displaces
neighboring structures, including those located in the midline, causing “midline shift” and, sometimes, herniation of brain tissue
through or around rigid structures, such as the falx cerebri, tentorium cerebelli, or foramen magnum. Supratentorial masses
typically cause herniation medially under the falx cerebri or downward through the tentorial incisura, whereas infratentorial
masses cause upward transtentorial herniation and downward herniation through the foramen magnum. Transtentorial herniation
classically results in pressure on the midbrain and the cisternal segments of oculomotor nerves, with secondary effects on eye
movement and pupillary constriction (the “blown pupil”). Transtentorial herniation may also result in stretching and
compression of the posterior cerebral arteries against the tentorium, and consequent unilateral or bilateral infarction of the
posterior cerebral artery distribution, resulting in sudden cortical blindness. Herniation of the cerebellar tonsils through the
foramen magnum can occur with supra- or infratentorial masses; tonsillar herniation, which is easily detected by MR, can lead
to respiratory compromise.
If a mass is identified, it must be determined whether the lesion arises from brain parenchyma or from extraparenchymal
structures, such as bony skull/skull base, meninges, or the subarachnoid space. Extraparenchymal lesions typically displace,
rather than invade, normal brain structures (Fig. 7-2): the cortex is displaced medially by the mass, and the brain is displaced
away from bone or dura, which may result in an enlarged cistern. Intraparenchymal masses tend to compress cisterns and
efface sulci. A well-defined margin separates the extraparenchymal mass from the brain; usually, little or no edema surrounds
the mass. Intraparenchymal masses often merge imperceptibly into the normal surrounding brain (Fig. 7-3) and may generate
considerable edema. Other characteristics that are suggestive of an extraparenchymal origin are a relative paucity of mass
effect for the size of the lesion, extension of the mass across the midline without involving a cerebral commissure, involvement
of bone, and relatively mild presenting symptoms. However, differentiating intra- from extraparenchymal masses is not always
easy. Intraparenchymal masses may be exophytic, thereby enlarging the adjacent cistern, whereas extraparenchymal masses
may invade the brain or compress vascular structures and elicit edema. Intraparenchymal masses may grow slowly and
generate 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 extraparenchymal 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 ΔR2* curve, which will show a return of relaxivity toward baseline level after the
passage of the bolus in an intraparenchymal tumor (Fig. 7-3B) but persistence of abnormal relaxivity in an extraparenchymal
tumor (Fig. 7-2B).
A detailed anatomical analysis is central to the diagnosis of brain tumor because it defines the resectability (e.g.,
cerebellar vs. hypothalamic PA), allows the neurosurgeon to choose the optimal approach, and may be a major indicator of the
nature of a tumor (e.g., ventral diffuse intrinsic pontine glioma vs. dorsal tegmental pontine or medullary PA). T1 imaging,
especially high-definition 3D-T1; T2 or FLAIR imaging or thin (2–3 mm) section 2D imaging in different planes; and
submillimetric T2 CISS/FIESTA imaging, if needed, all provide the precise location of the tumor (Table 7-2).
The structural characteristics (“texture”) of the tumor include the cellularity; the presence of cysts, necrosis, blood, or
calcification; and the vascularity (including tumor-induced angiogenesis) and vascular permeability (blood–tumor barrier).
Obviously, any abnormality of signal or metabolic profile, for example, should be evaluated in the context of age and
degree of brain maturation. These characteristics alone often permit the fairly confident identification of the tumor type; when
they do not, they still point toward its benign or malignant nature. Although CT cannot replace MR in this regard, it may be
helpful. Low attenuation will indicate high water content (e.g., low-grade glioma, tumor edema, or necrosis), whereas high
attenuation (close to that of gray matter) points to high cellularity (e.g., embryonal tumors). Avid enhancement indicates high
vascularity and vascular permeability. Cystic components, hemorrhage, and calcifications are also easily recognized, as are
surrounding edema and hydrocephalus. MR, however, is more sensitive and specific: by demonstrating reduced free
movements of water on both b1000 (“trace”) and ADC mapping images, DWI has become essential in the evaluation of brain
tumors because it clearly differentiates lesions with high cellularity and high nucleocytoplasmic ratio (“little blue cells”), such
as embryonal tumors (medulloblastoma, pineoblastoma, ependymoblastoma, retinoblastoma (RB), and atypical
teratoid/rhabdoid tumors [ATRTs]) and germinomas, from other tumors types, which possess large extracellular spaces instead.
Uncommonly, reduced diffusion may relate to an area of recent tissue infarction (24) or hemorrhage. Sometimes, in a tumor
with typically high diffusivity, such as an astrocytoma WHO grade I or II, an area of reduced diffusion makes one suspect a
focus of anaplasia, and hence, malignant transformation (24–26).
Figure 7-2 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.
Figure 7-3 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.
Table 7-2 Main Tumor Types per Location
Posterior fossa
Third ventricle
Hemispheres
BG, basal ganglia; Cranio, craniopharyngioma; CM, cistern magna; CPA, cerebellopontine angle; CPC, choroid plexus carcinoma; CPP, choroid plexus
papilloma; DIPG, diffuse intrinsic pontine glioma; DNET, dysembryoplastic neuroepithelial tumor; EP, ependymoma; GCT, germ cell tumor; GGG,
ganglioglioma; GM, gray matter; HGG, high-grade glioma; MB, medulloblastoma; PA, pilocytic astrocytoma; PB, pineoblastoma; PXA, pleomorphic
xanthoastrocytoma; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex; WM, white matter.
Tumoral cysts typically have content that appears different from CSF in the various MR sequences and on CT and MR;
contrast layering may occasionally be observed after intravenous contrast administration. Necrosis appears as loculations of
rather heterogeneous areas (sometimes harboring blood degradation products, best shown by SWI) with some peripheral signal
enhancement in postcontrast T1-weighted images; such an appearance usually reflects malignancy although it may be observed
in large nonmalignant tumors. Recent blood or blood residue within nonnecrotic tumor tissue or overt intratumoral bleeding
also suggest aggressiveness and hence, a higher grade of tumor. Vasogenic edema is well depicted in the surrounding white
matter on T2 images. In infiltrative tumors, it is rarely possible to safely differentiate vasogenic edema from tumor by using T2
signal. Because FLAIR imaging reflects the bound water only, it may be more reliably used to evaluate the real extent of tumor,
but even in a purely vasogenic edema, water may be bound to the molecules of the extracellular matrix.
Using DTI instead of or in addition to DWI allows the diffusion parameters to be further quantified, and the integrity of the
white matter tracts may be assessed with FA mapping or DTI tractography (24). Again, however, severe vasogenic edema,
tumor infiltration of the interaxonal spaces, or tumor necrosis may cause the directionality parameter of the water diffusion to
be lost. However, as noninfiltrative tumors displace the fascicles without invading them (27), and as inflammatory
demyelinating lesions may splay but maintain the fascicular pattern, DTI tractography is often helpful for the differential
diagnosis of brain parenchymal masses. In addition, together with fMRI, DTI tractography is important in the planning of
surgery to locate the eloquent cortex and the eloquent axonal bundles in the surgical field, and it may be included in the
neuronavigational data.
The vascularity of the tumor tissue and the leakiness of newly formed “angioneogenetic” tumor vessels are typically
evaluated with the intravenous administration of iodinated or gadolinium-based contrast media. Enhancement of the lesion
characteristically results from a combination of high vascularity and egress of contrast across the walls of abnormal vessels
into the stroma of the tumor (permeability). This enhancement may be diffuse, partial in a patchy manner, or ring-like, and it
may be intense or weak. Histologically, identical tumors may enhance differently in different patients and may differ in the
same patient on different studies too. Common in children, the PA is perfectly benign, its vascular bed is poor and yet very
leaky resulting in very significant enhancement. In a series of 140 patients, the enhancement pattern of PAs in any given patient
was found to vary on follow-up studies in the absence of any treatment, even in the absence of morphologic changes of the
tumor (28); indeed, confident diagnosis PAs (or of any tumor) is based upon knowing the broad spectrum of imaging
characteristics on conventional and advanced MR imaging (29).
As mentioned earlier, perfusion studies (DSC or ASL) can provide a quantification of the perfusion metrics (cerebral blood
volume, CBV; transit time, TT; cerebral blood flow, CBF) and thus inform about the tumor type and grade (Figs. 7-2 to 7-5)
(24), as the blood flow is always higher in malignant than in low-grade tumors. These studies may help to reveal high-grade
foci in an infiltrative tumor, directing the surgeon during biopsy or the radiation oncologist while planning irradiation. CBV is
also higher in a recurrent malignant tumor than in radionecrosis (which may mimic each other in conventional images).
Perfusion techniques may also assist in ruling out nonneoplastic tumor-like lesions (24). Given the role of angiogenesis in
tumor development and the fact that new therapeutic agents target vascular proliferation, some have proposed using perfusion
imaging as an indicator of treatment efficacy (30,31). Most reported studies, however, include gliomas only (31) and adult
rather than pediatric brain tumors (24,32).
In addition to perfusion, a morphologic evaluation of large arterial trunks is important when a tumor is prone to adhere to or
encase adjacent arteries; this is common in cases of posterior fossa ependymomas and in sellar or suprasellar lesions
surrounded by the distal internal carotid arteries, basilar artery, and components of the circle of Willis. For some tumors
originating from or invading the central skull base, evaluating the cavernous sinuses is also important to predict whether a
tumor may be completely removed or not and assist in the differential between infiltrative (e.g., invasive prolactinoma) and
noninfiltrative (e.g., craniopharyngioma) sellar tumors.
Proton MR spectroscopy has proved to be a useful marker of tumor types and of their aggressiveness in children (Table 7-
3). The combined use of MRI and MRS improves overall pretherapeutic diagnostic accuracy of pediatric brain tumors over
that of MRI alone (33). Several studies have demonstrated that, in neoplastic processes in general, NAA
(neuronal/oligodendrocytic marker) is decreased; Cho (membrane turnover, cellularity) is increased, and Cr remains stable
except in cases of profound energy failure (tumor necrosis). Lac and Lip are commonly increased in malignant tumors, too
(34,35). In addition, specific tumors may have suggestive metabolic markers or metabolic patterns on MR spectra: elevated
Taurine (Tau, 3.36 ppm) and Cr in medulloblastoma, high Lac in PA, and high myo-inositol (mI, 3.54 ppm on short TE MRS) in
choroid plexus papilloma (CPP) (35). Citrate has been demonstrated directly in a subset of pediatric grade II astrocytomas
destined for aggressive behavior (36). Additionally, 2-hydroxyglutarate has been demonstrated in adult-type IDH1 mutant
tumors by using proton MRS (37). Increased Cho/NAA ratio suggests a high tumor grade, and effective therapy usually
decreases the Cho peak and the Cho/NAA ratio, while Lac may increase. Tumor recurrence is expressed by increasing Cho and
the Cho/NAA ratio (Figs. 7-4 and 7-5) (35). Especially with infiltrative, nondiscrete cerebral tumors, advanced, quantitative
MR techniques may allow a more accurate assessment of response to therapy than size measurements (2D, 3D, or even
volumetric).
The differential diagnosis of a brain tumor is broad, as an area with abnormal signal or attenuation, some mass effect, and
enhancement may not necessarily be a tumor. A combination of structural and topographic criteria is used with the clinical data
(age at onset and evolution of symptoms) in the evaluation. In the floor of the third ventricle, hypothalamic hamartomas (HHs)
are developmental masses of hypothalamic gray matter typically associated with refractory epilepsy (gelastic seizures are
characteristic) and/or precocious puberty. They are easy to recognize because they do not grow, present the same attenuation on
CT and similar intensities on MR sequences as does the gray matter (sometimes slightly brighter on T2/FLAIR), and do not
enhance (see the specific description in the section on suprasellar tumors). Distinguishing other developmental, dysplastic
lesions, such as the gray matter heterotopia or the focal cortical dysplasia (both discussed in Chapter 5), has become less of a
problem nowadays because of modern, high-resolution imaging. Although not truly neoplastic, dysembryoplastic lesions, such
as a dermoid or epidermoid cyst, are included among the tumors and will be 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 MR
demonstrates that many cases previously diagnosed as aqueductal stenosis are due to dormant tectal masses or midbrain
tegmental masses, the nature of which are typically unclear; their diagnosis is discussed in Chapter 8 and later in this chapter.
Table 7-3 Main MRS Markers of Brain Tumors
CPP, choroid plexus papilloma; MB, medulloblastoma; PA, pilocytic astrocytoma; LGA, low-grade astrocytoma; A, astrocytoma.
Figure 7-4 Low-grade intraparenchymal glial tumor. A. Axial postcontrast T1-weighted image shows a homogeneous, sharply marginated,
nonenhancing mass (T) deep in the left cerebral hemisphere. B. Proton MR spectra (TE = 288 ms) in a two-dimensional array show that the
spectra within the mass have low NAA and creatine but only slightly elevated choline compared 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 PAs).
Sometimes, however, ascertaining the diagnosis of a tumor may be more intricate. Abscesses typically develop in the
context of infection (see dedicated paragraph in Chapter 11). Although they may appear morphologically similar to malignant
necrotic tumors, the enhancing rim typically is thin and regular, and the central pus cavity demonstrates strongly restricted
diffusion (Fig. 7-6): in contrast, the peripheral enhancing rim of necrotic malignant tumors is thick and irregular, and the
cystic/necrotic components generally show increased diffusion due to necrosis (38). The reduction of water motion may be
less apparent with small abscesses, possibly secondary to averaging of diffusion information from normal surrounding brain
tissue (39). Proton MR spectroscopy can also be a useful adjunct in differentiating a tumor from an abscess because the
elevated choline peak that is characteristic of most tumors is not present in abscesses; use of MRSI can be particularly helpful
in the differentiation of necrotic tumor from smaller abscesses (40,41). Aliphatic peaks of amino acids—alanine (at 1.5 ppm),
acetate (at 1.9 ppm), succinate (at 2.4 ppm), leucine, isoleucine, and valine (at 0.9 ppm) (42,43)—are seen instead (see
Chapter 11). A lactate peak is also seen in most pyogenic abscesses (40,41), but lactate is also commonly seen in tumors;
therefore, it 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 (PRESS) sequences using an echo time of 135 ms
(42). Other types of infections, such as cerebritis, are more difficult to differentiate from tumors, as they have variable
anatomic, metabolic, diffusion, and perfusion characteristics that reflect the type and acuity of the infection (44,45). Infections
are further discussed in Chapter 11.
Figure 7-5 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 ms) 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. E. Single-voxel proton MR spectrum (TE = 288
ms) from the center of a different PA 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 PAs have blood volume characteristics similar to
those of high-grade tumors. Such studies should never be interpreted without imaging correlation.
Large, mass-like (“tumefactive” or “pseudotumoral”), monofocal inflammatory lesions (see Chapter 3) may be present in
acute episodes of demyelination, such as in idiopathic inflammatory white matter diseases, including multiple sclerosis (MS),
or acute demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM). The clinical context, the modest
mass effect, the lack of complete ring enhancement, and a careful search of other associated lesions in the brain and spinal
cord, along with MR spectroscopy or advanced imaging such as DTI may help; otherwise, the evolution and the response to
anti-inflammatory treatment give a final answer (see discussion in Chapter 3). The presence of deep medullary veins running
radially through the lesion is suggestive of an MS plaque (Fig. 7-7). These tumefactive demyelinating lesions are uncommon,
but they have been reported for a long time in children and adults (46). Long echo MR spectroscopy is not useful in this
differentiation, as some demyelinating plaque masses may have a large choline peak (Fig. 7-7) and increased lactate and lipid
due to the inflammatory infiltrates that accompany them in the acute phase (47,48). Short echo proton spectroscopy may show
increased glutamate and glutamine in demyelinating plaques (49). Dynamic susceptibility-weighted perfusion imaging may
allow differentiation of these lesions, as demyelinating lesions have low cerebral blood volume 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 (50). DTI might help, as patients with tumefactive plaque would have corticospinal fibers that would be
few and truncated but in normal position; yet, patients with tumors would show dislocation and/or dispersion of those fibers
(51).
Figure 7-6 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 post contrast shows ring enhancement of the nodule; the
enhancement extends anteriorly along the falx (arrows) to the vicinity of the foramen cecum. Findings suspicious for nasal dermal tract were
also observed; surgery confirmed both the dermal fistula and the abscess.
Figure 7-7 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 ms) shows
a large choline peak (Ch) and a lactate peak (Lac, inverted at TE = 144 ms), 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.
Infarctions (see Chapter 4) are most easily distinguished from tumors by clinical presentation: infarcts are characterized by
an abrupt onset, and tumors by a slowly progressive or stuttering course. However, in young infants or in older children with
infarcts that occur in regions that do not cause obvious and immediate clinical deficits, the history is less useful. On imaging,
infarcts are distinguished by their location (in a vascular territorial 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
primarily cortical and may have an imaging appearance that is suggestive of acute infarction. DNETs in children presenting
with seizures and evaluated in the ER are commonly misdiagnosed as acute infarcts. DWI is the most useful technique if the
infarct is recent (first week) because it shows significantly reduced diffusion in an arterial supply territory, which would be
unusual for tumors. If differentiation is problematic, then a follow-up study should be obtained before a biopsy. If the
abnormality is an infarction, then ADC will “pseudonormalize” by the end of the first week and increase thereafter, while
cortical enhancement develops; mass effect progressively diminishes. DSC perfusion MRI can also be of use in differentiating
tumor from infarct because tumors are typically hypervascular (increased CBV), in contrast to hypovascularity (decreased
CBV) in acute infarcts. On proton MRS, if Lac is present at the acute/subacute phase, then the Cho peak, which is
characteristically increased in most tumors, is reduced or absent in infarctions.
Differentiation of tumors from vascular malformations, such as cavernous angiomas (see Chapter 12), is usually not a
problem because of the characteristic “target” or “popcorn” appearance of cavernomas on T2 and the “blooming” appearance
of the blood products on SWI (refer to Chapter 12). However, elucidating the cause of an apparently isolated spontaneous
intraparenchymal hemorrhage in a child may be challenging: if no arteriovenous malformation is demonstrated (tortuous,
serpiginous signal voids corresponding to arterial feeders and draining veins) and if the characteristic appearance of a
cavernous angioma is obscured by the abundance of fresh blood, then a hemorrhagic tumor—typically a highly malignant one—
may be difficult to rule out with the necessary degree of confidence. Careful examination of the adjacent parenchyma (edema in
the very early phase after the development of the bleeding is suggestive of an underlying tumor) and even faint enhancement
may reveal the tumoral origin of the hemorrhage.
Finally, although uncommon, differentiation of radionecrosis from recurrent tumor may be a real challenge in patients with
treated brain tumors; perfusion imaging may help by demonstrating that the perfusion is reduced in the radiation necrosis, and it
is expected to be increased in a residual/recurrent tumor (see the more detailed discussion in chapter 3). Nuclear medicine
techniques, particularly positron emission tomography using various tracers (18F-deoxyglucose, 11C-methionine), may also be
helpful because necrosis is characterized by decreased or absent uptake, whereas tumor tissue shows increased metabolic
activity and hence increased tracer uptake. Unfortunately, radiation-induced necrotic changes often coincide with
residual/recurrent tumors, particularly in high-grade gliomas.
Pretherapeutic assessment is the next mandatory step, and it is the role of imaging to provide many of the key elements to
help with the pretherapeutic management discussion. Therapeutic options are basically surgical removal (as complete as
possible without inducing new neurological or neurocognitive deficit), radiotherapy (except in the first years of life), and
chemotherapy. Typically, children with brain tumors are included in therapeutic protocols that have specific imaging
requirements before, during, and after completion of the treatment. The first feature to look for is whether the tumor is well
demarcated from the surrounding structures or not: this is the main criterion for complete resectability. A poorly demarcated
tumor is often infiltrative or invasive. Infiltration, the ability of a tumor to insinuate along anatomic structures, does not relate
to the tumor grade: an anterior optic pathway glioma, although fully benign, may infiltrate the hypothalamus or the basal
ganglia. Infiltration is not always apparent, and additional techniques, such as perfusion imaging, MR spectroscopy, or DTI,
may help in differentiating peritumoral edema from tumor infiltration; most of the studies, however, have been done in adults,
who present with tumor types different from those in children. Also, the current understanding of the biology of the brain
tumors suggests that the original BTSC may be in the SVZ, away from the bulk of the tumor. Furthermore, histopathological
studies suggest that tumors cells may be found in “normal-appearing” brain parenchyma, quite remotely from the visible tumor
site. In contradistinction with infiltration, invasion, the ability of a tumor to cross normal anatomic barriers, is a property of
malignant tissue only. For example, a PA of the pineal region will compress but not invade the adjacent callosal splenium, yet a
pineoblastoma will invade it easily. A unique way of certain brain cancers to disseminate is along the CSF spaces, forming so-
called drop metastases (medulloblastoma or germinomas mostly, but also some of the low- or lower-grade tumors, such as
pilomyxoid astrocytomas [PMAs] and ependymomas); on the contrary, metastases outside the theca have historically been
considered to be rare. However, systemic metastases (e.g., in lungs, bone, lymph nodes, liver) of high-grade tumors (e.g.,
medulloblastoma) are increasingly found, especially in highly aggressive tumor types and during later stages of the disease
(52–54). In addition to invasiveness, three common features of malignancy are surrounding vasogenic edema, necrosis, and
hemorrhage. Unlike in adults, enhancement of a brain tumor in children is not evidence of malignancy.
If the decision to remove the tumor is made, then presurgical assessment typically associates the acquisition of sequences
consistent with neuronavigation surgical tools (typically axial, enhanced 3D-GE T1 sequence such as MPRAGE/SPGR/TFE).
The so-called eloquent cortical areas, such as the sensorimotor area, or the major neurocognitive functions, such as language or
memory, may be located anatomically or functionally by using fMRI with task-specific cortical activation algorithms (Fig. 7-
8A and B) (55). Similarly, eloquent white matter tracts such as the corticospinal tracts or the optic radiations (especially the
Meyer loop along the medial temporal lobe) may be identified by using DTI (Fig. 7-8A and C) (56). DTI may also show
whether the fibers are dislocated by the tumor, infiltrated, or disrupted (Fig. 7-8C) (27,57–59).
In general, arteriography is not used for presurgical evaluation of neoplasms unless a highly vascular lesion is suspected
based on the presence of prominent vascular flow voids on MR or in the unlikely event that a vascular malformation cannot be
ruled out by noninvasive studies. For example, in the case of a suspected hemangioblastoma, 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 large tumors. However, because large tumors sometimes parasitize blood vessels,
arteriography can be misleading, demonstrating dural vessels supplying intra-axial lesions or intracerebral vessels feeding
extra-axial tumors.
Figure 7-8 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 PA 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.
Posttherapeutic follow-up neuroimaging is expected to demonstrate the degree of efficacy of treatment and uses
standardized, often multicentrically agreed-upon protocols. Typically, an early MR is requested shortly after surgery (ideally
within 24 hours) before the postsurgical repair processes make the analysis of the images more complex. It must include pre-
and postcontrast sequences so the extent of the resection (total, subtotal, partial) and the volume of residual tumor, if any, can
be appreciated. Early MRs must also show postsurgical complications such as a significant ischemia or hemorrhage in the
surgical field (DWI/ADC and GRE–SWI are mandatory), brain swelling, and ventricular size. Spinal studies may be difficult
to interpret for metastatic tumor spread in the early postsurgical period if droplets of blood clot or surgical debris are present
within the thecal sac or if subdural fluid collections develop (60). Later studies are usually scheduled according to therapeutic
protocols adapted to the histologic/biologic nature of the tumor, the modalities of application of the radio- and chemotherapy,
and the nature and combination of drugs administered. Follow-up studies are intended to evaluate the response to treatment of
the tumor (or the tumor residuum, if surgery resulted in subtotal resection) and/or for early detection of local (growing residual
tumor) or distant (in the form or CSF seeding) recurrence of the neoplastic process. MR is again preferred to CT, and the MR
assessment typically uses conventional imaging pre- and postcontrast, complemented with spinal imaging whenever a
possibility of metastatic dissemination exists. Brain tumors often have complex morphologies, especially after an incomplete
removal; rather than the residual volume, the three longest orthogonal diameters are commonly used for comparison from one
study to the next. Postcontrast T1 images may be used to evaluate the extent of the residual tumor (if the tumor is enhancing);
DWI may be used for the same purpose if the original tumor demonstrates a low (reduced) diffusivity. Enhancement of the
meninges and of the walls of the surgical cavity is almost always seen on contrast-enhanced postoperative MR studies. 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 (61,62). Nodular leptomeningeal enhancement is more ominous, and enhancement of the
pia or arachnoid should raise suspicion for subarachnoid tumor spread. Generally, postcontrast T2 FLAIR sequences are the
most sensitive in detecting leptomeningeal metastatic disease, both the so-called sugarcoating type and the nodular type, but it
is nonspecific, and other processes, especially infections, may present with similar appearance. Beside the diagnosis of
persistence, recurrence, or dissemination, conventional or advanced MR imaging may also detect unexpected or unwanted
early or delayed side effects of therapy, such as radiation necrosis (44,63), leukoencephalopathy, steno-occlusive vascular
disease, atrophy, vascular malformations such as telangiectasias and cavernous angiomas, and late secondary tumors (intra-
axial parenchymal brain tumors, meningiomas, or even bony tumors) (64,65).
Intraparenchymal tumors
Hemangioblastoma (uncommon) Cystic tumor with intensely enhancing vascular mural nodule
Internal heterogeneity
Ventral to brainstem
LGG, low-grade glioma; HGG, high-grade glioma; GM, gray matter; CSF, cerebrospinal fluid; JPA, juvenile pilocytic astrocytoma; ATRT, atypical teratoid–
rhabdoid tumor.
Histologies Classic (common), LC/A (very Classic, LC/A, D/N, MB-EN Classic, Classic, LC/A Classic, LC/A
rare) LC/A, D/N (rare)
(very rare)
Prognosis Classic: low risk (up to 90% OS) Classic: standard risk Typically Classic: Classic:
DN, MB-EN: low risk high-risk standard risk standard risk
LC/A: high risk
Frequent CTNNB1 mutation (→WNT PTCH1 mutation (→SHH pathway activation), TP53 PVT1-MYC, KDM6A,
genetic pathway activation), DDX3X SMO mutation (adults), SUFU mutation (infants), mutation GFI1/GFI1B GFI1/GFI1B
alterations mutation, TP53 mutation TERT promoter mutation structural structural
variants variants
V4, fourth ventricle; FoL, foramen of Luschka; CPA, cerebellopontine angle; CM, cisterna magna; LC/A, large cell/anaplastic; D/N, desmoplastic/nodular;
MB-EN, medulloblastoma with extensive nodularity.
The duration of symptoms in patients with medulloblastoma is usually short: approximately half of these patients will have
symptoms for less than 1 month prior to diagnosis. The most common symptoms are headaches, 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 old, increasing head size and
lethargy are frequent presenting symptoms. In older children and adults, ataxia is the symptom that usually initiates medical
attention. Rarely, and predominantly in patients with group 3 or group 4 medulloblastomas of higher metastatic potential,
paraparesis or symptoms referable to the cauda equina will result from tumor dissemination and compression of the intraspinal
neural structures by nodular metastases (74,81,82). Intrathecal metastases are present at initial diagnosis in approximately 30%
of patients (again, most commonly group 3 or group 4) and are a poor prognostic sign (83,84). Indeed, extent of disease at
diagnosis is the feature most predictive of prognosis in affected children (85).
Pathology
Approximately two-thirds of all childhood medulloblastomas are located in the midline and appear to be intraventricular; these
belong mainly to groups 3 and 4. Group 1 tumors (WNT activated) are most commonly found in the fourth ventricle (~40%),
but may be centered on the foramen of Luschka (~30%), located in the cerebellopontine angle cistern (~20%), or situated in the
cisterna magna (~10%). Group 2 tumors (SHH activated) are most commonly hemispheric (~75%); a few may originate from
the vermis. Rarely, SHH tumors appear to be midline intraventricular (<10%). Medulloblastomas of all groups usually form a
well-defined mass. If located in the fourth ventricle, the tumor may partially or completely obstruct CSF flow. Larger,
primarily midline, intraventricular tumors may project into the cisterna magna through the foramen of Magendie and rarely
extend further down to the level of the upper cervical spinal canal through the foramen magnum (74,75). Invasion of the
brainstem is seen in approximately one-third of patients (86).
Invasion of the leptomeninges via dissemination along CSF pathways is frequent in group 3 and group 4 but uncommon in
the WNT and the SHH subgroups (69). Intracranial subarachnoid tumor spread may be seen within the sylvian fissure and
cisterns of the posterior fossa and internal auditory canals, along with retrograde spread through the aqueduct into the lateral
and third ventricles. The infundibular recess of the third ventricle is a common location for intraventricular metastases,
especially in tumors with the LC/A histopathological phenotype (87). From any of these sites, tumor may reinvade the brain
parenchyma. Drop metastases to the intraspinal subarachnoid space are seen in approximately 40% of patients, most commonly
at the thoracic and lumbosacral levels (88–91). Rarely, “intramedullary” spinal metastases have been reported, but those are
likely primarily leptomeningeal metastases that may appear to be “intramedullary” due to aggressive invasion of the cord
parenchyma. Systemic metastases are rare and most commonly develop after tumor resection or recurrence. The skeleton is the
most common site of involvement, followed by lymph nodes and lung (88). Certain features (e.g., LC/A histopathology, MYC
amplification) may lead to early systemic metastatic dissemination in embryonal tumors (52).
It is increasingly recognized that “histology alone is inadequate for the diagnosis and classification of medulloblastoma”
(69); hence, the WHO histological classification of medulloblastoma (66,92) has lost some of its significance, as the molecular
classification better correlates with the well-documented clinical heterogeneity of the disease (e.g., clinical presentations, cure
rates). Furthermore, because similar histological types (classic, desmoplastic nodular, large cell) are seen in all of the
molecular groups (other than desmoplastic medulloblastoma, which is seen exclusively in the SHH subgroup (69)),
histopathological and molecular data are used in conjunction with other biological and prognostic qualifiers (TP53 mutation,
MYC amplification, chromosomal copy number variations, etc.) as well as with clinical data (degree of surgical resection, M
status) in risk stratification prior to or during treatment (93,94).
Histologically, more than half of medulloblastomas are of the classic type, composed entirely of completely undifferentiated
cell. The SHH subtype shows a bimodal age distribution: some are detected in infants and others in older children,
adolescents, and young adults (4). SHH-activated medulloblastoma, when associated with TP53 mutation, occurs in patients
aged 4 to 17 years, with a separate study showing the mean age of such patients to be 15 years (95). The desmoplastic
histopathological phenotype has a more benign course than the classic type does. Medulloblastomas with extensive nodularity
are also predominantly of the SHH subtype (69). They are located in the cerebellar hemispheres of patients younger than 3
years; their prognosis appears favorable (68–70,96). Group 3 and group 4 medulloblastomas are most often of classic or
large-cell histology and have the poorest prognosis (68–70,96).
Imaging studies
On CT, a typical medulloblastoma classically appears as a well-defined, hyperdense tumor of the cerebellar vermis (Fig. 7-
9A) or vermis and hemisphere. The spontaneous (i.e., without intravenous contrast administration) hyperdensity of these
tumors (and other embryonal tumors) is a result of their composition of small, round cells with a high nuclear-to-cytoplasmic
ratio and is an important clue in the differential diagnosis of common posterior fossa tumors in children. Isolated involvement
of the hemisphere is much less common and is suggestive of the desmoplastic variant in adolescents (78,79,97) and the
extensive nodularity variant in infants (98,99); these laterally situated tumors may be exophytic and mimic tumors of the
cerebellopontine angle (100). The lesion usually appears to be well demarcated from the surrounding parenchyma. Mild to
moderate edema surrounds the tumor in approximately 90% of patients. Hydrocephalus is present in approximately 75% 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 medulloblastomas—most commonly diffuse, but sometimes irregular—but may be absent (101,102).
Figure 7-9 Typical medulloblastoma. A. Noncontrast CT image shows a well-demarcated, rather homogeneous 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 medulloblastomas, including calcification in up to 20% and cystic
or necrotic, nonenhancing regions in close to 50% (102,103). The presence of intratumoral hemorrhage is uncommon but not
exceptional, which may be confusing at the initial diagnostic imaging evaluation. Although the presence of cystic, nonenhancing
regions within the tumor may sway the neuroradiologist toward the diagnosis of PA, the solid portions of PAs are usually
hypodense prior to the administration of IV contrast. Similarly, ependymomas, even those within the fourth ventricle, are
usually hypodense on nonenhanced CT (101). It is important 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 (Gorlin syndrome, described in Chapter 6) should be considered and other
manifestations of the syndrome should be sought (104). As patients with basal cell nevus syndrome have a propensity to
experience basal cell carcinomas in irradiated fields, the presence of the syndrome may lead to changes in therapy.
On MR, the appearance of medulloblastomas is variable. Tumor location and patient age are the most important factors in
prospectively making the correct diagnosis. The tumors are most commonly situated within the inferior vermis (Fig. 7-9B) and
can sometimes be seen originating from the inferior medullary velum: a midline inferior vermian tumor bulging ventrally in the
fourth ventricle in a child aged 5 to 10 years is likely to be a medulloblastoma. The most common appearance is that of a
round, slightly lobulated mass with isointense to normal gray matter on T1-weighted images. T2-weighted sequences typically
reveal a heterogeneous mass in which the solid portions are hypo- or isointense compared to gray matter (Fig. 7-9C). 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 (105)) (Figs. 7-9E and F to 7-11D and E) (106–108). The signal intensities presumably relate to the 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,
necrotic areas, blood degradation product depositions, and calcification (109). The enhancement pattern of the tumors after
intravenous infusion of paramagnetic contrast is variable and may be patchy or uniform (Figs. 7-9 to 7-11). Signal and
enhancement characteristics of hemispheric medulloblastomas in adolescents and adults are similar to those of fourth
ventricular medulloblastomas in children. Generally, imaging and histopathological phenotypes correlate poorly in
medulloblastomas. Features that have previously been considered to be atypical (e.g., cyst, hemorrhage) are, in fact, frequently
seen (110). A larger-scale multicenter study postulated that the “only MB variant with slightly different MR imaging features
seems to be the desmoplastic/nodular type” (111). Desmoplastic SHH tumors may incite desmoplastic reaction in the overlying
meninges, resulting in leptomeningeal enhancement that mimics a meningioma (Fig. 7-11) (112). It is important to be cautious in
interpreting tumors with this appearance in older children (second decade) and young adults.
The location and enhancement patterns of medulloblastomas may help to specify the molecular subgroup, although some
variations are seen (71). Tumors within or close to the foramen of Luschka, including the cerebellopontine angle cistern and the
cisterna magna, are likely to belong to the WNT subgroup (although WNT tumors may also appear to be in the midline/fourth
ventricle) (113). Tumors in the cerebellar hemispheres are likely to be of the SHH subgroup (although SHH tumors may also
develop in the midline). Tumors in the ventral vermis/fourth ventricle and associated with CSF spread are likely to be group 3
or group 4 tumors: if the tumor demonstrates an ill-defined tumor margin, then it is likely of group 3, but if it demonstrates little
or no enhancement, then it is likely to be of group 4 (71).
Figure 7-10 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.
Figure 7-11 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.
Proton spectroscopy, discussed in the introduction to this chapter, typically shows high choline, low creatine, low NAA,
and high lactate values in medulloblastoma, reflecting the tumor’s malignant nature (114–118). In addition, short TE spectra
show a significant taurine peak, which is characteristic of medulloblastomas (114,119).
CSF spread of tumor is poorly evaluated by noncontrast MR imaging. Therefore, paramagnetic contrast should be used in
evaluating patients’ tumors both prior to and after resection of the tumor. The most common locations for intracranial
metastases are the vermian and basilar cisterns, frontal horns of the lateral ventricles, the anteroinferior recesses of the third
ventricle, and the subfrontal region (Figs. 7-12 and 7-13). Metastases are not uncommon over the cerebral hemispheric
convexities either, but when contrast-enhanced T2 FLAIR imaging is used (which is the technique of choice for leptomeningeal
metastasis screening, see introduction of this chapter), sedation-related issues may complicate their confident identification
(120). Intraventricular (subependymal) metastases frequently show limited enhancement (Fig. 7-13D); this should not cause
confusion in the proper clinical setting, as periventricular nodular heterotopia (see Chapter 5) is rarely seen as an incidental
finding. MR is the primary imaging method with which to evaluate for the presence of drop metastases to the spinal cord or the
cauda equina (121,122). MR techniques for imaging the spine are discussed in Chapter 1. MR also seems to be more sensitive
than CSF cytology is in detecting subarachnoid spread of primary brain tumors, whereas CSF cytology is more sensitive in the
detection of hematologic tumors such as leukemia and lymphoma (123). On contrast-enhanced MR, drop metastases may
appear as a smooth, enhancing coating (“sugarcoating”) of the spinal cord or as enhancing foci in the extramedullary, intradural
space (Fig. 7-13) (also see discussion in Chapter 10 and Fig. 10-11). The most common location is along the posterior surface
of the spinal cord in the thoracic regions (along the arachnoid septum that attaches the dorsal cord to the posterior dura, known
as the septum posticum) (Fig. 7-13F); the caudal-most aspect of the thecal sac (along the cauda equina components) is also
frequently involved. In the first few weeks after posterior fossa craniectomy, however, artifacts (presumably from dependent
subarachnoid blood clots along the septum posticum or spinal subdural collections or even from “leakage” of contrast into the
subarachnoid and subdural space) are common (124,125). These artifacts can be impossible to differentiate from CSF spread
of tumor. These problems are best avoided by staging the tumor preoperatively with pre- and postcontrast scans of the
brain and spine. Alternatively, tumor spread to the spine can be assessed after waiting 2 weeks after surgery before
imaging (126).
Figure 7-12 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.
Another source of potential diagnostic problems is the presence of the so-called postoperative intraspinal subdural
collections (PISC). The overall incidence of these benign and transient fluid collections is about 15%. These fluid collections
are clinically silent and resolve spontaneously but show signal enhancement after intravenous injection of GBCAs that may be
misinterpreted by the less experienced as sugarcoating metastatic disease. These collections, during the first few weeks after
surgery, may significantly reduce the cross-sectional area of the thecal sac; therefore, evaluating the intrathecal space for
metastases may be unreliable (Fig. 7-14). Although these subdural fluid collections do not compress the intradural neural
structures, attempts at lumbar puncture may be difficult. Most (88%) of these fluid collections resolve or significantly improve
by 4 weeks after surgery (60).
Evaluation for possible early surgical complications is another important responsibility of postoperative imaging
surveillance. Such complications include PICA territory infarctions and “collateral damage” to cerebellar and brainstem
structures during tumor resection. Because gross total tumor resection, which improves prognosis, is the goal of surgery,
surgical damage is not uncommon. In most cases, the complications do not have clinical significance; however, cerebellar
mutism syndrome is one of the more consequential surgically induced complications in patients receiving surgery for
medulloblastoma or other midline intraventricular tumors in the posterior fossa (127). This devastating, complex,
neurological–neurocognitive and speech disorder develops in at least 25% of patients and is related to bilateral surgical
damage to components of the efferent cerebellar pathway. Cerebellar mutism syndrome develops within 48 hours post surgery,
and careful analysis of the dentate nuclei, superior cerebellar peduncles, and the upper pontomesencephalic tegmentum may
confirm the presence of the anatomical substrates of the condition. Cerebellar mutism may be a special form of speech apraxia,
with cerebellocerebral diaschisis being the putative mechanism of the supratentorial frontal lobe dysfunction (128,129). The
development of bilateral hypertrophic olivary nucleus degeneration–type changes a few months after the syndrome initially
develops may provide further imaging evidence (113). Affected patients typically improve but probably never completely
normalize; therefore, cerebellar mutism syndrome is one of the major determinants (besides chemotherapy- and radiation
therapy–induced brain injuries) of the long-term quality of life of medulloblastoma survivors (9,130).
Figure 7-13 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 common 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. E and F. Postcontrast sagittal T1-weighted images show enhancing tumor coating the
spinal cord. A focal lesion (arrows) at the C3 level appears to be invading the spinal cord. Note the hyperintensity of the vertebral bodies
secondary to prior radiation therapy.
Figure 7-14 Postoperative intraspinal subdural collections (PISC). Sagittal nonenhanced T2-weighted (A), contrast-enhanced T1-weighted
(B) and axial contrast-enhanced T1-weighted (C, D) images. The sagittal T2-weighted image (A) is difficult to evaluate, shows an “unusual”
appearance of the cauda equina, but sagittal T1-weighted image (B) clearly show the enhancing subdural fluid collections. In axial postcontrast
T1-weighted images (C, D), the reduction of the cross-sectional area of the thecal sac is well-demonstrated; cauda equina nerve roots are
tightly packed within the thecal sac.
Hematogenous dissemination of medulloblastomas has been rare since systemic chemotherapy has been added to the
therapeutic regimen (131). When extra-CNS spread occurs, it may be seen years after initial treatment, with a median interval
of 12 to 32 months (132). Because 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 (126). These
skeletal metastases are typically radiodense on plain films and CT; they are hypointense on T1-weighted images and show
enhancement after administration of paramagnetic contrast (126). Lymph nodes are another common site of extraneural
metastases in children and may be detected on studies of the spine (112).
Cerebellar Astrocytoma
The 2016 WHO classification of CNS tumors recognizes several astrocytic tumor types, some of which (e.g., glioblastoma,
oligodendroglioma) are rare in children but may occur. Those that are common or characteristic in the pediatric population
include the well-established entities of pilocytic and PMA, subependymal giant cell tumor, pleomorphic xanthoastrocytoma
(PXA) (and its anaplastic variant), and the more recently discovered entity of diffuse midline glioma (H3 K27M mutant) (4).
Astrocytomas are the most common brain tumor in children, accounting for 40% to 50% of primary pediatric intracranial
neoplasms (74,75,101,160). Approximately 60% of astrocytomas develop in the posterior fossa, with 40% in the cerebellum
and 20% in the brainstem. The WHO grading of pediatric astrocytomas (some of which are typically seen in the posterior
fossa; others are dominantly or exclusively supratentorial) varies from grade I (most benign) and grade IV (most malignant, see
Table 7-6).
Most cerebellar astrocytomas in children are of a specific histological type called JPA, which is a unique tumor and is
classified as grade I by the World Health Organization. JPAs are the most benign astroglial tumors of the central nervous
system (76). JPAs also occur in specific areas of the brainstem (e.g., medulla oblongata). In the pons, the most common
astrocytic tumors are high grade and are included in the group of diffuse midline gliomas (these tumors were previously
labeled as “diffuse intrinsic pontine glioma” or DIPG). Malignant astrocytomas (including glioblastoma) in the cerebellum do
occur in children (161) and have a poor prognosis (162).
JPAs constitute only 5.2% of all CNS gliomas (all ages included) but 33.2% of those in patients younger than 14 years. The
highest age-adjusted incident rates (1/100,000) are seen during the first 9 years of life. In children younger than 14 years, PAs
constitute 18% of all brain neoplasms (in adolescents aged 15–19 years, JPAs account for 9.6% of all primary brain tumors,
and in adults aged 20+ years, only 0.9% (1)). JPAs compose about 70% of all pediatric cerebellar astrocytomas (163). JPAs
are found with equal frequency in males and females. Anaplastic astrocytomas (AAs) (~5%–15% of pediatric cerebellar
astrocytomas) are more common in older children, usually occurring in the second decade of life (76,77,164). Glioblastomas
of the cerebellum are uncommon and can present at any age (161,165).
Figure 7-16 Embryonal tumor with multilayered rosettes (ETMR) in the brainstem. Axial nonenhanced T2-weighted (A), axial T1-weighted (B),
and contrast-enhanced T1-weighted (C) images. Relatively well-marginated, nonenhancing lesion (arrows) expanding the right hemipons.
In general, patients with cerebellar astrocytomas, regardless of the histologic characteristics, present with early morning
headache and vomiting, waxing and waning over a period of months and finally becoming persistent and acute (74). Cerebellar
signs, such as truncal ataxia or dysdiadochokinesia, are frequently present.
Table 7-6 WHO Grade I Is Benign, and Grades II to IV Reflect Increasing Degrees of Malignancy (4)
JPAs are slow-growing neoplasms. Prognosis is related to the extent of resection; therefore, the best prognosis is associated
with single hemispheric location, small size, and cystic tumors with posterior mural nodules (166). Patients with cystic JPAs
have an excellent prognosis, with the 25-year survival rate being 80% to 90% and good functional outcome in 75% to 80%
(160,167,168). The 25% of patients with solid cerebellar astrocytomas have a more guarded prognosis, with a 25-year
survival rate of approximately 40% (160). With either variety, malignant transformation of benign cerebellar astrocytomas is
exceedingly rare, but does occur (169). Spontaneous malignant features (anaplasia) are seen in less than 1% of cases;
malignant transformation after prior treatment (radiation and/or chemotherapy) is somewhat more common (1.8%) (25,170).
Interestingly, when anaplastic features are present, the biological behavior (and prognosis) of the tumors is similar to that of
WHO grade II or III diffuse astrocytomas (DAs) (171).
Gross total resection of JPAs by surgery is usually curative. Extension into the brainstem, seen in up to 25% of cerebellar
astrocytomas, renders complete resection difficult and reduces the likelihood of long-term survival (168,172). Tumors that are
not surgically accessible may be treatable by stereotactic radiosurgery (173).
Pathology
Cerebellar astrocytomas of childhood (typically juvenile pilocytic) may originate in the midline or in the cerebellar
hemispheres; the frequency of these locations has been debated (75,76,169,172). The tumor is usually large at the time of
presentation, with an average diameter of greater than 5 cm (75,76). These tumors can be cystic, solid, or solid with a necrotic
center (74,75). Most frequently, the cystic lesions have a tumor nodule (“mural” nodule) 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 (74,75,101). 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
may result in a polycystic appearance (174). Nonnecrotic solid tumors are seen in less than 10% of cases. Some authors
describe a fourth type, with a mural nodule and an enhancing cyst wall (172). The gross appearance does not correlate with
histologic type (164).
Histologic examination of PAs is characterized by a combination of piloid tissue (dense sheets of elongated bipolar cells
and an abundance of Rosenthal fibers) and loose glial tissue (composed of multipolar protoplasmic astrocytes and eosinophilic
granular bodies) (175). Calcification is seen on histologic examination in 20% of cerebellar astrocytomas, most commonly in
the solid variety. Tumoral hemorrhage is rare, particularly in the cerebellum (176), but it may occur and be massive (177). PAs
differ from most low-grade astrocytomas histologically in that they are vascular (175) and the endothelial cells within the
tumor have open tight junctions and fenestrations (178). The imaging implication of these “holes” in the vascular walls is a
profound enhancement of the tumors (see below).
A pilomyxoid variant (pilomyxoid astrocytoma, or PMA) with monomorphous features, lack of Rosenthal fibers, and
myxoid background has been reported (175); it was classified as a WHO grade II astrocytoma (66), less benign than the JPA.
PMAs are predominantly located in the forebrain, especially in the hypothalamic–chiasmatic region (57%), and only rarely in
the cerebellum (10%) or the fourth ventricle (5%) (179,180). In a single-institution series, about 10% of astrocytomas initially
diagnosed as JPA were reclassified as PMA. The mean age of affected children was 3.33 years (only 1 tumor was found in an
adult). The clinical course of PMAs is more aggressive (characterized by recurrence and/or metastatic dissemination within
the CSF spaces) than that of JPAs; hence, they usually require more aggressive therapies but OS may not be significantly
different from that of JPAs (179).
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 iso- to hypodense compared to normal white matter on noncontrast CT, with pilocytic
tumors nearly always hypodense; high-grade tumors may be hyperdense. Contrast enhancement is usually irregular, with half of
the lesions showing mixed attenuation (101). 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 (101). Tumors of pilocytic cytology show intense enhancement of their solid portions (181).
When the tumor is cystic with a mural nodule, the cyst is round or oval; the mural nodule may be round, oval, or plaque-like.
IV contrast administration results in an intense, homogeneous enhancement of the solid component (Fig. 7-17). The wall of the
cyst may appear slightly hyperdense on CT because of the compressed cerebellar tissue; if it does not enhance, the pathology of
the cyst wall almost never reveals a tumor (160); if the wall of the cyst enhances, tumor is usually found. When the cyst results
from necrosis of a solid astrocytoma, it may be unilocular or multilocular. A well-defined mural nodule is not seen; instead,
tumor enhancement surrounds the cyst and extends into the cerebellum (101,160). Noncystic tumors are usually round to oval,
lobulated, and well-defined masses that are iso- to hypointense precontrast and show heterogeneous to homogeneous
enhancement. Rarely, no enhancement is discernible; nonenhancing tumors are essentially never of pilocytic histology.
On MR, the appearance of cerebellar astrocytomas varies in size from small (Fig. 7-18) to large (Fig. 7-19); both solid and
cystic components are identified. In general, solid portions appear as low-signal-intensity masses (although not as low as CSF)
on T1-weighted sequences and as high-signal-intensity masses (although not as high as CSF) on T2-weighted and FLAIR
sequences (Figs. 7-18 to 7-20). Higher-grade tumors may manifest lower signal intensity on T2-weighted images, thereby
mimicking medulloblastoma (161). The signal intensity of pilocytic tumors is not as high on FLAIR images as on T2 (Fig. 7-
20); therefore, FLAIR images are less useful than conventional T2-weighted images are for differentiating PAs from higher-
grade tumors. Solid portions of tumor typically enhance with paramagnetic contrast (Fig. 7-19); therefore, it is possible to
distinguish predominantly solid tumors with central necrosis (Fig. 7-20) from cystic tumors (Fig. 7-19), as necrosis tends to
have irregular (Fig. 7-20), rather than smooth (Fig. 7-19), margins. As with CT, enhancement of the cyst wall indicates the
presence of tumor. It is sometimes difficult to differentiate a solid from a cystic mass with noncontrast MR when the solid
portion of the tumor is homogeneous. A tumor should not be assumed to be cystic merely because it demonstrates homogeneous,
low signal intensity on T1-weighted images 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 to reliably make this differentiation. Although the T2 characteristics will usually allow differentiation of PAs from
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 PAs will usually have higher Dav values (typically 1.25–
1.95 × 10−3 mm2/s) than the more cellular ependymomas and, especially, medulloblastomas have (105). However, there may
be more overlap with other types of gliomas and other less typical tumor pathologies, so it is important to consider all imaging
characteristics as well as the patient’s age.
Figure 7-17 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 arrows). 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.
As discussed earlier this chapter, the proton MR spectra of cerebellar astrocytomas vary considerably depending upon the
histologic characteristics of the tumor (114–118). Interestingly, however, significant differences have been reported between
the spectral composition of cerebellar astrocytomas and that of suprasellar PAs, with significantly higher myo-inositol and
glutamate/glutamine peaks in the suprasellar tumors and a trend toward lower creatine in the cerebellar tumors (115,182). Such
differences could be related to the fact that, although JPAs are characterized by a similar histological appearance 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 brain tumor biology earlier in this chapter) (18).
If a well-defined T2 hypointense focus is seen in JPA in conjunction with decreased diffusivity (low ADC), then focal
anaplasia should be considered. This finding should be brought to the attention of both the neurosurgeon and the pathologist to
allow proper sampling and evaluation of the area because the confirmation of anaplasia within a JPA has prognostic
implications (25).
Ependymomas
Ependymomas (in all CNS compartments) constitute 1.9% of primary CNS tumors in all ages, but 5.7% in those younger than
14 years (and only 3.6% in those between 15 and 39 years). They are the third most common CNS tumor in children younger
than 5 years (exceeded only by PAs and medulloblastomas). Pediatric intracranial ependymomas are more commonly
infratentorial (70%) than supratentorial (30%) and more commonly intracranial than intraspinal (see Chapter 10) (2,196). They
compose 15% to 20% of posterior fossa tumors in children, with their relative frequency diminishing in older children;
however, ependymomas tumors can present at any age (2,77). Preponderance is slightly increased in males (M:F = 1.3:1)
(197–199). Ependymomas of the posterior fossa have two age peaks: the first occurring between the ages of 1 and 5 years and
the second during the fourth decade. Affected patients frequently present with a long clinical history, with the delay in
diagnosis probably a result of the insidious onset of symptoms; nearly all (90%) affected children have nausea and vomiting
resulting from fourth ventricle obstruction and the resulting hydrocephalus and increased intracranial pressure (74,81). Other
signs and symptoms may 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) (196).
Figure 7-18 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
(arrows). D. Axial postcontrast T1-weighted image shows that the areas of hyperintensity on the T2 and FLAIR images are the areas that
enhance (arrows). These were felt to be areas of pilocytic tumor.
Pathology
Ependymomas were at one time assumed to derive from differentiated 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 that, similar to other CNS tumors, ependymomas result from mutated stem cells: those producing
ependymomas have been shown to be the radial glia cells (19). 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 (19,200). Ependymomas from different parts of the CNS are histologically similar but are
biologically and molecularly different diseases; hence, their clinical and prognostic features differ. Ependymomas recapitulate
the gene expression profiles of regionally specified (spinal, posterior fossa, and supratentorial) radial glia cells. Indeed, DNA
methylation profiling of ependymomas identified nine molecular subgroups: three subgroups are identified in each CNS
compartment (201). In each compartment-defined ependymoma group, subependymomas (WHO grade I) represent a distinct
subset. In the spinal canal, myxopapillary ependymoma (WHO grade I) is a specific entity (see later in Chapter 10). In the
supratentorial compartment, YAP1 and RELA fusions characterize two distinct entities (which may be WHO grade II or III,
depending on the absence or presence of anaplastic features), and RELA fusion-positive ependymoma is also included in the
2016 WHO classification (4). In the posterior fossa, besides the previously mentioned subependymomas, two subgroups (PF-
EPN-A and PF-EPN-B) are known. Although both subgroups may have WHO grade II and III histopathological phenotypes,
PF-EPN-A presents in younger children (99% of patients are younger than 8 years) and is associated with worse prognosis
than PF-EPN-B tumors, which are usually seen in young adults (81% of patients are older than 18 years). In PF-EPN-A, 30%
of the tumors were WHO grade II and 70% were grade III; in the PF-EPN-B subgroup, 59% were WHO grade II, and 41%
were grade III. As in medulloblastomas, risk stratification based on molecular tumor features proved to be superior to
conventional histological grading (201).
Figure 7-19 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 heterogeneous 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 PA is very hyperintense compared with brain parenchyma. This is typical 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.
In earlier versions of the WHO classification of CNS tumors, ependymoblastoma was listed among “embryonal tumors.”
More recent studies suggested that previously used histopathological criteria (“ependymoblastic rosettes”) are neither precise
nor specific; hence, the entity previously known as ependymoblastoma is not recognized, and most such tumors are now
included in the group of embryonal tumors with multilayered rosettes, discussed earlier in this chapter (202).
Figure 7-20 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 (arrows) 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. Postcontrast axial T1-weighted image shows that the solid peripheral portion of
the tumor (white arrows) enhances uniformly, as characteristic of PAs. The central nonenhancing region (black arrowheads) is necrotic tumor.
Most posterior fossa ependymomas are solid, with calcification in up to 50% of posterior fossa ependymomas and cysts in
approximately 20% (197). Approximately 20% of ependymomas are soft and deformable. Therefore, in contradistinction to
most brain tumors (which grow as steadily enlarging masses), ependymomas can insinuate themselves through the subarachnoid
spaces and around blood vessels and nerves, often surrounding and engulfing structures. As a result of their adherence to
surrounding brain and their invasive growth pattern, ependymomas are difficult to cure; removal of the entire tumor is
uncommon, and the recurrence rate is high (74,81).
Based on the location of the tumor center and the displacement patterns of adjacent parenchymal structures by imaging, two
subtypes of posterior fossa ependymomas have been proposed. Type I is the midfloor-type (anterior displacement of the
brainstem and involvement of the obex), whereas type II is the lateral type (lateral displacement of the brainstem, no
involvement of the obex area). Although this is not yet scientifically documented, some researchers believe that these locations
reflect the molecular subtypes of the ependymomas (PF-EPN-A and PF-EPN-B), and their distinction may be clinically
important for preoperative risk stratification. Risk of residual tumor in type II is more than twice as high as in type I, which
may have significant consequences for management and prognosis (203). Indeed, microanatomical localization of the posterior
fossa ependymomas has been correlated with postoperative survival (204).
Posterior fossa ependymomas do not invade the brainstem or the cerebellum, instead forming exophytic masses that grow
out of the ventricle into the surrounding cisterns. Midfloor, type I ependymomas likely (Fig. 7-22) originate from the caudal end
of the fourth ventricle near the obex, extend dorsally into the ventricle, toward the cisterna magna, and into the 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. Lateral, type II ependymomas originating from the lateral recesses/vestibular areas (Fig. 7-
23) extend laterally toward the cerebellomedullary and cerebellopontine 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 may originate from the ventricular roof (roof type) (Fig. 7-24),
extend caudally into and through the foramen of Magendie, and be totally resectable; these have a reported mean survival time
of 116 months (204). Thus, the goal of imaging should be not only to identify the tumor but also to categorize it according to
these criteria (203).
Figure 7-21 Rosette-forming glioneuronal tumor in the fourth ventricle. Axial nonenhanced CT (A), axial nonenhanced (B), and contrast-
enhanced (C) T1-weighted images, axial nonenhanced T2-weighted (D), diffusion-weighted (E), and ADC map (F) image of the brain. The
mass lesion in the fourth ventricle exhibits a small calcified focus (white arrow in A), slight hypointensity on T1 (black arrows in B), and minimal
signal enhancement in the postcontrast T1-weighted image (white arrow in C). In T2-weighted image, the mass is heterogeneous (white arrow
in D), and diffusion-weighted and ADC map images show diffusivity slightly increased to cerebellum (slightly darker in E, slightly brighter in F).
Figure 7-22 Midfloor-type ependymoma (from the caudal ventricular 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 medulloblastoma 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 dorsally into the cisterna magna and inferiorly toward the upper C-spine. The brainstem is pushed ventrally but is in the midline. 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 brainstem but rather extends dorsally, displacing the vermis. There is no or only little extension 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
possible, 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.
Figure 7-23 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 shows no enhancement of the tumor (T); enhancement is very variable in ependymomas.
Subarachnoid metastatic spread of benign ependymomas via cerebrospinal fluid is uncommon (~10%–12%), and the
propensity for subarachnoid spread correlates with histology (WHO grade III tumors more commonly disseminate (205,206))
and age of the patient (younger patients have a higher incidence of tumor dissemination (205)). 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, ependymomas rarely have CSF dissemination at presentation: the mean time from
diagnosis to dissemination is 6.8 years (205,207). Because late recurrence (both locally and remotely) is possible even after
apparent gross total tumor resection, prolonged postoperative surveillance of patients is necessary (208). Rarely, anaplastic
ependymomas may be complicated by hematogenous, extraneural, systemic metastases.
Figure 7-24 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 extension 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 demonstrates slight hyperintensity,
suggesting moderate tumor cellularity. E. Postcontrast T1-weighted image shows mild, patchy enhancement of the tumor (T), again illustrating
the variable enhancement of ependymomas.
Imaging studies
The most characteristic appearance of a posterior fossa ependymoma on CT is that of an iso- to hyperdense (compared to gray
matter) posterior fossa mass (Figs. 7-22 to 7-24), with punctate calcifications, small cysts, and moderate, heterogeneous
enhancement after intravenous contrast administration (101,160). Small lucencies are seen within the tumor in approximately
15% of cases, and nearly 50% will exhibit multifocal, small calcifications (Fig. 7-24); large, clump-like calcifications are
occasionally seen. Intratumoral hemorrhage is found in approximately 10% of patients (Fig. 7-24) (101,199).
On MR, 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 hypointensity. T2-weighted images reveal a mass that is
usually isointense with gray matter (Fig. 7-23); foci of high intensity (necrotic areas or cysts) and low intensity (calcifications
or hemorrhage) may be present within the tumor mass (Fig. 7-24). Fluid–fluid levels can sometimes be seen within the cysts.
Because of the marked variation in appearance 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 the
insinuation of CSF spaces (e.g., extension of the tumor through the fourth ventricular outflow foramina). Extension of tumor
through the foramen of Magendie to the cisterna magna and through the foramen magnum into the dorsal cervical subarachnoid
space, behind the cervical spinal cord (Fig. 7-22), is quite characteristic and nearly specific for ependymoma. Similarly,
extension of tumor from the lateral recess (Fig. 7-23) 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. 7-22B).
Also, because the tumor originates about the obex, the lowest part of the fourth ventricle appears blurred on the midline sagittal
plane and cannot be recognized on axial cuts (Fig. 7-22B and C). Axial cuts at this level show that the tumor is essentially
dorsal to the brain, quite symmetrical, and usually without significant extension lateral to the medulla (Fig. 7-22C). In these
cases, cranial nerves and arteries are usually not invaded; resection may be complete, and prognosis is good. Lateral-type
ependymomas originate in one of the lateral recesses and extend toward the CP angle cistern; the brainstem is displaced
contralaterally and is only partially seen in the midline sagittal plane (Fig. 7-23B). On thin section axial T2 images, the inferior
extremity of the fourth ventricle is free of tumor (Fig. 7-23C); tumor growth into the CP angle cistern and prepontine cistern
may be recognized (Fig. 7-23C), raising suspicion for involvement of cranial nerves and local arterial encasement (Fig. 7-
23B). In such cases, satisfactory resection is impossible. These lateral ependymomas may be completely extraventricular (Fig.
7-23). The rare roof-type ependymomas originate from the inferior vermis and extend into the ventricular lumen, through the
midline foramen of Magendie, into the cisterna magna, and dorsal to the upper cord (Fig. 7-24); 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 do. Astrocytomas involving 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 below the fourth ventricle and to push it upward.
DWI shows the solid portion of an ependymoma to be isointense to slightly hypointense compared with cerebellar white
matter (Dav values are intermediate between medulloblastoma and JPA, typically between 1.0 × 10−3 and 1.3 × 10−3 mm2/s
(105)) (Figs. 7-22 and 7-24); thus, they may be useful for differentiation from medulloblastoma or an ATRT, which have
considerably lower Dav values. Proton MR spectra show considerable heterogeneity (114). In general, ependymomas have
low NAA and moderately elevated choline and creatine. Short echo spectra (TE = 30 ms) show low to high myo-inositol,
although never as high as in CPPs (114,115). Unfortunately, no conventional or DWI semiologic feature is helpful in
confidently differentiating grade II ependymomas from anaplastic, grade III tumors (209).
Proton MR spectroscopy of medulloblastomas, cerebellar astrocytomas, and ependymomas
This subject was discussed briefly in the introductory section of this chapter. Metabolite ratios of proton spectra of posterior
fossa pediatric brain tumors have been published (114,115,118,210). In general, proton spectra of brain tumors yield high
choline (Cho) peaks and diminished peaks of creatine (Cr) and N-acetylaspartate (NAA), but different types of tumors have
different levels of Cho elevation and NAA and Cr diminution (114). Proton spectra of normal cerebellum in the pediatric
patient (at 1.5 T using echo time of 135 ms) yield an NAA/Cho ratio of 1.49 ± 0.36 and a Cr/Cho ratio of 1.13 ± 0.23, whereas
medulloblastomas yield an NAA/Cho ratio of 0.17 ± 0.09 and a Cr/Cho ratio of 0.32 ± 0.19 (210) and have elevated taurine
when studied with short echo time (114). Low-grade astrocytomas and ependymomas typically have NAA/Cho and Cr/Cho
values between those of medulloblastomas and those of normal cerebellum on using echo times of 135 ms 1.5 T (210); both
have elevated myo-inositol at 1.5 T with TE = 35 ms, which may help to differentiate them from medulloblastomas (114). It
has been suggested, therefore, that proton MRS may be useful in prospectively differentiating medulloblastomas from
astrocytomas and ependymomas (210). Harris et al. (115) suggest that ependymomas have higher creatine than do astrocytomas
or medulloblastomas and that the presence of high myo-inositol levels strongly suggests a diagnosis of ependymoma when a
short echo time (30 ms) is used at 1.5 T. 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 histologic subtype and the degree of histological malignancy (117,118); thus, there is considerable overlap among the
different tumor types in individual cases. Moreover, PAs, considered to be 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 ms (211)), features that are
usually associated with high-grade tumors. Finally, inflammatory lesions can have spectra that are identical to those of
malignant tumors (212). Therefore, although careful analyses of spectroscopy may, eventually, help to preoperatively
differentiate among different histologies of brain tumors (114), it still seems (even after more than 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. Indeed, the most robust and valuable technique is DWI in the
differentiation of embryonal tumors (medulloblastoma, ATRT) from other common posterior fossa tumors (JPA, ependymoma,
and choroid plexus tumors).
Brainstem Tumors
General concepts
Brainstem tumors represent 1.5% of all primary CNS tumors and 4.3% of CNS gliomas in the general population, all ages
included (1). In children and adolescents younger than 19 years, brainstem tumors account for 12% of all CNS tumors, and
brainstem gliomas account for 20% to 30% of infratentorial brain tumors. Males and females are affected with equal
frequency. The peak incidence of these tumors occurs between 3 and 10 years of age, although they can be seen at any age from
neonates to adults (75,218,219). MR imaging has simplified the diagnosis of brainstem tumors and provided information
identifying subgroups having different therapeutic options and prognoses (218,220): medullary tumors, pontine tumors,
mesencephalic tumors, and tumors associated with neurofibromatosis type 1 (NF1). Within each of these broad categories,
further separations can be made, primarily into focal and diffuse tumors (see Table 7-2). Although tumors of many different
histologies (astrocytomas, gangliogliomas [GGGs], hemangioblastomas, PNETs, Langerhans cell histiocytosis (LCH),
germinomas, lymphomas, glioblastomas, and others (221–226)) can develop in the brainstem, the vast majority are astrocytic
tumors (76,227). In general, dorsally exophytic tumors and other localized, markedly enhancing tumors are PAs (227); because
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 (228); these have a typical neuroimaging
appearance (T2 hyperintensity, slightly blurry margins, and variable magnitude and extent of enhancement), and at many
institutions, such tumors are treated without biopsy. However, 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 (suggestive of an embryonal tumor), 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 cavernoma, abscess, or nonastrocytic tumor. Such features
should be brought to the attention of the treating oncologist before therapy is initiated. Integration of clinical data with
imaging findings is also crucial because most brainstem gliomas (even high-grade tumors) have relatively modest neurological
manifestations (cranial nerve palsies, ataxia, long-tract signs) prompting the initial diagnostic imaging evaluation, whereas
several nonneoplastic processes (inflammatory, infectious, etc.) mimicking a brainstem tumor present with major neurological
deficits and severely altered consciousness.
Figure 7-25 Choroid plexus papilloma in the fourth ventricle. A lobulated mass lesion (M) within the fourth ventricle shows signal
heterogeneities on both T1-(A, B) and T2-weighted (C) images. After IV contrast injection, the mass shows avid, moderately heterogeneous
enhancement (D).
MR is the study of choice when imaging neoplasms of the brainstem because of its multiplanar capacity and lack of artifacts
from the bony structures of the skull base (229). 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 (230,231).
Diffuse versus focal brainstem gliomas
Pediatric brainstem gliomas include focal brainstem gliomas (typically low grade) (Fig. 7-26) and diffuse gliomas (typically
high grade) (Fig. 7-27). Location and robust conventional MR imaging features often allow accurate diagnosis of these tumors.
Diffuse neoplasms constitute up to 80% of all brainstem tumors and usually correspond to WHO grade III or grade IV.
These tumors, which typically arise from the ventral pons, were previously known as diffuse intrinsic pontine gliomas (DIPGs,
a term which is still used and likely will be used for some time by many investigators), but in the 2016 WHO classification of
brain tumors, they are included in the group of diffuse midline gliomas (H3 K27M-mutant), which also comprises other similar
tumors in the thalamus, in the spinal cord, and, rarely, in other supratentorial midline sites—all of these tumors are considered
to be WHO grade IV. About 80% of “DIPGs” have the H3 K27M histone mutation (232,233). Because the primary role of
histones is “packaging” DNA, thereby organizing DNA into structural units (nucleosomes), altered histones may increase or
decrease gene expression. The “histone code” is, therefore, part of the “epigenetic code,” and DIPGs are an example of the
role of epigenetic factors in tumorigenesis. The results of whole-genome sequencing including methylation, expression, and
copy number profiling, however, showed another recurrent activating mutation (ACVR1) in 20% of “DIPGs” and revealed that
another two molecular subgroups (MYCN and silent) exist within the group of “DIPGs,” highlighting the many possible
pathways to tumorigenesis in tumors presenting with the clinical, imaging, and histopathological phenotype of “DIPG”
(234,235). Other investigators found that, within the group of H3-K27M mutant tumors, the biological behavior (and response
to radiation therapy) may differ depending on whether the mutation type is H3.3 or H3.1, suggesting that the H3K27 mutation is
the putative founding event of tumorigenesis in most DIPGs but specific alterations in the two affected histone variants drive
distinct oncogenic mechanisms (236). Ultimately, H3 mutations may not generate tumors by themselves, but cooperate with
other factors (e.g., PDGFRA amplification or mutation, TP53 deletion) in the process of tumorigenesis.
Figure 7-26 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.
Figure 7-27 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.
On imaging, high-grade gliomas in the pons tend to smoothly enlarge the affected area (see Figs. 7-27, 7-29, 7-30, and 7-
32), without focal areas of exophytic tumor, although they can bulge anteriorly and surround the basilar artery. 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, midbrain, or cerebellar peduncles); this extension into an adjacent structure, caudally or
(especially) cranially, is a poor prognostic sign (237). Contrast enhancement is seen in up to 70% of high-grade gliomas on
scans at presentation, although it is sometimes subtle and/or limited to small areas within the lesion. Enhancement is common
after therapy and typically increases in both magnitude and enhancement.
Focal neoplasms represent about 20% of pediatric brainstem gliomas and typically develop outside the pons (medulla
oblongata or midbrain). These tumors are generally well marginated and involve less than 75% of the brainstem in the axial
plane (Figs. 7-28, 7-31, 7-33, and 7-34). Focal tumors often enhance but do not cross segmental boundaries to extend into
adjacent segments or structures; as a result, when they enlarge, they tend to become focally exophytic. Histologically, most
correspond to PAs (WHO grade I), with GGGs (WHO grade I) or fibrillary astrocytomas (WHO grade II) being seen only
rarely; however, WHO grade IV embryonal tumors (e.g., ETMR, see earlier in this chapter) may occasionally have this
appearance (228). Recent advances in basic neurobiology research have improved our understanding of core biological and
molecular features of these tumors (238). Duplication of chromosome 7q34, leading to fusion of the BRAF (and KIAA1549)
genes is present in 80% of all pediatric JPAs and approximately two-thirds of JPAs in the brainstem (239–241). Another
BRAF mutation (BRAF V600E) is present in 65% of PXAs, but has been found in JPAs in extracerebellar locations (i.e.,
brainstem and diencephalon) (242). The two mutations are mutually exclusive, and their confident discrimination may pave the
way to the development of targeted therapies. Small molecule BRAF inhibitors may be useful against BRAF-mutant tumors, but
sorafenib (a multikinase inhibitor) has been found to paradoxically accelerate tumor progression in BRAF-fused tumors,
showing the delicate, often incompletely understood interplay between the various primary and ancillary tumorigenetic
processes and pathways (243). Overall, focal neoplasms of the brainstem have a much better prognosis than do diffuse
neoplasms (230,231,244–247) because of their slow evolution and in spite of the fact that complete resection is usually
impossible.
Figure 7-28 Focal medullary glioma in patient with NF1. A. Sagittal T1-weighted image shows focal dorsal contour 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.
Medullary tumors
The medulla is the least common site of origin for tumors of the brainstem. Medullary tumors typically present in young
children with signs and symptoms of increased intracranial pressure (244,248). Dysfunction of lower cranial nerves may result
in difficulty in swallowing and nasal speech (247). Eventually, affected patients may develop hemiparesis or quadriparesis
(247).
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 and grow exophytically into the vallecula and cisterna magna, often causing upward and posterior displacement of
the inferior cerebellar vermis (Fig. 7-26). 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 (228); it may
also relate to the original rhombomeric segmentation. Uncommonly, these tumors may extend into the tegmentum pontis.
Therefore, dorsally exophytic tumors should be considered to be focal (228). The exophytic component may extend inferiorly
through the foramen magnum, dorsal to the cervicomedullary junction, superficially mimicking an ependymoma (Fig. 7-26).
Histologically, these tumors are typically PAs (248) and, therefore, are of low attenuation on CT and are bright on T2-weighted
MR images. Thus, they can be differentiated from midfloor-type ependymomas, which more closely resemble gray matter on
CT and T2-weighted MR images. Medullary PAs tend to invade the medulla in depth in addition to being exophytic, and
midfloor ependymomas tend to be almost exclusively exophytic from their site of attachment. In addition, dorsally exophytic
medullary tumors push the fourth ventricle upward, whereas ependymomas often originate within the fourth ventricle, grow into
the ventricle, and expand it. Dorsally exophytic medullary tumors inconsistently enhance after administration of contrast: when
enhancement is present, it may be homogeneous or heterogeneous (230).
Diffuse medullary tumors (Fig. 7-27) are more infiltrative neoplasms that typically extend rostrally into the pons or
caudally into the cervical spinal cord but do not have a large exophytic component. Although most of these tumors are WHO
grade II, diffuse medullary tumors have a significantly worse prognosis than do their dorsally exophytic counterparts (230),
possibly because they are more difficult for the neurosurgeon to adequately resect. On CT, diffuse medullary tumors may be
difficult to detect because of the extensive artifact 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 requires use of
sagittal T2-weighted or FLAIR MR sequences (Fig. 7-27). Their typical MR appearance is that of a diffusely enlarged
medulla, exhibiting T1 hypointensity and T2/FLAIR hyperintensity, which infiltrate into the caudal pons and rostral cervical
spinal cord. Enhancement is inconsistent and is usually focal or multifocal (230).
Focal medullary tumors (Fig. 7-28) are most commonly seen in the setting of NF1. They are not usually identified on CT
images. On MR, they appear as focal expansions of the dorsal medulla that exhibit T1 hypointensity and T2/FLAIR
hyperintensity. Enhancement is uncommon. These tumors exhibit slow growth, showing little change on sequential imaging
studies.
Cervicomedullary tumors involve portions of the lower brainstem and the upper cervical spinal cord. The exact point of
origin of these tumors is often difficult (or impossible) to determine at the time of the initial diagnostic imaging workup. These
tumors may originate in the cervical spinal cord and grow upward to invade the lower medulla, sometimes even the
cerebellum. Conversely, tumors primarily arising from the lower part of the medulla oblongata may grow toward the cervical
spinal cord. Tumors found to be “cervicomedullary” therefore may carry features of their spinal cord or lower brainstem
variants from the histopathological and imaging point of view. These tumors are discussed in Chapter 10. It will suffice to say
in this section that most of these tumors (84%) are of low histologic grade (WHO grade I and II). The most common WHO
grade I entities in this location are JPAs or GGGs; grade II tumors are typically DAs. Overall, the 10-year survival rate is
86.7% in these tumors, but multimodal therapies are needed (radiation, chemotherapy) because gross total tumor resection is
rarely possible and recurrences are still frequent (228,249).
Pontine tumors
The pons is the most common location of tumors originating in the brainstem. Unlike tumors in the medulla oblongata and the
midbrain, most pontine tumors are high grade (gliomas and embryonal tumors) (250). The classification of high-grade gliomas
and embryonal tumors has undergone major revisions. Most pontine high-grade gliomas (previously known as diffuse
intrinsic pontine glioma or DIPG) belong to the group of diffuse midline gliomas (see discussion in this chapter). As the
understanding of diffuse midline gliomas is still very incomplete, we continue to use the term DIPG in this edition of the book.
The entity of PNET has also been eliminated from the WHO classification of CNS tumors; therefore, we try to avoid the use of
this term as much as possible. However, these changes in nomenclature (with downstream clinical consequences) make the use
and extrapolation of prior literature data difficult, which should be kept in mind when trying to understand these tumors.
The classic presentation of a pontine tumor is of cranial nerve palsies, usually multiple, with pyramidal tract signs and
cerebellar dysfunction (ataxia and nystagmus) (74,218). Smaller, more focal tumors may present with isolated cranial
neuropathies (246). Hydrocephalus and signs of increased intracranial pressure are uncommon. The prognosis for most patients
is poor, with an overall 5-year survival rate of approximately 10% despite optimal therapy (218,230,231). Diffuse intrinsic
pontine gliomas (DIPGs), which are poorly circumscribed, are large, and often extend into the medulla and midbrain, are
WHO IV high-grade gliomas and have extremely poor prognoses, with a 2-year survival rate of only 7% (227,251). In fact,
because most patients with diagnosed “DIPG” do not get biopsy-based histopathological confirmation, many (and possibly all)
“DIPG survivors” may actually have misdiagnosed JPAs or other low-grade tumors. Rarely, pontine tumors may originate in
the tegmentum of the pons and extend dorsally into the fourth ventricle; these carry a much better prognosis, with 5-year
survival rates as high as 73% (227,230,231,244,246,252).
Diffuse intrinsic pontine gliomas (DIPGs) (Fig. 7-29) are infiltrative masses that are hypodense on CT, hypointense on T1-
weighted MR images, and hyperintense on T2-weighted and FLAIR MR images. In most cases, some degree of signal
enhancement is seen after intravenous administration of GBCAs. The enhancement may be subtle, sometimes appreciated in
subtraction images (Fig. 7-30) (253). Various more or less distinct tumor components have also been identified based on their
distinctive conventional and advanced MR imaging features (254,255). For example, T2 hypointense foci within the tumor
field exhibit low ADC and increased relative cerebral blood volume values and may correspond to foci of anaplasia
characterized by high cellularity and angioneogenesis (26). Expansion by the tumor will result in an increased sagittal
dimension of the pons and posterior displacement of the fourth ventricle. In addition, the floor of the fourth ventricle may
become flattened. In spite of the marked enlargement of the brainstem and its frequent bulging into the fourth ventricle,
hydrocephalus is uncommon in pontine gliomas. 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 peripherally along the
cranial nerves. Anterior growth frequently engulfs the basilar artery (particularly in fibrillary astrocytomas (227)), which
eventually lies within a deep groove bounded by tumor anteriorly and laterally (Fig. 7-29B). Histologically, the tumor cells
infiltrate widely along the fiber tracts of the brainstem so that one sees tumor cells intermingling intimately with neurons and
nerve fibers (74,256). This does not lead to immediate destruction of the fibers, but as the tumor evolves (and progresses),
destruction of the pyramidal and other long tracts within the brainstem may occur, which can be demonstrated by the use of DTI
and leads to increasing neurological deficit (57). Conversely, in low-grade focal tumors, DTI shows displacement, rather than
destruction of the white matter tracts in the brainstem. This information may be helpful in the presurgical evaluation of
brainstem tumors (i.e., to determine the resectability of the lesion) (257). Historically, conventional MRI features were found
to have no predictive value for survival, which may be explained by the relatively modest differences between the shortest and
longest OS times in patients with DIPG (258). More recently, a DWI–based metric (ADC) has been suggested to allow the
identification of two prognostically different subgroups in patients with DIPG. High ADC values (>1300 × 10−6 mm2/s) were
associated with a median survival of 13 months, whereas low ADC values (<1300 × 10−6 mm2/s) were associated with a
median survival of only 3 months, but overall outcome was dismal in both groups (259). Evaluation of response to therapy in
DIPG is difficult by conventional MRI because the imaging manifestations of treatment-related changes (e.g., tumor necrosis
induced by radiation therapy) may be indistinguishable from those indicating tumor progression during the first few months
after the initiation of therapies; hence, the neuroradiologist’s ability to differentiate between pseudoprogression and true
progression is often limited. Furthermore, longitudinal volume measurements of the tumor poorly correlate with the evolution
of advanced MRI biomarkers (e.g., Cho/NAA ratios) during the course of the disease (260).
Figure 7-29 Diffuse intrinsic 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 (arrowheads). Hydrocephalus 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 ms) 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 similarly located voxel in the cerebellum. This is characteristic
of high-grade glial neoplasms.
Figure 7-30 “Occult” enhancement in a diffuse intrinsic pontine glioma (DIPG) in the pons. Axial nonenhanced T1- (A) and T2-weighted (B)
images, contrast-enhanced T1-weighted (C) and subtraction T1-weighted (D) images. Signal enhancement of the mass (M) after IV contrast
injection is difficult to appreciate in the conventional postcontrast image (C), but after subtraction of the precontrast T1-weighted image (B)
from the postcontrast T1-weighted image (C), subtle enhancement is recognizable (D).
Focal pontine tumors (Fig. 7-31) are uncommon, constituting only approximately 10% of pontine tumors and, therefore,
less than 5% of brainstem tumors. 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 marginated. 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 (230,244,246,252). They are usually low-grade tumors,
often PAs.
Proton MR spectroscopy and perfusion imaging may be useful in differentiating low-grade tumors (Fig. 7-31), which have
lower choline peaks and smaller blood volume fractions, from high-grade tumors (Fig. 7-29). As discussed with cerebellar
tumors, however, PAs (WHO grade I) have relatively high choline peaks and lactate peaks and relatively high blood volumes,
thus potentially 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 into focal and diffuse groups by using imaging. In addition, many authors consider tectal
tumors as a distinct third group of midbrain tumors (261–263). In contrast to the predominance of diffuse tumors in the pons,
focal tumors are much more common in the midbrain. Patient presentation varies with the type of tumor. Diffuse midbrain
gliomas typically cause blurred vision or double 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 (252,262,264); upward gaze paresis (Parinaud sign) may be present
(262). Tectal tumors cause signs and symptoms of hydrocephalus (see Chapter 8); upward gaze paresis is conspicuously absent
(252,261,262,265).
Precise diagnosis of the different midbrain tumors by neuroimaging is important in case management. For example, focal
midbrain tumors are treated surgically but diffuse tumors are treated with chemotherapy/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 (261,265)).
Diffuse midbrain tumors (Fig. 7-32) are uncommon tumors that are centered in the midbrain but extend rostrally into the
cerebrum and caudally into the pons and, sometimes, medulla. These tumors have relatively little local mass effect and show
minimal enhancement (Fig. 7-32) after administration of paramagnetic contrast.
Focal midbrain tumors (Fig. 7-33) are typically sharply circumscribed masses that focally enlarge the affected area. The
tumor may be midline or eccentric within the cerebral peduncle. They are typically of low attenuation on CT, of low intensity
on T1-weighted MR images, and of high intensity on T2-weighted images. Hemorrhage or cysts are present in approximately
25% of focal midbrain tumors (76,256,262). The tumors occasionally extend superiorly into the thalamus and, less commonly,
inferiorly into the pons (230,266). Administration of contrast may show ring enhancement when the tumor is small; larger
tumors show homogeneous (Fig. 7-33) or heterogeneous enhancement (230).
Tumors of the quadrigeminal plate (Fig. 7-34), also called tectal gliomas, are discussed in the section on pineal region
tumors. These tumors are, in general, benign and are initially treated only by CSF diversion of the resultant hydrocephalus.
However, tectal gliomas can be progressive and even metastasize. Sequential neuroimaging studies (preferably MR) are
obtained to look for growth of the mass. Most will show no growth and can be followed without treatment
(252,261,263,265,267).
Brain stem 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 (268). The relative
frequency of sites of tumor origin differs, with the medulla (Fig. 7-28) being the most common site (68%–82%) in NF1, in
contrast to the marked pontine predominance in patients without NF1 (268–272). Although brainstem tumors of NF1 may have
an identical imaging appearance to those that occur outside the spectrum of NF1, their clinical behavior is often strikingly
different (268,270–272). Many patients with NF1 have no tumor-related symptoms, so their tumors are detected incidentally
(268,271). The most striking difference in brainstem tumors with NF1 involvement and those without is in tumor growth. In
follow-up periods averaging 3.75 to 4.3 years, only 32% to 42% of patients with NF1 showed radiologic progression and only
14% to 18% showed clinical progression of these tumors (268,269,271). Even patients with tumors that have imaging
appearances identical to diffuse pontine tumors often have relatively indolent clinical courses (268). Spontaneous remissions
have been reported (269). Therefore, the recommendation is that only those tumors that exhibit rapid or unrelenting growth on
serial images or that produce significant clinical deterioration should have intervention (268,271).
Figure 7-31 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 ms)
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.
Localized proton MRS may help in the differentiation of benign pontine enlargement (low-grade tumor?) of NF1 from
pontine gliomas with more guarded prognoses. Broniscer et al. (273) 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
do patients with more clinically aggressive pontine gliomas. Unfortunately, because metabolite levels detected by MRS vary
from scanner to scanner, this is a relative measurement and no absolute values are available to differentiate between these two
entities.
Figure 7-32 Diffuse midbrain glioma. A. Axial T1-weighted image shows a poorly marginated mass with foci of hyperintensity (arrows), likely
representing 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 heterogeneous enhancement in the cerebral peduncle and
extending into the temporal lobe (arrows). D. Postcontrast T1-weighted image shows heterogeneous 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.
Figure 7-33 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 surrounding 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. Pathology showed pilocytic
astrocytoma.
Hemangioblastoma
Hemangioblastomas are relatively rare benign tumors (WHO grade I) of vascular origin, with an incidence ranging from 1% to
2.5% of intracranial neoplasms. Approximately 70% of the cases are sporadic; the remaining 30% develop in the context of
von Hippel-Lindau disease (see Chapter 6), which is a dominantly inherited cancer predisposition syndrome. Mutations in the
VHL gene (on chromosome 3p25.3) are responsible for von Hippel-Lindau disease but can be found in many sporadic cases as
well (282). Hemangioblastomas developing in the context of von Hippel-Lindau disease are seen in patients who are an
average of 20 years younger than are those with sporadic cases; hence, fewer than 20% of hemangioblastomas occur in
children, with most being seen in young and middle-aged adults. However, sporadic hemangioblastoma has been reported in a
newborn (283). The incidence in males exceeds that in females (74–76). In von Hippel-Lindau disease, hemangioblastomas
occur in association with retinal angiomas, renal cell carcinoma (type I), pheochromocytoma (type II), endolymphatic sac
tumors, and tumors of the pancreas. Patients with hemangioblastomas may present with polycythemia, thought to result from
erythropoietin production by the tumor (74–76). Hemangioblastomas develop most commonly in the posterior fossa
(cerebellum to brainstem including, very rarely, in cranial nerves (284)), followed by the spinal canal (spinal cord to cauda
equina) and very rarely supratentorially. Patients with von Hippel-Lindau disease tend to have multiple hemangioblastomas of
the CNS in multiple compartments. Hemangioblastomas in the spinal canal rarely (<5%) develop in isolation (i.e., without
intracranial lesions).
Figure 7-34 Glioma of the quadrigeminal plate. A. Sagittal TWI shows an isointense to hypointense mass (m) expanding the tectal plate with
effacement of the intercollicular sulcus. The lateral and third ventricles are markedly expanded due to hydrocephalus. B. Sagittal T2 also
demonstrates the enlarged tectal plate and shows diffusely increased signal that extends around the aqueduct 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.
Pathology
Hemangioblastomas occur most commonly in the cerebellar hemisphere, especially the paramedian hemispheric area. Because
they originate from the surface of the cerebellar parenchyma, 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 symptomatic hemangioblastomas are solid; small, asymptomatic tumors are much more commonly solid (285). On
gross inspection, the solid portion 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. Angiography will confirm the vascular component of the tumor and will detect small
hemangioblastomas not seen on contrast CT. These small lesions can be reliably detected on contrast-enhanced MR images.
The most common MR appearance is that of a cystic mass with a vascular mural nodule (Fig. 7-35) (286). The cyst may be
hyperintense on T1-weighted images if hemorrhage has recently occurred. More commonly, cysts are hypointense on T1-
weighted images and hyperintense on T2-weighted images (286,287) (Fig. 7-35). Moreover, on T2-weighted and FLAIR
images, a peripheral rim of hyperintensity may be seen as the result of surrounding edema. Solid portions of tumor enhance
dramatically after intravenous infusion of paramagnetic contrast (288) (Fig. 7-35E 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 MR images 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 MR imaging allows identification of
small tumor nodules because they enhance intensely. Because of the dense vascularity of the tumor, MR angiography often
shows the main arterial feeder and even some branching (Fig. 7-35D). In addition, conventional arteriography may be
indicated to visualize the hypervascular nidus (Fig. 7-35F), and many neurosurgeons will order preoperative angiography of
all suspected hemangioblastomas to determine the location of the vascular pedicle prospectively. Preoperative 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 (285).
Spinal hemangioblastomas commonly (up to 85%) present with more or less extensive spinal cord edema and/or hydromyelic
changes, regardless of their size (289,290); therefore, patients presenting with unexplained cord edema/hydromyelia should be
evaluated by using contrast-enhanced MRI. Rarely, a previously asymptomatic spinal hemangioblastoma may be the source of
intramedullary bleeding (hematomyelia) or spinal subarachnoid bleeding; such complications have been reported in adults only
(the youngest patient was 20 years old at diagnosis) (291–295).
Figure 7-35 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. 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. Conventional angiogram, late arterial phase. This intense angiographic
blush (b) is characteristic of hemangioblastomas.
Extraparenchymal Tumors
Schwannomas
Schwannomas are tumors derived from Schwann cells, which form the myelin sheaths around the axons of nerves in the roots
and peripheral nervous system. Schwannomas account for approximately 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 (74,75,296). 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 (296). Schwannomas tend to occur at
the sites of ganglia or at the transition from oligodendroglial cells to Schwann cells (297). For example, vestibular
schwannomas tend to occur at the Scarpa ganglion, which lies within the internal acoustic canal, or in the cerebellopontine
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; the neoplasm, therefore, grows
centripetally into the nerve causing compression of the nerve and, hence, a neuropathy (298). However, if the schwannoma
occurs within the cranial cavity, then 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 8th cranial nerve, followed by the 5th, 9th,
and 10th cranial nerves. Other intracranial schwannomas are extremely rare, other than in the setting of NF2 (297).
Imaging studies
On noncontrast CT, schwannomas appear as hypo- 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 (297). 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 MR, schwannomas have prolonged T1 and T2 relaxation times (299–301). Large schwannomas often show
heterogeneity with areas of high or low signal intensity on T2-weighted sequences (Fig. 7-36); the areas of T2 hypointensity
are most likely caused by the byproducts 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 foramen rotundum in trigeminal schwannomas and the
internal auditory canal in acoustic schwannomas) and enlargement of adjacent CSF cisterns are easily demonstrated by MR.
Administration of paramagnetic contrast results in enhancement of solid portions of the tumor (Figs. 7-36 and 7-37) (301). An
example of schwannomas in the setting of NF2 is illustrated in Figure 7-37, and several examples are in Chapter 6. Small
schwannomas may also be detected on high-definition T2 imaging (CISS/FIESTA) as focal enlargements of the nerve.
Figure 7-37 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).
Imaging studies
Epidermoids
CT scans show epidermoids as low-attenuating, lobulated masses that occur in characteristic locations (Fig. 7-38). The
attenuation is often nearly 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 characteristic lobulated appearance (Fig. 7-38B). However, the diagnosis of
epidermoid by MR with FLAIR and diffusion-weighted sequences is so accurate that CT should only be used if MR is not
available. On MR, epidermoids appear as somewhat heterogeneous, mildly lobulated extra-axial masses with prolonged T1
and T2 relaxation times; enhancement is not seen after infusion of paramagnetic contrast (Fig. 7-39). Thus, as with CT, most
epidermoids have a signal intensity that is similar to that of 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. 7-40). Cisternal
epidermoids are identified by enlargement of the occupied cisterns and the characteristic lobulated appearance of the mass
(Fig. 7-39) (305). 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. 7-39) within the mass suggest that it is an epidermoid. Diagnosis is
confirmed by DWI, which shows diffusivity of a solid mass (signal intensity higher than that of brain tissue, Fig. 7-39D),
whereas cysts have characteristics of fluid (similar to CSF, Fig. 7-40D) (306,307). FLAIR (Fig. 7-41) and constructive
interference in steady-state (CISS) sequences improve the conspicuity of epidermoids (307,308) and are useful in
differentiating them from cysts. Alternatively, 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
magnetization transfer (309). Occasionally, epidermoids show T1 hyperintensity (310); 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 saturated (disappear), but the high signal from epidermoids will remain unaffected.
Figure 7-38 Epidermoid tumor: use of CT cisternography. A. Contrast-enhanced CT scan shows a low-attenuation, nonenhancing
suprasellar mass (arrows). Note that the margins of the mass are somewhat irregular and lobulated. B. After introduction of intrathecal
contrast, the contrast material can be seen to diffuse into the interstices of the mass, showing a characteristic lobulated appearance (arrows).
This lobulated appearance is very characteristic of epidermoid tumors.
Dermoids
The CT appearance of a dermoid is that of a fat-attenuation, extra-axial mass that is usually located in the midline. As with
epidermoids, enhancement is not seen after infusion of IV contrast unless the tumor is or has been infected (305). Whenever a
midline dermoid or epidermoid tumor is encountered, the occipital and nasofrontal 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 is MR for detection of the calvarial defect, although MR is more sensitive in
detecting the tumor (311). 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.
On MR, dermoids have hyperintense T1 and hypointense T2 signal with associated chemical-shift artifact, similar to
lipomas (Fig. 7-42) (for discussion of intracranial lipomas, see Chapter 5). The high signal intensity will disappear after fat
suppression is applied (Fig. 7-43). However, dermoids are typically less lobulated than are lipomas and will displace blood
vessels and nerves; lipomas, which derive from mesenchyme, engulf vessels and nerves (see Chapter 5). Because affected
patients often present with headaches from chemical meningitis, inspection of the subarachnoid spaces and cerebral ventricles
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 MR (312)).
Rarely, dermoid tumors 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, epithelial, 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 meningitis
(313–315); however, the cysts may be found incidentally (316).
Imaging studies show an extraparenchymal posterior fossa mass. The most common locations of enteric cysts are the
cerebellopontine angle and the prepontine cistern (313,314); however, they may be found in the fourth ventricle or in the
supratentorial subarachnoid spaces (315). 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 (317)
or show ring enhancement (315). On MR, T1-weighted images typically show the cysts to be hyperintense with respect to CSF
and hypo- or isointense with respect to brain parenchyma (Fig. 7-44); they may be heterogeneous (316). 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 (315). Rarely, a
fluid–fluid layer, or even air, may be identified (313,318). Associated anomalies of adjacent bone are rare (315). Differential
diagnoses include arachnoid cyst, which can have 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 of a solid, very different from those of CSF, but enteric cysts have diffusion characteristics similar to those of
CSF).
Figure 7-39 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 lobulated 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/mm 2) 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.
Teratomas
Intracranial teratomas are rare and account for only 0.5% of primary intracranial neoplasms. However, in children younger
than 15 years, they account for 2% of intracranial tumors. Moreover, teratomas are a significant fraction of the brain tumors that
are diagnosed in infancy (see section on “Tumors in First Year of Life” later in this chapter). Intracranial teratomas are more
common in males than in females, because of the preponderance of pineal teratomas in males. The clinical presentation
depends upon the location of the tumor. Hydrocephalus is common, as it is in other midline tumors (74,76).
Figure 7-40 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/mm 2) 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.
Pathology
Teratomas are most commonly found in the pineal and parapineal regions, followed by the third ventricular region (especially
its floor), the posterior fossa, and the orbits. Other than sacrococcygeal teratomas (see Chapter 9), teratomas are less common
in the spine than they are intracranially; 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 α-fetoprotein and β-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, bone, or even tooth-like structures. More malignant
areas of tumor show less differentiation (74,76).
Imaging studies
On both CT and MR, teratomas generally appear as sharply marginated, heterogeneous lesions in the midline or occasionally in
the cerebellopontine cistern. 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 suggested (Fig. 7-45A).
On MR, the presence of fat and soft tissue intensity together with punctate foci of low signal intensity (suggestive of calcium) in
a midline mass should raise the suspicion of teratoma (Fig. 7-45B and C). The author has seen several patients, however, in
whom teratomas were of homogeneous soft tissue intensity on both CT and MR. Teratomas with a homogeneous imaging
appearance are commonly malignant and are indistinguishable from many other types of intrinsic brain tumors by using 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 calcification than do benign teratomas (319). The degree of contrast enhancement is
variable. A lack of contrast enhancement suggests a low-grade tumor; however, the presence of enhancement does not ensure
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.
Figure 7-41 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/mm 2) 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.
Figure 7-42 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 ventricle (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 frontal 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 intensity
along the dorsal aspect of the dermoid in the left frontal horn.
Figure 7-43 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. Coronal T1-weighted image shows a lobulated heterogeneous hyperintense mass (large open black arrows) in left ambient
cistern, curved around the free edge of the tentorium cerebelli. Note droplets of fat (small black arrows) in the interhemispheric fissure 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.
Figure 7-46 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.
Figure 7-47 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.
Figure 7-48 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.
Figure 7-49 Langerhans cell histiocytosis involving the pons and cerebellar white matter. Axial T2-weighted image shows T2 prolongation in
the central pons (open arrows) and in the white matter of the cerebellar hemispheres (closed arrows). These are the most common sites of
parenchymal involvement.
Figure 7-50 Ecchordosis physaliphora. This notochordal remnant on the posterior aspect of the clivus is an incidental finding. A. Sagittal
midline CT. Loss of cortical continuity (arrow) at the level of the synchondrosis, suggesting a bony erosion. B. Sagittal midline T1WI shows a
well-demarcated mass (arrow) with a slightly lower signal intensity than the brainstem. C. After contrast administration, the mass shows
irregular enhancement. As long term follow-up demonstrated no change in this asymptomatic patient, ecchordosis was the final diagnosis.
Figure 7-51 Clivus chordoma. A. Sagittal T1-weighted image shows a large mass (large arrows) pushing the pons posteriorly and pushing
the pituitary gland (small arrows) anteriorly. The displacement of the pituitary implies an origin within the clivus. B. Postcontrast T1-weighted
image shows a nearly complete lack of enhancement of the tumor (arrows). C. Axial T2-weighted image shows lateral displacement of both
temporal lobes (arrows) and posterolateral displacement of the pons by the hyperintense mass.
Figure 7-52 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.
B. Axial T2-weighted image shows prolonged T2 relaxation time within the tumor. The fourth ventricle (white arrows) is markedly 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.
Chondrosarcomas
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 chondrosarcomas present in the pediatric
age group (347,348); the mean age of presentation is in the third decade (302,349). A disproportionate percentage (43%) of
chondrosarcomas in children are high-grade neoplasms with “unconventional” histology, most commonly the mesenchymal type
(347,348). Patients typically present with headache, sinus symptoms, proptosis, or cranial neuropathies. Rarely,
chondrosarcomas in children arise from the skull base. The most common locations are the petro-occipital, spheno-occipital,
and sphenoethmoidal synchondroses, presumably arising from cartilaginous rests. Extension into the cavernous sinus, sella
turcica, sphenoid sinus, or parapharyngeal space is common (350). On imaging studies, chondrosarcomas are heterogeneous
(59% on MR, 44% on CT) secondary to mineralization and prominent fibrocartilagenous elements. The nonosseous elements
have long T1 and T2 relaxation times and enhance heterogeneously after intravenous contrast administration. Because the
tumors often lie adjacent to fat in the marrow, infratemporal 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 because the appearance is essentially identical (Fig. 7-53). However, paramedian origin from the petroclival
synchondrosis and uniform enhancement favor the diagnosis of chondrosarcoma.
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 (discussed later in this chapter). The involvement of brain
parenchyma by neuroblastoma occurs in only 1% of cases (351). Sometimes, neuroblastoma can originate in the upper cervical
or skull base portions of the sympathetic chain. These primary neuroblastomas present as homogeneous, uniformly enhancing
extraparenchymal masses in the cerebellomedullary or cerebellopontine angles (352). Extracranial and intracranial
components 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 cranial neuropathy because of metastasis to the skull base (Fig. 7-54). 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 because an infant’s skull base normally
contains hematopoietic marrow that enhances (353). Thus, enhancement of marrow in an infant or young child with
neuroblastoma is not sufficient to establish a diagnosis of metastatic disease. Ewing sarcoma (both primary and metastatic
(354)) and leukemia, which can also involve the skull base, have identical neuroimaging appearances. Metastatic
neuroblastoma to the skull base, therefore, cannot be differentiated from them. The presence of orbital metastases in stage M
neuroblastoma patients is associated with decreased survival (355).
Figure 7-53 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).
Figure 7-54 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.
Reduced diffusion
The normal pituitary gland is classically described as mildly concave superiorly. The anterior lobe is T1 hypointense, and
the posterior lobe is T1 hyperintense because of the presence of hormonal secretion granules. However, the pituitary gland in
children changes with age, as it reflects the hormonal status of the child during development and afterward (see Chapter 2).
When it is pathologically hypoplastic (agenesis of the stalk, Kallmann syndrome), the small gland is associated with a small,
shallow sellar cavity. Other malformations, such as persistent craniopharyngeal canal, transphenoidal cephalocele, and
duplication, are uncommon. Rathke cleft remnants are truly malformations (e.g., cyst of the pars intermedia), but as they can
form expanding cysts, they will be described together with the tumors.
Table 7-8 Common Clinical Presentations of Hypothalamic and Pituitary Lesions
Hypopituitarism
Craniopharyngioma
Idiopathic
Craniopharyngiomas
Lymphocytic hypophysitis
Sarcoidosis
Hypothalamic–pituitary malformations
Hypothalamic glioma
Choriocarcinoma
Teratoma
Hypothalamic astrocytoma
Pituitary adenoma
Amenorrhea
Pituitary adenoma
The pituitary stalk connects the hypothalamus to the posterior pituitary lobe; it is associated with a venous portal system that
transports hypothalamic releasing factors to the anterior pituitary. Strictly speaking, the stalk is a bundle of axons; the
infundibulum (funnel, in Latin) belongs to the hypothalamus and is where the arcuate nucleus is located (Fig. 7-55). When the
stalk is agenetic, posterior pituitary hormonal secretions accumulate in the infundibulum (so-called ectopic posterior pituitary);
antidiuretic function is preserved while the endocrine functions are decreased, and the anterior pituitary gland is hypoplastic.
When patients have central diabetes insipidus, imaging of the hypothalamic–pituitary region is often ordered to exclude the
presence of a mass in the hypothalamus or the infundibulum. The posterior pituitary gland bright T1 signal typically is absent
(occasionally, this may be a result of dehydration). It can often be difficult to determine the presence of a mass, as the findings
at initial presentation may be absent or very subtle. In this setting, it is important to remember that diabetes insipidus results
from dysfunction of supraoptic or paraventricular nuclei of the hypothalamus. Infiltration of these nuclei can occur when the
infundibulum is still normal in size. As the stalk and infundibulum lack a blood–brain barrier and, therefore, normally enhance
after intravenous administration of paramagnetic contrast, one might find no imaging abnormality at the time of the initial
MR study. However, a normal scan does not necessarily imply absence of tumor. It is very important to reimage the patient at
regular (3–6 month) intervals in order to find the hypothalamic abnormality, be it tumor, granuloma, or lymphocytic infiltration,
and begin therapy soon. Remember that the stalk should be no more than 2.6 mm in its thickest portion on coronal and sagittal
MR images; greater thickness is highly suspicious for pathologic infiltration (see Chapter 2). Finally, the infundibulum and
stalk should taper smoothly from the tuber cinereum to the insertion into the neurohypophysis. Any abrupt changes in size,
nodular rounding, or effacement of the lumen of the infundibulum should raise suspicion for a mass.
Figure 7-55 Anatomy of the anterior third ventricle.
Three suprasellar cisterns may be described. The suprachiasmatic cistern is located above the plane of the optic chiasm
and proximal optic nerves; it contains the anterior communicating arteries (ACAs), which are attached to the superior aspect of
the chiasm by their chiasmatic branches. The position of the chiasm can be determined by visualization of the ACA when the
anatomy is otherwise blurred by a suprasellar mass effect. The true suprasellar cistern is located between the tuber cinereum
and the membrane of Liliequist; it surrounds the pituitary stalk. The interpeduncular cistern lays behind the sella, just beneath
the membrane of Liliequist. Although the membrane of Liliequist is insignificant in regard to determining mass locations, it
separates two embryologically distinct cranial territories, one of mesodermal origin (infratentorial), and one of neural crest
origin (supratentorial).
Craniopharyngioma
Craniopharyngioma accounts for 3% to 5% of all intracranial tumors, 15% of supratentorial tumors, and 50% of suprasellar
tumors in children. The incidence peaks between 10 and 14 years of age, with males more commonly affected than females.
Symptoms vary with the sellar or hypothalamic location of the tumor and the age of the patient. They typically consist of
headaches, visual field defects secondary to compression of the optic chiasm, and anterior pituitary dysfunction from
compression of the anterior pituitary and hypothalamic–pituitary portal system; hypothalamic dysfunction may be extremely
severe with major hyperphagia and obesity. Hypothalamic dysfunction at the time of diagnosis, severe hydrocephalus, and age
less than 5 years at presentation are associated with high hypothalamic morbidity (366).
Craniopharyngiomas are dysontogenic tumors with benign histology and malignant behavior. They have a tendency to invade
the surrounding brain tissue and to recur after a seemingly total resection. Although postulated to arise from remnants of the
craniopharyngeal duct, hence their name, their true origin is still uncertain. The adamantinomatous subtype in prevalent in
children; a squamous papillary subtype is prevalent in adults in the fourth to the sixth decade of life. Both may arise anywhere
along the pituitary stalk from the floor of the third ventricle to the pituitary gland, and even, rarely, below the sella in the
sphenoid bone.
Papillary craniopharyngiomas, which generally present in adults, are predominantly solid and seem to originate mostly in
the hypothalamus; cysts, when present, are small and contain straw-colored fluid (367,368). The tumor commonly originates
along the pituitary stalk; as a result, both the dorsum and tuberculum sellae are often eroded. By opposition to the lobulated
adamantinomatous type, which often forms large cysts, papillary craniopharyngiomas form smaller, round, primarily solid
masses.
In contrast, adamantinomatous craniopharyngiomas generally occur in children and adolescents, but also in adults. Recent
data seem to indicate that mutations in CTNNB1 result in an overactivation of the WNT/β-catenin pathway in the still
undifferentiated cells of the embryonic Rathke pouch (369). The tumor most often originates within the tuber cinereum,
therefore behind the optic chiasm (so-called retrochiasmatic type), or in the pituitary gland with a prechiasmatic extension (so-
called prechiasmatic type). Rarely, it is attached to the stalk or located in the infrasellar sphenoid bone. Adamantinomatous
craniopharyngiomas form lobulated masses with multiple (often very large) cysts. 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 interpeduncular and prepontine
cisterns to the level of the pons. Very large cysts that expand within the third ventricle or deep within the brain parenchyma do
not attach to the surrounding tissue: after drainage, the third ventricular walls or the parenchyma return to normal. In contrast,
craniopharyngiomas within the sella may adhere to the medial walls of the cavernous sinuses, but never invade their lumen.
They may also be adherent to the terminal carotid artery and the anterior circle of Willis. Pathologically within the
hypothalamus, the solid part of the tumor interfaces irregularly with normal brain tissue. It consists of a peripheral basal cell
layer of palisading epithelium, loose aggregates of epithelial stellate cells, nodules of anucleated ghost cells with eosinophilic
material (wet keratin), hemosiderin deposit, cholesterol, inflammation, and calcification (369). Cells with nucleocytoplasmic
accumulation of β-catenin gather to form whorl-like structures close to the invasive front (cell clusters); they express stem cell
markers (369). The cyst may contain either straw-colored fluid or a brownish, motor oil–like substance that is rich in
cholesterol crystals.
Surgeons divide craniopharyngiomas into three groups based on the consequences of their location upon surgical approach:
intrasellar, prechiasmatic, and retrochiasmatic. Intrasellar craniopharyngiomas are usually smaller; they involve the pituitary
gland and bulge upward and anterior to the chiasm; they are typically associated with a characteristic “clam-like” deformity of
the sella; they abut but do not distort the optic nerves, chiasm, or anterior cerebral arteries. Prechiasmatic craniopharyngiomas
originate in the sella and grow superiorly between the optic nerves, displacing the chiasm posteriorly and elevating the
anterior cerebral arteries (A2 segment); they rarely compress the third ventricle, but they may adhere to the chiasm and
develop huge interhemispheric cysts; cysts may also develop posteriorly toward the interpeduncular cistern. Retrochiasmatic
craniopharyngiomas originate and develop within the tuber cinereum; they may expand downward into the interpeduncular and
prepontine cisterns, even toward the CP angle cistern, where they may attach to the dura; by contrast, they never attach to the
basilar artery (before surgery). They may develop laterally, into the middle cranial fossae, or upward into the third ventricle
where they occlude the foramina of Monro (yet without adhering to the ventricular walls) and push the chiasm forward against
the tuberculum sellae. Rarely, craniopharyngiomas may develop as clival, nasopharyngeal, or sphenoidal masses (370,371).
On imaging, pediatric (adamantinomatous) craniopharyngiomas characteristically obey the rule of the “four 90%”: 90%
suprasellar, 90% solid/cystic, 90% calcified, 90% enhancing. On CT, the appearance is characteristic (101) and is best
appreciated on sagittal and coronal reformats. The cystic components usually (but not always) have low attenuation. The mass
is characteristically calcified, at least partially; the calcification may be in the form of a thin, circumferential rim around the
cyst (“egg shell” pattern), or chunks of calcium within the solid portion of the tumor (“popcorn” pattern). Intravenous
administration of iodinated contrast results in enhancement of the solid portion of the mass and of the walls of the cysts. CT
also shows a remodeling of the skull base, as well as the anatomy and pneumatization of the sphenoid sinus, which is useful to
know if a transsphenoidal surgical approach is contemplated. Therefore, a cystic, contrast-enhancing suprasellar lesion with
calcification is almost certainly a craniopharyngioma (Fig. 7-56). If any two of these components are present,
craniopharyngioma is a likely diagnosis. Because craniopharyngiomas may be 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.
On MR studies, craniopharyngiomas typically appear as multilobulated, multicystic suprasellar masses (Figs. 7-57 to 7-60).
The cystic areas may be isointense, or have different degrees of high or low signal intensity with respect to brain tissue on T1-
weighted sequences; the short T1 relaxation times, when present, are the result of very high protein content (372). Although
both the cystic and solid components tend to have high signal intensity on T2-weighted sequences, the cystic areas tend to have
higher signal intensity than the solid components (Figs. 7-57 and 7-59) (373). Cystic and solid components may be difficult to
distinguish from flowing CSF in the prepontine cisterns, but CISS/FIESTA imaging helps in this regard. It may also be difficult
to separate the lesion itself from the surrounding edema on FLAIR sequences, especially at the level of the optic nerves,
chiasm, and tracts. The solid portions of the tumor have a granular appearance on precontrast T1-weighted images, sometimes
showing heterogeneity as a result of small cysts and calcifications; most important, they enhance heterogeneously after
administration of paramagnetic contrast (Figs. 7-58 and 7-60). The thin walls of the cysts nearly always enhance (Fig. 7-58) as
does, occasionally, the cyst content (Fig. 7-59) (373). Occasionally, usually in adults, papillary craniopharyngiomas may be
seen that are entirely solid (Fig. 7-61). They have a heterogeneous appearance and enhancement characteristics that are
identical to the solid portion of cystic craniopharyngiomas.
Figure 7-56 CT of craniopharyngioma. Axial contrast-enhanced CT scan shows a low-attenuation suprasellar mass with multiple areas of
calcification (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).
Whatever the extension, the site of origin of the craniopharyngioma is best identified on thin coronal and sagittal T1
contrast-enhanced images. If the tumor developed from the tuber cinereum, the pituitary gland can always be differentiated
from the bulk of the tumor (Figs. 7-57 and 7-56); in contrast, the pituitary gland is indistinguishable from an intrasellar,
prechiasmatic craniopharyngioma (Fig. 7-61). A common surgical request is to locate the pituitary stalk preoperatively, but this
is usually impossible, even when a persistent posterior bright signal demonstrates its functional integrity. Another request is to
evaluate the condition and location of the optic chiasm, but when the mass is too large, its identification may be impossible and
its location can only be guessed from the position of the anterior communicating artery that is attached to it by its perforators.
When a hypothalamic craniopharyngioma is not too large, the chiasm may be seen bracing it anteriorly, bright on FLAIR. In the
case of a sellar craniopharyngioma, the chiasm typically is lifted upward by the superior extension of the mass; it may be
restored after a transsphenoidal debulking of the tumor. It is important to mention that even after the mass effect of the tumor
has been corrected by the drainage of the cysts (e.g., for instillation of interferon alfa), imaging the region shows that the
tumor often adheres to the chiasm.
Proton MR spectroscopy of pediatric craniopharyngiomas differs from that of other suprasellar tumors (374). The spectra
show no normal neural metabolites, only a broad lipid spectrum at 1 to 2 ppm; this allows differentiation from suprasellar
astrocytomas, which show a large choline peak and reduced but present N-acetylaspartate peak (374). In one study of ASL
perfusion in pediatric brain tumors, the perfusion was shown to be low in suprasellar craniopharyngiomas (375).
Differential diagnosis in patients with a craniopharyngioma is usually straightforward. Location and appearance are quite
characteristic. The presence of calcification with a granular and heterogeneous appearance of the solid portion of the tumor,
multiple cysts with diverse size and signal intensities, enhancement of cyst walls and bone remodeling all suggest the diagnosis
of craniopharyngioma. The large, occasionally giant size of the mass in about 25% of affected patients, with tumor expansion
into the middle cranial fossa, anterior cranial fossa, and posterior fossa (prepontine cistern) (Fig. 7-60) should suggest the
diagnosis too. Very rarely, when a craniopharyngiomas arises primarily in the third ventricle or in the optic chiasm (376),
hypothalamic gliomas may be a consideration, but they are uncommonly calcified and have a different (fairly homogeneous
with low T1 signal) cyst content and only rarely bleed (pilomyxoid variant). Rathke cleft cysts (see below) are nearly always
smaller than are craniopharyngiomas, typically oval or dumbbell shaped, with regular walls (377) (craniopharyngiomas are
more irregular) and are never calcified. Their MRI appearance of a single cyst that is bright on T1 and dark on T2 (sometimes
with a waxy nodule—see below) is quite characteristic. They typically do not enhance, but differentiating the cyst wall from
the enhancing enveloping pituitary tissue is not always possible. Hemorrhagic adenomas can generally be differentiated by the
marked hypointensity of the hemorrhage (from deoxy- or methemoglobin) on gradient echo sequences. Macroadenomas tend to
invade the lumen of the cavernous sinuses, and to some extent the adjacent tentorium as well, which craniopharyngiomas never
do; when invasive, they diffusely permeate the surrounding bony structures, which the craniopharyngiomas remodel. Cystic
adenomas present mostly off-midline, have a hypointense rim on T2, may have a fluid–fluid level, and are often septated
(378). Epidermoid tumors are uncommon in that location; they can have the CT density of CSF with foci of calcification, but
they present with reduced diffusion on MR and do not enhance with contrast. Fat-filled suprasellar dermoid cysts also are
uncommon; they are often diagnosed after they have ruptured and spilled their cholesterol content, which never happens to
craniopharyngiomas. Suprasellar arachnoid cysts can be differentiated from craniopharyngiomas by the absence of solid
component, of calcification and of enhancement.
Figure 7-57 Small craniopharyngioma. A. Axial noncontrast CT shows a calcified suprasellar mass (arrows). B. Sagittal 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
surrounding 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.
Figure 7-58 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. Sagittal 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 interpeduncular cistern and splaying the cerebral peduncles. The irregular margin of the tumor
with the cerebral peduncles does not necessarily imply invasion by the tumor.
Figure 7-59 Prechiasmatic craniopharyngioma. A. Sagittal midline T2WI shows large mass (arrows) expanding the sella with suprasellar
expansion; the lesion is mostly solid with a cyst (C) in the septum pellucidum; the pituitary gland cannot be recognized. B. Coronal T1WI
shows elevation of the optic chiasm (arrow), which is splayed over the mass; the pituitary gland cannot be recognized. Both cavernous sinuses
are compressed and effaced. C and D. Sagittal and coronal T1WI post contrast show that the mass is mostly solid and heterogeneously
enhances except for a cyst (C) at the top of it.
Figure 7-60 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 present. 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.
Pathology
Whatever its location and its macroscopic appearance, the pathology of the PA is characteristic. It presents with a biphasic
pattern made of a compacted piloid (hair-like) cellular component associated with a loosely cellular microcytic component.
The pilocytic component contains densely packed elongated astrocytes with abundant Rosenthal fibers and has a strong glial
fibrillary acidic protein (GFAP) expression. The loose cellular component contains multipolar glial cells and evidence of
regressive changes such as a nuclear pleomorphism and eosinophilic granular bodies, as well as occasional calcifications and
heparinized vessels. Mitoses are few.
Figure 7-61 Papillary craniopharyngioma in an adult. A. Axial contrast-enhanced CT scan shows an enhancing mass in the suprasellar region
(black arrows) situated between the two posterior clinoid 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).
Molecular genetics
From point of view of the molecular genetics, the NF1-associated optic pathways–hypothalamic PA have mutations of 17q that
include the NF1 gene (which produces neurofibromin), whose function is to suppress RAS, which itself transmits growth-
promoting signals down to the mTOR pathway (384,385); loss of function results in an increased proliferation of astrocytes.
Sporadic cerebellar PAs typically have a genomic rearrangement on 7q34 with fusion of the kinase domain of BRAF with the
gene KIAA1549; this results in the activation of the MEK cascade which, in turn, activates mTOR with consequent growth of
the glioma. This process is less commonly observed in supratentorial PAs (384–386). Other BRAF fusions have been
observed in PA in all locations. The BRAFV600E is reported in PMA (as well as in GGG, PXA, and DNET). NTRK fusions
are common in PA, but also in other low-grade gliomas. Mutations of FGFR1 and of its downstream targets are recurrent in
midline PA (brainstem, suprasellar) (384,386).
Depending upon the series, about a third of patients with gliomas of the optic chiasm–hypothalamus have clinical evidence
or a positive family history of NF1, and in patients with NF1, the prevalence of optic glioma is about 20% (387). NF1 patients
may develop tumors involving primarily, but not only, the optic nerves and/or the optic chiasm (other sites include
hemispheres, thalami, cerebellum, and the cord and brainstem). It is characteristically associated with the UBOs (for
“unidentified bright objects”, also called FASI for “focal areas of high signal intensity”), patches of high T2 and FLAIR signal
in the globi pallidi, thalami, brainstem, and cerebellum that are common in young children and disappears during adolescence.
The involvement of the optic nerves is commonly bilateral, so that a bilateral diffuse optic glioma is almost pathognomonic
for NF1; it is much less common in sporadic cases. By contrast, hypothalamic involvement is uncommon in NF1. These tumors
are PAs, and malignant changes are extremely rare. They almost never develop after the age of 10 years. The large majority
grow extremely slowly and their growth potential decreases progressively with patient age; optic pathway tumors may even
involute spontaneously, both within and outside the setting of NF1 (381).
CT should not be used for assessment of orbital masses unless MR is not available; the intracranial portions of the optic
nerves and the chiasm are not seen as well by CT as by MR. When fat suppression techniques are used, MR imaging shows all
portions of the optic nerves in the orbit, optic canals and cisterns, the optic chiasm itself, the optic tracts on either side of the
midbrain, and the hypothalamus and the third ventricle. In addition, MR allows the structures to be viewed in any plane; the
coronal and sagittal planes are especially useful 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. CT remains adequate for evaluation of the intraorbital portions of the
optic nerves if MR is not available or cannot be used.
If CT imaging must be used, the enlargement of the optic nerve by the tumor can be smooth and fusiform but is more
commonly lobulated. The use of bone windows often reveals enlargement of the optic canals (Fig. 7-62) as a result of pressure
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 appearance in that the nerves have a
characteristic downward kinking a few millimeters behind the globe, possibly as a result of nerve elongation (388).
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 heterogeneously 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.
MR imaging is optimal for showing the relationship of the mass to the chiasm, hypothalamus, and infundibulum. Moreover,
when fat saturation and paramagnetic contrast agents are used, the intraorbital and intracanalicular portions of the nerve are
demonstrated well (Figs. 7-63 and 7-64). Dedicated orbital sequences should include T1, fat-saturated T2 axial and coronal,
and fat-saturated T1 axial and coronal post contrast. MR 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 (389). 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. 7-64). Again, the nerves present a characteristic elongation and buckling, which results in a
“pointed i” appearance (390). Whether this appearance corresponds to a hamartoma or a true tumor is still debated (391). A
recent report suggests that orbital nerve tortuosity is indeed a predictor of a later optic glioma, but not a predictor that this
glioma will be clinically significant (387). PA of the optic chiasm and hypothalamus are almost always hypointense on T1-
weighted sequences and hyperintense on T2-weighted and FLAIR sequences (Figs. 7-65 and 7-66). When large and bulky,
tumors of the chiasm and hypothalamus are typically heterogeneous, with large cystic and solid components; the solid portions
typically enhance markedly after contrast administration (373). Although sagittal images best demonstrate the enlarged optic
chiasm and hypothalamus, the coronal plane is optimal for visualizing tumor invasion of the cerebral hemispheres and
identification of tumor in the optic canals, intracranial optic nerves, optic chiasm, and optic tracts, particularly when fat
suppression is used (Fig. 7-65C). The anterior cerebral artery, stretched over the top of the mass, often creates a small
indentation in the superior surface of the tumor mass (Fig. 7-66); it is commonly encased. High signal intensity extending from
the optic chiasm to the lateral geniculate bodies on T2 and FLAIR images may represent extension of tumor or edema within
the optic tracts. Similarly, extension of the signal abnormalities into the basal ganglia and thalami may reveal a tumoral
infiltration but also edema and even, if the patient presents with an NF1, massive associated UBOs. This makes a volumetric
evaluation of the tumor uncertain. In neuro-oncology, measurements are typically used to monitor the response of the tumor to
the treatments, but this is particularly difficult in the case of the optic pathways–hypothalamic tumors because of their complex
morphology and because their morphology may not reflect the precise extent of the tumor infiltration. In addition, contrast
enhancement patterns are of no help: contrast enhancement during follow-up has been shown to vary spontaneously even in the
absence of treatment and in the absence of changes in size or morphology of the tumor. This may be explained by the
degenerative changes that commonly affect the PA vasculature (392). As a result, the appreciation of the efficacy of
antiangiogenetic therapies is particularly uncertain.
Figure 7-62 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).
Figure 7-63 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 enlargement (arrows) of the
intraorbital optic nerve.
A recent study has 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 pathway is rare (2%). The elongated and tortuous appearance of the orbital portion of the optic
nerve is quite remarkable (dotted i sign) (390). In contrast, optic pathway gliomas in patients without NF1 affect the chiasm
(91%) much more commonly than the orbital nerve (32%); more than two-thirds extend beyond the optic pathway into the 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%) than in sporadic forms (95%) (393). Also, sporadic PA of the optic nerve is
typically unilateral; bilateral changes are more consistent with NF1.
Proton MR spectroscopy of suprasellar astrocytomas shows increased choline, diminished NAA, and lactate. This finding
may be useful in the differentiation of astrocytomas from craniopharyngiomas, which show no normal metabolites (only a lipid
peak at 1–2 ppm), and from pituitary adenomas, which show a choline peak only or no metabolites at all (374). It has been
recently suggested that the residual peak of NAA in PA might not actually reflect a decreased neuronal/axonal activity, but the
N-acetyl group of different chemicals such as the N-acetylated sugars (394).
Suprasellar optic GGGs (gangliogliomas) are rare, but do occur, and are likely to be related to the hypothalamus. Their
clinical presentation, radiologic features, and treatment are not different from those of the PA, but the prognosis is not as good
with disease progressing in one-third of the patients. NF1 seems to be a predisposing factor, as it was diagnosed in three of 23
cases published in the English literature (prevalence in general population is 1/2000–1/5000) (395).
The PMA (pilomyxoid astrocytoma) is a variant of the PA. It represents about 10% of what was previously diagnosed as PA
and occurs in younger children (396). The majority of cases develop in the suprasellar region (57%) (180). PMA is
characterized histologically by a myxoid matrix and an angiocentric arrangement of the bipolar cells, with no Rosenthal fibers
and no eosinophilic granular bodies. Like the GGG, the PXA, and the DNET, PMA is reported to express the BRAFV600E
mutation. Although now classified as a grade 1 astrocytoma (4), it is somewhat more aggressive than is PA, with more common
dissemination, and for that reason, it may be important to tentatively identify it at the time of diagnosis, before discussing the
therapeutic options. Because the tumor is not common, descriptions of the imaging features are not many, but appear to be
concordant (180,396,397). None however is specific to the PMA, as they overlap with the features of PA. In our experience
(11 cases), all suprasellar PMAs are located in the chiasma and hypothalamus and have no significant extension in the optic
nerves (Fig. 7-67); instead, they may extend toward the cisterns, basal ganglia/thalami, fornix and septum pellucidum, adjacent
basal frontal and temporal lobes, tegmental cap, and, in one case, one optic tract to the lateral geniculate nucleus; NF1 was
associated in two cases. The tumor appears well demarcated, more often purely solid than PA, with typically smaller cysts
when present. PMA presents with a hypoattenuation on CT, and calcifications are unusual. It is mostly isointense or
hypointense on T1WI and hyperintense on T2WI and FLAIR, with a solid portion typically more heterogeneous than in PA.
Like in PA, diffusion is not restricted. Hemorrhages or blood residues are observed more commonly than in PA. Enhancement
also is heterogeneous, with nonenhancing portions more common and more significant than in PA. Dissemination, at diagnosis
or later, is observed in about half the cases (180,396,397). MR spectroscopy is not significantly different in PA and PMA
(398). In one study, a higher blood flow was found in PMA than in PA (399).
Figure 7-64 Bilateral optic gliomas with intracranial extension to optic chiasm. A–D. Postcontrast axial T1-weighted images show bilateral
enlarged intraorbital 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.
Figure 7-65 Pilocytic astrocytoma involving most of optic pathways and extending into basal ganglia. A. Sagittal T1-weighted image shows a
large mass (arrows) originating 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 toward the optic nerves (arrowheads) and posteriorly toward the
optic tracts (arrows). C. Postcontrast fat-suppressed 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.
The differential diagnosis of optic–hypothalamic astrocytomas includes craniopharyngiomas, GCTs, and granulomatous
diseases such as tuberculosis and sarcoidosis. Presentation before age 5 years favors the diagnosis of PA, 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 GCTs and granulomatous diseases; moreover, these masses typically show isointensity to gray
matter on T2-weighted images, in contrast to the hyperintensity seen in astrocytomas, and a restricted diffusion on DWI.
Pediatric craniopharyngiomas 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 preceding
section). Obviously, extensive fusiform infiltration of the optic pathways, without or with extension to the hypothalamus, is
more suggestive of a PA.
Histologically, several types of GCTs are identified. Germinomas are composed of undifferentiated large cells with
abundant cytoplasm arranged in nests separated by bands of connective tissue. Embryonal carcinomas are composed of large
cells with many mitoses that proliferate in cohesive nests and sheets with zones of coagulative necrosis. Choriocarcinomas are
characterized by extraembryonic differentiation along trophoblastic lines. Endodermal sinus tumors (or yolk sac tumors) are
composed of primitive-looking epithelial cells linked to extraembryonic mesoblast. Mixed GCTs present more than one
histologic components (402).
Imaging characteristics
All histologic subtypes present with a high cellularity, which explains their CT (isodense to gray matter) and MR (isointense to
gray matter on T1WI and T2WI, mildly hyperintense on FLAIR, mildly reduced diffusion) appearances. As they have no
blood–brain barrier, they enhance avidly. MR spectroscopy reveals a high choline peak (indicating high cellular turnover) and
a large peak at 0.9 to 1.3 ppm (also probably due to high turnover). Mature teratomas differ, in that they are composed of fully
differentiated tissue elements from ectoderm, mesoderm, and endoderm, with their specific appearances (fat, bone, mucus).
Immature teratomas contain incompletely differentiated tissue elements (402).
The morphology of the tumor varies with its size at the time of imaging. Germinomas have typical MR imaging features
when they are small, appearing on MR as thickening the pituitary stalk and uniformly enhancing after administration of contrast
(Fig. 7-68). The normal hyperintensity of the posterior pituitary is characteristically absent (403). In a child presenting with
diabetes insipidus and thickening of the stalk, the most common differential is the LCH. The two conditions are difficult to
differentiate, but the presence of a small mass filling the infundibulum is in favor of a germinoma, while its absence favors a
diagnosis of LCH. The infundibulum is where the axons that carry the antidiuretic hormone (ADH) from the paraventricular and
supraoptic nuclei gather to form the pituitary stalk; therefore, infundibular infiltration by the germinoma results in a very early
diabetes insipidus. It is important to recognize that, at the time the child presents with diabetes insipidus, the suprasellar
germinoma may be so small (Fig. 7-68) that it is not visible yet on an imaging study. A repeat imaging study should be obtained
within 3 to 6 months, and, if still negative, a second repeat examination should be obtained after another 3 to 6 months; a
uniformly enhancing mass will often be found then in the infundibulum, and its biopsy will show a germinoma.
Figure 7-67 Heterogeneous large chiasmatic/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 foramina 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 postcontrast T1-weighted image shows heterogeneous enhancement of the mass. The dilated anterior interhemispheric
fissure (arrows) was the result of a cyst with nonenhancing walls extending anteriorly from the tumor. D. Axial T2-weighted image shows the
tumor extending into the interpeduncular cistern (arrows) and splaying the cerebral peduncles. The tumor has a prolonged T2 relaxation time.
Figure 7-68 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.
From the infundibulum, germinomas may extend ventrally along the pituitary stalk as well as into the anterior pituitary gland,
compromising the hypophyseal portal system (and the anterior pituitary itself) with resulting panhypopituitarism. The
germinoma may then infiltrate the dural lateral walls of the sella, invade the cavernous sinuses, and encase the cavernous
segments of the internal carotid arteries. The terminal ICAs, the circle of Willis, and the proximal portion of its branches may
be encased (in the suprasellar region) as well. Within the ventral third ventricle, the germinoma may extend toward the optic
chiasm (which may result in visual defects) and the lamina terminalis, as well as posteriorly along the tuber cinereum (Fig. 7-
69). Invasive tumors may also “creep” along the ventricular ependyma to invade the lateral ventricle (then obstructing the
foramina of Monro and resulting in obstructive hydrocephalus with periventricular edema) and across the ependyma, into the
midline structures (fornix, septum pellucidum, corpus callosum) and the deep hemispheric white matter (Fig. 7-70).
Subependymal veins may be encased along the way. This ependymal infiltration may develop (macroscopically at least)
separate from the primary tumor.
With large germinomas, CT shows homogeneous masses of gray matter attenuation that uniformly enhance after
administration of iodinated contrast. MR better shows an enhancing infundibulum-centered mass with a thick stalk and
expansion of the pituitary gland, or a third ventricular mass. If the tumor is large, it typically has a finely heterogeneous,
microcystic iso- or hypointense T1WI signal and isointense T2WI signal (Fig. 7-71). A low ADC value is characteristically
present but may be subtle. The mass is typically well demarcated, but when it invades the brain, it is surrounded by FLAIR
hyperintensity, which may represent tumor infiltration or surrounding edema, which possibly results from the invasion of local
veins. Blood or blood products may be seen, usually in NG-GCTs. Contrast administration results in diffuse, often intense,
enhancement and may reveal the presence of cysts of various sizes. Tumor may spread along the ventricular ependyma, basilar
cisterns, and spinal leptomeninges. It is important to acquire good coronal images to assess the invasion of the cavernous
sinuses. The bone of the sellar region may be infiltrated and eroded (rather than remodeled), as well. After treatment of a
germinoma, residual deformities and pial enhancement may persist. The diabetes insipidus does not recover, and the lack of a
posterior bright spot will persist forever (403), in contrast to diabetes insipidus from other causes, such as LCH.
Figure 7-69 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.
Figure 7-70 Suprasellar germinoma with subependymal metastasis. A. Midline sagittal T1WI with contrast. Small tumor mass (white arrow) is
seen in the chiasmatic and infundibular recesses of the third ventricle; metastatic dissemination (M) is seen in the vicinity of the foramina of
Monro. B. Axial image shows metastatic tissue forming a large nodule (M) in the left frontal horn and lining the septal and frontal horn
ependyma (white arrows) bilaterally.
Figure 7-71 Large suprasellar germinoma. A. Axial noncontrast CT image shows the suprasellar mass (arrows) that is hyperdense
compared to surrounding 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.
It is important to try to differentiate pure germinomas from nongerminomatous GCTs because the prognosis for pure
germinomas is good after treatment with appropriate chemotherapy and radiotherapy protocols (without surgery, other than
possibly for a biopsy). Unfortunately, other NG-GCTs have much more guarded prognoses. The diagnosis of NG-GCT can
often be suggested by imaging; intratumoral bleed is a good indicator that the tumor is not a pure germinoma (Fig. 7-72), but it
may not be present; the diagnosis then rests on the identification of tumor markers in the CSF and the blood; α-foetoprotein
(AFP), elevated in yolk sac tumors, and β-human chorionic gonadotrophin (β-HCG), elevated in choriocarcinomas. Easily
distinguished from each other on the basis of MR imaging, neither pure germinomas nor mature teratomas secrete diagnostic
hormones.
Mature teratomas differ from other GCTs on imaging. Although they may develop in the infundibulum and stalk and, from
there, extend toward the pituitary gland and/or the third ventricle like other GCTs, they appear lobulated, solid, and
(multi)cystic and contain fat and possibly calcification (the latter seen best on CT). After contrast administration, the solid
portions and walls of the cysts enhance. The components of the mass are diverse, histologically consistent with fibrosis, fat,
follicles, keratinocytes, and debris (404). Such a multicystic, calcified tumor in this region may suggest a craniopharyngiomas.
Although the cysts are not typically bright on T1 in a teratoma, as they would be in a craniopharyngiomas, the two tumors may
have very similar appearances and neither has reduced diffusivity. Another consideration in this region is a lipoma of the tuber
cinereum, which may be calcified; lipoma is, however, a dysplastic, not a tumoral, lesion; is never cystic; and does not
enhance. Immature teratomas, in contrast, seem to be more predominantly solid and enhance more avidly than do mature ones
(404). They may have low diffusivity and be fairly invasive, especially in the cavernous sinuses and, therefore, may be
impossible to differentiate from germinomas or NG-GCTs or, even, from pituitary macroadenomas.
Pituitary Adenomas
Tumors of the pituitary gland are uncommon in children, with pediatric patients constituting only about 2% of those with
pituitary adenomas; when pituitary tumors do become symptomatic in the pediatric age group, adolescents are usually affected.
The most common hormonally active pituitary adenomas in the pediatric age group are prolactin-secreting adenomas (PL)
(resulting in delayed menarche in the girls), ACTH-secreting adenomas (resulting in Cushing disease), and growth hormone-
secreting adenomas (GRH) (resulting in gigantism). About 25% of pediatric pituitary adenomas are nonsecreting (405);
affected patients typically present with delayed puberty, short stature, or (in females) primary amenorrhea. Compared to the
adult population, macroadenomas relatively are more common in children, and “microadenomas” (discrete, well-demarcated,
strictly intrapituitary nodule) are more often large in children, even above 10 mm, which is the generally accepted limit. For
that reason, we prefer to classify the adenoma as discrete or diffuse adenomas. Discrete adenomas are well circumscribed and
remain located in one side of the gland (even when they are big enough to compress and efface the other side, which can still
be appreciated by the displacement of the stalk). Diffuse adenomas, in contrast, involve the entire parenchyma of the pituitary
gland, typically present with a suprasellar expansion and, often, infiltrate one or both cavernous sinuses; they correspond to the
classic macroadenoma. Invasive macroadenomas are extreme, aggressive variants, which may extend into the third ventricle,
into the sphenoid body and along the tentorial dura. The fact that adenomas are often larger in children than in adult 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 this population; the shorter time to progression suggests that pediatric pituitary adenomas are more biologically
aggressive tumors; indeed, they sometimes appear extremely invasive. In addition, recent work suggests that mutations of the
AIP (aryl hydrocarbon receptor-interacting protein) and, especially, MEN1 (multiple endocrine neoplasia) might be
responsible for the more severe pituitary adenomas in the pediatric population (406,407).
Figure 7-72 NG-GCT. A. Coronal T1WI shows large, partially hemorrhagic suprasellar mass (M). B. Midline sagittal T2WI shows
heterogeneous multicystic and hemorrhagic (hypointense component) suprasellar mass (arrows). C. After contrast administration, midline
sagittal T1WI postcontrast image shows diffuse heterogeneous enhancement; note that the hemorrhage can no longer be distinguished.
Clinically, children with large pituitary tumors may present with headaches, short stature secondary to compromised
hypothalamic–pituitary function, or visual disturbance if the tumor extends into the suprasellar cistern. Rarely, children and
adolescents may present with pituitary apoplexy, a condition caused by sudden extensive tumor infarction or hemorrhage of a
pituitary adenoma with acute enlargement of the gland. Pediatric patients with pituitary apoplexy manifest acute headache and
visual loss, identical to their adult counterparts.
CT imaging may show the bony changes associated with a discrete, intrapituitary adenoma, but often fail to demonstrate the
microadenoma itself unless the more complex dynamic contrast perfusion technique is used: this consists of imaging
sequentially the gland while contrast is being injected. Typically, the adenoma and the rest of the gland enhance at different
times, so that the adenoma may be identified (408). This technique can further demonstrate whether the adenoma is supplied by
the venous portal system or by the hypophyseal arteries, that is, whether it is hypothalamus dependent or not, which may
determine the therapeutic strategy (409). In the case of a macroadenoma, CT demonstrates nicely the sellar and suprasellar
components of a macroadenoma, its mass effect on the surrounding structures, as well as the commonly associated cavernous
sinus invasion. Finally, CT may be useful to show an associated bony remodeling or permeation. It allows one to rule out the
diagnosis of a craniopharyngioma by demonstrating the lack of associated calcification.
MR imaging is now the imaging modality of choice. Noncontrast thin section (1–3 mm) coronal and sagittal T1 (pre and
post contrast) and T2 images should be acquired through the sella and suprasellar regions, all with a small field of view.
Microadenomas appear as discrete, well-demarcated, rounded intrapituitary masses with a diameter, by definition, of less than
1 cm. Typically iso- or hypointense on T1 sequences before contrast administration, and iso- or hypointense on T2 sequences,
they usually enhance less than the surrounding pituitary parenchyma after contrast administration (Fig. 7-73). However, some
enhance more, possibly due to a long delay between contrast injection and imaging; therefore, imaging should be performed as
soon as possible after the injection. Dynamic sequential postcontrast imaging is not needed for the MR diagnosis of this lesion,
due to the superior sensitivity of this modality as compared with CT and the lack of artifacts from the adjacent bone. Most
microadenomas are located laterally in the gland, as this correspond to the location of the PL-secreting and ACTH-secreting
cells. Associated findings include a depression of the portion of the sellar floor that is adjacent to the lesion (easier to see on
CT than on MRI), which may be very helpful for the diagnosis when the microadenoma is small (Fig. 7-74), upward convexity
of the gland above the lesion, and deviation of the pituitary stalk to the side opposite the lesion. The posterior pituitary
hyperintensity is typically preserved, but sometimes splayed by mass effect from the adenoma. Larger, but still discrete, well-
demarcated, lateralized tumors sparing a recognizable portion of the pituitary parenchyma may be observed, which are not
different by essence from the smaller ones. Microadenomas may infiltrate the dural wall of the ipsilateral cavernous sinus, so
that surgical removal of the adenoma may be perilous. Some microadenomas are finely heterogeneous on T1WI, T2WI, and
postcontrast sequences, suggesting tiny necrotic cysts; these may contain patches of blood at presentation (hemorrhagic
microadenomas) (Fig. 7-75). Others appear mostly or fully cystic, either dark or bright on T1 sequences (depending on the
composition of the fluid), and bright on T2 sequences, frequently with fluid–fluid layering in the cyst (Fig. 7-76). The major
differential diagnosis of a cystic microadenoma is a Rathke cleft cyst. It appears that the presence of hemorrhage and off-
midline location of the lesion are good indicators of a cystic microadenoma (378).
Figure 7-73 Discrete microadenoma (PL). A. Sagittal T1WI shows a round mass (M) occupying most of the anterior pituitary gland. B.
Coronal T2WI shows an irregular, hypointense mass (M) in the pituitary parenchyma on the right side. C and D. After contrast administration,
coronal and sagittal T1WI post contrast demonstrates the adenoma more clearly.
Figure 7-74 Small microadenoma (PL). A. Coronal T2 demonstrates a tiny area of remodeling (white arrow) on the left side of the sellar floor.
B. Coronal T1WI post contrast demonstrates the microadenoma (M), which enhances less than the normal parenchyma.
In contradistinction with the focal, discrete microadenomas, diffuse macroadenomas involve the entirety of the anterior
pituitary parenchyma, and this results in a significant mass effect. Sometimes the tumor is still enclosed within the sella at the
time of diagnosis. If the patient is an adolescent or young adult, caution must be exercised when interpreting the study, 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. 2-20). In contrast, as an adenoma grows, it remodels the sella and expands across the opening of the
diaphragma sella, resulting in significant suprasellar expansion (Fig. 7-77). This results in the lifting, stretching, and deformity
of the optic chiasm, stalk, and anterior third ventricle, as well possibly as the lateral infiltration and invasion of the cavernous
sinuses (Fig. 7-77C). Macroadenomas appear iso- or hypointense on T1 sequences and iso- or hyperintense on T2 sequences
and tend to enhance diffusely (but less than the normal pituitary parenchyma) (Fig. 7-77C). They may be finely heterogeneous,
hemorrhagic, necrotic, partially cystic, or cystic/hemorrhagic like the microadenomas. The posterior pituitary hyperintensity
may or may not be identifiable.
Figure 7-75 Solid, hemorrhagic microadenoma (PL). A and B. Coronal T1WI shows a round pituitary mass with central T1 hyperintensity
(white arrow) in A and C, and T2 hypointensity (black arrow) in B representing a small hemorrhage. The microadenoma grows exophytically
from the upper surface of the gland, presenting as a small focus of hemorrhage that appears separate from the gland.
Figure 7-76 Cystic and hemorrhagic microadenoma (PL). A large rounded mass (M) in the left portion of the pituitary gland, which appears
dark on T1WI (A) and bright on T2WI (B); this is consistent with a cystic structure; the sagittal T2WI (B) shows a fluid–fluid level (black arrows)
due to an intracystic hemorrhage.
Figure 7-77 Macroadenoma (PL). A. Midline sagittal T1WI shows a pituitary tumor expanding the sellar cavity and extending into the
suprasellar cistern to abut the optic chiasm (small white arrow); it has a low T1 signal similar to the brainstem. B. Midline sagittal T2WI shows
the tumor to be heterogeneous, with dark in signal in its intrasellar portion and bright in the suprasellar cistern; this is more likely necrotic than
cystic. C. Coronal T1WI post contrast shows the tumor (T) excavating the right side of the sellar floor (black arrows) and invading the right
cavernous sinus.
Finally, macroadenomas may be invasive, commonly infiltrating and filling the lumen of the cavernous sinuses and
surrounding the carotid syphons. In the suprasellar region, the constituents of the circle of Willis are typically stretched around
the mass, but they may also be encased. The dorsum sellae may appear to be destroyed, and the tentorium may be invaded (Fig.
7-78). This is less uncommon in children (usually teenagers) than in adults. Such invasive tumors may extend into the third
ventricle dorsally, and ventrally, into the sphenoid bone and even into the retropharyngeal spaces. In such cases, the bone is
permeated rather than destroyed; during treatment, it will recalcify and reappear within the tumor on CT imaging.
If increased hormonal secretion is found, the diagnosis of pituitary adenoma is easy in the face of a sellar/suprasellar tumor.
Otherwise, the differential includes Rathke cleft cyst (midline, specific appearance of the content) for the microadenomas, as
well as sellar craniopharyngioma (cystic but possibly solid, calcifications), and GCTs (loss of posterior pituitary bright
signal, stalk, and infundibular involvement) for macroadenomas. A case of suprasellar medulloepithelioma has been described
but is extremely exceptional (410). Lymphocytic hypophysitis is very uncommon in children (411); it is painful and may have
posterior pituitary and stalk involvement, anterior pituitary involvement, or both, with the related hormonal defects. T2-
weighted imaging showing periglandular and dural T2 hypointensity is indicative of sclerosis (412) and is often associated
with a dural tail after contrast administration; the final diagnosis is determined after biopsy. In the rare condition of a
deactivating PROP1 gene mutation, cystic hyperplasia of the intermediate pituitary lobe, resulting in an enlarged gland, may
be associated with combined hormonal deficits; diagnosis rests upon the identification of the gene mutation, and no surgery is
needed (413). Finally, pituitary apoplexy, typically a hemorrhagic complication of a pituitary tumor (usually previously
undiagnosed), manifests itself as a sudden-onset headache, and on imaging, a sellar mass with extension along the stalk is
identified. The mass shows homogeneous or heterogeneous high signal intensity on T1-weighted images secondary to the
intratumoral hemorrhage; the diagnosis is made by a combination of the history and neuroimaging appearance (414). This is an
emergency condition, as permanent visual loss may result if the acute compression of the optic chiasm is not rapidly relieved.
If this appearance is identified by the neuroradiologist, the referring physician must be contacted immediately, or the patient
should be referred to the nearest emergency department.
Figure 7-78 Invasive adenoma. A. Parasagittal T1WI shows the multilobular tumor (T) expanding the sella, lifting the diencephalon (black
arrow) and permeating the bone (note the image of the sellar ghost) to invade the sphenoid body, the clivus, and the retropharyngeal soft
tissues. B. Coronal T2WI shows the tumor extending into the cavernous sinuses, the right temporal fossa, the right frontobasal brain (large
white arrows), and in the left cavernous sinus (small white arrow). C and D. Sagittal and coronal T1WI post-contrast images demonstrate the
heterogeneous enhancement of the mass as well as its extension into the supra-, infra- and parasellar structures, with the encasement of the
internal carotid arteries (white arrows in D).
■■ Valdueza et al. have proposed a clinicotopographic classification of HHs. Type Ia hamartomas are small, with a
pedunculated attachment to the tuber cinereum, while type Ib hamartomas are small pedunculated masses attached to a
mammillary 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 mammillary 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 (429).
■■ Delalande and Fohlen proposed a surgical classification in four types. Type I hamartomas have a horizontal insertion and
may be symmetric or lateralized; they can be approached by a pterional route. Type II hamartomas have a vertical insertion
and grow into the ventricle; they can be approached by endoscopy. Type III hamartomas are a combination of type I and II
and need a combined surgical approach. Type IV hamartomas are too large to be surgically addressed (425).
■■ A more recent classification, proposed by Li et al. from a large series of 214 cases, correlates well with the clinical
expression of the disorder. Type I hamartomas are infratuberal and pedunculated (36%); type II are infratuberal and sessile
(12%); type III are transtuberal, bulging into both the interpeduncular fossa and the ventricle (straddling type, 41%); and
type IV are supratuberal intraventricular (11%). Precocious puberty was mostly associated with types I and II, epilepsy in
general, and gelastic seizures in particular were mostly associated with types III and IV. A combination of epilepsy and
precocious puberty was a feature of type II (15%) and mostly of type III (39%) (416).
Imaging findings
As CT is sensitive only to the presence of large HHs, MR is the study of choice: 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. 7-79); they are isodense with brain tissue.
Calcifications are uncommon; no enhancement is seen. Rarely, cystic components are present; if they extend into the adjacent
temporal fossa, the solid, nonenhancing tumor may be difficult to identify prior to shunting of the cyst.
MR is the study of choice, both for patients with precocious puberty and for patients with epilepsy. The former are
pedunculated anterior inferior hypothalamic masses (Fig. 7-80), while the latter are more posterior and not pedunculated. MR
demonstrates a well defined, round to ovoid mass that lies within the hypothalamus and typically involves the region of the
mammillary bodies, sometimes extending anterosuperiorly into the third ventricle (Fig. 7-79), inferiorly to be suspended from
the floor of the third ventricle (Fig. 7-82), or into the lateral wall of the hypothalamus (displacing the postcommissural fornix
and hypothalamic gray matter anteriorly) (Fig. 7-81) (418). Pedunculated or not, HH are isointense compared with gray matter
on spin-echo T1-weighted sequences, hypointense on inversion-prepared gradient echo T1-weighted sequences (418), and
isointense to slightly hyperintense on T2-weighted sequences (Figs. 7-79 to 7-82). They range in size from 3 to 70 millimeters
in diameter (416). The larger hamartomas are often heterogeneous on both T1- and T2-weighted images and some regions may
be quite hyperintense on T2-weighted and FLAIR sequences (Fig. 7-82); the regions of hyperintensity seem to correspond to a
histologically identified increased glial component (430). No enhancement is seen after intravenous administration of
paramagnetic contrast. Occasionally, large associated cysts (Fig. 7-83) are seen in the suprasellar cistern and 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.
Figure 7-79 Hypothalamic hamartoma within the floor of the third ventricle. A. Postcontrast CT scan shows soft tissue mass (arrows) filling
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 (arrowheads) filling the floor of the third ventricle. D. Axial T2-weighted image
shows the mass (arrow) in the floor of the third ventricle remaining isointense to gray matter.
We have performed proton MR spectroscopy on a single HH in a neonate; as expected, the spectrum was similar 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 frontal lobe (418,431). The increased myo-inositol seems to be
associated with the astrogliosis that is often seen in the hamartomas histologically (418,430), 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 (432); it is present in 5% of LCH patients at the time of diagnosis, but
in 10% to 50% on follow-up examinations (336,433). CNS involvement is most common in patients with multisystemic
disease (336). Involvement of the CNS in LCH starts with the development of granulomas in the subarachnoid space, with
subsequent invasion of the hypothalamus and infundibulum. The lesions consist of diffuse parenchymal infiltration by CD1a+
histiocytes, CD68+ macrophages, T cells and B cells with nearly complete loss of neurons and axons, and surrounding
inflammation (337). Ultimately, such granulomas may develop throughout the brain parenchyma (226,336), meninges, choroid
plexus (434), pineal gland (435), and spinal cord (436). Brain parenchymal lesions in LCH, which are very rare, are discussed
briefly in the posterior fossa masses 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
stalk (437) to a frank hypothalamic mass. Mild thickening of the stalk is best seen using MR (Fig. 7-84) where it can be
appreciated in both the sagittal and coronal planes. Larger hypothalamic masses are easily identified, generally centered in the
superior aspect of the stalk (Fig. 7-85). Small or large, the mass enhances markedly after intravenous infusion of paramagnetic
contrast (Figs. 7-84 and 7-85). Prior to the onset of diabetes insipidus, the posterior pituitary retains its normal short T1
relaxation time. With the onset of diabetes insipidus, the high signal in the posterior pituitary on T1-weighted images
disappears (Figs. 7-84 and 7-85). The differential diagnosis of a thickened, enhancing pituitary stalk or a larger mass centered
in the stalk includes GCTs, 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 considerations need to
be strongly considered in children with diabetes insipidus (438).
Figure 7-80 Pedunculated hypothalamic hamartoma (precocious puberty). A. Midline sagittal T1WI. There is a mass (M) in the upper
prepontine cistern, slightly darker than the brain tissue. B. Midline sagittal T2WI. The mass (M) is brighter than the brain tissue. It is attached by
a thin peduncle to the tuber cinereum. It is clearly separated from the mammillary body. C. Midline sagittal T1WI post contrast shows no
enhancement.
Figure 7-81 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.
Figure 7-82 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.
Figure 7-83 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 intensity 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.
Figure 7-84 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 in C is seen despite the presence of the infundibular lesion.
Figure 7-85 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.
Figure 7-87 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.
Rarely, Rathke cleft cysts can become infected, resulting in a pituitary abscess (447). 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 (447).
Lymphocytic hypophysitis
Lymphocytic hypophysitis is an autoimmune inflammatory infiltration 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,
stalk, infundibulum, and hypothalamus (448,449). It is primarily a disease of adults, but children may be affected. Patients
typically present with headache or impaired vision. Hypothalamic–pituitary dysfunction, most commonly diabetes insipidus,
elevated prolactin, and reduced gonadotropins, ACTH, and growth hormone may be found on endocrinologic testing
(450–452). MR imaging (the neuroimaging study of choice) shows an enlarged hypothalamus, infundibulum, and, sometimes,
pituitary gland. The enlarged regions typically show uniform enhancement after administration of paramagnetic contrast. The
imaging findings are identical to those of suprasellar germinomas and LCH (450,451,453). Differentiation must be made by
clinical presentation, laboratory studies, or biopsy (451,452).
Hemispheric Tumors
As previously stated, supratentorial tumors are more common than infratentorial tumors in children less than 2 years and older
than 10 years of age. By convention, supratentorial tumors are the tumors that involve the forebrain: the cerebral mantle, basal
ganglia and thalami, sellar and suprasellar regions, and pineal region. In spite of their common thalamic extension, primarily
midbrain tumors are classically associated with the hindbrain. In terms of frequency, the most common supratentorial tumors
are gliomas, more specifically the astrocytomas, with their many histologic low- and high-grade subtypes.
Oligodendrogliomas are uncommon in children. Supratentorial ependymomas and embryonal tumors are not exceptional.
Glioneuronal tumors are a specific group as they involve both the gray and the white matter; they are therefore observed in
relation to the cortex, particularly the mesial temporal structures or the basal ganglia; they comprise the various types of
GGGs, dysembryoplastic neuroepithelial tumors (DNETs), and the PXAs. GCTs are usually found in the sellar–suprasellar and
the pineal regions and, much less frequently, in the basal ganglia.
Traditionally, brain tumors have been classified by their histology (66), which reflects their macroscopic cellular structure
and is well reflected by standard MR imaging. Following the recent advances in deciphering the genetic/molecular processes
involved in tumorigenesis, the most recent classification of the World Health Organization incorporated, in addition, some
basic molecular parameters (4), which resulted in several significant conceptual changes. As an example, an adult DA
(formerly grade 2) and an adult AA (formerly grade 3) are now considered a single tumor defined by the same genetic
mutations (454,455). Pediatric DAs differ genetically from the adult tumors, which is why they rarely evolve to malignancy.
PAs along the basal neural tube (cord, medulla, optic pathways, and hypothalamus) are genetically different from those in the
dorsal structures (cerebellum, cerebral hemispheres); therefore, the tumors behave differently and have different courses and
prognoses. In general, other than being different, the “mutation burden” is less in pediatric tumor types than it is in their
adult counterparts, and this is reflected by the prognosis: although histologically similar, the hemispheric glioblastoma has a
better prognosis in infancy than in late adolescence or adulthood (384). Modern molecular genetics of brain tumors
demonstrate that tumor genomics and topography are correlated, which makes developmental anatomy an important component
of the diagnosis. Therefore, although “classic” histologic classification is still what matches the MR features best (because
histology corresponds to structure and structure is what MR morphologic imaging depicts), age and topography have become
major factors in terms of clinical approach of the brain tumors.
Other than structural imaging and anatomy, benign and malignant processes may be differentiated by the use of specific
techniques such as spectroscopy or diffusion imaging. DWI must always be part of the assessment of brain tumors: in every
low-grade glioma, it shows high diffusivity (Dav or ADC). In contrast, all embryonal tumors and (to a lesser extent)
ependymomas present with a reduced Dav (low ADC). On MR spectroscopy, large lactate, lipid, and amino acids peaks are
suggestive of malignancy, but there is an overlap with the findings in low-grade gliomas, which make the approach meaningless
if used in isolation (390). In addition, inflammatory and dysplastic lesions may have spectroscopic characteristics identical to
those of malignant neoplasms (212). Other evidence suggests that increased blood volume within the tumor, as demonstrated by
perfusion imaging (44,118), correlates with higher tumor grade and worsened survival (375,456). Whereas all of these
characteristics, when combined with imaging, can help to characterize a mass as a neoplasm (390,457), ascertaining the
histology of the neoplasm still requires biopsy or resection.
DTI provides a quantitative measurement of the diffusivity of the protons (assumed to reflect the extracellular spaces); a
mapping of the FA (the dominant directionality of the fibers voxel by voxel); and tractography, which extrapolates the course of
the white matter bundles, voxel by voxel, from the FA data. The quantitation of the diffusivity provides information that is, for
clinical purpose, already provided by diffusion imaging. By contrast, FA mapping and tractography of axonal fascicles are,
together with fMRI, useful in the presurgical assessment of hemispheric tumors to appreciate the structure of the tumor and to
help the neurosurgeon to avoid the so-called eloquent cortical functional areas and white matter tracts (27,390,457–459).
Interaction of a tumor with the surrounding white matter may occur in several ways: (a) by displacing adjacent fascicles
without altering their structure; (b) by inducing vasogenic edema, which decreases the anisotropy (axial diffusivity is
maintained; perpendicular diffusivity is increased by the accumulated interstitial water); (c) by infiltrating the bundle, thereby
decreasing the anisotropy as the extracellular spaces become fragmented; and (d) by destroying the axons of the bundles among
which it developed (458). Edema and disruption of white matter bundles may be considered as evidence of malignancy
(458,459); a simple displacement, as evidence of low-grade, noninvasive tumor (27); infiltration without edema would suggest
an infiltrative although low-grade tumor, such as a LGG or an oligodendroglioma.
This approach, however, has limitations: both edema and infiltration result in a similar decrease of FA and cannot be
differentiated; in cases with marked edema or infiltration, the FA may even be so low as not to allow one to differentiate either
from axonal disruption. Field et al. proposed to combine these parameters into patterns: simple displacement associated with
normal or decreased FA, with normal or mildly increased diffusivity (pattern 1); normal location and orientation of the fibers,
with substantially decreased FA and increased diffusivity (pattern 2); decreased FA and increased diffusivity and directionality
diffusely disorganized in a way not attributable to mass effect (pattern 3); and complete loss of anisotropy (pattern 4). They
suggest that patterns 1, 2, and 1 and 2 combined could be found in both benign and malignant tumors; that pattern 3 is found in
infiltrating gliomas only; and that pattern 4 is found in malignant tumors (459,460). However, all the studies were done in adult
brain tumors, and all lacked a precise histologic correlation to distinguish, for example, peritumoral edema from diffuse
infiltration by tumoral cells.
The major application of DTI in the assessment of the hemispheric tumors is tractography, which has been used to
demonstrate normal anatomy as well as for assessing “eloquent” structures in the presurgical assessment of hemispheric tumors
(461–463). Because tractography is an extrapolation of the average directionality in a voxel, it may be mistaken: the diffusion
process occurs on a molecular scale and a 1-mm voxel actually contains thousands of fibers crossing in many directions.
However, for large axon bundles, the basic assumption is that the chosen bundle follows a regular, “logical” course, maintains
a similar orientation from voxel to voxel, and corresponds anatomically to a known trajectory, according to which appropriate
regions are “seeded” (i.e., the regions in which only one major bundle is expected to pass are selected). From a point of view
of clinical practice, the usefulness of DTI tractography has been confirmed by the use that is made of it on an everyday
basis in neurosurgery.
Hemispheric Gliomas
Astrocytic tumors are the most common brain tumors in children: together, they make up approximately 30% of supratentorial
brain tumors, with a slight male predominance in most series. All pediatric age groups are affected, although there is a slight
peak at age 7 to 8 years. The traditional division is into four specific subtypes according to their histopathologic features: the
PA WHO grade 1 (PA), by far the most common in children, ubiquitous within the CNS, with its variant the PMA, the WHO
grade 2 DA, the WHO grade 3 AA, and the WHO grade 4 GBM (4). The subependymal giant cell astrocytoma (SEGA) occurs
in the context of a tuberous sclerosis (TSC); it develops in the ventricles and will be described together with the other
intraventricular tumors, along with a brief discussion in Chapter 6. Cortical-based gliomas will be considered separately in
this chapter, as epilepsy-associated tumors.
Recent progress in our understanding of the genome demonstrates significant differences between tumors in children and
adults and, in children, significant differences in the same histologic subtype in different locations. For example, in
contradistinction with adults who develop DA, AA, and GBM, no IDH-mutant tumor is found in children; this correlates with
the fact that DAs in children almost never evolve into a malignant AA. In general, low-grade gliomas in children have very
few genetic alterations; they all converge to an activation of the MAPK-ERK-PI3K pathway, which results in an activation of
cellular proliferation and survival processes (384,385,464). As for the tumor location, whereas all PA are characterized by a
BRAF-KIAA1549 fusion (384,385,464), upregulation of FOXG1, NEDD4L, L1CAM, and CXCL14 is observed in hemispheric
PAs only, while LHX2 is overexpressed in the optic/hypothalamic PA; thus, these alterations correlate with the location of
the tumor, but not its appearance on imaging (465). In DA, a fusion mutation of MYB, a point mutation BRAFV600E, and an
intragenic duplication of the tyrosine kinase domain of FGFR1 are the most common observed genetic alterations; again,
imaging correlates have not been identified.
Pilocytic astrocytomas
The PA is the most common, the most typical, and the most benign pediatric brain tumor. It may be found anywhere in the CNS:
spinal cord; medulla and cerebellum (about 50%); anterior optic pathways–hypothalamus (about 25%); and basal ganglia,
thalamus, and cerebral mantle (about 25%). Histologically, the tumor has a dual architecture, with solid nodular components
made of elongated bipolar cells and abundant Rosenthal fibers combined with loose glial components made of multipolar cells
(protoplasmic astrocytes), eosinophilic granular bodies, and multiple microcysts (which may coalesce to form the large cysts
that often characterize the tumor). PAs strongly express GFAP and are highly vascularized tumors, but the vessels may be
hyalinized, which explains the common presence of lactate on MR spectra. Tumor calcification is uncommon, but when
present, it may be prominent. PA on the brain surface tends to infiltrate the meninges. Macroscopically, PAs have a different
appearance in different locations: infiltrative in the cord and optic pathways–hypothalamus; exophytic in the brainstem; and
well circumscribed and solid/cystic in the cerebellum and cerebral mantle. In our experience, PAs within the cerebrum are
distributed evenly in all lobes; they are uncommon in the mesial temporal structures (466).
Anaplastic astrocytoma (grade 3) Solid necrotic, surrounding edema, enhancing; mildly reduced Dav in hypercellular nodules
Glioblastoma (grade 4) Large necrotic center, surrounding edema; reduced Dav in solid areas
Young infants. Solid part cortical, enhancing, invades meninges; cyst in white matter. Calcification common.
Normal Dav
Dysembryoplastic Neuroepithelial Cortical location, well circumscribed. Marked T2 hyperintensity; septations bright on FLAIR
Tumor
Ependymoma Anywhere between ventricle and cortex. Often huge, solid/cystic, calcified, enhancing. Intermediate Dav.
Primitive neuroectodermal tumor Young infants. Anywhere, compact heterogeneous, reduced Dav
CT of the brain is not necessary for diagnosis but is often the first study done to investigate the presenting symptoms. It
reveals four basic morphologies: solid, solid/cystic with nonenhancing cyst wall, solid/cystic with enhancing cyst wall, and
solid necrotic (172). The solid portion of the tumor tends to be iso- to hypodense prior to intravenous contrast administration.
After infusion of contrast, the solid portion may enhance completely, partially, or not at all. The tumor can be solid, sometimes
with a central area of necrosis, or both solid and cystic. The membrane of the cyst itself may enhance or not. Therefore, it is
important to administer contrast when cysts are detected, as the presence of an enhancing mural nodule (Fig. 7-88) makes the
diagnosis of cystic PA likely. The tumor is well demarcated, and there is no or only mild peritumoral edema. If the tumor
involves the cortex, it is more likely to be a GGG.
MR imaging is mandatory for the diagnostic and presurgical assessment. PAs typically appear as well-demarcated masses,
solid, cystic, or both. The solid portion is iso- or hypointense on T1WI as compared to the surrounding brain and hyperintense
on T2WI and FLAIR (Figs. 7-88 and 7-89). Increased diffusivity (Dav) is observed, as in all low-grade gliomas. FLAIR is
considered the best sequence to appreciate the extent of tumor. On T2 and FLAIR (better to differentiate its content from the
CSF), the cystic component(s) may be single or multiple, small, about the size of the solid nodule, or huge with expansion into
the adjacent ventricle. The fluid in the cyst typically appears brighter than the CSF on FLAIR due to its high protein content; it
may be hemorrhagic, with blood cell layering to form a fluid–fluid level. It may even be difficult to differentiate the cystic from
the solid tumor solely on a noncontrast MR. Little or no vasogenic edema is present in the surrounding white matter. The solid
portion demonstrates prominent enhancement in most cases; the wall of the cyst may or may not enhance. The solid or solid
necrotic subtypes are observed in about half the cases in our experience.
On MR spectroscopy, the solid portion of PA has a high Cho/Cr ratio reflecting the cellular proliferation, and a rather
decreased NAA/Cr ratio (211). Lactate is often increased, which can be explained by the hyalination of the vessel walls,
resulting in a degree of ischemia. A significant residual peak of NAA is observed, which is not expected in a tumor that
contains no neurons or axons: a recent report suggests that this peak is more likely to be related to the presence of other
chemicals carrying an N-acetyl group, such as N-acetylated sugars (394).
Diffuse astrocytoma
Diffuse astrocytoma (DA; WHO grade 2) is less common than is PA in children. As mentioned above, the tumor is genetically
different from the DA in adults, with a low mutation burden. Histologically, DA shows a high cellular density of fibrillary
astrocytes, with nuclear polymorphism, intercellular edema, and microcysts. The edges of the tumors are blurred as they
infiltrate the surrounding white and gray matter. No eosinophilic granular bodies or Rosenthal fibers (different from PA) and no
significant mitotic activity or vascular proliferation (different from AA or GBM) are identified. The temporal lobe is affected
more often than are the other lobes, in particular the mesial temporal lobe (466). DA in children almost never evolves into a
malignant astrocytoma; when it does, it occurs in late teenagers.
CT imaging, if performed, shows the tumor as a diffuse homogeneous, hypoattenuating lesion of white matter, associated
with mass effect, occasional microcalcification, and no enhancement. On MR imaging, the lesion appears as a homogeneous
mass that is hypointense on T1, hyperintense on FLAIR and on T2, and diffusivity similar to white matter. No blood elements
are seen on susceptibility imaging. The mass effect results in compression of the adjacent ventricle, midline shift, and
effacement of the adjacent pericerebral spaces. Uncommonly, the calvarium may be remodeled, which reflects the slow growth
of the tumor. The interface of the tumor with the surrounding brain, white matter, and cortex may be blurred, as it infiltrates the
surrounding parenchyma; the axons, however, are relatively spared, explaining the contrast between the extent of the tumor and
the (often) mild neurologic deficits. No surrounding edema or enhancement is usually identified, but the vessels within the
tumor may appear prominent (Fig. 7-90). MR spectroscopy may demonstrate low NAA, high choline, and high myo-inositol,
but no lactate or lipids. Perfusion studies demonstrate low CBV (457).
Figure 7-88 Cystic pilocytic astrocytoma (grade 1). A. CT without contrast demonstrates a low-attenuation lesion in the left anterior frontal
lobe. B. CT post contrast shows enhancement of a medial solid nodule (arrow) that was not apparent on the precontrast scan. C. MRI, sagittal
T1WI shows a hypointense lesion in the anterior frontal lobe. D. Axial T2WI better shows the lesion, with the solid nodule (black arrow) seen on
its medial aspect. E. Coronal FLAIR image shows the mass (M) as slightly brighter than the surrounding tissue. The hyperproteinaceous fluid in
the cyst does not cancel out. F. T1WI postcontrast coronal image shows enhancement of the solid portion of the tumor (T), but not the wall of
the cyst.
High-grade astrocytomas
High-grade hemispheric astrocytomas, either AA or GBM, are uncommon but do occur in children. They differ genetically
from adult tumors, with no IDH mutation (467), and also different locations, with those located in the hemispheres having a
better prognosis than those along the midline (brainstem, thalamus and basal ganglia) (468). Whereas the prognosis of an AA in
an adult is not much different from that of a DA (4), AAs in children are treated as high-grade gliomas like GBM. Clinically,
most develop in the hemispheres, with fewer in the basal ganglia, and present with headaches, vomiting, papilledema, seizures,
and neurologic deficits; the duration between the first symptoms and the diagnosis is short. Histologically, as compared with
DA, AAs have higher cellularity, distinct nuclear atypia, and high mitotic activity; they infiltrate the surrounding parenchyma.
In addition, GBMs manifest a significant degree of necrosis. Both are most commonly located in the frontal or the temporal
lobes (less commonly temporo-occipital or parietotemporal) and are typically large, with 60% above 4 cm in diameter.
Figure 7-89 Solid pilocytic astrocytoma (grade 1). A. Coronal T1WI shows well-demarcated hypointense mass (black arrow) in the parietal
lobe. B. Parasagittal T2WI shows the mass to be hyperintense and finely heterogeneous with surrounding edema (e). C. Axial FLAIR image
shows heterogeneity but with no significant cystic component and minimal hyperintense surrounding edema (e). D. Diffusion imaging shows
heterogeneity without reduced Dav. E. T1WI postcontrast image shows heterogeneous, diffuse, patchy enhancement of the mass (black
arrows).
Figure 7-90 Diffuse astrocytoma (grade 2). A. FLAIR imaging shows extensive homogeneous lesion (T) involving the posterior part of the left
hemisphere, brighter than the normal parenchyma, involving the cortex and white matter. B. Coronal T2WI shows a bright, well-demarcated
and homogeneous mass without edema. C. Diffusion image shows low diffusivity mass. This sequence seems to show that the cortex is less
involved than the white matter. D. T1WI postcontrast image shows no enhancement, but is traversed by prominent vessels, suggesting
increased blood flow. E. FA map fails to reveal any white matter tract in the mass, presumably due to disorganization of axons by tumor cell
infiltration, which contrasts with rather mild neurologic symptoms.
CT shows AAs as heterogeneous, hypoattenuating masses and GBMs as discrete, partly necrotic masses with irregular ring-
like or a patchy enhancement; hemorrhages and calcifications may be found. On MR, AAs usually demonstrate no necrosis,
hemorrhage, or enhancement but are heterogeneous on T2 and FLAIR as compared with a DA (Fig. 7-91). MRS demonstrates
high choline, low NAA, and low myo-inositol, and importantly, neither lipids nor lactate are increased (457). GBMs appear as
foci of hypercellularity (patches of moderately reduced Dav) and are often associated with patches of enhancement; necrotic
cysts are also typically surrounded by irregular rings of enhancement (Figs. 7-92 and 7-93). Microbleeds can be shown on
susceptibility imaging and are a marker of malignancy (Fig. 7-93). Peritumoral edema is almost always present and may be
difficult to differentiate from infiltrating tumor; this difference may be irrelevant, however, as tumoral nodules may be found in
the normal-appearing parenchyma at a distance from the core of the tumor. MRS shows high choline and low NAA, high lipids,
and high lactate, in contradistinction to AA (457). Histologic (and genetic) variants of GBM such as the epithelioid GBM or
the gliosarcoma demonstrate features that overlap those of the classic GBM.
Oligodendrogliomas
Although oligodendrogliomas are usually considered as rare tumors in children, they appear to be common in some reports
(469), suggesting that pathologists may not agree on the histologic criteria. They are usually felt to constitute approximately 1%
of pediatric brain tumors, compared with 5% to 7% in the general population. They differ genetically from the adult tumors,
with no IDH mutation and no combined 1p/19q codeletion, other than in rare late adolescent cases. A genetic defect associated
with the pediatric oligodendroglioma has not be found yet, except in rare cases of oligodendroglioma-like meningeal
carcinomatosis where a concurrent BRAF-KIAA1549 gene fusion and 1p deletion are common (470). Affected children (most
commonly males) typically present with seizures; other symptoms include headache, visual field defects, and weakness
(471,472). The prognosis seems to be better for the hemispheric oligodendrogliomas than for the centrally located tumors
(472). Histologically, the tumor involves the cortex as well as the white matter (but without demonstrating ganglion cells) and
is moderately cellular, with uniformly rounded hyperchromatic nuclei and prominent clear cytoplasm associated with a
delicate capillary network, microcalcifications, and commonly mucoid–cystic degeneration, but no or little mitotic activity
(473). The tumor may be anaplastic, with increased cellularity, increased mitotic activity, cellular atypia, endothelial
proliferation, and necrosis; neoplastic oligodendrioglial and astrocytic components (oligoastrocytoma, simple or anaplastic)
may be present (473).
Figure 7-91 Anaplastic astrocytoma (grade 3). A. FLAIR image shows compact, mildly heterogeneous mass surrounded with prominent
edema. B. T2WI shows a heterogeneous large mass with extensive midline shift and cavitation, surrounded by edema. C. Diffusion imaging
demonstrates reduced Dav in the noncavitary region of the mass (compare with Fig. 7-89D). D. T1WI postcontrast demonstrates patchy
enhancement in central regions of the mass that were of lower intensity in (B); these areas differentiate AA from DA.
Figure 7-92 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.
Figure 7-93 Glioblastoma multiforme (grade 4). A. Axial FLAIR image shows a large compact, heterogeneous mass (M), isointense to the
surrounding parenchyma with mild surrounding edema. B. Coronal T2WI shows the mass to be isointense to cortex. Some adjacent edema is
found. C. Gradient echo image shows hypointense blood components (B) strongly suggestive of a high-grade tumor. D. Sagittal T1WI
postcontrast image shows enhancement of the principal mass in the temporal lobe (black T), extending into the parietal lobe, where it shows
ring enhancement with central necrosis (white T).
The CT appearance of oligodendrogliomas in children is one of round to oval, sharply marginated masses that originate at
the cortical–white matter junction and are hypo- to isodense compared with gray matter prior to contrast infusion. Contrast
enhancement is variable, but usually only subtle. Calcification and cysts (Fig. 7-94) are common (472,474). As the lesions
grow slowly, the inner table of the calvarium may be remodeled or eroded when they are located at the periphery of the brain.
The MR appearance of oligodendrogliomas is nonspecific; they are most commonly sharply defined and mildly heterogeneous
with prolonged T1 and T2 relaxation times (474) and normal Dav. Regions of calcification may be hyperintense on T1-
weighted images or, if the calcification is dense enough, hypointense (Fig. 7-94A). Solid portions of the tumor may enhance
moderately after administration of paramagnetic contrast, but enhancement may be minimal or completely absent (Fig. 7-94D).
The presence of calcium and the absence of enhancement are associated with improved survival (474). A diagnosis of
oligodendroglioma may be raised when a tumor develops in the frontal lobe and is associated with calcification. Anaplastic
oligodendrogliomas have an appearance indistinguishable from high-grade astrocytomas, ependymomas, and PNETs: rim
enhancement and central necrosis.
Figure 7-94 Oligodendroglioma. A. Axial FLAIR imaging shows well-demarcated hyperintense, mildly heterogeneous lesion (O) in the
precuneus, with a central calcification (black arrow) represented by a lack of signal. B. Coronal T2WI shows a diffusely bright lesion with a
small central cyst (arrow). C. Diffusion imaging shows a high degree of diffusivity. D. Coronal T1WI postcontrast shows the lack of
enhancement.
When evaluating posttreatment oligodendrogliomas for recurrence, it is important to remember that low-grade
oligodendrogliomas have significantly elevated rCBV compared with low-grade astrocytomas and that both low-grade and
high-grade oligodendrogliomas have similar blood volumes (457,475,476), consistent with the increased microvessel density
seen in both low- and high-grade oligodendroglial tumors (477). 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 (477). Therefore, when
evaluating oligodendroglial tumor recurrence, proton MRS is superior to dynamic susceptibility-weighted perfusion imaging.
Gliomatosis cerebri
Gliomatosis cerebri is no longer considered a distinct entity; it is a particular spread pattern of many types of glioma (4). The
mechanism of this rare, diffuse parenchymal infiltration is not yet understood. It typically involves several lobes, including
central gray matter, both hemispheres asymmetrically, and, sometimes, the posterior fossa. The malignant cells are typically
astrocytic, but may also be oligodendroglial or mixed, distributed diffusely (type I), or be in additional local solid masses,
often of higher grade (type II) (478). Pathology shows diffuse proliferation of glia with destruction of myelin; diverse
histologic features of DA, AA, GBM, oligoastrocytoma, or anaplastic oligoastrocytoma compose a grade 2 (18%), grade 3
(70%), or grade 4 (11%) tumor. Angiogenesis is seen in the high-grade tumors only (478). As a result of the rarity of the
disease in the pediatric population, data about the molecular biology of the tumor are scarce. The outcome after treatment is
poor, with survival typically less than 2 years; it is longer for low-grade tumors and for the oligodendrocytic subtype (478).
Clinically, the most common symptoms are seizures (55%), symptoms of high ICP (37%), and cognitive/behavioral changes
(17%) (478). CT is of little use for the diagnosis, showing a medium attenuation tumor. MRI features are more diagnostic,
including in type I a diffuse, poorly defined area of increased signal on T2 and FLAIR sequences, asymmetrically involving the
white matter, corpus callosum, basal ganglia, and thalamus as well as the posterior fossa (Fig. 7-95); this is commonly
mistaken for inflammatory or demyelinating conditions, myelin metabolic disorders, or pseudotumor cerebri. In type II, local
masses develop with vascular proliferation, enhancement, and, sometimes, necrosis (478).
Diffuse leptomeningeal gliomatosis
In diffuse leptomeningeal gliomatosis, the leptomeninges are diffusely invaded by a glial tumor without any apparent intra-axial
primary tumor. Symptoms are usually headaches and other features of increased intracranial pressure, seizures, confusion, back
stiffness, and mild neurologic deficits involving particularly the cranial and spinal nerves. Imaging is characterized by diffuse
involvement of the leptomeningeal spaces, best seen on FLAIR (hyperintensity of the meninges) and on postcontrast studies
(enhancement on T1WI) (Fig. 7-96). The brain typically demonstrates hydrocephalus and diffuse parenchymal edema (Fig. 7-
96A). Special attention should be applied to looking for a primary tumor in the brain and in the cord, because this could be
the target of a specific treatment. The differential diagnoses include low- and high-grade gliomas, medulloblastomas and other
embryonal tumors, and GCTs. Imaging appearances are often misinterpreted as a meningitis, but signs of infection are lacking;
the specific diagnosis of gliomatosis can be made by a lumbar puncture only.
Supratentorial Ependymomas
As mentioned in the section on posterior fossa tumors, ependymomas were once assumed to derive from differentiated
ependymal cell rests found posterior to the occipital horns and along the tela choroidea (76). Current evidence suggests that,
like other CNS tumors, ependymomas result from mutated stem cells: those producing ependymomas have been shown to be the
radial glia cells (19); in the cerebral hemispheres, radial glia span the whole thickness of the brain mantle, explaining why
supratentorial ependymomas are characteristically extraventricular and may even be strictly intracortical (19,479). Very rarely,
for uncertain reasons, the tumor may even develop outside of the hemisphere (480). While they are histologically similar in
different parts of the CNS, ependymomas are biologically and molecularly different diseases in each location; therefore, their
clinical and prognostic features differ with location. In each compartment (cord, lower medulla, upper medulla,
hemispheres), ependymomas recapitulate the regional gene expression profiles. In the hemispheres, other than the
subependymomas, YAP1 fusion and RELA fusion characterize two distinct entities, with a better outcome for the former and a
poor outcome for the latter (201). In contrast, the classic distinction of grade II and grade III may not be significant because of
poor interobserver reproducibility (201,481).
Figure 7-95 Gliomatosis cerebri. A and B. Axial FLAIR images show a diffuse, ill-limited area of hyperintensity in the right frontal lobe,
extending to the left hemisphere through the corpus callosum, with a moderate mass effect. C. Coronal T2WI shows similar appearance. D.
Coronal T1WI post contrast reveals low intensity (black arrow) in the right frontal white matter, but no enhancement.
Supratentorial ependymomas constitute between 20% and 40% of childhood ependymomas (196), occurring in males more
commonly than females with a peak incidence between ages 1 and 5 years. The presenting symptoms reflect the location of the
tumor. Whereas signs of increased intracranial pressure with papilledema, focal seizures, and focal deficits are the most
common reasons for presentation (196), ventricular hemorrhage may signal the tumor’s presence. Usually, supratentorial
ependymomas originate in the SVZ (where the dormant radial glia are located) and extend across the mantle or, less commonly,
toward the ventricle. However, as the radial glia span the whole thickness of the mantle, ependymomas may develop anywhere
between the SVZ and the cortex; they may even be strictly intracortical (200,479). The tumor is characteristically large, solid
and cystic, often calcified, and, occasionally, hemorrhagic. When developing in young children, they may cause enlargement of
the hemicranium and remodeling and even erosion of the calvarium. Supratentorial ependymomas are identical histologically to
their infratentorial counterpart, but the clear cell variant is more common in the supratentorial space in children; it is also more
likely to recur or to be associated with ventricular and leptomeningeal metastases (482). The anaplastic subtype demonstrates
more vascularity and more necrosis. In contrast to DAs, ependymomas are considered to have fairly well-defined margins at
their periphery, which makes complete tumor resection at surgery more likely (483). However, some evidence suggests that
invasion of the surrounding parenchyma can occur along the axonal tracts and the small vessels and may even result in the
development of secondary tumor nodules (200).
Figure 7-96 Diffuse leptomeningeal gliomatosis cerebri. A. Axial FLAIR shows high-pressure hydrocephalus with periventricular interstitial
edema. The cisternal spaces in the pineal region (black arrows) are brighter than the parenchyma. B and C. Axial and sagittal T1WI
postcontrast images demonstrate diffuse leptomeningeal enhancement secondary to diffuse dissemination of tumor. No principal tumor was
found in the parenchyma. Histology disclosed a low-grade glioma.
On CT, ependymomas tend to appear as sharply demarcated tumors extending across the cerebral mantle and/or bulging into
the ventricle. They are often large, with solid and cystic components, the solid part being slightly heterogeneous, iso- to
hyperdense compared with normal brain on noncontrast CT scans; foci of calcification are commonly seen (Fig. 7-97). After
contrast administration, the solid portion of the tumor enhances variably. The diagnosis of ependymoma should be suggested
when a large isodense frontal or parietal juxtaventricular mass, with foci of calcification and cysts, shows heterogeneous
enhancement (484).
On MR, major characteristics of supratentorial ependymomas are the heterogeneity and juxtaventricular connection. The
heterogeneity results from the combination of solid tumor, calcification, cysts, necrosis, and, often, blood, which combine to
give a mixture of signal intensities with all imaging parameters (Fig. 7-98) (482,484,485). The typical tumor is large (up to 10
cm), solid, and cystic, usually in the frontal or parietal lobe (although it may also develop from the medial aspect of the
posterior temporal lobe, behind the thalamus, and must be differentiated from a thalamic tumor). The solid component may be
lobulated and iso-, hypo-, or hyperintense on T1 and on T2 as compared to surrounding parenchyma and is usually surrounded
by a rim of vasogenic edema. It is often hemorrhagic, particularly the anaplastic and the clear cell subtypes, and sometimes
necrotic. The solid, densely cellular portions show moderately reduced Dav. The associated cyst may be isointense or
hyperintense as compared to CSF, depending on its protein or blood residue content; it may be huge, filling the enlarged
ventricular lumen. After contrast administration, the cyst wall and the solid portion enhance, the latter typically diffusely but
heterogeneously (482,484,485). MR spectroscopy is nonspecific, with elevated choline and, occasionally, a lactate peak.
Perfusion shows increased CBV in the anaplastic subtype (484).
Figure 7-97 Supratentorial ependymoma. A. Axial noncontrast CT scan shows a hemispheric mass (arrows) that is isodense with gray
matter. A small focus of calcification (open arrow) is seen within the tumor mass. There is mild surrounding vasogenic edema. B. After infusion
of iodinated contrast, there is heterogeneous contrast enhancement.
The diagnosis is more difficult when the tumor develops in the cortex, which is not uncommon (9/49 supratentorial
ependymomas) (479). The tumor is typically mixed solid/cystic (Fig. 7-99A), but may be purely solid (Fig. 7-99B) and (on
CT) dense with calcification; the adjacent calvarium may be remodeled. On MR, the mass is hypointense on T1 and
heterogeneously hyperintense on T2, with surrounding edema and variable enhancement after contrast administration (479); as
in the other locations, Dav is reduced. It is important to assess precisely the cortical anatomy with fMRI or DTI prior to
surgery because of potential surgical injury to eloquent areas. Beyond the cortex, fully exophytic midline ependymomas have
been described in adults, usually mistaken for meningiomas (480).
The differential diagnosis of supratentorial ependymomas is broad. They can appear homogeneous on MR (and thus be
indistinguishable from low-grade astrocytomas) or ring enhancing with extensive edema (indistinguishable from a high-grade
astrocytoma or a PNET). When composing a differential diagnosis for a supratentorial brain tumor in a child, one should
remember that ependymomas are juxtaventricular masses seen primarily in young children. Schematically, a heterogeneous
midline tumor in a child in the first year of life (especially in the first 6 months) should first be considered a teratoma. Tumors
that are not primarily juxtaventricular but develop across the hemisphere should suggest diagnoses of PA, DAs, and high-grade
gliomas. Reduced diffusivity differentiates gliomas from ependymomas and, still more, from embryonal tumors. When
heterogeneity is seen in a supratentorial tumor that is off the midline and juxtaventricular, ependymomas, PNETs, and
ATRTs should be considered, especially if the child is between the ages of 1 and 5 years; both PNET and ATRT tend to
demonstrate a markedly reduced Dav. When a markedly heterogeneous intraventricular tumor with periventricular extension is
seen, the diagnosis of a CPC should be suggested.
Figure 7-98 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.
Figure 7-99 Cortical ependymomas: solid/cystic and solid appearances. A. T1WI post contrast shows the classic solid/cystic appearance.
The solid portion is located in the cortex; the cyst develops medially within the white matter without reaching the ventricle. B. T1WI postcontrast
image shows solid appearance; the cortical-based tumor is small and enhances uniformly with no characteristic feature to suggest the
diagnosis of ependymoma.
Figure 7-100 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 markedly 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.
Figure 7-101 Nearly homogeneous primitive neuroectodermal 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 hypointensity may
represent calcium or blood. B. Axial T1-weighted image shows the central area as hyperintense (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 abnormal signal on the noncontrast exams was blood due to the
necrosis.
Figure 7-102 Intraventricular primitive 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 hyperintense center. B. Postcontrast axial T1-weighted image shows
heterogeneous 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.
Hemispheric medulloepithelioma
Medulloepithelioma is the name given to a very rare tumor that typically presents in the first 5 years of life with headache,
nausea, and vomiting secondary to increased intracranial pressure (76,492). These tumors most commonly develop from the
optic nerves, but cases have been reported in the periventricular region of the cerebral hemispheres, as well as in the
suprasellar region (410), cerebellum, or brainstem. They are characterized histologically by a papillary, tubular, or trabecular
arrangement of cells with an external and internal limiting membrane that mimics the structure of the primitive neural tube
(76,492). 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 (76,492). Neuroimaging characteristics are similar to other
cerebral embryonal tumors, except that enhancement is uncommon or only faint after administration of intravenous contrast
material. On noncontrast CT, medulloepitheliomas are typically well-circumscribed, homogeneous masses that are iso- to
slightly hypodense (492). MR shows sharply marginated masses that are hypointense on T1-weighted images and hyperintense
on T2-weighted images; slight internal heterogeneity (often from hemorrhage or necrosis) may be seen, particularly in large
tumors (Fig. 7-103). The lack of enhancement in a malignant-looking mass should raise the possibility of a medulloepithelioma
(492).
Hemispheric atypical teratoid/rhabdoid tumor
ATRTs are neoplasms of unknown histogenesis that were named because their light microscopic appearance resembles that of
rhabdomyosarcoma. They are included in the group of embryonal tumors of the CNS in the last WHO classification, together
with the medulloblastoma (4). Genetically, they are characterized by the loss of the SMARCB1 gene on chromosome 22q11.2
(493). This gene is involved in the remodeling of the nuclear chromatin and plays a role in the control of cell proliferation and
differentiation, acting as a tumor inhibitor. ATRTs rarely arise in the brain, accounting for 1.3% of primary CNS tumors in
children, but represent 6.7% of CNS tumors before the age of 2 years (77); ATRT is primarily a malignant neoplasm of the
kidney (133,148,494). 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 disturbances. Prognosis continues to be dismal, with survival of less than 18
months in most cases (135). Some authors suggest that gross total resection improves prognosis, but the tumors are typically so
large at the time of presentation and the locations so challenging that total removal is not possible (136). 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.
Figure 7-103 Medulloepithelioma. T1WI (A), T2WI (B), and DWI (C) show a huge intraventricular tumor (T) with central hemorrhagic
necrosis, which blocks CSF flow to result in severe hydrocephalus. The solid portion of the mass is hypointense on T1 and T2, with strongly
reduced diffusivity (C) and only faint enhancement (D).
Pathologically, the tumors 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 cytoplasmic hyaline inclusions. These 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” (495).
On imaging studies, the tumors are usually intra-axial and large (averaging 5 cm in diameter) at the time of patient
presentation (Figs. 7-104 and 7-105). The masses are typically solid with areas of necrosis, hemorrhage, or calcification; the
solid regions are iso- to hyperdense to gray matter on CT (Fig. 7-104) and isointense to gray matter on MR (135). DWI reveals
reduced diffusivity compared with surrounding white matter (136). Areas described as cysts, but having the appearance of
necrosis (irregular walls, see Figs. 7-104 and 7-105), are present in nearly all at the time of presentation. Solid portions
enhance heterogeneously after infusion of intravenous contrast (136,148,494). Leptomeningeal tumor dissemination is present
in about 20% of patients at the time of presentation. Proton MR spectroscopy shows elevated choline and reduced NAA, but
these changes are not specific and have not been quantified (136). An ATRT cannot be differentiated from an ependymoma or a
PNET 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).
Figure 7-104 Atypical teratoid/rhabdoid tumor. A. Axial noncontrast CT image shows a large heterogeneous mixed hyperdense and
hypodense mass (arrows) in the left posterior parietal lobe, with anterior vasogenic edema. B. Axial T1-weighted image shows the
heterogeneous mass (arrows) appears grossly well marginated. C. Axial T2-weighted image shows that the solid portions of the
heterogeneous mass are isointense to gray matter. Hyperintense portions probably represent necrosis and hypointense portions likely
represent hemorrhage. D. Postcontrast T1-weighted image shows heterogeneous enhancement. The imaging appearance of these tumors is
identical to those of PNETs and ependymomas.
Figure 7-105 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 heterogeneity, 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 portion (black arrows).
Astroblastoma
The current concept of this tumor derives from the work of Bonnin and Rubenstein (496), who described a tumor of children
and young adults that is generally solid, well circumscribed, and defined histologically by the presence of astroblastic
pseudoresettes and prominent perivascular hyalinization. It is now classified as “CNS embryonal tumor NOS” in the WHO
classification (4), although recognition of astroblastoma as a distinct entity was supported by the work of Brat et al. (497), 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 (497). Presenting symptoms are typical of large cerebral tumors, most commonly headaches,
vomiting, and seizures.
Figure 7-106 Astroblastoma. Large cystic tumor with a mural nodule (arrow) that appears heterogeneous and microcystic on T1 (A), FLAIR
(B), and T2 (C) imaging. It enhances weakly after contrast administration (D). Heterogeneity and poor contrast enhancement help in
differentiating it from a cystic PA.
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 present, with the solid component typically hypointense on T1-
weighted images and heterogeneous (largely of gray matter intensity with small, cystic-appearing heterogeneities and,
commonly, calcification) on T2-weighted images (Fig. 7-106) (498). Relatively little vasogenic edema surrounds the mass,
which appears sharply marginated by imaging (but not on pathology). Solid portions of the tumor enhance heterogeneously; ring
enhancement is seen around tumor cysts (498,499). Benign astroblastomas cannot be differentiated from malignant ones by
imaging criteria. No data concerning proton spectroscopy or perfusion imaging has been reported. Our experience with a single
malignant astroblastoma revealed markedly increased blood volume.
Lymphoproliferative disorders
Lymphoproliferative disorders, including CNS lymphoma, can develop in patients who have immunodeficiency syndromes,
such as Wiskott-Aldrich syndrome, AIDS, and X-linked lymphoproliferative disease (517), as well as in those who have
undergone solid organ or stem cell transplantation and are immunosuppressed to prevent rejection. As a result of the
immunocompromise, lymphoid growth proceeds 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
cytomegalovirus infection, the specific immunosuppressive regimen, the allograft type, and young (pediatric) age (518–520).
Lung, liver, and heart transplant recipients generally have higher risks than do recipients of renal transplants, possibly because
of the different immunosuppressive regimens (521). Involvement of the CNS is less common than is involvement of the thorax,
abdomen, or head and neck (522). 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 posttransplant setting. Affected patients may present with
focal neurologic signs/symptoms, seizures, or signs of increased intracranial pressure (headaches, nausea, vomiting)
(518–521).
Imaging typically shows multiple lesions surrounded by extensive interstitial edema (521,522). As is typical with
collections of lymphocytes, the lesions are iso- 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 (521). Differentiation of benign lymphocytic proliferation from frank lymphoma or infection is usually not
possible by imaging alone, so biopsy is typically performed. 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 diffusion and proton spectroscopic
characteristics of benign lymphoproliferation have not been described.
On CT, the tumor is hypodense, often cyst-like looking. Calcification is not rare. On MR imaging, the lesion is hypointense
on T1WI, hyperintense on T2WI, and finely heterogeneous: cystic or microcystic components are present in about 30% to 40%.
The cysts appear as sharply defined areas of very long T1 and T2 relaxation and, often, give the tumor a characteristic
lobulated or multilobulated appearance (Figs. 7-108 and 7-109) (529). On FLAIR sequences, the delicate septations, which
delineate the cysts, appear bright, as the free water in the cysts is suppressed (530). Spontaneous hemorrhages have been
reported. Contrast enhancement is seen in 20% to 40% and is typically patchy (531). It may appear in a delayed manner during
the surveillance of a previously nonenhancing tumor.
Although DNETs were initially considered stable tumors, they may change with time: they may progressively enlarge;
postsurgical residue may progressively increase in size; or a recurrence may develop in situ after an apparently total removal
(528). The histology of the primary lesion may change from a classic DNET preoperatively to an oligoastrocytoma, a DA, a
malignant astrocytoma, or a glioblastoma (Fig. 7-110).
Because of the marked variability in imaging appearance, the diagnosis of DNET should be suggested any time a
primarily cortical 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. On imaging, the differential diagnosis of
DNETs is usually said to include GGGs, low-grade cortical gliomas, and purely malformative focal cortical dysplasias. As for
FCDs, the cortex, even dysplastic, always remains recognizable, and an FCD never bleeds or enhances after administration of
contrast. GGGs share with DNETs the same distribution and cortical involvement, and the same clinical features; however,
they usually elicit more mass effect and commonly contain large cystic components, except along the mesial temporal lobe
where they are rather infiltrative. Obviously, a DA or an oligodendroglioma may be confused with a DNET when they are
small, are well circumscribed, and involve the cortex. MR spectroscopy is reported to be normal in DNET except for elevated
myo-inositol, while high choline and low NAA are observed in glioma/GGG (529). Dynamic susceptibility-weighted
perfusion imaging in DNET shows lower CBV than normal cortex (529).
Figure 7-109 Large classic DNET. A. Sagittal T1WI shows classic multilobulated, multiseptated, sharply defined parietal mass. B. Axial
FLAIR imaging demonstrates the classic pattern of multilocular cortical-based tumor (M) with a dark matrix (water is suppressed) contrasting
the bright septa. C. Coronal T2WI demonstrates the multilocular pattern well. D. T1WI postcontrast shows no enhancement; note that there is
a significant local edema.
Gangliogliomas/Gangliocytomas
GGGs and gangliocytomas are tumors in which neurons and glia, usually astrocytes, participate in the neoplastic process; in
this sense, they differ from most primary CNS gliomas in which only the glia show neoplasia. GGGs and gangliocytomas (also
called ganglioneuromas) are uncommon tumors, constituting approximately 3% of brain tumors in children and approximately
6% of supratentorial pediatric brain tumors, but they are more common in the context of epilepsy, as most of them develop from
the cortex, especially in the mesial temporal lobe. GGGs are found in older children and young adults more frequently than in
younger children or infants (77), and gangliocytomas, almost always in young adults. Males are affected slightly more
commonly than are females (532,533). Although the presentation occurs most often during the late first decade or early second
decade of life (532), it is not uncommon for patients with these slowly growing neoplasms to present for evaluation in
adulthood. For the cortical-based tumors, the history tends to be one of long-standing focal epilepsy; affected patients present
with seizures, most commonly partial complex epilepsy (532). Complete removal of the cortical-based GG is generally
curative whatever the presentation.
Pathologically, the tumors tend to be small, firm, and well defined, with frequent calcifications and cysts; the glial
component demonstrates a BRAFV600E mutation (386). The differentiation between GGG and gangliocytoma is histological.
Dysplastic neurons (ganglion cells) are a consistent finding in these tumors; if neoplastic glial elements are present, the lesion
is called a GGG, and when dysplastic neuronal elements are found in the absence of neoplastic glia, the term gangliocytoma
(or ganglioneuroma) is used (534). (The tumor “gangliocytoma” should not be confused with the “dysplastic cerebellar
gangliocytoma” or Lhermitte-Duclos syndrome, which is a cerebellar cortical malformation described in Chapter 5.) The
glioma component most often is PA; sometimes, DA, rarely AA, and even GBM may occur (535,536). Temporal lobe GGGs
can be seen in association with, and have been suspected to cause, mesial temporal sclerosis (537). All GGG may be
surrounded by a dysplastic cortex, now classified as an FCD IIIB and felt to be secondary to the epileptogenic activity of the
principal lesion (524).
Figure 7-110 Atypical aggressive DNET. A and B. Axial and coronal FLAIR images demonstrate a fairly typical DNET (arrows) of the right
anterior insular–opercular cortex. C and D. Subsequent axial FLAIR imaging shows progressive tumor growth despite multiple surgical
resections of the mass (see hypointense right temporal resection cavity in C). Over the years, the lesion became metastatic via CSF, as
shown by right gyrus rectus lesion (arrow) in C.
Interestingly, the imaging appearance of the GGG differs with location: the neocortical temporal cortex versus the mesial
temporal structures (466). In the neocortical areas (either frontal, parietal or temporo-occipital), the CT appearance of a
GGG is that of a low-density, well-circumscribed, and often solid/cystic lesion with little mass effect or edema and cortical-
based but otherwise not different from a usual PA (Fig. 7-111). Only occasionally, the tumor can elicit surrounding edema (low
attenuation). 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. Calcification is seen in approximately 35% of GGGs on CT. Contrast enhancement is
variable; part or all of the solid portion of the tumor may enhance, but contrast enhancement may be completely absent.
Sometimes, the adjacent dura enhances. As with other slow-growing tumors, erosion and remodeling of the adjacent inner table
of the calvarium may be seen when the tumor is peripherally located within the cerebrum.
Figure 7-111 Gangliogliomas. A. Axial contrast-enhanced CT scan shows a lesion of mixed signal 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 attenuation 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.
On MR imaging, the neocortical GGG typically has sharp margins. The cortex is involved together with the adjacent white
matter. The tumor may be solid (Fig. 7-11B), cystic (Fig. 7-112), or cystic with a mural nodule or have an appearance of many
small cysts (Fig. 7-113). Signal intensity on T1-weighted sequences is variable (and often mixed); T2-weighted sequences
generally reveal high signal intensity. As with all gliomas, their diffusivity is normal or increased. Regions of slightly
shortened T1 relaxation, probably representing calcification, may be helpful in identifying these neoplasms (Fig. 7-113). Solid
portions of the tumor variably enhance (Fig. 7-111B), with the enhancement sometimes extending to the overlying dura. As on
CT, the peripheral location within the hemispheres and the erosion of the adjacent calvarium can be helpful in making the
diagnosis of GGG. GGGs may be difficult to differentiate from PAs, oligodendrogliomas, and DNETs.
Figure 7-112 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).
Figure 7-113 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.
In the mesial temporal structures the presentation is very different, with the GGG usually appearing as a poorly
demarcated, infiltrative mass that can extend from the amygdala and the temporal pole anteriorly, to the tail of the hippocampus
posteriorly (466). The location and infiltration make the complete surgical removal of the mass difficult. The tumor is often
difficult to appreciate on CT, and on MR, the appearance is variable: a solid mass with faint low T1, high T2, and FLAIR
signals and no or faint enhancement detected; cysts may be present but not as prominently as the GGG in other locations. The
T1 signal may be high if the lesion contains microcalcifications, which is not an uncommon feature of GGG. From a surgical
perspective, an MR-based anatomic classification of these mesiotemporal tumors has been proposed, taking into consideration
the primary location and the extension of the tumor to determine the surgical approach: group A tumors are confined to the
amygdala, uncus, hippocampus, and parahippocampus; group B tumors are located in the fusiform gyrus; group C tumors are
mesial tumors that extend laterally (combined features of groups A and B); and group D tumors are mesial tumors that extend
superomedially toward the temporal stem and basal ganglia (538).
Desmoplastic Infantile Ganglioglioma (Desmoplastic Astrocytoma of Infancy)
The DIG (also called desmoplastic infantile astrocytomas of infancy, in cases with a major predominance of the astrocytic
component) (539–542) is seen primarily in infants and young children, with a male predominance. Patients with DIGs typically
present in infancy with macrocephaly or partial complex seizures, the median reported age of presentation being about 5
months of age (542); rarely, affected patients may present later in childhood (543,544). Like the GGG, DIG is characterized by
the presence of both astrocytic and ganglionic cells, but also by a prominent desmoplastic stroma (predominantly fibroblasts).
Despite areas that appear to have a high number of mitoses mimicking high-grade anaplasia, the tumors demonstrate a
surprisingly benign clinical course.
Evaluation with neuroimaging typically reveals a huge tumor, typically solid and cystic, arising in the cerebral hemisphere
(545). The solid part is cortical and often calcified, whereas the cystic component develops in the white matter, typically quite
large but occasionally relatively small at the time of the initial imaging study (542). Involvement of multiple lobes is common
with a predilection for the frontal and parietal lobes. The peripheral solid component is iso- to hyperdense compared with gray
matter on CT and may be diffusely calcified; MR shows the tumor as isointense to cortex on T1, iso- or heterogeneously hypo-
or hyperintense on T2, and with corresponding iso- or hypointensity on FLAIR sequences. Diffusion images are usually normal
but exceptions may occur (546,547), possibly due to the desmoplastic reaction. The solid portion and the adjacent meninges
enhance markedly after the administration of contrast (Fig. 7-114); the adjacent arteries may be encased. Enhancement is not
seen in the walls of the cysts. Complete resection of the tumor may be curative, when it is possible, obviating the need for
chemotherapy or radiation (545,548). It seems that, in some cases at least, spontaneous regression is possible (549).
The suggestion of DIG as a possible diagnosis in infants with large, partly cystic tumors containing peripheral, plaque-
like solid components is important to clinical management because the histologic characteristics may be confusing. In
addition to the characteristic 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 patients were reported to have been
initially treated aggressively with chemotherapy for high-grade malignancies before the correct diagnosis was made (548,550).
DIGs are differentiated from cystic astrocytomas by the peripheral location and the relatively high density (CT) and short T2
(MR) 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, PXA, PNET, and
ependymoma. If the leptomeningeal component of tumor is large, meningioma and meningeal sarcoma are differential
considerations.
Figure 7-114 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.
Pleomorphic Xanthoastrocytoma
In some ways, PXAs are very similar to DIGs and desmoplastic astrocytomas. All are disproportionately common in young
patients, typically arise peripherally in the cerebral hemispheres and involve the meninges, and have good prognoses despite
histologic features that suggest high-grade malignancy. However, PXAs are rarely diagnosed in infants, being discovered most
commonly in adolescents and young adults. In addition, affected patients most commonly present with seizures because the
cortex is nearly always involved. The temporal lobe is the most common site (~50%), followed by parietal lobe (15%–20%),
frontal lobe (10%), and occipital lobe (5%–10%) (551). As in other mixed neuronal–glial tumors, gray matter structures such
as the basal ganglia, cerebellum, or spinal cord may be sites of origin (552).
Pathologically, PXAs arise in the periphery of the cerebrum and often extend into and involve the leptomeninges, although
invasion of the dura is rare. Cystic components are seen in about half of cases and 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- and multinucleated giant cells and eosinophilic granular bodies are present within the fibrosis
(551,552). BRAFV600E mutation is found in PXA in GGGs and in PMAs (386).
On imaging, the classic appearance of a PXA is that of a large well-circumscribed peripheral temporal lobe mass. Solid
components are isodense to gray matter on CT, isointense to gray matter on T1- and T2-weighted MR images (Fig. 7-115A and
B), and mildly hyperintense to gray matter on FLAIR images (Fig. 7-115C). In a recent study of the diffusivity in PXA,
measurements demonstrated mildly reduced Dav in relation to the normal brain (553). The near isointensity to gray matter
helps to differentiate these from common astrocytomas, which typically have higher water content leading to hypodensity on
CT and T1-weighted MR images and more hyperintensity on T2-weighted MR images. Intratumoral hemorrhage has been
reported (Fig. 7-115A and B). Solid tumor portions enhance homogeneously (Fig. 7-115D) or heterogeneously (if microcystic
change is present). Surrounding vasogenic edema may be prominent, and large or small cysts (Fig. 7-115) are present in about
half of cases; enhancement of the cyst wall is variable (554,555). Invasion of the leptomeninges is common, seen in more than
two-thirds of studies (Fig. 7-115D). As with all slow-growing, peripheral tumors, remodeling of the inner table of the
calvarium is occasionally seen.
Figure 7-115 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).
Differential diagnosis depends on the age of the patient. In infants, DIGs and PNETs can have very similar appearances. PAs
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 superficial location of the PXA. In older children and
adolescents, the main differential diagnoses should include high-grade astrocytomas, oligodendroglioma, and GGG.
Angiocentric Glioma
Initially reported under the name angiocentric neuroepithelial tumor (556), ACG (WHO grade I) is characterized by refractory
partial-onset epilepsy in children and young adults, usually without neurological deficit. The lesion is indolent and typically
neither the tumor nor the seizures recur after gross total resection (557). Cortical based (but thalamic or midbrain locations are
seen), it also involves the white matter, often but not always with a transcerebral extension to the ventricle. Although
homogeneous and compact, this tumor has infiltrative borders, extends into the subpial spaces, and infiltrates the Virchow-
Robin spaces. Histologically, elongated bipolar cells, assumed to originate from the radial glia, form rings around the vessels.
Extension into the white matter is associated with demyelination. No cellular atypia, mitoses, endothelial proliferation, or
necrosis is found. Some neuronal components have been identified, but it has been argued that they might be normal neurons
entrapped by tumor infiltration (557). Like other glioneuronal tumors, the tumor is surrounded by FCD, which today is
classified as FCD IIIB (524).
On imaging, the tumor appears as a homogeneous, cortical-based mass that is ill demarcated due to infiltration of the gyral
white matter, often with a transcerebral extension (“stalk”) toward the ventricular wall: the cortex typically is not
recognizable. The affected gyrus appears bulky with effacement of the adjacent sulci but without edema or significant mass
effect. On MR, the cortical component is described as bright on T1 and bright on T2/FLAIR and the white matter component as
dark on T1 and bright on T2/FLAIR, again with no contrast enhancement (Fig. 7-116) (556,558). The T1 hyperintensity of the
cortex is difficult to explain, as calcification is not usual in the reported pathology; it may reflect a hypercellularity. Diffusion
characteristics have not been reported. The surrounding FCD IIID is not apparent on MR.
Meningioangiomatosis
Meningioangiomatosis is a disorder that involves the cerebral cortex and, often, the overlying leptomeninges (75). This rare,
benign, hamartomatous lesion is often mentioned in association with type II neurofibromatosis (562), but this is controversial,
and it is considered as being usually sporadic (563). Patients typically present as children or young adults with seizures,
headaches, or dizziness (564); seizures may be explained by the development of a cortical dysplasia secondary to the vascular
malformation (FCDIIIC) (524). In addition, many cases are found incidentally (565). Meningioangiomatosis found in NF2 is
usually an incidental finding, does not typically cause seizures, and is often multifocal; neurologic exam is typically normal
(563). The cause is unknown.
The characteristic pathology reveals a cortical meningovascular fibroblastic proliferation with leptomeningeal calcification
(565). Histologically, the disorder is characterized by transcortical fascicles of vascular fibromeninges that contain central
capillaries. Adjacent cortex may contain neurofibrillary tangles or hyalinization (565).
Figure 7-116 Angiocentric glioma. A. Sagittal T1 image shows slightly hypointense mass (T) in the posteromedial left frontal lobe. B and C.
Axial FLAIR and coronal T2 images show well-demarcated, pseudosegmental medial frontal cortical–subcortical tumor with minimal mass
effect; the cortex remains visible within the tumor. D. Sagittal T1 post contrast shows mass effect but no enhancement.
Figure 7-117 Papillary glioneuronal tumor (PGNT). A. Sagittal T2 image shows well-demarcated hypointense frontal tumor (T). B and C. Axial
FLAIR and coronal T2 images show well-demarcated compact mass extending from the ventricle to the cortical–subcortical junction; it
appears heterogeneous with thin bright trabeculation on FLAIR (B); trabeculations are more difficult to identify on T2WI (C). D. Coronal T1
postcontrast image shows heterogeneous, ring-like and patchy central enhancement.
On CT scans, meningioangiomatosis appears as a peripheral cortical abnormality that is hyperdense prior to contrast
administration; this likely represents diffuse microcalcification of the cortex, which is associated with hypomyelination in the
subjacent white matter (564). Coarse calcifications and cysts (perhaps loculations of CSF) may be present; no significant mass
effect is noted. MR scans show cortical iso- to hypointensity compared with gray matter on T1-weighted images and
hypointensity with a hyperintense periphery on T2-weighted images (Fig. 7-118) (564). The subcortical white matter may be
hypointense on T1 and hyperintense on T2 and FLAIR. After contrast injection, enhancement is variable from none to faint to
intense within the cortex and filling the sulci.
Figure 7-118 Meningioangiomatosis. A. Coronal T1WI shows thick, almost pachygyric right inferomedial cortex with adjacent low-signal
subcortical white matter reminiscent of a focal cortical dysplasia. B. Axial FLAIR demonstrates hyperintense right frontal white matter and (to a
lesser extent) adjacent cortex. C. Sagittal T1WI postcontrast image shows no enhancement in this case. Meningioangiomatosis was
confirmed by the pathology. The parenchymal changes correspond to a FCD IIIC.
Isolated LGG of the basal ganglia (LGGBG) are uncommon (about 10% of the central LGG). They seem to be centered at
the genu of the internal capsule, close to the foramen of Monro, medial to the caudate and anterior to the thalamus, with
possible extensions into the lumen of the lateral ventricle, the depth of the frontal lobe or laterally, toward the basal ganglia
(Fig. 7-119). More often, masses within the basal ganglia are associated with, and assumed to be extensions of, anterior optic
pathway tumors in a context of NF1. In such a context, whether the masses in the basal ganglia are massive, dysplastic “UBOs”
or real neoplastic processes is debatable. Finally, the globus pallidus also may be invaded by a lateral extension of a lateral
subtype of thalamic tumor.
Unilateral thalamic LGGs are more common than LGGBG. MR provides good assessment of the location of the tumor
within the thalamus and of the possible routes of extension and, interestingly, demonstrates a specific pattern of extension for
each location. Three clearly distinct groups of thalamic tumors may be differentiated anatomically: juxtaventricular tumors,
inferior (caudal) tumors, and lateral tumors (466,569).
Figure 7-119 Low-grade glioma of the basal ganglia (PA). A. Axial T1WI shows a slightly hyperintense nodular mass (M) centered adjacent to
the right foramen on Monro, at the genu of the internal capsule rather than truly the basal ganglia. B. Coronal T2WI shows the tumor to be
hemorrhagic (H, low-intensity regions) and extend into the globus pallidus, with surrounding hyperintense edema. C. Coronal T1WI post
contrast shows diffuse, well-demarcated enhancement of the mass.
■■ Juxtaventricular LGGs are the most common (43%). The tumor is located in the medial thalamus and, accordingly, may
expand into the third ventricle (medial thalamic tumors), the body (peripheral, superolateral tumor), or the atrium
(peripheral, posterolateral tumor) of the lateral ventricle. It never extends laterally or inferiorly. It is surgically accessible
by a ventricular route. All four histologic subtypes (PA, LGG-NOS, PMA, GGG) are represented. The tumor typically is
fully or mostly solid with a relatively small cyst at the time of diagnosis (Fig. 7-120), possibly because it diagnosed early
due to the ventricular obstruction.
■■ The fairly homogeneous group of inferior LGG (30%) is characterized by a location of the bulk of the tumor into the
inferior thalamus (therefore different from the midbrain tumors with cranial extension) with a variable inferior extension to
the midbrain, either dorsally in the tegmentum and tectal plate or ventrally in the cerebral peduncle and tegmentum. The
superior and the medial thalamus are spared. Most of the cases extend toward the mesial temporal lobe, below the basal
ganglia and above the temporal horn (Fig. 7-121). Tumors of this group are solid more often than solid/cystic and are
accessible by a lateral subtemporal approach. Histologically, the PA and GGG subtypes are most common. Again, no
apparent correlation is found between the appearance of the tumor or its enhancement pattern and the histology.
■■ The last group of lateral LGG (27%) develops in the lateral thalamus. All grow laterally toward the internal capsule and
the globus pallidus (Fig. 7-122) or just posterior to them. The corticospinal tract cannot be recognized on FA mapping
because of the infiltration by the tumor process. This group is predominantly composed of PA, which are mostly
solid/cystic. Because the medial, superior, and inferior thalamus are spared, the surgical approach to the tumor is difficult.
Figure 7-120 Thalamic LGGs, juxtaventricular subtypes. A. Coronal T2 image shows tumor (diffuse astrocytoma) in the medial part of the
thalamus, bulging into the third ventricle causing hydrocephalus. B. Coronal T2 image shows a second tumor (pilocytic astrocytoma), more
hypointense and more peripheral in location, bulging into the body and atrium of the lateral ventricle. In both locations, a transventricular surgical
approach is possible.
Figure 7-121 Thalamic LGG, inferior subtype. Coronal T2WI shows the tumor (pilocytic astrocytoma) centered in the inferior part of the
thalamus and extending into the adjacent cerebral peduncle. In this location, a subtemporal surgical approach is possible.
Figure 7-122 Thalamic LGG, lateral subtype. A. Axial T2WI shows the tumor (PA) centered in the lateral thalamus and extending into the
adjacent posterior limb of the internal capsule and globus pallidus. B. FA map shows low intensity in the mass and does not allow identification
of the fibers of the corticospinal tract because of infiltration by the tumor cells. In this location, no direct surgical approach of the tumor is
possible.
Figure 7-123 Bilateral thalamic LGG. Coronal T2WI shows the tumor (DA) asymmetrically involves the entirety of both (hyperintense) thalami
and is limited to them, except for a minimal extension into the tectal plate (arrows). Note massive hydrocephalus due to compression of the
aqueduct of Sylvius.
Figure 7-124 Thalamic HGG, circumscribed subtype. Postcontrast axial T1WI shows a well-circumscribed, heterogeneously enhancing
mass (M) centered within the left posterior and lateral thalamus extending toward the posterior basal ganglia and the surrounding white matter,
displacing the left ventricular trigone (T). Mild enlargement of the frontal horns suggests compression of the distal third ventricle.
Figure 7-125 Thalamic HGG, diffuse subtype. Axial FLAIR image reveals a hyperintense, poorly defined (particularly laterally) tumor involving
the right thalamus and extending into the adjacent portions of the internal capsule, globus pallidus and striatum.
Bilateral thalamic HGGs have a different appearance from the bithalamic LGG. Bilateral, but always asymmetric, they
extend beyond the limits of the thalami, in contrast with the bilateral thalamic LGG. Their appearances are similar to those of
the two subtypes of unilateral thalamic HGGs described above (Fig. 7-126A and B). The largest lesion occupies the whole
thalamus and infiltrates the internal capsule, caudate, and lenticular nucleus laterally and, commonly, the midbrain and the
ipsilateral mesial temporal lobe. Medially, it appears to be continuous with the contralateral lesion across the third ventricle:
anatomically, it is not possible to identify from the images where the continuity is as the third ventricular lumen is as rule, fully
effaced. The rare instance in which a unilateral tumor becomes bilateral suggests that the extension may be through a process of
invasion across the ependyma, the massa intermedia, the cap of the midbrain, the tela choroidea, or the posterior wall on the
ventricle. The smaller contralateral tumor may be restricted to the thalamus or may similarly infiltrate the adjacent structures.
Like the unilateral HGG, bithalamic HGG may be hemorrhagic/necrotic at diagnosis or become so during its evolution.
Enhancement patterns vary from none to patchy to ring-like as they evolve.
Thalamic Oligodendrogliomas
Although sometimes reported to be as common as astrocytic tumors (573), oligodendroglial tumors are generally considered
very unusual in children, more so in the basal ganglia than in the hemispheres (566,569). They appear to be undistinguishable
from oligoastrocytomas in the same location and have a rather malignant appearance. Calcifications appear on CT; the mass
becomes heterogeneous, solid, and cystic on both MR and CT; and the lesion is better circumscribed than a malignant
astrocytoma, with no evidence of necrosis (566). These features however are not specific, and the diagnosis rests on biopsy
only.
Figure 7-126 Bilateral thalamic HGGs. A. Circumscribed subtype. Axial FLAIR shows relatively well-demarcated, partially necrotic tumor
occupying the right thalamus, the adjacent internal capsule, and most of the basal ganglia; the left thalamus is less extensively involved. B.
Diffuse subtype. Axial FLAIR shows tumor involving both thalami, larger on the right side where it also infiltrates the striatum and caudate
(arrows).
Ependymomas
Ependymomas of the thalamus are very uncommon and are not mentioned in most of the literature about thalamic tumors
(566–569). One series reported 3 ependymomas out of 45 thalamic tumors (574), which is similar to the personal experience
of the authors of this chapter. The tumor is solid, heterogeneous with foci of necrosis and hemorrhage in one case of clear cell
ependymoma. From the thalamus, it may extend in the adjacent ventricle or cisterns. It may be calcified on CT. It is rather
hypointense on T1WI, faintly hyperintense on T2WI and FLAIR images, and iso- to hyperintense to the rest of the thalamus on
diffusion imaging; there is some enhancement after contrast administration (Fig. 7-127). Postsurgical recurrence and metastases
occur. As mentioned above, another location for ependymomas may be the posterior mesial temporal cortex, which is adjacent
to the thalamus. Care should be taken to differentiate the two locations as a tumor of the cerebral mantle is more amenable to a
complete removal than is a thalamic tumor.
On imaging, the lesion typically involves the lentiform nucleus, but may extend to the caudate nucleus, the adjacent deep
white matter, the internal capsule, the thalamus and sometimes, the amygdala; bilateral involvement is not rare (577). The CT
appearance of a germinoma is that of an iso- 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 intravenous infusion of contrast. Germinomas of the basal ganglia can be differentiated from astrocytomas by their
high attenuation relative to white matter prior to contrast infusion.
On MR, findings may be subtle in small basal ganglia germinomas, showing only faint T1 shortening or T2 prolongation
without significant enhancement (576) (Fig. 7-128). Larger tumors demonstrate prolonged T1 relaxation times and iso- to
hyperintensity compared with gray matter on T2-weighted and FLAIR images. Restricted diffusion on DWI/ADC mapping
images is apparent in the majority of the cases (578). Heterogeneity is common in larger germinomas of the basal ganglia (Fig.
7-129); some degree of necrosis is present in 80% (50% are slightly necrotic; 30% are mostly necrotic) at the time of initial
imaging (579–581). The heterogeneity is most apparent on T2-weighted and contrast-enhanced images. Germinomas of the
deep gray matter tend to be large at the time of original imaging (579–581). The solid portions of germinomas strongly enhance
after infusion of paramagnetic contrast (Fig. 7-129), as do CSF-borne metastases to the brain and spine. At the time of
presentation, hemiatrophy is often present in the ipsilateral hemisphere and brainstem (582) and can be explained by a process
of long-lasting deafferentation.
Phi et al. (577) proposed a four-tiered classification of the basal ganglia germinomas, in which type 1 (the most common
and the most subtle) is characterized by patchy areas of bright T2 and FLAIR signal intensity with no or only faint
enhancement; type 2 appears as a small (<3 cm) lesion with nodular enhancement; type 3 corresponds to a basal ganglia type 2
lesion associated with enhancing ependymal seeding; type 4 is a large lesion (more than 3 cm) with avid enhancement and
mass effect; the lesions may be uni- or bilateral. It was felt that these patterns could correspond to different pathologies, type 1
being different from types 2 to 4 (577,583). Another classification was proposed recently, which doesn’t take the ependymal
seeding into account, but introduces the presence of intralesional cysts as a defining criterion: type 1 is made of ill-defined
signal abnormalities; type 2 of small mass lesions (<3 cm) with cysts; and type 3 is made of large mass lesions (more than 3
cm) with cysts (584). With time, lesions tend to evolve from types 1 to 2 or 3, meaning that discrete masses can grow out of the
initial infiltration. Early abnormalities consist of patchy areas of T2 and FLAIR signal abnormalities with irregular margins,
usually centered in the lentiform nuclei or, less commonly, the caudate nucleus with possible further growth into the internal
capsule, thalamus, and deep hemispheric white matter. In most patients, the tumor extension increases with time and the tumors
evolves into a type 2, and even type 3, with cysts. Intratumoral hemorrhage becomes more common with progression.
Ipsilateral atrophy of the hemisphere and brainstem is apparent from the start when the internal capsule and thalamus are
involved and always becomes worse with time, as the mass effect of the lesion grows (576,585). Similarly, contrast
enhancement is seen in a third of patients with type 1, in most patients with type 2, and all patients with type 3 tumor (584). MR
spectroscopy may be useful as it may demonstrate a large peak of lipids between 0.9 and 1.3 ppm (Fig. 7-128E), in addition to
a high choline peak (cellular turnover) and a low NAA peak (neuronal expression) (586,587). 18F-FDG PET would show a
relative hypometabolism in the basal ganglia as well as in the ipsilateral hemisphere and contralateral cerebellum; 11C-
methionine PET would show a hypermetabolism in the tumor or a recurrence (577).
The differential diagnosis includes gliomatosis, ischemia, and inflammatory disease. When a relatively shortened T2
relaxation time is present in an ill-defined mass centered in the basal ganglia, particularly in association with cysts or
hemorrhage, germinoma should be considered, along with lymphoma and PNET. Ipsilateral hemiatrophy is highly suggestive of
a germinomatous tumor.
Pineal Region Masses
Pineal region masses are an important group of pediatric brain tumors for several reasons (Table 7-10). A major reason is that
the pineal region, located in the center of the cranial cavity, is surgically and endoscopically difficult to approach and is
anatomically associated with important vascular and neural structures. As a result, it is a region where the diagnosis of the
nature of the tumors is radiologically the most difficult preoperatively, but knowledge of the diagnosis drastically alters
therapy: one of them, the germinoma, may be easily cured by chemo- and radiotherapy alone, while others, such as
pineoblastomas or ATRTs, need surgical removal.
The pineal region contains many important structures (Fig. 7-130). As suggested by its name, the pineal is centered near the
posterior wall of the third ventricle, which includes, craniocaudally, the suprapineal recess of variable size, the pineal gland
itself, its stalk and its recess, the posterior commissure, and the cranial opening of the aqueduct. The base of the pineal stalk
contains the habenular commissure (connecting the epithalamic habenular nuclei, which are involved, in a general way, in
“survival” processing). The pretectal posterior commissure connects the superior colliculi (involved in coordinating eye
movements and posturing control). The ependyma that extends around the posterior commissure from the habenular commissure
to the middle portion of the aqueduct forms the subcommissural organ, one of the circumventricular organs. Laterally, the
pineal region is continuous with the thalami; posteriorly, with the tectal plate and the aqueduct coursing below it. Anteriorly, it
is adjacent to the posterior, thalamic portion of the third ventricle with the massa intermedia. Posteriorly, it is adjacent to the
quadrigeminal cistern, which contains the posterolateral and posteromedial choroid arteries and the vein of Galen with its
main tributaries (internal cerebral veins, basal veins, preculminal vein). The quadrigeminal cistern, in turn, opens into the
velum interpositum anteriorly (roofed by the callosal splenium and fornix/hippocampal commissure), into the posterior fossa
inferiorly, and into the interhemispheric fissure divided by the falx, posteriorly.
The maximum diameters and section area of the noncystic pineal gland in children from birth to 5 years on sagittal midline
images are reported to be 7.9 mm (anteroposterior), 4.8 mm (craniocaudal), and 25.4 mm2 (surface area), with a slight
increase in size during this period (588). From another report of the same group, it appears that the pineal gland is at least
partly cystic (i.e., the cavum pineale was retained) in 56% of normal patients in that same age range. Measurements of a
normal cystic pineal gland should not exceed 10.8 mm for the cyst, 10.9 mm for the whole gland (anteroposterior), 7.7 mm
(craniocaudal), and 77 mm2 (surface area); the follow-up studies demonstrated that the cyst remains stable with time in 48%,
increases in 36%, and decreases in 16% (589).
Figure 7-128 Germinoma of the basal ganglia. Diffuse infiltrative subtype (type 1 of Phi et al.). A. Coronal T2WI shows a patch of ill-defined
bright signal (white arrow) lateral to the head of the left caudate nucleus. Axial FLAIR (B) shows similar ill-defined area of bright signal (white
arrow), while axial T1WI (C) shows small patch of very faint low signal (black arrow). D. Axial T1WI post contrast shows minimal enhancement
(white arrow) of uncertain significance. E. MR spectroscopy demonstrates a prominent lipid peak at 1.1 to 1.2 ppm (L) associated with low NAA
and a high peak of choline (Ch), strongly suggesting neoplasm.
Figure 7-129 Germinoma of the basal ganglia. 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 component (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. Postcontrast axial T1-weighted
image shows that the solid portion of the tumor (arrows) enhances nearly uniformly. Germinoma of the basal ganglia. Large nodular subtype
(type 4 of Phi et al.).
Table 7-10 Pineal Region Tumors in Children
Germ cell tumors Germinomas most common: gray matter intensity, restricted diffusion
other locations
Pineal parenchymal tumors Solid portions: gray matter intensity, reduced average diffusivity (Dav)
Vein of Galen varices (see Chapter 12) Look for signal void from flow
On imaging studies, the CT appearance of a germinoma is that of an iso- to hyperdense, well-marginated mass in the pineal
region, with an “engulfed” calcification (the pineal calcification is surrounded by tumor, in contradistinction with the
pineoblastoma, in which the “exploded” calcification surrounds the tumor) (592); this pineal calcification is more common in
children with germinomas than would be expected for the age of the child. If small, the mass may appear as a simple thickening
of the posterior wall of the third ventricle. Hydrocephalus is typically associated. Uniform enhancement of the solid portions of
the tumor is seen after intravenous infusion of contrast and may reveal small intratumoral cysts.
On MR, germinomas usually appear as well-marginated tumors, either round or lobulated. They are isointense to brain
parenchyma on T1WI and T2WI, appear bright on FLAIR (which allows a distinction from the pineoblastomas), have reduced
diffusivity on DWI, and enhance diffusely (Figs. 7-131 and 7-132). When they are small, they may be centered in the pineal
gland or more caudally in the posterior commissure. In most instances, however, they occupy the posterior wall of the
ventricle, projecting anteriorly into the ventricular lumen and posteriorly into the quadrigeminal cistern, within the fork of the
internal cerebral and basal veins. Laterally, germinomas tend to infiltrate the thalami, uni- or bilaterally. On FLAIR imaging,
the abnormalities may be seen to extend farther than the diffusion abnormality or the postcontrast enhancement. Inferiorly, the
tumor may compress or infiltrate the tectal plate as well, resulting in aqueductal obstruction. It is important to assess
postcontrast images and MRV to determine the involvement of the veins that gather toward the vein of Galen. In our experience,
isolated pure germinomas of the pineal region do not creep along the ventricular ependyma, even though they may seed into the
leptomeningeal cranial and spinal spaces; this finding however is not confirmed in other series (593).
Figure 7-131 Pineal germinoma, small. A. Sagittal T1WI shows isointense mass (white arrows) occupying the pineal gland as well as the
region of the posterior commissure; the central dark signal (small black arrow) is an “engulfed” calcification. B. Sagittal T2WI shows the tumor
to be dark due to the high cellularity; note the presence of central microcysts. C. Axial FLAIR shows the tumor (T) as bright; it infiltrates the
adjacent right thalamus. D. Postcontrast sagittal T1WI shows diffuse enhancement of the tumor that extends to the inferior aspect of the
callosal splenium (black arrow), encasing the internal cerebral veins.
Figure 7-132 Pineal germinoma, large. A. Sagittal T1WI shows a large mass (M) that is isointense to the brain tissue, occupying the whole
pineal region (tectal plate, cistern, velum interpositum, posterior third ventricle). B. Coronal T2WI shows the tumor to be heterogeneously iso-
and hyperintense (with hyperintense central necrosis). C. On axial FLAIR, the tumor appears bright; it infiltrates the adjacent parenchyma (note
blurred margins) (arrows). D. Postcontrast coronal T1WI shows marked enhancement of the solid portions of tumor, with infiltration of the
adjacent tissue, and likely encases the venous confluence.
Bifocal germinomas develop simultaneously, or are diagnosed simultaneously, in the suprasellar and the pineal regions
(Fig. 7-133). They affect boys and girls and are generally assumed to always be pure germinomas (402); this assertion,
however, is contended by some (593). Morphologically, the tumor may be predominant in either location, irrelevant of the
gender of the patient. Bifocal germinomas disseminate along the ependyma like the suprasellar germinomas (Fig. 7-134) (593).
This may support the hypothesis that bifocal germinomas are pineal germinoma with a secondary metastasis within the
infundibular recess; a primary suprasellar tumor seeding in the pineal gland has been reported as well (593). Metastases may
also be found in the subarachnoid spaces.
Figure 7-133 Bifocal germinoma. Sagittal T1WI post contrast shows two tumor masses (arrows) simultaneously in the infundibulum and in
the pineal regions.
Figure 7-134 Bifocal germinoma with ependymal dissemination. A. Coronal T2WI shows a large tumor (arrows) centered on the anterior third
ventricle and infiltrating the adjacent parenchyma. B. Axial FLAIR image shows intermediate signal tumor (black T) infiltrating the ependyma
and the adjacent deep white matter; the involvement of the subependymal veins explains the extensive associated edema. C. Sagittal T1WI
postcontrast image shows small masses in the pineal gland (p) and in the infundibulum (i), contrasting with large masses in the region of the
foramina of Monro (F) and in the callosal genu (G).
Teratomas
Pineal region teratomas are much less common than are germinomas, but like the germinomas, they occur almost exclusively in
males. The peak incidence of presentation is in the second decade. Clinically, teratomas are similar to other GCTs in that
affected patients may present with the Parinaud syndrome and hydrocephalus. Histologically, they contain various normal
tissues with fibrosis, fat, calcification, mucous cysts, follicles, debris, and keratin. Benign teratomas are usually sharply
marginated. On CT, mature teratomas appear as heterogeneous solid and/or cystic masses with calcification and sometimes
fatty tissue. On MR, the tumors appear multilocular, with mixed hypo-, iso-, and hyperintensities on T1WI and T2WI, relating
to the various tissues and various cystic contents (Fig. 7-136). Enhancement after contrast administration is variable, from none
or mild to strong and heterogeneous. Serum markers are not elevated (404). Pineal region teratomas tend to be noninvasive;
rarely, however, a malignancy may develop from a mature benign teratoma.
Immature teratomas typically have less well-differentiated cells and, therefore, less well-differentiated features. The
masses have a much more homogeneous appearance and may invade the surrounding structures. They are poorly marginated
and are surrounded by vasogenic edema. Neither calcification nor fat is seen. Significant patchy, ring-like, and nodular
enhancement is typically seen after administration of paramagnetic contrast. Serum AFP makers are always increased (404).
In the suprasellar region, GCTs are the only tumors that manifest reduced Dav on DWI/ADC. Many other highly cellular
tumors may originate in the pineal regions, such as a pineoblastoma and ATRT. MR spectroscopy may be useful if it
demonstrates a large peak of fat between 0.9 and 1.3 ppm, which is very suggestive of GCT (586,587). In our experience,
another finding that may help is that the FLAIR signal typically is increased in GCT compared with surrounding tissues, but not
in the pineoblastoma.
Figure 7-135 Nongerminoma germ cell tumor (NG-GCT). A. Sagittal T1WI shows large pineal region mass with a central focus of
hemorrhage. B. Sagittal T1WI post contrast shows partial, heterogeneous enhancement (arrow) of the tumor.
Figure 7-136 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 represent 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.
On CT, both pineocytomas and pineoblastomas are iso- to hyperdense compared to normal brain prior to contrast infusion
(Fig. 7-137). CT is important to demonstrate the mass, associated hydrocephalus, and calcification pattern. In pinealoblastoma,
the “exploded” calcification surrounds the mass, in contrast with the germinoma where the calcification is “engulfed” by it. On
MR imaging, pineoblastomas are usually more lobulated than are pineocytomas (596). Both are hypo- or isointense on T1WI
and mildly hyperintense on T2WI (Figs. 7-137 and 7-138), with the pineoblastoma more heterogeneous than the pineocytoma
(597). In our experience, pinealoblastomas always appear isointense to the surrounding tissues on FLAIR (Fig. 7-139A–D),
while germinomas always appear mildly hyperintense. Necrotic or cystic areas (hypointense on T1-weighted images and
hyperintense on T2-weighted images) are commonly seen in larger pineoblastomas (Fig. 7-137), and the solid portions of the
tumor enhance intensely after intravenous contrast administration (Fig. 7-138). Although both pineocytomas and
pinealoblastomas show marked enhancement, pineocytomas typically enhance more uniformly, while pineoblastomas have
more heterogeneous enhancement (596,597). Pineoblastomas are usually larger and more lobulated than are pineocytomas and
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 and their margins are more sharply demarcated (596) (Figs. 7-137 and 7-138). Diffusivity is somewhat
more reduced in pineoblastomas, but not enough to use as a differentiating feature (598,599). Pineoblastomas very rarely
bleed. 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 the extent of subarachnoid tumor, which enhances markedly
(600).
When associated with a RB, a pineoblastoma completes the triad that is known as a “trilateral retinoblastoma” (589).
The appearances of the pineal parenchymal tumors is nonspecific (601); germinomas and ATRTs may have very similar
features. To differentiate germinomas from pineoblastomas, the calcification pattern on CT (discussed above) is helpful; on
MR, the fact that the FLAIR signal of pineoblastomas is similar to that of the parenchyma can be useful. Also, as pineal GCTs
affect mostly boys, the diagnosis of pineoblastoma should always be considered first when a tumor with proper
characteristics is found in the pineal region of a girl. Before being recognized as a specific tumor, the uncommon pineal
ATRT was confused with the pinealoblastoma; it tends to be larger as it often extends from the pineal region to the vermis; it is
also often associated with early leptomeningeal metastases. The perfusion and spectroscopy characteristics of these tumors are
not published. Pineocytomas may be isointense with CSF: they are differentiated from pineal cysts by the presence of
trabeculae within the tumor mass and by diffuse, homogeneous enhancement after intravenous contrast administration.
Figure 7-137 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).
Figure 7-138 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 central regions
of hyperintensity that likely represent necrosis. 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 diffusion of the mass (arrows) compared with normal cerebral parenchyma.
Miscellaneous
Pineal atypical teratoid/rhabdoid tumor
ATRT was not identified as a specific tumor until 1996 (133). It affects very young children and may be found supra- or
infratentorially, with only 5% of the ATRT found in the incisural/pineal region. This embryonal tumor is characterized by a
combination of epithelial, neuroepithelial, and mesenchymal rhabdoid tumor cells (135) and by the biological marker INI1
(integrase interactor 1). It is a predominantly solid tumor, which is hyperdense on CT, isointense on T1WI, and hypointense
with heterogeneous tissue on T2WI and has low Dav (reduced diffusivity) on DWI/ADC (Fig. 7-141). Calcification,
hemorrhage, and necrosis are common, explaining the heterogeneous appearance of the mass. Solid tissue demonstrates diffuse
enhancement after contrast administration. Between 50% and 70% of the patients present with early leptomeningeal
dissemination at diagnosis, and ultimately, all will develop metastases during the evolution (135). The prognosis is dismal.
Papillary tumors of the pineal region
Identified in 2003, papillary tumors of the pineal region (PTPR) is a rare tumor that has been observed at all ages. It seems to
originate from the ependymocytes of the subcommissural organ (see the anatomic introduction of this section on pineal tumors).
Histologically, it shows a papillary pattern lined by epithelioid tumor cells with rosettes and perivascular pseudorosettes.
Reports on imaging findings are scarce. The tumor is well circumscribed and centered on the posterior commissure. It may
appear isointense on T1 in comparison with the brainstem, or sometimes bright, presumably because of the presence of
secreted proteins and glycoproteins (597,604). It appears bright on T2 and FLAIR sequences, as well, with some degree of
reduced Dav; enhancement is diffuse and heterogeneous (Fig. 7-142). From the subcommissural organ the tumor may infiltrate
the tectal plate, the pineal region, and the posterior thalamus bilaterally, often resulting in associated hydrocephalus.
Figure 7-139 FLAIR imaging in pineoblastoma. In different cases (A–D), the FLAIR signal of the tumor (T) is identical to the signal of the
parenchyma. This is in contradistinction with what is observed with the other reduced diffusivity tumor, the germinoma, in which the FLAIR
signal is always brighter than the signal of the parenchyma.
Figure 7-141 Pineal atypical teratoid rhabdoid tumor (ATRT). A and B. Sagittal T1WI and steady-state (CISS) images. Large, compact,
microcystic tumor (T) of the pineal region that is isointense to the parenchyma on both sequences. C. DWI demonstrates marked
hyperintensity indicating reduced diffusivity. D. T1WI post contrast shows no enhancement of the mass.
Figure 7-142 Papillary tumor of the pineal region (PTPR). A. T1WI shows a microcystic mass (T) that is predominantly isointense to the
parenchyma. However, some linear hyperintense signal change is seen at the anterior periphery of the tumor (white arrow) that is hypothesized
to reflect an excess of subcommissural organ secretion products (see text). The tumor otherwise has a low signal on T2WI (B), has a bright
signal on FLAIR (C), and diffusely enhances after contrast administration (D).
Pineal Cysts
It is sometimes difficult to appreciate whether the pineal gland is normal or not, especially if it is cystic. Small nonneoplastic
cysts of the pineal gland are common, incidentally found in up to 40% of autopsies (605,606). Reported normal values of the
normal cystic pineal gland have been provided in the anatomic introduction of the paragraph. These lesions are common in
infancy; we have seen them appear, disappear, and then appear again on sequential studies. This continues during adolescence
and their incidence is reportedly highest in the third decade (607). Their observation on imaging studies at any age is nearly
always incidental, as they are essentially never symptomatic unless complications, such as hemorrhage, ensue. Their cause is
not known; authors have postulated cystic degeneration of the gland, enlargement of microscopic cysts under hormonal
influence, and trapping and enlargement of the embryonic pineal cavity (608). Although many are too small to see on routine
imaging studies, pineal cysts are, nonetheless, a very frequent observation on MR studies of the brain, identified in up to 23%
of brain MR examinations (609,610). Pineal cysts are infrequently noted on CT scans, other than in retrospect, because they are
isointense with CSF in the surrounding cisterns. On MR, they are most commonly appreciated on the sagittal images, where
they cause pineal enlargement that frequently results in a slight impression on the superior colliculi or posterior third ventricle.
Most pineal cysts are small (2–4 mm in diameter) and are incidental findings (610,611). When imaged sequentially, they may
enlarge, shrink, or disappear entirely (589,611). If the MR appearance is classic for pineal cyst, these changes should not cause
concern.
When larger than 1 cm, pineal cysts may cause some diagnostic difficulty, especially because they are sometimes
hemorrhagic or heterogeneous (612,613). An important factor in the differentiation of cysts from neoplasms is that cysts are
rarely symptomatic unless they are large (above 20 mm) or neoplastic (pineocytoma); the resulting clinical features in these
circumstances may be Parinaud syndrome and/or hydrocephalus (614,615). In general, the MR appearance of pineal cysts is
that of isointensity with CSF on T1-weighted images and slight hyperintensity with respect to CSF on T2-weighted and FLAIR
images, because of their protein content. Their structure is best demonstrated on midline sagittal submillimetric FIESTA
imaging. When hemorrhage is present in the cyst, high signal intensity is seen in the cyst on both T1- and T2-weighted images
and the cyst may enlarge, resulting in symptoms from local mass effect (615,616); if the bleed is recent, it may appear black on
T2 with a fluid–fluid level. After intravenous administration of paramagnetic contrast, a crescent or rim of normal pineal gland
surrounding the cyst typically enhances. The scan should not be delayed after contrast administration, as the cyst itself will
enhance after prolonged delays, making differentiation from tumors impossible (617). The keys in making the diagnosis of
pineal cyst by MR are the absence of clinical manifestations, the characteristic location, the isointensity with CSF on T1-
weighted images, the absence of any internal structure within the lesion, and the presence of the typical rim of enhancement
around the cyst. Various strategies are recommended when a large (above 10 mm) cystic pineal is found incidentally on MR
imaging, without any related symptom and without compression of the tectal plate and aqueduct, from a simple clinical
surveillance to MR follow-ups.
Ventricular Tumors
Hemispheric intraventricular tumors are rather uncommon in children. Other than the SEGA originating from the region of the
foramina of Monro in a context of TSC, the most common by far are tumors originating from the choroid plexuses of the lateral
ventricles (Table 7-11).
Subependymal giant cell astrocytoma TSC; vicinity of the foramina of Monro; calcification; avid enhancement
T2 hypointensity
Ependymoma From the ventricular wall, large, solid, cystic, calcified, and enhancing
TSC results from mutation of either TSC1 or TSC2, which codes for hamartin and tuberin, respectively. These proteins
normally act as suppressors in the PI3K/AKT3/mTOR pathway. Activation of this pathway is also documented in the cortical
tubers, which are histologically similar to focal cortical dysplasias (FCD IIB, see Chapter 5). Males and females are equally
affected. The tumor may be diagnosed at any age, but peak occurrence is between ages 5 and 10 years. When the affected child
does not have TSC, the clinical presentation is almost always that of hydrocephalus. Rarely, the tumors can undergo malignant
degeneration and invade surrounding brain (74,76,618,621).
SEGAs usually arise from the wall of the lateral ventricle near the foramina of Monro, but they may also develop in other
locations along the ventricles. Typically, they grow slowly and produce hydrocephalus when they obstruct the foramen. They
may be single or multiple and are postulated to arise from the subependymal nodules (SENs) that are part of TSC (see Chapter
6); in fact, the tumors bear histological similarity to the SENs. Giant cell astrocytomas tend to be sharply defined and
homogeneous on pathologic examination. They usually are mostly intraventricular, but they may also be embedded deep in the
adjacent brain tissue. Calcification is common. Although usually histologically benign, some show evidence of anaplasia
(76,618); they may need to be removed when they result in hydrocephalus. In the last decade however, the use of rapamycin or
rapamycin analogs has been shown to reduce the volume of the tumor; unfortunately, the tumor expands again when the
treatment is discontinued (619,622).
The CT and MR findings of TSC are described in Chapter 6. Briefly, the characteristic CT appearance of the SEGA is that
of a hypo- to isodense, often calcified, well-demarcated, rounded lesion originating from the ventricular wall, most commonly
in the region of the foramen of Monro, and usually producing hydrocephalus when it becomes large enough. Other
subependymal masses, both calcified and noncalcified, are usually present in the same region in the setting of TSC. After the
infusion of IV contrast, giant cell tumors always uniformly enhance. MR also reveals a well-circumscribed, ovoid, or rounded
mass, most commonly in the region of the foramen of Monro, and extending into the lumen of the adjacent lateral ventricle.
Typically, the mass is hypointense to isointense with brain tissue on T1-weighted sequences (Fig. 7-143) and hyperintense on
T2-weighted and FLAIR sequences, with Dav similar to surrounding parenchyma. If surgery is contemplated, it is important to
evaluate how far the tumor is embedded in the parenchyma, as a deep insertion makes surgery more perilous. Multiple smaller
SENs are almost always present if the child has TSC. Moreover, on MR, 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 and FLAIR sequences (see Chapter 6). Infusion of Gd-DTPA results in uniform enhancement of the
SEGA and SENs, but typically not of the tubers. As stated in Chapter 6, SEGAs 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 suspicion of anaplasia.
Figure 7-143 Subependymal giant cell astrocytoma (SEGA). A. Axial FLAIR image shows a compact, homogeneously bright intraventricular
mass (M) centered at the foramen of Monro. Associated univentricular hydrocephalus. B. Coronal T1WI postcontrast image shows that the
enhancement is heterogeneous (this is due to the presence of calcification in the lesion; see Chapter 6 for more illustration).
Figure 7-146 Choroid plexus villous hyperplasia. A. Axial FLAIR image shows prominent dilation of the ventricles and of the anterior
pericerebral spaces; the choroid plexuses (arrows) are large bilaterally. B. Coronal T1WI postcontrast image shows massive ventriculomegaly
with effacement of the superior pericerebral spaces; choroid plexus hyperplasia is again seen.
Figure 7-147 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, and the hyperintense regions (black arrowheads) are areas of
necrosis. The solid portion of the tumor has signal characteristics similar to gray matter. Subcortical white matter (small white arrows) is
spared. 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.
Other related glioneuronal tumors such as a DNET or a GGG may also (uncommonly) develop from the septum pellucidum.
Finally, meningiomas can develop within the ventricles because the pia participates in the formation of the choroid plexus.
They are uncommon in general in children and less so in the ventricles. They may develop in association with NF2, however.
The most common location is the atrium of the lateral ventricle, away from the foramina of Monro, so the tumor may become
large before eliciting symptoms of elevated intracranial pressure. These are pathologically and radiologically identical to
meningiomas in other locations (Fig. 7-149). MR spectroscopy demonstrates high choline (cellular turnover); variable amounts
of lactate, lipids, and alanine (doublet at 1.47 ppm); and low NAA and creatine. Perfusion imaging shows a high blood volume
(642).
Figure 7-148 Central neurocytoma. A. Sagittal T1WI shows a large heterogeneous mass (M) centered in the septum pellucidum, with a
signal intensities similar to those of the normal parenchyma. B. Axial FLAIR image shows heterogeneous bright signal with intrinsic cysts. C.
Axial T2WI shows heterogeneously bright (multicystic) and isointense signals, separated by patches of dark signal that reflect calcification. D.
Coronal postcontrast T1 image shows heterogeneous enhancement within the mass.
Figure 7-149 Meningioma of the tela choroidea of the forebrain; a very large tumor occupying both lateral ventricles and the third ventricle (A–
D). The mass is of low intensity on T1WI as well as on FLAIR (A, B). On T2WI (C), it has central signal similar to gray matter with hypointense
periphery. The entire mass enhances avidly after contrast administration (D); this appearance is similar to the appearance of the more
common dura-based meningiomas.
Extra-Axial Tumors
Sharply marginated
Marked T2 hypointensity
Extraosseous Ewing sarcomas are very rare tumors that are histologically identical to PNETs but are distinguished by their
dural origin/attachment, by strong membrane expression of the MIC2 gene product (CD99), and by demonstration of the
chromosomal translocation t(11,22)(q24;q12) (660).
On imaging, meningiomas, plasma cell granulomas, meningeal fibromas, myofibromas, and meningeal sarcomas have
nearly identical imaging features; they can only be differentiated by histology. The diagnosis of malignant fibrous histiocytoma
may be suggested if the child presents with hemorrhage into the tumor (661). CT studies have revealed heterogeneity of all
these tumors. Approximately one-half of patients with meningiomas have associated hyperostosis and half have intratumoral
calcification. All pediatric meningeal-based tumors are iso- to hyperdense compared with normal brain on precontrast CT, and
the solid portions of the tumor show diffuse contrast enhancement. Cystic and necrotic changes are more frequent in pediatric
patients than in adults, possibly because of the larger size at the time of diagnosis. Rapid growth or the presence of atypical CT
features, such as hemorrhage, heterogeneous enhancement, cyst formation, or poorly defined margins, suggests a malignant
tumor such as meningeal sarcoma, extraosseous Ewing sarcoma, or meningeal PNET (647,648); 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 (650,652,662). On MR studies, pediatric meningeal tumors are generally large
masses that arise from the dura, the choroid plexuses, or the arachnoid of the sylvian fissures. They typically have smooth,
well-defined margins (whether benign or malignant) and are isointense to gray matter on T1-weighted sequences and iso- to
hyperintense to gray matter on FLAIR and T2-weighted sequences. Cystic and necrotic areas, if present, have prolonged T1
and T2 relaxation times compared to the solid portion of the tumor, which shows uniform enhancement after intravenous
infusion of paramagnetic contrast. Hemorrhage, heterogeneity, reduced diffusivity (compared with gray matter), and indistinct
margins favor sarcomas or meningiomas with higher degrees of malignancy (648), but this feature is not reliable. Densely
calcified areas have very low intensity, whereas areas that are less densely calcified may appear iso- or hyperintense on
noncontrast T1-weighted images.
As stated in the section on imaging characteristics at the beginning of this chapter, perfusion imaging may be useful to
differentiate meningeal tumors from intraparenchymal tumors in that neuroepithelial tumors show a return to baseline of
relaxivity after the bolus of contrast has passed through the tumor, but meningeal tumors show persistence of abnormal
relaxivity due to absence of blood–brain barrier and pooling of contrast in the interstitium. In addition, meningiomas tend to
have large blood volumes compared to normal brain parenchyma (44).
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 (663–665).
Arteriography can be helpful in affected patients, especially if a characteristic homogeneous tumor blush is seen 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 sometimes extend to the pia and parasitize blood flow from intracerebral vessels
and may, thus, incorrectly suggest a primary intracerebral tumor. Similarly, intracerebral tumors can parasitize flow from
meningeal vessels to mimic meningeal tumors.
Infantile myofibromatosis
Infantile myofibromatosis is a condition in which mesenchymal pseudotumors develop in the skin, subcutaneous tissues,
skeletal muscle, bone, and/or visceral organs of children (646). When infantile myofibromas involve the skull and brain, they
most commonly present as calvarial or dural masses (646). By radiologic criteria, these masses are very difficult to
differentiate from meningiomas, when they are dural based, and from LCH when they arise within the calvarium. Infantile
myofibromas appear on CT and MR as well-demarcated, homogeneous calvarial or dural masses that are isodense to gray
matter on CT and iso- 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 (646,666). Because the
imaging 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 of dural-based masses in neonates and
infants, an age group in which meningiomas are extremely rare.
Leukemia and lymphoma
Metastases to the brain and meninges from systemic malignancies are rare in childhood, with the exception of childhood
leukemia and lymphoma. Leukemias account for 30% of all childhood malignancies and are the most common cancers
diagnosed in children (667). 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 unilateral
involvement of cranial nerve VII) will be detected (667). 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. (668) found that 31% of children with acute lymphocytic leukemia have enlarged ventricles
before treatment. These findings suggest that the ventricular enlargement may represent hydrocephalus, not atrophy, and would
be caused by the disease, not by the treatment. Meningeal and parenchymal metastatic disease is far less common than is
enlargement of the ventricles and sulci. Children with acute myelogenous leukemia may present with focal signs or symptoms
due to the development 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 (101). When
lymphomas or aggregates of leukemic cells involve the brain, they appear on CT as masses of iso- to hyperdense signal prior
to contrast enhancement; they enhance uniformly after contrast administration (Fig. 7-150) (667). Of interest, leukemic
infiltrates may grow through the calvarium or an orbital wall without any apparent radiologic evidence of bone involvement
(Fig. 7-150). On MR, these masses tend to be slightly hypointense with respect to brain on T1-weighted sequences and iso- to
slightly hyperintense on FLAIR and T2-weighted sequences. All lesions show diffuse and prominent enhancement after
infusion of IV contrast (Fig. 7-151). There are no characteristic locations within the brain, and indeed, the disease can affect
the cerebral parenchyma, meninges, cranial nerves, dura and epidural space, calvarium, or orbits (Figs. 7-150 and 7-151).
Indeed, when the disease is predominantly or entirely arachnoid in location, the only imaging abnormality may be enhancement
of cranial nerves (usually resulting from “sugarcoating” of the nerves by arachnoid tumor) 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), and hemorrhage and infarction
(see Chapter 4) are all common sequelae of the treatment of leukemia and lymphoma (667,669,670). The diagnosis of these
treatment-related changes can sometimes be aided by the use of volumetrics, morphometry, perfusion imaging, and DWI (671).
Figure 7-150 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 destruction 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 substantial
mass effect with subfalcine herniation (arrows) of the right frontal lobe.
The most common imaging finding of calvarial LCH is that of a well-defined mass involving the calvarium. On CT, a
sharply circumscribed skull lesion is identified with differential involvement 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. 7-152A and B). MR 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 (Fig. 7-152C and D). The lesion may occasionally displace the underlying brain.
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 (332). Histologically, these lesions are granulomas consisting of a mixture of histiocytes, foamy
macrophages, multinucleated giant cells, lymphocytes, plasma cells, and eosinophils (337). 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. 7-153). The reason for this marked T2 hypointensity is not known, but it may be related to a severe fibrotic reaction of the
choroid or meningeal tissue to the LCH involvement. These lesions enhance intensely and uniformly after administration of
intravenous contrast (Fig. 7-153). The choroid plexus and dural lesions are rarely the cause of clinical presentation. They are
more commonly found incidentally in children with known multisystemic LCH, conditions previously known as Hand-
Schüller-Christian and Letterer-Siwe diseases (332).
Figure 7-152 Langerhans cell histiocytosis involving the calvarium. A. Axial CT image using wide windows 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.
Figure 7-153 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 temporal horns of the lateral ventricles. The tentorial mass (white arrowheads) is equally heterogeneous, with areas of
isointensity and areas markedly hypointense 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.)
Extramedullary hematopoiesis
Extramedullary hematopoiesis refers to the development of hematopoietic 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 falx cerebri (672). Rarely, it can occur in the epidural space of the head or spine (673),
possibly due to transformation of multipotential cells into marrow or direct extension of hematopoietic cells from marrow into
the epidural space (673,674). Clinically, extramedullary hematopoiesis is usually asymptomatic, but neurologic signs and
symptoms can result from compression of adjacent tissue in the brain or spine (see Chapter 10 for discussion of spinal
manifestations). Headaches, seizures, hemiplegia, altered consciousness, and cranial neuropathies are the most common
manifestations of intracranial disease (675).
Imaging studies typically show multiple intracranial extramedullary 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 MR, the lesions are typically slightly
hyperintense to cerebral cortex and T1-weighted images and iso- to hypointense on T2-weighted images. Enhancement is
diffuse, but heterogeneous (675). Nuclear medicine studies can be useful to confirm the diagnosis, as sulfur colloid is taken up
by macrophages and thus traces the reticuloendothelial system (676). Thus, uptake of Tc99m sulfur colloid within the masses
strongly supports the diagnosis 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 Cephalocele section entitled “Fontanelle Dermoids and Other Calvarial Masses of Childhood.” Calvarial masses
from LCH were discussed in the previous section.
Neuroblastoma metastases are 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 central nervous system 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 characteristically involve the orbit and calvarium. On CT, calvarial metastases 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. 7-154). 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 MR, the metastases appear
as soft tissue intensity masses originating within the calvarium (Fig. 7-155). They enhance markedly, on both CT and MR, after
administration of contrast. The elevated periosteum enhances, as well, which may be a helpful sign in differentiating metastatic
tumor from the normal hematopoietic marrow of childhood.
Figure 7-154 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.
Figure 7-155 Metastatic neuroblastoma to calvarium and dura. A. Axial contrast-enhanced CT scan shows calvarial metastases with
intracranial extension (black arrows) in the right frontal, right parietal, 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).
Table 7-13 Most Common Brain Tumors in the First Year of Life (886 Cases) (677)
Ependymoma: 11%
Teratoma, dermoid: 6%
The clinical manifestations of tumors presenting in the first year of life differ as well. Focal neurological deficits are
almost always absent because of the immaturity of the central nervous system. More than half of infants with infratentorial
tumors present with macrocephaly, vomiting, increased sleepiness, seizures, and developmental delay. 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%. Infants with hypothalamic–chiasmatic gliomas typically
present with decreased appetite, poor weight gain, and abnormal eye movements.
Treatment of very young children also differs from that in the older age group (681–683). 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 findings), the large bulk of tumor found at presentation,
and the reduced radiation dose used in this age group. Reduced radiation dosage is necessary because of the immaturity of the
brain and the high incidence of subsequent vasoocclusive disease and developmental retardation 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. Presently, most centers use surgery,
postoperative chemotherapy, and delayed radiation; results are mixed (684–686). On the other hand, tumors that are highly
malignant in grown patients may be less so in neonate, because the genetic abnormalities may be different and also because the
mutation burden in neonate may be less (384).
Figure 7-156 Congenital tumors A and B. Teratoma in a newborn. Sagittal T1-weighted image (A) shows an enormous, 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 cervicomedullary 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 cerebral hemispheres. The margins of the tumor appear sharp, suggesting
displacement rather than invasion of the brain. Pathology showed craniopharyngioma.
Ocular Tumors
Retinoblastoma
RB is the most common intraocular malignancy in childhood, accounting for 11% of all cancers in the first year of life (689). It
most often presents in early childhood with leukocoria or “cat’s eye reflex.” Other conditions resulting in this presentation are
listed in Table 7-14. RB is primarily a tumor of infancy; 70% to 80% of RBs occur in infants less than 2 years old, with no
gender or race predilection (689). Multifocal tumors are common, with a 30% incidence of bilateral tumors and a 30%
incidence of multifocal retinal tumors in affected children (690,691); the incidence of bilaterality is higher in patients younger
than 1 year old at presentation (689). Heritable RB 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 >90% penetrance (689). Most patients with RBs have a mutation on the RB1 gene at chromosome 13q14, 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 RBs ultimately developed nonocular neoplasms, most commonly soft tissue
sarcomas (692). The cessation of radiation treatment 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). Likewise, 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 (692–694) are no longer seen.
In 4% to 7% of patients with bilateral RBs, a small cell tumor will eventually develop intracranially (typically in the
midline); this condition is referred to as “trilateral retinoblastoma.” Affected patients present with ocular tumor at an earlier
age (mean 6 months) than do those with sporadic or unilateral tumors (695,696). The incidence of trilateral RB is higher in
children with a family history of RB than in those with no family history (697). The intracranial tumor, which is histologically
identical to the intraocular tumors, may develop in the pineal region (classically the most common and now assumed to be a
pineoblastoma; see section on pineoblastoma in this chapter) (698), but also the suprasellar region, or fourth ventricle (rare)
(697,699–702). It is rarely present at the time the ocular tumors are detected, usually appearing after a latency period of about
2 to 3 years (695,696).
Prognosis of trilateral RB is very poor, and the incidence of subarachnoid tumor spread is high (695,697,703). Recent work
suggests that neoadjuvant intravenous chemotherapy might reduce the incidence of this intracranial complication (704).
A special mention must be made of the diffuse infiltrating RB, a clinically and pathologically distinct variant that
constitutes 1% to 2% of RBs (705–707). Both clinically and radiologically, diagnosis of diffuse RB is more difficult than is
that of the more common nodular type. Patients are typically older (average of ~6 years) and present with pain, redness, or
decreased vision in the affected eye; leukocoria is relatively uncommon (24%). Ophthalmologic examination typically shows a
whitish, exudative-appearing, and flocculent material in the vitreous or anterior chamber, suggesting inflammation or infection.
No family history can be elicited in the vast majority of affected patients.
As RB patients are highly sensitive to ionizing radiation, CT is not recommended; the combination of fundoscopy,
ultrasound, and specific MR sequences is extremely efficient at detecting calcification, and tumor infiltration is better assessed
by MR than by CT (698,708). If CT is performed, the usual appearance of RB is a calcified mass, of any size, within the globe.
The mass arises from the retina, but the borders may be ill defined, making the retinal origin unclear. At least 95% of these
tumors have large, small, single, or multiple calcifications (Fig. 7-157); virtually, all enhance after contrast administration. The
tumor may extend through the sclera into the orbital lymphatics or through the optic nerve intracranially; both pathways of
extension can be well visualized by CT (Fig. 7-157), but use of CT in neonates should be avoided if possible, and MR is the
optimal diagnostic tool, performed under general anesthesia to avoid unwanted eye movements. Either 1.5 T or 3 T MRIs may
be used; but surface coils are often needed with the lower resolution of the 1.5 T magnets. A recommended protocol suggests a
dedicated orbital field of view with thin axial T1WI (1 or 2 mm), axial and oblique T2WI sagittal, axial CISS/FIESTA, and
axial and sagittal oblique (698,708); the use of fat saturation is not recommended by some authors, as it decreases the signal-
to-noise ratio (698). T1WI images show the presence of blood and of proteinaceous fluid under the retina; the RB is mildly
hyperintense with respect to the vitreous; T2WI and CISS/FIESTA provide details about the tumor, retina, and choroid and
sclera; T1WI postcontrast demonstrates the enhancing components of the tumor, the optic nerves (invaded in 7%), the choroid
and sclera (invaded in 23%–42%), and the anterior eye segment changes (rarely involved) (698); a complementary study of the
brain after contrast administration using T1WI as well as FLAIR is warranted (Figs. 7-157 and 7-158). MR, therefore, is an
excellent modality for the evaluation of patients with suspected RB. In addition, follow-up imaging studies, which are intended
to identify tumor along the optic nerves or intracranially, should include both orbits and brain.
Table 7-14 Causes of Leukocoria in Children
Figure 7-157 Bilateral retinoblastomas. A. Axial noncontrast CT through the globes shows calcified masses arising from the retina bilaterally
(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 intracranial tumor of trilateral RB has CT and MR characteristics identical to that of the intraocular tumor. CT shows a
hyperdense mass that is usually heavily calcified and enhances prominently and heterogeneously (709). MR 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. Heterogeneous enhancement is seen after administration of paramagnetic contrast (699,700,709).
Figure 7-158 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.
Figure 7-159 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.
The appearance of diffuse infiltrating RB is different, as this form is characterized by diffuse infiltration of the various
layers of the retina. Vitreous invasion is frequent, and extension to the anterior chamber can occur via the ciliary processes and
the iris. No discrete nodular mass, as typically seen in RB, is present; instead, a diffuse, homogeneous, uniformly enhancing
mass is detected (Fig. 7-159). Calcification may be too minimal to detect by ocular ultrasound or CT (Fig. 7-159). Typically,
only a single eye is involved. These tumors appear to be less biologically aggressive than typical RBs; therefore, extension
into the optic nerve or through the sclera is very rare. If any calcification is seen, the diagnosis of RB should be suggested. If
no calcification 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 are
correlated with toxocara canis exposure, and low birth weight (for retinopathy of prematurity) must then be utilized to make
this distinction (710).
A very rare cause of leukocoria is medulloepithelioma, a rare embryonal intraocular neoplasm of young children that arises
from the medullary epithelium of the ciliary body (Fig. 7-163). These tumors sometimes calcify, due to the presence of a
hyaline cartilage component found in 30% of teratoid medulloepitheliomas (718,719). They can be differentiated from RBs if
they originate from the ciliary bodies, but when they arise from the retina, differentiation may be impossible. Ultrasound may
show cystic collections within the tumor, while on CT, medulloepitheliomas appear as dense, irregular, enhancing solid masses
with cysts. On MR, they appear 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 contrast
(713). If cystic areas are present, the enhancement may appear heterogeneous. Calcification may be present in teratoid
medulloepitheliomas; extension may develop along the optic nerve or via the ciliary veins, best appreciated by MR. Presence
of an extension beyond the globe portends a poor prognosis.
Figure 7-162 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 posterior 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. Moreover, a streaky density is seen extending toward the head of the optic nerve through the vitreous
(arrows). This represents a persistent hyaloid canal and confirms the diagnosis of persistent hyperplastic primary vitreous.
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 tissues (725,726).
Figure 7-163 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 uniform enhancement of the mass and thickening of surrounding soft
tissues. Medulloepitheliomas can mimic inflammatory disease, both clinically and on imaging.
Hemangiomas
Hemangiomas, formerly referred to as capillary hemangiomas (727), are the most common vascular masses to present in the
orbits of young children. These malformations, which have a slight (3:2) female predominance, 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 (725,726).
Hemangiomas can develop anywhere in the orbit; anterior lesions are most commonly 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 (728). Some orbital hemangiomas may
be associated with cerebral and vascular anomalies of the PHACES syndrome (see Chapter 6).
CT of orbital hemangiomas shows 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 (extraconal, more common), inside the muscle cone
(intraconal, less common), or both. Rarely, they spread intracranially through the orbital fissures. Diffuse enhancement is seen
after intravenous administration of contrast. MR is the diagnostic modality of choice. It shows the tumor as a well-marginated
mass, slightly hyperintense compared to extraocular muscles and hypointense compared to fat on T1WI (Fig. 7-164). On T2WI,
hemangiomas are hyperintense compared to muscle and fat, and hypointense compared to fluid, and not suppressed on fat-
saturated sequences. Curvilinear flow voids, representing blood vessels, are typically present within and at the periphery of
the mass (Fig. 7-164), a useful finding in differentiating hemangiomas from more aggressive lesions, such as
rhabdomyosarcomas. Dark, fibrous septa may be seen between the hyperintense lobules on T2-weighted images. Avid
enhancement, usually homogeneous, is observed on T1-weighted fat-suppressed images after contrast administration (Fig. 7-
164). The affected orbit is often enlarged, probably as a result of the congenital nature of the lesion (726,729). As the mass
involutes, fat develops within it, making it more hyperintense on T1-weighted images and less hyperintense on T2-weighted
images. Hemangiomas are most easily differentiated from other orbital tumors by the curvilinear flow voids within and at the
periphery of the mass.
Combined venolymphatic malformations: lymphatic malformations (lymphangiomas) and venous
malformations (cavernous hemangiomas)
Orbital lymphatic malformations and venous malformations are part of a spectrum of disorders involving both the lymphatic
and venous systems (730); nonetheless, some are primarily lymphatic, while others are primarily venous. Therefore, the
disorders within this section will be separated with the understanding that these malformations essentially always contain both
components.
Most lymphatic malformations (formerly called lymphangiomas) are diagnosed 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 or from reactions of the lymphatic system to upper
respiratory infections (731). They 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 (732,733). This permeation of the intra- and extraconal
compartments makes complete resection nearly impossible. Pathologically, lymphatic malformations are composed of
abnormal venous channels that are associated with enlarged lymphatics, particularly in the eyelids and conjunctivae. 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 (730).
Figure 7-164 Orbital hemangioma (formerly capillary hemangioma). 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.
On CT, lymphatic malformations are lobulated, heterogeneous, poorly defined lesions that cross anatomic boundaries such
as the conal fascia and orbital septum (Fig. 7-165). 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 mild and located along the periphery and in the stromal framework (720,729). On MR,
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. 7-166). The variations of intensity are the
result of differing amounts of blood and protein in the cysts. Fluid–fluid levels may be present within the cysts (Fig. 7-166); if
present, they are strongly suggestive of lymphatic malformation. Heterogeneous enhancement follows intravenous
administration of paramagnetic contrast (726). 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-
166).
Figure 7-165 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.
Figure 7-166 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 component (arrowheads) is more homogeneous and of lower signal intensity,
more compatible with a venous component. C. Postcontrast axial T1-weighted image shows heterogeneous enhancement (arrows and
arrowheads).
A subset of lymphatic malformations is associated with developmental venous anomalies of the brain; in one series, this
amounted to 28% of orbital lymphangiomas, with 14% (1/7) presenting with intracranial hemorrhage (734). At birth, these
patients generally had a visible superficial component, followed by episodes of sudden proptosis associated with deep orbital
hemorrhages. Visual outcome was poor (20/200 or less) in four (57%) of seven cases. The orbital lesions were diffuse with
superficial and deep components (100%) involving the intra- and extraconal spaces (57%). The affected orbit was expanded in
all patients; the inferior orbital fissure was expanded with extension into the pterygopalatine fossa in 82%, while the superior
orbital fissure was always involved, with extension into the middle cranial fossa in 43%. Anterior extension into soft tissues of
the face, forehead, and palate were relatively common. In contrast, lymphatic malformations without noncontiguous intracranial
vascular anomalies were more anterior, less diffuse, and less likely to extend into the soft tissues of the face, have associated
vascular lesions, or have a poor visual outcome (734). It was recommended that the intracranial vasculature should be
evaluated in all orbital lymphangiomas, especially those that are diffuse.
Cavernous malformations of the orbit (formerly known as cavernous hemangiomas (727)) are uncommonly identified in
children, becoming symptomatic more often in young and middle-aged adults (725,735). They typically present with painless
proptosis that remains unchanged with Valsalva maneuvers, differentiating them from orbital varices, which enlarge during
Valsalva (725). When located anteriorly, they present earlier and often extend to the forehead, temporal region, or cheek. On
CT, cavernous 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 (729). On MR, cavernous malformations appear as
homogeneous, well-defined, round or ovoid, slightly lobulated masses that are usually intraconal (Fig. 7-167). 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. 7-167) after
intravenous infusion of paramagnetic contrast (726).
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 (731). Therefore, contrast-enhanced study of the brain should
be obtained along with the orbital study. The vascular malformations are most commonly developmental venous anomalies or
cavernous malformations, but AVMs and AV fistulae may rarely be found; the intracranial anomaly may be ipsilateral or
contralateral to the orbital lesion (731).
Figure 7-167 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 contrast shows diffuse, slightly
heterogeneous enhancement.
Orbital varices
Orbital varices are venous malformations that occur in the retrobulbar 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 MR,
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, images obtained in a
supine position without Valsalva may be normal; if the proper history is obtained, further scans should be obtained during
maneuvers. CT is a better study because of the shorter imaging times that allow scanning to be performed during a Valsalva
maneuver (726,729).
Orbital Cysts
When retro-ocular cysts are seen in infants and children, the most common 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 (724,736).
Colobomas and their embryogenesis are discussed in Chapter 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. 7-168 and 7-169). MR, especially
with high-resolution CISS/FIESTA, 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 imaging sequences. Contrast enhancement is not seen (724,736,737).
Figure 7-168 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).
Figure 7-169 Bilateral colobomas with cysts. Axial T1-weighted image shows bilaterally small globes with cysts extending from the posterior
midline of the globes. The left globe and colobomatous cyst are hyperintense secondary to subretinal hemorrhage. (This figure courtesy Dr.
Sylvester Chuang, Toronto.)
Plexiform neurofibroma
Plexiform neurofibromas are highly vascular, poorly defined, and diffusely 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 NF1. 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 (725). They appear on both CT and MR as serpiginous, irregular, poorly marginated masses that
surround and engulf normal orbital structures (Fig. 7-171). 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
(740). Although any portion of the obit 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. 7-171). On CT, the masses appear as serpiginous lesions isodense with the
extraocular muscles that do not respect fascial boundaries. On MR, it is easier to appreciate the multiple serpiginous enlarged
nerve fascicles coursing 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 heterogeneous (726,729).
MR 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.
Figure 7-170 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) extension of the mass through the orbital walls. Normal orbital structures are
compressed medially by the intraorbital component (small white arrows) of the mass.
Figure 7-171 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).
Neoplasms 18%
Lymphoma
Soft tissue sarcoma (especially rhabdomyosarcoma)
Neuroblastoma
Carcinoma (especially thyroid)
Adapted from Vazquez E, et al. US, CT, and MR imaging of neck lesions in children. Radiographics 1995;15:105–122.
Figure 7-172 Orbital dermoids. A and B. Axial image (A) and sagittal reformation (B) from a CT scan show a sharply demarcated fat density
mass (arrows) superior to the left ocular globe. C and D. Axial precontrast and postcontrast fat-suppressed T1-weighted images in a different
patient show the high signal of the dermoid (arrow) to be suppressed, confirming the fatty nature of the lesion.
A nice review of a large series of masses involving the pediatric face and neck was given by Vazquez et al. (743). They
published a review of 145 pediatric patients from 1 day to age 18 years who presented to their practice with neck masses. The
results of this review are summarized below and in Table 7-15. Congenital lesions is the largest group, constituting 40% of
these masses, including 19 thyroglossal duct cysts (31%), 15 lymphangiomas (25%), 8 branchial cleft anomalies (13%), 6
dermoids (10%), 6 cases of tracheal stenosis (10%), 3 teratomas, 2 lingual thyroid glands, and 2 cases of thyroid gland
hypogenesis. Benign tumors and tumor-like conditions were the second largest group of pediatric neck and face masses. This
group constituted 19% of 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 papillomatosis, and 1 plexiform neurofibroma. 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 malignant tumors were soft tissue sarcomas (23%, of which two-thirds were
rhabdomyosarcomas), carcinomas (19%, most commonly thyroid carcinoma), and neuroblastoma (arising from the cervical
sympathetic chain, 19%). Inflammatory lesions were the next largest group of masses (12%), with cervical adenitis from
mycobacterial infections or catscratch fever (10 cases, 62%) being the most common cause in this group. In this regard, it is
important to remember that more than 90% of mycobacterial cervical lymphadenitis in children is due to nontuberculous
mycobacterial (usually Mycobacterium avium–intracellulare); this predilection is in marked contrast to adults in whom
tuberculous cervical lymphadenitis is more common (744). The authors also reported three cases (19%) each of sialadenitis
and retropharyngeal abscess (from tonsillitis or trauma). Masses of vascular origin (10%) constituted the smallest group.
Jugular vein varices (fusiform dilations of the vein secondary to presence of jugular venous valves) accounted for 60% of
these vascular masses. Cervical hemangiomas were the only other diagnosis of significant frequency, constituting 33% of the
masses in this group. The authors note, however, that a pulsatile cervical mass in a child should raise suspicion for a cervical
carotid artery aneurysm, which has the greatest clinical significance. Cervical carotid aneurysms may be congenital (usually
secondary to connective tissue disorder such as Ehlers-Danlos, Marfan, Kawasaki, or Maffucci syndromes), posttraumatic, or
postinfectious.
Figure 7-173 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, extending 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.
Third branchial anomalies are very rare. They usually consist of cysts or fistulas. The cysts are most frequently located just
proximal to its external opening at the anterior border of the sternocleidomastoid 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 hypoglossal 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 originating 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%) (755). On CT and MR, 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. 7-175 to 7-177), the
diagnosis is straightforward. Pointing of the cyst medially toward the carotid sheath or posteriorly deep to the
sternocleidomastoid muscle (Fig. 7-176) 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 infection 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 sternocleidomastoid muscle, along a path that extends
between the internal and external carotid arteries (752). When branchial cleft cysts become infected, the walls thicken and
enhance and the contents become more proteinaceous. Under these conditions, it becomes difficult to differentiate the infected
cyst from a necrotic lymph node (752,756). Differentiation can often be made by the fact that infected branchial cleft cysts
incite less surrounding edema than do 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 (757). Therefore, nontuberculous mycobacterial infection should always remain in the differential diagnosis
of any cervical cyst with a thick wall.
Figure 7-174 Thyroglossal duct cyst. A. Sagittal T2-weighted image with fat suppression shows a hyperintense 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, markedly hyperintense mass (arrow) within the tongue base. C. Coronal
postcontrast T1-weighted image with fat suppression shows the thin-walled mass (arrows) with complete lack of enhancement.
Thymic cysts
Thymic cysts are rare remnants of the third branchial pouch and, perhaps, should be classified as a variant of branchial cleft
cysts (756). 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 thymopharyngeal duct, which subsequently involutes. Failure of complete involution 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 (756). Up to 50%
are continuous with the mediastinal thymus via direct extension of the cyst or by connection to a solid cord or vestigial remnant
of thymic tissue (758). Lesions are almost always adjacent to or within the carotid sheath, frequently splaying the carotid artery
and jugular vein.
Figure 7-175 First branchial cleft cyst. Axial T1-weighted image shows a cyst (arrows) anterolateral to the parotid gland in the subcutaneous
fat.
Figure 7-176 Second branchial cleft cysts. Axial CT images show characteristic location of the cysts (c) between the sternocleidomastoid
muscle and the submandibular 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.
Vascular Malformations
Venolymphatic malformations
As discussed in the section on 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 result, the nomenclature of disorders of these systems has
changed (727). The lesions formerly known as lymphangiomas and those formerly known as venous hemangiomas are now
combined into an entity known as venolymphatic malformation (730). As discussed earlier, many of these malformations are
primarily lymphatic, while others are primarily venous. Therefore, lymphatic malformations and venous malformations will be
discussed separately while keeping in mind that venous malformations nearly always have 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. 7-178). The septae may enhance on MR. If the cystic spaces are very
large, the lesion is referred to as a cystic hygroma (Fig. 7-179). One important characteristic of lymphatic malformations and
other congenital lesions of the neck (venous malformations, hemangiomas, neurofibromas, branchial cleft cysts) is that they
cross anatomic fascial boundaries (759). Infections and neoplasms are unlikely to cross these boundaries until late in the
course of the disease; therefore, the presence of a mass in multiple fascial compartments suggests a congenital lesion.
Fluid–fluid levels are common in cystic hygromas. As a result of their crossing of fascial planes, lymphatic malformations
often involve multiple muscles, nerves, and blood vessels. 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 (756); in addition, MR is
better able to identify intralesional hemorrhage and fluid–fluid levels. As with other cystic masses of the neck, the diagnosis of
lymphatic malformations only becomes difficult if hemorrhage or infection ensue. Infection causes increased echogenicity
(US), increased attenuation (CT), and T1 and T2 shortening (MR) as well as enhancement and thickening of the cyst wall.
Hemorrhage results in rapid enlargement of the malformation. After hemorrhage, echogenicity increases on sonography,
attenuation increases on CT, and the fluid changes from water intensity to the intensity of blood breakdown products on MR.
Lymphatic malformations of the face are often associated with intracranial developmental venous anomalies.
Figure 7-177 Second branchial cleft cyst. Axial T1-weighted (A) and T2-weighted (B) images show a well-defined homogeneous lesion
(arrows) with long T1 and long T2 relaxation times lying between the submandibular gland and sternocleidomastoid muscle.
Figure 7-178 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 mass (arrows) to be very hyperintense (presumably fluid) with
multiple septa. The more hypointense, presumably solid medial component (s) is parotid gland. C. Fat-suppressed postcontrast T1-weighted
image shows the parotid (s) enhances (black arrows) but the tumor (arrowheads) does not.
Venous malformation is the name given to venolymphatic malformations with predominantly venous components. These
lesions were formerly known as cavernous hemangiomas (727), but they are not hemangiomas as they do not involute over time
and may involve bone. They are uncommon in children, presenting more frequently in young and middle-aged adults (725) with
a painless, slow-growing bluish mass, often in the face or in the skeletal muscles of the head or neck (masseter, pterygoid,
trapezius, sternocleidomastoid); the lesion remains unchanged with Valsalva maneuvers. They range greatly in size, from a few
millimeters in diameter to involvement of much of the face. When large, they may compress the airway (760). On CT, venous
malformations appear as homogeneously enhancing round or ovoid masses that often contain calcified phleboliths and may
cross fascial planes (729). On MR, 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 images, and
enhance strongly after intravenous infusion of paramagnetic contrast (Fig. 7-180) (726). It is important to recall, however, that
variable amounts of lymphatic malformation may result in T1 shortening of part of the venous malformation, resulting in
the presence of fluid–fluid levels (Fig. 7-181). These findings should not confuse the reader, but should strengthen the
diagnosis of venolymphatic malformation.
Figure 7-179 Large infantile venolymphatic malformation (cystic hygroma). A and B. Sagittal and axial T2-weighted images of a fetus show a
multiloculated hyperintense lesion (arrows) involving the face and neck. Note the marked enlargement of the face due to the large
lymphangioma. C. Postcontrast 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.
Goyal et al. have proposed a classification for venous malformations, defining 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 (761). Response to ethanol sclerotherapy varies with grade, with best response in grade 1 lesions, and worst
response in grade 3 lesions. Venous malformations of the face are commonly associated with associated anomalies, a condition
that has been called PHACES syndrome (Posterior fossa malformations, facial Hemangiomas, Arterial anomalies, Cardiac
anomalies and aortic coaction, Eye anomalies, and Sternal clearing and/or Periumbilical raphe) (762–764) (see Chapter 6).
Therefore, a thorough examination should always be carefully performed on these patients; the brain and intracranial vessels
should be assessed when imaging studies of the head or neck are performed.
Figure 7-180 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.
Figure 7-181 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. Postcontrast 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.
Benign Tumors
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 convenience of the reader. Neurofibromas are masses composed of fibroblasts and nerve cells and develop distally,
from the nerves rather than from the roots. They occur most commonly in NF1 but may occur sporadically. The neck is a
common location for neurofibromas, with an estimated occurrence of 25% to 30% in patients with NF1 (768). They are usually
ovoid, sharply marginated masses that typically occur in the region of the carotid sheath, although they can develop anywhere
that nerves run. Solitary neurofibromas have slightly greater signal intensity than does 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. 7-184 and examples in Chapter 6)
(769–771); this has been referred to as the “target sign” (772). The central area of decreased intensity is probably related to
the known dense central core of collagen within these lesions (769,771). Collagen has a low mobile proton density and,
therefore, is of low signal intensity on T2WI. After contrast administration, enhancement is variable, but usually heterogeneous.
Schwannomas are tumors of Schwann cells that are most commonly sporadic but are seen with increased prevalence in NF1
and NF2; they develop preferentially from nerve roots devoid of fibroblasts, sensory more commonly than motor, but may also
develop distally. Imaging manifestations of schwannomas of the neck are similar to those in other regions of the body. When
peripheral, they are most common in and around the carotid sheath but may be seen anywhere in the neck, as well-defined,
usually ovoid, masses that may cross fascial planes. On CT, the masses are isodense with neck muscles. On MR, they are
isointense with muscle on T1-weighted images and hyperintense compared with muscle on T2-weighted and FLAIR images.
Contrast enhancement is variable but usually homogeneous.
Figure 7-183 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 hyperintensity of the mass. The heterogeneity results from the cystic degeneration of portions of the mass. C. Postcontrast T1-
weighted image with fat suppression shows nearly uniform enhancement.
Plexiform neurofibromas are seen only in the setting of NF1. They are locally aggressive congenital lesions composed of
tortuous cords of Schwann cells, axons, fibroblasts, and collagen in an unorganized intercellular matrix (773). They tend to
progress along the nerve of origin (usually small, unidentified nerves), their branches, and their anastomoses causing distortion
and compression of the adjacent structures. On CT, plexiform neurofibromas tend to be of low attenuation and usually do not
enhance after administration of intravenous contrast. On MR, the curvilinear masses are heterogeneous, crossing facial
boundaries throughout the neck (Fig. 7-185) and nearly always surrounded by fat (nerves in the neck mostly run through fat).
They are hypointense compared with brain on T1WI and hyperintense on T2WI (774). When fat suppression is used, high-
quality T2 images nicely show the multiple swirling enlarged nerves coursing through the tissue (Fig. 7-185B). Enhancement
after administration of paramagnetic contrast is variable, although at least a portion of the tumor usually enhances (Fig. 7-
185C).
Teratomas
Although neonatal head and neck teratomas are reportedly very rare (775,776), 2 to 3 are seen per year in our department,
accounting for up to 10% of all neonatal teratomas (775,776). Most are detected prenatally by obstetrical sonography
(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 (775), early surgery to decompress the airway results in a good prognosis
for about 90% of affected neonates (777).
Figure 7-184 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).
Imaging is useful more for assessing the anatomic extent of the tumor than for establishing a diagnosis. CT may be useful for
identification of fat or calcium, which increases confidence in the diagnosis of teratoma. However, MR 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. 7-186). 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 homogeneous. 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.
The differential diagnosis varies with the appearance of the tumor and the precise location. For predominantly cystic
masses, the main differential 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 differential includes craniopharyngioma, dermoid, cephalocele (is the
brain exiting through the skull defect or being pushed away by an extracranial mass?), and sarcoma. If the lesion is largely fatty,
dermoids and lipomas are considerations, although large lipomas and large dermoids are uncommon in neonates.
Figure 7-185 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 heterogeneity of the mass (arrows) and the hyperintense swirls of thickened, curvilinear
nerves that compose the tumor. C. Postcontrast fat-suppressed T1-weighted image shows heterogeneous enhancement of the tumor
(arrows).
Figure 7-186 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.
Aggressive Tumors
Rhabdomyosarcomas/rhabdomyomas
Rhabdomyosarcomas are the third most common primary childhood malignancy of the head and neck, following intracranial
brain tumors and RBs in frequency. They constitute 4% to 8% of all malignant tumors in children less than 15 years old; 43%
of rhabdomyosarcomas arise before age 5 years, and 78% before age 12 years (778). Forty percent of rhabdomyosarcomas
arise in the head and neck, with the orbit and nasopharynx most commonly 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 (779–781).
Rhabdomyomas are much less common than are rhabdomyosarcomas, constituting only 2% of all tumors of striated muscle
in the pediatric age group (782). 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 (783). Their most common locations are the head and neck, including the oral cavity,
retroauricular area, and orbit (782,784). Rhabdomyomas are well-circumscribed, homogenous masses without necrosis or
hemorrhage. Adjacent bones are remodeled but not invaded or destroyed. MR imaging reveals low signal on both T1- and T2-
weighted images; administration of intravenous contrast results in uniform enhancement (784,785).
Clinically, it is useful to classify rhabdomyosarcomas of the head and neck by site of origin (786). Three major groups are
identified: (a) parameningeal, (b) orbital, and (c) other head and neck locations. The parameningeal group, consisting of
tumors originating in the middle ear, nasopharynx, 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 extra- 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 cavernous sinuses and middle cranial fossae (787). Lymphatic spread and hematogenous spread are 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. 7-187). If
calcification is present, it is typically due to destruction of adjacent bone (788). 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 (789).
Usually, an extracranial or petrosal mass is also visible (779–781,790). The MR findings are usually those of a mass that is
isointense to muscle on T1-weighted images and hyperintense to muscle on T2-weighted images (Figs. 7-188 to 7-190). The
tumors are often heterogeneous on T2-weighted images due to presence of necrosis and hemorrhage. When tumors invade the
paranasal sinuses, MR helps to differentiate tumor from retained secretions. Extension of tumor through a foramen or fissure is
more easily visualized with MR 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 MR 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 (791). This sign may help in specificity of MR diagnosis. Contrast enhancement also aids in
the identification and localization of tumor that extends through the skull base foramina into the extradural space (779,792).
The identification and localization of extracranial tumor, however, may be more difficult after contrast administration, as the
enhancing neck muscles and enhancing tumor can both become isointense with fat. Contrast-enhanced MR imaging of the neck,
therefore, should always include fat saturation pulses (Figs. 7-188, 7-190, and 7-191). Although the CT and MR findings are
not specific, the diagnosis of rhabdomyosarcoma can be suggested from imaging studies because it is, by far, the most common
primary extracranial tumor that invades the cranial vault in childhood. When available, MR is the imaging modality of choice
for these tumors because the coronal and sagittal sections allow evaluation of possible invasion of the cavernous sinus and the
extradural space. Moreover, MR better defines ports for irradiation because of its multiplanar capability.
Figure 7-187 Rhabdomyosarcoma. A. Axial contrast-enhanced CT through the middle 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 cavernous sinus (arrows) and widening the superior
orbital fissure (open arrows).
Nasopharyngeal carcinoma
Although nasopharyngeal carcinoma is rare in children with an incidence of less than 1% of all childhood cancers, carcinoma
of the nasopharynx has a predilection for adolescents and teenagers (793). Indeed, although rhabdomyosarcoma and lymphoma
are more common causes of nasopharyngeal masses in younger children, nasopharyngeal carcinoma is more common in
adolescents (793). These tumors are typically of the nonkeratinizing variant and are associated with Epstein-Barr virus (794).
Affected children typically present 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 nonspecific
and the clinical suspicion for tumor is usually low (795). 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 parents or physicians for further investigation.
Figure 7-188 Nasopharyngeal 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 hyperintense compared to skeletal
muscle. C. Postcontrast T1-weighted image shows homogeneous enhancement (arrows) of the tumor.
Figure 7-189 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 compared with surrounding muscle. C. Postcontrast axial T1-weighted image shows moderate homogeneous
enhancement of the mass (arrows).
Figure 7-190 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
invasion though the foramen ovale (large arrow) is seen.
Figure 7-191 Rhabdomyosarcoma with intracranial invasion. Value of fat suppression. A. Noncontrast axial T1-weighted image shows a
nasopharyngeal 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 enhancing 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.
The main imaging characteristic for differentiating nasopharyngeal carcinoma from 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 asymmetric (796). Another feature distinguishing carcinoma is local spread of the
mass, typically posteriorly through the pharyngobasilar fascia toward 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 (796). 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, histologically 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, orbit, and middle cranial fossa is often seen by the time of presentation. Affected patients typically
present with nasal obstruction and recurrent epistaxis. In advanced cases, proptosis or cranial neuropathies may develop
(779,797,798).
CT typically shows a sharply marginated, homogeneous soft tissue mass in the nasopharynx and 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. 7-192)
(779,797,798). MR shows the mass to be hypo- to isointense compared with muscle on T1-weighted images; although most are
iso- to slightly hyperintense compared with muscle on T2-weighted images (Figs. 7-193 to 7-195), the lesions are occasionally
very hyperintense. Marked, fairly uniform enhancement is seen after intravenous administration of paramagnetic contrast (Figs.
7-193 to 7-195). Punctate and curvilinear regions of low signal intensity can be seen on both T1WI and T2WI, representing the
prominent tumor vessels that are characteristic of these tumors; however, tumor vessels are not always seen by MR and their
absence in a mass otherwise typical for juvenile angiofibroma should not negate the diagnosis (779,798). 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 pterygopalatine 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 mesodermal origin that typically involve the skull, dura, or face.
They often occur adjacent to cranial sutures and may be initially mistaken for dermoids. Patients typically present with a mass
and discoloration of adjacent skin. The tumors secrete high levels of vanillomandelic acid and homovanillic acid in the urine,
which can be used to make a preoperative diagnosis and to identify tumor recurrence at an early stage. Local resection is often
curative (799,800). 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 these characteristics have been present in the same
patient in different areas of tumor. MR shows a soft tissue mass that is isointense to muscle on T1WI and iso- to hyperintense to
muscle on T2WI. 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 (799,800).
Miscellaneous
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 (801).
Figure 7-192 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.
Figure 7-193 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. C. Coronal post-contrast 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).
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, is nontender,
and cannot be separated from the sternocleidomastoid muscle. There may be a history of breech presentation or forceps
delivery, which raises the question of trauma and hematoma as the cause of the mass (802,803). 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 sonography, CT, or MR. Sonography is usually diagnostic, showing
focal or diffuse enlargement of the sternocleidomastoid muscle with variable echogenicity. Often, a hypoechoic rim (thought to
represent compressed normal muscle) is present. CT shows a focal enlargement of the sternocleidomastoid muscle. If contrast
is administered, variable enhancement is seen. On MR, the mass is isointense to normal muscle on T1-weighted images and
slightly hyperintense on T2-weighted images and shows similar enhancement to normal skeletal muscle (Fig. 7-196) (804).
Occasionally, enhancement is heterogeneous; this should not dissuade one from making the diagnosis of fibromatosis colli if all
other features are consistent with it.
Neuroblastoma
Neuroblastoma of the neck is discussed in Chapter 10 in the section of extradural neoplasms.
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 MR imaging (Fig. 7-197). Affected bone is expanded and will
enhance dramatically. A noncontrast CT scan (Fig. 7-198) with bone algorithm will show the classic “ground-glass”
appearance of fibrous dysplasia, confirming the proper diagnosis.
Figure 7-194 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 sphenopalatine 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 enhancement. Arrows show extension of tumor into the skull
base.
Figure 7-195 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 pterygopalatine 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 coronal T1-weighted image with fat saturation shows
intense, fairly uniform enhancement. Black arrows show extension of tumor into the skull base.
Figure 7-196 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 hyperintense compared with
muscle. C. Postcontrast T1-weighted image shows mild uniform enhancement of the mass approximately equal to that of surrounding muscle.
Figure 7-197 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 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.
Figure 7-198 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 cortical bone. This appearance is called a “ground-glass” appearance. 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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Hydrocephalus
Charles Raybaud
Introduction
CSF and CSF Spaces
Anatomy
Development
Secretion and Absorption of the CSF
CSF Dynamics and Related Disorders
Diagnosis of Hydrocephalus
Clinical Presentation
Imaging Tools
Imaging Features of Hydrocephalus
Specific Etiopathogenic Contexts
Conclusion
Introduction
Hydrocephalus is one mechanical complication of many different diseases. It may be defined as a process in which the
cerebrospinal fluid (CSF) compartment is actively enlarged at the expense of the brain tissue. It may develop at any age and
is common in all age groups, but especially so in children. The basic nature of hydrocephalus is relatively easy to understand:
as the ventricles actively increase in size, which results in a progressive compression of the brain tissue, some CSF must be
diverted in order to avoid damage to the brain. Establishing the diagnosis also is relatively simple (in most cases): increased
ventricular size, effacement of the subarachnoid spaces, macrocephaly, and, typically, an obstruction somewhere along the CSF
pathway; common examples include midline tumors, aqueductal stenosis (AS), and arachnoid loculations. It is also important
to remember that hydrocephalus is a “mechanical” disease, and as such, it may be a consequence of many different brain
diseases (neoplasia, malformation, infection, hemorrhages, etc.), which make its evaluation more complex in individual
patients.
Obstructive hydrocephalus is still commonly understood on the basis of concepts formulated early in the last century by
Dandy and Blackfan (1): CSF is produced by the ventricular choroid plexuses and absorbed by the peripheral meninges; its
transventricular and extracerebral circulation results from a corresponding arteriovenous pressure gradient; an obstruction
anywhere along this path can cause CSF accumulation upstream. Communicating hydrocephalus is a subset of the condition in
which no ventricular obstruction is found. This concept implies that for the CSF to circulate in normal individuals, the
intraventricular pressure must remain higher than the extracerebral pressure, and this model is not really corroborated by facts.
Pericerebral spaces are maintained in normal subjects, as is demonstrated by MR imaging; in addition, the normal tuber
cinereum is convex upward. Both of these features indicate that the intraventricular pressure is not higher than the cisternal
pressure. An “accumulation” of fluid preventing its peripheral absorption would be expected to result in progressively
increasing intracranial pressure (ICP), but pressure may remain normal for months (or years) in patients with chronic
hydrocephalus. The presence of stable ventriculomegaly with isolated AS proves that CSF may be absorbed within the
ventricles. Indeed, clinical practice demonstrates that different pathophysiologic processes may result in different subtypes of
hydrocephalus of different degrees of severity, with different radiologic pictures, different therapeutic approaches, and
different prognoses (2).
In the decades following the seminal concepts of Dandy and Blackfan, new facts have emerged. In the 1950s, Bering
demonstrated that heavy water could exchange freely between the CSF spaces, the parenchyma, and the blood (3,4), implying
that the parenchyma can easily contribute to both the production and the absorption of CSF. His later experimental studies of
obstructive hydrocephalus without or with choroid plexectomy suggested that the ventricular enlargement could be explained
by the loss of the normal dampening of the systolic pressure wave (5,6). This was better demonstrated by further experiments
of Pettorossi and Di Rocco (7–9). In the 1990s, the advent of MR imaging made noninvasive studies of the CSF dynamics
possible in normal human subjects: it was then demonstrated that the force upon CSF resulting from arterial pulsations is much
stronger, and displaces much larger CSF volumes, than the mean arteriovenous gradient (10–12). In the last two decades, the
identification of the aquaporin (AQP)-mediated water channels in the choroid epithelium (AQP1) (13), the ependymal cells
(AQP4), and the perivascular, subependymal, and subpial astrocytic end feet (AQP4) (14) provided cytologic support to the
concept that water can easily cross any interface between the CSF spaces, the parenchyma, and the vessels.
The first part of this chapter will review the anatomy and development of the CSF spaces, the processes involved in the
production and absorption of the CSF, the forces driving the movements of the CSF, and how these factors may mechanically
result in hydrocephalus. The second part will address the diagnostic issues of hydrocephalus: clinical presentation, imaging,
and diagnostic features, including a review of the specific subtypes relating to different etiopathogenic factors or contexts. The
last part will deal with the treatments of hydrocephalus: the surgical techniques, the results, and the complications.
Anatomy
The Container: Skull and Spine
CSF and interstitial fluid (ISF) together form the extracellular fluid compartment of the central nervous system (CNS). CSF is
contained within the ventricles and arachnoid spaces and surrounds the brain and spinal cord. It acts as a transportation
medium as well as a cushion for the neural tissue, protecting it from mechanical damage. The immersion of the brain reduces
its weight substantially (~97%), hence lessening the effects of both intracranial and extracranial forces.
The skull is composed of the vault and the base. Although the base is traversed by many nervous and vascular foramina, the
mature skull may be considered a closed box, except for the foramen magnum that opens into the spinal canal. The dura that
lines the inner calvarial table forms folds that project into the cranial cavity to form the falx cerebri in the sagittal plane, and
the tentorium cerebelli between the brain and the cerebellum. Between the insertions of the falx and tentorium on the calvarial
dura run the dural superior sagittal, transverse, and sigmoid venous sinuses, which themselves are lined with arachnoid villi.
Blood is conveyed into the internal jugular veins through the jugular foramina when the body is supine, but through numerous
other veins and dural venous channels, into the neck and the spinal venous system when the body is erect (25). Within the
insertion of the falx on the tentorium, the triangular-shaped straight sinus conveys the venous blood of the vein of Galen into the
torcular Herophili and the transverse sinuses. On either side of the sella turcica, the complex plexular cavernous sinuses drain
the orbital and sylvian veins toward the pterygoid plexuses and petrosal sinuses. While the mature skull is rigid, the fetal and
infantile skulls are more plastic due to the fibrocartilaginous sutures and fontanelles. In volume, relative to the spinal canal, the
cranial cavity is also much larger in fetuses and infants than in adults.
The spinal canal is enclosed by the vertebral bodies, the neural arches and ligaments from the foramen magnum to the
sacral segment. Unlike in the skull, the dura is not attached to the bone but separated from it by the epidural fat and epidural
veins. It also forms 30 pairs of nerve sheaths around the 30 pairs of emerging spinal nerves in the intervertebral foramina. This
anatomy confers enough elasticity to the meningeal sac to accommodate the pulsatile craniospinal influx of CSF at each cardiac
stroke.
Development
Choroid Plexuses
The closure of the neural tube occurs by about 28 postconceptional days in the human (see Chapters 5 and 9). Until then, the
apical (future ventricular) surface of the neuroepithelium is bathed in the primitive amniotic fluid and fed directly from it. After
it closes, the neural tube is surrounded by the meninx primitiva, which itself is invaded by rostral “branches” (only primitive
capillaries at this stage) of the developing cardiovascular system, from which nutrients diffuse into the neuroepithelium (29),
and fluid produced by the neuroepithelium fills the central lumen (30,31). Rostral segments of the neural tube expand to form
the basic pattern of the ventricular system: prosencephalic (forebrain), mesencephalic (midbrain), and rhombencephalic
(hindbrain) vesicles. During the second gestational month (5–7 weeks), the midline dorsal meningeal mesenchyme invaginates
into the lumen of the fourth, lateral, and third ventricles to form the choroid plexuses of the ventricular system, while the
prosencephalon divides dorsally and forms the cerebral hemispheres. The water channel AQP1, which transports water across
the plexular epithelium, is expressed from the very early stages of plexular development in the rat fetus (32) and as early as the
seventh week in the human fetus, first in the tela choroidea of the fourth ventricle and then, 1 week later, in all choroid plexuses
(33). Enzymes used for CSF secretion have been demonstrated in a 9-week human fetus (34). Choroid plexuses are composed
of a secretary cuboidal epithelium limiting a stromal core of capillaries and connective tissue (choroid interstitium) (21). The
vessels present a fenestrated endothelium allowing water and small molecules to egress into the stroma. Joined by tight
junctions, the epithelial cells form the blood–CSF barrier and act as active transporters (for water, ions, proteins, nutrients,
and neurotrophic factors) from the plexular stroma to the CSF. Microvilli on their apical surface increase the surface area of
the choroid plexuses up to 200 cm2 in humans (21). Cells of the immune system (macrophages, dendritic cells, Kolmer
epiplexus) are associated with the plexus, sometimes being transported through them as the plexus does not have a blood–brain
barrier (21,35). Microglia from the choroid plexus colonize the CSF and subsequently invade the deep cerebral parenchyma as
early as 5.5 weeks (21,36). The choroid plexuses deliver, and the ventricular CSF carries oxygen, glycogen, proteins, and
growth and neurotrophic factors to the periventricular germinative zone (21,31,37,38). This function of the choroid plexuses
persists in later gestation as a significant complement to parenchymal vessels and remains important in postnatal life
(31,39,40). The choroid plexuses may also remove endogenous and exogenous substances from the CSF (41,42). Their
importance is reflected by their size: they fill approximately 75% of the ventricular lumen during the third month of gestation
and reach their largest size about 26 to 28 weeks. It has been suggested that they might play a role in the expansion of the
cerebral ventricles by maintaining an optimal hydrostatic pressure (43). This could also result from their arterial pulsatile
force (see below). Although histologically similar, the choroid plexuses present different and specific molecular secretion
patterns (“secretome”) in the lateral, as compared with the fourth, ventricles that are consistent with correspondingly specific
forebrain and hindbrain receptors (21).
Ependyma
For most of the first two trimesters, the ventricles are lined with the undifferentiated germinative ventricular epithelium. True
ependyma differentiates from the radial glia as the ventricular zone (“germinal matrix”) regresses, to form a continuous lining
at about 26 to 28 weeks (44,45). In adults, large areas of it disappear (45). The water channel AQP4 is expressed along the
ventricular lining of the hippocampus after 14 weeks and sometime before 22 to 23 weeks in the ependymal and subpial layers
of the neocortex: the expression being strongest at about 28 weeks, when the ependyma is complete (46).
Ependymal cells are ciliated cuboidal cells, each with an average of 16 motile cilia measuring approximately 13 μm in
length. The coordinated beating (28–40.7 Hz frequency) of this ciliated epithelium is believed to direct neurotrophic factors
and guidance molecules from the plexuses toward their targets along the ventricular walls, to “clean” the ventricular wall,
notably the recesses, from deposits and to facilitate CSF flow in narrow channels (30,31,45). It has been shown in the mouse
embryo that the initial orientation of ciliary beating depends on the direction of the ventricular CSF flow (47). In fetal, but also
in more mature, brains, the ependyma supports the progenitor cells of the subventricular zone (48). Vascular endothelial growth
factor (VEGF) is expressed in the fetal ependyma during the second half of gestation (45). The ependyma is altered by
hydrocephalus (45), although some ependymal repair might occur (49). The ependymal denudation that results from fetal
hydrocephalus has been associated with and is felt to be the cause of the development of periventricular nodular heterotopia
(see Chapter 5) (50).
Extracerebral Spaces
The extracerebral CSF spaces develop during the second month when the meningeal layers differentiate. The intercellular
spaces of the meninx primitiva enlarge progressively and coalesce to form a fluid-filled trabeculated (sub)arachnoid space
(51,52), limited peripherally by the arachnoid layers of the dura mater (53) and centrally by the pia that covers the surface of
the cortex. It also forms the arachnoid septations and the sheath of the leptomeningeal blood vessels, thereby limiting the
perivascular spaces (PVS). The pia also ensheaths the vascular intraparenchymal perforators, thereby forming the Virchow-
Robin spaces (VRS), a combination of subpial space and PVS (this will be detailed in the following section of this chapter)
(54–57). The leptomeningeal “liquefaction” process begins ventral to the pons and midbrain at 5 weeks, extends both caudally
and rostrally at 6 weeks, develops dorsally to the fourth ventricle at 7 weeks, and becomes generalized (if not completed yet)
about 8 weeks (52). This is before the opening of the fourth ventricular outlets, which are not identified in humans before
weeks 11 to 12, as a result of the process of expansion and attenuation of the caudal, medullary part of the rhombencephalic
roof (Blake pouch) (27,58). In the fetus, the pericerebral spaces (as demonstrated by fetal MR imaging) are prominent until
close to term, but they are smaller in premature babies of similar gestational age (2); this likely reflects the decrease of
intracranial water associated with the venous pressure drop that occurs at birth when the pulmonary bed opens and the cardiac
circulation reorganizes (59). This implies that, in the fetus, the growth of the skull is driven by the CSF pressure rather than by
the growth of the brain: the brain expands within the CSF without being constrained by the cranial vault. This is likely true
during childhood as well. High venous pressure (and low arterial pressure) means that the fetal intracranial arteriovenous
gradient is less than that of the (postnatal) infant. The vascular pulsatility also is less, as the CBF is assumed to be much lower
in fetuses than it is after birth (59,60); at this stage, it may be more prominent in the plexuses than in or around the parenchyma.
Arachnoid Villi
It is generally assumed that fetuses and infants have no functional arachnoid villi, which progressively appear during childhood
(so-called immaturity of the absorption sites). However, although no apparent arachnoid villi are found in fetuses, depressions
in the dural sinus walls have been described as early as 26 weeks; although these do not become true villi until much later, they
may already be functional (61). Other absorption sites such as the nasal lymphatics under the cribriform plates seem to be
functional very early.
CSF Absorption
Obviously, the absorption rate of the CSF in a normal situation equals its production rate: 0.35 mL/min or 500 to 600 mL a day.
One study using intrathecal infusion in adult subjects found that absorption does not occur at pressures of 68 mm H2O or below
and that it increases linearly with an increasing ICP to reach about 1.5 mL/min at a pressure of 250 mm H2O; it was not
measured above that level (15) (the normal range of ICP in the supine position is 100–180 mm H2O or 8–15 mm Hg).
Therefore, the normal absorption capacity of the system is ample as long as the absorption mechanisms are intact. These
mechanisms are described below.
Transdural absorption
CSF absorption is known to occur across the arachnoid villi (forming Pacchionian granulations), in which arachnoid tissue
protrudes into the lumen of the dural venous sinuses across their wall. Although fetuses and infants have no or only few
apparent arachnoid villi, depressions in the dural sinus walls have been described as early as 26 weeks, becoming true villi
only much later (61). Anatomically, the villi appear to be one-way valves, which open at a pressure difference of 20 to 50 mm
of water (61); drainage depends on the presence of a CSF–venous sinus hydrostatic pressure gradient (some evidence suggests
that absorption may be by pinocytosis instead) (61,78). In addition to the villi, other transdural drainage routes exist: dural
clefts along the parasagittal dura (different from the classic villi) (79); venous plexuses of the cavernous sinuses or around the
internal carotid artery and pituitary gland in the sellar region (80); olfactory nerve fibers across the cribriform plate toward the
nasal mucosa and lymphatics (81); optic nerves sheaths toward the orbital lymphatics (82,83); and other cranial and spinal
nerve outlets with their own arachnoid villi (61,84). It is not known whether these different pathways are hierarchical, depend
on age and maturation (61,84,85), or are simply synergetic, but all contribute to the CSF absorption. Importantly, all are
“passive” routes dependent on a CSF–peridural pressure gradient only.
Parenchymal absorption
Although absorption of the CSF by the brain has been denied on the basis of tracer studies, it has been shown that water
(labeled with deuterium) would diffuse easily from the ventricles to the parenchyma and, from there, to the blood (3,4,22).
This view was strengthened in the last two decades by the identification of the aquaporins water channels AQP1 and AQP4,
which transport water only—not ions, and not tracers other than water labeled with hydrogen isotopes deuterium or tritium
(13,14,20,32,33,46,65–67,73). AQP4 is strongly expressed in the ependymal cells and subependymal astrocytic end feet of the
ventricular walls. The transport of water between CSF and ISF may occur in both directions, according to pressure and
osmolarity gradients; the ventricular walls may adjust to specific contexts by removing (or providing) water from (or to) the
ventricular CSF. In animal experiments, it was found that acute occlusion of the aqueduct does not modify the intraventricular
pressure and produces no ventricular dilation over a 2-hour period, supporting the hypothesis that most of the CSF produced by
the choroid plexus during that time was absorbed by the ventricular surface (86,87). The same group showed that there is no
outflow of CSF from a cannulated aqueduct when CSF pressure is normal (70). Although such experiments may be criticized
for their nonphysiologic conditions, the results and conclusions are consistent with the clinical example of chronic untreated
ventricular obstructive hydrocephalus: water (not necessarily “complete” CSF with its solutes) is clearly absorbed by the
ependyma. As the pericerebral CSF is obviously produced by the brain surface/VRS as well, ventricular water may be
transported to the ISF and, from there, to the parenchymal capillaries as well as to the arachnoid spaces across the brain
surface and VRS.
Figure 8-1 Models of CSF circulation: bulk flows. A. Traditional model (vertical bulk flow). This model postulates that the CSF, secreted by the
choroid plexuses, would flow along the ventricles, then into the cisterns, and then toward the convexity to be absorbed at the level of the
arachnoid villi. B. Modern model (transverse bulk flows). The new models stipulate that the CSF secreted in the lateral, third, and fourth
ventricles is absorbed locally at the corresponding ependymal levels, allowing specific signaling molecules to be secreted and reach their local
subependymal targets at each level. Similarly, the pericerebral CSF produced by the brain surface is absorbed transdurally at the periphery.
Volumes Ratio
Cerebral blood flow 50 mL/100 g/min, brain 1300 g 650 mL/min 100%
Data partly from Enzmann DR, Pelc NJ. Cerebrospinal fluid flow measured by phase-contrast cine MR. AJNR Am J Neuroradiol 1993;14:1301–1307.
Figure 8-2 Model of CSF circulation: pulsatile flow. The volume of the blood entering the skull at each systole needs to displace a similar
volume of fluid. Most represents the systolic–diastolic flow across the capillary bed and into the veins. A small amount of CSF is also displaced
toward the more compliant spinal dural sac. The force of the cerebral pulsation is directed outward mostly: the volume of CSF displaced
across the tentorium is almost 10 times the volume of CSF displaced across the aqueduct.
This model of ventriculomegaly developing because of a transmantle pulsatile force gradient is sometimes contended
because of the absence of any measurable transmantle pressure gradients in patients with communicating or noncommunicating
hydrocephalus (109). Such measurements are obviously made at equilibrium (hydrocephalus develops much too slowly to
measure the dynamics of the process) and in the closed cranium. The stability of a mass on the ground does not rule out the
force of gravity.
Figure 8-3 The intracranial systolic pressure wave. A. At each systole, the influx of blood into the skull results in a pressure wave. The normal
systolic–diastolic pressure wave of the CSF causes three peaks: P1 (systolic pressure), P2 (viscoelastic response of the vessels,
parenchyma, and dural sac, i.e., the compliance), and P3 (venous systolic wave). In the normal conditions of compliance, P1 > P2 > P3. B. If
the compliance is decreased (the impedance is increased), the shape of the curve is changed with P2 ≥ P1 > P3. This means that in the case
of a ventricular obstruction, P2 is higher than P1 within the ventricle, but not outside of it (where the compliance is maintained), and a
transmantle pressure gradient occurs at each systole that results in a progressive ventricular dilatation. In addition, by impeding the proper
systolic–diastolic circulation through the vascular bed, this abnormal systolic P2 may compromise the venous absorption of ISF and, as a
consequence, the transependymal absorption of CSF.
Clinical Presentation
The clinical presentation of childhood hydrocephalus may be chronic or acute. In chronic hydrocephalus, the most important
and most consistent clinical finding is an excessive rate of head growth. An enlarging head circumference in a child is not, by
itself, of concern (as it actually allows the preservation of brain volume), but an excessive rate of head growth (as compared
with normal standards) demonstrated by serial head circumference measurements should raise the clinical suspicion of a
developing hydrocephalus. In infants and young children, macrocrania is nearly always found at presentation. The forehead is
disproportionately large (frontal bossing), the skull is thin, the sutures may be separated, the anterior fontanelle may be tense,
and the scalp veins often are dilated. Ocular disturbances are frequent and include paralysis of upward gaze (“setting sun”
appearance), 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, which are more directly exposed to the compression and stretching by the dilated
lateral ventricle than the more lateral corticospinal and corticobulbar axons that supply the upper extremities and the face.
Although occasional cases of arrested hydrocephalus have been documented, a slow, progressive deterioration is more usual.
An acute decompensation also may occur, with rapidly increasing ICP (Table 8-2). Factors that relate to the prognosis of
hydrocephalus 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), in addition to the underlying cause. The development of a high ICP is also associated with
poor prognosis.
Acute hydrocephalus typically presents clinically with signs of increased ICP; headaches are very common, nausea and
vomiting are seen frequently, and obscuration of consciousness and lethargy are seen in severe cases, occasionally with
strabismus. As the cause of the disease in children is often a midline tumor, neurological symptoms may also reflect
involvement of the suprasellar, mesencephalic, or posterior fossa structures. The evolution of the disease in children is often
rapid; therefore, macrocephaly is often absent or mild. In infants and very young children, a persistent downward gaze (the
“setting sun” sign) or a bulging fontanelle may be early, important signs of high-pressure hydrocephalus. The fundoscopic
examination typically reveals papilledema. In children older than 2 years, the neurologic presentation consists of symptoms
resulting from increased ICP (see above) and focal deficits referable to the primary lesion; these symptoms occur prior to
significant changes in the head size. Although each of the specific lesions that result in hydrocephalus has some special
features, certain clinical characteristics are common to all hydrocephalic patients. In most, the increased ICP results in an early
morning headache that improves after being upright for a while (allowing the CSF to re-equilibrate by lowering the venous
pressure). Papilledema and strabismus are frequent. Pyramidal tract signs are more marked in the lower extremities, as
described above. Hypothalamic–pituitary dysfunction may be caused by compression of the hypothalamus, pituitary stalk, and
pituitary gland that results from the enlarged anterior recesses of the third ventricle. Perceptual and motor deficits and visual–
spatial disorganization result from stretching of parietal and occipital lobe axons around the dilated atria and posterior horns of
lateral ventricles (117). Cognitive disorders may also result from compression of the hippocampi and stretching of the
septocingulate fibers of the septum pellucidum, the fornices, and the hippocampal commissure. Clinical evidence of increased
ICP, often related to hydrocephalus in children, is an absolute neuroradiologic emergency as the child may decompensate,
suddenly and irreversibly, at any time from midbrain compression (due to transtentorial herniation) or medullary compression
(from foramen magnum herniation) or from a circulatory arrest. Draining some fluid from the ventricles may suffice to
significantly lower the pressure and save the brain and the life of the child. MRI ideally, or CT if MRI is not immediately
available, must be performed to identify the cause of the intracranial hypertension and reveal the presence of a drainable
hydrocephalus.
In hyperacute hydrocephalus, a steep increase of the ICP develops from entrapment of CSF in the ventricles secondary to
obstruction the CSF spaces and the compression of the ventricular pathway, typically at the midbrain. CSF is still secreted as
long as there is an arteriovenous gradient, but cannot escape into the arachnoid spaces or be absorbed by the ventricular walls
because of the high ICP. The ICP therefore increases exponentially (tamponade effect), with a high risk of a cerebral
circulatory arrest. This situation can only be reversed by a direct removal of ventricular fluid by ventricular puncture, or
external ventricular drainage.
Such a situation may arise as a complication of acute brain trauma, decompensating tumoral hydrocephalus, meningeal
infection, or shunt dysfunction in chronically shunted hydrocephalus. The dominant symptom is an alteration of the state of
consciousness.
Imaging Tools
Magnetic Resonance Imaging (MR Imaging)
MRI and mature hydrocephalic brain
MR imaging is the best tool for the study of hydrocephalus, its causes, and its consequences. The study must address, and the
report must describe, many aspects of the disease, including specific morphologic features, site(s) of obstruction, effects of
hydrocephalus on the brain, recognition of the cause and its specific impact on the brain tissue, and CSF dynamics. This can be
accomplished with a relatively simple (and rapid) imaging protocol (Fig. 8-4).
■■ Three-dimensional, high-resolution (millimetric) T1 imaging with reformatting in orthogonal (or any appropriate) plane
illustrates the location and severity of ventriculomegaly in addition to the general brain morphology.
■■ Coronal T2-FSE demonstrates the rounding of the lateral ventricles, especially the temporal horns with the medial
compression of the hippocampus, as well as stretching of the septum pellucidum (which is sometimes torn, especially in
congenital hydrocephalus) and, posteriorly, of the hippocampal commissure (which often is displaced to run vertically
instead of the usual horizontal orientation). The evaluation of ventricles (size and shape) for comparative follow-up studies
should be made in this (coronal) plane by measuring the longest transverse diameter of the atrium of the largest lateral
ventricle. We prefer this measurement to the Evans’s index (generally used in adult hydrocephalus) because the ventricular
dilatation in pediatric hydrocephalus is typically more prominent in the posterior part of the hemispheres due to the
vulnerability of the white matter during the brain development (118,119) and, possibly, because the thin parietal bones
allow greater ventricular expansion.
Figure 8-4 MRI for hydrocephalus. Normal images. A. Midline sagittal T1, thin section (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, and basilar, interpeduncular, 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-definition CISS/FIESTA (1.0 mm or less) image is optimal for depiction of the third ventricle
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 mammillary bodies. This sequence is not appropriate for demonstrating the flow voids.
■■ Sagittal thin T2-FSE images best demonstrate the gross morphology of the midline structures and the major ventricular and
cisternal CSF flow voids. The corpus callosum and septum pellucidum are stretched, and the fornix is displaced inferiorly
and separated from the splenium by the distorted (verticalized) hippocampal commissure. The anterior third ventricle
demonstrates rostral bulging of the lamina terminalis, along with widening of the supraoptic and infundibular recesses, and
flattening or inferior convexity of the normally superiorly convex tuber cinereum. The suprapineal recess may be prominent
also, but the extent varies with individual anatomy. The aqueduct is well demonstrated; its appearance varies with the
location and severity of the obstruction: sometimes normal-looking, sometimes compressed, sometimes occluded with or
without proximal widening, or (often) dilated. The aqueductal CSF flow void must be evaluated on this sagittal T2-FSE
sequence, as it becomes more prominent when either the velocity or the amplitude is increased (103,120). Two factors
may, singly or in association, increase the amplitude of the pulsatile movements of CSF in the aqueduct: one is the
effacement of the pericerebral space, which redirects the arterial pulsations medially; the other is the decrease of
compliance that results in an increased P2 peak of the pulse wave, as discussed previously. In contrast, a flow void is
rarely seen in normal young infants with a large elastic pulsatile fontanelle and a small spine because pulsations are
directed centrifugally (from the center of the brain to the periphery). Finally, sagittal T2-FSE images beautifully show the
fourth ventricle, the cisterna magna, and the posterior fossa cisterns along with prominent, basilar artery-related signal
voids in the prepontine cistern. Obviously, this sequence may also show a midline mass in the suprasellar, velum
interpositum, quadrigeminal, fourth ventricular, or retrocerebellar regions.
■■ High-definition, thin (submillimetric) sagittal steady-state T2 imaging (FIESTA/CISS) images are extremely important in
the assessment of hydrocephalus, providing clear images of thin membranes in the ventricles, aqueduct, or cisterns; it is
especially important for presurgical planning of a third ventriculostomy in order to determine the patency of the
interpeduncular cistern. Postventriculostomy, together with sagittal T2-FSE, CISS demonstrates both the anatomic (patent
ventriculostomy) and the functional (transventriculostomy flow void) results of the procedure. It may also reveal cisternal
obstructing membranes that were not apparent before the ventricles were decompressed.
■■ Axial FLAIR sequences show the axial ventricular morphology and the parenchyma. In hydrocephalic patients with a high
ICP, the ependymal indentation of the stretched subependymal veins and bright signal in the periventricular and deep white
matter suggest subependymal venous compression and lack of ISF absorption in the territory of the deep medullary
tributaries. In contrast, periventricular bright FLAIR signal in chronic hydrocephalus suggests defective myelination,
secondary to the particular vulnerability of the oligodendroglial precursors (118). The two should not be confused.
■■ Although it is generally considered that T2-FSE sequences demonstrate the aqueductal flow void as well as phase-contrast
CSF-flow imaging, several dedicated sequences have been promoted to enhance the demonstration of the CSF flow:
steady-state free precession (121); spatial modulation of magnetization (SPAMM) (122); reversed fast imaging with steady-
state precession (PSIF) (123); 3D sampling perfection with application-optimized contrast (3D-SPACE) (124). The most
recent, a time-spatial labeling inversion pulse (Time-SLIP) technique uses spin labeling of the water molecules to show
CSF oscillation (125), but their rapid diffusion outside the area of interest may somewhat blur the picture. Dynamic
cardiac-gated cine phase-contrast imaging is another way of demonstrating the flow; it is very popular as it allows one to
quantify the CSF motion in groups of subjects or patients (10,126). Special techniques that take advantage of the relative
phase angle changes 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. 8-5) (10) and have been proposed for the functional assessments of the
shunts. CSF motion, however, is so dependent upon so many different factors that the reliability of the measurements in
individual patients is uncertain.
■■ Other techniques. Diffusion tensor imaging (DTI) analyzes the effects of microstructural changes in the parenchyma upon
water motion (mean diffusivity [MD], fractional anisotropy [FA]); it may demonstrate a periventricular stretching of the
white matter tracts (127). 1H MR spectroscopy can be used to identify changes in the energy metabolism (128). In arterial
spin labeling (ASL) perfusion imaging, the blood–water itself is labeled by the MR sequence and serves as an intrinsic
contrast medium that is used to investigate the blood flow noninvasively (89,129). Pseudocontinuous ASL (pCASL) is
currently considered to be the most accurate ASL technique in children but, in newborns and young infants, the very short
distance between the site of labeling in the neck and the site of imaging in the brain, in addition to the rapid heart rate of
very young babies, makes its utility rather variable. Positive contrast cisternography or ventriculography have been
suggested and are considered safe (130) but have failed to gain real acceptance as the trend in brain imaging is toward
minimal invasiveness; its additional value is questionable given the versatility of MR. MR venography (MRV) may
demonstrate an acquired or developmental venous compromise, primary or secondary to the hydrocephalus. Other
sequences that may assist in the etiologic assessment are susceptibility imaging (blood residues), diffusion imaging
(abscess, epidermoid cyst), or postcontrast T1 (leptomeningeal enhancement).
■■ “Fast” MR scanning is a technique that uses single-shot, ultrafast imaging sequences. Just like a “quick” CT, it alleviates the
need for sedation/anesthesia and is often used in our practices instead of CT because of mounting concerns regarding the
use of ionizing radiation in the follow-up of hydrocephalus in children (see Chapter 1) (131). These heavily weighted T2
sequences are adequate for assessing the ventricular/cisternal size and morphology and to show the position of the shunt,
but they have poor sensitivity and specificity for parenchymal changes (Fig. 8-6).
Finally, as hydrocephalus may occasionally be caused by, or associated with, a spinal disorder (tumor or malformation or
syringomyelia), spinal imaging may be necessary when no intracranial cause is identified. The protocol should include sagittal
T2 sequences of the whole spine; axial T2, 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 masses, fluid, or blood.
MRI and immature hydrocephalic brain
Imaging strategy in young infants is essentially the same as it is in more mature children, but a few technical points should be
emphasized. In the absence of myelin, the T1 and T2 values of the parenchyma are much longer than in the mature brain, which
implies that, in TSE/FSE sequences, both T1-weighted and T2-weighted the TR should be much longer; for T2 images, the TE
should be lengthened as well. FLAIR sequences are essentially noncontributory in the setting of hydrocephalus. The immature
calvarium is quite expandable due to the fontanelles and thin bones; with the small size of the spinal canal relative to the skull,
the CSF displacement by the arterial expansion at systole is directed peripherally (pulsations of the fontanelle) rather than
caudally, so that there is no CSF movement and, consequently, no flow void within the aqueduct of a newborn infant (Fig. 8-7).
Due to the incomplete development of the subcortical white matter, the field of the deep medullary tributaries of the
subependymal veins appears more extensive across the thickness of the cerebral mantle relative to the territory of the
subcortical veins, compared with adults; therefore, periventricular interstitial edema appears more extensive than in a mature
brain, and there is greater diffusivity of the interstitial water. This periventricular edema may be more difficult to recognize
against the background of high parenchymal water content on T1WI and T2WI images. Also, fibrotic changes in the ventricular
walls allow better appreciation of a periventricular rim of low signal contrasting with the bright signal of both the CSF and the
white matter on T2WI. Finally, because of the characteristics of hydrocephalus in infants, the use of CISS/FIESTA to
demonstrate arachnoid septations, or susceptibility-weighted sequences to demonstrate blood residue is particularly useful in
the assessment of the hydrocephalic brain in this age group.
Figure 8-5 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.
The main technique for assessing the fetal brain is T2WI imaging using a single shot fast spin-echo (SSFSE) sequence,
which shows parenchymal and ventricular anatomy nicely. Contrast in the fetal brain depends mostly on the cellular density, as
gray and white matters have a similarly high content of water (90%). Additional T1WI sequences are used to show fat,
calcification, and acute or subacute blood. Magnetic susceptibility sequences demonstrate blood or blood residues. Diffusion
imaging is not of much use in the evaluation of fetal hydrocephalus other than in the context of an acute event. Diffusion-
weighted imaging also helps to distinguish tissue types. MR spectroscopy and DTI are not used in the standard clinical routine,
and no contrast is typically administered in pregnant women (134–136). The anatomy of the brain, the appearance of the
parenchyma, and, especially, the progression of gyration must be correlated with the age, in weeks, of the fetus.
CT Scanning
Together with MR imaging, CT remains a commonly used modality in many institutions to evaluate hydrocephalus. CT is faster
and very simple, and data are easily reformatted in multiple planes on modern scanners (Fig. 8-8). Periventricular interstitial
edema is readily apparent on CT, and calcification 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 significant doses of
ionizing radiation (see Chapter 1). Therefore, in our practices, initial evaluation of the brain is based on MR, as it is fast, is
accurate, gives off no ionizing radiation, and is equally (or more) sensitive to small narrowings in the CSF pathways. If CT is
to be used for follow-up, the implementation of a low-dose technique actually limits evaluation mostly to assessment of
ventricular size (Chapter 1).
Figure 8-7 Midline sagittal T2-FSE in a neonate. Because of the large, open fontanelles, the parenchymal systolic CSF pulsations are
directed outward; as a result, no flow void is seen within the aqueduct (white arrow, compare with Fig. 8-4B).
Figure 8-8 3D-CT imaging. Nice demonstration of the ventricular 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 radiation dose delivered, especially concerning in children. In most instances, a very low-dose CT (see
Chapter 1) is used to check ventricular size.
Ultrasonography
Head ultrasound is the modality of choice for the screening of fetuses, neonates, and infants suspected of having hydrocephalus.
It is noninvasive, can be performed at the bedside, and gives a good evaluation of the ventricular size and morphology. It is
also sensitive to (if not specific for) 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 ICP is an important factor
in the differentiation of hydrocephalus from atrophy; therefore, it is important to know that innovative approaches with
transfontanelle sonography may allow assessment of ICP noninvasively. Taylor and Madsen (137) studied the hemodynamic
response to fontanelle compression in infants with ventriculomegaly, and used Doppler sonography to determine resistive
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 ICP. However, a significant correlation was found
between the changes in resistive index during fontanelle compression in children with elevated ICP, with the maximum change
in resistive index significantly higher in infants who subsequently required shunting than in infants who did not (p = 0.001)
(137). Thus, the need for shunt placement may be determined by assessment of resistive indices with and without fontanelle
compression.
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, these measurements are rarely necessary.
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. 8-9A): the septum pellucidum is stretched and
may even be torn (Fig. 8-9B). The part of the fornix that forms the hippocampal commissure (the psalterium), normally
transverse, becomes verticalized on each side of the midline (Fig. 8-9D, compare with Fig. 8-4C), so that the posterior part of
the fornix seems to be detached from the undersurface of the splenium on the midline sagittal cut (Fig. 8-9A, compare with Fig.
8-4A).
In rare cases of chronic severe obstructive hydrocephalus (usually AS), the ventricular anatomy may be compounded by a
ventricular diverticulum, inferior expansion of the medial wall of the ventricular atrium behind the thalamus, into the velum
interpositum, quadrigeminal, and supracerebellar cisterns (Fig. 8-12) (141,142). This is because the inferomedial portion of
the atrial wall (hippocampal commissure) is the thinnest and has the largest surface of the ventricular system and has, therefore,
the highest wall tension. If not treated, these atrial diverticula can compress the midbrain with the risk of significant
neurological complications; they can be mistaken for arachnoid cysts in the region of the quadrigeminal cistern (Fig. 8-12C).
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. 8-12B).
The third ventricle is normally slit-like, mildly wider anteriorly (hypothalamic portion) than posteriorly (thalamic portion).
It is enlarged in both atrophy and hydrocephalus, but in hydrocephalus, it commonly develops rounded recesses: anteriorly, the
supraoptic and infundibular recesses and posteriorly, the suprapineal recess. On sagittal images (Figs. 8-9B and 8-13A), the
anterior wall of the third ventricle (lamina terminalis), normally straight, becomes convex anteriorly and the tuber cinereum,
usually convex upward, becomes straightened or convex downward. This may compromise the hypothalamic nuclei and
fascicles in the infundibulum and diminish the flow within the hypothalamic–pituitary portal venous system along the stalk,
resulting in hypothalamic–pituitary dysfunction. 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 interpeduncular cistern (Figs. 8-9A and B
and 8-13A) sometimes wrapping the head of the basilar artery. The pulsating dilated anterior third ventricle may be so huge as
to erode the dorsum sellae (Figs. 8-9A and 8-13A). When hydrocephalus is severe and chronic, the floor of the third ventricle
may even rupture spontaneously, creating an internal drainage pathway that allows CSF to escape from the ventricular system
into the subarachnoid space (143). The disproportionate enlargement of the recesses of the third ventricle 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 posterior third ventricle, provide a great deal more resistance to
expansion. It is important to note that even with a significant ventricular enlargement the lateral walls of the third ventricle
(i.e., the thalami) remain parallel to each other, but the massa intermedia becomes elongated and thinner (Fig. 8-9E). 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. 8-13B) than at the level of the thalami: a rounded, circular posterior third ventricular lumen
would indicate the presence of a cyst, usually a suprasellar cyst with superior expansion (Fig. 8-14). The normal suprapineal
recess may be small or prominent depending on the individual anatomy; a dilated suprapineal recess of the third ventricle may
sometimes expand into the posterior incisural space, displacing the pineal gland inferiorly and, occasionally, elevating the vein
of Galen. Further posterior enlargement of the pineal recess may compress the tectum from the posterior direction, resulting in
thinning of the tectum and narrowing of the aqueduct (144). As a rule, the anterior (supraoptic and infundibular) recesses seem
to enlarge earlier and to a greater degree than the posterior (suprapineal) recess. Caudally, the dilatation may involve the
proximal aqueduct with consequent shortening of the tectum in the rostral–caudal direction (144) (Fig. 8-13A). The short, thick
tectum should not be mistaken for a neoplasm; isointensity with normal brain tissue on T2/FLAIR images and the absence of
contrast enhancement exclude a tumor.
Figure 8-9 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. 8-4A).
Anterior third ventricular recesses are massively dilated, and the massa intermedia is 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 hippocampi. D. Posterior coronal T2 image shows that the hippocampal commissure (black arrows), normally transverse,
is vertical and stretched by the enlarged ventricles (compare with Fig. 8-4C). 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 interstitial edema, resulting from the
increased intraventricular pressure that compresses the subependymal veins, preventing fluid resorption and resulting in the accumulation of
interstitial fluid there.
Figure 8-10 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.
Figure 8-11 Various methods in the radiographic diagnosis of hydrocephalus. 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 commensurately with the bodies of the lateral ventricles is probably the most sensitive 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 (bottom). The ventricular index in both instances is 39%; however, the ventricular 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 demonstrated by the markedly increased frontal horn radius in the patient
with hydrocephalus (top) as opposed to the patient with atrophy (bottom). Overall, no one measurement is completely accurate in the diagnosis
of hydrocephalus; 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 of Dr. E. Ralph Heinz, Durham, NC.)
Figure 8-12 Ventricular diverticulum. Axial FLAIR (A), coronal T2 (B), and sagittal T2 (C) images show expansion 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.
Figure 8-13 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 or on the duration or early occurrence of hydrocephalus. B. The anterior (hypothalamic) portion of the
third ventricle presents a more rounded appearance than the more posterior interthalamic portion (see Fig. 8-9E).
Figure 8-14 Rounded appearance of the third ventricle; suprasellar cyst. A. Axial T2-weighted image shows the whole third ventricle, including
its interthalamic portion appearing rounded. B. Sagittal FIESTA image shows a huge suprasellar cyst displacing the ventricular floor upward.
The cerebral aqueduct (of Sylvius) is a narrow craniocaudal curved channel that connects the third and fourth ventricles.
When the aqueduct is narrowed or occluded, obstructive hydrocephalus develops (AS) (Figs. 8-9 and 8-13). Occlusion may be
intrinsic (ependymal, usually postinflammatory) (Fig. 8-15) or extrinsic; the latter may be caused by a tegmental or a tectal
mass lesion (Figs. 8-9 and 8-13) or by an extrinsic compression of the midbrain. It has been suggested that, in some instances
at least, AS may result from compression by expanded temporal lobes (Fig. 8-16); in this situation, the hydrocephalus may be
primarily nonobstructive in nature with aqueductal narrowing being a result, rather than a cause, of the dilatation of the lateral
ventricles (144). In contradistinction, the aqueduct typically is dilated when the fourth ventricle is obstructed, either due to the
force exerted by the CSF or the mechanical effect of a mass expanding the ventricular lumen (Fig. 8-17). A moderate flow void
is observed in the normal aqueduct on the sagittal midline T2-FSE–weighted image as a result of the moderate velocity of CSF
traveling from the larger posterior third ventricle to the larger superior fourth ventricle (103) (Fig. 8-4B). This flow void
disappears if the aqueduct is occluded (Figs. 8-9A and 8-15), but its presence does not exclude a (true) stenosis; indeed, flow
velocity is increased by the stenosis, resulting in further reduction of signal intensity as the aqueductal diameter is diminished
(Fig. 8-18). The amplitude of the aqueductal CSF pulsations is also increased in communicating hydrocephalus; this is
generally explained by a decrease of meningeal compliance with a “rebound” effect (thereby “pushing” the CSF), but it may be
less specific and result from the effacement of the pericerebral (subarachnoid) spaces redirecting the arterial pulsatility
medially toward the ventricular CSF (Figs. 8-5A and 8-19 to 8-21).
Figure 8-15 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.
Figure 8-16 Extrinsic aqueductal stenosis. A. Sagittal T2-weighted image in a patient with congenital hydrocephalus. Note huge dilation 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.
The fourth ventricle in hydrocephalus ranges from normal to markedly dilated, depending on the site of the obstruction.
When the obstruction in obstructive hydrocephalus is located above it, the ventricle is normal (Figs. 8-9, 8-13, 8-15, 8-16, and
8-18). It is often normal in nonobstructive hydrocephalus, as well (Figs. 8-18 and 8-22), so it must be remembered that
triventricular hydrocephalic dilation does not necessary mean AS! In most cases of nonobstructive hydrocephalus, however,
the fourth ventricle is mildly dilated (Figs. 8-5 and 8-19). Elevated CSF pressure tends to expand the calvarium and to
decrease the volume of the brain, so that ventricles and basal cisterns may be large (Fig. 8-22A); anatomy normalizes after
shunt placement, which results in slowing of the growth of the skull (Fig. 8-22B). When the cisterna magna is obstructed but
still communicates with the fourth ventricle, a posterior rotation of the vermis may occur; this is not a malformation but just
hydrocephalus. Finally, the fourth ventricle may become hugely dilated when both inflow and outflow are obstructed,
especially if the lateral ventricles are decompressed by a ventriculoperitoneal shunt; this condition is called an “isolated fourth
ventricle.”
Figure 8-17 Aqueductal dilation. Large tumor (anaplastic ependymoma) expanding the fourth ventricle and occluding its outlets results in
hydrocephalus with a dilated aqueduct.
Appearances of the ventricular system usually reveal the level of the obstruction in obstructive hydrocephalus: the
ventricles (or portions thereof) proximal to the obstructed segment of CSF flow are dilated, and the fluid in those ventricles (or
the dilated segment) must be diverted. Obstruction occurs more easily and is therefore more common, at locations where the
ventricular lumen is narrow, most commonly the foramina of Monro or at the aqueduct, but a lateral ventricle may become
occluded by an intraventricular mass, which might be located such that it causes dilation of only a portion of the ipsilateral
atrium, occipital and temporal horn. This is important because it tells where the CSF diversion must be located; it will be
discussed in more detail when dealing with specific causes of hydrocephalus.
Figure 8-18 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.
A surgical classification of hydrocephalus describes several subtypes. Univentricular hydrocephalus occurs when the
obstruction is located at one foramen of Monro, the affected lateral ventricle is dilated and rounded, and the septum pellucidum
bulges toward the normal side; the most common cause is SEGA in tuberous sclerosis (see Chapter 6). 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, or a suprasellar cyst or tumor with intracranial extension (in such a case, whether the
obstruction sits at the foramina or within the third ventricular lumen doesn’t make any difference). Triventricular
hydrocephalus results from an occlusion in the distal third ventricle, cerebral aqueduct, or upper fourth ventricle; common
causes are inflammatory AS and midbrain, pineal region, or posterior third ventricular tumors. Quadriventricular
hydrocephalus is seen when a mass occupies the lower fourth ventricle or when an obstructive process (typically infection)
compromises the fourth ventricular outflow foramina. A variant of this is seen when the outlets of the cisterna magna are
occluded (e.g., fibrous arachnoiditis of the posterior fossa cisterns) resulting in the cisterna magna (the “fifth ventricle”)
becoming dilated together with the four ventricles (Fig. 8-23).
Figure 8-19 Hydrocephalus with patent, rather wide aqueduct. A. Midline sagittal FIESTA 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 FSE T2 shows prominent flow void through the aqueduct, explained by increased amplitude of the CSF pulsatility through the
aqueduct, which may relate either to the restriction of the cisternal CSF circulation with reduced compliance or to the pulsatility being redirected
inward by the effacement of the pericerebral spaces.
Figure 8-20 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.
Figure 8-21 Communicating hydrocephalus, midline sagittal T2 image shows communicating hydrocephalus with normal fourth ventricle.
Note prominent signal voids in aqueduct and fourth ventricle.
Figure 8-22 Cerebral deformities caused by hydrocephalus. Infant with macrocephaly. A. At age of 2 months, midline sagittal T1 shows huge
dilation 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.
In case of chronic nonobstructive 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 expansion of the lateral ventricles. Note
that the sylvian fissures may be quite dilated in this situation. Such a pattern, however, which is fairly typical for normal-
pressure hydrocephalus (NPH) in the elderly, is uncommon in children.
Figure 8-23 Quadriventricular hydrocephalus associated with dilated cistern magna, due to occluded cistern magna outlets.
It is generally assumed that the increased pressure within the ventricular system necessarily causes compression of the brain
tissue against the inner table of the skull and consequent diminution of pericerebral and sulcal size. In pediatric patients,
however, this conclusion may be misleading when both atrophy and chronic hydrocephalus are combined to enlarge both the
ventricles and sulci.
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. The failure of measurements such as the bicaudate index and the Evans ratio to accurately
differentiate hydrocephalus from atrophy reflects this difficulty. Finally, a specific variant of hydrocephalus in infants is the
idiopathic external hydrocephalus (benign enlargement of the pericerebral spaces), in which the ventricles are less enlarged
than the pericerebral spaces, because the weakness of the cranial vault at that age allows the CSF to accumulate around the
brain. Knowledge of the head size of the infant is therefore essential in establishing the proper diagnosis; a large or a too
rapidly enlarging head suggests hydrocephalus, whereas a small or stable (nonincreasing) head circumference is more
compatible with atrophy.
Herniation
Increased supratentorial pressure with ventricular dilatation 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 midbrain and the aqueduct may be
compressed, and the vessels in the adjacent cisterns are stretched and compressed with resulting ischemia/infarction. If
increased pressure and hydrocephalus occur in the posterior fossa, cerebellar tissue may herniate both upward through the
tentorial incisura and downward through the foramen magnum, with similar compressive effects on the midbrain and medulla.
Circulatory arrest
Secretion of CSF persists as long as a blood flow is maintained in the skull; however, absorption is decreased when the
venous pressures are too high. As neither CSF nor the brain parenchyma is compressible, the main complication of a rapid
increase of intraventricular pressure/ICP is the effacement of the vascular bed, with resultant compression of (a) subependymal
veins within the ventricles, (b) cortical veins against the cranium, and (c) engorged intracerebral capillaries in between. The
resulting increased capillary pressure causes brain edema and, as a consequence, further herniations. Eventually, herniated
tissue can fill the tentorial incisura or the foramen magnum, further increasing the pressure to a point where intracranial
circulatory arrest occurs because the perfusion pressure cannot overcome the ICP. This situation may occur early, in hyperacute
hydrocephalus, or, as a late, 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 cannot penetrate the
parenchyma. The risk of decompensation and death is such that any case of intracranial hypertension must be considered
an immediate neuroradiologic emergency.
Imaging chronic parenchymal changes
Although acute changes of hydrocephalus may be reversible after treatment, some (ependymal damage, gliosis, and abnormal
myelination) may leave permanent injuries (118). On imaging, the most obvious morphological impact of hydrocephalus on the
brain tissue is chronic ventriculomegaly. Ventriculomegaly may result from two different, possibly associated, processes: (a)
displacement of the cerebral mantle outward to fill the pericerebral spaces (19) followed by (b) degeneration of the brain
tissue. The loss of white matter may be striking in chronic hydrocephalus, especially in the posterior parts of the hemispheres
(Fig. 8-25). Pallor of the parenchyma (mostly periventricular) on FLAIR imaging correlates with histologic myelin loss (145)
(not to be confused with the acute periventricular edema; the clinical context is critical to differentiate the two processes). DTI
has been used to show microstructural changes associated with the stretching (rather than compression) of the tracts in the
white matter lateral to the ventricles (increased FA, increased longitudinal diffusivity but unchanged ADC) but not in the
corpus callosum (decreased FA with increased ADC); these changes revert after treatment (127). In early antenatal-onset
hydrocephalus (e.g., Chiari II), neurons migrate abnormally due to ependymal injury, resulting in detachment of the radial glia
and consequent periventricular and subcortical gray matter heterotopia. Abnormal gyration with many small gyri (stenogyria)
may ultimately result. Demyelination and axonal degeneration have a similar MR appearance, a ribbon of bright T2/FLAIR
signal in the paraventricular white matter, accompanied by some loss of brain volume. Axonal degeneration, however, does not
necessarily imply permanent neuronal loss (153); in addition, 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 thickness before shunting. Subependymal fibrosis and sclerosis may appear in young infants as a hypointense
ventricular wall interposed between the bright CSF and bright periventricular white matter on T2-weighted images.
Obstructive Hydrocephalus
Chronic ventricular obstructive hydrocephalus (compensated)
Aqueductal stenosis
AS is the cause of approximately 20% of pediatric patients with hydrocephalus. AS is hydrocephalus in its simplest form: a
single obstruction by a stable lesion causing (mostly) stable ventriculomegaly over months or years, with no symptoms of
increased ICP. AS is a generic term applied to all obstructions of the aqueduct. It may refer to a true stenosis with normal
histology (usually due to an adjacent mass), to an occlusion by a cluster of ependymal cells, or to “forking,” the term used to
describe formation of a small septum from a glial overgrowth that has become stretched or a focal postinflammatory gliosis
(154–157). It may result from an isolated event (malformative, postinflammatory or neoplastic) or be a result of a more
extensive and complex pathology such as a TORCH infection, meningitis, intraventricular hemorrhage (IVH), malformation, or
tumoral hydrocephalus (110) (Figs. 8-9, 8-10, 8-12, and 8-15). As with many causes of hydrocephalus, aqueductal narrowing
restricts the ventricular space, thereby reducing ventricular compliance and leading to a slow increase of the ventricular size.
The effacement of the pericerebral spaces causes the arterial pulsatility to become redirected inward, resulting in progressive
increase of the intraventricular amplitude of the systolic pressure wave. The process being slow, the axonal fibers may become
elongated by intrinsic growth without being stretched, and the macrocephaly allows the cerebral volume to be maintained.
Eventually, the ventriculomegaly reaches a level of stability in which the systolic force is in balance with the viscoelasticity of
the mantle, and preservation of ependymal CSF absorption, together with expansion of the ventricular surface, may compensate
for the continuing CSF production. The cause being focal (aqueductal lesion), the brain tissue is typically not injured, and in
the absence of high pressure and edema, the functions of the subventricular zone may remain unaffected. The water transported
by the ependymal and astrocytic (subependymal and subpial) AQP4 channels may be absorbed into the parenchyma and,
subsequently, to the subpial space and VRS toward the arachnoid. This condition usually may remain subclinical for years until
a decompensation develops and results in increased ICP, characteristically without a clear explanation; a minor trauma and
infection have been suggested as potential causes (110), as have a fusion of the sutures and progressive venous compression
initiating a vicious circle of decreasing absorption. Such decompensations may develop quickly as the pericerebral spaces are
already effaced by the ventricular expansion; the developing pressure increase needs urgent CSF diversion. Importantly,
because the obstruction is focal and isolated, hydrocephalus due to a simple AS is the best indication for an endoscopic third
ventriculostomy (ETV).
The incidence of AS ranges from 0.5 to 1 per 1000 births with a recurrence rate of 1% to 4.5% in siblings (155). The onset
of symptoms is usually insidious and may occur at any time from birth to adulthood. As in all types of hydrocephalus, the
symptoms depend upon the cause of the stenosis and on the age of the patient at the time of onset. In typical AS, the aqueduct is
focally narrowed, generally either at the level of the superior colliculi or at the intercollicular sulcus (154,156). In many
instances, the stenosis is accompanied by branching of the aqueduct into a dorsal and a ventral channel, with the dorsal channel
often divided into a group of several ductules. This aqueductal forking (157), described in the previous paragraph, may be
accompanied by fusion of the quadrigeminal bodies, fusion of the third nerve nuclei, and molding or beaking of the tectum,
suggesting a developmental origin. In other 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 AS may be a secondary phenomenon and result from a communicating hydrocephalus and secondary
compression of the midbrain by the dilated cerebral hemispheres (158) (Fig. 8-16).
The CT appearance of benign AS is dilation of the lateral and third ventricles with a normal-sized fourth ventricle. This
appearance is not diagnostic, however, since the fourth ventricle is also normal in a significant percentage of patients with
nonobstructive hydrocephalus. Sagittal reformats are useful to better demonstrate the third ventricular changes (typically
associated with adjacent bony sellar changes) as well as the occlusion of the aqueduct, and the normality of the hindbrain and
posterior fossa cisterns; this view also show significant tectal masses, if present. The posterior third ventricle should also be
carefully scrutinized for the presence of a mass in the mesencephalon or posterior thalamus. This is better appreciated on MR;
therefore, any patient in whom triventricular hydrocephalus is discovered with CT should be further evaluated by MR.
The MR findings in AS are more specific but are, nonetheless, quite variable. On MRI, simple AS appears as triventricular
hydrocephalus with a stretched corpus callosum, septum pellucidum and hippocampal commissure, rounded temporal horns,
bulging lamina terminalis and tuber cinereum, and dilated supraoptic, infundibular, and (individual anatomy permitting)
suprapineal recesses. The pericerebral spaces are effaced over the hemispheric convexities. The ventriculomegaly usually is
more pronounced in the posterior part of the hemispheres. The supratentorial compartment of the cranium is enlarged,
sometimes with a low tentorium and small posterior fossa, depending on the age of the fetus or of the child when
hydrocephalus developed. Cerebriform markings are sometimes prominent along the inner table of the skull, the dorsum sellae
is eroded, and the sellar cavity itself is widened. CISS/FIESTA imaging is warranted not only to document the aqueductal
obstruction (proximal, distal, or global) but also, above all, to ascertain the patency of the cisterns, as an ETV would be
useless in the presence of cisternal loculation. It has been noted that patients with severe hydrocephalus generally have stenosis
in the proximal aqueduct, either at the level of the superior colliculi or at the entrance to the aqueduct immediately below the
posterior commissure (144), whereas mild hydrocephalus is more often associated with obstruction in the distal aqueduct; in
this scenario, the dilated proximal aqueduct will displace the quadrigeminal plate posteriorly. MR can nearly always
differentiate benign AS from neoplastic AS: tectal and tegmental gliomas that compress and obstruct the aqueduct appear as
high signal intensity masses on T2/FLAIR images (Fig. 8-9E) and enhance uncommonly. An aqueductal web is a special case
of AS in which a thin membrane of brain tissue situated in the distal aqueduct prevents the flow of CSF into the fourth
ventricle. The membrane is postulated to result from a small glial occlusion of the caudal aqueduct that becomes an attenuated
sheet of tissue secondary to prolonged pressure and dilatation of the canal above it (159); imaging shows a thin membrane
separating a dilated aqueduct from a normal-sized fourth ventricle (Fig. 8-15B). The importance of recognizing isolated
aqueductal webs is that an ETV (see section on Treatment of Hydrocephalus) usually results in complete resolution of the
hydrocephalus. It may also be possible to perforate the membrane via fiberoptic ventriculoscopy (160); either method obviates
the need of an indwelling shunt. Early results of such endoscopic aqueductoplasties in some centers have been promising
(160,161), with advantages including restoration of the normal physiology of the CSF with less trauma and less vascular risk
than an ETV. However, it is also carries a higher risk, as it may result in oculomotor or trochlear palsies or in a Parinaud
syndrome (160), and a growing tectal or pineal region mass must be excluded beforehand.
In the so-called X-linked AS, hydrocephalus seems to be only one small part of the disorder. Indeed, the condition is best
called CRASH for Callosal dysgenesis, Retardation, Adducted thumb, Spasticity, and Hydrocephalus (it is also known as X-
linked hydrocephalus, Bickers-Adams syndrome, and hereditary stenosis of the aqueduct of Sylvius [HSAS]) (162,163). This
rare hereditary disorder is caused by mutation of the L1CAM gene on Xq28 (164). This cause is important, not only because of
the risk for future siblings being similarly affected but also because affected patients have a poor neurological outcome despite
early shunting. This complex malformation is allelic with (has the same chromosomal location as) the so-called MASA
(Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs) syndrome (163) and Hirschsprung disease, with the overall
phenotype dependent upon the precise mutation. L1CAM (L1 cell adhesion molecule) controls the axonal fasciculation
process, which directs axons to follow a preestablished path; thus, CRASH is above all a disorder of the white matter
development. It has been suggested that L1CAM should be investigated in any X-linked disorder associated with corpus
callosum anomalies. As with many genetic disorders, the size and locations of mutations and epigenetic modifications
determine the severity of the disease (165). Pathologic studies show that, in addition to hydrocephalus, affected patients have
malformations of cortical development (see Chapter 5) with poor differentiation and poor maturation of cortical neurons being
identified on histologic examination of the brain. Indeed, some authors have suggested that the aqueduct is narrowed by
compression and is not primarily stenotic. Other pathologic features include absence or diminution of the size of the
corticospinal tracts, fusion of the thalami, fusion of the colliculi, absence of the septum pellucidum, and small or absent corpus
callosum (see Chapter 5). MRI reportedly shows enlargement of the massa intermedia (thalamic fusion), abnormal flattening of
the mesencephalic tectum, a small brainstem, diffuse hypoplasia of cerebral white matter, and (unexpectedly) a patent sylvian
aqueduct (162). Others’ reports and the authors’ experience suggest 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 (Figs. 8-26 and 8-27).
Figure 8-26 CRASH syndrome. A. Fetal brain imaging at 25 weeks of gestation demonstrates nonspecific moderate obstructive
hydrocephalus (obstruction not shown). B. Postnatal imaging on day 1 demonstrates massive ventriculomegaly with markedly reduced white
matter volume. The disease results from the mutation of the L1CAM gene that controls the axonal fasciculation during development.
Hydrocephalus in Chiari II is associated with a large massa intermedia and hypothalamic adhesion; AS with a dysmorphic
tectal plate, hypoplastic falx and tentorium resulting in an upward “towering” of the upper cerebellum across a wide tentorial
incisura; small, crowded posterior fossa with a concave clivus and wide foramen magnum; and downward descent of the
vermis and fourth ventricle into the cervical canal with a resulting deformity of the lower medulla (170). The frontal horns are
“onion shaped,” and ventricles enlarge to a greater degree in the posterior part of the hemispheres, with excessive thinning of
the posterior medial hemispheric walls, commonly in association with dysgenesis of the posterior corpus callosum.
Postshunting, the corresponding part of the interhemispheric cistern becomes dilated (no recovery of the mantle). The very
early onset of hydrocephalus probably explains this poor development of the posterior white matter, which is typically
associated with a stenogyria (170). Periventricular heterotopia is common, likely resulting from early alteration of the
ependymal resulting in detachment of radial glia (see Chapter 5). The anterior third ventricle also is dilated, but because the
posterior fossa is small (and therefore crowded), the prepontine cistern is effaced and performing an ETV may be problematic.
It is an important clinical concept that patients with the MMC–Chiari II malformation who develop occipital headaches at
night probably have a shunt malfunction. Fatal shunt malfunctions may result in brain stem 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 C1 and C2 or by the foramen magnum. These patients may be
subjected to unnecessary decompressions of the foramen magnum and C1-C2 instead of adjustment or replacement of the
ventriculoperitoneal shunt. It is important to recognize that the fourth ventricle is normally a thin vertical slit in the Chiari II
malformation (Figs. 5-178 and 5-179). The presence of a normal-appearing or enlarged fourth ventricle in these patients
suggests a shunt malfunction or an isolated fourth ventricle that needs CSF diversion.
Cystic malformations of the roof of the rhombencephalon (hindbrain) may also result in simple mechanical
hydrocephalus. The cystic mass, however, is located in the posterior fossa, thus effacing the prepontine and interpeduncular
cisterns, so that ETV may not be an option. They are related to a failure to open the fourth ventricular outlets, with (true
Dandy-Walker malformation) or without (persisting Blake pouch) partial vermian agenesis. Present before the completion of
the dura, these malformative cysts in addition present with a high-located and/or incomplete tentorium.
Acute ventricular obstructive hydrocephalus (high intracranial pressure)
This group of patients comprises children in whom a clinically increased ICP is associated with a ventricular obstruction and a
rapidly developing accumulation of ventricular CSF. Common in children, midline tumors (and midline-compressing tumors)
are both obstructive and progressively expanding. The global mass effect and the high ICP result from the addition of (a) the
volume of the tumor, (b) the degree of hydrocephalus, and (c) the associated brain edema. As the diagnosis typically is made
when the high ICP has become clinically apparent, some degree of ventricular dilatation must have been there for some time,
and the clinical decompensation may have occurred when the veins became compressed by the increasing combined mass
effects. Once present, high ICP will only increase; the associated venous compression results in more swelling and edema
(especially the compression of the subependymal veins with the resulting periventricular interstitial edema), reducing ISF/CSF
absorption by the parenchyma, while CSF secretion continues as long a brain perfusion pressure is maintained. In such a
situation, the intensity of the clinical presentation requires an urgent MR assessment followed by an urgent relief of the ICP. On
imaging, the characteristic feature of acute obstructive hydrocephalus is the periventricular FLAIR hyperintensity in the
territory of the deep medullary veins with associated ventriculomegaly and the mass of the causal tumor. This edema may
appear to be more extensive in very young infants because the draining venous system of the subcortical white matter is still
poorly developed (see above) (171). The causal tumor is typically evident with its local mass effect, infiltration, etc.
Leptomeningeal metastases may be present and contribute to the processes of hydrocephalus and brain swelling.
Tumors and arachnoid cysts can grow into and obstruct the foramina of Monro from a number of locations. Masses in the
lateral ventricles, such as choroid plexus tumors or (very rarely) a meningioma, may cause obstruction at the foramina of
Monro but also of any intermediate segment of the ventricle; a common example is isolating the temporal horn. Masses
originating in the third ventricle can grow anteriorly or superiorly to obstruct the foramina of Monro or posteriorly and
inferiorly to obstruct the cerebral aqueduct, as well as the midportion of the ventricle. Suprasellar tumors
(craniopharyngiomas, chiasmatic–hypothalamic gliomas, germ cell tumors) may grow upward to the foramina of Monro,
pushing the floor of the third ventricle superiorly. Septal tumors or cysts may also be involved. In children with tuberous
sclerosis, giant cell tumors (SEGA), which originate adjacent to the foramina of Monro, often grow medially and obstruct the
foramina (see Chapters 6 and 7).
The most common cause of sylvian aqueduct obstruction-related acute hydrocephalus in children is a tumor of the pineal
region (see Chapter 7); germ cell tumors in boys (germinoma, endodermal sinus tumor, embryonal cell carcinoma,
choriocarcinoma, teratoma), tumors of pineal origin (pineoblastoma, pineocytoma in young adults mostly but also rarely in
teenagers), astrocytomas (from the pineal gland, tectal plate, thalamus, or tegmentum of the midbrain), meningiomas (from the
tentorium, uncommon in children), supravermian arachnoid cysts, or arteriovenous malformations of the vein of Galen may all
cause hydrocephalus from compression of the aqueduct (in vein of Galen arteriovenous malformations, a component of
increased venous pressure also contributes to the hydrocephalus). CT identifies many of these lesions, but MR is more efficient
because it has inherently better contrast resolution. Posterior third ventricular masses are seen as discrete masses within the
ventricle, whereas tumors of the pineal gland occupy the quadrigeminal cistern and tumors of the tectal plate are seen on MR as
bulbous tectal masses with prolonged T2 relaxation and poorly defined margins. Germ cell tumors and pineoblastomas present
with restricted diffusivity on diffusion imaging. Thus, MR is essential to differentiate benign AS from stenosis secondary to a
tumor in children with aqueductal narrowing.
It is interesting that the most common brainstem tumor, the diffuse intrinsic pontine glioma (DIPG), does not typically result
in hydrocephalus, likely because it is located ventrally. In contrast, most children with tumors of the fourth ventricle and
cerebellum have hydrocephalus by the time of presentation (see Chapter 7). The most common posterior fossa neoplasms in the
pediatric age group medulloblastomas, cerebellar astrocytomas, and ependymomas (see Chapter 7) often present as a result of
hydrocephalus; imaging studies may show the tumor obstructing the CSF flow directly in the fourth ventricle, compressing its
outlets, or extrinsically compressing the aqueduct and/or the ventricle.
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
mechanism(s) of the hydrocephalus in these cases is not obvious, but a number of hypotheses have been proposed: (a)
increased viscosity and osmolarity of CSF secondary to elevated CSF protein concentration; (b) obliteration of the cisterna
magna and upper cervical arachnoid spaces due to rostral extension of tumor; (c) restriction of the thecal space and poor
buffering of the systolic pressure wave; and (d) 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 (b) unlikely. Virtually all reported cases have very high CSF protein content;
therefore, it is likely that osmolarity and dissemination of tumor through CSF play a role in the development of hydrocephalus
in these patients (172).
Bacterial meningitis, either granulomatous or purulent, may be associated with hydrocephalus in both the early and the
late stages of the disease. The acute presentation results from the association of inflammatory brain edema with poor CSF
absorption and impaired flow of purulent CSF along the inflamed ventricles and cisterns. In children with a rigid calvarium,
the ventricles may dilate only minimally (or not at all) despite high CSF pressure, and CSF circulation/resorption may be poor,
because the ventricles are compressed by the swollen brain (“hyperacute” hydrocephalus). This may result in a tamponade
effect. The diagnosis rests on the ventricles not being effaced (in spite of the brain edema) and being rounded, especially at the
temporal horns (Figs. 8-28 and 8-29). (Similar imaging and pathogenesis may be observed in posttraumatic malignant
swelling; instead of being effaced by the brain swelling, the entrapped ventricles become rounded, with a resulting ventricular
tamponade.) On the contrary, young infants with more elastic, open fontanelles and sutures may develop enlarged ventricles
within a few days (Fig. 8-30). A combination of a ventriculitis, an ependymitis, and paraventricular abscesses is not unusual at
that age, sometimes with purulent “melting” of significant portions of the parenchyma and inflammatory “subdural effusions”
that may evolve into true empyemas. In all, the meningeal inflammation results in a leptomeningeal enhancement and may be
complicated by a vasculitis with arterial or venous thrombosis and ischemia (Figs. 8-28 and 8-30). Later in the course of the
disease, when the infection has been checked, both the circulation and the absorption of the CSF may remain compromised and
result in hydrocephalus. The periventricular fibrosis prevents the ependymal absorption; ependymal and leptomeningeal
fibrosis obstructs the ventricular and the arachnoid CSF pathways. The fibrotic dural sites can no longer absorb the CSF,
either. The membranous partitions of the CSF spaces as well as residual postinfectious or postischemic parenchymal
cavitations create multiple independent cavities (such as an isolated fourth ventricle), each with its own accumulation of fluid,
making surgical treatment particularly difficult (173).
MR assessment at the acute stage is useful in looking for evidence for meningitis (leptomeningeal enhancement), for its
complications (reduced diffusion suggesting abscesses, empyemas, fluid effusions, arterial or venous thrombosis, and
ischemia), and for a developing hydrocephalus. In late stages, MR assessment focuses on the obstruction sites (high-definition
CISS/FIESTA), the degree and pattern of CSF circulation abnormalities, and the infection-related parenchymal sequelae
(cavitation, gliosis, fibrosis, hypomyelination) (Fig. 8-31).
Carcinomatous meningitis resembles infectious meningitis in that it may cause hydrocephalus with meningeal enhancement
(Fig. 8-32) after administration of intravenous contrast, and differentiation of subarachnoid tumor from infection is not possible
at this time by imaging. A number of neoplastic processes can involve the subarachnoid spaces diffusely (see Chapter 7). The
most common of these in children are medulloblastoma, germinoma, leukemia, and lymphoma; it can also be seen in a variant
of pilocytic astrocytoma, the pilomyxoid astrocytoma (174). Patients with CSF seeding of tumor (also called carcinomatous
meningitis) typically present with headache, stiff neck, cranial nerve palsies, and neurocognitive obscuration. Hydrocephalus
occurs only later in the course of the disease. As with infectious meningitis, ventricular enlargement is the most common
manifestation of this process on ultrasound, CT, and unenhanced MR scans. Occasionally, diffuse pial enhancement may be
seen on contrast-enhanced CT. On MR, in addition to ventriculomegaly and brain swelling, the signal of the CSF in the sulci
may be abnormally high on FLAIR, and reduced diffusion may be observed, depending on the nature of the primary tumor.
Significant enhancement of the subarachnoid spaces and cranial nerves (particularly cranial nerves 5 and 8) is typically seen
on contrast-enhanced T1WI scans (Fig. 8-32) and still better demonstrated on postcontrast FLAIR imaging.
Figure 8-28 Tuberculous meningitis, entrapped ventricles. A 15-year-old girl. A. Coronal FLAIR, anterior. The ventricles are hardly expanded
but clearly rounded; together with the mild periventricular interstitial edema (large white arrows), this indicates a high intracranial pressure; note
patchy signal changes (small arrows) in the left thalamus and basal ganglia. B. Axial FLAIR. Same ventricular appearance. Severe ischemic
changes involving the thalami, capsules, and basal ganglia, more so on the right side (arrows). Note interstitial edema at the tips of the frontal
and occipital horns. C. Coronal T1 postcontrast. Similar ventricular appearance; diffuse meningeal enhancement. However, in this example, the
rigidity of the skull prevented the ventricles from dilating and interstitial edema from developing.
Posthemorrhagic hydrocephalus
IVH in premature infants is a leading cause of pediatric hydrocephalus, developing in low birth weight premature infants
within a few days after birth, as a result of injury to veins of the germinal matrix (ventricular zone), which are precursors of the
subependymal veins. As discussed (with more details) in Chapter 4, it is classified in three grades: Gr1 (isolated germinal
matrix hemorrhage), Gr2 (associated ventricular hemorrhage with normal ventricles), and Gr3 (ventricular hemorrhage with
ventriculomegaly). It is often complicated by a thrombosis of the subependymal veins, which results in a periventricular
hemorrhagic infarction (PVHI—previously called Gr4) in the territory of their tributaries. It may be associated with other
parenchymal injuries (periventricular leukomalacia, oligodendroglial injury, punctate white matter lesions) and is commonly
associated with cerebellar bleeds (see Chapter 4). It is generally estimated that about 50% of the prematures with IVH will
develop significant ventriculomegaly and that at least half of these will require some kind of diversion procedure (175–177).
The processes that lead to active hydrocephalus develop in 2 to 6 weeks: (a) ventriculomegaly develops because of the
intraventricular blood; and (b) ependymal and leptomeningeal inflammation results in a release of TGF-β1, which, in turn,
induces an increase of extracellular matrix protein and collagen synthesis, with secondary subependymal gliosis/fibrosis and
adhesive arachnoiditis (176,177). When a PVHI develops, the parenchyma that is infarcted as a result of the venous occlusion
becomes necrotic and, with time, leaves a paraventricular porencephalic cavity that often becomes continuous with the
ipsilateral lateral ventricle. Obviously, this may be associated with any other types of HIE injury, and it may be further
complicated by the parenchymal effects of hydrocephalus.
Figure 8-29 Hydrocephalus associated with tuberculous meningitis. Midline sagittal (A), coronal (B), and 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.
Figure 8-30 Neonatal purulent GBS meningitis, early hydrocephalus. MRI done at 7 days. A. Axial T2-FSE shows early hydrocephalus with
moderate dilatation of the ventricles. Note infarction (arrows) in the territory of the right lenticulostriate arteries. B. Postcontrast coronal T1 at
frontal horns. Marked ventricular dilatation with effacement of the pericerebral spaces, infarcts in the right basal ganglia (large white arrows),
and left frontal ependymal (small white arrow) and diffuse leptomeningeal enhancement.
Figure 8-31 Multisegmental postmeningitic hydrocephalus. Midline sagittal T2 (A), lateral sagittal T2 (B), and axial T1 postcontrast (C) images
demonstrate the multiple intraventricular and parenchymal loculations of hydrocephalus.
Figure 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 meningitis), mainly overlying
the cerebellar folia.
During the first weeks, when the premature is still unstable, the acute/subacute stage of PVHI is generally diagnosed by
ultrasonography. It may be complemented by MR imaging using no sedation (very young prematures move little) with the help
of a dedicated MR-compatible incubator and specially adapted head coil and ear plugs. Together with the ventricular size and
distension, MR assessment appreciates the volume and extent of the ventricular hemorrhages, the extent of any PVHI, the extent
of the subarachnoid blood, the involvement of the cerebellum, and the associated parenchymal HIE lesions (Fig. 8-33). In the
chronic stage, MR can assess the progression of the ventriculomegaly and the evolution of parenchymal sequelae (notably the
post-PVHI paraventricular porencephaly), and by a careful T2-FSE and CISS/FIESTA imaging, it identifies any ventricular and
cisternal obstructions in order to help evaluate for the possibility of a third ventriculostomy (Fig. 8-34).
Figure 8-33 Posthemorrhagic hydrocephalus. Baby girl born at 25 weeks; MRI showed IVH3 and PVHI. A. Axial T2GE at age 6 weeks (31w
GA) demonstrates a large, left hemispheric periventricular hemorrhagic venous infarction (with cavitations, black arrows), markedly edematous
white matter, bilateral ventriculomegaly, and blood residues lining the ependyma (right greater than left). B. Sagittal T2-FSE at the same age
demonstrates quadriventricular dilatation. Note the narrowing of the aqueduct contributing to the dilated third and fourth ventricles.
Figure 8-34 Posthemorrhagic hydrocephalus in a former premature infant. A. Midline sagittal FIESTA image shows severe hydrocephalus,
dehiscent septum pellucidum, and an obstructed aqueduct. Low signal intensity around the brain stem 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) and choroid plexuses and walls of the lateral ventricles (C and D).
Nonobstructive Hydrocephalus
Pathophysiologic considerations
“Communicating” hydrocephalus was initially defined by an absence of any ventricular obstruction (1). However,
extraventricular obstruction is a common cause of hydrocephalus (see above) through a mechanism similar to that of
ventricular obstruction. For that reason, we prefer the term of nonobstructive hydrocephalus to describe conditions in which
no obstruction is demonstrated anywhere within the ventricular or extraventricular spaces. Such cases occur less commonly in
children than in adults, and a commonly postulated explanation is a compromise of CSF absorption mechanisms, such as
obstruction of the arachnoid villi (91). The effects of venous pressure on hydrocephalus are more complex. Capillary–venous
channels are by far the most important outlet for systolic influx in the cranium (Table 8-1). Increased central venous pressure,
therefore, corresponds primarily with decreased compliance, narrowing the pressure gradient across the absorption sites and
thereby decreasing CSF absorption (a) at the level of the arachnoid villi, (b) at other transdural absorption sites, and (c) within
the parenchymal capillaries. This may happen when conditions such as achondroplasia cause a stenosis of the jugular foramina
superimposed upon an effacement of the craniocervical venous channels due to the stenosis of the bony cervical canal. Most
commonly, however, the respective roles of poor absorption, decreased compliance (inelastic brain or theca, venous
restriction), and undiagnosed obstruction in individual cases of nonobstructive hydrocephalus are difficult to sort out (90).
NPH, initially diagnosed by pneumoencephalographic studies in elderly adults (to prove that the CSF pathway was patent
between the lumbar puncture site and the lateral ventricles), supported the hypothesis of abnormally functioning arachnoid
villi. Radionuclide or cisternographic CT studies in these patients have shown a pooling of the tracer in the ventricles
(178,179), and more recent quantitative MR flow studies have suggested an inversion of the CSF net flow from the cisterns to
the ventricles (180), consistent with ventricular absorption palliating a peripheral absorption failure (knowing that only water,
not the tracers, can be transported by the ependymal AQP4). The observation that the amplitude of the aqueductal CSF flow
void was increased in such cases of nonobstructive hydrocephalus (103,181,182) was interpreted as a loss of the brain CSF–
dural sac system buffering capacity of the arterial pressure wave (183,184). Although this was considered a diagnostic test of
NPH, another interpretation might be that, with the pericerebral spaces being effaced, the pulsation wave is redirected
medially (as mentioned earlier). Indeed, NPH appears to be heterogeneous and all pathogenetic models may, therefore, be
challenged. In children, several patterns of apparently nonobstructive hydrocephalus have been attributed to an imbalance of
CSF secretion/absorption, all in very young children. The most common is the benign idiopathic external hydrocephalus
(associated with a low ICP); the much less common choroid plexus papilloma-associated hydrocephalus, on the contrary,
typically presents with increased ICP.
Figure 8-35 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 obstruction must be located somewhere else. The patient was treated by endoscopic fenestration of the third ventricle and
cyst. B. Midline 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.
Accumulation of fluid with ventricular enlargement may result from skull base abnormalities in a number of syndromes,
including achondroplasia (188) (Fig. 8-36), craniofacial syndromes that result in multisutural craniosynostosis (Apert
syndrome, Carpenter syndrome, Pfeiffer syndrome, Crouzon syndrome, and others described in Chapter 5, Section VI.D) (189),
and the Marshall-Smith syndrome (a syndrome of accelerated osseous maturation and CNS malformations). One might
postulate that the ventricular enlargement in all of these syndromes results from the diminished venous outflow through the
small jugular foramina as well as through the plexuses of the foramen magnum, all resulting from hypoplasia of the skull base
(190) (Fig. 8-36D). The mechanism of the fluid accumulation is believed to be an increase in dural sinus pressure, leading to a
decreased pressure gradient from the subarachnoid spaces to the sinuses across the arachnoid villi. In addition, the arterial
systolic inflow may not being properly buffered through the vascular bed because of the increased pressure in the dural sinuses
and, thus, the decreased compliance of the system (12). The resultant increased amplitude of the systolic wave results in
expansion of the calvarium and ventricles in infants until the pressure normalizes or the hydrocephalus becomes stabilized.
Typical imaging signs of hydrocephalus are not reliable in these patients. For example, the temporal horn enlargement may
result from the expansion of the middle cranial fossa, and the frontal horn enlargement may be the result of the enlarged anterior
fontanelle, not necessarily from increased intraventricular pressure. Also, in case of early sutural synostosis, the bodies and
trigones of the lateral ventricles may not enlarge until a cranial expansion has been performed. The indication for shunting in
these patients seems to be based primarily on the presence of severe ventricular dilation or evidence of persistent intracranial
hypertension such as papilledema. One study suggested that the ICP normalizes in patients with craniosynostosis syndromes 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) (190).
Similarly, progressive head enlargement in infants can also result from thrombosis of the dural venous sinuses, presumably
via the same mechanism. MRV can be helpful to detect obstruction of the dural venous sinuses in children with increased CSF
pressures with no other obvious cause. As 2D time-of-flight MRV may show apparent narrowing of the distal transverse and
sigmoid sinuses as a result of complex flow (sometimes by the presence of an arachnoid granulation or flow from the vein of
Labbé) in those areas, time-resolved contrast-enhanced MRV (see Chapter 1) is the study of choice to evaluate the venous
sinuses. However, MRV cannot determine the pressure differential across foci of narrowing in the dural venous sinuses.
Therefore, in difficult cases, a catheter venogram may be indicated to measure pressures in the sinuses. Keep in mind,
however, that it is not always easy to determine whether the venous stenosis that causes the hydrocephalus or the elevated
ICP that effaces the veins.
Normal-pressure hydrocephalus (NPH) in children is a form of hydrocephalus in which a pressure gradient occurs
between ventricles and brain parenchyma, despite the finding of normal CSF pressure at the time of lumbar puncture. NPH
mainly affects elderly individuals and is poorly understood, possibly resulting from diverse mechanisms. Children may be
affected, but it is never an easy diagnosis and often more difficult in children than in adults. Intermittently high pressure
probably results from a compromise of normal compensatory pressure mechanisms (191) including compliance (e.g., of the
venous system). The fluctuating high pressures may combine with impaired regional CBF to cause ventricular enlargement and
parenchymal destruction. The most common (presumed) causes of NPH are unidentified arachnoid damage interfering with
normal CSF absorption and loss of elasticity of the dural sac. Causative events include neonatal intraventricular and arachnoid
hemorrhage, spontaneous subarachnoid hemorrhage, intracranial trauma, infections, and surgery. Among the pediatric
population, NPH is most commonly seen in those who have underlying neurological pathology such as complications of
meningitis or germinal matrix/IVH (192). 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 nonobstructive
hydrocephalus. Measurements of CSF flow with flow-sensitive MRI methods have demonstrated that the CSF stroke volume
(volume 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; at the same time, ICP monitoring reports a sixfold increase of the CSF pulse
pressure (12). This association of decreased stroke volume and increased pressure wave reflects the loss of brain compliance:
the arterial expansion resulting from the cardiac systole is decreased, and the arterial pulse wave, instead of being transmitted
to the CSF (because of the loss of compliance), is transmitted directly to the vascular lumen. Thus, the intravascular pressure is
increased in capillaries and veins, preventing the normal absorption of CSF by the parenchyma. Because the pulse wave is
transmitted into the vessels rather than the pericerebral 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 combined increased pressure in the vessels and the ventricles results in a slowly progressive loss of brain tissue
(12). The demonstration of a significant increase of the CSF stroke amplitude at the aqueduct using cine phase-contrast imaging
in cohorts of patients as compared with normal controls (193) has been interpreted as a confirmation of this model. On
conventional MRI, this is expressed as a significantly increased signal void in the aqueduct on sagittal T2-FSE/TSE imaging.
However, an alternative explanation for this phenomenon is that the ventriculomegaly effaces the pericerebral spaces,
redirecting the full volume of the systolic stroke medially to the ventricles and therefore across the aqueduct.
Infantile benign idiopathic external hydrocephalus, also called benign enlargement of the subarachnoid spaces in
infancy or benign arachnoid collection of infancy, is a common and specific form of chronic nonobstructive hydrocephalus
that occurs in infants. It is characterized, in a child from a few months to less than 2 years, by macrocephaly with moderately to
markedly enlarged anterior subarachnoid spaces, including the anterior interhemispheric fissure, and mildly enlarged lateral
ventricles, more so anteriorly as well. Morphologically, it appears as if the brain was growing freely in a markedly enlarged
head with enlarged CSF spaces. Other than the macrocephaly, the child is normal: no clinical feature is attached to this
condition. Often familial, it mostly affects boys and, less commonly, babies born preterm (194). The postulated (not
documented) explanation is immaturity of the arachnoid villi with poor CSF absorption, but the process is not really
understood (194). Indeed, pathways of CSF absorption other than the arachnoid villi exist in infants, either parenchymal or
transdural. Whatever the cause of the slowly accumulating CSF, the immature membranous skull grows disproportionately
more than the brain, and this results in the characteristic appearance (12,195). The disproportion diminishes when the fusion of
the sutures limits the growth of the head, but the affected children commonly are and remain macrocephalic; of note,
macrocephaly may often be observed in the father as well. The morphologic pattern of external hydrocephalus is not different
from the pattern of prominent pericerebral spaces observed in the normal fetuses (Fig. 8-37), which normally disappears
shortly after delivery, even in premature babies, presumably because of the venous pressure drop associated with the opening
of the pulmonary circulation (Fig. 8-38) (see above). Of note, an excessive prenatal prominence of the ventricles and
pericerebral spaces has been related to later-onset benign external hydrocephalus in infants investigated both pre- and
postnatally (196). Other than “immaturity” of the arachnoid villi, suggested etiologies include restriction of the venous
drainage: similar hydrodynamic conditions are observed in patients with achondroplasia, in which the venous outflow is
severely impaired (see above); in an infantile form of pseudotumor cerebri, in which an idiopathic external hydrocephalus in
infants and toddler on one hand; and in pseudotumor cerebri (idiopathic intracranial hypertension) in older individuals. These
conditions share a common venous pathogenesis, which depends only on whether the skull is expandable (external
hydrocephalus) or not (pseudotumor cerebri) (186,187,197). Some have further hypothesized that children who present with an
idiopathic benign external hydrocephalus in infancy might be prone to develop classic NPH at an advanced age, when the
development of brain vasculopathy would limit the appropriate CSF absorption by the brain tissue (198).
Figure 8-37 Fetal brain imaging: normal pattern reminiscent of the postnatal external hydrocephalus. Prominent pericerebral spaces in
fetuses at 25 weeks (A), 28 weeks (B), and 33 weeks (C).
On MR imaging, the diagnosis of a benign external hydrocephalus rests on the demonstration of the characteristic
morphology of a macrocephaly with enlarged anterior CSF spaces within and mostly outside the brain (Figs. 8-39 and 8-40).
The fluid must be CSF-like on every sequence and be traversed by the usual arachnoid bridging veins to rule out subdural
collections such as subdural hygromas (Fig. 8-40).
Acute nonobstructive hydrocephalus
Hydrocephalus related to choroid plexus papillomas is also assumed to result from an imbalance between CSF secretion and
absorption, but in this case, the high level of CSF secretion is postulated to overwhelm the capacity of absorption. However,
hydrocephalus is not constant: out of a personal series of 16 cases of supratentorial choroid plexus papillomas, significant
hydrocephalus was noted in only 9 (56%). Choroid plexus papillomas affect infants and young children in the same age range
as the idiopathic external hydrocephalus. The tumor usually develops within one lateral ventricle, but the hydrocephalus is
usually (but not always) bilateral and often symmetric (199) (Fig. 8-41). The ventricular dilation may be associated with
prominent enlargement of the posterior fossa cisterns. Effacement of the pericerebral spaces by the dilated ventricles
distinguishes this disorder from idiopathic external hydrocephalus. Four main features characterize the tumor: (a) it usually
floats in the CSF of the ventricular atrium without incarceration; (b) it produces huge amounts of CSF (up to several liters a
day) (200–202), and AQP1 is strongly expressed in the tumor (203); (c) it is hypervascular, therefore strongly pulsatile (200);
and (d) the CSF is xanthochromic with a high protein level (200,201). Clinically, affected patients have macrocephaly and
increased ICP with the relevant clinical symptoms. However, the mechanism of disease remains highly debated; obstruction of
the ventricles may play a role when the mass is in, or close to, the midline, but this is uncommon. Repeated microbleeds could
obstruct the absorption sites, but hydrocephalus typically disappears after removal of the tumor (200). The hyperpulsatility of
such a highly vascular mass may play a role, as suggested in the cases of asymmetric ventriculomegaly, but this should be
associated with some degree of decreased compliance to dilate the cavities. By default, the CSF overproduction is generally
accepted as the most likely explanation for the hydrocephalus. In addition to ventricular obstruction or compression,
hypersecretion of CSF is also mentioned, but apparently not documented, as a possible factor of the hydrocephalus associated
with the choroid plexus carcinomas (204).
Figure 8-38 Brain imaging in the premature: the pericerebral spaces are effaced, presumably because of the venous pressure drop that
occurs around birth. Similar gestational ages as on Figure 8-37: 24 weeks (A), 28 weeks (B), and 33 weeks (C).
Figure 8-39 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.
Figure 8-40 Benign enlargement of the subarachnoid spaces. Fluid accumulation in this disorder is assumed to result from a poor CSF
absorption in a young child (absorptive hydrocephalus) and causes disproportionate growth of the skull as long as the sutures are open, but the
brain size remains normal. As a consequence, the extracerebral spaces, not the ventricles, are dilated (A). The diagnosis of arachnoid (vs.
subdural) collection rests upon the demonstration of bridging veins crossing the fluid space (demonstrated in A and B, white arrows). This
enlargement of the pericerebral spaces regresses in the toddler when the growing potential of the sutures becomes lost.
Bilateral choroid plexus villous hyperplasia (or hypertrophy) is a severe but rare disease; less than 25 cases have been
reported in the literature (205). It is the only subtype of hydrocephalus that cannot be relieved by CSF shunting alone, as
shunted patients rapidly (hours or few days) develop ascites. The condition may be discovered early in a fetus or a neonate or
later in an infant or, less commonly, a child. It is revealed by a clinically severe hydrocephalus associated with a bilateral
hyperplasia of the choroid plexuses of the lateral ventricles, sometimes reported as bilateral choroid plexus papillomas, as
both condition may appear to be associated on histological examination (206–208). Only 17 case reports were published since
CT and MRI are available (205–220). At diagnosis, the patients present with macrocrania; imaging shows symmetric dilatation
of the lateral ventricles with effacement of the pericerebral spaces and significant dilatation of the interpeduncular and
posterior fossa cisterns (206,209–215). Only one report mentions possible hyperplasia of the fourth ventricular plexus (211).
The imaging appearance of the villous hyperplasia is different from the appearance of a choroid plexus papilloma. The choroid
plexuses of the lateral ventricles are involved diffusely, bilaterally and symmetrically with hypertrophic villosities (Fig. 8-42),
in contrast to with papillomas, which typically appear as discrete compact masses attached to one choroid plexus. The
distinction is most apparent after administration of contrast. In all reported cases, the initial placement of a
ventriculoperitoneal shunt failed to relieve the hydrocephalus, and in all but one, the patients rapidly (in hours or few days)
developed ascites. When it was measured, the CSF production was extremely high for age, up to several liters a day (205–
211,214–220). In all the cases, bilateral plexectomy, secondarily performed by coagulation or excision, was initially
successful in reducing the hydrocephalus. However, the choroid plexus has the potential to regrow from residual fragments, so
the treatment works only temporarily. An immunohistochemical study, performed in one case, showed decreased AQP1
expression in the hyperplastic choroid plexuses, presumably down-regulated by the “uncontrolled” overproduction of CSF
(217).
Figure 8-41 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.
Figure 8-42 Hydrocephalus and choroid plexus hyperplasia. Sagittal T2 (A), axial FLAIR (B), and contrast-enhanced coronal T1 (C) images
show massive symmetrical enlargement of the ventricles, as well as of the posterior fossa, and suprasellar and anterior interhemispheric
cisterns; choroid plexuses are bilaterally hyperplastic. The mechanism of the hydrocephalus is assumed to be an overproduction of CSF.
Fetal Hydrocephalus
Pathophysiologic considerations
Fetal hydrocephalus is still poorly defined, poorly understood, and poorly diagnosed. It is often included into general groups
such as “macrocrania” (221) or “ventriculomegaly” (222,223), both of which may occur without hydrocephalus. Even in the
age of genetics and MR, recent reports on “fetal hydrocephalus” or “congenital hydrocephalus” unwittingly describe cases of
holoprosencephaly, hydranencephaly, microcephaly with large ventricles, encephalocele, and agenesis of corpus callosum
(224–227). Epidemiologic studies of “congenital hydrocephalus” rely on registries and lack a precise definition as well
(228–231). Even the medical terminology may be deceiving. In the uncommon entity that used to be called “X-linked
hydrocephalus” and now identified as CRASH (for Callosal hypoplasia, Retardation, Adducted thumbs, Spasticity,
Hydrocephalus), the ventricles are large and the aqueduct may not be patent, but the primary disorder is a failure of the white
matter to develop properly due to a defect of the L1CAM gene (Xp28) that controls the axonal fasciculation (165) and, even if
associated with hydrocephalus, it is a disorder of the white matter (Fig. 8-27). The Walker-Warburg syndrome, another
disorder sometimes mistaken for hydrocephalus, was actually first described as a “HARD syndrome” for Hydrocephalus,
Agyria, Retinal Dysplasia, but it is now identified as the most severe phenotype of the cobblestone brain, a cortical
overmigration disorder associated with muscular dystrophy (see Chapter 5).
In postnatal infantile or childhood hydrocephalus, the disease is understood as a disorder of the secretion/absorption and/or
of the hydrodynamics of the CSF, singly or in association (see above). In the fetus, little is known about the normal physiology
of CSF. Fluid is present within the lumen of the neural tube even before the formation of the choroid plexuses and, therefore, is
a transudate. True CSF secretion from the plexus may begin about week 7 in the fourth ventricle, and week 8 in the third and
lateral ventricle, when AQP1 and enzymes become expressed in the choroid plexuses (33). While the ventricles begin to
communicate with the subarachnoid spaces at weeks 11 to 12 when the roof of the fourth ventricle opens (58), ependymal
AQP4 (which mediates ventricular absorption) is not expressed until much later, about week 22 (week 18 for the hippocampal
alveus) (46). Similarly, although the subarachnoid spaces develop from weeks 6 to 8 (52), subpial AQP4 that could mediate
extraventricular CSF production is not expressed until week 22 either (46), and the dural depressions that prefigure the
arachnoid villi are not observed before week 26 (61). The arteriovenous gradient is small throughout the gestation, the
placental–cardiac circulation pattern in the fetus being associated with low arterial and high venous pressures, probably
explaining the normal feature of prominent pericerebral CSF spaces in fetuses that corresponds morphologically to the benign
external hydrocephalus in infants, and disappears shortly after birth, even in prematures. As mentioned before, this presumably
happens because of the drop of the venous pressure and rise of the arterial pressure that occurs with the separation from the
placenta and the opening of the pulmonary circulation. Except for the choroid plexuses and germinal matrices, brain tissue is
minimally perfused until the thalamocortical connectivity develops after week 22, and the intracranial pulsatility must be very
weak in fetuses as compared to infants. In addition, the intracranial–extracranial pressure gradient that exists in infants is
necessarily counterbalanced in utero by the pressure of the amniotic fluid. In fetal obstructive hydrocephalus, the ventricular
pressure is higher than the amniotic pressure in selected surgical cases in which treatment was attempted in utero; this
suggested that ventriculoamniotic shunting could represent a possible treatment (232). The accepted pathogenesis of the Chiari
II complex abnormalities, which is based on the assumption that the myelocele-related CSF leak results in a low ICP supports
this concept that, even in normal fetuses, the ICP is higher than the amniotic pressure.
Imaging hydrocephalus in the fetus
Ultrasonography is the primary tool to investigate fetal hydrocephalus, MRI being necessary in selected cases only. The
diagnosis of ventriculomegaly is made when the fetal sonogram shows a lateral ventricular atrium that is larger than 10 mm
(233). The sizes of the third and fourth ventricles can also be measured from transverse ultrasound images and from coronal
(lateral ventricular atria, third ventricle) and sagittal (fourth ventricle) MRI images. The diameter of the third ventricle should
be less than 3.5 mm on ultrasound and less than 4 mm on MR, while the fourth ventricle diameter should be less than 4.8 mm on
sonography and less than 7 mm on MRI (234). Whatever the cause, the presence of fetal ventriculomegaly suggests that the
brain development may be abnormal and justifies a more thorough investigation with fetal MRI. Differentiating between simple
ventriculomegaly and true hydrocephalus is not necessarily easy, because hydrocephalic fetuses may have a nearly normal head
circumference and because ventricular expansion does not necessarily efface the typically prominent subarachnoid space that
is observed over the cerebral convexity in fetuses. The measurement of the biparietal diameter may be more useful than the
head circumference (see below). Assessment of the ventricular morphology may also help, as a rounded configuration of the
ventricles, especially of the temporal horns, indicates increased pressure. If 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, while this layering commonly disappears in cases of destructive ventriculomegaly (235). Aqueductal occlusion or
stenosis can be suspected when the posterior fossa appears normal; evaluation is best on sagittal views of the midbrain. A
common feature of hydrocephalus in the fetus is a rupture of the septum pellucidum, which may be impossible to differentiate
from a developmental absence of the septum. MR imaging is useful in demonstrating the cause of hydrocephalus (AS, hindbrain
malformations, hemorrhages, infection, vein of Galen malformation, extracerebral cyst or, rarely, tumor).
In a personal series (which excludes Chiari II malformations), fetal hydrocephalus was defined by the association of a
ventricular enlargement (above 10 mm, measured as the largest transverse atrial diameter on the coronal cuts at the level of
the choroid plexuses) with a demonstrable cause (all cases, therefore, were obstructive hydrocephalus) and associated with
an increased biparietal diameter (≥2 gestation weeks above average). The cases were divided in two groups according to the
time of diagnosis. Cases initially identified by the US performed about midgestation were considered as early-onset
hydrocephalus (48 cases, MR study done between 19 and 29 weeks). Cases identified by late US were assumed to have been
normal at midgestation and to have developed only later; they were therefore considered as late-onset hydrocephalus (12
cases, MR study done between 32 and 38 weeks). In 7 cases of early-onset hydrocephalus, a follow-up MR study was done
after the 30th week (either pre- or postnatally), and in 4 cases of late-onset hydrocephalus, it was done postnatally between 38
and 48 weeks (gestational age). In addition, autopsy was performed in 9 aborted fetuses (all early-onset cases).
In the early-onset group (48 cases), hydrocephalus appeared before the midgestation sonogram. In addition to two siblings,
it was characterized by a high prevalence of twin pregnancies (9/48 or 19%; the prevalence in the general population is 3.3%).
Fetopathology confirmed the diagnosis in 9 cases, and follow-up imaging in 7 cases. The morphologic features revealed three
degrees of severity: mild, moderate, and severe, all with an increased biparietal diameter and evidence of ventricular
obstruction. (These morphology-based degrees of severity do not necessarily match the atrial diameters, but demonstrate some
correlation with them.) In each of the groups, the imaging features were remarkably consistent. Mild hydrocephalus was shown
in 7 patients, characterized by ventriculomegaly and macrocephaly, a preserved cerebral mantle and patent pericerebral spaces
(Fig. 8-43A). Moderate hydrocephalus was found in 23 patients, featuring ventriculomegaly, macrocephaly, stretching and
thinning of the cerebral mantle, and partially effaced pericerebral spaces (Fig. 8-43B). Severe hydrocephalus in 17 patients
demonstrated ventriculomegaly, macrocephaly, and a stretched and focally dehiscent cerebral mantle with a complete
effacement of the pericerebral spaces (Fig. 8-43C). A dehiscent septum pellucidum was common and somewhat correlated
with the degree of severity, found in 29% of the cases of mild hydrocephalus, 65% of the cases of moderate hydrocephalus and
94% of the cases of severe hydrocephalus (Fig. 8-43B and C). In 7 cases with follow-up imaging (2 in utero and 5 after birth),
the degree of severity remained unchanged in 6 and was increased (from moderate to severe) in 1.
Isolated AS (57%) is divided into the three groups. In the past, fetal AS has been successively postulated to result from a
primary developmental defect, a TORCH infection, a “back compression” from the dilated lateral ventricles, or a dormant
juxta-aqueductal tumor. In rodents, it has been associated with disorders of the ciliary epithelium, and to abnormalities of the
SCO, but this seems not to apply in humans. The prevalence of twin gestations suggests a developmental origin, however. Not
surprisingly, rhombencephalosynapsis and mesencephalosynapsis (RES/MES) are common causes of human fetal
hydrocephalus (Fig. 8-44); the authors found these in 9/48 cases, as opposed to an estimated 1/1,000,000 in the general
population (236) with no more than 100 postnatal cases published in the literature (237). The high prevalence of RES/MES in
fetal hydrocephalus (21%) was already recognized in a fetal pathologic series of 40 cases (238) and, in a short, mostly
neurosonographic study of 11 cases (239); no etiologic factor or genetic abnormality has been associated with this, other than
to say that the absence of midline structures in the mid-hindbrain in these disorders appears to affect the cerebral aqueduct, as
well. Other malformations associated with fetal hydrocephalus included Dandy-Walker malformation in 2/48 cases and
CRASH syndrome (L1CAM defect). All together, intrinsic cerebral disorders explained 87% of the cases of early fetal
hydrocephalus. By contrast, extrinsic causes are uncommon (13%) including evidence of a previous, presumably causal
hemorrhage (4 cases, subacute in 3) and compression by a leptomeningeal cyst or a dilated dural sinus with an arteriovenous
dural fistula (1 case each).
Figure 8-43 Early fetal obstructive hydrocephalus (diagnosed at midgestation). Morphologic patterns (MR imaging done at 23–24 weeks),
coronal cuts. A. Mild early fetal hydrocephalus pattern. Ventricles are moderately enlarged, the cerebral mantle is preserved with its white
matter layering, and the pericerebral spaces are maintained; the septum pellucidum is seen. B. Moderate early fetal hydrocephalus pattern.
Ventricles are more enlarged, the mantle is thinned, and the pericerebral spaces are partly effaced; dehiscent septum pellucidum. C. Severe
early fetal hydrocephalus pattern. The ventricles are markedly dilated and the cerebral mantle is thinner; in addition, there is a dehiscence of the
mantle on the left (black arrows), and the pericerebral spaces are fully effaced.
The development of ependymal denudation has been reported in congenital hydrocephalus in laboratory animals (114,240),
in Chiari II–related hydrocephalus (241), in fetal communicating hydrocephalus (48), and in postnatal hydrocephalus (45,118).
Presence in such diverse contexts suggests that it is an effect, rather than the cause, of hydrocephalus. This phenomenon is not
readily observable with MRI, but the role of the ependyma in the differentiation and migration of neuronal progenitors (50,242)
would explain the significant number (5 cases) of ependymal nodules, possibly heterotopia, in our series, as well as the high
incidence of heterotopia in the Chiari II–associated hydrocephalus (170,243). Ependymal damage might also explain the
unusually common defects of the septum pellucidum in fetal (as compared with postnatal) hydrocephalus. In animals, it has
been suggested that ependymal denudation could interfere with the development of the SCO and cause hydrocephalus, but
again, the significance of the SCO is controversial in humans (24,244). It is worth noting that hydrocephalus did not prevent
the development of the gyration in the 7 fetuses in whom later MR follow-up was performed.
Figure 8-44 Early fetal obstructive hydrocephalus associated with rhombencephalosynapsis. Coronal cut through the posterior head shows
hydrocephalus with a small, rounded cerebellum.
Figure 8-45 Late fetal obstructive hydrocephalus (normal at midgestation, diagnosed in last weeks before delivery). A. Mild late fetal
hydrocephalus pattern. Ventricles are mildly dilated and rounded, the parenchyma is not significantly stretched, the pericerebral spaces are
patent; the septum pellucidum and its cavum are preserved. B. Moderate late fetal hydrocephalus pattern. Ventricles are moderately dilated and
the pericerebral spaces are partly effaced; the septum pellucidum is intact. C. Severe late fetal hydrocephalus. Severe ventricular dilatation
with effacement of the pericerebral spaces; the septum pellucidum is dehiscent. Note small heterotopion in right temporal horn (arrow), likely
due to disruption of ependymal wall secondary to excessive expansion.
For the group of 12 patients with late-onset fetal hydrocephalus, midgestion ultrasound was considered unremarkable;
therefore, it may reasonably be assumed that hydrocephalus developed during the second half of gestation. Autopsy (performed
in 1 of the cases) and postnatal follow-up (in 3) confirmed the MR findings. As in the early-onset hydrocephalus group, cases
were classified as mild (in 1 case with macrocrania and ventriculomegaly, preserved mantle thickness and patent pericerebral
spaces), moderate (5 cases, macrocrania and ventriculomegaly, thinned cerebral mantle and partly effaced pericerebral
spaces), or severe (6 cases, macrocrania and ventriculomegaly, laminated mantle, effaced pericerebral spaces) (Fig. 8-45).
The only intrinsic abnormality identified was isolated AS seen in 2 cases, including one with ependymal nodules. Extrinsic
causes dominated: 5/12 cases showed ventricular hemorrhages, 4 subacute and 1 chronic, while 4/12 showed aqueductal
compression by a leptomeningeal cyst and 1/12 showed compression by vermian mass. A similar analysis of 17 postnatally
diagnosed cases of congenital hydrocephalus (diagnosed in the neonatal period) also showed extrinsic causes to be more
common than intrinsic ones. Of the 11 extrinsic cases, 7 had midline cysts, 2 had hemorrhages, and 2 had masses, while the 6
intrinsic cases included 5 with AS and 1 with rhombencephalosynapsis; the latter were morphologically similar to early fetal
cases and probably undiagnosed in utero.
Myelomeningocele, Chiari II complex, and hydrocephalus in the fetus
Beyond the MMC, which should be considered the primary lesion, Chiari II patients present postnatally diverse hindbrain
(cerebellar upward and downward herniation), midbrain (posterior–inferior beaking), forebrain (large massa intermedia,
callosal dysgenesis, gray matter heterotopia) as well as dural and cranial abnormalities (see Chapter 5 and Miller et al. (170)).
MR imaging at midgestation demonstrates the lumbosacral defect, a small posterior fossa (“banana” sign) with herniated
cerebellum, mild to moderate ventriculomegaly, typically no visible pericerebral space, and a small calvarium (“lemon” sign)
(Fig. 8-46). As the Chiari II features result from leakage of intraventricular CSF through the open MMC and consequent low
ICP, the small ventricles and, conceivably, preserved pericerebral spaces can be expected. The apparent paradox can be
explained by the differences in rate of maturation of the brain and bone. Low CSF pressure prevents the normal expansion of
the cranial cavity, and both the posterior fossa and the calvarium remain very small. The continuing growth of the cerebellum
results in its upward and downward herniation out of the posterior fossa and the obstruction of the fourth ventricle and the
filling of the pericerebral spaces. The posterior fossa obstruction, however, results in supratentorial ventriculomegaly, still in
combination with the small calvarium. As the posterior fossa synchondroses may close prematurely because of the low ICP,
only an early surgical repair of the MMC (about midgestation) permits both posterior fossa re-expansion and the
disappearance (or at least a partial regression) of the Chiari II deformity with consequent amelioration of the secondary
hydrocephalus.
Figure 8-46 Fetal myelomeningocele–Chiari II malformation in a 25-week fetus. A. Sagittal craniospinal cut. Note the extensive dorsal bony
defect in the lumbar area (arrows); the neural “placode” is well seen lining the defect anteriorly, with only a mild degree of bulging; the posterior
fossa is small, narrow, and funnel shaped with a large foramen magnum; the cerebellum is deformed, is stretched inferiorly, and has high
signal intensity suggestive of edema. B. Coronal head cut. Significant ventriculomegaly with effacement of the pericerebral spaces but
associated with a small head circumference.
Ependymal denudation is reported in Chiari II–associated fetal hydrocephalus. This is another factor that could, as much as
the compression from the upward herniation of the cerebellum, explain the AS, as well as the poor development of the mantle
and the high incidence of nodular heterotopia, by interfering with the development of the cell-producing subventricular zone
(241,243). Early onset and long duration of the hydrocephalus may explain the common loss of white matter in the posterior
hemispheric (including the callosal bundle) and the associated stenogyria. Other abnormalities, such as the prominent massa
intermedia or the common hypothalamic adhesion, have no obvious developmental explanation.
Clinical Data
Even after treatment, hydrocephalus remains a potentially severe disease. In a series of 128 hydrocephalic children (mostly
tumor or MMC patients) treated before 1970 (i.e., before the CT era) and followed over 40 years, the total mortality was 48%.
Excluding the tumor cases, the mortality was still 39%, death occurring mostly in the first decade after surgery. In 8%, the
mortality was related to shunt problems. Only 3/128 patients had become shunt independent (245). More recent series report a
globally better outcome due to advances in imaging, shunt technology, and surgical techniques; however, hydrocephalus
remains a serious condition. A study of 1973 patients treated from 1980 to 2007 reported a mortality rate of 18% in the first
two decades, and 6.3% afterward (246). Morbidity is also high, with 20% of the patients needing shunt revision(s) for
infection, occlusion, or hypo- or hyperdrainage. The overall prognosis was worse for children diagnosed at birth because the
causes are more severe, including MMC, ventricular/parenchymal hemorrhages, and meningitis (246). The most common
neurological sequelae were neurocognitive (48%) or motor (46%), but epilepsy (23%), behavioral disorders (15%), visual
(14%) or endocrine (14%) defects, and obesity (9%) were also common (246).
In addition to the ICP, the prognosis of hydrocephalus depends on its severity, its duration, and the age of its occurrence.
Severity and duration of hydrocephalus relate to associated parenchymal injuries: chronic ischemia, ependymal loss and
impact on the cellular lineages, axon degeneration, etc. The age of occurrence affects outcome in a complicated manner,
dependent on both the impact of the causal disease and the vulnerability and plasticity of the still-developing brain tissue.
Bacterial meningitis, for example, combines the effects of (a) diffuse toxic injury with parenchymal edema and high ICP, (b)
developing arterial and venous vasculitis and ischemia, (c) inflammatory ependymal destruction, (d) parenchymal abscess
formation, (e) astrogliosis and fibrosis, and (f) multiloculated obstruction of the CSF pathways, thereby allowing little
potential for anatomical and functional recovery. Similarly, posthemorrhagic hydrocephalus in a premature baby combines with
the arrested production of interneurons in the hemorrhagic germinal matrix (247), the destruction of axonal bundles in the area
of a PVHI, or a more diffuse PVL to produce far more impact on the prognosis than the hydrocephalus itself. In contrast,
hydrocephalus due to a midline arachnoid cyst or an isolated AS has a purely mechanical effect, and the tissue repair and
compensation processes after restoration of a patent CSF pathway may be sufficient for normal recovery. Even though the
prognosis of fetal hydrocephalus is often postulated to be dismal, there are some examples showing that, at least from a
morphologic point of view, this is not necessarily the case. Sensorimotor connectivity is not completed until the end of the
second month post term (248) and later for the association cortices; the signaling pathways for axon collaterals’ growth and
branching are, therefore, still present in the immature brain. The subplate (where the axonal collaterals multiply and connect to
the overlying cortex) (249) is the most distant part of the white matter from the ventricles and assumed to be the least exposed
to the deleterious effects of hydrocephalus. Even when the deep white matter is destroyed (PVL, PVHI), the subplate can be
mostly preserved (171) and can serve as a “collateral” bypass for the thalamocortical fibers, allowing for functional
compensation (250–253). In contrast, the myelination process may limit the restoration potential of the immature brain. While
the electrical activity of the axon is a potent inducer of myelination (254,255), it has been demonstrated in traumatic injuries of
the cord in rodent that myelin-associated inhibitors (MAIs) present on oligodendrocytic membranes limit axonal regeneration
in vivo (256). Their inhibitory influence seems to enhance normal maturation by limiting the potential for excessive axonal
development (and consequent aberrant connectivity), thereby stabilizing the cortical circuitry (256). However, it is possible
that in pathologic situations (e.g., hydrocephalus), the axonal repair that occurs in normal, unmyelinated immature infant’s
brain may be prevented by the MAIs in older children with more advanced myelination.
Ventriculoperitoneal Shunts
Shunt systems are composed of a ventriculostomy tube, a reservoir (optional), a valve, and a peritoneal, or rarely atrial, tube.
The ventriculostomy tube is inserted through brain parenchyma either into the frontal or into the occipital horn of the lateral
ventricle via a small calvarial burr hole. This is attached to a reservoir, which lies with the valve in the subcutaneous tissues
over the calvarial defect. The valve is set at a certain pressure, above which drainage occurs; it also sets the compliance level.
Some valves are pressure adjusted with an external magnetic device; although these magnetic devices are not a
contraindication to MR imaging, it is almost always necessary to reset the valve after the study. The presence of the shunt and
valve system restores the compliance of the system and allows both dampening of the systolic pressure wave and drainage of
the accumulated fluid. 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 ventriculostomy tube and the
reduction in ventricular size resulting from its placement. In principle, the tip of the ventriculostomy tube should lie in the parts
of the lateral ventricles devoid of choroid plexus; the frontal and occipital horns are favored. The tube is hypointense on most
MR sequences and has high attenuation on CT. Restoration of the pericerebral spaces of the convexity should be apparent soon
after the placement of a shunt; if the location of the shunt tip is appropriate and the pericerebral spaces are unchanged after 2 to
3 days, the patency of the shunt system should be questioned. If the cerebral mantle measures 2 cm or more in thickness after
shunting, patients usually attain average intellectual development (258). Lumboperitoneal shunts have been proposed to treat
chronic nonobstructive hydrocephalus, but are not favored generally in children because of a high rate of complications,
especially the development of a chronic cerebellar tonsillar herniation (acquired Chiari I deformity) and of scoliosis (257).
Shunting devices have limitations. Being foreign bodies, they may become infected. They may become obstructed; when the
ventricles get smaller, the choroid plexus, but also glia, ependymal cells, and other ventricular debris may block the holes or
“colonize” the catheter. Shunts may break because of the mobility of the head. With increasing head size and decreasing
ventricular size, the intracranial segment may become too short. With even more growth of the child, the extracranial segment
also may become too short, resulting in an inability of the peritoneum to absorb the CSF properly, which results in the
formation of peritoneal cysts. Both underdrainage and overdrainage may occur. For all those reasons, shunt revisions are
needed all too often, and the morbidity and mortality are not negligible (257).
Following the development of the endoscopic techniques in surgery, endoscopic third ventriculostomy (ETV) was
proposed as an alternative to shunts and has become a major and very popular technique to re-establish an outlet to the CSF
flow if obstructed CSF flow occurs anywhere caudal to the tuber cinereum. It restores compliance to the CSF pressure wave
and, in the case of poor ventricular absorption, diverts ventricular CSF toward the peripheral absorption sites. Importantly, it
cannot ever result in CSF overdrainage. ETV is performed by perforating the anterior part of the floor of the third ventricle.
To do that, from a burr hole located about the level of the coronal suture about 2.5 cm off the midline, the endoscope is
advanced across the lateral ventricle and the foramen of Monro toward the tuber cinereum. The ventricles and the foramen of
Monro must be sufficiently enlarged to allow the surgeon to advance the endoscope without injuring the ependymal veins or the
fornix. The fact that the tuber cinereum is stretched and expanded minimizes the risk of significant hypothalamic injury. The
position of the dorsum sellae, mammillary bodies, and basilar artery must be identified, and the space between them must be
large enough to be opened in the midline without injuring blood vessels. Anterior ventricular coaptation secondary to the
previous infection or the occasional presence of an interhypothalamic adhesion (more common in Chiari II malformations)
must be recognized, as it makes the approach to the tuber cinereum either more difficult or impossible. ETV is most useful in
obstructive hydrocephalus, but only when CSF flows freely in the cisterns; if loculations are present or an expanded fourth
ventricle effaces the cistern, normal CSF flow will not be restored. Therefore, preliminary imaging (mostly CISS/FIESTA)
must have demonstrated the patency of the suprasellar, interpeduncular, and prepontine cisterns and their free communication
with the rest of the pericerebral spaces. As discussed earlier, obstructive hydrocephalus in children most often results from
obstruction in the region of the sylvian aqueduct, fourth ventricular outflow foramina, or cisterna magna. If the basal cisterns
are loculated from posthemorrhagic or postmeningitic hydrocephalus, restoration of a compliance and diversion of the fluid
toward distant absorption may not be possible. ETV may also be used to perform a septostomy to restore communication
between the lateral ventricles after obstruction of a foramen of Monro, to bypass the aqueduct and fourth ventricle in cases of
communicating hydrocephalus. Studies have shown that ETV results in successful resolution of hydrocephalus in 71% of
children so treated (259); when it fails, a second attempt may be made, but in most patients, a ventriculocisternal shunt is then
preferred (259). Interestingly, even when the ETV is efficient, the ventricular size remains larger than in patients treated with
ventricular shunts (260). Advantages of ETV include a more physiologic CSF circulation, lower incidence of infections, and
better response of infection to antibiotic therapy. Third ventriculostomies, however, are less useful in young infants, in whom a
higher incidence of parenchymal and vascular injuries is reported and the communication through the floor of the ventricle is
more likely to close spontaneously (261).
Figure 8-47 Evaluation of the brain response to treatment of aqueductal stenosis. A. Coronal T2 imaging before the ETV demonstrates
rounded ventricles and complete effacement of the pericerebral spaces. B. After completion of the ETV, the ventricles are still prominent but
less rounded (note temporal horns), and the pericerebral spaces are well seen over the convexity (white arrows) and in the interhemispheric
and sylvian fissures.
Figure 8-48 Evaluation of the brain response to treatment. Third ventricular craniopharyngiomas: axial FLAIR images (A) before shunting, (B)
4 days after shunting, and (C) 6 months after shunting. Note the diminished ventricular size and reduced high signal intensity of periventricular
interstitial edema (arrows in A).
The postoperative assessment of hydrocephalus may disclose the presence of a segmentation of the CSF spaces that,
because of mechanical distortion of the brain, was not apparent before treatment. This is typically associated with septic
meningitis, but other inflammatory processes, as well as multicystic arachnoid malformations, may be involved. Posttreatment
imaging may disclose previously unobservable cisternal loculations or segmentation of the ventricles. A distinction is made
between a uniloculated hydrocephalus, in which only one segment of the fluid spaces is isolated (such as a “trapped” or
“isolated” fourth ventricle), and a multiloculated hydrocephalus in which several independent cavities have developed (173).
In the former, treatment may be relatively simple, either by shunting or by cannulation and stenting of the aqueduct, whereas the
surgical treatment of multiloculated hydrocephalus may be extremely complex: the multiple loculations may involve ventricular
and cisternal segments as well as parenchymal cavities. These are made more severe when a ventricular shunt decreases the
ICP, because it creates a pressure differential between different cavities. Treatment options include insertion of multiple
shunts, ETV, and visual or endoscopic fenestration of the cavities (173). For the neuroradiologist, using high-definition imaging
(mostly CISS/FIESTA) is important to demonstrate the precise anatomy of the various encysted segments with their mutual
anatomic relationships. It may also be necessary to provide data necessary for a neuronavigation approach.
Functional Assessment of ETV and Shunts
Endoscopic third ventriculostomy
Although sonography, CT, or MR can be used to assess shunted hydrocephalus, MR is the study of choice for the assessment
of patients treated with third ventriculostomy. In children who have undergone a successful ETV, the reduction in ventricular
size is usually slower and less dramatic than in those who have been treated using ventricular shunts (260). This difference in
rate of the ventricular size reduction may result from the fact that indwelling ventricular shunt catheters dampen the pulsations
of CSF emanating from the parenchyma better, or to a decreased rate of absorption capacity of the meninges in affected
children (260). The pressure wave of the basilar artery pulsating just below the ventriculostomy site may also contribute to this
paradox; in normal individuals, the upward convexity of the tuber cinereum suggests that the local cisternal pressure is higher
than the ventricular pressure. Imaging assessment of the third ventriculostomy is also aimed at demonstrating the opening in the
floor of the third ventricle. It may demonstrate a lack of opening of the third ventricular floor or an underlying suprasellar
cisternal loculation that was not apparent preoperatively. A detailed morphological analysis can be provided by using
CISS/FIESTA submillimetric imaging; it is not sensitive to flow but demonstrates the ventriculostomy well and can identify
occlusive septations in the surrounding cisterns that may have been hidden preoperatively (when the cisterns were compressed
by the hydrocephalus). Complementary information can be acquired with flow-sensitive sequences; thin sagittal 3 mm fast
spin-echo T2 sequences show hypointensity in the region of the ventriculostomy secondary to rapid pulsatile flow as
sensitively as cine phase-contrast studies (267) (Fig. 8-49). Phase-contrast MR flow studies can be used to quantify ratios of
CSF flow velocities in patients with third ventriculostomies (126), with the ratio of velocity of CSF in the prepontine space to
that in the anterior cervical spinal subarachnoid space being significantly higher in patients with patent third ventriculostomies
than in normal patients. Those patients with lower velocity ratios require revisions (126,268). Steady-state free precession
sequences show 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 (123) (Fig. 8-50). CSF flow-sensitive sequences (SPAMM, PSIF,
3D-SPACE, Time-SLIP) rely on detecting flow in the anterior third ventricle and the suprasellar, interpeduncular, and
prepontine cisterns, and it is likely that all of them work, as well. Therefore, as is often the case, choice of the precise
technique to be used should depend upon which techniques are available on the MR scanner being used and technique(s) with
which the imaging physician is most comfortable.
Shunt malfunction
Shunt malfunctions are manifested clinically by symptoms of increased ICP, persistent bulging of the anterior fontanel, an
excessive rate of head growth in the infant, or seizures. On imaging studies, one finds persistent effacement of pericerebral
spaces or an increasing ventricular size. Imaging consists of sonography in infants; in older children, SSFSE/HASTE MR has
largely replaced CT in most institutions, providing rapid assessment of ventricular size and catheter location without sedation
or ionizing radiation (233,269–271). It is important to remember that shunt failure does not always result in a ventricular
enlargement when the pericerebral spaces are already effaced. As the parenchyma itself cannot be compressed, ventricles
remain unchanged but ICP may increase dramatically: symptoms (headaches, vomiting, decreasing level of consciousness)
are always more important to consider than the ventricular size, and it is the effacement of the pericerebral spaces that is
the clue to the diagnosis. Also, some patients have considerable scarring and fibrosis in and around the ventricular walls,
causing decreased brain compliance such that no or minimal enlargement of the ventricular system may be apparent in the
presence of shunt malfunction (see subsequent section on the slit ventricle syndrome). The most common cause of malfunction
is occlusion of the ventricular catheter by the choroid plexus, ependyma, or glial tissue growing into the lumen of the catheter.
This diagnosis can only be inferred from the imaging studies, which will show enlarging lateral ventricles in spite of a well-
placed ventriculostomy tube and intact connections of the shunt system.
Another cause of shunt failure, disconnection of the shunt components, can occur at any point within the system, most
commonly where the various components are joined. Although the site of shunt malfunction (ventricular portion vs. peritoneal
portion) can often be determined clinically, plain film studies of shunt components (Fig. 8-51C) or, much less commonly,
positive contrast plain film radiography or radionuclide studies are sometimes necessary. If radionuclide studies are
performed, both dynamic and static studies should be obtained. The localizer (“scout”) image from a CT scan will sometimes
show a disconnection at the valve that is not appreciated on the axial images; therefore, the scout image should always be
analyzed. 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 radiopaque and, therefore, often appears as a discontinuity of
the shunt system on plain radiographs. It is essential to communicate with the treating neurosurgeon or perform a positive
contrast or radionuclide study in order to differentiate a disconnection from the presence of a radiolucent shunt component.
Figure 8-49 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 and hyperintensity in C) across the defect in the floor of the ventricle. D. Sagittal T2-weighted image demonstrates 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.
In principle, using special techniques described in Chapter 1, CSF flow can be analyzed by MR techniques to assess flow in
ventricular catheters and in connecting tubing (272); when done properly and calibrated carefully, flow rates within the shunt
can be calculated (273). However, CSF production and absorption and, therefore, CSF flow may vary by a factor of 10 over a
1-hour period, depending on physical activity, blood pressure, position, breathing, dreaming, etc., even though the average rate
remains within the established normal limits (63). The daily average of 0.35 mL/min is less than the volume displaced at each
arterial pulsation. In addition, an unknown amount of the CSF produced in the ventricle may be absorbed in the ventricle and/or
transdurally in shunted patients when an appropriate ICP is maintained. Therefore, the velocity of the CSF flowing through the
shunt is typically well below the minimum detectable rate. The clinical value of the shunt study is made even more uncertain by
the fact that the CSF flow varies with position (e.g., upright vs. supine), leading to the conclusion that the amount of CSF flow
being diverted from the ventricle depends on many physiological and physical parameters, which escape clinical
measurements. The bottom line is that lack of detection of CSF flow on an MR study is not diagnostic of shunt failure and,
other than for research, dynamic studies of shunt function are not as useful as isotopic studies in a given patient.
Figure 8-50 Failed endoscopic third ventriculocisternostomy. A. Coronal T2 image shows persistent evidence of hydrocephalus, 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.
Complications of Shunts
Shunt infections
The risk of infection associated with ventricular shunting has decreased steadily over the years, with current estimations
between 1% (274) and 5% to 10% (257), higher in infants (275). Most shunt infections develop shortly after insertion, but as
many as 10% may develop months to years later, usually as a result of systemic infection, peritonitis, trauma, or surgery (246).
The main clinical manifestation is fever, which is usually intermittent and low grade; redness and swelling may be apparent
along the subcutaneous shunt track, and peritonitis may develop. Anemia, dehydration, hepatosplenomegaly, and stiff neck can
also be presenting signs. The only aspects of shunt infection seen on brain imaging studies are the inflammation around the
shunt, sometimes with developing abscesses, and evidence of ventriculitis, characterized on contrast-enhanced imaging studies
by enlarged lateral ventricles with an irregular, enhancing ventricular wall (Fig. 8-53). Occasionally, multiple fluid loculations
develop and distort the brain, resulting in a confusing image; fortunately, these are increasingly uncommon. In the vast majority
of these cases, the fluid loculations result from ischemic or toxic parenchymal damage and result in white matter cavitation.
The treatment of hydrocephalus then becomes much more difficult, as infection contraindicates the placement of any permanent
device until it is fully eradicated, and any ventricular loculation or parenchymal cavitation transform a simple hydrocephalus
into a complex one. As mentioned above for the multiloculated hydrocephalus, each loculation must be drained separately. The
use of the fiberoptic ventriculoscopy to fenestrate the loculations has aided the treatment of these cases. In order to guide the
ventriculoscopy, it is essential to image the affected patients in three orthogonal planes; ideally, a three-dimensional image is
acquired and multiple contiguous images can be viewed in three orthogonal planes at a workstation for neuronavigation.
Figure 8-51 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.
Subdural collections
Clinically significant subdural collections are now uncommon after shunting, occurring in about 5% of patients (adults and
children) (276). They develop in the weeks or months following the treatment of the hydrocephalus. It is hard to tell if they
develop initially as subdural blood collections (Fig. 8-54) or as simple hygromas, which may subsequently become
hemorrhagic (Fig. 8-55). Although often considered as being related to overdrainage, the reason why ventricular collapse
would result in a subdural collection, rather than a simple expansion of the subarachnoid spaces, is difficult to understand. The
collection might be initiated by the burr hole and the placement of the drain, but that would not explain why they are less
common after an ETV, which is a longer procedure that crosses more tissue layers, than after a shunt placement. Potentially, the
arachnoid septations have not enough time to adapt and, therefore, “pull” the inner dural cellular layers inward, inducing the
inner dural capillaries to bleed. In the case of a hygroma, where ISF accumulates instead of blood, neoangiogenesis could
occur in the inner membrane, as in the evolution of posttraumatic hygromas (277), and secondarily bleed (Fig. 8-55). Whatever
their mechanism, these collections tend to attenuate and subsequently spontaneously disappear. Rarely, they may become
chronic; they have been suspected of being the origin of the occasionally observed fibrous meningeal thickening.
Figure 8-52 Ventricular CSF egress along the track of the shunt. A. Edema surrounding the shunt. B. Cystic cavitation dissecting the white
matter along the shunt. C. CSF flowing along the shunt and across the burr hole into the scalp. Note the presence of a CSF flow void (black
arrow) from the ventricle to the scalp.
When present, the subdural collections have an appearance similar to traumatic subdural hematomas (see Chapter 4) (Figs.
8-54 and 8-55); however, surgical decompression of postshunt subdural hematomas is very uncommonly needed, as the
ventricular decompression already results in a considerable buffer to increases in ICP. 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 likely caused by drilling of the burr hole and are almost never of clinical significance.
Large subdural hemorrhages, which can result in a secondary increased ICP, are usually seen in children over 3 years of age
after drainage of very enlarged ventricles. The use of high-pressure valves in the shunting of these patients has reduced their
incidence. Hygromas or hemorrhagic hygromas may develop secondarily within weeks and are usually not concerning, as they
evolve and disappear over months (Fig. 8-55).
Using contrast-enhanced MR or CT, chronic subdural hematomas can be distinguished from postshunt meningeal fibrosis
(meningeal callus (278)), in which a thick collagenous scar develops in the deep dural layers, presumably as a reaction to
preexisting chronic subdural hematoma (278). Whereas the liquid portions of chronic subdural hematomas will not enhance
after administration of contrast, meningeal fibrosis enhances dramatically, presumably as a result of vascular granulation tissue
intermixed with the collagen bundles in the subdural space.
Figure 8-53 Shunt infection. A. Axial CT, day 0, in a febrile child not feeling well with headaches shows an essentially unremarkable study with
mild ventriculomegaly and patent pericerebral spaces. B. Axial CT on day 2 shows mild hyperattenuation in the region of the shunt track in the
right posterior temporal lobe (white arrow). C. Axial CT postcontrast on day 4 shows rim enhancement (arrows) strongly suggestive of abscess
formation along the track of the shunt and along the walls of the atrium (ventriculitis).
Slit ventricle syndrome
Shunted hydrocephalic patients may become symptomatic from shunt failure even if the ventricles are small on ultrasound, CT,
or MR. Patients who exhibit this phenomenon have been labeled as having the “slit ventricle syndrome” (279,280). Some
debate exists as to what constellation of clinical and/or pathological findings define this syndrome. It has become clear that
there are multiple different entities lumped together under this name; therefore, affected patients may require several different
treatments. Di Rocco has divided slit ventricle syndrome into three groups: (a) patients with inability of the ventricles to
expand due to stiffness at the subependymal level (normal ICP), (b) patients with chronic low pressure from overdrainage or
siphoning of CSF through a shunt catheter or chronic CSF leak (low ICP), and (c) patients with craniocerebral disproportion
secondary to early suture fusion, the acquired craniosynostosis preventing the ventricles to expand if the shunt doesn’t work
(high ICP) (281). Rekate (280) has a different classification of the various disorders composing the slit ventricle syndrome. He
divides them into (a) extremely low-pressure headaches, probably from siphoning of CSF from the brain by the shunt, (b)
intermittent obstruction of the proximal shunt catheter, (c) normal volume hydrocephalus (in which the buffering capacity of the
CSF is diminished, see following paragraph), (d) intracranial hypertension associated with working shunts (probably linked to
venous hypertension), and (e) headaches in shunted children unrelated to ICP 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 #3, which may show calvarial thickening, imaging cannot differentiate these
categories. It was suggested that patients with symptoms of shunt malfunction in the absence of ventricular enlargement require
an emergency shunt function study, followed by revision of the ventricular catheter and valve (282).
Figure 8-54 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 collections of different signal
intensity, associated with ventricular compression.
Figure 8-55 Development and evolution of subdural collections after ventriculoperitoneal shunt placement in an 8-month-old infant with Chiari
II–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 collections of intermediate attenuation, higher on the right than on the left. C. Three months postsurgery, the CT shows that
the ventricles have enlarged, but both collections are much smaller. Their attenuation remains increased. D. Four months postsurgery, 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 postsurgery, the collections have completely resolved. Ventricles are slightly larger, commensurate with the amount of subdural
fluid resorbed.
The syndrome most commonly referred to by the name “slit ventricle syndrome” is the result of a combination of (a)
decreased intracranial volume, (b) resultant diminished CSF buffering capacity (diminished ability to compensate for the
normal variations in ICP), (c) diminished brain compliance, and (d) possibly intermittent or partial shunt obstruction.
Intracranial volume decreases because shunting causes an immediate reduction in CSF pressure and ventricular and, hence,
brain size. Thus, the CSF pressure and 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 ICP. Thus, unless the shunt is functioning perfectly, patients have
recurrent episodes of increased ICP, but because of the small size of the CSF spaces and the compression of the brain within
the small calvarium, the lateral ventricles do not enlarge.
Affected patients typically present with recurrent, transient symptoms of shunt failure. Imaging studies, however, will show
small ventricular size (Fig. 8-56). Shunt function studies show the shunt system to be patent, although flow may be low.
Treatment is shunt revision or replacement with higher valve opening pressure. If this fails, bilateral temporal craniectomies
that expand the volume of intracranial CSF can be done. Theoretically, the expanded intracranial space is better able to
compensate for the transient changes in ICP 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 progressive calvarial
thickening. Such thickening may or may not be associated with premature synostosis of the cranial sutures; either way, the
result is a diminished reservoir of CSF to buffer the normal variations in ICP.
Other than that, it is important for the radiologist to know that the presence of very small ventricles after placement of a
ventriculoperitoneal shunt is not diagnostic of, or even suggestive of, the “slit ventricle syndrome.” This syndrome is a
clinical, not a morphologic, syndrome. Small ventricles are not, in the majority of cases, a problem; they are the desired result
of many surgeons after treatment of hydrocephalus, and even when extremely small, their only implication in the vast majority
of patients is that the shunt is functioning.
Intracranial hypotension and craniocerebral disproportion
In addition to the early development of subdural collections and the isolated delayed “slit ventricle,” excessive depletion of
CSF may lead to the progressive development of the imaging constellation characteristic of intracranial hypotension, which is
identical to that 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 not much different from those of intracranial
hypertension, but its therapeutic goals diametrically opposed. The main symptom is a postural headache exacerbated by
standing and relieved by reclining. Other nonspecific neurological manifestations may be observed, including coma. When the
condition is chronic, head MR imaging is diagnostic, showing a characteristic constellation of otherwise nonspecific
abnormalities (283): diffuse dural enhancement and thickening (100%) (Fig. 8-57D–F) and the venous distension sign (100%)
due to the venous engorgement related to the low ICP (283) (Fig. 8-57D and F). Dural thickening may be seen without contrast
administration on FLAIR images; venous distension may be recognized on T1 imaging without contrast, as well, from the
suggestive convexity of the sinus walls (283); it is the first sign to resolve after normalization of the ICP (283). Other features
may include subdural hygromas or hematomas, crowding of the cisterns, downward brain herniation (acquired Chiari I
deformity) (Fig. 8-57F), and increased height of the pituitary gland with convex upper border (283) (Fig. 8-57F).
Figure 8-56 Slit ventricles. A. Initial CT scan demonstrating significant hydrocephalus. B. First postsurgery 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.
Downward brain herniation (acquired Chiari I deformity) is a result of a combination of a major reduction of the skull
capacity due to thickening of the calvarium (from CSF diversion), a possibly induced premature closure of the sutures, and
expansion of the facial sinuses (284). If the child is still young and the brain continues to grow, the developing craniocerebral
disproportion is associated with progressive filling of the extracranial spaces and progressive tonsillar descent, which, itself,
may be associated with a low medullary, high cervical cord compression. This may be further complicated secondarily by the
development of intracranial hypertension that can only be relieved by a decompressive supratentorial craniotomy (284). The
imaging picture is one of a small posterior fossa with tonsillar herniation through the foramen magnum, small ventricles,
markedly reduced pericerebral CSF spaces and, possibly, prominent thickening of the calvarium (284). Clinical features
suggest intracranial hypertension with symptoms pointing to the lower brainstem (284). This appearance differs from another
variety of acquired Chiari I deformity that has been described as a fairly common complication in the context of
lumboperitoneal shunting (285) (Fig. 8-58), generally assumed to be caused by the CSF pressure imbalance between the
cranium and the spine (this explanation has been challenged (286)).
Figure 8-57 Postshunt 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. 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 postcontrast 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.
Figure 8-58 Iatrogenic Chiari I secondary to placement of lumboperitoneal shunt. Midline sagittal T2-weighted image shows elongated
cerebellar tonsils herniating through the foramen magnum.
Other complications
Other complications resulting from ventriculoperitoneal shunting are much less common. Complications within the abdomen
typically result from the shunt becoming too short while the child grows and its peritoneal end remaining in the same area
instead of being displaced by the bowel movements: these include ascites, pseudocyst formation, perforation of a viscus or of
the abdominal wall, intestinal obstruction, and catheter degradation. Very rarely, patients may develop a granulomatous
reaction adjacent to the shunt tube, which appear on imaging as irregular, contrast-enhancing masses along the course of the
shunt tube. Calcification may be noted within the mass.
Conclusion
Hydrocephalus is a mechanical complication of many different diseases that may, itself, result from different pathophysiologic
processes. It is common in children, particularly during the first months of life. It remains a severe, potentially lethal disease,
with a high level of morbidity, even after it has been surgically treated. Always associated with a loss of compliance of the
brain and theca to the force of arterial pulsations, it becomes more severe when the CSF absorption is compromised, be it by
an inflammatory process or increased ICP. Although the diagnosis of hydrocephalus is easy to make when large and tense
ventricles are associated with an effacement of the pericerebral spaces, imaging should, in addition, provide evidence of an
obstruction (nonobstructive hydrocephalus being a diagnosis by exclusion), any parenchymal changes due to the causative
disease, and any complications of the hydrocephalus. It is important to remember that the brain and brain diseases are
different at different ages; hydrocephalus is a different disease in the fetus, the premature, the infant, the young child and the
adolescent. Treatment is based on the removal of the obstruction (tumor, arachnoid cyst) when possible and, if not on the
diversion of the CSF intracranially (ETV) or extracranially (VPS) to restore system compliance to the CSF dynamics and
restore appropriate CSF absorption. Postsurgical imaging will last for years, ascertaining the efficacy of the treatment and
evaluating any complications and their impact.
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Congenital Anomalies of the Spine
Erin Simon Schwartz and A. James Barkovich
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 Abnormal Disjunction
Disorders Resulting from Premature Disjunction: Spinal Lipomas
Syringohydromyelia
Definition
Clinical Presentation and Course
Classification and Causes
Theories of Pathogenesis
Imaging
Recent work has shown marked complexity of the process of neural tube closure, involving cellular events such as
convergent extension (a fundamental and conserved collective cell movement that forms elongated tissues during embryonic
development (14)), apical constriction (constriction of the apical surfaces of the cells in prospective anterior portion of the
dorsal visceral ectoderm (8)), and interkinetic nuclear migration (15), as well as precise molecular control via the
noncanonical Wnt/planar cell polarity pathway, Shh/BMP signaling, and the transcription factors Grhl2/3, Pax3, Cdx2, and
Zic2 (15–17). In mammals, this process is regulated by more than 300 genes (18); biomechanical inputs into neural tube
morphogenesis have also been identified. Nutritional factors are also important; several rodent studies show that folic acid
reduces neural tube closure defects (NTDs) and others have shown that inositol reduces NTDs in some strains of mice in
which folate does not work (19). No definitive results have been published at the time this chapter was being written (19).
Here, we review these cellular, molecular, and biomechanical mechanisms involved in neural tube closure, based on studies of
various vertebrate species, focusing on the most recent advances in the field.
Figure 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, 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.
Figure 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 distal-most conus medullaris, the filum terminale, and the terminal
ventricle (D).
Neurulation Anomalies
The process of separation of the neural tube from the cutaneous ectoderm during closure of the neural tube is known as
disjunction. After disjunction, the cutaneous ectoderm fuses in the midline, dorsal to the closed neural tube. At the same time,
perineural mesenchyme 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 (36). The
mesenchyme normally remains isolated from the newly formed central canal of the spinal cord because the neural tube closes
immediately prior to, or simultaneously with, disjunction. Recently, a number of papers have found suggestions that gene
dysregulation associated with both neuronal development and axonal growth and guidance (37) and loss of protein function
(38), inflammatory factors (37), and epigenetic factors such as histone 3 levels and protein methylation (39,40) are important
factors in the growth and closure of the spinal cord. As these functions are investigated and better understood, it is likely that
our knowledge of these factors will change our approach to the treatment of neural tube defects.
Whatever the genetics and posttranscriptional modifications involved in neural tube development, defective disjunction can
explain a number of diverse pathologic lesions. For example, focal unilateral premature disjunction of the neural ectoderm
from the cutaneous ectoderm (prior to closure of the neural tube) allows the perineural mesenchyme to gain access to the neural
groove and come in contact with the primitive 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 (41,42). Therefore, focal premature disjunction of neural ectoderm from
the superficial ectoderm could explain the development of spinal lipomas and lipomyelomeningoceles (43) (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 disjunction. 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 epithelial-lined tract of the typical dermal sinus (44). The tract should prohibit
mesenchyme from migrating between the neural ectoderm and cutaneous ectoderm at that site, forming a focal spina bifida as is
commonly seen in children with dermal sinus tracts. Moreover, the adhesion 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 myelomeningocele) can be explained a large
area of nondisjunction (Figs. 9-2 and 9-4). These concepts will be discussed in more detail in later sections of this chapter.
Figure 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.
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 (59).
Spina bifida refers to incomplete closure of the bony elements of the spine (lamina and spinous processes) posteriorly (60).
Open spinal dysraphism (OSD) includes the myelocele, a midline plaque of neural tissue that lies exposed at and is flush
with the skin surface, and the myelomeningocele, 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. 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 (35) (Table 9-1). Included in the category of closed spinal dysraphism with a subcutaneous mass
are lipomas with dorsal defect of the bony spinal 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 (split-cord malformation, dorsal dermal sinus, caudal regression syndrome, segmental spinal
dysgenesis, neurenteric cyst, and dorsal enteric fistula).
(Hemi)myelomeningocele
(Hemi)myelocele (also known as myeloschisis)
Adapted from Tortori-Donati P, Rossi A, Cama A. Spinal dysraphism: a review of neuroradiological features and embryological correlations and proposal
for a new classification. Neuroradiology 2000;42:471–491.
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, maternal 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 10-fold increase in risk for siblings of affected children
compared to the general population (83,84). Strong evidence 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 (85). 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 (86).
Offspring of women whose diet is supplemented with folate have a significantly reduced incidence of neural tube defects
(87–90). This has led to investigations of genes involved in folate metabolism as being potentially related to development of
OSD. 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 (12). Offspring of obese women (defined as
weighing more than 70 kg) have an increased incidence of neural tube defects, possibly because women with high body mass
indices have low folate levels compared with nonobese women, even when controlling for folate intake (91).
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 cutaneous ectoderm at the skin surface (nondisjunction). The
region of open spinal cord, located at the skin surface and open to the air in the posterior 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 tissue. Thus, the pedicles and lamina (which
are formed from this mesenchyme) are everted, facing posterolaterally instead of posteromedially (Fig. 9-4). As a result of the
external rotation of the lamina and pedicles, 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 (59).
The vertebral bodies can be nearly normal or can have anomalies of segmentation ranging from a single hemivertebrae to a
jumbled mass of malsegmented vertebral components. Segmentation anomalies result in a short radius kyphoscoliosis in
approximately one-third of patients with myelomeningoceles (59). Another 65% of affected patients develop a (less severe)
kyphoscoliosis as a result of a neuromuscular imbalance (92).
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 for OSD are most commonly performed in the fetus; the defect is often detected in mid or late second
trimester. The OSD itself is fairly easily seen by the absence of the posterior elements of the spinal column at the affected
level, by the posterior fossa contents extending caudally through the foramen magnum and, in many cases, by ventriculomegaly.
In general, when the OSD is uncovered and opens to the amniotic fluid, hindbrain herniation is more severe because the
rostrocaudal pressure gradient is increased (Fig. 9-5E–G). Early (prenatal) repair is very important in these cases to minimize
these consequences.
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 typically 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. Neuroradiologic examination of the spine is indicated if patients deteriorate neurologically
in spite of adequate treatment of hydrocephalus, if they have an unusual neurological examination, such as an asymmetric lower
extremity neurological deficit, which should raise suspicion that the patient has a split-cord malformation and hemiOSD.
HemiOSD
Cameron (93), Emery and Lendon (94), and Pang (95) showed that between 31% and 46% of patients with OSD have
associated split-cord malformation. The spinal cord may be split above (31%), below, (25%) or at the same level (22%) as
the OSD (94). In addition to the patients with frank split-cord malformation, 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 (94).
Figure 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 (asterisk)
mark a wet cloth covering the placode. C. Axial T1-weighted image shows the spinal cord (arrowheads) 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).
The hemiOSD, a special form of OSD with split-cord malformation, is observed in less than 10% of patients with OSD
(94,96). In the hemiOSD, one of the two hemicords exhibits a small OSD, which tends to lie on one side of the midline,
whereas the other hemicord is either normal, tethered 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 neurological function on the side of the hemiOSD but normal or nearly normal function
on the normal side (96). 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, and any other anomalies that may alter the surgical approach.
Split-cord malformation (diastematomyelia) is discussed more fully later in this chapter.
Postoperative complications
After repair of an OSD, patients usually have a stable neurological deficit. Deterioration in neurologic function, therefore,
suggests the presence of a complication. There are five major causes of postoperative neurological deterioration in this group
of patients: (a) the spinal cord and placode may be tethered by scar or by a second, previously unrecognized malformation; (b)
the dura may be pulled too tightly when approximated over the placode, forming a constricting dural ring; (c) the spinal cord
may be compressed by a an inclusion cyst (the all inclusive term for a dermoid or epidermoid tumor (97)) or an arachnoid
cyst; (d) ischemia may occur because of vascular compromise; and (e) there may be syringohydromyelia (98,99).
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 diagnosis of retethering may be suggested or
verified by demonstrating diminished motion of the cervical spinal cord by phase-contrast MR imaging (100,101). 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 (101). In patients with spinal cord tethering, this motion is damped and
the cord velocity is reduced (100,101). 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 diagnosis have still not been established in
large-scale trials. Therefore, this technique is not widely used at the time that this edition is being written.
Figure 9-7 Hemimyelocele. A. Axial T2-weighted image shows the lower thoracic level split-cord malformation and osseous spur (white
arrow) dividing the two canals containing asymmetrical hemicords (black arrows). B. Axial T2-weighted image at a slightly lower level reveals
postsurgical changes of a repaired myelomeningocele (now appearing as a flattened placode, white arrow) involving the right-sided hemicord in
the thoracolumbar region. The repaired hemicord has retethered at the surgical site (white arrow). The central canal of the left hemicord is
dilated (black arrow). C. Coronal T2-weighted imaging through the level of the myelomeningocele repair in this markedly scoliotic patient shows
the hypointense osseous spur (white arrow) separating the smaller, slightly hyperintense right hemicord (black arrow), which terminates
tethered to the dura surrounded by epidural fat. The larger left hemicord (black arrowheads) continues more caudally.
Associated malformations are common. Split-cord malformation (Figs. 9-7 and 9-8) or dermal sinuses are seen in up to
46% of patients with OSD. Hydrocephalus 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.
Spinal inclusion cysts (dermoids and epidermoids) can appear as developmental tumors or as tumors that result from
lumbar puncture or OSD repair (98,102–104). They may be more common following in utero OSD repair (79); however, this
cannot be confirmed until large numbers of patients who have undergone fetal myelomeningocele repair have had long-term
follow-up. On imaging studies, inclusion cysts 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 (105–108). It is not usually possible to distinguish
between dermoids and epidermoids by CT; on MR, some dermoids will show a markedly shortened T1 relaxation time. Both
forms of inclusion cysts may be difficult to identify by MR 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
(106). The mass can be confirmed by imaging using a FLAIR sequence, on which CSF is hypointense and the inclusion cyst is
hyperintense, or by diffusion-weighted imaging, on which the inclusion cyst will have high signal intensity in contrast to the
hypointense CSF.
Figure 9-8 Myelomeningocele with split-cord malformation in a 28-week fetus. A. Sagittal RARE imaging shows the lumbosacral posterior
osseous defect and dorsal herniation of the placode (black arrow) into and across the myelomeningocele sac. Note also the Chiari II
malformation of the brain, including hydrocephalus, reduced subarachnoid spaces, and hindbrain herniation. The lower extremity is gracile with
fixed hip hyperflexion, knee extension, and clubfoot deformity (white arrow). B and C. Axial and coronal RARE images demonstrate the dual
spinal cords (white arrows in B and C) within the dysraphic lumbar spinal canal, just proximal to the level at which they traverse the posterior
osseous defect to enter the myelomeningocele sac (black arrows in B).
Figure 9-9 Epidermoid tumor in a patient who underwent fetal myelomeningocele repair. A–D. The epidermoid (arrows) can be difficult to
detect by routine sagittal and axial T1 and T2 MR sequences. E. Sagittal FLAIR with fat suppression shows the epidermoid clearly (arrow).
Diffusion imaging can also be valuable (see Chapter 7).
Arachnoid cysts can be congenital (true cysts) or acquired (arachnoid 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 MR 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 insult. Sonography, CT myelography, or MR 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 standard MR sequences (they may be more readily detected with 3D imaging techniques) 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) (94,109). The exact frequency
depends upon the efficacy of treatment of the patient’s hydrocephalus (109,110). The hydromyelia in repaired OSD is likely a
result of the passage 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 MR, 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 junction down to the placode.
Untreated hydromyelia can cause the rapid development of scoliosis (109,111,112). 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 hydromyelia 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. Magnetic resonance
is the imaging study of choice in these circumstances (111–113).
The Chiari II malformation
The Chiari II malformation is an anomaly of the cervical spinal cord, brain stem, and hindbrain that is observed in varying
degrees in all patients with myelomeningoceles. Because of the close association of Chiari II malformations with OSD, a brief
discussion is appropriate in this section, in spite of the fact that this malformation is discussed extensively in Chapter 5.
The Chiari II malformation can be best considered as an entity in which the posterior fossa is too small (114) due to
collapse of the ventricular system from leakage of CSF through the open neural tube. As a result of the small bony posterior
fossa and the rostral-to-caudal pressure gradient resulting from the CSF leakage, normal contents of the posterior fossa are
pulled caudally and, as a consequence, distorted as they are squeezed out through an enlarged foramen magnum. The brain stem
is pulled/stretched inferiorly and narrowed in the anteroposterior diameter, often lying at the level of the foramen magnum or in
the cervical spinal canal. The cervical spinal cord is displaced inferiorly and the upper cervical nerve roots have to ascend
toward their respective neural foramina. The medulla is also displaced inferiorly. In 70% of patients, it folds caudally at the
cervicomedullary junction, dorsal to the cervical spinal cord (which is tethered by the dentate ligaments and therefore limited
in its vertical descent), forming a characteristic cervicomedullary kink (Figs. 5-178 and 5-179). The cerebellar vermis often
herniates inferiorly, forming a tongue of tissue posterior to the medulla that usually extends down to the C2 or C4 level. Rarely,
it extends down into the upper thoracic segments of the canal. The cerebellum wraps around the brain stem (Fig. 5-179). The
fourth ventricle is vertical in orientation (Figs. 5-178 and 5-179), extending inferiorly between the medulla and cerebellar
vermis; occasionally, it extends down below the medulla, posterior to the cervical spinal cord, in a cyst-like fashion. The
quadrigeminal plate is stretched posteriorly and inferiorly (Figs. 5-178 and 5-179). The small posterior fossa and the
downward herniation of its contents result in a low-lying, abnormally vertical tentorium cerebelli (115–118). Many of these
changes improve or completely resolve after fetal repair of the OSD, as discussed in Chapter 5.
Figure 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 L5 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.
Late/Incomplete Disjunction: Dorsal Dermal Sinuses and Sinus-Like Tracts (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
late and 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 adherence 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 sacrococcygeal,
72 were lumbosacral, 12 thoracic, 2 cervical, and 30 occipital; the remaining 10 were mostly ventral to the skull and spinal
column (119). 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 paramedian) dimple or pinpoint ostium that is
frequently associated with a hyperpigmented patch, hairy nevus, or capillary angioma (120). The patients become symptomatic
either by infection or because of compression of neural structures by an associated inclusion cyst. Meningitis or abscesses in
the subcutaneous, epidural, subdural, subarachnoid, and/or subpial spaces may develop as a result of bacterial ascent through
the sinus tract (121–123); meningitis is a risk factor for poor outcome (124). Occasionally, the meningitis is chemical in nature,
resulting from the release of cholesterol crystals or other contents of inclusion cysts into the cerebrospinal fluid (124,125).
The related spinal dermal sinus-like stalk has been reported as a discrete, albeit rare, entity (44,126). These patients do
not have a tract with an epithelial-lined lumen communicating with a cutaneous orifice, but rather a solid stalk of connective
tissue, fat, and occasionally neural tissue, that runs from a skin dimple without an ostium (usually covered by cutis aplasia, a
translucent layer of thin, parchment-like skin (126)) to the intradural space or spinal cord. The dural sleeve associated with the
stalk was directed toward the skin surface, unlike the dural sleeve of the dermal sinus, which is directed toward the spinal
cord; this observation suggests an etiology distinct from that of the dermal sinus. The authors postulate that disjunction between
cutaneous and neural ectoderm occurred, but that intervening mesodermal cells may have formed a tight, persistent connection
between the two. Patients with the sinus-like stalks have a different clinical presentation, usually one of a tethered cord
(impaired reflexes, sensory deficit, sphincter signs); both infection and neurologic disability due to an associated (epi)dermoid
are rare (126,127).
Pathology
Pathologically, dermal sinuses are thin, epithelium-lined channels that course inward from the skin surface through the
subcutaneous tissues, extending into the spinal canal in 50% to 70% of cases. The sinus may reach the dura without passing
through it; in such cases, the dura and arachnoid are tented dorsally at the attachment of the sinus tract to the dura. This tenting
may be the only manifestation of the sinus tract on myelography. If they pass through the dura, the sinuses may empty into the
subarachnoid space or may traverse the subarachnoid space to terminate within the conus medullaris, filum terminale, a nerve
root, a fibrous nodule on the dorsal aspect of the cord, or an inclusion cyst (Fig. 9-11) (128–130). About half of dorsal dermal
sinuses end in inclusion cysts. Conversely, 20% to 30% of inclusion cysts are associated with dermal sinus tracts (129–133).
Dermal sinuses can be midline or paramedian in location. Those with midline orifices are usually associated with midline
dermoid tumors. Paramedian orifices are more commonly 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 varies from patient to patient. Therefore, the complete course
of each dermal sinus must be determined by narrow, contiguous, or volumetrically acquired sections above and below the level
of the external orifice.
The bony abnormalities associated with dermal sinuses are variable. Bone abnormalities may be absent if the dermal sinus
extends intraspinally through a ligamentous defect at the interspace between 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 (129,131).
Figure 9-11 Schematic of dorsal dermal sinus. A tuft of hair, nevus, or hemangioma frequently marks the ostium of the sinus. The dura is
often tented when the sinus penetrates the dura. The sinus may terminate in a CNS structure, the dura, or external to the dura. Inclusion cysts
develop along the course of the sinus in 50% of affected patients. (Reprinted with permission from Barkovich AJ, Edwards MSB, Cogen PH.
MR evaluation of spinal dermal sinus tracts in children. AJNR Am J Neuroradiol 1991;12:123–129.)
When an inclusion cyst is present, adjacent nerve roots are frequently bound down to the capsule of the cyst. The cord may
be displaced and compressed by extramedullary inclusion cysts or expanded by intramedullary lesions (106). 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
(106,123,134).
Imaging
Sonography, CT, and MR can all demonstrate the subcutaneous and extracanalicular extent of the dermal sinus and sinus-like
tracts (Figs. 9-12 to 9-14). MR best demonstrates intramedullary inclusion cysts (Figs. 9-13 and 9-14) and shows the lipomas
and split-cord malformations that are more common in patients with dermal sinus-like stalks than in dermal sinuses (127). T1-
weighted images with wide window settings best show the subcutaneous portion of the sinus tracts; narrow 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) or, better, steady-state (FIESTA, CISS) images in the sagittal and axial planes
best show the sinus tract as a hypointense linear or curvilinear structure on MR (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
(106), FLAIR images (135,136), and/or diffusion-weighted images (136,137) will help to identify intraspinal extramedullary
inclusion cysts, which may have signal intensity identical to CSF on standard T1- and T2-weighted images. The administration
of paramagnetic contrast (which results in enhancement of some sinus tracts (138)) 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 contrast best
demonstrates the intraspinal portion of the dermal sinus and small extramedullary inclusion cysts in older children. Thus, in
those rare cases in which the intraspinal anatomy is not clearly defined after high-quality MR, a CT myelogram should be
considered.
As mentioned, extramedullary inclusion cysts may be difficult to visualize with MR using standard T1- and T2-weighted
sequences. Steady-state sequences (CISS, FIESTA) are far superior in their detection (Fig. 9-16). Ruptured and infected
inclusion cysts are even more difficult to identify, as no distinct mass is seen. Instead, the subarachnoid space has a “smudgy,”
slightly heterogeneous appearance (Fig. 9-14) that cannot be differentiated from arachnoiditis by MR techniques. FLAIR and
diffusion-weighted images can be very helpful in this setting (135,136); they will guide the surgeon to remove as much tumor
as possible.
Figure 9-12 Dorsal dermal sinus with dermoid (inclusion cyst) adjacent to conus medullaris. A. Sagittal T1-weighted image shows the dermal
sinus (black arrowheads) coursing through subcutaneous 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 arrowheads) 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 L3, 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 a dermoid.
Figure 9-13 Lumbar dorsal dermal sinus with intramedullary dermoid (inclusion cyst). A and B. Sagittal T1-weighted and T2-weighted images
show an intramedullary mass (asterisk) that has similar 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)
coursing down the dorsal aspect of the subarachnoid space and then terminating (black arrow) at the mid L5 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 coursing (white arrowheads) below
the L5 spinous process and (black arrowheads) through the subcutaneous fat. The ostium is marked by the small white arrow.
For detection of associated intraspinal abscesses, pre- and postcontrast MR 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 contrast reveals
ring-enhancing masses (139). Diffusion-weighted images show reduced diffusion within the abscess. Every attempt should be
made to show the associated dermal sinus.
Figure 9-14 Dorsal dermal sinus with infected dermoid inclusion cyst 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 cannot be determined from this study whether the heterogeneous signal is
the result of clumping of nerve roots from infection or from the inclusion cyst. At surgery, this patient was found to have a large, infected
epidermoid at the L5-S1 levels and an epidural abscess at the L3-L4 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 L5 level. The contents of the thecal sac (white arrows) are of heterogeneous high signal intensity. This was found to be
an infected dermoid tumor at surgery. The black arrowhead points to the sinus tract coursing through subcutaneous fat.
Patients with cervical myelocystoceles and those with cervical myeloceles present as neonates with a dorsal midline cystic
mass, usually 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 malformations (142). Occasionally, infants have mild abnormalities of muscle strength or of
tone (67,140). These deficits become more noticeable during the first year of life, the patients becoming spastic or weak in the
arms or legs (143). By the end of the first decade, some sort of motor deficit is usually present, often requiring orthopedic
intervention (143). The head size is often enlarged (67).
Figure 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).
The diagnosis is made by identification of spinal cord tissue protruding dorsally through a bony spina bifida into the dorsal
subcutaneous soft tissues (Fig. 9-18). 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 the 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 (67,141). Care should be taken to examine the entire spinal axis, as other malformations, such as dermal
sinuses, split-cord malformations, and Chiari II malformations, may be present (67,144). The diagnosis can be made by MR or
by ultrasound. CT myelography is less useful, because of its invasive nature and radiation exposure and because it does not
detect the focally enlarged central canal.
Figure 9-16 Lumbosacral inclusion cyst following fetal myelomeningocele repair. A. Sagittal T2-weighted FLAIR imaging with fat suppression
demonstrates the heterogeneously hyperintense bilobed mass expanding the distal spinal cord (upper two white arrows) and filling the distal
thecal sac (lower two white arrows). Note the dorsal osseous defect and the overlying residual soft tissue changes from myelomeningocele and
in utero surgical repair. The spinal cord has become retethered by the mass. B. Sagittal thin section steady-state image better reveals the
dilated central canal of the lower thoracic spinal cord (arrow), the internal heterogeneity of the inclusion cyst, and the long segment of
attachment to the posterior wall of the thecal sac. C and D. Sagittal diffusion-weighted image (C) and apparent diffusion coefficient map (D)
show the varying, heterogeneous diffusivity within the proximal and distal portions of the lesion.
Figure 9-17 Schematic of myelocystocele. This is an occult, skin-covered, spinal dysraphism in which the spinal cord (which has a
syringohydromyelia) and the arachnoid are herniated through a posterior spina bifida. The cyst is in continuity with the central canal of the
spinal cord. Myelocystoceles 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.
Spinal lipomas can be divided into three principal groups: (1) intradural lipomas (3%–5%); (2) lipomas with dorsal
defect, encompassing lipomyeloceles and lipomyelomeningoceles (75%–85%); and (3) lipomas deriving from the caudal cell
mass (10%–15%). Group 2 can be divided into dorsal, caudal, and combined or “transitional”
lipomyeloceles/lipomyelomeningoceles (149,150). 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) fibrolipomas of the filum
terminale. Both are almost always associated with tethering of the spinal cord. Terminal lipomas and fibrolipomas of the filum
terminale are best classified as anomalies of the caudal cell mass. Terminal 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 section on anomalies of the caudal cell mass. In contrast to the anomalies 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 central 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.
Figure 9-18 Cervical myelocystoceles. A. Sagittal RARE image through the cervical spine in a 22-week fetus shows ventral compression of
the cervical spinal cord by the ependyma-lined cyst (asterisk), which extends posteriorly through a spina bifida into the subcutaneous tissues
to form a skin-covered dorsal mass (white arrow) covering the neck and occiput. The spinal cord separation due to the cystic dilation of the
central canal can be seen traversing the spinal canal (black arrow). B. Axial RARE image shows ventral displacement and compression of the
cervical spinal cord (white arrows) by the large myelocystocele (asterisk). C. Sagittal T2-weighted image through the cervical spine of a
different patient shows similar compression of the ventral spinal cord (black arrows) by the very large cyst (asterisk), which extends dorsally
through the bony spina bifida into the posterior subcutaneous soft tissues. The upper cervical spinal cord is expanded and shows T2
hyperintensity (white arrow), indicating interstitial edema and, likely, a presyrinx state. D. Axial thin section steady-state imaging better depicts
the distinction between the intramedullary cyst (asterisk) and the surrounding meningocele components. The malpositioned ventral and dorsal
nerve roots can be seen arising from the ventral aspect of the spinal cord bilaterally (white arrows).
An important concept in the imaging evaluation of spinal lipomas is that these lipomas are largely but not exclusively
composed of normal fat (148). More importantly, fat cells dramatically increase in size during infancy (151). In fact, the
proportion of body fat increases from 14% of body weight at birth to 25% at age 6 months (152). As a result, lipomas may be
missed or be considered inconsequential when imaging is performed in the fetal or neonatal period, only to be found much
larger at a subsequent imaging study (153). This potential for growth should be kept in mind when deciding on the optimal
time for imaging neonates with spinal anomalies. Another aspect of this concept is that a spinal lipoma can diminish in size if
the patient loses weight (154). Therefore, control of body weight may, in some instances, be a conservative method of
managing affected patients (154).
MR is the imaging modality of choice for the evaluation of patients with spinal lipomas. The short T1 relaxation time of fat
results in characteristic high signal intensity of the lipoma on T1-weighted sequences. MR allows the full extent of the lipoma,
and its relationship to the neural placode, spinal cord, and roots of the cauda equina, to be fully evaluated.
Intradural lipomas appear on imaging studies as focal, round to oval, masses that most often lie dorsal to the spinal cord
(Figs. 9-20 and 9-21) and may expand the spinal canal (Fig. 9-21). Lipomas have a very low attenuation on CT and, therefore,
can be detected on studies without intrathecal contrast (Fig. 9-20). They are easily identified on T1-weighted MR images by
their lobulated shape and high signal intensity (Fig. 9-21). Their fatty nature can be confirmed, if necessary, by use of fat
suppression pulses. MR best identifies compression of the spinal cord.
Figure 9-20 Intradural lipoma CT. A. Axial CT image shows a low-attenuation mass (arrows) filling much of the spinal canal and the interface
with the displaced and compressed spinal cord on the left side of the canal. B. Curved sagittal CT reformation of the lumbosacral spine
demonstrates the low-attenuation lipoma (black arrows) and multiple osseous anomalies of segmentation (often incorrectly called “fusion”) in
the vertebral bodies and posterior elements (white arrows).
Figure 9-21 Intradural lipoma MRI. Sagittal (A) and axial (B) T1-weighted images show the hyperintense lipoma (arrows) dorsal to the
compressed spinal cord. The spinal canal is expanded by the mass.
Associated malformations
Lipomas with dorsal defect are commonly associated with other anomalies; an active search for these anomalies should always
be performed when evaluating the imaging studies of affected patients. Sacral hypogenesis is seen in about 25% of patients
with lipomas affecting the conus medullaris (148). Anorectal malformations (including imperforate anus, anorectal stenosis,
and anal malposition), genital, and urinary tract anomalies are seen in 5% to 10% of affected patients. If anal or genital–urinary
anomalies are present, the incidence of sacral anomalies increases to more than 90% (148); these patients are best classified
as having anomalies of the caudal cell mass. Terminal split-cord malformation may accompany lumbosacral lipomas in up to
10% of affected patients (148). Less commonly, inclusion cysts, dermal sinuses, hamartomas, angiomas, or arachnoid cysts
may be present. Thus, it is crucial to look for other anomalies whenever lipomyelomeningoceles and lipomyeloceles are
identified.
Figure 9-24 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 arrow) 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.
Figure 9-25 Lipomyelomeningocele in a 34-week fetus. A and B. Sagittal and axial RARE images show the tethered placode (white arrow),
which is attached to a dorsal lipoma through a posterior osseous defect. The meningocele (black arrows) can be seen extending into the fetal
subcutaneous fat. C. Axial 2D FLASH image depicts the placode (white arrow) in immediate continuity with the immediately dorsal hyperintense
lipoma and the more lateral hyperintense subcutaneous fat.
Figure 9-26 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.
Figure 9-27 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. 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.
Figure 9-28 Terminal ventricle. A and B. Sagittal ultrasound and sagittal T2-weighted image show a focal prominence (arrows) of the caudal-
most 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.
Figure 9-29 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.
Figure 9-30 Fibrolipoma of the filum terminale in an infant; importance of axial images through the L5-S1 levels. A. Sagittal T1-weighted
image shows the conus terminating near the bottom of L2. No fat is seen in the filum. B. Axial T1-weighted image at the L3-L4 level shows
normal cauda equina without any abnormality of the filum terminale. C. Axial T1-weighted image at the L5 level shows the thick, fatty filum
(arrow) in the dorsal aspect of the thecal sac. D. Different patient. Axial T2-weighted image at the L5 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.
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 myelography (59). 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 L5-S1 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 precise level of the conus when the sagittal images are viewed (168). In a series of thirty-one 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. 9-32) (198). Increased awareness of the signs and symptoms of spinal cord tethering have prompted some
neurosurgeons to section the filum terminale more frequently, even in the setting of a normal MR (58,199); however, a small
prospective, randomized trial of filum terminale transection in children with urinary incontinence did not show a statistically
significant difference in outcome when compared with medical management (200).
Figure 9-31 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.
In a small number of studies, phase-contrast MR was reported to be useful in detecting diminished motion of the cervical
spinal cord in patients with spinal cord tethering (100,101). 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 (101). In patients with spinal cord tethering, this motion is damped and the cord velocity is reduced (100,101). After
release of the tethering, normal motion returns in about 1/3 of patients (101).
Figure 9-32 Examples of 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 L5-S1 level is
always greater than 1 mm in these patients. Note the dilated central canal (black arrowheads in B), present in 20% to 25% of patients with
tethered spinal cord. C. Axial T2-weighted image at the S1 level shows nerve roots as linear hypointense structures exiting ventrally, indicating
that this is the spinal cord, not a thick filum. D–F. Tethered spinal cord with a tail. Sagittal T2-weighted imaging (D) shows the markedly
elongated distal spinal cord, extending all the way to the abnormally low termination of the thecal sac at the S4 level (small white arrow). The
normal thecal sac should terminate at the S2 level. A portion of the 13-cm tail can be seen behind the lumbar spine soft tissues (large white
arrowhead). Axial T1-weighted images at the L4 (E) and S3 levels (F) show the low termination of the spinal cord but no apparent fat deposition.
The tail (arrows) can be seen posteriorly in both images.
Clinical signs at presentation range from isolated deformities of the feet or minor distal muscle weakness to complete
sensorimotor paralysis of both lower extremities (51,204). 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 present. 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 (51). The
clinical scenario 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 neurologic symptoms, have cord tethering superimposed upon agenesis of the lower sacral
nerve roots (51,207).
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 (50). The caudal-most two or three vertebral bodies are
often fused and dysplastic (Figs. 9-33 and 9-34). The bony canal immediately rostral to the last intact vertebra may be severely
narrowed as a result of bony excrescences originating 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 (204). The major neural anomaly is hypoplasia of the distal spinal cord, which is typically
more severe ventrally than dorsally, resulting in a characteristic blunted or “wedge” shape of the cord terminus (Figs. 9-33 and
9-35) (50). Such blunting is seen in essentially all children with partial or complete sacral agenesis and termination of the
spinal cord above the level of the first lumbar vertebra (51). 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 (130,208).
Figure 9-33 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.
Figure 9-34 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 show a small, dysplastic sacrum (black arrows), which is fused with the lower lumbar vertebrae.
Figure 9-35 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 column is normal except for the sacrum. S2 is dysplastic and the S3, S4, and S5 segments and the
coccyx are absent. B. Axial T1-weighted image shows substantial dilation of the central canal of the spinal cord.
The spinal cord may be tethered in sacral agenesis; Pang (51) found tethering of the spinal cord in all patients with
lumbosacral hypogenesis in whom the conus terminated below the L1 level. They also found a correlation with level of the
conus and severity of the sacral hypogenesis. Termination of the conus above L1 is highly correlated with sacral malformations
ending at S1 or above, whereas conus termination below L1 is highly correlated with sacral malformations ending at S2 or
below (51). 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 (209); at the very least, the release of the tethered cord is likely to prevent
neurological worsening (148). Tethering may be associated with a thick filum terminale (65%), terminal myelocystocele
(15%), terminal hydromyelia (10%), or terminal lipoma/lipomyelocele (10%) (51). 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. 9-34).
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. 9-33 and 9-34). Moreover, assessment of the level and shape
of the conus medullaris will determine whether tethering is present. MR 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 L1 level (Figs. 9-33 and 9-35) (46,50). 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. 9-34); typically the cord will terminate below the L1 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. 9-35), lipoma
(Fig. 9-34), or the presence of bony spinal stenosis (46,50).
Figure 9-36 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.
Imaging studies demonstrate direct continuity of the meningocele with the subarachnoid space and the presence of a cyst in
continuity with the central canal of the spinal cord (Fig. 9-37) (210,212,213). Because the cyst does not communicate with the
meningocele, myelography 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. 9-37) (210,212–215). The cyst may show delayed opacification with water-
soluble intrathecal contrast, similar to a hydromyelia. 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.
Sacrococcygeal Teratoma
Sacrococcygeal teratomas are rare congenital tumors that develop in the lower sacrum. They are thought to arise from
persistence or reactivation 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 (59). 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 (220–222). 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; more proximal spinal involvement is rare and suggests a more aggressive lesion.
Figure 9-37 Terminal myelocystoceles; fetuses and infants with sacral masses. A and B. Terminal myelocystocele in a 21-week fetus.
Sagittal transvaginal ultrasound image (A) shows an expanded, low-lying, syringohydromyelic spinal cord (white arrow) in continuity with a large
cystic mass (asterisk) and surrounded by the dilated subarachnoid space (black arrows). Sagittal RARE image (B) shows the low-lying spinal
cord separating around the terminal myelocystocele (asterisk) separating it from the surrounding dilated subarachnoid space (white arrows).
Note the absence of the Chiari II malformation in this closed spinal dysraphism. C. 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 termination (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 myelocystocele. D. 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.
If a sacral malformation is associated with a sacrococcygeal teratoma, it suggests the rare familial form of tumor, which has
an autosomal 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.
Figure 9-38 Anterior sacral meningocele. A and B. Lateral view and sagittal CT reformation from a lumbosacral myelogram show the
extension of the intrathecal contrast through an anterior sacral osseous defect and into the presacral space (arrows). C. Axial bone window
from a CT myelogram shows the dysplastic 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 anomalies to determine whether nerve roots of the cauda equina are
floating within the meningocele before the meningocele is ligated.
Figure 9-39 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.
Figure 9-40 Cystic sacrococcygeal teratoma. A. Sagittal T1-weighted image shows a cystic mass (type 3 teratoma, arrows) centered at the
coccyx. B. Postcontrast 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).
The sporadic and familial forms of sacrococcygeal teratomas are indistinguishable on imaging 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 components, and calcification, the tumors are variably heterogeneous. Adequate CT
evaluation necessitates opacification of the bowel, the ureters, and bladder by the use of contrast agents to evaluate the
relationship of the tumor to the pelvic viscera. Intraluminal 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, intermediate signal from soft tissue, and low signal from calcium on
T1-weighted images (Figs. 9-39 and 9-40). The tumors are usually lobulated and sharply demarcated. When mostly cystic (Fig.
9-40), intravenous contrast administration may be necessary to identify a solid component in the wall of the cyst. Images
should be carefully evaluated to exclude rare, but crucial to identify, spinal canal involvement.
Classification
The term “split notochord syndrome” refers to a spectrum of anomalies that are believed to result from splitting or deviation of
the notochord with a persistent connection between the ventrally located endoderm and the dorsally located ectoderm (225).
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 (225–227). 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 diverticulae, 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 (225,226). Dorsal enteric
(enterogenous) cysts (which are derived from the intermediate part of the tract) are enteric-lined cysts which may be
prevertebral, retrovertebral, or intraspinal (225,226). Dorsal enteric diverticulae are tubular or spherical diverticulae that
arise from the dorsal mesenteric border of the bowel. These diverticulae 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 diverticulae far upward from the small bowel through the mesentery and diaphragm into the mediastinum.
Occasionally, the diverticulae will extend to the anterior surface of the vertebra or into the spinal canal (225). If there is
involution of the portion of the diverticulum near the gut, a prevertebral dorsal enteric cyst is formed (226). Finally, in some
patients, the dorsal enteric fistula may close at multiple sites. In these patients, one may find combined, noncommunicating
elements of the split notochord syndrome; for example, intestinal diverticulae, mediastinal enteric cysts, and intraspinal
enterogenous cysts may be present.
Figure 9-42 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.
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 including hemivertebrae, abnormal
segmentation, partial fusions, and scoliosis 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 (230).
Some neurosurgeons believe that both CT and MR are required for proper preoperative imaging analysis of a neurenteric
cyst (237). CT shows vertebral anomalies in about 50% of affected patients; vertebral body clefts, butterfly vertebrae, and
anomalies of segmentation are most common (236). Three-dimensional reformations may be valuable for surgical planning.
The spinal canal may be focally expanded. MR, however, shows most of the vertebral anomalies and, more importantly, shows
the cysts and their relationship to the spinal cord (Figs. 9-43 to 9-46). MR typically shows a cyst lying ventral to and
compressing the adjacent spinal cord (Figs. 9-44 and 9-45) (230,231,235). However, the cyst may lie dorsal to the cord (Fig.
9-45) or partially or completely within the cord (Figs. 9-43 and 9-46); it is most important to define the cyst and its
relationship to the spinal cord. The cyst contents may be similar to CSF (Figs. 9-43 and 9-46) or may be proteinaceous,
shortening the T1 relaxation time and resulting in relatively (compared to CSF) high intensity on T1-weighted images (Figs. 9-
44 and 9-45) (237). If the cyst is creamy or has xanthogranulomatous changes, it may have a heterogeneous appearance on both
T1- and T2-weighted images (229,238). Occasionally, this heterogeneity may mimic a nodule and suggest the presence of a
neoplasm (239); in such cases, administering intravenous paramagnetic 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. However,
similar information can be obtained noninvasively with MR. Coronal images through the spinal column (Figs. 9-45 and 9-46)
identify abnormal vertebrae. The cyst may be difficult to detect if it is small and its contents are very similar to cerebrospinal
fluid; FLAIR and steady-state imaging may be helpful. However, the displacement and distortion of the spinal cord by the cyst
facilitates detection (Fig. 9-43). In addition to evaluating the spine, it is important to look for associated fistulae and
mediastinal or abdominal cysts.
Figure 9-43 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 anterior osseous defect (d) and the
hyperintense cyst (arrows in C) resulting in lateral deviation of the spinal cord.
Clinical Presentation
The signs and symptoms of SCM may appear at any time of life. Females are affected much more commonly than males
(95,246,247). Cutaneous 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 (248). Half of affected
patients manifest orthopedic problems of the feet, particularly clubfoot. A specific neuro-orthopedic syndrome (242),
consisting of weakness and muscle wasting in one leg, often associated with an ipsilateral clubfoot, is seen in about half of
patients with lumbar SCM (249). Scoliosis is common in older children and adults (250) and is a common reason for clinical
presentation in these age groups, along with low back pain, sciatica, and perianal dysesthesias (248,251). SCM is responsible
for approximately 5% of congenital scoliosis (247). Neurologic symptoms are nonspecific and may be indistinguishable from
other causes of cord tethering (59,95,224,246,247,251–253).
Figure 9-44 Neurenteric cyst associated with SCM. A and B. Sagittal T1-weighted images shows 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.)
Figure 9-45 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 hemivertebrae (arrows) at the level of the cyst.
Embryology
SCM most likely develops as a result of splitting of the notochord (224,245). If the cells forming the notochord, in the course
of their migration from the Hensen node, encounter an obstacle such as an adhesion 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
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.
Figure 9-46 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.
The spinal column is nearly always abnormal in patients with SCM (Figs. 9-48 and 9-50) (175,246). The lamina is often
thick and may be fused with the ipsilateral or contralateral lamina of adjacent vertebrae (Fig. 9-50); 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. The
intersegmental laminar fusion is almost always at the level of the SCM (241,246). Anomalies of the vertebral bodies (Fig. 9-
48) including hemivertebrae, butterfly vertebrae, block vertebrae, and decreased disc height are observed in a high proportion
of cases. Kyphoscoliosis (Figs. 9-49 and 9-51) resulting from the osseous anomalies is seen in more than half of patients.
Another anomaly of the spinal column that is associated with partial or complete SCM is the Klippel-Feil anomaly, a
condition defined as two or more consecutive unsegmented vertebrae at the cervical level (261,262). 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 most commonly involves C2-C3 or C5-C6; and group 3 in which patients have separate thoracic or lumbar levels of
nonsegmentation in addition to cervical involvement (49,261,263). 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 (261). 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 (49,261,263). In such patients, anomalies have been identified in the decussation of the corticospinal tracts (264) and
mirror movements may be detected on physical exam (261). A third cause is associated bony abnormalities of the
craniocervical junction (265). Other causes of neurologic dysfunction are associated CNS anomalies, which are reported to
include occipital encephaloceles, Chiari malformations, Dandy-Walker malformations, Duane syndrome, nasofrontal and
posterior fossa inclusion cysts, and syringohydromyelia. Associated visceral anomalies include Sprengel deformity (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 (49,261,263,265).
Figure 9-48 Split-cord malformation with bony spur, scoliosis, and vertebral anomalies. A. Coronal T1-weighted image shows thoracic
dextroscoliosis with multiple anomalies of vertebral segmentation (asterisk) 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. Sagittal 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.
Figure 9-49 Split-cord malformation 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).
Lateral Meningocele
Thoracic Lateral Meningocele
Thoracic lateral meningoceles are cerebrospinal fluid-filled protrusions of dura and arachnoid that extend laterally through an
enlarged neural foramen. They then course anteriorly through the adjacent intercostal 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 slight weakness.
Type 1 neurofibromatosis is present in approximately 85% of patients with lateral thoracic meningoceles (274,275). The
preferential thoracic location has been postulated to result from lesser development of the paraspinal musculature at this level
and the relatively high-pressure differential between the negative thoracic pressure and the pressure of the CSF in the thoracic
subarachnoid space (276). Less common predisposing conditions include Marfan, Ehlers-Danlos, and Lehman syndromes, the
latter being a rare disorder caused by mutations in terminal exon 33 of the NOTCH3 gene and characterized by joint
hypermobility, hypotonia, and distinctive facial features as well as skeletal, cardiac, and urogenetical anomalies (267).
Patients with lateral thoracic meningoceles may have a sharply angled scoliosis in the upper thoracic spine, convex toward
the meningocele, which is located near the apex of the curvature (275). 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
(277).
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 (59).
Figure 9-54 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.
Teratoma
Teratomas are neoplasms containing tissues belonging to all three germinal layers at sites where these tissues do not normally
occur. Excluding sacrococcygeal teratomas (discussed earlier in the chapter), these neoplasms constitute 0.15% of all
intraspinal tumors (59). Males and females are affected equally, usually presenting with pain and myelopathy. All ages are
affected.
Figure 9-55 Complex dorsal meningocele. A. Sagittal thin section steady-state image shows a lumbar dorsal meningocele (asterisk)
protruding through a large osseous defect. The conus medullaris is dysmorphic and terminates abnormally low, extending to the L3 level (black
arrow). A filum terminale cyst (long white arrow) is present, and the central canal (short white arrow) is dilated. B. Axial T2-weighted imaging
shows the meningocele extending dorsally through an unusually wide osseous defect.
Figure 9-56 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.
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 tissue (278–280). 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 differentiated (281).
The appearance of spinal teratomas is extremely variable. The tumor may be solid, partially or wholly cystic, unilocular, or
multilocular. In general, the more immature the histology, the more the lesion resembles astrocytomas and ependymomas, with
fairly homogeneous, enhancing soft tissue and associated cysts (282) (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 intra- or extramedullary; whatever their location, they
usually 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.
The spinal canal may be normal or may be focally widened by erosion of the pedicles and laminae. Other osseous
anomalies are uncommon.
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; therefore, neurologic deficits and hydrocephalus are usually not present (59,285).
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 midthoracic, thoracolumbar, or lumbar regions and
may be associated with cutaneous angiomas (286). 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 (286). On MR, they are
reportedly isointense with spinal cord on both T1- and T2-weighted images (287). Rarely, hamartomas may contain functioning
choroid plexus and present with syringohydromyelia (Fig. 9-58).
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 cervicomedullary junction. Therefore, we have included the
topic in this chapter. Syringohydromyelia is characterized by the presence of longitudinally oriented cerebrospinal fluid-filled
cavities within the spinal cord; the adjacent cord often is damaged, with reactive astrogliosis from the CSF pulsations. When
the cavity is limited to a dilated central canal of the spinal cord, the term hydromyelia has been applied, reserving the term
syringomyelia for spinal cord cavities extending lateral to, or independent of, the central canal. On detailed pathologic or
radiologic exam, most cavities 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 represent 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 (288–291).
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. found that 12/794 patients (1.5%) had a focal filiform enlargement of the central canal, exclusive of terminal
ventricles (292). 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 recommended 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.
Another classification system is based upon the way the syrinx communicates 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 reality, these hydromyelic cavities often dissect into, and are thus eccentric within, the
surrounding spinal cord tissue (289,291). Communicating syringomyelia is the form that is associated with the Chiari
malformations (Fig. 9-59) and with syndromes with decreased size of the foramen magnum, such as achondroplasia (Fig. 9-60)
(316,317). Dandy-Walker malformations (see Chapter 5) can also be associated with syringohydromyelia, 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 cerebrospinal fluid pulsations) that is transmitted to the central canal through the obex, causing the canal to
dilate. Rupture of the ependymal lining results in cyst extension into the substance of the spinal cord (Fig. 9-61B). Gardner’s
theory was modified by Williams (321), who favored a pressure differential between the intracranial and spinal cerebrospinal
fluid as the cause for formation of the syrinx (Fig. 9-61C). 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 spinal fluid. In patients with the Chiari I
deformity, or other causes of obstruction within the cerebrospinal fluid spaces, the initial surge forces cerebrospinal fluid into
the intracranial space; however, the cerebrospinal 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. 9-61C). 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 (321,322).
Figure 9-60 Syringomyelia secondary to achondroplasia. A. Sagittal T1-weighted image shows small clivus, long infundibulum, 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 C2. The craniocervical junction is compressed by the narrow foramen magnum. B. Axial T2-weighted image confirms the
intramedullary cyst (arrow) at the craniocervical junction.
Ball and Dayan (323) 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 deformity) 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. 9-61D), 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. supports this
concept (312), as does animal work showing the development of intramedullary edema and subsequent cyst formation after
constriction of the thecal sac (324).
Aboulker (325) 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 parenchyma or along the posterior nerve roots. Long-standing spinal cord edema
may eventually cause cavitation within the cord parenchyma (Fig. 9-61D).
Heiss et al. (326) emphasized the importance of the ectopic, compressed cerebellar tonsils in the progression of
syringomyelia, suggesting that the tonsils partially occlude the foramen magnum and 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.
Other forms of syringomyelia have been described, including traumatic syringomyelia, tumor-associated syringomyelia,
syringomyelia secondary to arachnoiditis, and “idiopathic” syringomyelia (315). Clearly, communication with the fourth
ventricle via the obex is not the underlying mechanism of the formation of the syrinx in all cases. However, extension of the
cavity within the cord (or even into the brain stem or thalami, a condition known as syringobulbia (327,328)) 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 subarachnoid spaces above and below it and (b) extension of the cavities as a result of CSF
accelerations from increased thoracoabdominal pressure and distention of the epidural venous plexus (Fig. 9-61C) 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. 9-62 and 9-63) before the syrinx extends rostrally (the “presyrinx” (289,329)). Moreover, 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.
Figure 9-61 Diagrammatic representations of pathophysiologic theories concerning syringohydromyelia. A. In the normal situation, CSF flows
from the aqueduct into the fourth ventricle, out the fourth ventricular foramina, and into the cisterna magna, basilar cisterns, and spinal
subarachnoid space. The central canal of the spinal cord is usually incompletely patent 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 direction 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.
Figure 9-62 Very large, 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 marked enlargement of the entire spinal cord (filling the entire spinal canal) from
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.
Figure 9-63 Enlarging syrinx resulting from arachnoiditis. A. Sagittal T1-weighted image shows that the ventral thoracic subarachnoid space
(black arrowheads) 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.
Figure 9-64 Posttraumatic syringomyelia. Sagittal T1-weighted image shows a holocord syrinx with multiple septae. The spinal canal is
narrowed in the upper lumbar region by a fractured vertebral body (arrows) from a motor vehicle in the past.
Supporting these observations, Koyanagi and Houkin have proposed that reduced compliance of the posterior spinal veins
due to blocking of the CSF pulse wave after cardiac systole (see the hydrodynamic 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 (329)) and subsequent syrinx formation (330).
Imaging
MR is unquestionably the diagnostic modality of choice in the diagnosis of and the evaluation of treatment of
syringohydromyelia and syringobulbia (289,327). In order to properly assess syringes by standard MR imaging, it is necessary
to obtain thin (≤3 mm) sagittal T1-weighted images, followed 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. 9-59,
9-62 to 9-64). If the cavity extends into the medulla (Fig. 9-65), it is called syringobulbia. The process usually enlarges the
affected region of spinal cord or medulla. Often, there will be multiple incomplete septations within the syrinx cavity, giving a
“beaded” appearance (Figs. 9-59 and 9-62). If T2-weighted sequences are used, increased signal intensity may be seen within
the parenchyma at the rostral or caudal end of the cavity (Fig. 9-63). 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 cavity,
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” (329). If flow is rapid and compensation techniques are not used, the syrinx cavity may
be hypointense on T2-weighted sequences (Fig. 9-59A) as a result of CSF pulsations within the cavity (289,331). Cine high-
resolution imaging techniques, particularly with high-field strength systems, have been reported to increase the visualization of
arachnoidal adhesions (332).
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 myelography 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 (333). When very eccentric,
a syrinx may be difficult to differentiate from an extramedullary (arachnoid) 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.
Figure 9-65 Syringobulbia and presyrinx. A and B. Sagittal T2-weighted (A) and T1-weighted (B) images of the brain stem and cervical spine
show syringohydromyelia 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 brain stem 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.
Techniques have been developed that allow assessment of CSF flow in the cerebral ventricles and at the foramen magnum
by phase-contrast MR (334–336). The technique used at UCSF is described in Chapter 1 and illustrated in Chapter 5 (in the
section on Chiari I deformities). 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 deformities have altered CSF dynamics at the foramen
magnum and are, therefore, at risk to develop syringomyelia (338). It has been demonstrated that the foramen magnum
obstruction in Chiari I deformity 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 deformity is present and CSF flow at the craniocervical
junction flow 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 discussed 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 decompression of the
subarachnoid space with a fascia lata graft (340).
A recent technique has been described in which a cardiac-gated cine balanced steady-state free precession study of a syrinx
has been used to evaluate CSF motion within the syrinx cavity (341). The images showed how the syrinx changed shape as the
pulse wave of CSF is generated with downward displacement of the tonsils, how the shape of the syrinx itself is altered
(narrowing at the rostral end and widening caudally) during systole, and how the pressure gradient is reversed (syrinx
widening at the rostral end and narrowing caudally) during diastole. The authors suggest that this type of imaging may aid in
determining when diversion of the syrinx fluid by syringoperitoneal shunting is indicated.
Static MR imaging 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 posterior 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 (342,343). Some CSF should be seen anterior 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 appearance and CSF should be seen on all sides. Measurements of the distance of the bottom of the tonsils below the
bottom of the foramen magnum can be used; some studies have shown, in adults, that it should lie no more than 6 mm below the
level of the foramen magnum as measured on sagittal images (344,345). However, the tonsils may lie considerably lower in
children; indeed, many children with low tonsils (indeed, as far as 10 mm below the foramen magnum) are completely
asymptomatic and remain so for many years (295,346–348). Moreover, the tonsils appear to ascend during development, as the
studies show a lower incidence and a lesser degree of tonsillar ectopia in older children (295,346–348). Moreover, cerebellar
tonsils may be low because of decreased intraspinal pressure (e.g., from a CSF leak) or increased intracranial pressure (from
hydrocephalus or a mass). Therefore, low cerebellar tonsils in children are usually a normal variant and can have many
causes: pushed down by hydrocephalus or masses, pulled down by intracranial hypotension, or may appear to be low
because of a minor variant of the skull base. No treatment should be performed unless the patient is judged to have
symptoms of increased intracranial pressure by an experienced physician and the many potential causes are considered.
Then a careful review of imaging should be performed to determine whether the tonsils are compressed, CSF flow is
reduced and increased tonsillar motion is shown in the foramen magnum of a resting patient on cine MRI.
MR of the craniocervical junction may also show stenosis of the foramen magnum, as in achondroplasia; masses at the level
of the foramen magnum, such as schwannomas and meningiomas; cysts; herniated tonsils; or arachnoidal loculations. Any mass
or narrowing at the foramen magnum 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 place 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, MR shows mild dilation of the central canal in up to 25% of patients with a tethered
spinal cord (Fig. 9-31) (168). The exact cause of this dilation is not known. However, the mild dilation 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 (197). Only if symptoms persist after the release of the tethered cord
should the dilated central canal be evaluated further.
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 tonsillar ectopia (the Chiari I deformity) have spinal cord neoplasms as well (289). 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 contrast should always be given on the follow-up MR scan.
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Neoplasms of the Spine
A. James Barkovich
Extramedullary Tumors
CSF Dissemination of Intracranial Neoplasms
Tumors of the Spinal Column
Meningeal Tumors
Tumors of the Nerve Roots and Nerve Root Sheaths
Extraspinal Tumors Invading the Epidural Space
Tumors of the spinal cord in children are slowly growing masses with clinical manifestations that are often subtle and slowly
progressive. The widespread use of magnetic resonance imaging has greatly facilitated the diagnosis of spinal tumors,
allowing earlier detection and therapy. Although the neoplasms that involve the pediatric spinal cord are similar to those
affecting adults, the incidence and the presentation of the various tumors are often quite different. In this chapter, the
epidemiology, clinical manifestations, and pathologic/radiologic manifestations of intraspinal neoplasms in children are
discussed.
Intramedullary Tumors
Clinical Presentation
Intramedullary (intrinsic) neoplasms of the spinal cord constitute 4% to 10% of neoplasms of the central nervous system in
children (1–4) and approximately one-third of spinal neoplasms of childhood (2,5–7). All age groups are affected; however,
intramedullary tumors are most frequently seen in children toward the end of the first decade and beginning of the second
decade of life. Males and females are equally affected (8–11). Spinal neoplasms are relatively less common in children than
adults; the ratio of intracranial to intraspinal neoplasms in children varies between 10:1 and 20:1 (as compared to 5:1 in
adults) (11).
Figure 10-1 Cervical spinal cord astrocytoma; comparison with demyelinating plaque. A. Sagittal T2-weighted image shows hyperintensity
within the cord extending from the foramen magnum to the bottom of C6. At C2-C3, the lesion is ovoid and the cord is expanded (large white
arrows), strongly suggesting the presence of tumor. The less expanded portion (small white arrows) probably represents edema or, possibly, a
“presyrinx.” B. Contrast-enhanced sagittal T1-weighted image shows heterogeneous enhancement (white arrows) of the ovoid, expanded
region of the cord. C and D. Sagittal T2-weighted image (C) and contrast-enhanced T1-weighted image (D) show a demyelinating plaque. The
lesion (arrows) is flame shaped and causes minimal mass effect.
The availability of MR has facilitated the diagnosis of spinal tumors; nonetheless, the patient’s course often will have been
punctuated by exacerbations and remissions of symptoms, possibly due to alteration in the edema surrounding the neoplasm (6).
Weakness with numbness or pain is the most common presenting complaint (11,12). The most common type of pain, occurring
in approximately 70% of patients, is spinal pain. This pain is dull and aching in quality and is localized to bone segments
adjacent to the tumor (11). The cause of this pain is unknown but may result from distention of the dural tube by the swollen
spinal cord (11). Sometimes children will complain of nocturnal pain that awakens them from sleep (6). The second most
common type of pain seen in children is radicular (root) pain, which is indistinguishable from pain caused by compression of
a nerve root by an extramedullary process (11). Finally, some patients manifest tract pain, a vague, burning type of pain
associated with paresthesias. The burning and paresthesias typically occur caudal to the tumor and are believed to result from
infiltration of the lateral spinothalamic tracts by tumor (11).
Children of different age groups often present with very different symptomatology. Young children and infants often have
severe pain, motor regression, weakness, or frequent falls (2,6), whereas older children more commonly present with
clumsiness, progressive scoliosis (thoracic tumors), torticollis (cervical tumors), gait disturbance, sphincter disturbance, or
spinal deformity (4,11–13). Weakness of the extremities is a common finding in all patients. In tumors of the cervical spinal
cord, the most common location in children, upper extremity weakness may or may not be accompanied by weakness of the
lower extremities, neck pain, muscle atrophy, dysesthesias, or hyperreflexia (4). Although sensory levels may be present, they
are less common in intramedullary than extramedullary tumors. Sphincter dysfunction, when present, may not occur until late in
the course of the illness (9,14,15); early presentation may indicate a high-grade (fast-growing) tumor (16).
Up to 15% of patients with spinal cord tumors may present with symptoms of increased intracranial pressure, most likely a
result of either greatly elevated CSF protein content, which blocks the normal CSF pathways and impairs CSF resorption, or
blockage of the foramen magnum by cervicomedullary tumors (see Chapter 8) (12,17,18). The increased intracranial pressure
does not misdirect the diagnostic workup if the patients have signs of an intraspinal process on physical exam. However,
patients having no signs or symptoms of a spinal process may suffer from a considerable delay in diagnosis.
Pathology
The most common histologic type of spinal cord tumor in children is astrocytoma (60%), followed by ependymoma (15%–
30%) (3,6,12,19–22). Thus, the relative incidence of intramedullary spinal cord tumors in children is quite different from that
in adults, in whom more than half of intramedullary tumors are ependymomas. Another difference from adults is that the
myxopapillary ependymoma, a benign (WHO Grade I) form of ependymoma that constitutes 40% to 50% of spinal
ependymomas in adults (usually at or below the conus medullaris), is rare in children, composing only 8% to 12% of spinal
ependymomas in childhood (21,23,24); most pediatric ependymomas appear to be WHO Grade II (cellular, papillary,
epithelial, or clear cell). Malignant astrocytomas and glioblastomas of the cord are relatively more common in children than in
adults, constituting as many as 50% of pediatric astroglial spinal cord tumors (25,26). Other intramedullary tumors may
develop in children, including gangliogliomas and gangliocytomas (27–29), germinomas (3,19,30,31), primitive
neuroectodermal tumors (PNETs) (32,33), atypical teratoid/rhabdoid tumors (16,34–36), oligodendrogliomas (37),
pleomorphic xanthoastrocytomas (19,38), melanocytomas (19), teratomas (39), and Langerhans cell histiocytosis (3,40). Very
rarely, intramedullary tumors may be metastases from fourth ventricular tumors (that presumably seed via the obex into the
central canal of the spinal cord) (41).
Just as with their intracranial counterparts, the extent of resection of spinal tumors is the primary determinant of the rate of
recurrence and the expected length of survival (42). Astrocytomas are generally more difficult to completely resect than are
ependymomas; thus, patients with astrocytomas have poorer postoperative courses and shorter survival (12,43,44). Histology
of the tumor is also an important factor in determining expected survival. In one study, 10-year survival for pilocytic
astrocytomas of the spinal cord was 81% as compared to 15% for diffuse fibrillary astrocytomas (45) and even worse for
glioblastoma multiforme, where subarachnoid spread is found in up to 60% of cases (46). Among patients with fibrillary
astrocytomas, the grade of the tumor was the most significant predictor of survival (45). Among ependymomas, too, high tumor
grade (but not histology—there does not appear to be any difference in the biologic behavior of the different histologic types of
WHO Grade II ependymomas (3)) was the most significant variable for prediction of dissemination through the cerebrospinal
axis (47); dissemination is a grave prognostic factor.
Intramedullary neoplasms tend to be located more rostrally in children than in adults (1,11). Nearly 50% of intramedullary
tumors in children are cervical or cervicothoracic, as compared with 28% in adults. Intramedullary tumors in children usually
occupy a small number of cord segments; however, the extent of cord involvement is often increased by the presence of cysts
rostral or caudal to the tumor. Such peritumoral cysts have been reported in 40% of spinal cord astrocytomas (48) and in up to
80% of ependymomas (49,50).
Imaging
Magnetic resonance is the modality of choice for imaging patients with suspected or known intramedullary neoplasms. MR of
most intramedullary tumors will show an enlarged spinal cord with T1 hypointensity and T2/FLAIR hyperintensity at the
location of the tumor (Figs. 10-1 to 10-7) (22,51,52). As in the brain, tumors with high cell density, such as PNETs and
atypical teratoid/rhabdoid tumors, have relatively little free water and therefore show less T2 hyperintensity (32,36,53),
although this characteristic seems less reliable in the spinal cord than in the brain (54). The regions of abnormal T1 hypo- and
T2 hyperintensity within the expanded cord may represent tumor, necrosis, cyst, or edematous cord (“presyrinx,” Fig. 10-1)
(55); therefore, intravenous administration of paramagnetic contrast (Figs. 10-1, 10-2, 10-5 to 10-7) is essential. In 20% to
40% of patients, cysts are present caudal or rostral to the solid portion of the tumor (Figs. 10-1 and 10-5) (11,48,56); this
number may be as high as 80% in ependymomas (49,57,58). These cysts may result from secretion of fluid by the tumor or by
obstruction of normal CSF pathways within the cord and subarachnoid space; the latter should be considered syringomyelia
(see Chapter 9). The solid portion of the tumor often cannot be differentiated from the cyst without intravenous administration
of contrast (Fig. 10-5). Axial and sagittal T1-weighted sequences may be of use in defining the full extent of the associated
cyst. The full extent of the cyst is not critical information, however, because it usually resolves after resection of the tumor and
elimination of the obstruction. Contrast enhancement is usually nodular, heterogeneous (Figs. 10-2, 10-4, and 10-5), or ring-
like (Fig. 10-7); although there are exceptions (59,60), enhancement is seen in the large majority of intramedullary spinal
neoplasms in children (22,51,52,61). The region of contrast enhancement corresponds to the solid portion of the tumor and
usually assists in distinguishing the solid portion of the tumor (which typically enhances) from cyst and necrosis (which do not
enhance, although contrast may leak into a cyst lined by tumor as in Figure 10-5).
Astrocytomas (Figs. 10-1 and 10-2) are usually located more eccentrically in the spinal cord and enhance with variable
intensity (sometimes, not at all), and the enhancement is less sharply demarcated from the nonenhancing tissue than in
ependymomas (Figs. 10-4 and 10-5) (62). The tumor margins of astrocytomas usually extend beyond the enhancing tissue.
Figure 10-2 Cervical spinal cord astrocytoma extending upward into medulla. A. Sagittal T2-weighted image shows expansion of the spinal
cord and medulla from the obex (large black arrow) to the T1-T2 level (white arrow). The slight hyperintensity extending down to the T2-T3 disc
level (small black arrow) likely represents edema. B. Sagittal T1-weighted image shows that the tumor mass (T) is of low signal intensity and
the expanded cord is widening the spinal canal. C. Postcontrast T1-weighted image shows peripheral enhancement of the periphery of the
tumor from the obex (white arrow) to the lower half of T2 (white arrowhead), close to the bottom of the hyperintensity in (A).
Figure 10-3 Cervicomedullary astrocytoma. A. Sagittal T1-weighted image shows a partially cystic mass (black arrows) in the mid and upper
cervical spinal cord. A frank cyst (c) is present from C4 to C6. A dorsally exophytic component (white asterisk) is seen at the craniocervical
junction. B. Sagittal T2-weighted image shows multiple components in the cervical spinal cord. The lowest component (small white arrows)
likely represents vasogenic edema. The next most rostral component, of high signal intensity (large white arrows), likely represents a tumor-
associated cyst. The next component (large white arrowheads) likely represents solid tumor with high cellularity. The most rostral component
(large black arrowheads) likely represents solid tumor with high water content/low cellularity. C. Postcontrast sagittal T1-weighted image shows
minimal enhancement of the more cellular solid component of the tumor at C2-C3, and marked enhancement of the dorsally exophytic
component near the cervicomedullary junction. The white arrows point to the displaced cervicomedullary junction. This marks the presumed
level of the pyramidal decussation. High-grade tumors break through the horizontally oriented axons at this level to invade the medulla, whereas
lower grade tumors displace the decussation and expand dorsally, as in this case.
Figure 10-4 Spinal cord ependymoma A. Noncontrast sagittal T1-weighted image shows enlargement of the spinal cord (black arrows) with
heterogeneous prolonged T1 relaxation within the upper thoracic spinal cord. B. Sagittal T2-weighted image shows that the area of widened
spinal cord (white arrows) is very sharply marginated. This type of sharp demarcation is characteristic of low-grade ependymomas. Small
areas of vasogenic edema are present rostral and caudal to the mass. C. Postcontrast sagittal T1-weighted image shows the tumor to
enhance heterogeneously.
Figure 10-5 Thoracic ependymoma with holocord syringomyelia. Sagittal T1- (A) and T2- (B) weighted images show a nearly completely
fluid-filled spinal cord with a solid tumor component (black arrows) in the lower thoracic region. Contrast-enhanced T1-weighted image (C)
shows that the solid portion of the tumor enhances (black arrows), along with the cystic portion above it (large black arrowhead), suggesting
that the enhancing cyst is a tumor cyst rather than an associated syrinx. Sagittal T2-weighted image of the cervicothoracic spine (D) shows
that the syrinx extends into the medulla (syringobulbia). Axial T2-weighted image (E) shows the tumor to be extremely heterogeneous with
cysts (hyperintense) and mineralization/hemorrhage (hypointense).
Ependymomas are usually located centrally within the spinal cord (Figs. 10-4 and 10-5); the margin of tumor enhancement
is sharper and corresponds to the margin of solid tumor (23,24,58). A finding of T2 hypointensity at the superior and inferior
borders of the mass (Fig. 10-5), indicating prior hemorrhage, is suggestive of ependymoma (63); this sign is seen in only about
20% of ependymomas, however (50). Remember that imaging findings of intramedullary tumors are not always diagnostic: in a
large series, the presence of associated syringomyelia (rostral or caudal cyst) was the only imaging sign that independently
differentiated ependymoma from astrocytoma (58), and it is not 100% diagnostic.
Germinomas and gangliogliomas (Figs. 10-6 and 10-7) are typically sharply circumscribed, as well. Heterogeneity of the
tumor on T1-weighted images is said to be suggestive of ganglioglioma (Fig. 10-6) (49), although astrocytomas may have a
similar appearance (Fig. 10-1).
No specific MR characteristics allow differentiation of benign from malignant spinal cord tumors in children, although the
presence of leptomeningeal spread at the time of presentation suggests malignancy (64). In practice, preoperative
differentiation of these tumors is of little clinical importance because the operative approach does not differ. It is much more
important to determine whether the tumor is intramedullary or extramedullary and to accurately identify the level of the solid
portion of the tumor.
The differentiation of tumor-associated syringomyelia from congenital or posttraumatic syringomyelia is difficult, even
impossible, without administering paramagnetic contrast. Edema with reactive astrogliosis, which has the same signal
characteristics as tumor (T1 hypointensity and T2 hyperintensity), is frequently present at the caudal and rostral ends of benign
syrinx cavities (see Chapter 9) (65,66); this finding may be a “presyrinx” that is slowly evolving into true syringohydromyelia
(55). Although the presence of anomalies of the craniocervical junction such as cerebellar tonsillar ectopia, occipitalization of
the atlas, and the Klippel-Feil anomaly suggest that a syrinx is nonneoplastic, these anomalies can occur in conjunction with
spinal cord tumors as well (65,67). Moreover, the expansion of the intramedullary tumor with resulting obstructed CSF flow in
the spinal subarachnoid space can cause a syringohydromyelia (Figs. 10-2 and 10-5) identical to that seen associated with
tonsillar ectopia (65,66) or other causes of obstruction of the subarachnoid spaces (55). Patients with typical
syringohydromyelia (see Chapter 9) and an obvious cause for the syrinx, such as a Chiari I malformation, do not need a
postcontrast MR sequence. However, if any question exists regarding the cause of the syrinx, paramagnetic contrast should be
administered to look for enhancing tumor. If an area of contrast enhancement is present within or adjacent to the syrinx, the
diagnosis of tumor-related cyst should be strongly considered. Rarely, an enhancing inflammatory mass can cause cavitary cord
disease.
Figure 10-6 Cervicomedullary ganglioglioma. A. Sagittal T2-weighted image shows a hyperintense mass extending superiorly to the obex
(small white arrows) and caudally to the C4-C5 intervertebral disc (large white arrows). C. Axial T2-weighted image shows heterogeneous T2
prolongation in the medulla. The ventral medulla (arrow) is relatively spared. B and D. Postcontrast sagittal (B) and axial (D) T1-weighted
image at the C1 level shows enhancement (white arrow), representing the tumor, in the central and left posterolateral portion of the spinal cord.
Rarely, intramedullary tumors have disseminated throughout the subarachnoid spaces by the time of presentation; the
imaging appearance is identical to that of CSF spread from intracranial tumors (Figs. 10-8 and 10-9) (37,38,68). Although this
finding is generally associated with higher tumor grade, dissemination may be found in low-grade tumors, as well, particularly
those that develop in CSF spaces (choroid plexus tumors, ependymomas, medulloblastomas, etc.) (37,68,69). Such patients
may initially come to medical attention because of signs of increased intracranial pressure. It is important to remember, as
discussed in Chapter 8, that CSF dissemination of spinal tumors can cause hydrocephalus and that the spine should be
investigated in children (or adults) with unexplained hydrocephalus who worsen despite CSF diversion.
Figure 10-7 Spinal cord ganglioglioma. A and B. Sagittal T1-weighted (A) and T2-weighted (B) images show marked expansion of the spinal
canal by a large cervicomedullary mass, suggesting that the mass has been present for many years. Central areas (c) of cavitation or cyst are
seen. C. Postcontrast T1-weighted image shows high-intensity enhancement around the cystic/cavitary regions.
Congenital intramedullary tumors, such as lipomas, teratomas, hamartomas, dermoids, and epidermoids, are discussed in
Chapter 9.
Extramedullary Tumors
Approximately two-thirds of all intraspinal tumors of childhood are extramedullary; of these, 50% are extradural and 10% to
15% are intradural (70,71). Extramedullary neoplasms can be classified by a number of different criteria; they will be
classified in this chapter by their site of origin. Clinically, patients with extramedullary tumors present with signs of
progressive myelopathy. Presentation is similar to intramedullary tumors in that weakness, predominantly of the lower
extremities and trunk, is the most common presenting symptom. Diffuse back pain and radicular (“root”) pain are frequently
present. Torticollis, upper extremity weakness, scoliosis, and urinary incontinence are other common signs and symptoms
(10,72). The histological type of tumor cannot be predicted by its clinical presentation.
Figure 10-8 Drop metastasis from a medulloblastoma. Sagittal postcontrast T1-weighted MRI images (A–D) through the entire spinal canal
show multiple lesions (white arrows) on the surface of the spinal cord and on the roots of the cauda equina along the entire length of the spinal
cord and thecal sac.
Figure 10-9 MRI of drop metastases from a low-grade astrocytoma. Sagittal and axial contrast-enhanced T1-weighted images show a few
small enhancing nodules at the level of the medulla (small white arrows in A) and along the dorsal spinal cord (black arrows in A–C). Note that
large metastases are located at the bottom of the thecal sac (white arrows in B and D), indicating that gravity is a factor in the location of drop
metastases in less aggressive tumors.
As discussed in Chapter 7, artifacts are common on MR exams of the spine in the first few weeks after posterior fossa
craniectomy (83). These artifacts, presumably from postoperative spinal subdural collection and perhaps from “leakage” of
contrast into the subarachnoid space, can be very difficult to differentiate from CSF spread of tumor (Fig. 10-10). Therefore, it
is essential to stage the tumor preoperatively or to wait at least 2 weeks after surgery before performing the imaging study.
(84).
Osteogenic Sarcoma
Although osteogenic sarcomas account for approximately 20% of all sarcomas, they rarely affect the spine; indeed, less than
5% of osteosarcomas arise in the spine (105). Spinal osteosarcomas develop primarily in adults; only five pediatric cases
have been reported (106). Patients most commonly present in the second decade with localized pain or a mass (107).
Osteosarcomas are distributed uniformly throughout the spinal column (105) and have an extremely variable gross pathologic
appearance, ranging from soft and friable to firm with marked calcification (101). Most tumors arise from the posterior
elements, with partial secondary involvement of the vertebral body; the body is more frequently involved in sacral tumors
(105). The imaging findings vary as much as the gross pathology. On CT or plain films, the vertebral involvement may be
purely lytic, predominantly sclerotic, or a combination of the two (93,105,108). Intrathecal contrast is often necessary to define
the degree of involvement of the spinal canal, which is narrowed in more than 80% of affected patients (105). MR shows the
tumor primarily as an area of prolonged T1 and T2 relaxation time when compared to normal bone marrow. Tumors that are
heavily ossified may be dark on T2 and, especially, T2*-weighted images. Fluid–fluid levels may be seen, particularly in those
tumors with telangiectatic histology. As with other bony tumors of the spine, MR is the preferred way to assess extraosseous
spread of tumor and the degree of cord displacement and cord compression (109).
Figure 10-14 Giant cell tumor. A and B. Sagittal (A) and axial (B) CT images show collapse of the T2 vertebral body (white arrow in A) with
associated expansion of the laminae (white arrows in B) and spinous process (white arrowhead in A). Expansion of the bone makes
Langerhans cell histiocytosis unlikely. C and D. Sagittal T1- (C) and T2- (D) weighted images show soft tissue (white arrows) extruded from the
collapsed vertebra and abnormal tissue (large white arrowhead) within the expanded spinous process.
Chordoma
Chordomas are extremely rare in the spinal canal of children; intracranial chordomas are discussed in Chapter 7. They arise
from rests of notochord cells and primarily involve the clivus and the sacrum, with 50% arising in the sacrum; only about 15%
of chordomas involve the vertebrae above the sacrum (101). Chordomas grow slowly by erosion and compression of adjacent
structures; they rarely metastasize. On imaging studies, chordomas appear as lytic lesions causing destruction of one or more
adjacent vertebrae. Sclerosis is commonly seen in the bone adjacent to the tumor. Extension to the paravertebral soft tissues is
not uncommon; destruction of the intervertebral discs can occur when the vertebral bodies are involved. On CT, irregular
spicules of calcification are almost always seen within the tumor mass (93). The MR appearance of chordomas is similar to
other primary bone tumors; they are sharply defined, destructive lesions with prolonged T1 and T2 relaxation times when
compared to nervous tissue; the presence of very high signal intensity on T2 images favors the diagnosis of chordoma. Contrast
enhancement is variable; however, the absence of contrast enhancement or presence of faint enhancement, especially with a
honeycomb appearance that corresponds to the low T1 signal within the mass, in conjunction with very high T2 signal (Fig.
10-15) strongly favors a diagnosis of chordoma, as most other tumors of the pediatric spinal column show significant
enhancement.
Osteoblastoma
Osteoblastomas account for less than 1% of primary bone tumors. The presenting symptoms, usually pain of many months’
duration, occur most commonly in males during the second and third decades of life. Because the tumors are usually 2 cm or
greater in diameter when they present, pain secondary to compression of nerve roots or spinal cord is sometimes part of the
presentation (101,115).
On imaging studies, osteoblastomas are well-defined, solitary masses that most commonly originate in the posterior
elements (93,115). CT and radiographs show lytic lesions with a variably thick sclerotic rim (Fig. 10-17); extension into
surrounding soft tissues is common. Calcification or new bone formation may be seen within the lytic area (93). Thus, CT
studies are diagnostic. On MR, osteoblastomas are well-defined masses showing slight hypointensity on T1-weighted images
and hyperintensity on T2-weighted images as compared with normal bone (116). They most commonly originate in the articular
facets, pedicles, and lamina (Fig. 10-17) (117,118). Contrast enhancement is variable but usually mild (116) and often
heterogeneous (Fig. 10-17E). Occasionally, osteoblastomas may generate widespread edema in the surrounding bone,
suggesting diffuse infiltration of tumor (119).
Figure 10-15 Cervical chordoma. A and B. Axial (A) and coronal (B) T2-weighted images of the cervical spine show a very hyperintense
mass in and around the lateral masses of the vertebral column from the bottom of C2 to the top of C7 (large white arrows). The left lateral
aspect of the C5 body (small white arrows) is involved. C. Contrast-enhanced T1-weighted image shows faint enhancement of the mass
(arrows).
Figure 10-16 Ewing sarcoma of the sacrum. Coronal images show a large heterogeneous mass (white arrows) within the sacrum and
growing into adjacent soft tissues that is isointense to muscle on T1-weighted images (A) and hyperintense on T2-weighted images (B) and
shows moderate heterogeneous enhancement (C).
Meningeal Tumors
Meningioma
Although meningiomas account for 25% to 45% of all spinal tumors, they are extremely uncommon in children, with an
incidence of 2% to 3% of pediatric intraspinal tumors (123). The histological, clinical, and therapeutic features are similar to
meningiomas occurring in later life. The tumors are primarily intradural and extramedullary, although they occasionally extend
into the extradural compartment. Patients usually present with spinal cord or nerve root compression (93). Plain film and CT
myelography may be necessary if MR is unavailable or contraindicated; they reveal meningiomas to be smoothly marginated
masses that are isodense to skeletal muscle; calcification may be present as early as end of the second decade (Fig. 10-18A).
MR is the imaging modality of choice because it clearly demonstrates the homogeneous extramedullary lesions that are
isointense with spinal cord and surrounded by cerebrospinal fluid. As with intracranial meningiomas, the masses are dural
based and sharply marginated. They are isointense to hypointense compared with gray matter on T1- and T2-weighted images
(Fig. 10-18B). Infusion of paramagnetic contrast results in homogeneous enhancement (Fig. 10-18C) (80,124).
Figure 10-17 Spinal osteoblastoma. A. Axial CT image shows a lytic, sharply marginated mass (white arrows) involving the left vertebral body,
pedicle, and lamina; a faint osseous matrix can be seen within the mass. B and C. Sagittal (B) and coronal (C) T1 images show an expansile
mass (black arrows) slightly hyperintense to edema and hypointense to marrow expanding the left pedicle and articular elements. Note the
narrowing of the spinal canal in (C). White arrows in (B) point to edema in the vertebral body anterior to the mass. C–E. Axial T2 (D),
noncontrast T1 (E) and contrast-enhanced T1 (F) images show the heterogeneous mass narrowing the central canal and extending anteriorly
into the vertebral body (small arrows) while expanding and destroying the pedicle, lamina, and transverse process on the left (large arrows).
Meningeal Cyst
Clinical and imaging characteristics
Meningeal cysts, although not true neoplasms, may occur in childhood and act as expanding masses causing cord compression.
As discussed in Chapter 5, extraparenchymal meningeal cysts may be congenital (true arachnoid cysts) or acquired (arachnoid
loculations). In children, most meningeal cysts are located dorsal to the thoracic spinal cord; they may be extradural or
intradural. Extradural cysts may develop secondary to a congenital or an acquired dural defect with resultant herniation of
arachnoid, CSF (125,126), and sometimes spinal cord (127) through the defect. Intradural cysts may be the result of congenital
deficiencies within the arachnoid or adhesions from prior infection or trauma. Presenting symptoms of both intra- and
extradural cysts are usually intermittent pain and weakness that may be accentuated in the upright position; the accentuation of
symptoms may be related to gravitational filling of the cyst and subsequent cord compression (71).
The best sequences for identification of spinal cysts are steady-state sequences (CISS, FIESTA), which can be acquired
volumetrically, allowing reformation in any plane. The cyst wall will appear as very hypointense, thin, and curvilinear and the
contents usually isointense to CSF (Figs. 10-19 and 10-20). Large cysts may be seen on MRI as sharply marginated,
nonenhancing, homogeneous masses that remain isointense to CSF on all sequences (Fig. 10-20). Arachnoidal adhesions, small
cysts, and cysts with thin walls are usually more difficult to see (Fig. 10-19), so the diagnosis is suggested by identifying
displacement and compression of the spinal cord at the site of the arachnoid loculation/cyst. The cyst may be isointense to CSF
or may exhibit higher signal intensity than adjacent CSF because fluid in the cyst is less pulsatile than free-flowing fluid. When
the spinal cord is herniated through a dural rent into an extradural arachnoid loculation, the diagnosis is made by the
characteristic finding of focal distortion or displacement of the cord (typically ventrally) without an identifiable mass on MR
or CT myelography (127). Herniation of the spinal cord through a dural rent is an adult disorder, in our experience, and will
not be further discussed here.
Figure 10-18 Spinal meningioma. Sagittal reformatted CT image (A) shows a partly calcified mass (white arrow) in the dorsal spinal canal.
Sagittal T2-weighted image (B) shows the isointense (to spinal cord) mass (black arrow) and the ventrally displaced, edematous, and
compressed spinal cord (black arrowheads). Sagittal contrast-enhanced T1-weighted image (C) shows the mass (white arrow) to
homogeneously enhance.
Figure 10-19 Spinal cyst in a young child with a large cutaneous melanotic nevus. Thin-section (2 mm) T2 image shows anteriorly displaced
spinal cord. Notice multiple curvilinear stria (arrows) in the dorsal subarachnoid space, with the spinal cord pushed anteriorly. The best way to
image these patients is by using steady-state (CISS, FIESTA) imaging techniques.
Classification
Other types of meningeal cysts can occur in the spine. Nabors et al. (128) have proposed a classification for spinal meningeal
cysts. Type I cysts are extradural meningeal cysts without nerve roots. This group is composed primarily of the thoracic
extradural arachnoid cysts (herniating through dural rents), which commonly occur in adolescents, and sacral meningoceles
(see Chapter 9), which most commonly present with localized sacral pain in adults. Type II cysts are extradural meningeal
cysts that contain nerve roots. Most type II cysts are Tarlov cysts or spinal nerve root diverticula; they almost always present in
adults. Type III cysts are intradural arachnoid cysts. In this group are the true arachnoid cysts and arachnoid loculations
described in the prior paragraph. Type III cysts typically present in childhood or adolescence and are most commonly located
dorsal to the spinal cord at the thoracic level. A fourth type of cyst, developing between layers of dura in the cervical region
(129), has been described in adults. Affected patients typically present with cervical myelopathy in middle age. Interested
readers are referred to adult textbooks or to the neurosurgery literature for more information (129).
Figure 10-20 MR of spinal arachnoid cyst. Sagittal T1-weighted image (A) shows a homogeneous, CSF-intensity, sharply marginated mass
(open white arrows) just ventral to the mid-thoracic cord. Sagittal T2-weighted image (B) shows that the mass remains homogeneous and
isointense to CSF. Postcontrast T1-weighted image (C) shows absence of enhancement.
Figure 10-21 Cervical schwannoma in a 17-year-old with left arm weakness. A. Sagittal noncontrast T1 image shows a paraspinous mass
(white arrows) eroding the posterior vertebral bodies (arrowheads) of C5 and C6. B. Postcontrast T1 axial image shows the enhancing mass
(M) displacing and compressing the spinal cord (c) to the right and enlarging the left neural foramen (black arrowheads).
Neuroblastoma
Neuroblastomas, the most common extracranial tumors (and the fourth most common tumors) of childhood, arise in the
sympathetic nervous system of infants and children (136). They most often originate in the adrenal medulla (35%–40%) but can
occur in the extra-adrenal retroperitoneum (30%–35%, most commonly the upper lumbar area), the posterior mediastinum
(20%), the neck (5%), and the pelvis (2%–3%) (136,138). Affected children may become symptomatic from local pain,
abdominal distention, malaise, irritability, weight loss, or neurologic deficit (136,139). Metastases to bone, including the
spine, are frequent and sometimes result in spinal cord compression (140). Cord compression may result from direct extension
of tumor into the spinal canal through neural foramina; however, cord compression as an initial manifestation of the disease is
rare (136,141).
When assessing affected patients for spinal cord or cauda equina compression, MR is the study of choice. If MR is not
available or is contraindicated, CT myelography should be performed. CT will show a paraspinous mass extending through the
neural foramen into the epidural space with displacement and compression of the thecal sac (Fig. 10-22). Destruction of the
adjacent bone may be present. When cord compression results from extension of bony metastases, irregular destruction of the
vertebral body is seen, with extension of the soft tissue mass into the spinal canal and displacement and compression of the
thecal sac by the mass. MR optimally shows the paraspinous or bony mass and the extension of the tumor into the spinal canal,
without the need for intrathecal contrast (Figs. 10-22 and 10-23). On noncontrast images, the mass appears relatively
homogeneous and is nearly isointense to nervous tissue. After contrast administration, the mass enhances heterogeneously (Fig.
10-23). Coronal images are most helpful to visualize the full extent of tumor in the spinal canal (Fig. 10-22C); axial images
best show the resultant cord displacement and compression (Fig. 10-22D).
Figure 10-22 Neuroblastoma: demonstration of tumor in the spinal canal. Posteroanterior chest x-ray (A) shows a large left-sided superior
mediastinal mass (large white arrows). Some rib erosions are seen (small black arrowheads). Axial contrast-enhanced CT image (B) shows
the neuroblastoma mass (n), the rib erosions (large black arrows), and the presence of enhancing tumor in the spinal canal, surrounding the
hypodense spinal cord (black arrowheads). Coronal T2-weighted image (C) shows the neuroblastoma mass (n) extending into the canal
through a widened neural foramen (white arrows) and displacing the spinal cord (black arrowheads) to the right. Axial T1-weighted image (D)
shows the large neuroblastoma mass (n) extending through the widened neural foramen (white arrows). This plane better shows the tumor
compressing and nearly completely surrounding the thecal sac and spinal cord (c).
Two aspects of imaging findings have recently been emphasized by an international group, who cited the importance of
communication using common terminology when reporting results of an MR for neuroblastoma (142). The first key aspect is
the stage of the disease, based upon newly defined criteria. Stage L1 refers to localized tumors not involving vital structures
(as defined by a list of specific image-defined risk factors [IRDFs], see below), confined to one body compartment (neck,
chest, abdomen, pelvis). Stage L2 indicates local–regional tumor with presence of one of more IRDFs; these tumors may
involve adjacent body compartment, such as a left-sided abdominal tumor involving the ipsilateral chest or a pelvic tumor with
inguinal lymph node involvement. Stage M refers to distant metastatic disease, such as nodes at the thoracic inlet from an
abdominal tumor. Stage MS refers to metastatic disease in patients younger than 18 months, with dissemination limited to skin,
liver, and/or bone marrow. The second key aspect is the reporting of IRDFs, which are critical to assessment of disease stage
and, later, to disease response. These include encasement of major blood vessels (aorta; vena cava; carotid, vertebral, or
subclavian arteries); compression of trachea or principal bronchi; extension to skull base; encasement of superior mesenteric
artery, iliac vessels, or origin of celiac axis; intraspinal extension to more than one-third of the canal in the axial plane, filling
of the perimedullary subarachnoid spaces, or abnormal cord signal; infiltration of pericardium, diaphragm, kidney, liver,
duodenopancreatic block, or mesentery; invasion of a renal pedicle; pelvic tumor crossing sciatic notch, or lower mediastinal
tumor infiltrating the costovertebral junction between T9 and T12 (142).
Figure 10-23 Enhancement of adrenal neuroblastoma. Postcontrast T1-weighted images show the enhancing paraspinous tumor (white
arrows in A) coursing through the dilated neural foramina (white arrows in B and C) to enter the epidural space. The tumor (denoted by n in
figure C) displaces the thecal sac to the left side of the canal while extending into the anterior and posterior epidural spaces.
Neuroblastoma may have metastases to the spinal column at the time of presentation. As the spine of young children often
has red marrow and, therefore, enhances, identification of metastases may be difficult. Meyer et al. studied this problem and
determined that neuroblastoma metastases have homogeneous low signal intensity on T1-weighted images with heterogeneous
enhancement after intravenous administration of paramagnetic contrast (143). STIR images show homogeneous or
heterogeneous hyperintensity. The combination of T1 hypointensity and postcontrast heterogeneous hyperintensity had the
highest accuracy in detecting tumor (143). The imaging appearance of metastases of neuroblastoma to the skull and skull base
is discussed in Chapter 7.
Ganglioneuroma
Ganglioneuromas represent tumors of the sympathetic nervous system that are at the benign end of the neuroblastoma–
ganglioneuroblastoma–ganglioneuroma spectrum (136). The predominant cell type is the mature ganglion cell (gangliocyte). In
contradistinction to neuroblastomas, which usually present in early childhood, ganglioneuromas often do not present until the
second or third decade (144). Males and females are equally affected. The most frequent site of origin for ganglioneuromas is
the posterior mediastinum; abdominal sites are also common, but the neck and the pelvis are somewhat unusual locations
(145,146). Ganglioneuromas do not metastasize; when the spinal canal is involved, it is the result of a “dumbbell” mass
extending from the paraspinous region through the neural foramen into the epidural space (as in Fig. 10-23). Calcification is
frequently present within the tumor. Although the calcification does not allow differentiation from neuroblastomas, it does
differentiate these masses from neurofibromas, schwannomas, and peripheral PNETs, which rarely calcify.
Ganglioneuroblastoma
Ganglioneuroblastomas are tumors of the sympathetic nervous system that are intermediate between neuroblastoma and
ganglioneuroma; they are composed of both mature gangliocytes and immature neuroblasts. Ganglioneuroblastomas, which are
considerably less common than neuroblastomas or ganglioneuromas, tend to become symptomatic in young children; both sexes
are affected equally. As with ganglioneuromas, the posterior mediastinum and abdomen are the most common sites of origin.
Although they are less histologically and biologically aggressive than neuroblastomas, their behavior is similar to
neuroblastomas in that they can metastasize to bone or extend directly into the spinal epidural space through the neural
foramina (93,140). Extension either from the vertebral bodies or from the paraspinous sympathetic ganglia into the spinal canal
can result in nerve root or spinal cord compression.
As the preceding paragraphs illustrate, all the tumors in the neuroblastoma–ganglioneuroblastoma–ganglioneuroma spectrum
can have an identical appearance on imaging studies. When a paraspinous mass is seen in the suprarenal area extending into the
spinal canal or if diffuse bony metastases are present, the most likely diagnosis is neuroblastoma. However, when a
paraspinous mass is seen to extend through the neural foramen into the epidural space in the posterior mediastinum, lower
abdomen, pelvis, or neck, the differentiation between the three tumors in this spectrum is not possible by imaging studies alone.
MR should be the imaging procedure of choice because the full extent of paraspinous and epidural tumor can be defined
noninvasively and without the use of ionizing radiation. Moreover, the ability to obtain images in the coronal plane is
invaluable in the assessment of spinal canal involvement. If CT is performed, intrathecal contrast is necessary in order to fully
define the extent of spinal epidural involvement.
Infantile Hemangioma
Infantile hemangiomas are the most common tumor of infancy, typically developing in the dermis during the first few weeks of
life, with the proliferative phase reaching a plateau at 9 to 10 months of age, followed by slow involution over 5 to 7 years
(158). Involvement of the CNS by infantile hemangiomas is rare; they are most commonly found incidentally in the basilar
cisterns (often extending into skull base foramina) although they can rarely extend in the supratentorial compartment of the
cranial vault (159). When they involve the spine, infantile hemangiomas are most commonly extradural masses that are
continuous with an overlying cutaneous hemangioma (159). When the lesions are large and threaten to cause symptoms due to
mass effect, corticosteroids are administered to accelerate regression. In the absence of treatment, surrounded or adjacent
structures may be damaged by mass effect and vascular “steal” phenomenon with resultant ischemic injury (Fig. 10-28).
MRI is the imaging study of choice. As with hemangiomas elsewhere in the body, the round to lobulated masses are iso- to
hypointense compared with skeletal muscle on T1-weighted images, and hyperintense compared to muscle on T2-weighted
images. They may be intraspinal, extraspinal, or both; the extraspinal component typically extends laterally through the neural
foramina, and then curves anteriorly around the vertebral bodies (159). Large curvilinear, hypointense flow voids are seen
within the mass, if imaging is performed during the proliferative phase. Contrast enhancement is intense and uniform. If they are
imaged on CT, hemangiomas are iso- to hyperintense on noncontrast images, and show intense enhancement. When the
proliferative phase ends, the hemangioma slowly shrinks and undergoes fatty metamorphosis. If the spinal cord has suffered
chronic ischemia, it may be focally shrunken (Fig. 10-28).
Figure 10-25 Non-Hodgkin lymphoma; this patient presented with cauda equina syndrome. Noncontrast T1-weighted (A), T2-weighted (B),
and contrast-enhanced T1-weighted (C) images show abnormal signal intensity and enhancement of multiple lumbar vertebrae. An intraspinal
mass (arrows) is seen at the L2 level, adjacent to the abnormal vertebrae. Axial postcontrast T1-weighted image (D) shows the enhancing
tumor mass markedly compressing the thecal sac (white arrowheads) from both sides.
Extramedullary Hematopoiesis
Extramedullary hematopoiesis is encountered in diseases with chronic overproduction of red blood cells. It is a very rare
disorder in children, being seen primarily in those with thalassemia. The most common sites of involvement are the liver and
spleen. Paravertebral involvement, which is less common, usually results in thoracic masses. Rarely, hematopoietic tissue
develops in the epidural space, possibly from transformation of primitive hematopoietic rests within the epidural space or by
direct extension of bone marrow from the adjacent vertebral bodies. The epidural tumor compresses the spinal cord, causing
myelopathy.
Figure 10-26 Peripheral primitive neuroectodermal tumor. Sagittal noncontrast T2-weighted image (A) shows a heterogeneous extradural soft
tissue mass (white arrows) in the caudal spinal canal. Axial images showed no paraspinal component. Postcontrast sagittal T1-weighted image
(B) shows faint patchy enhancement (white arrows) of the heterogeneous mass with most regions being relatively hypointense (similar to gray
matter).
Figure 10-27 Extraosseous Ewing sarcoma. A. Coronal T2-weighted image shows an extramedullary soft tissue mass (white arrows), slightly
hyperintense compared to the laterally displaced spinal cord (c). The tumor exits the spinal canal (large white arrowhead) through an enlarged
right C7 neural foramen. B. Coronal T2-weighted image a little anterior to (A) shows the enlarged roots and trunks of the brachial plexus (white
arrows), infiltrated by tumor.
Figure 10-28 Involuting extradural hemangioma. Sagittal T1-weighted image (A) shows severe atrophy (white arrows) of the upper thoracic
spinal cord and disruption of the posterior epidural fat. Contrast-enhanced sagittal (B) and axial (C) T1-weighted images show homogeneous
enhancement of the involuting epidural hemangioma (white arrows) within the spinal canal.
Figure 10-29 Epidural extramedullary hematopoiesis. Sagittal T2-weighted image shows multiple nodules (black arrows) of variable size in
the epidural space. These findings are nonspecific, and this diagnosis should be considered mainly in children with thalassemia or other long-
standing chronic anemias.
On imaging studies, regions of extramedullary hematopoiesis are nodular masses that are isointense to white matter on
noncontrast MR images (Fig. 10-29). Intense homogeneous enhancement is seen after intravenous administration of
paramagnetic contrast (160,161). These characteristics are not distinctive, being similar in appearance to most of the
extramedullary tumors discussed in this chapter. Therefore, the diagnosis of extramedullary hematopoiesis should be
considered primarily in the setting of thalassemia or other long-standing chronic anemias.
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Infections of the Developing and Mature Nervous System
Gary L. Hedlund, James F. Bale Jr., and A. James Barkovich
Introduction
Congenital and Perinatal Infections
General Concepts
Cytomegalovirus
Herpes Simplex Virus: Congenital and Neonatal Infections
Lymphocytic Choriomeningitis Virus
Rubella Virus
Treponema pallidum (Syphilis)
Toxoplasma gondii
Varicella-Zoster Virus
Zika Virus
Parechovirus
Human Immunodeficiency Virus
Other Congenital or Perinatal Infections
Disorders Mimicking Congenital Infections
Viral Infections
General Concepts
Herpesviruses
Nonpolio Enteroviruses
Arthropod-Borne Viruses
Influenza Virus
Rabies
Nipah Virus
Chronic Viral Infections
Cerebellitis
Rasmussen Encephalitis
Immune-Mediated Encephalitis and Parainfectious Leukoencephalopathies
Fungal Infections
General Concepts
Neonatal Candidiasis
Aspergillosis
Coccidioidomycosis
Cryptococcosus
Other Fungal Infections
Parasitic Infections
Neurocysticercosis
Cerebral Toxocaral Disease
Cerebral Malaria
Sarcoidosis
Infection/Inflammation of the Spine and Spinal Cord
General Concepts
Discitis and Osteomyelitis
Spinal Empyema
Spinal Cord Infection and Inflammation
Introduction
The clinician who cares for infants, children, and adolescents often faces the challenge of identifying the typical or uncommon
manifestations of potentially life-threatening infectious diseases. Although infections of the pediatric central nervous system
(CNS) constitute a small proportion of all pediatric infections, delays in the diagnosis and treatment of CNS infections can
have catastrophic consequences. Despite safe vaccines that can prevent several viral and bacterial diseases and effective
antimicrobial medications that can be used to treat many viral, bacterial, fungal, or parasitic disorders, infections of the
developing or mature nervous system remain major causes of permanent neurodevelopmental disability and death worldwide.
This chapter describes selected infections of newborns, infants, children, and adolescents, beginning with congenital and
perinatal period and continuing with acquired infections (1,2). For these disorders, common or rare, we describe the
epidemiology, clinical manifestations, and characteristic imaging features (3,4) in the hope that the information will aid in the
early identification and treatment of these infectious disorders. Information regarding immune-mediated disorders that may
mimic infectious diseases can be found in Chapter 3.
General Concepts
Infections of the fetus and neonate differ from those of older children and adults in that they can damage the nervous system
while it is developing; the manifestations and outcomes of these infections differ depending upon the gestational stage at the
time of infection, the immune status of the mother, and the neurotropism of the infectious pathogen. Clinicians must appreciate
that the gestational age of the fetus at the time of the insult can be more important than the nature of the insult. In general,
infections during the first two trimesters can result in congenital malformations, whereas those that occur during the third
trimester or in the immediate postnatal period manifest as destructive lesions (5).
Another feature of these early infections is an altered biological response to injury. As described in Chapter 4, the
immature brain does not respond to injury by astroglial reaction; instead, the immune response in the brain repairs the damage,
removes abnormal cells, and compensates for missing tissue. The immune-mediated inflammatory response, which contributes
to the damage produced by viral infection at later ages, is absent or less pronounced in the fetus and newborn infant (4,6).
Nearly 40 years ago, physicians at Emory University, Atlanta, Georgia, and the United States Centers for Disease Control
and Prevention coined the term TORCH, an acronym that denotes Toxoplasma gondii, Rubella, Cytomegalovirus, and
Herpesviruses and emphasizes these agents as important potential causes of congenital and perinatal human infections (5,7).
Despite remarkable advances in vaccine prevention and antiviral therapy in the subsequent decades, several of these agents, as
well as a few more recently recognized pathogens, remain major causes of permanent CNS injury in children (5,7). In addition
to cytomegalovirus (CMV), Toxoplasma gondii, rubella virus, and herpes simplex virus types 1 and 2, the clinical and imaging
features of other important agents, including lymphocytic choriomeningitis virus (LCMV), parechoviruses, varicella-zoster
virus, and Zika virus, are chronicled in Table 11-1 and discussed in the text of this chapter.
Infectious pathogens can be transmitted to the fetus via two main pathways (5,7). Bacteria can ascend from the cervix to the
amniotic fluid, whereas T. gondii, rubella, cytomegalovirus, and other viruses, including the Zika and LCMV, are generally
transmitted via the transplacental route. This section describes the imaging appearance of malformations caused by these
intrauterine infections, in contrast to those caused by ischemia or gene mutations, as well as the infections that occur during the
third trimester or perinatally that result in destructive brain lesions (5,7–9).
Table 11-1 Selected Congenital and Perinatal Infections
Cytomegalovirus Jaundice, hepatomegaly, splenomegaly, Intracranial Ca++, microcephaly, ventriculomegaly, neuronal migration anomalies,
rash microcephaly, chorioretinitis, IUGRa, pretemporal, germinal matrix zone and/or cerebellar cysts, WMc regions of T2
SNHLb hyperintensity
Herpes simplex Microcephaly, vesicular rash, cataracts, Multifocal T2 hyperintense lesions, basal ganglia involvement, hemorrhage, watershed
virus IUGR distribution lesions, extensive encephalomalacia
Human Anemia, hydrops fetalis Confluent cerebral hemispheric WM T2 hyperintensity, diffusion restriction, and
parvovirus B19 polymicrogyria
LCMVd Microcephaly, hydrocephalus, May precisely mimic CMV, microcephaly, hydrocephalus, and Ca++
chorioretinitis
Rubella virus Jaundice, rash, cataracts, congenital heart May cause lobar destruction and extensive encephalomalacia, atrophy, lenticulostriate
disease, microcephaly, IUGR, osteopathy, vasculopathy on US, may have periventricular and basal ganglia calcification. Cortex may
SNHL show Ca++
Toxoplasma Jaundice, hepatomegaly, hydrocephalus, Intracranial Ca++ less extensive than CMV, +/− hydrocephalus, lack of cortical
gondii seizures, chorioretinitis malformations
Varicella-zoster Microcephaly, cicatrix, cataracts, Horner Hydrocephalus, cerebellar aplasia, polymicrogyria, necrosis of deep GMe and cerebellum
virus syndrome
Zika virus Microcephaly Microcephaly, Ca++ at gray/white matter junction, ventriculomegaly, and polymicrogyria
Scalp rugae
Spasticity/abnormal tone
Contractures/arthrogryposis
SNHL
aIntrauterine growth retardation.
b Sensorineural hearing loss.
cWhitematter.
dLymphocytic choriomeningitis virus.
eGray matter.
Cytomegalovirus
Epidemiological studies from many different locations indicate that 0.25% to 1% of all infants shed CMV in urine or saliva at
birth, a finding consistent with congenital infection. Approximately 3000 to 4000 infants are born annually in the United States
with the clinical features of congenital CMV disease (10). An additional 30,000 to 35,000 infants are born annually in the
United States with CMV in their urine or saliva (CMV infection), but lack clinical symptoms at birth (10). Detailed natural
history studies indicate that infants with asymptomatic congenital CMV infections have very low rates of adverse sequelae
except for sensorineural hearing loss (11). By contrast, infants with congenital CMV disease, particularly those with abnormal
imaging studies, have high rates of neurodevelopmental sequelae (12–14). Transmission of CMV results from direct contact
with infected secretions, especially saliva, or transfusion of blood products or transplantation of organs from CMV-
seropositive persons (15).
Clinical manifestations in infants with congenital CMV disease include jaundice, hepatomegaly, splenomegaly,
microcephaly, hearing loss, chorioretinitis, and petechial or purpuric skin rash; laboratory studies can show thrombocytopenia,
direct hyperbilirubinemia, and elevated serum transaminases (16). The majority of infants with congenital CMV disease have
permanent neurodevelopmental sequelae, including microcephaly, cerebral palsy, cognitive impairment, sensorineural hearing
loss, visual abnormalities, and seizures. Sensorineural hearing loss can progress after birth, in both infants with congenital
CMV disease and those who were without symptoms at birth (17). By contrast, the vast majority of CMV-infected infants who
lack signs of infection, either at birth or subsequently, have normal neurodevelopmental outcomes. Steinlin et al. (18) have
described a characteristic clinical syndrome in patients who are infected with CMV during the third trimester. Characteristics
of the syndrome include microcephaly with sensorineural hearing loss, hyperactivity and associated behavioral problems,
reduced apprehension for pain, and, sometimes, ataxia and hypotonia.
The diagnosis of congenital CMV infection can be established by detecting CMV in the infant’s urine or saliva during the
first 3 weeks of life by using cell culture or the polymerase chain reaction (PCR) (15,16). PCR analysis of newborn blood
spots (Guthrie cards) can be used to establish the diagnosis retrospectively, but this method lacks sufficient sensitivity and
specificity for the screening of infants for CMV for the routine diagnosis of congenital CMV infection (19,20). Treatment with
ganciclovir can diminish the risk of sensorineural hearing loss and improve neurodevelopmental outcomes in infants with CMV
disease (21).
The mechanism of CNS injury in congenital CMV disease has not been determined with certainty (22). Some have
speculated that the virus infects and damages the rapidly growing cells of the germinal matrix, causing the deposition of
calcium in the periventricular region, and perturbs the migration of neuronal cell populations, resulting in abnormalities of the
cerebral and cerebellar cortices (22). Others postulate a primary vascular target by the virus, with hematogenous seeding of the
choroid plexus and viral replication in the ependyma, germinal matrix, and capillary endothelia. These events result in brain
injury secondary to fetal brain ischemia (23). Whatever the underlying cause, affected infants and children are typically
microcephalic with diminished white matter, anterior temporal lobe cysts, astrogliosis, cerebral calcifications, delayed myelin
maturation, or dysmyelination. More severe cases have cortical malformations (agyria, lissencephaly, pachygyria, and
polymicrogyria) and cerebellar hypoplasia (Table 11-2) (24–28). These disorders can be detected by imaging, as described in
the following section.
Calcifications
Cerebellar hypoplasia
Cerebral cortical abnormalities
• Polymicrogyria
• Cortical cleft dysplasia
• Schizencephaly
• Hippocampal dysplasia
• Lissencephaly
Cysts
White matter abnormality
Imaging
Fetal MRI is more sensitive than is antenatal sonography in detecting the combination of malformations and destructive lesions
caused by CMV. These include microcephaly, cerebral cortical abnormalities, cerebellar hypoplasia, white matter lesions, and
temporal lobe or polar abnormalities such as enlarged temporal horns, abnormal white matter, and temporal polar cysts (29).
Fetal brain MR imaging is able to demonstrate CMV-associated abnormalities before 24 weeks of gestation and can
demonstrate evolving infection-related changes. Even when level II fetal US results have been reported as normal, performing
fetal MRI in the third trimester can be helpful in the detection of new cerebral malformations and destructive lesions and can
accurately monitor the evolution of previously defined lesions (Fig. 11-1).
Figure 11-1 Fetal congenital CMV infection. Twenty-eight weeks of gestation. A. Axial T2-weighted fetal MRI image shows bilateral
periventricular germinolytic cysts (arrowheads) and abnormal gyri (arrows). B. Coronal T2-weighted image demonstrates diffuse polymicrogyria
(arrows). (Courtesy of Catherine Adamsbaum, MD, Paris, France.)
Findings on cross-sectional imaging vary depending upon the degree of brain destruction and the timing of the injury, timing
of imaging, and imaging modality. Postnatal, transfontanelle cranial ultrasound may show branching curvilinear
hyperechogenicities in the basal ganglia and/or punctuate subependymal hyperechogenicities (mineralization) (Figs. 11-2 and
11-3). The pattern of basal ganglia involvement is called “lenticulostriate vasculopathy” (30,31). It is seen in children with
congenital infections of many types and is also described in children with trisomy 13, trisomy 21, prenatal drug exposure,
congenital heart disease, and a variety of anoxic and toxic injuries to the developing brain (31,32). Postmortem studies have
described evidence of a mineralizing vasculopathy as the cause, whereas other studies suggest altered perfusion, perhaps the
result of impaired autoregulation (33,34). Lenticulostriate vasculopathy is a nonspecific finding, and the diagnosis of
congenital infection should not be strongly considered unless other supportive findings (parenchymal regions of
hyperechogenicity, intraventricular septations, periventricular necrosis [germinolytic cysts], anterior temporal white matter
lesions, and/or abnormalities of sulcation) are also seen by fetal imaging (US or MRI) or postnatal US, CT, or MRI (Fig. 11-4)
(35–37). Antenatal cranial sonography may offer predictive information for the fetus infected with CMV but may underestimate
the presence of anterior temporal lobe or temporal polar abnormalities (38). On CT and MR, some patients, presumably
infected during the first half of the second trimester, demonstrate agyria or lissencephaly with a thin cortex, cerebellar
hypoplasia, delayed myelination, marked ventriculomegaly, germinal zone cysts, anterior temporal lobe cysts, and
periventricular calcification (Figs. 11-3 to 11-6). Those injured later, presumably in the middle of the second trimester, have
more typical polymicrogyria, less ventricular dilatation, and less consistent cerebellar hypoplasia; schizencephaly and
infoldings of cortical dysplasia can be seen (Figs. 11-6 to 11-8) (39,40). Patients infected near the end of gestation or in the
early postnatal period have normal gyral patterns, mild ventricular and sulcal prominence, and damaged periventricular or
subcortical white matter with scattered periventricular calcification or hemorrhage (Figs. 11-7 to 11-9) (12,18,24,28,41,42).
FLAIR images, particularly in the first year of life, provide relatively poor contrast between gray and white matter; therefore,
T2-weighted images are essential to identify cortical malformations (Figs. 11-6 and 11-7), the detection of which helps
establish the diagnosis of congenital CMV.
Figure 11-2 Neurosonographic features of congenital CMV infection. A. Parasagittal sonogram shows linear hyperechogenicity (arrows) within
the basal ganglia consistent with lenticulostriate mineralizing vasculopathy. Note the focus of periventricular hyperechogenicity (arrowhead)
corresponding to calcification on CT (not shown). B. Coronal sonogram shows multiple subcortical and periventricular foci of
hyperechogenicity confirmed by CT (not shown) to represent calcification (arrows). Also note the left germinal matrix cyst (arrowhead). C.
Parasagittal sonogram in a microcephalic newborn demonstrates extensive linear and punctuate periventricular hyperechogenicities (arrows)
representing calcification. There is moderate ventriculomegaly. D. Parasagittal sonogram shows a cyst of the caudothalamic germinal matrix
zone (arrow) and focal peritrigonal hyperechogenicities (arrowheads) consistent with calcification.
Figure 11-3 Congenital cytomegalovirus infection. A. Coronal sonogram in this microcephalic newborn shows moderate ventriculomegaly
and multifocal periventricular hyperechogenicities (arrows). B. Axial noncontrast CT shows extensive periventricular calcification. Note the
moderate ventricular dilatation and overlap of the coronal sutures reflecting underlying brain injury and poor brain growth. C. Axial T1-weighted
image at the level of the enlarged lateral ventricles demonstrates ependymal T1 shortening (arrows) representing calcification. D. Axial T2-
weighted image shows less conspicuous T2 shortening at sites of known calcification (black arrows). E. Axial T2-weighted image 3 years later
shows persistent ventricular enlargement and near-complete absence of periventricular T2 hypointensities. In time, the microglial cells or
Hortega cells will remove calcium and hemorrhage.
Figure 11-4 Congenital CMV infection. A. Coronal cranial ultrasound shows basal ganglia linear hyperechogenicities consistent with
lenticulostriate vasculopathy (arrows). Also note the focal dilation of the temporal horns (arrowheads). B. Axial T2-weighted image
demonstrates bilateral cystic temporal horn dilation (curved arrows). Hyperintense white matter is identified anterior to the temporal horns.
Damage to the white matter may be seen in those infected at any gestational age. Potential causative factors include primary
CMV infection, host inflammatory and immune response including cytotoxic T-cell response, and injury to oligodendroglial
cells. These white matter lesions are static like those of periventricular leukomalacia. van der Knaap et al. (43) have
described a distinct pattern of white matter abnormalities in neonates with congenital CMV infection. Some of these patients
lack gyral anomalies; in such patients, multiple white matter lesions typically involve the deep white matter, often sparing
immediate periventricular and subcortical white matter, with the largest lesions often in the parietal lobes (Figs. 11-7 and 11-
8). In patients with gyral anomalies, white matter abnormalities may be diffuse or multifocal (Figs. 11-3, 11-5, 11-6, 11-7, and
11-9). Abnormalities of the temporal polar regions are strongly suggestive of congenital CMV infection. Dilation of the
temporal horns may be detected as early as 20 weeks of gestation, with subsequent evolving temporal lobe white matter T2
hyperintensity (swelling) and, ultimately, the formation of temporal polar cysts (Figs. 11-4, 11-7, and 11-9) (43). The apparent
selective vulnerability of the temporal lobe regions to congenital CMV infection and the pathological underpinnings remains
unexplained.
In affected newborns and infants, the white matter lesions demonstrate diffusivity (also called apparent diffusion coefficient,
ADC) values that are increased; fractional anisotropy (FA) values (which represent a measure the degree of diffusion
anisotropy) are decreased (43).
Figure 11-5 Congenital cytomegalovirus infection in a neonate. A and B. Axial T1-weighted images show the agyria, markedly hypoplastic
cerebellar hemispheres (white arrows), and periventricular calcifications (black arrows) common in this disorder.
Calcifications can be seen on CT as foci of high attenuation (Figs. 11-3, 11-5, and 11-6). Although calcifications can be
detected on MR in neonates and young infants as foci of short T1 and T2 relaxation times (Figs. 11-3 and 11-6), they are much
more easily and reliably detected on CT than on MR in older infants and children. Although dogma has suggested that
congenital CMV CNS infection is predictably associated with cerebral calcifications, the prevalence of calcification may be
less than 70%. Differentiation of calcification from hemorrhage may be difficult by either CT or MRI (24). Including
susceptibility-weighted imaging (SWI) and SWI filtered phase maps into the routine MR examination aids in the differentiation
of SWI hypointensities of blood products (paramagnetic) from calcifications (diamagnetic). The SWI filtered phase map of
calcifications is hyperintense (Fig. 11-10) (44). Clinicians should recognize that calcification is not uniquely specific for
congenital infection, as any injury to the brain, including those caused by ischemia, genetic syndromes, metabolic errors, and
nonspecified neurodegeneration, can cause dystrophic calcification (45–47). MR is the imaging examination of choice for the
detection of cortical malformations, myelin abnormalities (delay and demyelination), germinal zone cysts, and cerebellar
hypoplasia/dysplasia. When these features are present in a child with microcephaly, developmental delay, sensorineural
hearing loss, and seizures, a diagnosis of congenital CMV should be considered (24).
Figure 11-6 Cortical dysgenesis and congenital cytomegalovirus infection. A. Axial noncontrast CT image shows extensive intracranial
parenchymal calcification and shallow sylvian fissures strongly suggesting an accompanying neuronal migration anomaly. B. Axial T1-weighted
image demonstrates foci of T1 shortening (arrows), which correspond to calcification on CT. Note the simplified perisylvian sulcation. C. Axial
T2-weighted image through the posterior fossa shows a hypoplastic cerebellum. Cystic change (arrow) and folial dysgenesis are noted. D.
Axial T2-weighted image shows the cortical dysgenesis of the cerebrum to best advantage; this is most likely diffuse polymicrogyria. Note the
subtle foci of T2 shortening corresponding to calcification (arrows) and the occipital periventricular cysts.
Figure 11-7 Infant with congenital cytomegalovirus infection. A. Sagittal T1-weighted image shows diffuse polymicrogyria (arrows). Also note
temporal horn dilation (curved arrow) and T1 prolongation of anterior temporal lobe white matter. B. Axial T2-weighted image at the level of the
temporal horns shows bilateral temporal horn dilation and T2 prolongation of temporal lobe white matter. C. Axial FLAIR image shows simplified
sulcal gyral pattern consistent with bihemispheric polymicrogyria (arrows) and confluent regions of cerebral hemispheric white matter T2
prolongation.
Figure 11-8 Congenital cytomegalovirus infection with focal clefting and encephalomalacia. A. Axial noncontrast CT image shows bilateral
frontal lobe subcortical hypoattenuating regions (black arrows) and sparse parenchymal calcification (white arrow). B. Parasagittal T1-weighted
image shows several areas of subcortical encephalomalacia (black arrows), manifested as hypointensity. C. Axial T2-weighted image
demonstrates the encephalomalacic regions to be continuous with the subarachnoid space as clefts (white arrows). Also note the other patchy
bihemispheric regions of white matter hyperintensity. D. Axial FLAIR image shows to best advantage the confluent regions of bihemispheric
white matter hyperintensity and the hypointense subcortical white matter clefts (black arrows). E. DTI-derived axial color-encoded fractional
anisotropy (FA) map demonstrates a loss of coherence (hypointensity and distortion of normal tracts, as well as predominant superior–inferior
orientation, manifested as blue color) in the periventricular corticospinal tracts (white arrows).
Figure 11-9 Congenital cytomegalovirus infection and white matter disease. A. Parasagittal T1-weighted image demonstrates an anterior
temporal lobe subcortical cyst (white arrows). Also note confluent T1 prolongation within the parietal white matter (black arrows). B. Coronal T2-
weighted image demonstrates anterior temporal cysts (black arrows). Note the multifocal areas of central and subcortical white matter T2
prolongation (white arrowheads). C and D. Axial FLAIR images at the level of the lateral ventricles and centra semiovale show bilateral
asymmetric patchy regions of white matter FLAIR hyperintensity.
Figure 11-10 Susceptibility-weighted imaging (SWI) and Ca++ detection. A. Axial NECT in a patient with tuberous sclerosis complex
demonstrates focal periventricular high-attenuation calcified tubers. B. Axial SWI image shows focal hypointensities where CT demonstrated
calcifications. C. Axial filtered phase map of the SWI image demonstrates the calcified tubers as hyperintense foci (arrows). This demonstrates
the value of SWI filtered phase maps in discriminating hemorrhage (paramagnetic and SWI-hypointense, filtered phase map hypointense) from
calcification (diamagnetic and SWI hypointense, filtered phase map hyperintense).
Pathologically, HSV can infect and severely damage many brain regions, with resultant necrosis, cellular debris,
macrophages, mononuclear inflammatory cells, calcification, and hypertrophied astrocytes (56). The pial–glial membrane
remains intact, and the ependyma and choroid plexuses are notably spared, in contrast to their involvement in congenital CMV
and toxoplasmosis infections (57).
Imaging
The radiologist must consider neonatal herpes simplex encephalitis (HSE) in the neonate whose cranial imaging in the second
to third weeks of life demonstrates diffuse cerebral edema and the presence of leptomeningeal enhancement, with or without
parenchymal hemorrhage.
Sonographic findings are often subtle, initially showing nonspecific diffuse parenchymal hyperechogenicity and normal
ventricles; parenchymal echogenicity subsequently increases with associated ventricular compression (58,59). The ventricles
eventually enlarge as encephalomalacia develops (59). MRI is the study of choice in neonates with suspected herpes
encephalitis (60–63), with imaging features of HSV type 2 encephalitis consisting of multifocal lesions (67%), temporal lobe
involvement (67%), deep gray matter injury (58%), hemorrhage (66%), watershed pattern of injury (40%), and occasional
involvement of the brain stem and cerebellum (63). In neonatal HSV encephalitis, diffusion-weighted MR imaging is critical to
making an early diagnosis, monitoring disease progression, and detecting rare CNS relapses (64–66). Diffusion imaging
depicts early cellular necrosis, which is seen as hypointensity (reduced diffusion) on average diffusivity (Dav) images (65,66).
In this acute stage of disease, standard MR imaging is often normal (Fig. 11-11) (61,63). Subtle hyperintensities may or may
not be seen on T2-weighted images in the late acute and early subacute stages of infection. As the infection progresses (at the
end of the first week), diffusion imaging becomes less helpful and standard spin echo imaging more helpful (61,63). Early
proton MR spectroscopy shows elevated lactate and, often, reduction of N-acetyl aspartate (NAA) in affected regions (Fig. 11-
12) (61,63). After 1 or 2 days, CT and MR show patchy, multifocal areas of injury (low attenuation on CT, T1 hypointensity,
T2 hyperintensity, and regions of reduced diffusion), affecting gray and white matter (Figs. 11-11 to 11-13), which progresses
in prominence and extent of involvement during the course of the next several days. Hemorrhage is a common finding in
neonatal herpes encephalitis, seen in up approximately two-thirds of patients (Fig. 11-14) (63). Contrast enhancement, although
minimal, occurs early in a meningeal pattern (Fig. 11-14) (63). Near the end of the first week of disease, there are often regions
of cortical gray matter injury (increased attenuation on CT, T1 hyperintensity, and T2 hypointensity on MR) that persists for
weeks to months(61,63,67). Loss of brain substance occurs rapidly, often as early as the second week. Eventually, severe,
diffuse cerebral atrophy ensues with profound cortical thinning and encephalomalacia; in the end stage, the brain often appears
multicystic (Fig. 11-15E). Punctate or curvilinear gyral calcifications may also be seen as a late finding. The cerebellum is
injured in about half of the affected patients (61,63,67).
Figure 11-11 Early diffusion-weighted imaging in neonatal herpes simplex encephalitis. A. Axial noncontrast CT in a seizing 3-week-old
female shows diffuse hypodensity. B. Axial T2-weighted image shows normal gray matter and white matter differentiation without cortical
blurring. Cortical blurring is an indicator of early peripheral edema. C. Axial apparent diffusion coefficient image shows reduced diffusion within
the left temporal lobe (arrows) and occipital poles. Diffusion-weighted imaging is particularly valuable in the early phase of neonatal herpes
encephalitis where injury of tissue is manifested as regions of reduced diffusion.
Although the white matter changes in neonatal herpes encephalitis are nonspecific (Figs. 11-12 to 11-15), early reduced
diffusion, parenchymal hemorrhage, and a meningeal pattern of enhancement in the proper clinical setting should lead to a
suggestion of the diagnosis of neonatal HSE. It is important for the radiologist to remember that neonatal herpes simplex
encephalitis demonstrates nonpatterned MR abnormalities. The clinical presentation and imaging appearance of herpes
encephalitis in older children and adults (HSE) (usually caused by herpes simplex virus, type I) is quite different than neonatal
HSV infection, primarily reflecting infection of the temporal lobe and insular cortex, limbic structures (61).
LCMV infection should be considered among infants who have chorioretinitis in association with congenital hydrocephalus
or microcephaly, lack hepatosplenomegaly, and have negative microbiologic studies for the more common pathogens such as T.
gondii and CMV (71). As with most congenital infections, the severity of the infection is related to the fetal age at the time of
infection, with earlier infections being more severe (72). First trimester infection typically results in spontaneous abortion,
whereas second and third trimester infections strongly resemble those of toxoplasmosis and CMV, with predominant disease
being located in the CNS (73). The most prominent clinical feature is chorioretinitis, seen in about 90% of infected neonates,
which is lacunar and resembles the retinal lesions in Aicardi syndrome (see Chapter 5) and toxoplasmosis. Hydrocephalus,
seen in more than 50% of affected neonates, results from necrotizing ependymitis and aqueductal obstruction (70,71). Other
infants with congenital LCMV virus infections can have microcephaly and intracranial calcifications (70,71). Seizures
commonly develop during the first year of life. Long-term outcome is generally poor, with mortality as high as 35% and severe
neurologic sequelae in more than 60% of survivors (71).
Figure 11-13 Leukotropic neonatal herpes simplex encephalitis. A. Axial T1-weighted image shows bilateral frontal white matter foci of T1
shortening (arrows) likely representing coagulative necrosis of the white matter. There was no corresponding GRE blooming. Also note the
focal right germinal zone hemorrhage (arrowhead). B. Axial T2-weighted image demonstrates corresponding T2 shortening (arrows). C.
Coronal T2-weighted image shows more hypointense foci within the centrum semiovale of the cerebral hemispheres (arrows). D. Axial
diffusion-weighted image shows bifrontal and left peritrigonal foci of hyperintensity (arrows). E. Axial apparent diffusion coefficient image
confirms the bright diffusion-weighted signal abnormalities to represent sites of reduced diffusivity (arrows). As the encephalitis becomes less
acute, standard spin echo images become more useful and diffusion-weighted imaging less useful. F. Axial color-encoded fractional anisotropy
image (F) at the location of previously described reduced diffusion shows disturbance of white matter fiber track coherence: increased
anisotropy in corpus callosum but decreased in the frontal and occipital white matter (arrows).
Figure 11-14 Hemorrhagic neonatal herpes simplex encephalitis. A. Axial T1-weighted image in a 3-week-old neonate demonstrates right
thalamic and left temporal lobe T1 shortening confirmed on GRE imaging to represent hemorrhage. The deep cerebral nuclei and temporal
lobes are common sites of injury in neonatal herpes encephalitis. B. Coronal T2-weighted image depicts the multifocality of brain parenchymal
involvement that occurs in 67% of neonatal herpes encephalitis. Note the bilateral frontal, right basal ganglia, and left parafalcine parenchymal
hemorrhages (T2 shortening) and associated edema (T2 prolongation). C. Coronal GRE shows cortical, subcortical, and basal ganglia regions
of blooming hypointensity representing multifocal hemorrhage. D. Axial T1-weighted contrast enhanced image at the level of the lateral
ventricles demonstrates bilateral subinsular foci of T1 shortening (arrows). Prior to contrast, no corresponding hyperintense lesions were seen.
Imaging
Imaging studies of neonates and infants with LCMV may overlap in neonates and infants with congenital toxoplasmosis and
CMV infections (7). Timing of this congenital infection dictates the pattern of CNS injury. Hydrocephalus can be seen by
sonography, CT, or MR (Fig. 11-17) (71,74,75). Periventricular calcifications, when present, are most easily seen by CT as
high attenuation punctate periventricular lesions (Fig. 11-16) (69,72). Calcifications on MRI may be very subtle, showing
punctate hyperintensity from T1 shortening when calcium molecules are less densely packed (and the paired outer shell
electrons of water can transiently bind to them), hypointensity from T2 shortening or absence of water in tightly packed
crystals, and hyperintensity on SWI filtered phase maps. MR may also show a cortex composed of multiple small, shallow
sulci, the appearance of which suggests polymicrogyria (Fig. 11-17). These findings strongly suggest congenital infection, but
the final diagnosis must be made by serologic and microbiologic studies.
Rubella Virus
Prior to widespread implementation of the measles–mumps–rubella vaccine, epidemics of rubella (German measles) occurred
worldwide at 6- to 9-year intervals. During the 1962–1965 pandemic, the last major US rubella outbreak, approximately
20,000 infants were affected by congenital rubella syndrome (CRS); there were more than 10,000 fetal deaths and 2000
neonatal deaths (76). CRS largely disappeared from the US and other developed nations by the late 1980s because of
immunization programs (77) but remains a major health concern in many regions of the world, with more than 100,000 cases
estimated by the Centers for Disease Control and Prevention (CDC) to have occurred worldwide annually during the first
decade of the current millennium. Humans represent the only reservoir of rubella virus, and transmission results from contact
with virus-contaminated respiratory secretions (76).
Figure 11-15 Progression of neonatal herpes encephalitis to cystic encephalomalacia. A. Axial T1-weighted image in a preterm neonate with
new-onset seizures shows a focus of hemorrhage within the right parietal lobe (arrow). There are multiple bilateral centrum semiovale foci of
T1 shortening. GRE imaging confirmed hemorrhage in multiple white matter sites. The simplified sulcation and gyration pattern was attributed
to prematurity. B. Axial T2-weighted image shows a focal hemorrhage with hematocrit effect in the right parietal white matter. T2 signal is
prolonged throughout the white matter. C. Coronal T2-weighted image shows symmetric temporal and frontal white matter T2 hyperintensity.
Note the subtle hypointensity within the right temporal white matter (arrow) that corresponded to hemorrhage on GRE. D. Axial apparent
diffusion coefficient image at the level of the temporal lobes 14 days after symptom onset shows increased diffusivity throughout the white
matter (regions of hyperintensity). E. Axial FLAIR image at 5 years of age shows extensive cystic encephalomalacia.
Figure 11-16 Lymphocytic choriomeningitis virus (LCMV). Axial noncontrast CT images (A–C) show a diffuse array of small calcifications
involving subcortical and periventricular white matter and internal capsules. This microcephalic infant with chorioretinitis had a “negative”
clinical/laboratory evaluation for TORCH infection. The imaging studies of neonates and infants with LCM may be identical to those of neonates
and infants afflicted with congenital CMV and toxoplasmosis.
Figure 11-17 Lymphocytic choriomeningitis virus. A. Axial noncontrast CT image shows marked hydrocephalus and hypodensity of the white
matter, but no calcifications. B. Axial T2-weighted image shows abnormal sulcation (arrows) of the frontal lobes.
Infants with CRS differ from those with congenital infections with either T. gondii or CMV by lower rates of
hepatosplenomegaly and jaundice, high rates of cataracts, and the presence of congenital heart disease, typically patent ductus
arteriosus (78). Microcephaly, chorioretinitis, sensorineural hearing loss, and the classic “blueberry muffin” rash, a sign
indicating extramedullary hematopoiesis, are common in infants with CRS. The diagnosis can be established serologically,
virologically, or molecularly, using the PCR. As no specific therapy for CRS currently exists, survivors have high risks of
neurodevelopmental sequelae, including microcephaly, vision loss, cognitive impairment, and sensorineural hearing loss (79).
On pathologic examination, brains of affected infants are microcephalic with ventriculomegaly resulting from loss of brain
tissue. Multiple small areas of liquefactive necrosis and gliosis with calcification are seen in the periventricular white matter,
basal ganglia, and brain stem; these result from a prominent vasculopathy (78). Myelination is typically impaired (78,80), but
the encephalitis is usually not progressive after infancy.
Imaging
The appearance of the brain on imaging studies varies depending upon the timing of in utero infection. Early infection will
result in congenital anomalies, whereas late infection will result in a nonspecific generalized edema, gliosis, and loss of brain
tissue. Ultrasound may show nonspecific lenticulostriate vasculopathy (see discussion under CMV) (30,31). CT typically
shows ventriculomegaly, multifocal regions of hypodensity throughout the cerebral white matter, often in association with
periventricular and basal ganglia calcification and cysts (Fig. 11-18) (81,82). Calcification may also be seen within the cortex.
In severe cases, nearly total brain destruction and microcephaly are present (83). MR imaging may show ventriculomegaly,
multifocal regions of white matter prolonged T2 relaxation (T2 hyperintensity), or myelination delay/destruction (82,84,85).
Frontal dominant white matter lesions showing T2 hyperintensity have been reported following congenital rubella and CMV
infections (28). High-resolution CT of the temporal bones may show malformations of the inner ear structures. Enhanced MR
imaging may show enhancement of the cochlea (cochleitis) (86).
Figure 11-18 Congenital rubella. A. Axial noncontrast CT demonstrates subtle cerebral calcifications (arrows). B and C. Axial T2-weighted
images show patchy regions of periventricular white matter hyperintensity (arrows) most consistent with regions of demyelination and/or
gliosis. (Courtesy of Majda M. Thurner, MD, and Elsevier.)
Imaging
The most common imaging findings are leptomeningeal enhancement, hydrocephalus, and infarction (Fig. 11-19). Cisternal
inflammatory exudative involvement (inflammation, fibrosis, and gumma formation) investing the pituitary gland and
infundibulum may lead to persistent hypoglycemia, diabetes insipidus, and hypopituitarism (90,91).
Toxoplasma gondii
Congenital toxoplasmosis, the result of intrauterine infection with the ubiquitous intracellular parasite, Toxoplasma gondii, is
the second most common congenital infection, after CMV, in many regions of the world. Rates of congenital toxoplasmosis
range from less than 0.1 in many areas to 1 per 1000 live births in highly endemic regions. The seroprevalence of
toxoplasmosis among adults, a measure of acquired infection with T. gondii, is highest in France; intermediate in Latin
American, sub-Saharan Africa, and central Europe; and lowest in North America, Southeast Asia, and Oceana (92).
Toxoplasma gondii infects birds and many mammals, especially felines, worldwide (93). Infected domestic cats, a major
source of human disease, excrete vast quantities of oocysts; human infection results from ingesting undercooked meats that
contain viable T. gondii tissue cysts or foods contaminated with infectious oocysts.
Figure 11-19 Congenital syphilis. Axial T2-weighted image shows watershed ischemia in the right cerebral hemisphere and severe ischemic
damage in the left cerebral hemisphere. Ischemic injury is due to invasion of perivascular spaces by an inflammatory infiltrate. (Courtesy of
Robert A. Zimmerman, MD, Philadelphia, PA.)
The clinical and laboratory manifestations of congenital toxoplasmosis, as implied by the TORCH acronym, resemble those
of congenital CMV disease and consist of hepatosplenomegaly, jaundice, chorioretinitis, petechial or purpuric rash,
thrombocytopenia, elevated serum transaminases, and hyperbilirubinemia (94). Chorioretinitis is very common. In contrast to
CMV, macrocephaly (a sign of intrauterine or postnatal hydrocephalus) and chorioretinitis (a potential cause of visual
impairment) are common in infants with congenital toxoplasmosis. The diagnosis is established by detecting T. gondii-specific
IgM or IgA in the infant’s serum. Analysis of paired sera from the infant and the infant’s mother can be useful; the absence of T.
gondii-specific IgG or IgM in the infant’s serum and the absence of T. gondii-specific IgG in the mother’s serum argues
strongly against congenital toxoplasmosis. Prolonged postnatal therapy with pyrimethamine and sulfadiazine and early shunting
of T. gondii-induced hydrocephalus substantially improve the long-term prognosis for infants with congenital toxoplasmosis
(95,96). As many as 85% of untreated infants with congenital toxoplasmosis have chorioretinitis, and mortality in untreated
infants can be as high as 15% (97). Survivors of congenital toxoplasmosis are at risk for cerebral palsy, cognitive impairment,
and epilepsy (96); the risk of sequelae is reduced when antimicrobial therapy is initiated early (96,98,99).
Pathologically, a diffuse inflammatory infiltration of the meninges is found, with large and small granulomatous lesions or a
diffuse inflammation of the brain. Hydrocephalus is frequent, most often caused by an ependymitis occluding the cerebral
aqueduct (46,100). Porencephaly or hydranencephaly may occur if the disease is severe and occurs in the second trimester
(101). In contrast with congenital CMV infection, malformations of cortical development, such as lissencephaly,
polymicrogyria, and schizencephaly are not typical features of congenital toxoplasmosis.
Imaging
The findings on cross-sectional imaging may be similar to those in CMV. As in congenital CMV, fetal brain imaging often
detects early destructive changes (102). Calcifications are common; they usually involve the basal ganglia, periventricular
regions, cerebral cortex, and subcortical white matter (more scattered in distribution than CMV) (Figs. 11-20 and 11-21). It is
important to recognize that the predilection for calcium in the periventricular regions is less common than with congenital
CMV infection. Fetal imaging (US and MRI) reveals ventriculomegaly, echodense (US) and T2 hypointense (MRI)
calcifications of the cerebral parenchyma, and parenchymal cysts (102). In the neonate, cranial sonography may show
shadowing parenchymal hyperechoic foci, which correspond to calcifications detected by CT (103). Due to the inflammatory
nature of this disease and aqueductal obstruction, hydrocephalus is more common than in CMV (Figs. 11-20 and 11-21). As
with CMV, the spectrum of potential abnormalities ranges from relatively mild disease, with a few periventricular
calcifications and mild atrophy, to severe disease with near-total destruction of the cerebrum accompanied by diffuse cerebral
calcifications (Fig. 11-20). Diebler et al. (104) have related the severity of the brain involvement to the date of maternal
infection, noting that infection before 20 weeks is generally accompanied by severe neurological findings, including
microcephaly, hydrocephalus, tetra- or diplegia, seizures, mental retardation, and blindness. CT revealed dilated ventricles,
areas of porencephaly, and extensive calcifications, particularly in the basal ganglia (Fig. 11-20), that may exhibit a tram-track
morphology (105). Infection between 20 and 30 weeks leads to a more variable outcome; on CT, sparse (Fig. 11-21) or
multiple periventricular calcifications and ventricular dilation are typical findings (Fig. 11-20). Infection after the 30th week
of gestation is generally associated with mild clinical and imaging abnormalities, with CT findings of small periventricular and
intracerebral calcifications that are only rarely accompanied by ventricular dilatation (104). An important differentiating
feature between congenital toxoplasmosis and congenital CMV infection is the absence of cortical malformations in
toxoplasmosis (a common occurrence in congenital CMV). The brain calcifications of congenital toxoplasmosis may resolve
slowly in some infants after antitoxoplasma therapy (106). Therefore, the disappearance of calcification over time should not
cause confusion if the diagnosis was established at birth on the basis of characteristic ocular findings and serologic testing.
Figure 11-20 Congenital toxoplasmosis. A and B. Axial noncontrast CT images in a newborn show extensive parenchymal calcifications that
are predominantly cortical and subcortical in location. Also note moderate ventriculomegaly. Hydrocephalus is more common in toxoplasmosis
than CMV infection. C and D. Axial and coronal T2-weighted images show multiple foci of T2 hypointensity corresponding to CT confirmed
calcification (black arrows). Also note the subcortical cysts (c). Ventriculomegaly is moderate.
Figure 11-21 Congenital toxoplasmosis with minimal cerebral calcification. A and B. Noncontrast axial CT images show sparse parenchymal
calcification (arrows). Calcification was not present on the initial CT studies in the neonatal period. Note the presence of ventricular shunt
catheters. Congenital toxoplasmosis is often associated with ependymitis and resultant hydrocephalus.
Varicella-Zoster Virus
In unimmunized populations, the rate of varicella infection (chickenpox), acquired through contact with the respiratory
secretions of infected children, ranges from less than 1 to 3 per 1000 pregnancies, and very few (<2%) of these pregnancies
result in infants with the congenital varicella syndrome (107,108). Infants with this disorder, like those with congenital HSV or
LCMV infections, generally lack typical signs of congenital infection, such as jaundice, hepatosplenomegaly, or
petechial/purpuric rash. Infants with congenital varicella infected before 20 postconceptional weeks may suffer spontaneous
abortion or embryopathy with microcephaly (resulting from cerebral destruction), cataracts or chorioretinitis, limb or digit
hypoplasia, and a characteristic pattern of skin scarring known as a cicatrix (108,109).
Figure 11-22 Congenital varicella-zoster virus infection. A. Axial T1-weighted image in a microcephalic term newborn shows extensive
bilateral periventricular T1 shortening consistent with coagulative necrosis. SWI showed no evidence of hemorrhage or calcification. B. Axial
T2-weighted image shows no significant abnormality. Note the normal cortical ribbon at this level, unlike polymicrogyria often observed in
congenital CMV infection. C. Axial ADC map demonstrates scattered foci of reduced diffusion (arrows).
Imaging
Polymicrogyria involving the cerebral hemispheres and necrosis of white matter and deep gray nuclei and cerebellum have
been reported in autopsy studies (110). Two MR studies have been reported, emphasizing variable findings likely reflecting the
timing and severity of infection. One report describes hydrocephalus and cerebellar aplasia, while the other describes
destruction of the temporal and occipital lobes with marked ventricular dilation in those areas, but normal cerebellum, basal
ganglia, and frontal/parietal lobes (59,111). As with many of the previously described congenital CNS infections, MRI may
lack specificity but does allow a full appraisal of brain injury and malformations (Fig. 11-22). Although retrospective
diagnosis can be challenging, intrauterine infections with VZV can be established by serological or virological methods.
Zika Virus
First isolated from a rhesus monkey in the Zika Forest of Uganda in the late 1940s, Zika virus belongs to the Flaviviridae, a
family of RNA arboviruses that includes West Nile, St. Louis encephalitis, and yellow fever viruses. Prior to 2000, human
infections were rare (112). In 2007, Zika virus appeared in Micronesia, and in the fall of 2013, an outbreak of Zika virus
affected nearly 30,000 persons or more than 10% of the population of French Polynesia. Most infected persons had a mild
viral syndrome with low-grade fever, conjunctivitis, arthralgias, and a maculopapular rash, but some experienced Guillain-
Barré syndrome approximately 1 week after Zika virus infection (113,114). The virus continued eastward, and in early 2015,
cases of Zika virus appeared in Brazil, transmitted to humans by Aedes aegypti, a mosquito species prevalent throughout the
Americas.
Approximately 80% of cases in the Brazil outbreak occurred asymptomatically. In contrast to the Polynesian outbreak, the
Brazilian epidemic was associated with a marked increase in the numbers of infants born with microcephaly and intracranial
calcifications, compatible with intrauterine transmission of Zika virus (115). In addition to microcephaly and intracranial
calcifications, congenital Zika virus syndrome can be associated with lissencephaly, polymicrogyria, passive
ventriculomegaly, arthrogryposis, sensorineural hearing loss, fetal brain disruption, optic nerve hypoplasia, and abnormalities
of the retinal pigment (116–120).
Zika virus infection should be suspected in infants with microcephaly and intracranial calcifications who lack
microbiological evidence for the agents commonly associated with congenital infection, especially CMV. The diagnosis of
Zika virus infection can be established by serologic testing of maternal and infant sera for Zika virus–specific IgM and
neutralizing antibodies (plaque reduction neutralization test) and RT-PCR testing of the infant’s serum, urine, or CSF for Zika
virus RNA (121). Because there is no available vaccine or antiviral treatment, Zika virus represents an ominous, potential
threat to the offspring of pregnant women who visit or live within the host range of Aedes aegypti mosquitoes, including a
considerable portion of the United States.
Imaging
The scope of brain abnormalities and corresponding imaging findings resulting from congenital Zika virus infection are
protean, the most severe manifestation being fetal brain disruption sequence (120,122). As with other congenital CNS
infections, the unique qualities of the viral pathogen and the timing of fetal infection can lead to a range of possible injury
patterns and malformations; however, postmortem histological findings have revealed gaps in the pial limiting membrane in
affected (personal communication, Dr. Fernanda Tovar Moll, Rio de Janeiro). As discussed in Chapter 5, the cobblestone
malformations (a form of polymicrogyria) that result from these gaps may look like lissencephaly, pachygyria, or
polymicrogyria depending upon the number and size of the gaps, and that is what is seen in children with congenital Zika
infection. MRI remains the most useful imaging tool to fully appraise the scope of CNS abnormalities (116,120).
In their retrospective review of neuroimaging and autopsy data of 45 neonates with proven or presumed congenital Zika
virus infection, Soares de Oliveira-Szejnfeld and colleagues chronicled the brain imaging findings associated with congenital
Zika infection (120). Cerebral calcifications were reported in all 45 neonates. Calcification located at the gray matter—white
matter junction was the most common location followed by periventricular and deep cerebral nuclear (basal ganglia and
thalami) regions (Fig. 11-23). In our experience, the precise locations of the calcifications are difficult to define in many
patients because the volume of white matter can be extremely diminished and the cortex, therefore, very close to the cerebral
ventricles. Calcifications are also seen within the brain stem and cerebellum in about 10% of patients.
Figure 11-23 Congenital Zika virus infection. Axial noncontrast CT in a microcephalic newborn shows bilateral cerebral hemispheric
calcifications predominantly at the gray matter/white matter junctions. Also note the simplified sulcal gyral pattern and widened lateral cerebral
fissures consistent with extensive bilateral polymicrogyria (arrows). Overlapping of the cranial sutures reflects micrencephaly. (Courtesy of
Andres Pessoa, MD, Fortaleza, Brazil.)
Cranial ultrasound reveals calcifications as shadowing or twinkling hyperechoic foci, nonenhanced CT (NECT) of the brain
shows high-attenuation punctate or chunky calcium deposits (Fig. 11-23). On MRI, calcium in a loose hydration matrix
demonstrates T1 (hyperintense) and T2 (hypointense) shortening (Fig. 11-24). Susceptibility-weighted MR imaging (SWI)
demonstrates focal hypointensities at sites of calcium deposition. To distinguish calcification from blood products, the SWI
filtered phase map shows calcification as focal hyperintensity. Blood products (paramagnetic) appear hypointense (see
discussion under congenital CMV).
Ventriculomegaly was identified in all patients, many of these affected neonates showing ventricular septa. The causal
factors for ventriculomegaly in these microcephalic patients likely include both impaired CSF absorption and parenchymal
volume loss; one of the authors (AJB) has seen sequential studies where the ventricles enlarge as the volume of white matter
diminishes in the absence of head growth (excluding hydrocephalus from impaired absorption of CSF). Abnormalities of the
corpus callosum ranging from dysgenesis to absence was observed in 94% of the neonates; as the partial or complete callosal
absence is usually associated with worse cortical disease and decreased white matter, it is possible that the callosal anomaly
is secondary to axonal injury/regression. Cortical abnormalities occurred with a similar prevalence. As discussed above, the
cortex may appear as localized cortical dysgenesis (~30%), polymicrogyria (~55%), or agyria (12%) depending on the
number and size of defects in the pial limiting membrane; these are cobblestone malformations (see Chapter 5), a form of
polymicrogyria (Fig. 11-24) (120). Cerebellar parenchymal abnormalities were noted in 82% of patients spanning a spectrum
from hypoplasia to severe dysgenesis involving the cerebellar hemispheres and vermis (120).
Figure 11-24 Congenital Zika virus infection. A. Sagittal T1-weighted image demonstrates decreased cranial-to-facial ratio consistent with
microcephaly. Also note the frontal lobe region of T1 shortening consistent with calcification at the gray matter/white matter junction (arrow). B.
Axial T1-weighted image confirms regions of T1 shortening consistent with calcifications (arrows). C. Axial T2-weighted MR image shows
diffuse bilateral cerebral hemispheric simplified sulcal gyral pattern consistent with polymicrogyria (arrows). (Courtesy of Lara Brandao, MD,
Rio de Janeiro, Brazil.)
Parechovirus
Neonatal infections with parechovirus, a picornavirus with at least 16 types, can produce neonatal encephalitis and permanent
injury to the developing CNS. The cases reported to date suggest to us that parechovirus infection should be considered in
infants who have sepsis-like illnesses, especially when accompanied by rash, irritability, and seizures. CSF pleocytosis
appears to be an uncommon feature of this infection, although cerebrospinal fluid should be obtained to exclude other
conditions, particularly neonatal HSV infection (123–126). Parechovirus infection can be confirmed by reverse transcription
PCR analysis of blood or cerebrospinal fluid (using enterovirus-specific primers) or by culturing the virus from cerebrospinal
fluid, stool, or nasopharyngeal secretions. At present, no specific antiviral therapy exists for this disorder.
Imaging
The imaging abnormalities reported have shown bilateral confluent regions of cerebral hemispheric white matter abnormality
(125). Cranial sonography may show nonspecific increased echogenicity of the central white matter, NECT demonstrates
diminished attenuation of the white matter, and MRI shows diffuse confluent T1 and T2 prolongation and diminished diffusivity
on diffusion-weighted imaging (DWI) and average diffusivity maps (Fig. 11-25) (124–126). Amarnath and colleagues have
pointed out that MRI abnormalities in neonatal parechovirus leukoencephalopathy may be misinterpreted as hypoxic ischemic
injury of the brain (127).
HIV infection in infants can be confirmed by serial serum PCR assays with the first test in the immediate newborn period, a
second test during the first or second month of age, and a third test after 4 months of age. If two samples are positive for HIV,
the infant is considered infected; two successive negative tests make infection unlikely. In children and adolescents, serologic
studies using ELISA and western blotting can identify HIV infection, and PCR monitoring of virus load guides the treatment of
HIV. Current antiretroviral therapy relies upon combinations of nucleoside/nucleotide analogue reverse transcriptase
inhibitors, protease inhibitors, and nonnucleoside analogue reverse transcriptase inhibitors. These antiretroviral strategies and
refined treatments for the infectious or neoplastic complications improve the survival and the quality of life of pediatric
patients with HIV. Combined drug regimens, using antepartum and intrapartum therapy of the HIV-infected woman and
postpartum therapy of exposed infants, can prevent perinatal HIV transmission (132).
Pathologically, the brains of affected children show atrophy (decreased brain weight), infiltration of microglial nodules,
multinucleated giant cells containing viral particles, and calcification. Calcium is found both in the cerebral parenchyma and in
small and medium-sized blood vessels; inflammation is always present in the surrounding tissue (133).
Imaging
Neuroimaging recapitulates the pathological findings of meningoencephalitis, atrophy, and calcific vasculopathy (134). The
most common finding on imaging studies of affected patients is lymphadenopathy in the head and neck, found in greater than
95%, and lymphoepithelial cysts, most commonly in the parotid gland (135). The most prominent intracranial findings are
atrophy, with consequent prominence of the subarachnoid spaces and ventricles, and calcification of the basal ganglia and
subcortical white matter (Fig. 11-26) (136). Calcification is seen in patients who were infected in utero with the
encephalopathic form of the disease (137); children with the highest HIV viral load have the most marked calcification on CT
(138). Subcortical calcification is most common in the frontal lobes but can occur in other areas of the cerebrum, as well.
Myelopathy is often present in children with AIDS; affected children present with spasticity (139). Pathologic findings consist
of corticospinal tract degeneration, myelin pallor, and sparing of the posterior columns (140). The majority of affected patients
have associated encephalopathy; therefore, imaging studies of the spine in children with HIV myelopathy are uncommon.
Figure 11-26 Encephalitis secondary to congenital AIDS. A. Axial noncontrast CT image at age 1 year shows mild prominence of the
ventricles and subarachnoid spaces with mildly increased attenuation in the basal ganglia (arrows). B. Follow-up axial noncontrast CT image at
age 2 years shows marked calcification of the lentiform nuclei (straight arrows) and subcortical frontal white matter (curved arrows).
Other CNS pathology in pediatric HIV infection includes intracranial hemorrhage (from immune thrombocytopenia and
aneurysmal arteriopathy) and infarction (136,141–143). Clinical stroke occurs in about 1% of children with congenital HIV
infection; however, some autopsy series have found infarction in as many as 30% of affected children (144,145). Aneurysmal
arteriopathy (Fig. 11-27), primarily involving large vessels, seems to be a common cause of infarction in these patients
(141,145,146). Arteriopathy may result from the HIV virus itself or from superinfecting organisms, such as cytomegalovirus or
varicella-zoster (146).
Proton MRS in pediatric HIV infection shows the NAA/Cr ratio to be normal in children with static disease; in patients
with progressive encephalopathy NAA/Cr is significantly lower than in controls or nonencephalopathic HIV patients
(147,148).
Rarely, intracranial neoplasms develop in pediatric patients with HIV. The most common intracranial neoplasm is
lymphoma, reported in less than 5% of affected patients; the basal ganglia and thalami are the intracranial structures most
commonly involved (139,142,149,150). Leiomyomas and leiomyosarcomas are also common and should be considered when
extraparenchymal masses are seen in the patients with AIDS (151). CNS infections are quite rare in pediatric patients with
HIV infection; toxoplasmosis, the most common infecting organism in adults with AIDS, is conspicuously uncommon in
affected children. In our experience, CMV and PML are the most common infections in pediatric AIDS; PML is being seen
more commonly, probably because infected children are surviving longer. The appearance of PML in these children is identical
to that in adults, with areas of low attenuation on CT and prolonged T1 and T2 signal on MRI without significant mass effect or
enhancement (152).
Figure 11-27 Aneurysmal arteriopathy in an HIV-infected child. A. Axial time-of-flight (TOF) MRA source image at the level of the anterior
clinoids shows enlarged supraclinoid carotid arteries (arrows). B. Axial TOF MRA image at the level of the pentagonal cistern shows fusiform
aneurysms of the middle cerebral artery M1 segments (arrows).
Fetal brain disruption sequence, a prominent complication of congenital Zika virus syndrome (116,120), represents a
severe destructive (“encephaloclastic”) process of the developing brain. Cases have also been linked to in utero twin demise,
placental infarction, maternal cocaine or alcohol use, and vascular events (163). Tuberous sclerosis complex, an autosomal
dominant disorder due to mutations in the TSC1 or TSC2 gene (see Chapter 6), commonly produces periventricular
calcifications that are sometimes mistaken for the calcifications of congenital CMV, LCMV, or toxoplasmosis infections (164)
but can be distinguished from those with congenital infections by the presence of hypopigmented skin lesions (“ash leaf spots”)
and imaging features, such as cortical tubers and subependymal giant cell tumors, which are not observed in infants with
congenital infections. When taken by pregnant women, isotretinoin, an analogue of vitamin used to treat severe, cystic acne,
can produce several CNS defects, including hydrocephalus, microcephaly, cortical dysplasia, and intracranial calcifications
that may mimic those due to intrauterine infections (165). Adams-Oliver syndrome, a rare autosomal recessive or dominant
disorder due to mutations in several genes (ARHGAP31, DLL4, NOTCH1, RBPJ, DOCK6, or EOGT), causes aplasia cutis
congenita of the scalp, terminal transverse limb defects, and intracranial calcifications mimicking those of congenital CMV
infections (Fig. 11-29) (166).
Bacterial Meningitis
General Concepts: Clinical Features and Causes of Bacterial Meningitis
The agents causing bacterial meningitis in pediatric populations differ considerably according to the age of the child and
child’s immune status. Meningitis is more common in premature than in full-term newborns and more common in the first
months of life than later in infancy (4,88,167). In older children, meningitis is uncommon even when predisposing factors are
present, because the subarachnoid space tends to resist infection in normal children; the exceptions are those few organisms,
such as Citrobacter spp. and Cronobacter (Enterobacter) sakazakii, which display a tropism for the CNS and particularly the
white matter (168,169). Immunization with vaccines for Haemophilus influenzae, Neisseria meningitidis, and Streptococcus
pneumoniae has altered dramatically the epidemiology of bacterial meningitis in many regions of the world (1,167).
Neonatal Meningitis
In the neonate, a large number of gram-positive and gram-negative organisms, including Streptococcus agalactiae (group B
streptococcus), Escherichia coli, Staphylococcus species, Listeria monocytogenes, and Pseudomonas species, cause
bacterial meningitis and sepsis (Table 11-3) (170). In many hospitals, group B Streptoccocus is the most common organism
associated with neonatal meningitis (170–172). Citrobacter species cause less than 5% of cases of neonatal meningitis but
produce brain abscesses in approximately 75% of Citrobacter-infected infants (173). The early signs of neonatal bacterial
meningitis are often subtle, consisting of low-grade fever, poor feeding, somnolence, or “fussy” behavior; later, vomiting,
lethargy, and seizures can ensue. The physical examination can be nonspecific, showing somnolence, irritability, hyperreflexia,
and a full or bulging fontanelle. Meningeal signs are usually absent. This is particularly the case with early-onset neonatal
meningitis where clinical manifestations may include hypotension, apnea, and/or jaundice. Systemic manifestations can also
include shock and signs of disseminated intravascular coagulopathy (DIC) (2,173).
Table 11-3 Selected Causes and Imaging Features of Neonatal Bacterial Meningitis
Group B Leptomeningeal enhancement, ischemic/infarctive injuries in perforator distributions, +/− vascular distribution infarction, + white
Streptococcus matter lesions (scattered or confluent)
Citrobacter Rapidly cavitating lesions of the cerebral white matter, “squared” rim enhancing abscesses
species
Enterobacter Like Citrobacter exhibits a tropism for cerebral white matter. Large rim enhancing cavitary lesions
species
The child or adolescent with bacterial meningitis typically has fever, headache, somnolence, and manifestations of
meningeal irritation, such as the Kernig sign (involuntary spasm of the hamstring muscle provoked by knee extension with the
patient supine) and the Brudzinski sign (flexion of the legs provoked by flexion of the neck). Systemic signs can include
pneumonia in children with pneumococcal or H. influenzae meningitis and septic arthritis, petechiae, purpura, or signs of DIC
in children with meningococcal or H. influenzae meningitis Management of bacterial meningitis in infants, children, and
adolescents consists of treatment with organism-specific antibiotics and management of complications, such as seizures,
increased ICP, subdural effusions, subdural empyema, hydrocephalus, stroke, or brain abscess (4). In rare instances, bacterial
meningitis can recur. Factors that predispose to recurrent meningitis include immunodeficiency, such as HIV infection;
complement deficiencies or agammaglobulinemia; anatomical defects, such as basal skull fracture or dermal sinuses; or
abnormalities of the cochlea, such as Mondini dysplasia (178).
Table 11-4 Common Causes of Bacterial Meningitis in Infants, Children, and Adolescents
Infants
Gram Positive
Staphylococcus aureus
Staphylococcus epidermidis
Gram Negative
Escherichia coli
Citrobacter species
Listeria monocytogenes
Pseudomonas aeruginosa
Mycobacterium tuberculosis
Neisseria meningitis
Streptococcus pneumoniae
Pathophysiology of Meningitis
Bacterial meningitis results from hematogenous seeding of the choroid plexus, a highly vascular, intraventricular structure that
produces cerebrospinal fluid (CSF, see Chapter 8), or from the direct inoculation of bacteria into the CSF via penetrating
trauma, CSF leak, or a bacterially contaminated ventriculoperitoneal shunt (179–181). Rarely, meningitis may develop
secondary to bacterial invasion via a dermal sinus tract (see Chapter 9). When organisms enter via the choroid plexus, they
typically spread into the ventricles, causing ventriculitis; then to the subarachnoid spaces, causing meningitis; and subsequently
into the perivascular spaces causing vasculitis (181). Because the CSF generally lacks intrinsic cellular or humoral immune
response elements, bacteria can multiply unchecked, leading to the clinical signs of headache, fever, stiff neck, vomiting, and
somnolence or coma.
Inflammatory cytokines, especially tumor necrosis factor, participate in the host responses to bacterial infection and
contribute to the pathogenesis of meningitis and, sometimes, complications such as effusion, empyema, ventriculitis,
hydrocephalus, sensorineural hearing loss, venous thrombosis/infarction, and arterial spasm/occlusion/infarction (181). The
endotoxins that are released as a result of bacterial cell death and the resultant cytokine–driven meningeal inflammation can
cause diffuse cerebral edema, ICP, and altered cerebral blood flow (CBF). Liposaccharides from the bacterial cell walls
disrupt the blood–brain barrier, allowing invasion of microorganisms into deeper cerebral structures (4,181,182). The
pyogenic infection spreads along the leptomeningeal sheaths of penetrating cortical vessels in the perivascular spaces;
endothelial cells swell, proliferate, and narrow the vessel lumen within 48 to 72 hours of the initial infection. Moreover,
inflammatory cells infiltrate the vessel wall, allowing foci of necrosis to develop in the arterial walls and, occasionally,
induce arterial thrombosis (183). A similar process occurs in the veins, where mural necrosis and thrombi can partially or
totally occlude the lumen. Venous thrombosis, more frequent than arterial thrombosis, is particularly common when meningitis
is associated with a subdural empyema; the vein thromboses along its course through the infected subdural space (184,185).
Overall, cerebral infarctions (arterial and venous) can be seen in up to 30% of neonates with bacterial meningitis (184,186).
Moreover, extension of the infectious process through obstructed vessels into brain parenchyma can result in cerebritis and
abscess formation.
Fibrinopurulent inflammatory exudate can accumulate within the ventricular system, throughout the basal cisterns, and
around the spinal cord, resulting in obstruction of normal CSF circulation and resultant hydrocephalus. Proliferation of
ependymal or glial cells within the cerebral aqueduct and involvement of the arachnoid villi exacerbate the imbalance between
CSF production and absorption, as does thrombosis of subependymal veins. Hydrocephalus may spontaneously resolve after
resolution of the infection; it must be differentiated from passive ventricular enlargement that results from injury to, and
resorption of, cerebral white matter, a process that evolves over several weeks (4).
Ventriculitis occurs in 30% of affected patients and is especially common in neonates, with a prevalence as high as 92%
(187). Ependymal changes are minimal early in the course of the infection; however, in severe or prolonged meningitis,
cellular infiltration of the subependymal perivascular spaces and glial proliferation may occur, resulting in overgrowth of the
ependymal lining and obliteration of the aqueduct (46). Thrombosis commonly develops in the subependymal and
periventricular veins, resulting in periventricular white matter injury that may be very severe (46).
The CSF in bacterial meningitis shows a neutrophilic pleocytosis with elevated protein content and reduced glucose
content; the Gram stain reveals leukocytosis and gram-positive or gram-negative bacteria. The etiologic diagnosis of bacterial
meningitis is confirmed by culturing a specific bacterial pathogen, but cultures can be negative when children receive oral
antibiotics prior to CSF sampling. Partial treatment can sterilize the CSF and modify the white blood cell count, but the protein
and glucose content usually remain abnormal. In children with imaging or clinical signs of increased intracranial pressure
(ICP), antibiotics must be initiated empirically and lumbar puncture deferred until the intracranial pressure normalizes
(4).
Ventriculitis
Ventriculitis is a common early complication of neonatal meningitis, particularly that caused by Escherichia coli. Bacteria
enter the ventricles via the choroid plexuses and multiply as a result of diminished CSF flow, reduced secretion of CSF by the
choroid plexus, and the relatively feeble intrinsic immune responses of CSF (4,6,194,196). The presence of intraventricular
debris, which often layers dependently within the occipital horns of the lateral ventricle, is the best imaging sign of
ventriculitis (Fig. 11-35). High-resolution cranial sonography will show hyperechogenic intraventricular debris and ependymal
thickening (Fig. 11-35A and B) (188). The viscous dependent pus exhibits reduced diffusion on DWI (Fig. 11-35D) (199,202).
After administering intravenous contrast, enhancement of the inflamed ependyma is seen on both CT and MR, with MR
exhibiting greater sensitivity (Fig. 11-35E) (203). The ventricles are nearly always dilated due to reduced CSF absorption. A
more ominous complication of ventriculitis is necrosis of periventricular white matter (Fig. 11-36), due to obstruction of
subependymal and periventricular veins or necrosis of white matter from the release of (a) endotoxins, lipopolysaccharides
from gram-negative bacteria, (b) teichoic acid from gram-positive organisms, and (c) cytokine-induced inflammation (6,204).
Ultimately, multiple loculations may form in the ventricles, as a result of septa caused by astroglial response to infection;
ultrasound and MR detect the septa with greater sensitivity than does CT (Fig. 11-35A and B) (188,203).
Hydrocephalus
Hydrocephalus is evaluated well by all imaging modalities; MRI, however, is most effective at localizing the level of
obstruction and full appraisal of associated complications (see Chapter 8). Contrast-enhanced CT or MR is required when
ventricular enlargement is unexplained, the diagnosis is uncertain, or a complication of meningitis is suspected (Fig. 11-37).
Hydrocephalus complicating meningitis indicates altered CSF circulation and/or resorption, which may occur at several levels
(Fig. 11-38) (4,6,194), reflecting the intense inflammatory reaction and purulent exudates within the interventricular
communications pathways, basal cisterns, sulci, and perivascular spaces (Figs. 11-37 and 11-38).
Figure 11-34 Subdural empyema, a complication of sinusitis. A and B. Axial T1 (A) and T2 (B) weighted images show a left parafalcine and
left frontal subdural empyema (arrows). C. Axial diffusion-weighted image demonstrates hyperintensity (arrows) of the empyema secondary to
the viscous nature of the purulent material. D. Coronal postcontrast T1-weighted image shows the empyema fluid (e) to be slightly
hyperintense to CSF. There is underlying meningeal enhancement and outer dural enhancement. Note the moderate mass effect and left to
right subfalcial herniation. Intracranial empyemas may evolve remote from the infected paranasal sinus. Thus, whole brain imaging is
warranted when evaluating for suspected complications of sinusitis. E. Axial postcontrast FLAIR image clearly demonstrates the meningeal
(inner) and endosteal (outer) margins of subdural compartment empyema enhancement.
Figure 11-35 Ventriculitis secondary to Escherichia coli. A and B. Coronal (A) and parasagittal (B) cranial sonograms show septated material
filling and expanding the lateral ventricles (arrows). Note the hyperechoic thickening of the frontal horn ependyma (ependymitis, arrowheads in
B). C. Axial T2-weighted image shows dependent debris (d) within the atria of the lateral ventricles. There is evidence for early ventricular
obstruction. D. Axial diffusivity image shows hypointense signal within the occipital horns (arrows) and the right sylvian cistern subarachnoid
space (arrowheads) consistent with reduced diffusion from highly viscous purulent material. E. Axial postcontrast T1-weighted image
demonstrates dependent ventricular debris (d) and the thickened enhancing ependyma (white arrowheads) in ventricular trigones and occipital
horns. Also note the prominent leptomeningeal enhancement within the sylvian cisterns.
Figure 11-36 White matter necrosis secondary to ventriculitis. A. Axial T1-weighted image shows proteinaceous debris (white arrowheads)
layering in the posterior portion of the lateral ventricles. Early white matter necrosis is seen as mixed areas of hyper and hypointensity (small
white arrows) in the frontal lobes. Poor gray matter–white matter contrast is seen in the entire cerebrum. B. Axial T2-weighted image shows
extensive white matter necrosis (white arrows) seen as hypointensity of the white matter with some surrounding hyperintense edema. C.
Postcontrast T1-weighted image shows better, the extent (small white arrows) of frontal necrosis. Some of the necrosing tissue (white
arrowheads) is enhancing. The walls of the lateral ventricles (black arrowheads) are enhancing posteriorly. D. Follow-up postcontrast T1-
weighted image 6 weeks later shows hydrocephalus and cavitation of the frontal lobes. Note that proteinaceous debris (white arrowheads)
layering dependently within the ventricles. Some loculations (L) have formed adjacent to the ventricles.
Figure 11-37 Early hydrocephalus secondary to non–type b Haemophilus influenzae meningitis. A and B. Axial noncontrast CT images
demonstrate infectious debris adjacent to the falx cerebelli (arrows) and dilation of the temporal horns (arrowheads) and third ventricle. The
cerebrum is low in attenuation and there is absence of gray matter–white matter contrast. C. Coronal postcontrast T1-weighted image from
MR 48 hours following the CT shows progressive dilation of the lateral and third ventricles. D. Axial postcontrast FLAIR image at the level of the
basal cisterns demonstrates diffuse enhancement of the basal cisterns (white arrows). CSF flow is obstructed at this level.
Figure 11-38 Hydrocephalus following Escherichia coli meningitis. A. Four weeks following the completion of therapy for E. coli meningitis,
Axial T2-weighted image in this infant with a bulging anterior fontanelle shows focal encephalomalacia of the brain stem secondary to remote
brain stem infarction (arrow). There is moderate dilation of the temporal horns. B. Axial T2-weighted image at the level of the third ventricle
demonstrates moderate dilation of the lateral ventricles and third ventricle. There is stretching of the massa intermedia (black arrowhead). Also
note the lack of normal hypointense signal within the cerebral aqueduct (black arrow), indicating disturbance of normal CSF flow. This
represents postmeningitic noncommunicating hydrocephalus.
Figure 11-39 Sagittal sinus thrombosis secondary to meningitis. A. Noncontrast CT scan shows high attenuation in the torcular herophili
(arrows) at the junction of the straight sinus (also hyperdense and thrombosed) and the superior sagittal sinus. The presence of high density
within blood vessels in a child beyond the first few months of life is extremely suspicious for sinus thrombosis. B. Sagittal T1-weighted image
shows high signal intensity in the posterior half of the superior sagittal sinus (black arrows). The straight sinus (white arrowheads) also appears
thrombosed. C. Coronal FLAIR image shows high signal intensity (arrow) within the superior sagittal sinus, supporting the diagnosis of sagittal
sinus thrombosis. D. Axial T2-weighted image shows hyperintensity in the sagittal sinus (white arrows), suggesting the presence of
extracellular deoxyhemoglobin, present in subacute clot. E. 2D time-of-flight MR venogram shows absence of flow-related enhancement in the
superior sagittal sinus, confirming the diagnosis of thrombosis.
Figure 11-40 Streptococcus pneumoniae meningitis, venous thrombosis and cerebral ischemia. A. Axial T2-weighted image shows right
cerebral convexity regions of subcortical T2 prolongation (edema) (arrows). B. ADC map shows reduced diffusion involving the right
frontoparietal convexity (arrow). C. Axial SWI shows numerous right convexal serpentine hypointensities consistent with slow flow or thrombus
within convexity veins (arrows). D. Axial T1-weighted following intravenous contrast shows filling defects (clot) within the right convexity veins
(arrows). E. Sagittal post-IV contrast 3D SPGR image demonstrates clot within the right transverse venous sinus (arrow).
Venous ischemia and infarcts are diagnosed by their characteristic location and appearance. Typically, ischemia and
infarcts that arise from sagittal sinus thrombosis are parasagittal (Fig. 11-40); infarcts from thrombosed internal cerebral veins,
straight sinus, and vein of Galen involve the thalami. Infarcts from vein of Labbé, transverse sinus, or sigmoid sinus thrombosis
involve the temporal lobe. Smaller cortical/subcortical infarcts are often seen over the cerebral convexities (Fig. 11-41). On
CT, venous infarcts are usually poorly delimited, hypoattenuating, or mixed attenuation areas involving the subcortical white
matter and producing a slight mass effect on ventricular structures. The low attenuation is probably due to localized cerebral
edema (vasogenic and cytotoxic), whereas high attenuation areas within the brain parenchyma usually represent hemorrhage.
Following intravenous contrast administration, a lack of expected venous opacification is seen (venous clot may be detected),
adjacent sulcal/gyral enhancement is noted, and adjacent parenchymal hypoattenuation (edema) is appreciated (209). On MR,
early venous infarcts may be identified by visualization of prolonged T1 and T2 relaxation times in characteristic regions of
the brain parenchyma, SWI hypointensity within the adjacent venous structure(s), and low ADC values in regional parenchyma
(Fig. 11-41). Another early and important imaging sign of venous infarction is visualization of thrombus in the deep medullary
veins with surrounding cavitation. Of note, reduced parenchymal diffusivity in the setting of venous thrombosis lacks
sensitivity in predicting venous infarction. With venous ischemia and infarcts, diffusion appears to be heterogeneous, with
areas of increased, normal, and decreased diffusion (Fig. 11-41) (210). The variable diffusion characteristics are likely related
to the combination of interstitial and cytotoxic edema found in venous infarcts. In addition, part of this heterogeneity may be
due to the frequent presence of hemorrhagic tissue, which makes diffusivity values unreliable. Twenty-five percent of venous
infarcts are hemorrhagic and have an imaging appearance that varies from large subcortical hematomas to petechial
hemorrhages admixed with edematous brain parenchyma (Fig. 11-40) (207,209). The hemorrhages are generally subcortical
and often multifocal with irregular margins. They are occasionally linear in nature, indicating hematoma in and around the vein;
this appearance is quite specific.
Figure 11-41 Cortical vein thrombosis and cerebral ischemia secondary to Neisseria meningitides meningitis. A. Coronal GRE image shows
several convexity cortical veins demonstrating diminished signal indicating cortical vein thrombosis or slow venous flow. B. Axial postcontrast
T1-weighted image shows thick enhancement within the left intraparietal sulcus (large white arrows). Note the linear hypointense filling defect
(small black arrow) consistent with thrombosed cortical vein. The adjacent cortex shows T1 hypointensity consistent with edema. Also note the
bilateral frontal effusions. C. Axial average diffusivity image shows evidence of increased diffusivity (interstitial edema, white arrows). There is
reduced diffusivity (hypointensity, white arrowheads) adjacent to the lateral intraparietal sulcus, suggesting injured tissue. Cortical venous
occlusion leads to regional venous hypertension, breakdown of the blood–brain barrier and, sometimes, ischemic injury. D. DTI-derived color
fractional anisotropy image through the cerebral convexities shows a loss of coherence (decreased anisotropy, arrows) of water motion in the
region of the cortical occlusion and in the subcortical white matter tracts, reflecting interstitial edema and, possibly, microstructural white matter
injury.
Advances in MR venography (Fig. 11-41) have greatly aided the diagnosis of venous sinus thrombosis by MR (211–214).
Gadolinium-enhanced 3D gradient echo techniques, reformatted as thin sections in multiple planes, are superior to 2D TOF
venography in the detection of intracranial venous thrombosis (see Chapter 1, Fig. 11-41) (214). False-negative and false-
positive pitfalls exist with 2D TOF and to a lesser extent 3D non–contrasted MRV techniques including “flow gaps,” which
may simulate venous thrombosis (215). Additionally, it is important to remember that time-of-flight MR angiography is
acquired using T1-weighted images. Both moving blood and subacute clot are hyperintense; thus, the results of a time-of-flight
venogram may be equivocal. Patients with hyperintensity of an intracranial venous sinus detected on T1-weighted images
should, therefore, have either contrast-enhanced MR venography, phase-contrast venography, novel non–contrast fluid-
suppressed methods for flow-independent venography, or CT venography (Fig. 11-41) (212,216). CT venography techniques
are comparable to contrast-enhanced 3D MR venography for the detection of intracranial venous thrombosis (212,217,218) but
are less desirable in the pediatric population because of the ionizing radiation (see Chapter 1).
Cavernous sinus thrombosis is an uncommon sequela of meningitis; it is more commonly the result of paranasal sinus,
dental, or ocular infection (219–221). CT of cavernous sinus thrombosis shows an enlarged, outwardly convex cavernous sinus
with enhancing adjacent meninges (222). Ipsilateral or contralateral orbital veins may be enlarged and thrombosed (Fig. 11-
42) (223). On MR, signal intensity of cavernous sinus thrombus varies depending on the state of infection, inflammation, and
clot evolution (therefore, the signal intensity of the sinus alone should not be relied upon to make the diagnosis). Direct
visualization of nonenhancing clot confirms the diagnosis (Fig. 11-42). The cavernous sinus may be enlarged and the cavernous
carotid artery narrowed or occluded (224,225). T2 prolongation may be seen in the adjacent clivus or petrous apex (225).
With infection by aggressive organisms, a mycotic aneurysm of the cavernous carotid artery may develop. Therefore, it is
useful to acquire an MR arteriogram of the cavernous carotid arteries if septic thrombophlebitis of the cavernous sinus is
suspected.
Arterial infarction
Focal cerebral parenchymal abnormalities seen in patients with bacterial meningitis are typically attributable to ischemia,
infarctions, and/or cerebritis (226). Arterial infarctions in the setting of meningitis usually result from arteritis secondary to
involvement of the perivascular spaces and, subsequently, the arterial walls by the infection; this process is likely mediated by
endotoxins, cytokine driven, or immunologically mediated (226). Widespread vasculopathy may lead to extensive white matter
cytotoxic edema, acute demyelination and, ultimately, to necrosis (226). Although both CT and MR can diagnose the arterial
complications of bacterial meningitis, contrast-enhanced MR with DWI is the examination of choice. The regions of ischemia
and infarction may be in the distribution of perforating arteries, widespread throughout the cerebral hemispheric white matter,
or sharply marginated and confined to a specific vascular territory. Diffusion-weighted MR imaging is mandatory in this
setting, as it will detect infarctions earlier than CT or conventional MRI (Figs. 11-43 to 11-45) (227). Large or small vessels
may be affected. When major vessels, such as the middle or anterior cerebral arteries are involved, large cortical infarctions
result (Fig. 11-45). Use of arterial spin labeling to assess regional perfusion may supply additional information regarding
areas at risk due to low perfusion. Group B Streptococcus, Streptococcus pneumoniae, Escherichia coli, tuberculous, and
syphilitic meningitis can be associated with infarction including lacunar-type infarcts in the distribution of perforating vessels
involving the brain stem, basal ganglia, white matter, and vascular territorial infarctions (Figs. 11-19, 11-43, and 11-44)
(227,228). DTI may give insight into white matter structural injury that may accompany meningitis. This is particularly relevant
for the neonate with meningitis where there is known vulnerability of periventricular white matter to oxidative and
hypoxic/ischemic injury that may occur in the context of meningitis (229). Magnetic resonance proton spectroscopy (MRS) may
be useful to assess for evidence of anaerobic metabolism within injured tissue, demonstrating lactate and necrosis (Fig. 11-
43E). Mitochondrial impairment is demonstrated by reduction of NAA (Fig. 11-43E).
Tuberculous Meningitis
Meningitis is one of the most common extrapulmonary manifestations of infection with Mycobacterium tuberculosis and
closely associated with miliary tuberculosis. CNS mass lesions (“tuberculomas”), meningovasculitis, and miliary involvement
of the CNS can all occur in children with tuberculosis (230,231). Risk factors for tuberculous CNS disease in children and
adolescents include exposure to a family member with tuberculosis, birth or extended travel in regions endemic for
tuberculosis, exposure to a (former) prison inmate, and HIV infection. CNS involvement usually becomes clinically apparent
within 6 months of the initial infection (232,233). Meningitis in childhood due to M. tuberculosis begins with headache,
vomiting, irritability, or lethargy, and, when untreated, affected patients develop cranial nerve palsies (particularly CNs II, IV,
and VII), focal deficits, or signs of ICP (177). Fever is not always present. Examination of the CSF reveals a mixed or
predominant lymphocytic pleocytosis, elevated protein (usually between 100 and 500 mg/dL), and mildly reduced glucose
(234). The diagnosis of tuberculous meningitis can be established by PCR detection of mycobacteria in the CSF and supported
by a positive tuberculin skin test or detection of interferon-gamma release in whole blood samples exposed to M. tuberculosis
antigens (232,234). Treatment consists of combined antituberculous therapy with a four-drug regimen and administration of
corticosteroids; even with therapy, death or significant morbidity is possible, especially when treatment is delayed.
Figure 11-42 Cavernous sinus thrombosis in the setting of sphenoid sinusitis/meningitis. A. Axial contrast-enhanced CT shows enlarged
tubular serpentine thrombosed superior ophthalmic veins (white arrows). Note the thrombus within the cavernous sinuses (arrowheads) and the
extensive preseptal and postseptal edema. B. Axial T2-weighted fat-saturated image confirms enlarged tortuous thrombosed superior
ophthalmic veins (arrows). C. Axial postcontrast axial fat-saturated T1-weighted image shows the thrombosed orbital venous structures as
nonenhancing elements. Enhancement is due to multiple small collateral veins. Note the diffuse pre- and postseptal edema. D. Axial
postcontrast T1-weighted image through the cavernous sinus demonstrates thrombus as large hypointense filling defects (black arrows).
The meningovascular manifestations of tuberculosis, such as cerebral infarction, have a substantial impact upon
neurodevelopmental outcome (235). Acute hydrocephalus, caused by the intense meningeal reaction associated with
tuberculous meningitis, requires ventriculoperitoneal shunt placement. If untreated, tuberculous meningitis rapidly progresses
to death, with average disease duration of only 3 weeks (236). Even with current treatment regimens, tuberculous meningitis
has considerable morbidity and mortality (234).
The bacilli are distributed within the brain and meninges throughout the CNS but do not multiply as readily as they do in
other organs. Meningitis probably results from rupture of small tuberculomas in the cortex, spinal cord, leptomeninges, or
choroid plexus (180,237). CNS manifestations usually become apparent as tuberculous meningitis, tuberculoma, tuberculous
abscess, or spinal leptomeningitis within days after miliary spread; a gelatinous exudate fills the pia-arachnoid along the basal
cisterns, particularly the prepontine cistern, where it infiltrates and produces inflammation along the walls of the meningeal
blood vessels. The small cortical blood vessels and perforating vessels become affected as the exudate spreads into the
Virchow-Robin spaces, causing infarction of surrounding brain tissue. Outcome is directly related to the location and extent of
these infarctions (238). The basal ganglia and thalami are affected in almost half of cases (239,240); suprasellar cisternal
inflammation and involvement of the posterior hypophysis may lead to the syndrome of inappropriate antidiuretic hormone
secretion (241). The thick exudate blocks the subarachnoid spaces, causing hydrocephalus. Infiltration of the perineurium of the
cranial nerves causes neuropathies, particularly of cranial nerves II, VI, and VII. Small tubercles over the convexity of the
brain may involve the leptomeninges, while deeper lesions may infiltrate the periventricular area.
Figure 11-43 Multiple perforator arterial infarctions from Group B Streptococcus (S. agalactiae) meningitis. A. Axial T2-weighted image shows
innumerable basal ganglia foci of T2 prolongation. Note the subinsular regions of T2 hyperintensity and heterogeneous left perifrontal white
matter signal (coagulation necrosis of white matter, black arrow). B. Axial T2-weighted image at the level of the centrum semiovale
demonstrates heterogeneous white matter signal intensity (arrows). C and D. Average diffusivity images corresponding to (A and B) show
markedly reduced diffusivity corresponding to tissue injury. Note the confluent reduced diffusivity within the centrum semiovale. E. Proton
spectroscopy (TE = 35 ms) of the right basal ganglia demonstrates a large lactate/lipid (L/L) and lipid (Li) peaks. Lactate is an indicator of
anaerobic metabolism and lipid results from cell necrosis. There is mild decline of NAA and elevation of the excitatory neurotransmitter
glutamate and glutamine (Glx).
Figure 11-44 Multiple arterial infarctions from Streptococcus pneumoniae meningitis. A. Axial noncontrast CT shows multiple wedge-shaped
cortical and subcortical regions of diminished attenuation (white arrows). Numerous basal ganglia/thalami foci of low attenuation are also seen
(arrowheads). B. Axial T2-weighted image shows better the regions of peripheral and central T2 hyperintensity representing edema (cytotoxic
and vasogenic in type). C. Axial diffusion-weighted image shows multiple sites of ischemic injury as areas of hyperintensity. D. Axial average
diffusivity image 6 days after initial diagnosis demonstrates evidence of early pseudonormalization. Relatively few areas of subtle frontal and
occipital reduced diffusivity (white arrows) and central basal ganglia and periventricular foci of reduced diffusion (arrowheads) are still seen.
Imaging
It serves the radiologist well to remember that the imaging manifestations of CNS Mycobacterium tuberculosis result from the
military spread of disease and are as diverse as the clinical presentation; manifestations range from focal and/or diffuse basilar
leptomeningeal exudate to more localized abnormalities (granulomatous meningitis, tuberculoma, cerebritis, abscess, and
stroke) anywhere within the cerebrum or cerebellum. More specifically, ventriculomegaly is present in 50% to 77% of affected
patients, most often secondary to hydrocephalus (237,242). In more advanced disease, the basal cisterns are partially or
completely filled by the purulent tuberculous exudate, which can extend into the spinal subarachnoid space (Fig. 11-46). On
noncontrast CT or MRI, the exudate appears higher in attenuation (CT) and signal intensity (T1, T2 FLAIR, and SWI
sequences) than CSF; it may be overlooked on T2-weighted MR images, because the high-intensity CSF signal will obscure the
cisternal disease unless small field-of-view (FOV) MR techniques are used (Fig. 11-47C). Following intravenous contrast, the
involved cisterns variably enhance (Figs. 11-46 and 11-47B) (238,242–245). Although the exudate usually fills the basilar
cisterns bilaterally and symmetrically, about 10% of affected children have more regional disease, typically affecting the
sylvian fissure, and less commonly the ambient or quadrigeminal plate cisterns (246). FLAIR imaging (particularly delayed
postcontrast FLAIR) improves conspicuity of cisternal and leptomeningeal pathology (191). Tuberculous cranial
pachymeningitis has been reported but is very rare (247).
In tuberculous meningovasculitis, infarcts are typically seen in the basal ganglia and thalami in the subacute phase of
tuberculous meningitis as a result of purulent exudates infiltrating the perivascular spaces and resulting in vasculitis (240,248).
The caudate nuclei, hypothalami, and medial thalami are most commonly affected (239). The infarcts appear as low density
regions on CT and areas of prolonged T1 and T2 relaxation time on MR. When the meningitis is unilateral, the infarcts occur
on the affected side (246,248). Cortical infarctions can result from involvement of cortical vessels but are less common
(236,242,248). The recognition of unexplained focal pediatric brain ischemia in the setting of suspected inflammatory or
infectious disease should provoke a consideration of Mycobacterium tuberculosis and herpes zoster (231). Antedating the
imaging features of tuberculous ischemia and infarction, the more subtle MR findings of nodular granulomatous meningitis may
be observed (Fig. 11-48).
Figure 11-45 Middle cerebral artery infarct. Non–type b Haemophilus influenzae meningitis. A. Axial T2-weighted image shows blurring of the
gray and white matter of the left insular and posterior temporal regions (white arrows). B. Axial postcontrast T1-weighted image shows left
frontotemporal leptomeningeal enhancement (arrowheads) and subdural fluid accumulation (f). C. Axial diffusion-weighted image demonstrates
left MCA territory signal hyperintensity. There is increased signal within the left frontal subdural collection (arrow). D. Axial average diffusivity
image confirms tissue injury (low signal intensity) in the left MCA territory. Also note the low signal intensity within the left sylvian cistern fluid
collection (f). A subdural empyema was surgically drained.
Single or multiple punctate or ring-enhancing foci of enhancement, representing tuberculomas, within the cerebrum or
cerebellum may be seen within the gray or white matter or at the junction of the gray and white matter. Multiple lesions are
more common above the tentorium, and solitary lesions more common below the tentorium (Figs. 11-46B, 11-48B, and 11-49B
and C) (230,249). Tuberculomas are most often parenchymal but can be dural based (230,250). On noncontrast CT, they may
be isodense to slightly higher in attenuation compared to brain parenchyma. The early imaging characteristics of small
tuberculomas may be very subtle (Fig. 11-48) (231). For tuberculomas less than 2 mm in size, solid enhancement is typical
(Figs. 11-48 and 11-49), whereas larger lesions more typically manifest a ring of enhancement (Fig. 11-50B and E). On T1-
weighted images, tuberculomas exhibit an isointense center adjacent to a rim of high signal intensity surrounded by a complete
or partial rim of slight hypointensity. On T2-weighted images, granulomas are homogeneously or heterogeneously hypointense
(Figs. 11-48C and 11-50D) (230,251). When present, miliary tuberculomas appear as leptomeningeal nodular enhancement
and/or multiple small nodules that show T2 hypointensity and uniformly enhance (Fig. 11-48A) (230). When they involve the
white matter, miliary foci may elicit significant vasogenic edema (252). Tuberculomas uncommonly calcify. Proton MR
spectroscopy of tuberculomas shows nonspecific elevated choline, decreased NAA, and elevation of lipid peaks at 0.8 to 1.2
ppm (253,254).
Rarely, the central caseous component of the tuberculoma may liquefy, forming a tuberculous abscess. These are generally
larger, and elicit more vasogenic edema, than granulomas. Their imaging appearance differs from tuberculomata in that the
central portion of a tuberculous abscesses is hyperintense on T2-weighted images, in contrast to the central T2 hypointensity
seen in tuberculoma (238). This difference likely results from their different compositions: tuberculous abscesses are
composed of nonspecific inflammatory cells, such as polymorphonuclear cells, whereas tuberculomas are granulomata
composed of epithelioid cells and giant cells mixed with predominantly mononuclear cell infiltrates around a central area of
caseation (179). Proton MRS of tuberculous abscesses shows only a choline peak, a lactate peak, and a broad lipid peak
(255). This spectrum allows differentiation from untreated bacterial abscesses, which also show aliphatic peaks of amino
acids, possibly alanine (at 1.5 ppm), acetate (at 1.9 ppm), succinate (at 2.4 ppm), and leucine, isoleucine, and valine (at 0.9
ppm) (Fig. 11-54G) (256–259), but not from treated abscesses or neoplasms.
Figure 11-46 Tuberculous meningitis. A. Postcontrast axial T1-weighted image shows marked enhancement of the basilar cisterns. Note how
the suprasellar cistern, medial sylvian fissures, interpeduncular cistern, and ambient cisterns all markedly enhance (arrows). B. Postcontrast
T1-weighted image through the centrum semiovale demonstrates meningeal enhancement on the right (narrow arrows) and two enhancing
tuberculomas (large arrows) at the gray–white junction of the parietal lobe. C. Axial T2-weighted image shows several tuberculomata in the
parietal white matter of the right hemisphere (arrows). D. Postcontrast T1-weighted image show diffuse subarachnoid space and meningeal
(open white arrows) enhancement. A tuberculoma compresses the spinal cord at the C7 (open black arrow).
Reports in the literature vary regarding findings on diffusion-weighted images of tuberculomas. Some authors report slightly
increased diffusivity (higher ADCs) in tuberculomas compared to normal brain parenchyma and tumors and significantly
higher diffusivity than in bacterial abscesses. Others report decreased diffusivity while still others report diffusion
characteristics similar to normal brain (260–262). These conflicting results suggest that diffusivity varies from unknown
causes; at this time, DWI is not helpful in establishing this diagnosis.
Figure 11-47 Tuberculous meningitis. Value of delayed postcontrast and small FOV heavily T2-weighted MR imaging. A. This 12-year-old
male with neck stiffness, cranial neuropathies, a high risk social environment for TB, and a positive whole blood QuantiFERON-TB Gold test
(QFT-G) demonstrates subtle interpeduncular cistern enhancement (arrow) on postcontrast T1-weighted image. B. Delayed (5 minute) axial
T1-weighted contrast-enhanced image shows improved conspicuity of basal cisternal enhancement (arrows). C. Axial T2-weighted FIESTA
image shows serpiginous hypointense prepontine filling defects consistent with gelatinous exudates (arrows).
Figure 11-48 Nodular tuberculous meningitis and tuberculomas. A. Axial postcontrast T1-weighted image shows nodular leptomeningeal and
cortical enhancement (arrow). B. Coronal postcontrast T1-weighted image shows small cerebellar tuberculomas (arrows). C. Coronal T2-
weighted image shows subtle cortical T2 hypointensities characteristic of small tuberculomas (arrow).
In infants, empyemas most commonly are a complication of purulent meningitis, by encystment of a portion of the
subarachnoid space, extension of meningitis (particularly Pneumococcus) from the subarachnoid to the subdural compartment,
or by purulent transformation of a subdural effusion (196). Older children initially present with fever, stiff neck, headache, and
lethargy; they subsequently develop symptoms and signs of space-occupying lesions with blurred vision, focal neurological
findings, and focal seizures (180,264). When these symptoms develop in association with a head wound, otitis media,
mastoiditis, or sinusitis, an empyema should be suspected and the evaluation should be directed toward identifying the location
of the empyema. The most common source of intracranial empyema in this age group is a direct extension of otitis media or
sinusitis into the epidural or subdural spaces. Other, less common causes include postoperative infection of a craniotomy
cavity, posttraumatic infection of an extraparenchymal hematoma, osteomyelitis, orbital cellulitis, direct penetrating trauma,
congenital osseous defects (such as dermal sinuses and encephaloceles), sepsis with metastatic infection, and contamination of
a subdural effusion (179,197,265).
Figure 11-50 Cerebellar tuberculoma. A. Precontrast axial CT image shows a hyperdense mass in the left cerebellar hemisphere, generating
a small amount of vasogenic edema. B. Postcontrast CT shows uniform ring enhancement. C. Axial T1-weighted image shows that the wall of
the mass (arrows) is hyperintense. D. Axial T2-weighted image shows that both the wall and the center of the mass are hypointense. This
hypointensity is characteristic of tuberculosis. Moderate hyperintense edema surrounds the lesion. E. Postcontrast axial T1-weighted image
shows uniform ring enhancement. When a solitary, ring-enhancing posterior fossa mass is seen in children, the diagnosis of tuberculosis
should always be considered, especially in endemic areas. Central T2 hypointensity is strong support for the diagnosis of TB.
Pathology studies have shown that the pus in these patients is commonly both intra- and extradural (266). As a result,
differentiating intradural from extradural abscesses is impractical, even if the collection of pus is predominantly in one
compartment or the other. Convexity empyemas are the most common, and outnumber parafalcine empyemas by two to one
(197). Paratentorial collections are less common and are usually the result of an extension of a preexisting empyema.
Empyemas can be accurately localized to the extradural space if they are bilateral (extending across the midline) or if they
displace the falx from the inner table of the skull. In the more common lateral convexity empyema, these signs cannot be used,
and localization is less accurate.
On imaging studies, empyemas are seen to cause widening of the extracerebral space with compression of adjacent sulci
(Fig. 11-34). Although empyemas secondary to sinusitis or otomastoiditis in older children more commonly develop ipsilateral
and in close proximity to a neighboring source of infection, they may not be contiguous with the infected site; frequently, they
are contralateral to the infected sinus or middle ear cavity/mastoid. Thus, imaging of the entire brain following intravenous
contrast (CT or MRI) is mandatory in the setting of suspected complicated sinusitis or otomastoiditis (Figs. 11-34 and 11-55).
Common locations include the interhemispheric fissure, along the tentorium cerebelli, or along the floor of the anterior or
middle cranial fossae (196). In newborns and young infants, cranial sonography using high near-field resolution ultrasound
transducers to image the extraparenchymal spaces may be useful to distinguish debris-containing infected collections from
sterile ones in newborns and young infants (188). Infected collections appear as heterogeneous or hyperechoic collections,
often with hyperechoic fibrinous strands, and a thick, hyperechoic inner membrane. Sterile effusions appear as uniform,
anechoic extraparenchymal collections (188).
No CT attenuation or spin-magnitude MR characteristics are definitive for distinguishing empyemas from nonpurulent
collections. With MRI, empyemas are slightly hyperintense to CSF on T1, T2-weighted, and T2 FLAIR imaging (Fig. 11-34)
(267). Diffusion-weighted MR imaging should routinely be performed, as reduced diffusion is seen in empyemas (Fig. 11-
34) but not in effusions (199–201). Loculation within the empyema is seen in approximately 50% of affected patients. In the
early stage of empyema development, vasogenic edema is minimal in adjacent brain. If low attenuation on CT or T1 and T2
prolongation on MRI is detected in the adjacent parenchyma, consider associated cerebritis, which occurs concurrently with
empyemas in approximately 20% of affected patients; alternatively, consider ischemia secondary to venous and/or arterial
occlusion (197). After about 1 to 3 weeks, postcontrast imaging may show endosteal and dural enhancement with subdural
empyemas (Fig. 11-34D). It is not certain whether the enhancement represents a capsule around the pus or cortical enhancement
secondary to ischemic cortical damage. This enhancement is sometimes seen best on postcontrast FLAIR images, which may,
therefore, better show the extent of the extraparenchymal abnormality (Fig. 11-34E). If extra-axial collections are seen in
association with sinusitis, otitis, or orbital cellulitis, an empyema should be strongly suspected. Cross-sectional imaging
should be postcontrast, multiplanar, and encompass the whole brain (197).
Bacterial Cerebritis
Cerebritis, the earliest stage of a purulent brain infection, is a focal or multifocal suppurative process that may resolve or
evolve to frank abscess formation. If cerebritis is not successfully treated medically, the affected portion of the brain liquefies
and a surrounding capsule of granulation tissue and collagen forms, resulting in an abscess. The pyogenic organisms that cause
cerebritis gain access to the brain by one of four routes: (a) hematogenous spread from a distant infection or generalized
sepsis, (b) extension of contiguous infections (such as in the middle ear or paranasal sinuses) either directly or as a result of
septic thrombophlebitis of bridging veins, (c) via a penetrating CNS injury, or (d) in association with a cardiopulmonary
abnormality, such as a cyanotic congenital heart lesion or a pulmonary arteriovenous malformation. Congenital defects of the
overlying bone, such as in encephaloceles or dermal sinus tracts, can also be a source of infection (179,268). Pathological
examination of cerebritis shows that inflammatory cells infiltrate the brain; tissue necrosis, and frank edema ensue. The
surrounding edematous brain tissue has a consistency very similar to the area of cerebritis.
Cerebritis may be difficult to distinguish clinically from a cerebral abscess. The distinction is important, however, because
cerebritis frequently responds to appropriate antibiotic therapy, and surgery is contraindicated. Once cerebritis has evolved to
an encapsulated abscess, however, but surgery is often necessary because the antibiotic therapy may not reach parts of the
infection through the pus and necrotic tissue.
During the early phases of cerebritis, cranial sonography will show poorly defined disorganized echo architecture of the
brain; both CT and MR will show evidence of increased water in the affected tissue (ill-defined areas of low attenuation on
CT and prolonged T1 and T2 relaxation times on MR, Fig. 11-51) (188,269). Ill-defined foci of enhancement may be seen after
infusion of contrast (Fig. 11-51D). Mild to moderate mass effect is usually present. Sequential imaging studies are imperative
in determining whether the process responds to antibiotic therapy or whether it progresses to abscess formation. The few
reported cases of diffusion imaging in cerebritis suggest that water diffusion is reduced, similar to the reduction seen in
abscesses (270).
Brain Abscess
Brain abscess, a potentially life-threatening infection of the CNS, occurs at all ages. Like bacterial meningitis, the pathogenesis
of brain abscess most often involves hematogenous bacterial seeding of the brain or direct inoculation of bacteria into the brain
parenchyma via penetrating trauma or the presence of a foreign body (271). As noted earlier, cerebral abscesses may also form
as a result of direct spread of bacteria from infections of contiguous structures, including the paranasal sinuses or middle ear.
In contrast to bacterial meningitis, which typically results from a single bacterial pathogen, brain abscesses can be
polymicrobial and may involve both anaerobic and aerobic bacteria as well as fungi or parasites. Organisms identified in
pediatric brain abscess include the streptococcal and staphylococcal species, several gram-negative bacteria, nocardia
species, and Cryptococcus neoformans. Neonatal brain abscess commonly results from infection with Citrobacter spp.,
Enterobacter spp., and gram-negative bacteria, such as E. coli, that can cause early- or late-onset neonatal sepsis, meningitis,
and abscess formation (272). Risk factors for the development of brain abscess in children include congenital heart disease,
sinusitis, untreated otitis media, penetrating CNS trauma, chemotherapy for malignancies, immunosuppressive therapy, and
underlying immunodeficiency disorders, especially HIV infection (Table 11-5) (273).
Figure 11-51 Neonatal Citrobacter koseri meningitis rapidly progressing from cerebritis to abscess. A. Axial diffusion image shows extensive
bifrontal white matter hyperintensity (increased diffusion). B. Axial T2-weighted image shows heterogeneous signal within the frontal lobes,
blurring of the gray–white matter interface and focal left frontal white matter hypointensity (black arrow) secondary to hemorrhage. Also note the
edema involving the genu of the corpus callosum (black arrowhead). C. Coronal GRE image demonstrates frontal lobe regions of hypointense
“blooming” (arrows) representing hemorrhagic necrosis. D. Axial postcontrast T1-weighted image shows bifrontal hypointense regions with
patchy cortical–subcortical enhancement (arrowheads), likely representing cerebritis. The mass effect is less marked than its volume would
indicate, suggesting that it results from superinfection of a white matter infarction. E. Repeat MRI 5 days later shows significant progression of
disease. Axial diffusion-weighted image demonstrates large confluent frontal white matter regions of hyperintensity (white arrows) consistent
with abscess cavities. F. Axial T2-weighted image shows left frontal subcortical white matter hypointensity (black arrows) consistent with
cerebral necrosis and abscess debris. Note the adjacent frontal lobe edema and left-to-right subfalcine herniation. G and H. Axial and coronal
postcontrast T1-weighted images show large frontal lobe rim enhancing abscesses. Neonatal brain abscesses may have an incomplete
enhancement rim due to the newborn’s immature immune status.
The signs and symptoms of brain abscess in the pediatric population depend upon patient age, the size and location of the
space occupying lesion, the pathogen(s), and host immune factors. In neonates and young infants, the clinical signs of brain
abscess can be subtle, and clinicians must be alert for this possibility in the fussy or somnolent infant and in infants with gram-
negative bacterial meningitis, especially due to Citrobacter spp. Two major clinical syndromes have been described with
neonatal brain abscesses (274–276). More commonly, infants have an acute or subacute evolution of signs of ICP (vomiting,
bulging anterior fontanelle, separated sutures, and enlarging head). The initial diagnosis in these infants is often congenital
hydrocephalus. Less commonly, the infant has an acute onset of fulminating bacterial meningitis, which differs little from the
clinical manifestations of meningitis alone; imaging is critical in identifying and properly treating the abscess. Opportunistic
pathogens causing brain abscess in neonates can cause considerable CNS damage, particularly in premature neonates with
immature immune responses.
Table 11-5 Cerebral Abscess: Predisposing Conditions
Imaging
On ultrasound (often the initial study performed in the neonate suspected of having meningitis, cerebritis, or abscess), the
abscess appears as a region of altered echo texture, with variable echogenicity of the inner debris, often with hyperechoic
margins, and enhanced through sound transmission (188,280). Echogenic debris may show mobility within the abscess, with
debris usually in a dependent location (Fig. 11-52).
Noncontrast CT images reveal a mass demonstrating low attenuation with a thin wall of slightly increased attenuation. After
contrast administration, a ring of enhancement representing the abscess wall and surrounding inflammatory tissue encircles the
low attenuation center in older children; the ring may not be complete in neonates (Fig. 11-53). The enhancing wall is thin
(usually around 5 mm), located at or near the gray matter–white matter junction, and is surrounded by low attenuation edema.
The inner margin of the ring tends to be smooth and regular. The capsule is thinner on its medial aspect of the abscess in
approximately 50% of patients, resulting from the decreased vascularity of the medially positioned white matter as compared
to the laterally located gray matter (Fig. 11-54D) (268,278). The abscess may point toward the ventricle. The early cerebritis
stage (stage I), therefore, usually can be recognized by CT and treated with antibiotics. Late cerebritis (stage II) has a CT
appearance that cannot be distinguished from Stages III and IV.
The MRI features of pyogenic brain abscesses are often characteristic (281,282). On MR, stage I cerebritis appears as an
area of heterogeneous hyperintensity on both T1- and T2-weighted images; patchy enhancement is seen after administration of
paramagnetic contrast. In the late stage II cerebritis/early abscess, the abscess wall is hyperintense on T1-weighted imaging
and slightly hypointense on T2-weighted sequences; the center of the abscess is heterogeneous on both imaging sequences. The
developing abscess wall is slightly thicker but less sharply marginated in stage II than in stages III and IV when it is better
defined. The abscess wall enhances strongly in stage II; on delayed images, the center of the abscess will also enhance. In
stage III (subacute abscess), the abscess wall is hyperintense on T1 and hypointense on T2-weighted images and enhances
intensely after contrast administration (Fig. 11-54). The abscess center is uniformly hypointense on T1-weighted images and
uniformly hyperintense (similar to cerebrospinal fluid) on T2-weighted sequences and does not enhance. In stage IV (the
chronic phase), the abscess wall is isointense on T1-weighted sequences and markedly hypointense on T2-weighted
sequences; the abscess center is isointense to slightly hypointense on T1-weighted sequences and hyperintense on T2-weighted
sequences. The low signal intensity of the capsule on T2-weighted images in stage IV is thought to be secondary to enhanced
T2 relaxation by decreased free water in the collagenous tissue of the capsule and, perhaps, a small amount of blood or free
radicals (281–283). Although abscesses in stages II through IV all exhibit ringlike enhancement following paramagnetic
contrast infusion, much better edge definition is seen in the enhancing wall of stage II lesions than in stages III and IV.
Figure 11-52 Neonatal cerebral abscess (Enterobacter spp.), utility of cranial sonography. A and B. Coronal and parasagittal cranial
sonogram images in a neonate demonstrate rounded deep white matter abscesses with hyperechoic borders (arrows). Swirling internal debris
was observed. C. Axial postcontrast T1-weighted image shows multiple deep white matter rim enhancing abscesses. Note the bulging of the
deep right frontal abscess into the lateral ventricle (white arrows). Rupture of an abscess into the ventricle portends a poor prognosis.
The imaging differential diagnosis for cerebral abscess includes cystic and necrotic neoplasms (primary and metastatic),
resolving cerebral hematoma, and tumefactive demyelination. Diffusion imaging and DTI metrics are helpful in the
differentiation of abscess from cystic or necrotic tumors (281,284). Abscesses typically show reduced diffusion
(hyperintensity on DWIs, Fig. 11-54C); hypointensity on diffusivity (Dav) maps and at least a part of the abscess may show
increased anisotropy (similar to that of myelinated white matter, Fig. 11-54E) (284,285). The diffusivity may be reduced either
because the pus within the abscess is viscous and reduces the motion of free water or because the cells and proteins within the
abscess are highly concentrated but mostly dead, so there is little active transport of proteins or water molecules (286). In our
experience, late cerebritis also shows reduced Dav and can therefore be differentiated from tumor. In contrast, the
cystic/necrotic components of most tumors generally show increased Dav due to cellular necrosis and increasing size of the
intercellular spaces (286,287). The reduction of water motion in abscesses may be less apparent with small abscesses,
possibly secondary to averaging of diffusion information from normal surrounding brain tissue (288). In addition, abscesses in
preexisting cavities such as postoperative cavities may have diffusion characteristics of necrotic tumors or cysts (289).
Diffusion imaging is also the study of choice for following abscesses under treatment. Abscesses that are responding to
antibiotic therapy will start to show normalization of diffusion characteristics within 1 to 2 weeks after initiation of therapy
even though complete resolution may require months; as the abscess resolves, regions of reduced Dav will remain within the
cavity, but the size of the cavity shrinks. If the area of reduced Dav increases in size or the abscess cavity itself increases in
size, it should raise suspicion of resistance to the antibiotics being used (290). If the abscess has been aspirated, susceptibility
from hemorrhage can mimic reduced Dav on the echoplanar diffusion-weighted images or Dav maps; in this situation, adding a
GRE or SWI sequence will help to detect blood in the abscess cavity (290). For the radiologist, accurate diagnosis of
cerebral abscess is imperative to direct appropriate interventions and therapy.
Figure 11-53 Cerebellar abscess secondary to seeding via a dermal sinus tract. A. Axial noncontrast CT image shows ill-defined low
attenuation mass (arrows) in the cerebellum. B. After administration of iodinated contrast, two distinct masses (arrows) with smooth,
enhancing walls are seen. C. Examination of CT bone window shows an occipital defect (arrows) secondary to a dermal sinus tract. After
shaving the patient’s head, the orifice of the sinus was found.
Perfusion MR imaging may be a useful tool to separate infection from neoplasm: in regions of cerebritis or margins of an
abscess cavity reveal reduced relative cerebral blood volume (rCBV, Fig. 11-54F) and CBF, with prolonged mean transit time
(MTT), whereas gliomas (particularly those of high histologic grade) have elevated rCBV and CBF with decreased MTT
(281,291).
Susceptibility-weighted imaging (SWI) sequences aid in differentiating pyogenic from fungal cerebral abscesses and in
distinguishing abscesses from necrotic brain tumors. The SWI sequence combines phase and magnitude information that can
detect susceptibility differences of cerebral tissues. The SWI dual rim sign is an MR imaging feature characteristic of
pyogenic abscess (292): the two concentric rims of the pyogenic abscess wall are seen, with the inner rim demonstrating SWI
hyperintensity and the outer, hypointensity (Fig. 11-55) (292). In contrast, fungal brain abscesses show a complete hypointense
rim on SWI and lack the dual rim sign (246). SWI can also be useful in differentiating pyogenic brain abscesses from necrotic
glioblastomas. Toh and colleagues have demonstrated that T2 images are not useful in this task, as a hypointense rim may be
seen in both pyogenic brain abscesses and necrotic glioblastomas; however, pyogenic abscesses demonstrate the dual rim sign
on SWI, whereas necrotic glioblastomas lacked the dual rim sign and typically showed broken or irregular SWI hypointense
rims (293).
Proton MR spectroscopy may aid in differentiating abscess from neoplasm and possibly in differentiation between bacterial
pyogenic abscesses and those caused by mycobacteria or fungi (294–296). The MRS options available to the radiologist
include single-voxel spectroscopy (SVS) and two-dimensional magnetic resonance spectroscopic imaging (MRSI), the latter
being particularly helpful in providing a spatial distribution of metabolic concentrations of the cavity wall and adjacent
abscess tissues. Therefore, MRSI is more suitable for differentiating pyogenic abscess from necrotic tumor (297). SVS and
MRSI provide similar infection-related metabolic information of the cavity (297), but MRSI allows assessment of the wall of a
necrotic tumor, which shows the presence of choline, creatine, and NAA peaks on proton MRS (albeit in abnormal ratios, see
Chapter 7). Abscesses do not show any of these normal peaks (298). Within the cavity of bacterial abscesses, MRS detects the
aliphatic peaks of amino acids, sometimes including alanine (at 1.5 ppm), acetate (at 1.9 ppm), succinate (at 2.4 ppm), and
leucine, isoleucine, and valine (at 0.9 ppm) (Fig. 11-54G) (256–259). Lipid and lactate peaks are also seen in almost all
pyogenic abscesses, whether aerobic or anaerobic (Fig. 11-54G) (295,299–301). The peaks of alanine, lactate, leucine,
isoleucine, and valine can be confirmed by the fact that they are inverted on point-resolved spectroscopy (PRESS) sequences
using an echo time of 135 to 144 ms (258). Tuberculous abscesses seem to contain only lipid, without amino acids or lactate
(295). Fungal abscesses are similar to pyogenic abscesses but seem to frequently contain several broad peaks between 3.6
and 3.8 ppm that have been tentatively assigned to the disaccharide trehalose (295). Thus, proton MRS may be useful in
differentiating among the types of organisms responsible for abscesses. Ultimately, however, the abscess usually needs to be
aspirated to more precisely identify the organism and its antibiotic sensitivities.
Figure 11-54 Cerebral abscess. Value of MRI and MRI adjuncts. A. Axial T1-weighted image shows a hyperintense abscess capsule (arrows)
surrounding hypointense abscess (a). B. Axial T2-weighted image shows a hypointense abscess cavity wall (arrows). Note the moderate
surrounding vasogenic edema. C. Axial diffusion-weighted image shows internal signal hyperintensity (characteristic of bacterial abscesses).
D. Axial postcontrast T1-weighted image demonstrates strong enhancement (white arrows) of the abscess capsule. Note that the medial wall is
slightly thinner. E. DTI-derived FA image shows increased anisotropy (red) within the outer portions of the abscess cavity. Note the lack of
signal coherence and decreased FA values (hypointensity) within the subcortical projection fibers surrounding the abscess cavity and within the
right peritrigonal fiber tracts, probably due to interstitial edema. FA may be a better indicator of active inflammation than postcontrast T1-
weighted images. F. Cerebral blood volume map from an axial gradient echo dynamic susceptibility contrast magnetic resonance image (DSC
MRI) demonstrates reduced rCBV in the abscess (white arrows). Note the reduced rCBV within the vasogenic edema (white arrowheads). In
addition, CBF was reduced and MTT was prolonged in the abscess. Necrotizing tumors, particularly those high-grade gliomas, typically show
elevated rCBV and CBF with decreased MTT. G. Proton spectroscopy (TE-288) of the abscess cavity, shows a lactate doublet at 1.33 ppm
(Lac), acetate peak at 1.9 ppm (Ac), and alanine at 1.5 ppm (Al). Lactate results from anaerobic glycolysis. Acetate, lactate, and succinate
have been affiliated with the products of fermentation from infecting organisms.
As the brain abscess evolves, the center of the abscess contains mostly debris and necrotic tissue, while bacterial colonies
and leukocytes are seen primarily in the inner layer of the capsule; therefore, it is recommended that the abscess capsule be
included in the region of interest chosen for acquisition of the spectrum (302). Treatment with antibiotics results in the
disappearance of all peaks except lactate (255). Garg et al. have suggested that acetate and succinate resonances are present
only in abscesses caused by obligate and facultative anaerobes; this observation suggests that MRS may, ultimately, be useful
in identifying the causative organism (294,299).
Aspiration of abscess contents, followed by Gram stain, culture, and antibiotic sensitivity analysis with subsequent medical
therapy, is now the treatment of choice for patients with brain abscesses. Stereotactic CT and MRI have proven helpful in
planning the surgical drainage of affected patients. Moreover, serial CT or MR is valuable in assessing the response to medical
therapy (257,281,282). Medical management is particularly indicated in children with multiple abscesses, those with
abscesses in critical areas of brain, or those with severe underlying illnesses (180). Close monitoring with imaging is
necessary to ensure expected response; if the cavity has not decreased in size by the 10th day of treatment, repeat aspiration is
indicated (303).
Cat-Scratch Disease
Cat-scratch disease (CSD), caused by the gram-negative bacillus Bartonella henselae, affects children or adults in many
regions of the world but especially those living in the more humid areas of the Southern and Midwestern United States
(304,305). More than 10,000 children and adults in the United States, most commonly children between the ages of 5 and 9
years, acquire CSD annually (305). The disorder is typically associated with a papule at the site of inoculation, fever, malaise
and prominent regional adenopathy; the majority of affected patients have only a single enlarged lymph node that reflects
drainage of the bacterium from the initial site of infection, a hallmark of this disease. Potential systemic manifestations of CSD
include hepatitis, osteomyelitis, neuroretinitis, fever of unknown origin, endocarditis, and the oculoglandular syndrome of
Parinaud, which consists of a granuloma of the conjunctiva and regional adenopathy. Neurologic complications, affecting
approximately 2% of children with CSD, reflect the underlying pathology of perivascular lymphocytic infiltrates and
microglial nodule development within the brain (306). A wide range of neurological abnormalities have been reported,
including seizures, encephalopathy/encephalitis, optic neuritis, expressive aphasia, and stroke (296,307,308). The diagnosis
can be established serologically or by detection of the bacterium by culture, PCR, or Warthin-Starry silver staining of biopsy
tissue. Given the slow growth of the B. henselae, cultures must be incubated for at least 3 weeks (305). In most patients, CSD
resolves spontaneously. Treatment of systemic complications consists antibiotic therapy tailored to the specific complication,
for example, doxycycline or erythromycin for neuroretinitis or an aminoglycoside and doxycycline or ceftriaxone for
endocarditis. Corticosteroids may have a role in certain CNS complications, such as CSD–associated acute disseminated
encephalomyelitis (ADEM).
Figure 11-55 Cerebral abscess (Streptoccocus intermedius—member of the Strep. milleri group known to cause suppurative infections)
presumed to arise hematogenously and remote from an antecedent infected right frontal sinus. A. Axial T2-weighted image shows a complex
right cerebral convexity intra-axial abscess with heterogeneous internal signal, hypointense cavity wall, and adjacent parenchymal T2
prolongation (edema). B. Postcontrast T1-weighted image shows three ring-enhancing lesions. The outer gray matter abutting walls were
thicker than the inner white matter abutting walls. C. Axial SWI shows the inner hyperintense wall of the largest abscess cavity, characteristic of
pyogenic abscesses (double wall sign) (arrow).
Imaging
Cerebral vasculitis and focal infarction have been documented in CSD (309,310). Other MRI findings include nonspecific
focal T2 prolongation within the thalami, basal ganglia, and white matter (MR findings more commonly seen in encephalitis
caused by respiratory viruses). More advanced neuropathologic abnormalities that have been reported include laminar
necrosis involving the temporal, parietal, and occipital lobes (311). Optic neuropathy with short segment enhancement at the
junction of globe and optic nerve has been reported as a distinctive neuroimaging finding with CSD (308).
Lyme Disease
Lyme disease, a common tick-borne disease caused by the spirochete Borrelia burgdorferi, can occur in children and older
adults but, in the United States, principally affects those living in New England, the Great Lakes Region, and Northern
California (312). Lyme disease represents the most common vector-borne disease in the United States. A similar condition,
commonly called Bannwarth syndrome, occurs in Europe. When the CNS is involved, many use the overarching term,
neuroborreliosis. The epidemiology of human disease in the United States reflects the distribution of white-footed mice
(Peromyscus leucopus), white-tailed deer (Odocoileus virginianus), and the tick vectors, Ixodes scapularis and Ixodes
pacificus (313–315).
Clinical manifestations of Lyme disease consist of early localized disease characterized by a large erythematous rash
(erythema migrans), fever, malaise, headache, facial palsy, papilledema, and myalgias; early disseminated disease
characterized by arthralgia/arthritis, cardiac conduction defects, and neurological deficits (Bell palsy, radiculopathy,
meningitis, meningoencephalitis, or a pseudotumor cerebri–like syndrome); or late-onset disease consisting of arthritis,
polyneuropathy, and/or encephalopathy (313,316–319). The mechanism for neurological involvement is unclear but may
involve direct invasion by the Borrelia organism or an autoimmune phenomenon, as seen with ADEM (320).
The diagnosis can be established serologically (using enzyme-linked immunosorbent assay and Western blot) and culture
methods in some instances (313,318). The CDC currently recommends a two-tiered diagnostic strategy, beginning with an
immunofluorescence or enzyme immunoassay and if either is positive or equivocal, Western blot for IgM and/or IgG,
depending upon the timing of infection (321). The method and duration of treatment, using doxycycline, amoxicillin,
erythromycin, cefotaxime, ceftriaxone, or penicillin, depend upon the clinical manifestations and complications of Lyme
disease.
Imaging
NECT is usually normal in Lyme disease, although focal areas of decreased attenuation (typically within the central white
matter) have been reported (313,322). MRI detects an abnormality in about 25% of affected patients. Agarwal et al. and other
authors have summarized their experience with MR imaging and neuroborreliosis, describing multiple subcortical and
periventricular white matter lesions similar to those of multiple sclerosis (MS), nerve root, and meningeal enhancement
(313,315,323,324). Van Snick et al. (325) recently reported an acute pontine stroke in a patient with neuroborreliosis.
Regarding the MS-like lesions of neuroborreliosis, diffusivity and magnetization transfer characteristics in the normal
appearing gray and white matter has been found to be normal, allowing imaging differentiation (326). Nonspecific involvement
of white matter and deep gray matter structures may be observed (Fig. 11-56). In children with cranial neuropathy, MRI
following intravenous contrast may show leptomeningeal enhancement with or without enhancement of the affected cranial
nerve (Fig. 11-57); the enhancement is best appreciated if small FOV, fat-suppressed T1-weighted imaging is utilized (Fig. 11-
57) (327,328). In the chronic form of neuroborreliosis, MR may be normal or show periventricular hyperintensities on FLAIR
and T2-weighted images (329). When the spinal cord is involved, MR shows early enhancement of the pial surface followed
by nonspecific T2 prolongation and enhancement of the cord parenchyma (330).
Figure 11-56 Lyme disease. Axial T2-weighted image shows multiple foci of T2 prolongation (arrows) within the thalami. (Courtesy of William
Kelly, MD, Palm Desert, CA.)
Figure 11-57 Lyme disease. Axial fat-suppressed postcontrast T1-weighted images show enhancement of the right seventh and eighth
cranial nerves (white arrowheads in A), left sixth nerve (white arrow in A), and left fifth nerve (white arrows in B).
Early clinical manifestations consist of fever, malaise, headache, and myalgias or arthralgias, with maculopapular and
petechial rashes, starting on the wrists and ankles, usually appearing after the fourth day of the illness (335). The characteristic
rash begins as an erythematous macular rash that blanches with pressure, evolving to a maculopapular and then to a petechial
rash. Involvement of the CNS occurs in approximately 50% of affected patients. Neurological symptoms and signs include
headache, alteration of consciousness, confusion, hallucinations, seizures, and meningismus, which can progress to focal
neurologic deficits (ataxia, tremor, or impaired motor function), stupor, and coma (335). Without adequate and specific
treatment, patients can experience shock, purpura fulminans and death. Although the diagnosis can be established serologically,
Rocky Mountain spotted fever must be suspected clinically in persons with rash, fever, thrombocytopenia, and hyponatremia;
doxycycline therapy should be initiated empirically. With early and appropriate treatment, infected patients recover
uneventfully; with late or inadequate therapy, death or severe sequelae are possible (331,335,336). Although cases in the
United States have increased in recent years, the case fatality rate has declined to less than 1% due to prompt recognition and
treatment (331).
Imaging
Neuroimaging reflects the underlying pathology. In Rocky Mountain spotted fever, NECT may show discrete or confluent foci
of low attenuation typically involving the cerebral white matter. MRI has demonstrated numerous small punctate foci of T2
prolongation scattered throughout the cerebral white matter. Some lesions show reduced diffusivity. The lesions typically
completely resolve after therapy (315,334).
Viral Infections
General Concepts
As many as 100 viral species in 13 different families have been associated directly or indirectly with CNS infection
(337–339). Because viral infections begin with entry and replication in the skin, conjunctiva, or the mucosal surfaces of the
gastrointestinal, respiratory, or genital tracts, several host factors, including the gastric pH, local immune responses, integrity
of the skin or mucosal barriers, affect viral invasion of human tissues. Most viruses reach the CNS hematogenously and enter
the CNS via the choroid plexus or directly through vascular endothelium (337–340). Most CNS infections develop if the virus
evades host defense mechanisms in the setting of adequate magnitude and duration of viremia, the latter a direct reflection of
effectiveness of viral replication at extraneural sites. In contrast, other viruses, such as the rabies virus and certain
herpesviruses, use neural pathways to reach the CNS (337,340,341). The rabies virus infects neuromuscular junctions, enters
nerve endings, and travels by retrograde axonal transport to the neurons of the spinal cord from which it ascends to the brain.
Neural transmission also participates in the pathogenesis of adult-type herpes simplex virus type 1 encephalitis and in the
mucocutaneous reactivations of herpes simplex virus type 1, herpes simplex virus type 2, and VZV.
Many viruses can infect children and cause encephalitis (Table 11-6); among the most important are the herpesviruses, the
nonpolio enteroviruses, and a heterogeneous group of RNA viruses that are commonly called “arboviruses” to indicate their
arthropod-borne origins (338,339,342). Many other viruses have been implicated as important agents associated with
childhood encephalitis, including H1N1, influenza A, influenza B, adenovirus, RSV, parainfluenzae, and human
metapneumovirus (HMPV), a group collectively called the respiratory viruses.
Table 11-6 Selected Causes of Encephalitis in Childhood
Viral
Chikungunya virus
Cytomegalovirus
Dengue virus
Epstein-Barr virus
La Crosse virus
Nipah virus
Nonpolio enteroviruses
Rabies virus
Varicella-zoster virus
Nonviral
Bartonella henselae
Borrelia burgdorferi
Legionella pneumophila
Mycobacterium tuberculosis
Mycoplasma pneumoniae
Rickettsia rickettsii
Treponema pallidum
Immune-mediated encephalitides
Neuro-Behçet disease
Rasmussen encephalitis
Common clinical manifestations of encephalitis, irrespective of the viral cause, include fever, headache, vomiting, seizures,
focal deficits, lethargy, or coma (337,342,343). Fever, a common but not invariable feature, ranges from low grade to 40°C or
higher. The neurologic examination of children or adolescents with encephalitis may reveal hyperreflexia, ataxia, cognitive
disturbances, or focal deficits, such as aphasia or hemiparesis. Severely affected children may have features of increased ICP,
including pupillary, respiratory, and postural abnormalities. Seizures, partial or generalized, affect 15% to 60% of pediatric
patients with encephalitis. Partial seizures greatly increase the chances that a child has HSV encephalitis, but partial seizures
can also occur in relatively mild cases of encephalitis due to the nonpolio enteroviruses or the La Crosse encephalitis virus.
Occasionally, the first clinical manifestations of HSE will be the acute onset of the anterior opercular (Foix-Chavany-Marie)
syndrome, characterized by partial paralysis of the face, pharanyx, and jaw (344). Finally, several noninfectious conditions,
such as the immune-mediated encephalitides discussed in Chapter 3, produce symptoms or signs that mimic those of infectious
encephalitis.
All viruses affecting the CNS exhibit two major pathological features: neuronal degeneration and inflammation. Although
some viruses, such as poliovirus, produce specific clinical symptoms, most viruses can produce a number of different clinical
syndromes that depend on the location of the CNS affected by the virus. Epstein-Barr virus (EBV), as one example, can be
associated with encephalitis, optic neuritis, myelitis, Guillain-Barré syndrome, or acute cerebellar ataxia (342). Thus, clinical
syndromes can show considerable overlap. Not surprisingly, the imaging findings overlap, as well. Therefore, it is very
difficult to differentiate among most viral infections based on imaging or clinical criteria. Some viruses, however, have
predilections for the meninges, others for specific gray matter structures, and still others for the white matter, and these features
can be useful for narrowing the differential diagnosis (342). For example, mumps, nonparalytic polio, coxsackievirus, and
lymphocytic choriomeningitis can all cause meningitis. Encephalitis results from infection with herpes simplex type 1, measles,
arboviruses, and rabies. Leukoencephalitis (involving exclusively the white matter) is caused by subacute sclerosing
panencephalitis (SSPE), progressive multifocal leukoencephalitis, and western and eastern equine encephalitis (Table 11-7)
(342,345,346).
A severe immune-mediated complication of some infectious triggers (influenza A, influenza B, HHV-6, herpes simplex virus
infection, and Mycoplasma pneumoniae) is acute necrotizing encephalopathy (ANE, discussed in some depth in Chapter 3).
Pathologically, infection appears to trigger a systemic cytokine response, perhaps representing an exaggerated immune
response to the infectious agent. This disorder is characterized by noninflammatory hemorrhagic necrosis and exhibits an acute
clinical onset of encephalopathy and absence of CSF pleocytosis. The CSF does show elevated levels of interleukin (IL-6). It
carries a 30% mortality. Key MRI findings include symmetric thalamic and brain stem tegmentum T1 and T2 prolongation. The
cerebral and cerebellar white matter may be involved as well as the internal capsules and lentiform nuclei. Reduced diffusion
and petechial hemorrhage are common in affected areas (Fig. 11-63) (342,345–347).
The presence of neuroimaging abnormalities at the time of clinical presentation has significant prognostic value in
patients with viral encephalitis (274,348–350). Imaging is one of two factors (the other being the presence of focal neurologic
signs) that accurately predicted poor short-term outcome in a series of children with encephalitis (337). More importantly,
neuroimaging can help to separate viral encephalitis from metabolic/toxic disorders and parainfectious encephalitis (also
called acute disseminated encephalitis or ADEM, see Chapter 3). Rapidly raising the specter of specific CNS viral infections
(e.g., HSE) with the aid of imaging leads to rapid therapeutic intervention and diminishes morbidity and mortality. As MRI
gives, by far, the most information among imaging tools, it remains an important diagnostic tool in the early evaluation of
encephalopathic children.
Bartonella henselae (CSD) May cause vasculitis and stroke, T2 hyperintense lesions in thalami, basal ganglia, and WM
Epstein-Barr virus encephalitis Shows tropism for deep gray matter structures, nonspecific involvement of cortex and hemispheric WM,
cause of optic neuritis
HSV encephalitis in neonates Multifocal lesions with T2 prolongation, deep gray matter involved, hemorrhage common, watershed injury
HSV encephalitis of childhood and Limbic system involvement, asymmetric–bilateral, hemorrhage, deep gray matter spared
adolescence
Japanese encephalitis T2 prolongation of lesions involving thalami and hypothalami, minimal enhancement, reduced diffusion of
lesions
Lyme disease Subcortical WM T2 hyperintense lesions, periventricular WM lesions which mimic MS, nerve root and
meningeal enhancement
Measles encephalomyelitis Predominant involvement of thalami, corpus striatum, and cerebral cortex with T2 hyperintense lesions
Mycoplasma pneumoniae encephalitis Leptomeningeal infiltration, may resemble primary angitis enhancement of nerve roots, subcortical WM T2
hyperintense lesions
West Nile virus encephalitis Bilateral basal ganglia and thalamic T2 hyperintense lesions
Early in the course of viral encephalitis, essentially all viruses result in an increase in water content of the affected regions
of brain (338). The imaging findings reflect this feature, consisting of patchy areas of hyperechogenicity on sonography, low
attenuation on CT, low signal intensity on T1-weighted MR images, and high signal intensity on T2-weighted and FLAIR MR
images (Fig. 11-58). Early in the course of the disease, DWI shows the abnormalities with higher sensitivity and more clarity
than conventional T1, T2, and FLAIR imaging sequences (351). The presence of reduced average diffusivity (Dav) within T2-
weighted and FLAIR “bright” lesions may identify lesions at risk for necrosis (351). Wong and colleagues have reported the
association of early reduced Dav upon clinical outcome in children with viral encephalitis (352). Magnetic resonance
spectroscopy (MRS) may also contribute to the diagnosis, as infectious encephalitis typically shows a decline of myo-inositol
(mI) and the elevation of glutamine and glutamate (Glx). MRI with MRS appears to be significantly more sensitive to the
detection of viral encephalitis than other imaging studies and is, therefore, the imaging study of choice. DWI is a critical
adjunct to routine MRI and in many cases provides the earliest clue to the diagnosis of viral encephalitis (353).
Figure 11-58 Rubeola encephalitis. Note involvement of specific anatomic structures. A. Axial CT scan shows low attenuation within both
thalami, the bilateral lentiform nucleus (large arrowheads), right caudate head (small arrowheads), and left frontal white matter (arrows). B. Axial
T1-weighted image shows extensive T1 shortening involving the basal ganglia (large arrows), posterior thalami (arrowheads), and temporo-
occipital cortex (small arrows). C. Axial T2-weighted image shows T2 prolongation within the cortex, basal ganglia, and the anterior cingulum
(arrows). D. Coronal FLAIR image shows symmetric involvement of the cingulum both above the corpus callosum (solid arrows) and in the
medial temporal lobe (open arrows). E. Follow-up axial T2-weighted image shows severe basal ganglia and white matter atrophy.
A few viral infections have specific sites of brain involvement, probably resulting from a specific route of infection or from
molecular interactions between proteins expressed on the surface of the virus and receptors on the surfaces of host cells
(342,347). Respiratory viruses as a group have not historically been considered to exhibit neural tropism. However, bilateral
thalamic and basal ganglia T2 prolongation, variable DWI alterations, and variable SWI signal abnormalities have been
reported with these agents which can cause childhood encephalitis (354). Similarly, other viruses may affect specific regions
of the brain, resulting in symmetric changes in structures such as the hippocampi, cingula (Fig. 11-58), thalami, hypothalami
(Fig. 11-59), substantia nigra, or basal ganglia (Fig. 11-58) (338,347,355). This region specific, symmetric involvement of the
brain should not dissuade the interpreting physician from the diagnosis of viral infection in the proper clinical setting; indeed,
regional specificity is a characteristic of many viral encephalitides. A few viral infections have fairly specific clinical or
radiographic features and will be discussed in some depth in the following sections (Table 11-7).
Herpesviruses
Six members of the herpesvirus family (species of the family Herpesviridae—DNA viruses) are known to cause neurologic
disease in children (342). Of these, neonatal HSV and congenital CMV infections have been discussed in detail under
congenital infections. Herpesvirus-1 (HSV-1), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and human
herpesvirus-6 (HHV-6) will be discussed in the sections that follow (Table 11-8) (50,61).
Figure 11-59 Japanese encephalitis. A. Axial T2-weighted image shows nearly symmetrical T2 prolongation (open white arrows) bilaterally in
the thalami and hypothalami. B. Postcontrast axial T1-weighted image shows minimal enhancement of the periphery of the involved central
regions. C. Diffusion-weighted image through the level of the diencephalon shows reduced diffusion (high signal intensity, arrows) in the
affected deep gray nuclei.
Table 11-8 Neurological Manifestations of the family of CNS Herpes Infections Beyond 4 Weeks
The characteristic CT findings in HSE in childhood and adolescents do not appear until several days after the onset of
symptoms making CT an insensitive test for the early investigation of suspected HSE (49,61). Initially, poorly defined areas
of low attenuation and mass effect develop in the cortex and subcortical white matter of the anteromedial temporal lobe (Fig.
11-60E) with extension to the frontal and parietal cortex. The lentiform nucleus tends to be spared. Occasionally, small foci of
high density, representing hemorrhage, may be seen within the involved brain tissue (Fig. 11-60E). Gyral enhancement is
frequently seen in the involved areas after intravenous administration of contrast; enhancement does not usually appear until the
low density in the region can be identified (366,369,370).
The imaging differential diagnosis of HSE includes nonherpes viral encephalitis, autoimmune encephalitis (e.g., NMDA
receptor Ab–associated limbic encephalitis), vasculitis, and paraneoplastic limbic encephalitis. The health history (including
pace of clinical illness), appropriate laboratory testing, and MR imaging findings in aggregate often clinch the diagnosis.
Generally speaking, the odds of HSE are lower if the cerebral lesions are outside of the limbic system and if there is
bilateral temporal lobe involvement (371).
In summary, HSE can have a variable imaging appearance depending upon the age of the child at the time of infection and
the timing of imaging. The appearance can range from classic limbic system encephalitis to diffuse cortical injury to a focal
vascular territory infarction. Therefore, clinicians must have a high index of suspicion for HSE in all children, irrespective
of age, who experience seizures and altered mental status, especially in the setting of fever and focal neurological findings.
Varicella-Zoster Virus
VZV, the cause of chickenpox (varicella) and shingles (zoster), has been associated with numerous neurological conditions,
including acute ataxia, myelitis, stroke, postherpetic neuralgia, Bell palsy, Ramsay-Hunt syndrome, aseptic meningitis,
encephalitis, congenital varicella syndrome, and Reye syndrome (372). CNS complications affect less than 0.1% of children
with varicella; indeed, immunization has virtually eliminated chickenpox and VZV-related disorders in many regions of the
world. Acute cerebellar ataxia, by far the most common CNS complication of chickenpox, usually begins approximately 10
days after the onset of the rash; ataxia preceding the chickenpox rash or after varicella vaccination has been reported, with
truncal ataxia, dysmetria, vomiting, and irritability being common clinical features (373). Children may also have headache
vomiting, aphasia, hemiparesis, or signs of ICP (374). Stroke or, rarely, herpes zoster ophthalmicus has been reported in
children after varicella (372,375). Usually occurring within 4 to 8 weeks of varicella or zoster infection, these disorders
produce focal deficits, headache, lethargy or somnolence, and, occasionally, seizures. The diagnosis of VZV infection can be
established by detecting VZV-specific IgM in serum or VZV DNA in CSF using PCR (372). Children with VZV-induced ataxia
require supportive care, whereas children with VZV encephalitis or myelitis should receive acyclovir. Corticosteroids may be
of value in children with stroke or myelitis (372).
Imaging
Imaging studies in children with varicella-induced acute ataxia may show diffuse cerebellar swelling (CT low attenuation and
MRI T2/FLAIR hyperintensity) (Fig. 11-61) (372,376–378). Large and small lesions may also be seen at the cortical-white
matter junction of the cerebral cortex and in the basal nuclei (379).
Multifocal leukoencephalopathy, the most common CNS complication of chickenpox, may result from small vessel
arteriopathy and represents another pattern of VZV “encephalitis.” Imaging studies show patchy, typically small foci of low
attenuation on CT, or T1 hypointensity and T2/FLAIR hyperintensity on MR, in the cortex and subcortical white matter caused
by VZV involvement of the small vessels supplying the cortex and subcortical regions (380). Lesions rarely enhance but will
show reduced diffusion early in the course of the disease (61).
Children with delayed onset of focal neurologic deficits after chickenpox or herpes zoster ophthalmicus are presumed to
have a varicella-mediated angiitis involving large vessels (372,381). In almost all such cases, neuroimaging shows an MCA
distribution infarction (Fig. 11-62), most commonly in the putamen and caudate nucleus, with a variably sized injury to MCA-
perfused portions of cerebral cortex (382–387). MRA, CTA, or catheter angiography may be normal or may show
vasculopathy, with narrowing or irregularity (“beading”) of the distal internal carotid artery and the proximal anterior and
middle cerebral arteries (Fig. 11-62B) (385–388).
Other viral infections, such as the California encephalitis virus, can also cause basal ganglia infarctions (389). In addition,
carotid artery dissection can cause basal ganglia stroke in pediatric populations. Therefore, the imaging findings of young
children with stroke must be interpreted in conjunction with the available medical history. The overall prevalence of VZV-
associated neurological conditions in childhood has declined dramatically with the widespread use of the VZV vaccine (390).
It is worth remembering when constructing the differential diagnosis that pediatric patients with basal ganglia/thalamic
germinoma (tumor of high nuclear to cytoplasmic ratio) may present with unilateral motor weakness and early MR imaging
studies may mimic ischemia (see Chapter 7).
Epstein-Barr Virus
EBV accounts for approximately 5% of acute encephalitis in children, causing fever, headache, altered consciousness, and
seizures (including acute status epilepticus) (391,392). In early epidemiology studies of HSE, EBV was the most common
infectious agent mimicking HSV encephalitis. “Alice in Wonderland” syndrome, a neurological manifestation of EBV infection,
causes personality changes and illusions of distorted size, shape, or distance (metamorphopsia) (393). Other neurologic
conditions linked to EBV infections include optic neuritis, Guillain-Barré syndrome, acute hemiplegia, acute ataxia, and the
lymphoproliferative syndrome in immunocompromised children (391). Therapy consists of supportive care; most children
recover completely, although permanent sequelae or death can occur.
Figure 11-61 Acute cerebellitis secondary to herpes varicella-zoster. A. Axial T2-weighted image shows large confluent regions of cerebellar
T2 prolongation. Note the compression of the fourth ventricle (arrowhead). B. Sagittal T1-weighted image shows early signs of upward
transtentorial herniation. Note the distortion of the cerebral aqueduct (black arrow), compression of the pons (black arrows), swelling of the
cerebellum with effacement of the cistern magna. C. Axial average diffusivity image shows increased diffusivity (hyperintensity, arrows) in
regions of T2 abnormality.
Figure 11-62 Varicella-mediated angiitis. A. Axial FLAIR image shows an acute infarction (hyperintensity), (arrows) in the posterior right
putamen. B. Maximum-intensity projection image from a 3D time-of-flight MR angiogram shows narrowing (arrows) of the supraclinoid internal
carotid artery and the proximal anterior and middle cerebral arteries.
Imaging
Patients with EBV encephalitis may show multiple foci of low attenuation (CT) or prolonged T1 and T2 relaxation (MR) in the
cerebral cortex/subcortical white matter, thalami, basal ganglia, and, sometimes, brain stem or cerebellum. EBV encephalitis
has also been reported to cause transient widespread cortical and splenial lesions (394). Rarely, EBV may cause
chorioretinitis and optic neuritis. Importantly, EBV can exhibit a tropism for the deep cerebral nuclei. Therefore, the presence
of T2 or FLAIR hyperintensity in the basal ganglia and thalami should, in the proper clinical setting, raise the
consideration of EBV encephalitis (61). The lesions do not typically enhance after intravenous administration of contrast (61).
Diffusivity is normal. MRS may be a useful adjunct, as it is reported to show reduced NAA with mild elevation of choline and
elevated excitatory neurotransmitters (Glx), the latter suggesting an infectious etiology (395)
Nonpolio Enteroviruses
Spread by the fecal–oral route, the nonpolio enteroviruses (coxsackie, echoviruses, and enteroviruses 68–71) can cause
pharyngitis, herpangina, gastroenteritis, hand-foot-and-mouth syndrome, neonatal sepsis, and disorders of the central or
peripheral nervous system. Children infected with the nonpolio enteroviruses occasionally have acute encephalitis with fever,
seizures, somnolence, coma, or focal deficits (399). Affected children may have focal features that can resemble HSE (400).
Enterovirus 71, in addition to being associated with encephalitis and aseptic meningitis, can cause an acute neurologic
disorder with unilateral or bilateral flaccid paralysis that can resemble poliomyelitis or Guillain-Barré syndrome (401).
Entervoirus D68 has been linked to acute flaccid myelitis, a disorder of children associated with cranial nerve palsies and
limb paralysis due to involvement of spinal cord motor neurons (402–404).
Newborns or young infants infected with nonpolio enteroviral infections can have a disseminated illness that resembles
bacterial sepsis or disseminated HSV infection. Clinical features consist of fever, respiratory distress, seizures, lethargy,
shock, or disseminated intravascular coagulopathy; cardiomyopathy can complicate severe infections, especially those due to
coxsackieviruses, and may be fatal in some infants (405). In this young patient group, CNS involvement may include acute
hemorrhagic necrotizing encephalitis that tends to spare the basal ganglia (405).
Figure 11-64 Enteroviral-71 rhombencephalitis. A. Sagittal T1-weighted image shows poorly marginated T1 hypointensity (arrow) involving the
lower pons and upper medulla. B and C. Sagittal and axial T2-weighted images show T2 hyperintensity within the pontomedullary lesion
(arrows). ADC images showed increased diffusivity.
The diagnosis of enteroviral infections is made best by detecting enteroviral RNA in CSF or serum using reverse
transcription (RT)-PCR (339,399). Infants and children with severe nonpolio enteroviral infections have been treated with
pleconaril, a novel antiviral drug with efficacy against several RNA viruses including the rhinoviruses and enterovirus D68,
although controlled trials suggest that pleconaril therapy is associated with only modest shortening of enteroviral disease-
related symptoms (406).
Imaging
The imaging manifestations of the nonpolio enteroviruses are diverse, including minimal leptomeningeal enhancement in the
setting of aseptic meningitis, encephalitis, rhombencephalitis (Fig. 11-64), cerebellitis (Fig. 11-61), acute transverse myelitis
with or without associated radiculitis, acute flacid myelitis (Fig. 11-86), arteriopathy and Guillain-Barré syndrome
(61,400,401,403).
Arthropod-Borne Viruses
Several viral pathogens capable of producing CNS infections are transmitted to humans by ticks and mosquitoes (338,339).
The incidence of tick-borne encephalitis (TBE) is increasing in many countries. In addition to the tick-borne diseases of CSD
and Lyme disease discussed previously, the neurotropic viruses in the flaviviridae family remain important pathogens. It is
recognized that humans and other mammals serve as natural hosts to these neurotropic viruses. Additionally, among the human
diseases caused by the neurotropic flaviviruses, only Japanese encephalitis is more frequent than TBE (315). Although they
represent members of several viral families, these viruses are commonly considered the “arboviruses” because of their
arthropod-borne mode of transmission. Arboviruses of importance include the alphaviruses (including eastern equine
encephalitis virus, western equine encephalitis virus, and Venezuelan equine encephalitis virus), the flaviviruses (including
Japanese encephalitis virus—a significant health problem in Southeast Asia, the Far East and the Indian subcontinent, St. Louis
encephalitis virus, West Nile virus, dengue virus, Zika virus, and several agents associated with TBE in Europe, Asia, and
North America), the bunyaviruses (La Crosse encephalitis virus), and a reovirus (the Colorado tick fever virus) (338).
Although the majority of human infections with these viruses do not result in symptoms, each of these viruses can cause
meningitis or encephalitis in children and adolescents (342). The clinical manifestations of the arboviral encephalitides
(headache, fever, seizures, and alterations of consciousness) are nonspecific; therefore, MRI can play a major role in
identifying the most likely pathogen. Management consists principally of supportive care, since none of the currently available
antiviral medications possess specific activity against these viruses.
The child or adolescent suffering from TBE may present with a range of clinical symptoms and signs including headache,
myalgias, seizure, behavioral changes, ataxia, orofacial dyskinesia, hemiparesis, and encephalopathy, all mostly secondary to
immune-mediated demyelination or acute nonimmune demyelination. CSF analysis shows pleocytosis, and the serum in the
acute phase of illness demonstrates tick-borne–specific IgM antibodies. The typical spectrum of cranial imaging
abnormalities includes T2 hyperintense lesions of the thalami, substantia nigra, basal ganglia, brain stem, cerebellum, cerebral
cortical, and hemispheric white matter (Fig. 11-59) (407); the typical diencephalic involvement of Japanese encephalitis aids
in its differentiation from HSE.
Dengue fever, caused by a Flavivirus (RNA virus), which infects approximately 100 million individuals each year, has
variable clinical manifestations ranging from headache and myalgias to profound encephalopathy. As a result, the CNS
cerebral spinal axis imaging findings are varied. Reports have identified reduced diffusivity and T2 hyperintensity within the
thalami, hippocampi, temporal lobes, pons, and spinal cord. Dengue may also present as acute hypoxic injury (408). Given
their mode of transmission, these infections are more common in warmer weather (spring, summer or fall), reflecting the
activity and geographic distribution of the transmitting arthopods.
Many of these viruses have spread around the world and have contributed to considerable human disease. Eastern equine
encephalitis has the highest mortality rate of US arboviral illness, ranging from 30% to 50% (409). By contrast, La Crosse
virus encephalitis, one of the more common US arbovirus diseases among school-aged children, is rarely associated with fatal
infections (410,411). Identified in Uganda in 1937, West Nile virus appeared in Egypt and Israel in the 1950s and affected
humans infrequently. Beginning in the mid-1990s, human outbreaks began to cause fatal encephalitis among persons living in
Israel, Algeria, and Romania (412). In 1999, West Nile virus infection first appeared in the United States. Its activity in New
York that year was the harbinger of a massive epidemic that by 2003 had affected the entire continental United States, causing
nearly 15,000 recognized cases of which a substantial proportion were neuroinvasive, particularly among adults (413–416).
WNV has become the most common cause of epidemic meningoencephalitis in North America. Although western equine
encephalitis virus and St. Louis encephalitis virus have been associated historically with large US outbreaks, these viral
infections are relatively infrequent.
Several closely related, tick-borne flaviviruses of Europe, Asia, and North America can produce encephalitis among
children and adults living in these regions (331,332,417,418). Patients with European TBE often have a biphasic illness,
experiencing headache, malaise, myalgia, and low-grade fever during the initial, viremic phase. Approximately 20% to 30% of
infected individuals have a second, neurologic phase with headache, high fever, somnolence, coma, convulsions, cranial nerve
palsies, or paralysis that can mimic Guillain-Barré syndrome. Such patients have relatively high rates of neurologic sequelae.
Powassan virus, a tick-borne Flavivirus endemic in eastern Canada and the northeastern United States, occasionally causes
encephalitis in children (331,419).
Imaging
With the growing use of MRI in the investigation of neurological disorders, the radiologist should be familiar with the more
characteristic MRI features of TBE. The presence of bilateral thalamic (symmetric or asymmetric) T2 hyperintensities, with
or without additional lesions within the putamen and/or caudate nuclei, is the most common abnormality. Other imaging
abnormalities include T2 hyperintensity of the cerebellum, brain stem, and anterior horn cells of the cervical spinal cord (315).
Not surprisingly, the imaging findings among the Arboviruses are as diverse as its members. Japanese encephalitis
typically demonstrates T2/FLAIR hyperintensity and reduced diffusion (in the acute phase) of the posteromedial thalamic
nuclei, substantia nigra, corpus striatum, cerebral cortex, brain stem, cerebellum, and, occasionally, the white matter (Fig. 11-
59) (61). The thalami and substantia nigra are involved in nearly all cases and the hippocampi and corpora striata are involved
in two-thirds of infected patients. La Crosse encephalitis may precisely mimic the imaging features of HSE (411). Eastern
equine encephalitis may show multifocal T2 hyperintense lesions involving the brain stem, cortex, and periventicular white
matter. Neuroinvasive West Nile virus infections can manifest in a diverse array of imaging abnormalities, including aseptic
meningitis, meningoencephalitis, and focal T2/FLAIR hyperintensity of the basal ganglia, thalami, and substantia nigra
(413,420,421); these imaging findings may mimic Japanese encephalitis. WNV encephalitis may also show reduced diffusion
of the white matter of the corona radiata, internal capsule and deep gray matter structures, pons, and midbrain (421–424).
Stroke (associated with CNS WNV vasculitis) has also been described (425).
Dengue virus, an arthropod-borne Flavivirus, exists endemically in tropical and subtropical regions, and more than 100
million persons are infected with this virus annually, causing high fever, headache, myalgia, bone pain, rash and easy bruising,
or hemorrhagic fever, a more severe disease associated with intense abdominal pain, dyspnea, vomiting, or death due to shock
or congestive heart failure (426). Rarely, dengue virus causes encephalitis with fever, seizures, weakness, and alterations in
consciousness (427). The imaging findings are diverse, with lesions of the frontal, temporal, and occipital lobes, as well as
brain stem and spinal cord, exhibiting T2 hyperintensity and variable diffusivity (427).
Chikungunya virus, a mosquito-borne Alphavirus observed in southern Europe, India, Latin America, and Southeast Asia,
can occasionally be associated with neurological complications, ranging from fever, myalgia, vomiting, and rash to neuropathy,
febrile seizures, and encephalitis (428). The diagnosis can be confirmed by detecting chikungunya virus–specific antibody
responses and enzyme-linked immunosorbent methods; therapy consists of supportive care. MR findings are nonspecific,
reflecting an encephalomyeloradiculitis (429) and sometime suggestive of ADEM (430).
Influenza Virus
Influenza virus can be associated with encephalitis or encephalopathy (261,431). The onset of neurologic symptoms and signs
occurs a few days to a week after the first signs of influenza A infection. The novel H1N1 influenza A begins as a seasonal
febrile upper respiratory infection; some cases progress to encephalopathy. The pathogenesis of this disorder may include
immune or toxin-mediated endothelial injury, perivascular edema, and demyelination; the virus is not found in CSF or serum.
However, elevated proinflammatory cytokines are found. Young children with preexisting neurological disorders (e.g.,
cerebral palsy or Down syndrome) seem particularly vulnerable to the neurological complications of H1N1 (432–434).
Figure 11-65 H1N1 encephalitis complicated by ANE. A. Axial T1-weighted image in an encephalopathic teenager with trisomy 21 shows
numerous deep hemispheric and peripheral regions of T1 prolongation. Note the compression of the lateral ventricles. B. Axial T2-weighted MR
image shows numerous deep hemispheric and peripheral cortical and subcortical regions of T2 prolongation. C. SWI shows innumerable
parenchymal hypointensities (hemorrhages).
Imaging
MRI features of the brain in influenza encephalitis range from focal encephalitis to diffuse edema. Key MRI features of H1N1
encephalitis include bilateral thalamic, perirolandic, medial temporal lobe, and cerebellar regions of T1 and T2 prolongation.
Meningeal enhancement has been described (Fig. 11-65). Transient T2 prolongation and reduced diffusion of the callosal
splenium have been reported with influenza A encephalitis (Fig. 11-66). However, it is important to remember that any edema
of the callosal splenium results in reduced diffusion, because splenium axons are the most tightly packed in the brain, giving the
free water molecules little area in which to diffuse. As a result, reversible splenial lesions can be seen in many conditions that
cause posterior cerebral edema; other reported causes include infections with rotavirus, measles, mumps, HHV-6, EBV, and
Salmonella spp.; 0157 Escherichia coli–associated hemolytic uremic syndrome; and noninfectious considerations that include
diffuse axonal injury, MS, epilepsy, hypoxic–ischemic injury, antiepileptic drug usage, and febrile infection–related epilepsy
syndrome (FIRES) (261,394,435,436).
Figure 11-66 Reversible lesion of the splenium associated with influenza A. A. Sagittal T1-weighted image shows swelling and T1
hypointensity within the splenium (arrows). B. Axial FLAIR image demonstrates splenial hyperintensity (white arrows) and, more subtly, in the
callosal genu (arrow head). C. Average diffusivity image show reduced diffusivity (hypointensity) in the splenium and genu (arrows). The
imaging abnormalities were absent on a follow-up MRI 1 month later.
Rabies
Human rabies cases range from 1 per 100,000 to 1 per one million persons per year in Africa and Asia, resulting in several
thousand deaths annually (341,437,438). By contrast, the United States has fewer than five indigenous cases of human rabies
per year, and certain regions (Australia, Finland, Japan, New Zealand, Norway, and Sweden, among others) are currently
rabies free (341). Rabies virus persists endemically in bats, raccoons, skunks, and foxes in the United States and in wild
canines or other mammals in many regions. Wounds that allow the virus to gain subcutaneous access resulting from exposure to
unvaccinated, rabid animals (dogs, raccoons, etc.) remain the major source of human rabies worldwide (341). Human rabies
typically begins nonspecifically with chills, fever, headache, sore throat, malaise, nausea, or abdominal pain; pain or itching at
the site of inoculation commonly occurs as an early feature. Neurologic features of rabies consist of agitation, hypersalivation,
delirium, and occasionally opisthotonic posturing. Hydrophobia, present in 20% to 50% of patients, produces spasms of the
laryngeal muscles, diaphragm, and accessory respiratory muscles. Seizures can occur, and patients with rabies encephalitis
eventually lapse into a fatal coma. Rabies-induced Guillain-Barré syndrome produces bulbar dysfunction, facial diplegia,
cardiac dysrhythmia, coma, respiratory arrest, and death. The diagnosis of human rabies can be made by detecting rabies virus-
specific antibodies in serum or CSF, rabies virus in saliva by culture or RT-PCR, or rabies virus antigens in skin biopsies
(341). Treatment consists of supportive care, although patients have survived with modest neurological sequelae after
treatment with ribavirin, amantadine, and drug-induced coma (439).
Imaging
CT in rabies typically shows diffuse or focal low attenuation in the basal ganglia, periventricular white matter, hippocampus,
and brain stem. MRI in the early phase of the disease shows ill-defined T2 hyperintensity in the cerebral cortex, basal ganglia,
deep cerebral white matter, hippocampi, brain stem, and spinal cord. In the later phases of the disease, enhancement may
appear in the brain stem, spinal cord, and cervical spinal nerve roots after intravenous contrast administration (440). Thus, the
imaging findings correspond well to the pathologic findings of neuronal necrosis and demyelination in the basal ganglia,
thalami, and brain stem (441).
Although rabies is an important infection with brain stem involvement, the more practical clinical and imaging differential
diagnostic considerations for children in developed countries who present with signs and symptoms suggesting infectious or
parainfectious rhombencephalitis (progressive encephalopathy, ataxia, and ophthalmoplegia) without a relevant health history
exposure to rabies should include Bickerstaff brain stem encephalitis, Miller-Fisher syndrome, and Guillain-Barré syndrome.
In addition, patients who present with these phenotypes warrant evaluation for infectious associations or triggers including
influenza A/B, enterovirus, Lyme disease, Mycoplasma pneumoniae, EBV, and Mycobacterium tuberculosis. The CSF
analysis in these patients typically shows albuminocytologic dissociation and elevation of anti-GQ1b antibodies. Steroids and
other immunosuppressants may be beneficial (442). Bickerstaff encephalitis is characterized clinically by the disturbance of
consciousness and pyramidal signs; Miller-Fisher is characterized by the triad of ataxia, external ophthalmoplegis, and
areflexia; Guillain-Barré, which involves demyelination of the peripheral nervous system, results in progressive ascending
limb weakness with bulbar involvement and without ophthalmoplegia and ataxia. In patients who fit the Bickerstaff
encephalitis phenotype, MRI has shown T2 hyperintensity involving the posterior pons, often extending to the periependymal
surface of the rhomboid fossa of the fourth ventricle (442).
Table 11-9 Imaging Findings of Selected Forms of Chronic Encephalitisa
Postrubella panencephalitis (rare) Rubella virus •• T2 prolongation of cortex and subcortical white matter progresses to
atrophy
Subacute sclerosing panencephalitis Measles virus •• T2 prolongation cerebral cortex and subcortical white —extends to
periventricular white matter
•• Bilateral but asymmetric
Variant Creutzfeldt-Jakob disease Prion •• Progressive T2 hyperintense lesions of basal ganglia, thalami, and
cerebral cortex
aSee Chapter 3 for additional information regarding immune-mediated disorders of the CNS.
Nipah Virus
In the fall of 1998, cases of severe encephalitis appeared in Malaysia; electron microscopy of tissues from infected patients
identified a paramyxovirus, named Nipah virus after Kampung Sungai Nipah, the Malaysian village in which the virus first
appeared (443,444). During the initial outbreak, 265 cases of encephalitis affected persons as young as 10 years of age, and
nearly 40% of affected individuals died; many survivors had neurological sequelae. Clinical manifestations included fever,
headache, vomiting, cough, cerebellar signs, seizures, autonomic dysfunction, and coma (445). The initial outbreak of Nipah
encephalitis resulted from contact with pigs or with pig excrement and fruit bats (genus Pteropus) were identified as a natural
reservoir of the virus (446). During subsequent outbreaks in India and Bangladesh, person-to-person spread, as well as
foodborne transmission, has been documented (447). Ribavirin therapy has been associated with improved outcome.
Imaging
MR abnormalities reported in Nipah encephalitis including widespread foci of T1 hyperintensity within the cortex of affected
individuals, likely indicating cortical necrosis (448). Early MR imaging would likely show T2 prolongation and reduced Dav
in the regions that later show T1 shortening.
Figure 11-67 Subacute sclerosing panencephalitis (SSPE), progression of disease. A. Early SSPE. Axial T2-weighted image shows patchy
T2 prolongation (arrows) in the right parietal and occipital cortex and left subcortical white matter. B. Later phase of SSPE. Axial T2-weighted
image 3 months later shows much more extensive T2 prolongation involving the cerebral hemispheric cortex and white matter bilaterally. C.
Single-voxel proton spectroscopy (PRESS) of the right parietal white matter (TE = 35 ms) demonstrates marked elevation of myo-inositol (mI),
significant decline of NAA and elevation of choline (Ch).
Imaging
Imaging shows involvement predominantly of the thalami, corpus striatum (caudate nucleus and putamen), and the cerebral
cortex, which show T2/FLAIR hyperintensity and reduced diffusion in measles encephalomyelitis (Fig. 11-58) (450).
Scattered foci of T2/FLAIR hyperintensity may develop in the white matter as the disease evolves. Ultimately, T1
hyperintensity (possibly secondary to calcification or hemorrhage) and atrophy may ensue (Fig. 11-58).
MRI, sensitive to the cerebral abnormalities in SSPE, is the neuroimaging examination of choice (Fig. 11-67). The CT
findings in SSPE are nonspecific, and in the early course of the disease, CT will be normal. Eventually, diffuse atrophy is
accompanied by multifocal areas of low attenuation in the periventricular and subcortical white matter (454). MR may be
normal in the first 3 months after the onset of clinical signs and symptoms. Diffusion-weighted MR imaging may demonstrate
altered diffusivity before other MRI changes are appreciated (455). Subsequently, hyperintensity develops on T2-weighted and
FLAIR images in the cerebral cortex and subcortical white matter (Fig. 11-67A) (456). Most commonly SSPE is bilateral but
asymmetric, typically involving the parietal and temporal lobes (456–458). Mass effect and contrast enhancement may be
present in these early phases. As the disease progresses, T2/FLAIR hyperintensity extends into the periventricular white matter
and the corpus callosum (Fig. 11-67B). Diffuse atrophy develops as the disease progresses into its final stages (456). Basal
ganglia involvement is seen in 20% to 35% of affected patients (458). T2/FLAIR hyperintensity of the brain stem, in particular
the midbrain, pons, and middle cerebellar peduncles has been reported, although it is not certain whether such involvement can
be isolated or is only seen in conjunction with cerebral involvement (454,459). There appears to be a correlation between the
severity of brain involvement on MR and the stage of the disease (457). The results of MR spectroscopy vary according to the
stage of SSPE (460,461). Not surprisingly, NAA is reduced and myo-inositol is increased in late stages of the disease (Fig. 11-
67C) (454,460–462).
Chronic enteroviral encephalopathy, an uncommon condition, occurs in boys with X-linked agammaglobulinemia and,
occasionally, in patients with other immunodeficiencies or immunosuppression induced by chemotherapy for malignancy (463).
Systemic features include hepatitis and a dermatomyositis-like rash; neurological manifestations include weakness,
somnolence, dementia, headaches, seizures, paresthesias, and ataxia. The diagnosis can be established by detecting enteroviral
RNA using RT-PCR. However, enterovirus is not always detected. Therapy consists principally of immunoglobulin
replacement, often with high-titered enterovirus-specific preparations. Imaging may demonstrate nonspecific
meningoencephalitis with atrophy. Limbic encephalitis mimicking the MRI appearance of HSE has also been reported (464).
Progressive multifocal leukoencephalopathy (PML), a CNS demyelinating disorder of immunocompromised hosts, results
from CNS reactivation of the JC polyoma virus (131,465). This virus commonly infects most humans asymptomatically, but in
the setting of immune dysfunction, the virus reactivates, infects oligodendrocytes, causes demyelination and progressive CNS
dysfunction, and often leads to debility and death. Conditions associated with PML include HIV infection and other disorders
associated with reductions in CD4+ and CD8+ lymphocyte counts, such as malignancy or immunosuppressive therapy with
natalizumab for MS (466). PML can occur after therapy with novel immunomodulating agents used to treat rheumatologic,
gastrointestinal and dermatologic conditions (466,467). Clinical manifestations of PML consist of ataxia, paralysis, visual
impairment and cognitive dysfunction. In patients with HIV infection, PML may improve during immune reconstitution with
combined antiretroviral therapy, but, in other immunocompromising conditions, PML commonly ends in death due to the
absence of specific antiviral chemotherapy (468). The diagnosis of PML can be confirmed by detection of JC virus DNA in
CSF using PCR. The imaging appearance of PML in children is identical to that in adults, characterized by single or multiple
areas of decreased attenuation (CT) or prolonged T1 and T2 relaxation times (MR) in white matter; the lesions lack mass
effect and reportedly do not enhance after administration of contrast material (468), although the authors have rarely seen a
faint rim of enhancement on MRI. The most common locations are the frontal and parieto-occipital regions, but any myelinated
area of the brain, including the corpus callosum, thalami, and basal ganglia, can be involved.
Cerebellitis
Cerebellitis is an uncommon pediatric disorder, characterized by infectious, inflammatory or toxic cerebellar dysfunction
typically (but not always) of acute onset with fever and meningismus. Additionally clinical findings may include abnormal
spontaneous eye movements, myoclonic jerks, truncal ataxia, dysarthria, nausea, headaches, tremor, and altered mental status.
Cerebellar edema can obstruct the fourth ventricle, with resultant acute hydrocephalus. A history of recent viral illness can
often be elicited. Symptoms usually resolve spontaneously over weeks to months, although permanent disability, and even
death due to cerebellar herniation may ensue in some cases (377,469–471). Therefore, decompressive surgery is sometimes
necessary in order to prevent herniation of the cerebellum (471). The many causes of acute cerebellitis or cerebellar
dysfunction include lead intoxication (see Chapter 3), cyanide poisoning, demyelinating disease, hemophagocytic
lymphohistiocytosis, drug exposure (metronidazole and fentanyl), and vasculitis. Infectious causes of cerebellitis include
influenza, rubeola, pertussis, typhoid fever, coxsackievirus, poliovirus, varicella-zoster, mumps, rotavirus, HHV7, HSV1, and
EBV (377,469,471). Some cases may be a manifestation of ADEM (see Chapter 3) (377). Although less common than viral
associations, bacterial causes should always be considered, including Mycoplasma pneumoniae, Coxiella burnetii,
legionellosis, Corynebacterium diphtheriae, and, rarely, Streptococcus. In the context of suspected infectious/parainfectious
cerebellitis, it is rare to find direct viral and/or bacterial invasion of the cerebellum. Therefore, the consideration of cytokine
or immune mediated injury should always be raised. Anti–glutamate receptor antibodies (glutamate receptors are expressed in
cerebellar Purkinje cells) have been identified in cerebellitis (472). Cerebellar leukoencephalopathy can also be of
paraneoplastic etiology, seen in association with noninfectious histiocytic disorders of the Langerhans and non-Langerhans cell
types. In these patients, the clinical presentation may include cognitive decline, ataxia, and spasticity. Lung and breast cancers
(more common in adults) have also been associated with cerebellitis. Rarely, cerebellitis may be recurrent and episodic and of
familial etiology (472).
Imaging
Imaging in patients with acute cerebellitis reveals lesions of ill-defined low attenuation with CT, while MR reveals T1
hypointensity and T2/FLAIR hyperintensity involving both gray and white matter of the cerebellar hemispheres (Fig. 11-61)
(61,377). Noninfectious histiocytic disorders have MR findings of T2 hyperintensity involving the white matter and cerebellar
nuclei (472). When bilateral, the diagnosis is straightforward, but when cerebellar involvement is unilateral (hemicerebellitis),
it is important to remember that not all hemispheric cerebellar tumefactions are neoplastic (473): pediatric hemolytic
streptococcal infections have been associated with hemicerebellitis (474). Although unusual, the acute presentation of
hemicerebellitis in children of inflammatory, infectious, or postinfectious etiology warrants thoughtful clinical monitoring,
avoiding a default impression that the “tumefaction” is neoplastic and thereby reserving surgical procedures only for those
children demonstrating clinical deterioration (475,476). Contrast enhancement is varied, predominantly pial, and may be seen
in the subacute phase. Cerebellar atrophy is often seen in the chronic phase of the disease (61,377).
Rasmussen Encephalitis
Rasmussen encephalitis, a disorder characterized by seizures, progressive hemiplegia, and psychomotor deterioration
(477–479), is an important cause of intractable epilepsy in childhood. Patients are typically normal until onset of seizures,
which usually occurs between the ages of 14 months and 14 years (mean 7 years). The most common pattern of seizures is
partial motor (or focal) epilepsy, a condition characterized by clonic movements, usually localized to the face or upper
extremities. In some patients, the episodes persist over long periods, either continuously or with only brief interruptions,
leading to epilepsia partialis continua (480); however, patients may also have generalized tonic–clonic seizures, partial
complex seizures, postural seizures, and somatosensory seizures (479–481). Ultimately, nearly all patients develop a fixed
hemiplegia. EEG shows focal slow or epileptiform activity contralateral to the motor manifestations (477–481); other
symptoms include, in order of decreasing frequency, homonymous hemianopsia, sensory deficits, dysarthria, dysphasia, and
personality changes (481). Patients deteriorate progressively unless the affected regions of brain are surgically resected
(477,481–484). The following diagnostic criteria have been proposed:
A. Children who develop epilepsia partialis continua and meet at least one of the following criteria to suggest the diagnosis of
chronic encephalitis:
1. Progressive neurologic deficit at the beginning or after the onset of epilepsia partialis continua but before the start of
treatment
2. Progressive hemispheric atrophy on CT, MRI, or both, with or without attenuation or signal abnormalities
3. Presence of oligoclonal or monoclonal banding on CSF examination
4. Biopsy evidence of chronic encephalitis
B. Children who do not have epilepsia partialis continua but have focal epilepsy and biopsy evidence of chronic encephalitis.
They may, in addition, meet criteria 1, 2, or 3.
Pathologic examination of the affected brain shows focal or widespread parenchymal injury with microglial nodules and
perivascular T-cell lymphocytic infiltration; atrophy ensues in the cerebral cortex and white matter (483). Although a viral
etiology was once proposed, no infectious pathogen has been linked to Rasmussen encephalitis (484). An immune etiology has
also been postulated, given the histopathology of Rasmussen encephalitis and the onset of seizures in rabbits immunized with
glutamate receptor GluR3 protein (485). Although detection of GluR3 antibodies is neither sensitive nor specific for
Rasmussen encephalitis, an immune-mediated pathogenesis is supported, nonetheless, by the favorable response to
plasmapheresis, intravenous immunoglobulin (IVIG) or immunosuppressive therapy with corticosteroids, tacrolimus, or
azathioprine (484). Further investigations have implicated T-lymphocytes in the pathogenesis of this disorder, but the precise
pathogenesis of Rasmussen encephalitis remains enigmatic at this time (484).
Figure 11-68 Rasmussen encephalitis, early findings. A and B. Axial FLAIR images show hyperintensity in the left insula (small arrow in A),
left thalamus (arrowhead in A), and blurring of the cortical white matter junction due to subcortical white matter hyperintensity in the medial
frontoparietal region (arrows in B). The caudate and putamen are commonly involved in Rasmussen encephalitis.
Imaging
Initial imaging studies in children with Rasmussen encephalitis are typically normal. Over time, hyperintensity develops in the
cerebral cortex and subcortical white matter on T2-weighted and FLAIR images (Fig. 11-68), followed by onset and
progression of atrophy (Fig. 11-69) (486,487). The frontal and temporal lobes are most commonly affected, usually with
associated atrophy in the insular and periinsular cortex (Fig. 11-69) (486). Progressive T2/FLAIR hyperintensity and atrophy
in the ipsilateral basal ganglia (caudate and putamen) is eventually seen in about 65% of affected patients (Fig. 11-69)
(486–488). Proton MRS may become positive earlier than MR imaging, showing reduced NAA and creatine in the white matter
of the affected hemisphere (489). The MRS findings may reflect a combination of progressive encephalitic damage and
fluctuating seizure effects in which neuronal injury and recovery may occur (490). With short echo times (TE = 35 ms),
elevated glutamate/glutamine may be identified, possibly secondary to neurotransmitter release resulting from the nearly
continuous seizure activity (491). Diffusion tensor imaging demonstrates increased diffusivity and decreased FA of the affected
hemisphere (492). 18F-fluorodeoxyglucose PET shows reduced glucose uptake throughout the affected portion of the
hemisphere (493). Ictal SPECT may also be useful in the early detection of the epileptogenic focus, showing increased uptake
in actively seizing regions (494,495).
Figure 11-69 Rasmussen encephalitis, later stage. A and B. Axial T1-weighted images show atrophy of the right hemisphere, involving both
cortex and white matter. The right lentiform nucleus (white arrows) is small and hyperintense. C and D. Axial FLAIR images show abnormal
hyperintensity of the affected basal ganglia (arrows) and cortex (arrowheads). E. Average diffusivity image shows hyperintensity (arrows) in the
medial right posterior frontal lobe, indicating tissue loss and increased Dav values with decreased anisotropy in the affected portions of the
brain.
The appearance of increasingly frequent simple partial seizures in a previously healthy child, aged 1 to 15 years (most
commonly 3–6 years), with normal neuroimaging initially should suggest the possibility of Rasmussen encephalitis
(494,496).
Fungal Infections
General Concepts
Several fungal pathogens, including Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum as well as
several species of Candida and Aspergillus fungi, can infect the CNS of infants, children or adolescents (274). Certain
infections, such as those with Coccidioides immitis and Histoplasma capsulatum, affect otherwise healthy persons, but many
disorders, including cryptococcosis, candidiasis and aspergillosis, occur much more often in infants, children, or adolescents
with immunocompromising conditions, including prematurity, congenital immunodeficiency disorders, HIV infection, bone
marrow transplantation, chemotherapy, or malignancy. The clinical features can reflect chronic basilar or diffuse meningitis, an
invasive encephalitic process, or focal lesions (abscesses) of the cerebrum, brain stem, cerebellum or spinal cord. Diagnosis
of fungal CNS infections relies predominantly on culturing the organism from the CNS or tissues (498). Effective therapy is
particularly challenging in many cases given that CNS invasion often occurs in the setting of immunodeficiency. The following
material provides representative examples of common fungal infections of the CNS; others are described in Table 11-10. These
organisms most commonly cause meningitis, although meningoencephalitis, intracranial thrombophlebitis, and brain abscess
can also develop (232). For practical purposes, fungal infections of the nervous system can be divided into two principal
categories: (a) those induced by pathogens and (b) those produced by saprophytes in patients whose resistance to infection is
lowered by conditions such as diabetes, leukemia, and lymphoma or by the prolonged use of antibiotics, corticosteroids,
cytotoxic drugs, or immunosuppressive agents. The latter group of infections is referred to as opportunistic.
Imaging
An important concept is that opportunistic infections in immunologically compromised children may have a different clinical
or imaging appearance than do infections in immunocompetent children. For example, fungal abscesses may not have a
sharply marginated capsule or a complete capsule if the immune response of the affected child is impaired (Fig. 11-70).
Mycotic infections of the nervous system are uncommon in children and their manifestations are identical to those in adults;
they are reviewed here only briefly.
Neonatal Candidiasis
Candidiasis occurs primarily in the neonatal period, particularly among premature infants weighing less than 1000 g and those
with central lines, undergoing invasive procedures or receiving multiple antibiotics (499). Causative organisms include
Candida albicans, Candida parapsilosis, and Candida tropicalis. Clinical features of neonatal candidiasis consist of
meningitis or meningoencephalitis with a bulging fontanelle, seizures, lethargy, or coma. The diagnosis of neonatal candidiasis
can be challenging, however, given that the clinical manifestations are often subtle, and cultures of blood or cerebrospinal fluid
can be negative in the presence of true infection. Definitive diagnosis is nonetheless established by positive blood or
cerebrospinal fluid cultures. Amphotericin B alone or in combination with other antifungal medications, such as fluconazole
and 5-fluorocytosine, is used to treat neonatal candidal infection (500). The outcome ranges from complete recovery to death,
but many survivors of neonatal candidiasis have higher rates of cerebral palsy, vision loss, or deafness than expected based on
their prematurity alone.
Table 11-10 Selected Fungal Infections of the Central Nervous System
Aspergillus species Fever, cough, headache, seizures, focal deficits Invasive CNS infection, cavitary, partial rim enhancement, hyperintense T2
rim, +/− hemorrhagic
Blastomyces Fever, cough, malaise, headache, meningeal signs, Ring-enhancing lesions, edema, vasculitis, infarctions
dermatitidis focal deficits
Candida species Sepsis, somnolence, poor feeding, bulging Meningitis resembles other granulomatous diseases, infarction, hemorrhage,
fontanelle, lethargy, coma miliary pattern
Coccidioides Fever, headache, obtundation, meningeal signs Hematogenous spread, thick basilar granulomatous meningitis,
immitis hydrocephalus, mimic of TB meningitis
Cryptococcus Fever, headache, meningeal signs Hydrocephalus, ischemic changes from vasculitis, cortical atrophy,
neoformans pseudocysts
Histoplasma Fever, cough, headache, meningeal signs, focal Hematogenous spread, meningeal enhancement, infarction, edema,
capsulatum deficits vasculitis
Figure 11-70 Aspergillus abscess in an immune compromised child. A and B. Axial T2-weighted and FLAIR images show a poorly defined
mass (arrows) in the right frontal lobe. C. Axial postcontrast T1-weighted image shows an enhancing capsule (arrows) only around the
posterior margin of the abscess.
Imaging
Candida infection may spread hematogenously, with subsequent meningitis in infants, especially those born with congenital
anomalies such as intestinal malrotation, meconium ileus, or hydrocephalus requiring shunt placement. Candida meningitis can
also be a complication of immune suppression, surgery, or extensive burns. When Candida invades the nervous system
primarily, it usually progresses to gross abscess formation; in those patients in whom invasion is a complication of antibiotic
therapy, diffuse cerebritis with widespread microabscesses and, sometimes, meningeal inflammation more commonly develops
(Fig. 11-71) (265,501,502). As with other granulomatous meningitides, Candida can invade the walls of blood vessels,
producing vasculitis that results in infarction and hemorrhage (265,501,502).
Candida meningitis resembles other granulomatous meningitides (see the section on tuberculous meningitis) in that exudate
fills the basilar cisterns and markedly enhances after infusion of intravenous contrast. Candida infiltrates are enhancing lesions
of the brain with no specific features (Fig. 11-71). An intraventricular Candida fungal mass has been reported as a
manifestation of refractory Candidiasis in an immunocompetent neonate (503). As with many fungal abscesses, Candida
abscesses differ somewhat from pyogenic abscesses in that the walls are thicker and less sharply defined. Additionally,
diffusion studies reveal higher average diffusivity values within fungal abscesses as compared to pyogenic abscesses (295).
Figure 11-71 Multiple Candida infiltrates due to systemic candidiasis in a preterm neonate. A. Axial T2-weighted image shows bilateral
germinal matrix hemorrhages (arrows) and several small areas of white matter hypointensity (arrowheads) representing parenchymal injury. B.
Postcontrast axial T1-weighted image shows multiple small enhancing foci representing areas of Candida infiltration in the cerebral
parenchyma.
Aspergillosis
Aspergillosis of the CNS, a life-threatening disorder most often due to Aspergillus fumigatus, occurs most frequently in
premature infants or in children with malignancies, especially leukemia, or undergoing immunosuppresive therapy. Because the
fungus enters the body via the lungs, pulmonary symptoms, such as cough, dyspnea, chest pain, wheezing, or hemoptysis, can be
the initial or prominent features. When the infection disseminates, systemic or neurologic symptoms like fever, headache,
seizures, or focal deficits (including cerebral septic infarctions) ensue (277,504). The diagnosis of aspergillosis can be
established by culturing the organism from specimens obtained by bronchoscopy or biopsy and supported by the
histopathological features of biopsy tissues. Culture is relatively insensitive, however; PCR can be used to detect the organism
(498). Despite therapy with amphotericin B and other antifungal agents, CNS aspergillosis is often fatal, especially when the
organism invades brain parenchyma and causes multiple CNS lesions.
Imaging
Imaging features include meningeal enhancement, ring-enhancing lesions, hemorrhages, brain edema, and complications due to
the angioinvasive nature of aspergillus including infarctions (lacunar and territorial), hemorrhage, and formation of mycotic
aneurysms (Fig. 11-70) (505). Diffusion imaging has proven helpful in the early characterization of cerebral aspergillus
lesions, which show low diffusivity within small circular lesions (506). The imaging characteristics of Aspergillus brain
infection may show overlap with CNS infections caused by the Mucoraceae family and Nocardia asteroides.
Coccidioidomycosis
Infections with Coccidioides fungi, endemic in the Southwestern United States, are most common in the central valley of
California, southern Nevada, central and southern Arizona, southern New Mexico, and western Texas. The CNS tends to be
involved secondarily, usually from hematogenous dissemination after a systemic infection (502,507). Symptoms are mainly
headache, low-grade fever, weight loss, and progressive obtundation, with minimal meningeal signs.
Pathologically, the leptomeninges are thickened and congested due to formation of multiple granulomas, most frequently in
the basal cisterns (502). Communicating hydrocephalus usually ensues. Noncommunicating hydrocephalus can result from
ependymitis within the cerebral aqueduct or fourth ventricle. As with other basilar meningitides, a perivasculitis or true
vasculitis may result in vessel occlusions and infarctions.
Imaging
Imaging findings reflect the pathologic changes. The basilar cisterns are often filled by granulomatous, opaque, thickened
meninges, and after administration of intravenous contrast, the basal cisterns and other cisternal spaces enhance markedly.
Hydrocephalus is almost always present. The imaging appearance of Coccidioides meningitis is identical to that of
tuberculous meningitis, with enhancing tissue that shows low diffusivity filling the subarachnoid spaces, predominantly in the
basal regions. Parenchymal lesions are unusual in Coccidioides meningitis (a differentiating point from Mycobacterium
tuberculosis). Rarely, infarcts are seen as a result of vasculitis (507,508).
Cryptococcosus
Cryptococcosus, one of the most common fungal infections of the human nervous system of adults, is unusual in children. Adults
are more commonly affected because of greater exposure and because of the predilection of cryptococcal infection to cause
disease in immunocompromised individuals (265,501). Symptoms usually reflect meningeal involvement; occasionally,
neurologic signs or alterations in mental status may predominate. Definitive diagnosis can be established by cerebrospinal
fluid analysis using culture or antigen detection (509). Pathologically, the majority of cases with cerebral involvement
demonstrate meningitis. As in other fungal and granulomatous infections, the exudate is found mainly in the basilar cisterns,
although it may be diffuse throughout the subarachnoid spaces (510). A predilection for the choroid plexus results in
ventriculitis with occasional secondary trapping of the temporal horn(s) of the lateral ventricle(s) (511). Parenchymal mass
lesions rarely occur.
Imaging
Imaging patients with CNS cryptococcosus most commonly show hydrocephalus, cortical atrophy, pseudocysts, and ischemic
changes from the vasculitis. The pseudocysts appear as areas of low attenuation (CT) or prolonged T1 and T2 (MR) in the
basal ganglia that do not enhance after administration of intravenous contrast (512). In the presence of a trapped temporal horn
without an obvious associated mass, cryptococcosus should be a strong consideration (513). Following contrast
administration, enhancement of the granulomatous exudate in the basal cisterns occurs. In rare cases, parenchymal mass lesions
can be visualized enhancing in either a ring or solid fashion (509–511).
Parasitic Infections
Parasitic infections of the CNS remain major causes of neurological morbidity in much of the world. Several protozoan and
parasitic disorders can involve the pediatric nervous system, including cysticercosis, toxoplasmosis, sparganosis, malaria,
toxocariasis, schistosomiasis, paragonimiasis, echinococcosis, amebiasis, and coenurosis, among others (Fig. 11-72)
(501,515,518,519). Only cysticercosis, echinococcus (Fig. 11-73, common in Australia, New Zealand, Latin America, Central
Europe, and Mediterranean countries) and toxoplasmosis commonly affect the CNS of children or adolescents in resource-rich
nations (520). Neurocysticercosis is among the most common causes of acute hydrocephalus and new-onset seizures in much of
the world, while malaria affects many thousands of persons annually in tropical climates, particularly Africa and Southeast
Asia. This section describes the features of three important conditions: neurocysticercosis, visceral larval migrans, and
cerebral malaria. Several other parasitic conditions and their clinical and neuroimaging manifestations are summarized in
Table 11-11.
Figure 11-72 Amebic meningoencephalitis. Balamuthia mandrillaris A. Axial T2-weighted image shows innumerable cerebral hemispheric
lesions with marginal T2 prolongation and inner T2 shortening. B. Axial postcontrast imaging shows numerous ring-enhancing lesions.
(Courtesy of Charles M. Glasier, MD, Little Rock, AR.)
Neurocysticercosis
Neurocysticercosis, perhaps the most common parasitic disorder affecting the CNS, reflects human infection with larvae of the
pork tapeworm Taenia solium (521,522). Humans represent both intermediate and definitive hosts for T. solium and sustain
infestation by harboring the worm and shedding vast quantities of viable eggs. Pigs serve as intermediate hosts in the life cycle
of the parasite. Although neurocysticercosis (invasion of the CNS by T. solium larvae) can occur at any age with the possible
exception of infancy, the disorder peaks during the third decade of life. The disorder occurs endemically in Mexico, Central
and South America, India, Africa, and China, but neurocysticercosis is becoming increasingly prevalent in several other
regions, including the United States (523). Clinical manifestations of neurocysticercosis include headaches, seizures, focal
neurologic deficits, cranial nerve abnormalities, or signs of increased ICP, such as papilledema or altered alertness. Seizures,
the most common manifestation of acute or inactive neurocysticercosis, can be generalized, focal with secondary
generalization, or focal with localized seizure activity (522). Mental status changes, visual disturbances, and behavioral
abnormalities are other potential clinical features. Obstructive or communicating hydrocephalus, a potentially life-threatening
complication of neurocysticercosis, can complicate active or inactive infection (524). Symptoms of hydrocephalus include
headache, vomiting, diplopia, or visual disturbances, especially when larvae invade the subarachnoid space and acutely
obstruct the lateral, third, or fourth ventricles.
Figure 11-73 Echinococcus cyst. A and B. Axial T1 (A) and T2 (B) weighted images show a large, sharply marginated, nonenhancing mass
(arrows) that is isointense to CSF.
Amebic brain abscess (Entamoeba Headache, coma, seizures, focal Ring-enhancing lesions, odd looking lesions, can mimic neoplasms
histolytica) deficits
Amebic meningitis (Naegleria fowleri) Headache, coma, seizures, Enhancing leptomeninges most prominent around olfactory bulbs
(Acanthamoeba sp.) meningeal signs
Cerebral malaria (Plasmodium Seizures, headache, coma Generalized cerebral edema multiple cortical, thalamic infarctions,
falciparum) hemorrhage
Neurocysticercosis (Taenia solium) Seizures, hydrocephalus Four forms: parenchymal cysticerci, leptomeningitis, intraventricular
cysticerci, and racemose cysts
Paragonimiasis (Paragonimus Seizures, focal deficits Hemorrhage, infarction; conglomerated, multiple ring-enhancing
westermani) lesions
Schistosomiasis (Schistosoma sp.) Ataxia, paralysis, cranial Granulomatous encephalitis, central linear enhancement surrounded
neuropathies, coma, seizures by multiple punctuate nodules
Toxoplasmosis (Toxoplasma gondii) Congenital infection, brain abscess Ventriculomegaly, scattered Ca++
Visceral larva migrans (Toxocara canis) Headache, behavior change, Meningoencephalitis, linear arborizing calcifications, retinal
seizures, focal deficits detachment
The diagnosis of neurocysticercosis relies upon the correlation of clinical features and neurodiagnostic studies (498,521).
Serologic studies, using the enzyme-linked immunotransfer blot, have excellent sensitivity and specificity in patients with
extraparenchymal CNS disease or multiple cysts, but serologic diagnosis is less sensitive when patients have solitary lesions
(498). The diagnosis of neurocysticercosis is made clinically in many instances (523). Treatment of cysticercosis should be
based upon the activity of the infestation and the location, number, and size of CNS lesions (521). Antiparasitic treatment
should be considered in active parenchymal infestations, particularly when lesions are numerous; most authorities suggest
albendazole with corticosteroids as the treatment of choice. Hydrocephalus can be managed using endoscopic techniques
(524,525).
Imaging
The four forms of cysticercosis described in the pathology literature are (a) parenchymal cysticerci, (b) leptomeningitis, (c)
intraventricular cysticerci, and (d) racemose cysts (526,527). Although each form has its own particular appearance on CT and
MR, most patients experience multiple exposures to the organism. Therefore, it is important to remember that a patient may
harbor more than one form at the same time.
Parenchymal cysticercosis, the most common form, produces a variety of symptoms and signs that develop when the death
of the parasite elicits an inflammatory reaction. Although cysts can be located anywhere in the brain, they most commonly
occur in the cerebral gray matter, followed by the brain stem, cerebellum, and spinal cord (501,521,526,527).
Intraparenchymal cysticerci can be either solid or cystic. Solid lesions are often associated with punctate calcifications
whereas cystic foci commonly have a rim of enhancement (Fig. 11-74) (528–533). The scolex, seen as an area of signal void
when calcified, is often best detected on MRI on FLAIR images (533). When the cysticercus dies, it stimulates local
inflammation and breakdown of the blood–brain barrier; as a consequence, contrast enhancement is seen. Both calcified and
cystic components tend to be located in the gray matter and usually have surrounding hyperintense interstitial edema when
visualized on T2-weighted or FLAIR MR scans prior to the initiation of therapy (Fig. 11-74). The edema resolves during
treatment. Although the calcifications within the lesions are seen better by CT, MR more clearly demonstrates cortical lesions
(adjacent to the skull) which may be obscured by beam hardening artifact inherent to CT (532–534). Completely calcified
lesions of cysticercosis do not enhance or elicit edema (531) Some authors propose that the calcifications represent dead
organisms; however, the inflammation which may develop around calcified cysticercal lesions after the initiation of therapy
raises the possibility that the calcified lesions are still viable (534). It reportedly takes approximately 4 to 7 years for the dead
larvae to calcify; however, calcification has been documented in children younger than 3 years with well-documented
cysticercosis (534). The time required for children to become infected and the time necessary before the organism dies explain
why calcifications are much less common in the pediatric age group than in adults with cysticercosis (529). The only
significant differences in the imaging findings between adults and children with cysticercosis are: (a) calcifications are more
commonly seen in adults, and (b) diffusely homogeneously enhancing lesions are more commonly seen in children (529). Most
children have single lesions when initially imaged (535). Cystic parenchymal lesions have diffusion characteristics of CSF
(536); therefore, it is important to identify other features of the organism. T2-relaxometry has been employed as a noninvasive
method to differentiate cysticercal cysts from tuberculomas (537). Proton MRS typically shows lactate (doublet at 1.33 ppm),
succinate or pyruvate (singlet at 2.4 ppm), alanine (doublet at 1.5 ppm), acetate (multiplet at 1.9 ppm), and an unassigned peak
at 3.3 ppm, but in our experience the features of the spectrum vary from patient to patient (538).
The leptomeningitis form of cysticercosis is seen on noncontrast CT and MR studies as soft tissue filling the basilar
cisterns. After intravenous contrast administration, as with other granulomatous meningitides, the involved subarachnoid
spaces markedly enhance (see Figs. 11-46, 11-47, and 11-75) (539). Granulomas are commonly present within the
subarachnoid space; these may calcify (Fig. 11-75); their enhancement characteristics are similar to those of parenchymal
granulomas. Hydrocephalus and vasculitis (with resulting infarction) are common when leptomeningitis is present (Fig. 11-75).
Intraventricular cysticerci are especially important to identify because affected patients can die suddenly from acute
ventricular obstruction. If acute hydrocephalus develops in association with punctate parenchymal calcifications (Fig. 11-
76) or other evidence of cerebral cysticercosis, the presence of an intraventricular cyst should be suspected.
Intraventricular cysts are difficult to identify on CT unless contrast is introduced into the ventricular system. MR is superior to
CT in the identification of intraventricular cysts because the scolex (head) of the parasite can be identified within the ventricle
as a soft-tissue intensity nodule (Fig. 11-76) (531–533). Thin T1-weighted images optimize detection of the scolex, and use
steady-state sequences such as CISS or FIESTA helps to identify both the scolex and the cyst wall as regions of hypointensity
in the hyperintense CSF (540). If the cyst is in the third ventricle, imaging in the sagittal plane is optimal, while for fourth
ventricle cysts, imaging in the coronal or sagittal plane allows better appreciation of the degree and nature of the ventricular
distortion. If surgical removal of an intraventricular cyst is contemplated, imaging should be performed in close temporal
proximity to the surgery, since these cysts can migrate through the ventricular system (541). Diffusion imaging is not helpful, as
the lesions have diffusion characteristics similar to CSF (536).
Racemose cysts are multilobular, nonviable (lacking a scolex) cysts located in the subarachnoid space; they are often
accompanied by chronic leptomeningitis (528). They are often quite large, up to several centimeters in size. Although sterile,
these lesions can grow by proliferation of the cyst wall and, consequently, may be amenable to medical therapy. Racemose
cysts are most common in the cerebellopontine angle, suprasellar region, sylvian fissures, and the basilar cisterns. On CT, they
appear as large cystic lesions whose margins may enhance after intravenous contrast infusion. The inner septations are not
easily seen on CT (Fig. 11-77) (530). On MR, multiple cysts of varying size are seen, clustered together like grapes (Fig. 11-
77) (541). Diffusion-weighted images are not useful to differentiate these from other types of cyst, as the diffusion
characteristics of the cyst fluid are similar to those of CSF (492). Proton spectroscopy shows a prominent pyruvate or
succinate peak at 2.4 ppm, and may show alanine at 1.5 ppm, lactate at 1.3 ppm, or acetate at 1.9 ppm (542).
When the symptoms suggest spinal involvement, MR is the preferred imaging technique. Thin (preferably 1–2 mm) section
images will demonstrate the cyst as a sharply marginated mass that focally expands the cord and is isointense with CSF. Thin
section imaging will reveal the scolex within the cyst as a small area of T1 hyperintensity or T2 hypointensity. Cord edema
often extends one to three vertebral segments above and below the cyst (543). The wall of the cyst enhances as a thin, smooth
rim on T1 images after intravenous administration of paramagnetic contrast (543,544). Racemose cysts appear as CSF-
intensity masses in the subarachnoid space, often displacing the spinal cord. In rare situations where MR is not available,
myelography (conventional or CT) may be useful to detect the racemose form of the disease as intradural, extramedullary
masses which move with tilting of the patient in the head-up and head-down positions (545). Arachnoiditis, if present, results
in a partial or complete block to contrast flow.
Cerebral Toxocaral Disease
The principal cause of visceral larva migrans (the systemic manifestation of Toxocaral disease), the ascarid Toxocara canis,
infects wild and domestic canines throughout temperate and tropical regions (546). Infected dogs shed vast quanities of ova
that remain viable in soils for many months. In edemic areas as many as one-third of soil samples contain T. canis larvae, and
humans become infected by ingesting eggs present in fomites or contaminated soils. Clinical features suggesting visceral larva
migrans include cough, fever, malaise, abdominal pain, weight loss, hepatosplenomegaly, or skin rash. Neurological
manifestations include headache, behavioral changes, seizures and rarely, focal neurological deficits (547). The diagnosis is
established by detecting peripheral blood eosinophilia and T. canis-specific IgG and IgM in human serum; serologic studies
can be negative when disease is localized to the eye. Less commonly, other ascarids, including those infecting cats (T. cati) and
racoons (Baylisascaris procyonis), cause human neurological disease.
Figure 11-74 Parenchymal cysticercosis. A–C. Axial T1-weighted, T2-weighted, and coronal FLAIR images show a ring-enhancing lesion
(arrows) with surrounding vasogenic edema (arrowheads). Note that the center of the lesion is of low signal intensity on the T2-weighted and
FLAIR images. D. Postcontrast axial T1-weighted image shows marked ring enhancement (arrows). E. Diffusion-weighted image shows the
lesion (arrows) as hypointense, indicating increased diffusion and differentiating it from a bacterial abscess. F. Proton MR spectrum (TE = 26
ms) shows abnormal peaks from lipids (broad singlet at 0.9 ppm), lactate (doublet at 1.33 ppm), succinate or pyruvate (singlet at 2.4 ppm),
alanine (doublet at 1.5 ppm), and acetate (broad peak at 1.9 ppm).
Figure 11-75 Meningeal cysticercosis. A. Postcontrast CT image shows enhancement in the suprasellar and sylvian cisterns (arrowheads)
and along the tentorium (arrows). The temporal horns of the lateral ventricles are dilated secondary to hydrocephalus. B. Bone window CT
image shows punctate calcifications within the suprasellar and sylvian cisterns (arrowheads). C and D. Postcontrast axial T1-weighted images
show multiple enhancing nodules in the suprasellar cistern, temporal lobe, and inferior sylvian cisterns.
Figure 11-76 Intraventricular Cysticercus. A and B. Axial noncontrast CT images show acute hydrocephalus. Multiple punctate calcifications
(arrows), suggesting parenchymal cysticercosis, are present in the cerebral parenchyma. No definite lesion is seen in the third ventricle. C.
Sagittal T1-weighted image shows the cysticercal cyst (arrows) in the posterior third ventricle and the rostral opening of the aqueduct. D.
Postcontrast axial T1-weighted image shows that the posterior third ventricular cyst (arrows) does not enhance.
Figure 11-77 Racemose cerebral cysticercosis. A. Axial contrast enhanced CT shows several cystic lesions (arrows) in the region of the right
sylvian fissure. B. Coronal T1-weighted image shows septated cystic mass (arrows). C. Axial T2-weighted image shows a moderate amount
of edema surrounding the cysticercal cysts within the sylvian fissure (arrowheads). This degree of edema was not appreciated on either the CT
or the T1-weighted MR image.
Figure 11-78 Visceral larval migrans. A and B. Axial noncontrast CT images in a patient with shunted hydrocephalus demonstrate subtle
linear and branching cerebral parenchymal calcifications (arrows). These calcifications had become more conspicuous over 9 months.
Imaging
Several imaging abnormalities have been described in patients with neurotoxocarosis, including intracranial calcification (Fig.
11-78), parenchymal atrophy, nonspecific meningoencephalitis, vasculitis and inflammation of the optic nerves and other
cranial nerves (547,548). Xinou et al. (471) described MR findings of cortical and subcortical lesions with T2 prolongation
and enhancement (549).
Cerebral Malaria
Cerebral (severe) malaria, due to infection with Plasmodium falciparum, occurs predominantly in the southern hemisphere,
especially in India, Southeast Asia and sub-Saharan Africa (550) Children account for 75% of deaths due to severe malaria in
the tropical regions of Africa. Malaria causes chills, fever, headache, nausea, vomiting and malaise, often in cycles every 1 to
4 days. Patients with severe malaria have a multi-organ system, sepsis-like disorder with renal, hepatic and hematologic
disease and cerebral signs and symptoms, including seizures, coma, focal deficits and features of cerebral edema. Serologic
and molecular studies, such as PCR, can be used to detect malaria infections, but identifying parasites on a Giemsa-stained
blood smear examined by an experienced laboratorian is the gold standard for the diagnosis of malaria (498,550).
Treatment of severe cerebral malaria consists of supportive care and administration of a rapidly effective, artemisinin
compound (artesunate, artemether, artemotil, dihydroartemisinin) in combination with longer-acting drugs, such as doxycycline,
clindamycin, sulfadoxine–pyrimethamine, atovaquone–proguanil or mefloquine (551–553). Several clinical factors, including
age, pregnancy, HIV infection, and others, influence the specific antimalarial regimen. Current guidelines are available from
the US Centers for Disease Control and Prevention (552) and WHO (551). Children who survive cerebral malaria are at risk
for epilepsy and motor and cognitive deficits.
Imaging
Imaging abnormalities in cerebral malaria include multiple cortical and thalamic regions of edema and infarction, parenchymal
hemorrhage, and the premoribund pattern of generalized cerebral edema (550,554–556).
Sarcoidosis
Sarcoidosis, a granulomatous disease of unknown etiology, occurs worldwide. The disease is particularly common in the
southeastern region of the United States and has a much higher incidence among African-Americans than among other races
(557). Sarcoid involves the nervous system in 10% of affected individuals, both adult and pediatric (558,559). The disease is
unusual in children, however, and only 6% of all cases involve pediatric populations (558). The age of onset in adults is
usually the third and fourth decades of life, whereas most affected children are between 9 and 15 years old when signs and
symptoms appear.
In order of descending frequency, presenting clinical manifestations of pediatric neurosarcoidosis consist of seizures,
aseptic meningitis, cranial neuropathy (most commonly involving cranial nerves VII, II, and VIII), hydrocephalus, hypothalamic
dysfunction, hydrocephalus, focal neurological signs secondary to intracranial masses at other sites, intraspinal masses,
encephalopathy or vasculopathy, seizures, myelopathy, and peripheral neuropathy (Table 11-12) (558–562). Children evolve to
an adult pattern as they progress through adolescence (560); a review of 23 published cases of CNS sarcoidosis in children
found that pediatric disease does not differ significantly from that of adults (559). Sarcoidosis is characterized pathologically
by widely disseminated noncaseating granulomas. The most frequently involved tissues are the lymph nodes, lungs, skin, eyes,
and bone. Basal or diffuse granulomatous leptomeningitis is the most common form of neurological disease in persons with
sarcoidosis; the infundibulum, the floor and anterior walls of the third ventricle, and the base of the frontal lobes are frequently
involved (563). Granulomas can form in the extradural and subdural spaces, leptomeninges, brain parenchyma, spinal cord,
optic nerves, or peripheral nerves (558).
Meningoencephalopathy 45 65
Seizures 40 <10
Hydrocephalus 10–30 25
Myelopathy 5 10
Peripheral neuropathy 0 20
Imaging
The imaging findings in neurosarcoidosis can include hydrocephalus, one or more parenchymal nodules (typically located in
enlarged perivascular spaces) that enhance homogeneously after contrast administration, edema in periventricular white matter
(manifested as low density on CT and prolonged T1 and T2 on MR), or diffuse enhancement of the basal meninges and
tentorium (Fig. 11-79) (563–568). Extraparenchymal masses may mimic meningiomas (565,566). The single or multiple
smoothly marginated parenchymal nodules may be located at the base of the brain or scattered throughout the hemispheres;
some will calcify (567). The parenchymal lesions lack surrounding vasogenic edema. They are isodense with gray matter prior
to contrast infusion on CT; on MR, they are isointense to gray matter on T1-weighted images and iso- to hyperintense on T2-
weighted images (565,567). The granulomas enhance uniformly after administration of intravenous contrast
(563,564,567–569). Imaging studies are valuable not only in the diagnosis of intracranial sarcoidosis, but also in its follow-up.
Imaging abnormalities including cranial nerve enhancement and spinal lesions will often resolve with immunosuppressive
therapy. Enhancing dural and parenchymal lesions are less likely to respond optimally to therapy (563)
General Concepts
Inflammatory/infectious disorders of the spine and spinal cord, although uncommon in children, can have devastating effects
when the disorders are not recognized promptly (570). Inflammatory disorders of the spine, such as discitis, can present with
back pain, irritability, limp and refusal to walk or lie supine. The neurological examination is usually normal, although some
young children may exhibit the Gower sign. Fever is an inconsistent feature. Pediatric patients with pyogenic infections of the
disk space or osteomyelitis of the adjacent bony structures may exhibit similar clinical features and commonly have fever,
erythema, localized pain and laboratory evidence of infection, such a peripheral leukocytosis with a left-shift and elevations of
the erythrocyte sedimentation rate or C-reactive protein. Staphylococcus aureus is the most common pathogen associated with
discitis and pyogenic infections, although other organisms, such as Kingella kingae, can be detected (570).
Inflammatory disorders of the spinal cord, such as transverse myelitis, can begin insidiously over a few days with vague
pain in the back or abdomen. In contrast, acute flaccid myelitis may progress to paralysis quickly. Neurological abnormalities,
hallmarks of the spinal cord involvement, consist of weakness, arreflexia or hyperreflexia, incontinence, and sensory
dysfunction, the latter often corresponding to a dermatomal level. In acute flaccid myelitis, weakness with sensory sparing may
be seen. Additionally, in contrast to children with acute transverse myelitis, children with acute flaccid myelitis can have
cranial neuropathies, but lack involvement of spinal sensory pathways (403,571).
Imaging
With greater access to safe pediatric sedation practices and MRI, Gallium and technetium bone scans have become less
commonly used in the investigation of suspected spinal infection. That being said, if performed it is important to recognize that
Gallium and technetium bone scans can show abnormalities early, sometimes as early as 1 week after symptoms; however,
discitis is not excluded by a normal gallium or technetium bone scan and they are nonspecific even when positive (578).
MR is the study of choice; it is more sensitive than plain films or CT, particularly when fat suppression is used, and has
higher specificity than that of radionuclide scanning for the detection of early spondylodiscitis (579,580). On MR, the affected
disc space is narrowed and often is of low intensity on T2-weighted images (Fig. 11-80) (581,582). An associated phlegmon
may be identified extending into the epidural space from the affected disc (Fig. 11-81) (583). If the disc or the adjacent
vertebral body is of high signal intensity on T2-weighted images (Fig. 11-81), a disc space abscess with adjacent osteomyelitis
should be suspected (581,582). Enhancement of the adjacent vertebral body after administration of paramagnetic contrast is
strong evidence of vertebral osteomyelitis (Fig. 11-81) (579,581,582). If not detected early in the course of the disease,
vertebral osteomyelitis may result in vertebral collapse and a marked spinal deformity. After treatment, changes in the
vertebral body do not completely recover for up to 24 months, while the abnormal signal intensity of the disc persists for up to
34 months (583). The best predictor of favorable treatment response is the disappearance of associated phlegmon; increasing
T2 hyperintensity may be seen within the adjacent vertebral bodies in the face of improving symptoms and laboratory measures
of infection and is not a reliable sign of treatment response (584).
Figure 11-79 Examples of neurosarcoidosis. A. Axial T2-weighted image shows areas of mild hyperintensity (arrows) in the middle cerebellar
peduncles. B and C. Postcontrast axial T1-weighted images show patchy enhancement of the brain stem, cerebellar parenchyma, and
temporal lobes. D and E. Axial and coronal postcontrast T1-weighted images show enhancing parenchymal nodules (arrows), dilated
perivascular spaces, and a dural based nodule (arrowhead) over the left posterior frontal convexity.
Figure 11-80 Intervertebral discitis, late phase. A. Lateral plain film shows sclerosis of the endplates of L2 and L3 (arrows) with narrowing of
the disc space. B. Sagittal T1-weighted image shows hypointensity of the L2 and L3 vertebral bodies (arrows). The intervertebral disc space is
narrowed, but no associated soft tissue mass is seen. C. Sagittal T2-weighted image shows hyperintense vertebral bodies (arrows) with
narrowed disc space. A small ventral soft tissue mass (arrowheads) is seen. D. Postcontrast sagittal T1-weighted image shows enhancement
of the narrowed L2-L3 disc space and adjacent vertebrae (arrows). The ventral soft tissue mass (arrowheads) enhances uniformly.
If extensive erosive destruction of the vertebral body is seen with an associated soft tissue mass ventral or dorsal to the
spinal column, consideration should be given to tuberculous or Coccidioides spondylitis. In such cases, CT best shows the
destruction of the bone, but MR best shows the soft tissue component that may compress the spinal cord, the extension of the
soft tissue mass beneath the anterior and posterior longitudinal ligaments, and the relative sparing of the intervertebral disks
(Fig. 11-82). All of these features allow differentiation from pyogenic discitis/osteomyelitis.
Spinal Empyema
Organisms can invade the spinal epidural space hematogenously and induce fever, back pain and meningeal signs suggesting
meningitis (585). The diagnosis is sometimes established serendipitously during lumbar puncture when pus is encountered
during cautious introduction of the spinal needle; organisms associated with spinal epidural abscess include staphylococcal or
streptococcal species and occasionally Brucella species or Bartonella henselae, the cause of CSD (586). Like other
suppurative parameningeal infections, treatment consists of surgical drainage and administration of appropriate antibiotics.
Although extremely rare in childhood, infections of the spinal epidural space (spinal empyemas) are important to recognize
because a delay in diagnosis can result in permanent neurologic injury. Predisposing conditions in children include sepsis, the
presence of indwelling vascular catheters and the use of spinal instrumentation for scoliosis (587). Although the clinical course
of spinal empyemas can be acute, rapidly progressive or chronic, the acute course, resulting from blood-borne, metastatic
infection, is the most common. Chronic empyemas are most often caused by direct extension of spinal osteomyelitis, which may
be the result of hematogenous spread of infection or of direct infection from spinal instrumentation (587,588). Classically,
hematogenous spinal epidural abscesses follow a typical clinical pattern (265,589,590): (a) within 2 weeks after an infection,
a backache develops; (b) the back pain is enhanced by movement or straining and accompanied by local spinal tenderness; (c)
within a few days, radicular pain develops, followed by; (d) symptoms of spinal cord compression that can include weakness
and impaired sphincter control. Paraplegia can be complete within a few hours or days in untreated patients (587,588,590).
Pathologically, the infection is usually limited to the dorsal aspect of the canal in blood-borne empyemas, whereas the
ventral canal is initially affected when infection extends from the vertebral body (Fig. 11-83). The anatomy of the epidural
space limits extension to vertical spread and results in the extradural compression (265,588). If compression of the spinal cord
persists long enough, thrombosis of spinal vessels may develop, leading to spinal cord infarction and permanent paraplegia
(179). Lateral extension into the paraspinous muscles is common.
Imaging
MR is the imaging modality of choice for detecting empyemas of the spine (589). When the empyema results from an extension
of discitis, plain films or CT of the spine may show narrowing of the affected disc space and erosion of the adjacent vertebral
body endplates. Radionuclide scanning may show increased uptake, helping to identify the affected site. However, neither of
these techniques should replace MR as the imaging modality of choice unless MR is contraindicated or unavailable. A
mass is typically seen extending rostrally and caudally in the dorsal epidural space, compressing the thecal sac. The mass is
usually of soft tissue or liquid attenuation on CT. On MR, the epidural collection has a variable appearance on T1-weighted
images. Most commonly, it appears as heterogeneous hypointensity in the dorsal epidural fat; uniform or peripheral
enhancement is seen after intravenous administration of paramagnetic contrast (Fig. 11-84). Less commonly, the empyema may
be homogeneously isointense or slightly hyperintense compared to CSF on precontrast T1-weighted images. Identification and
diagnosis are facilitated by the use of fat suppression pulses on the postcontrast sequences (Fig. 11-84). The empyema is
isointense or hyperintense to CSF on T2-weighted images. Poorer prognosis is associated with ≥50% narrowing of the spinal
canal or craniocaudal length greater than 3 cm (Fig. 11-84) (591). Diffusion imaging is less helpful in the spine than the
brain, as susceptibility artifact from adjacent bone, swallowing artifact from throat and esophagus, pulsation artifacts from the
heart and great vessels, and peristalsis from the stomach and bowels distort evaluation of the fluid collection. However, if
diffusion imaging of the spine can be performed without artifact, the finding of reduced diffusivity within the extradural
collection (in the absence of hemorrhage) strongly supports the diagnosis of empyema (199,351).
Figure 11-81 Spinal epidural phlegmon, discitis, and osteomyelitis. A. Sagittal T1-weighted image shows abnormal hyperintensity of the
vertebral endplates and narrowing of the L5-S1 disc space (arrows). In addition, abnormal hypointense infiltration (phlegmon) (arrowheads) is
present within the epidural fat posterior to the L5 and S1 vertebral bodies. B. Sagittal fat-suppressed FSE T2-weighted image shows well-
demarcated increased signal intensity of the upper portion of the S1 vertebral body (white arrows). The disc space (large white arrowheads) is
narrowed and there is abnormal hypointense material extending both ventrally under the anterior longitudinal ligament and posteriorly under the
posterior longitudinal ligament. Abnormal hyperintensity is present posteriorly (black arrowheads) in the epidural fat and anteriorly (small white
arrowheads) at the L5 and S1 levels, representing phlegmon and abscess. C. Postcontrast fat-suppressed T1-weighted image shows
abnormal enhancement of the L5-S1 disc and the adjacent vertebral endplates (white arrowheads), confirming the presence of discitis and
adjacent osteomyelitis. The enhancement posteriorly in the epidural fat and anteriorly in the prevertebral space (white arrows) shows the
presence of phlegmon. D and E. Precontrast and postcontrast fat-suppressed axial T1-weighted images show the phlegmon (arrows), low
intensity in (D) and enhancement in (E) extending into the epidural and neural foraminal fat posterior to the disc and anterolaterally into the
prevertebral fat and left psoas muscle.
Figure 11-82 Tuberculous spondylitis. A. Sagittal T1-weighted image shows a mid thoracic gibbus vertebrae and a large paraspinous
abscess with ventral (v) and dorsal (d) components. Note the associated marked cord compression (arrowheads). B. Sagittal T2-weighted
image shows preservation of the intervertebral discs abutting the gibbus vertebrae. Note the large paraspinous abscess in the ventral region (v)
and the hypointense signal within the dorsal abscess component (d). Similar hypointensity has been described with CNS tuberculomas. C.
Sagittal postcontrast T1-weighted image shows better the large nonenhancing fluid collection in the large ventral subligamentous abscess (v).
The dorsal extradural abscess has less fluid and, therefore, was less hypointense in (B).
When the abscess is the result of osteomyelitis, the adjacent disc space is usually narrowed and pus often extends ventral to
the vertebral bodies as well as into the ventral epidural space. The abscess is generally isointense to the cord on T1-weighted
images and hyperintense to the cord, but iso- to slightly hypointense to cerebrospinal fluid, on T2-weighted images (Fig. 11-
81) (592,593). Although CT better demonstrates erosion of the vertebral endplates by the inflammatory process, MR
demonstrates prolonged T1 and T2 relaxation time within the disc and adjacent vertebral bodies and investing paraspinal soft
tissues. The changes are best seen on STIR images and on fat-suppressed T2-weighted images. Postcontrast, fat-suppressed
T1-weighted images show enhancement of infected bone (Fig. 11-81) and is the most sensitive method for detecting vertebral
osteomyelitis (594). Diffusion imaging, if available for the spine, can be useful for confirming the presence of pus (which has
relatively reduced diffusivity). The sagittal images show the rostral to caudal extent of the abscess and are invaluable in
localizing associated discitis or osteomyelitis. MR is more specific than CT or CT myelography because of the increased
sensitivity to enhancement of the empyema, to the presence of pus, and to the involvement of adjacent bone. Moreover, the
danger of entering the abscess by a lumbar puncture is removed.
Figure 11-83 Coccidioidomycosis causing vertebral body destruction. A. Lateral radiograph of the cervical spine does not show normal C4 or
C5 vertebral bodies. The normal cervical lordosis is reversed. There is prevertebral soft tissue thickening (arrows). B. Sagittal reformation of a
cervical CT shows nearly complete destruction of the C5 vertebral body (arrow). Note the prevertebral soft tissue mass. The intervertebral
discs are difficult to evaluate. C. Fat-suppressed sagittal FSE T2-weighted image shows the nearly complete destruction of C5. The
intervertebral discs (large arrowheads) appear normal, suggesting that this is not bacterial discitis/osteomyelitis. An epidural mass (small
arrowheads), not seen on the CT, is present as is the prevertebral mass (arrows). D. Postcontrast sagittal T1-weighted image shows
enhancement of the epidural coccidioidoma (arrowheads), but not the intervertebral discs, confirming that this is not a discitis. The prevertebral
mass is not seen because a saturation band has been placed too close to the vertebral bodies.
Figure 11-84 Spinal epidural empyema. A. Sagittal T1-weighted image shows an extensive dorsal epidural abscess (a) extending from T12 to
S2, slightly hyperintense to CSF with linear peripheral regions of T1 hyperintensity. There is marked compression of the spinal subarachnoid
space. B. Postcontrast sagittal T1-weighted image shows marked enhancement of the abscess walls and heterogeneous marginal and
internal septal enhancement of this epidural abscess. C. Axial postcontrast T1-weighted image shows the hypointense epidural abscess (a)
filling the lumbar spinal canal. Note the striking enhancement of the abscess walls and the marked compression of the crescentic-shaped
thecal sac (arrows). (Courtesy of Palani Rajaneeshankar, MB, BS, MD, DNB and L. Santiago Medina, MD, MPH, Miami, FL.)
Imaging
The imaging characteristics among many of the pathogens that cause intrinsic cord disease show considerable overlap.
However some agents such as West Nile virus, nonpolio-enteroviruses (EV71 and D68) may cause a clinical poliomyelitis and
exhibit tropism for the anterior gray matter columns (Figs. 11-85 and 11-86) (595–598).
Figure 11-85 West Nile virus myelitis. A. Sagittal T2-weighted image shows linear T2 hyperintensity within the ventral cervical cord (arrows).
B. Axial T2-weighted image confirms the T2 signal abnormality to involve the anterior horn gray matter of the cervical cord (arrow).
Figure 11-86 Acute flaccid paralysis. Enterovirus (EV-D68). A and B. Sagittal and axial T2-weighted images show central gray matter
hyperintensity within the spinal cord (arrows).
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Anomalies of the Cerebral Vasculature: Diagnostic and
Endovascular Considerations
Steven W. Hetts, Philip M. Meyers, Van V. Halbach, and A. James Barkovich
Introduction
Technical Considerations in Pediatric Neuroangiography and Intervention
Indications
Preprocedural Planning
Fluid and Contrast Limitations
Vascular Access
Catheter Choice
Endovascular Occlusion
Postprocedural Patient Care
Arteriovenous Fistulas
Intracranial Dural Arteriovenous Fistulas
Direct Carotid-Cavernous Fistulas
Vertebral Fistulas
Intracranial Aneurysms
Saccular Aneurysms
Infectious (Mycotic) Aneurysms
Traumatic Aneurysms
Introduction
Cerebrovascular disease is uncommon in children and adolescents. In children under the age of 15, the average annual
incidence of cerebral vascular disease unrelated to trauma or infection ranges 2.5 to 3.1 per 100,000 population (1–4).
Pediatric vascular disease can be grossly divided into occlusive vascular disease and causes of intracranial hemorrhage.
Occlusive vascular disease and its imaging manifestations were discussed in Chapter 4. This chapter discusses cerebral
vascular anomalies and cerebral vascular disorders amenable to endovascular intervention.
Vascular malformations are the cause of nearly all nontraumatic intracranial hemorrhages in children beyond the neonatal
stage. Tumors, the next most common cause of hemorrhage, occur far less frequently (5,6). Therefore, any child presenting with
spontaneous intracranial hemorrhage should be evaluated for child abuse (see Chapter 4) and for vascular malformations.
The treatment of pediatric cerebrovascular disease continues to advance rapidly. Endovascular techniques now permit
palliation or cure of many disease entities. In VOGMs, for example, morbidity and mortality have been significantly reduced
using endovascular techniques compared with conventional surgery. Consequently, a premium is placed upon the rapid
recognition of treatable illness to facilitate prompt and appropriate intervention. This chapter discusses pediatric
cerebrovascular disorders, with consideration toward endovascular management when indicated.
Indications
The indications for cerebral arteriography in the pediatric population continue to evolve. Many clinical questions can now be
adequately addressed using noninvasive methods including magnetic resonance imaging (MRI), ultrasound, or computed
tomography (CT). An effort to avoid exposure of a child to radiant energy is important according to the ALARA principle for
use of medical radiation (10–12); therefore, MRI/MRA and ultrasound are used whenever possible, and radiation dose is kept
as low as possible, while still obtaining diagnostic quality exams, when CT and radiographs are acquired.
X-ray dose limitation during pediatric neurointerventional procedures has become an area of significant attention in the past
few years. Orbach and colleagues have estimated that long neurointerventional radiology procedures (e.g., embolization of an
intracranial arteriovenous fistula) can result in brain-absorbed doses in young children such that their lifetime risk for CNS
tumors is significantly increased (13). For children who are already at an increased risk for cancers, such as infants with
ocular retinoblastomas due to loss of the Rb tumor suppressor gene, ALARA principles are even more important. Working with
a medical physicist to optimize imaging parameters and technique settings for pediatric neurointerventions, as well as
emphasizing the use of roadmap techniques over DSA techniques whenever possible, can markedly reduce radiation dose to
the child (14).
The most common indications for cerebral arteriography are unexplained cerebrovascular accident (CVA); posttraumatic
neurological deficit, stroke, or hemorrhage; functional neurologic testing prior to epilepsy surgery using the Wada technique;
evaluation and treatment of craniofacial and cerebrovascular anomalies; and preoperative embolization of vascular neoplasms.
The number of diagnostic pediatric cerebral arteriograms has diminished as x-ray CT techniques (including helical CT, CT
angiography, and CT perfusion), MRI and MRA, and transcranial Doppler (TCD) have evolved. Meanwhile, marked
improvements in microsurgical and endovascular techniques require information for surgical planning that catheter
arteriography alone can provide. It is possible that diagnostic catheter arteriography may ultimately be left to those centers
where therapeutic procedures are performed, if necessary. In this way, the optimal arteriographic series to suit the needs of the
interventional neuroradiologist or neurosurgeon can be obtained.
Preprocedural Planning
Catheter angiography is an invasive procedure; thus, preoperative planning, as for any surgical procedure, is critical. The
indications must be reviewed in light of all previous imaging studies, prior surgical procedures, and evolution of the anatomic
pathology. Discussion among the angiographer, referring clinician, consultants, the patient, and the patient’s family should
result in consensus on goals and expectations for treatment. It is important that the angiographer obtains a tailored history and
physical examination in order to identify specialty-specific factors such as allergies, medications, and renal or hematologic
diseases that could delay or alter performance of the angiogram. Preprocedural physical examination including neurologic
evaluation is also important so that any changes during the procedure can be quickly recognized and expeditiously treated.
Evaluation of the extremities, including lower extremity pulses, is relevant to selection of a site for vascular access. Unique
risks to pediatric angiography are the development of leg length discrepancy and claudication due to injury of the femoral
artery and femoral capital necrosis due to injury of the foveolar artery. Other complications of diagnostic angiography include
stroke, iodinated contrast reaction, renal failure, and puncture site hematoma (15–18). In general, catheter cerebral
arteriography can be performed with a minimum of risk (0.3%) at experienced centers (8).
Prior to embolization of an arteriovenous malformation (AVM), an echocardiogram possibly including a “bubble test” is
warranted to evaluate for the presence of right-to-left intracardiac shunts. It is possible for embolic materials or thrombus to
pass through an AVM into the normal venous drainage and the right side of the heart. Ordinarily, these small emboli will be
filtered by the pulmonary vascular bed and in small numbers without any clinically significant consequences. Intracardiac
shunts, common in pediatric patients with certain cerebrovascular malformations, could cause such emboli to pass from the
right heart into the left heart and recirculate into the arterial system. The presence of intracardiac shunts means that great care
must be undertaken during the embolization procedure to avoid the use of agents likely to pass through the cerebral AVM with
resultant embolization to the systemic circulation (19). Pulmonary arteriovenous shunts are also a clinical concern in young
patients with hereditary hemorrhagic telangiectasia syndrome (HHT, also known as Osler-Weber-Rendu disease). In such
patients, assiduous attention to eliminating all air from venous access lines is required in order to lower the risk of air
embolism–induced stroke. Clear communication with practitioners providing anesthesia or intravenous medications
preoperatively, intraoperatively, and postoperatively is imperative. The use of air filters on intravenous lines (e.g., 0.22
micron filters) can also reduce the risk or air embolism in patients with intracardiac or pulmonary shunts (20).
The importance of preoperative preparation in regard to the pediatric patient cannot be overemphasized (21,22).
Medications (including iodinated contrast) can cause dramatic shifts in intravascular fluid volume and vasomotor tone. An ill
child may appear hemodynamically stable but, in actuality, may be exerting maximal physiological mechanisms to maintain
blood pressure, systemic, and cerebral perfusion. Administration of sedatives, anesthetics, or vascular contrast can cause
hemodynamic collapse in a volume-depleted child. As children undergoing cerebral arteriography may have elevated
intracranial pressure (ICP), adequate ventilation is essential to prevent buildup of CO2 (and consequent elevation of ICP) that
could result in herniation syndromes or hinder cerebral perfusion. Occasionally, manipulation of ventilation rate and blood
pressure may be necessary to modulate arterial carbon dioxide levels and vasomotor tone. Changes in the pCO2 can be used to
enhance cerebral arteriographic resolution, to reduce the volume of contrast, or to assist distal microcatheter manipulation
(23). However, in children with suspected ischemic stroke, especially in the setting of moyamoya disease, blood pressure
should be supported while maintaining normal pCO2. These children will stroke if overventilated. Therefore, the pCO2
should only be manipulated by highly experienced personnel and in the presence of ICP monitoring in order to prevent cerebral
hypoperfusion and herniation syndromes. Careful monitoring during the administration of sedative medications and vascular
contrast is essential.
Vascular Access
Arterial access is the first critical step in performance of any pediatric neuroangiographic procedure. A child’s vessels are
small in caliber, prone to spasm, highly mobile, and elastic. These factors often conspire to make arterial access a daunting
challenge. Use of real-time ultrasound guidance during micropuncture access to the femoral artery has made a femoral artery
puncture significantly easier in the past decade than in prior eras, however. Improper technique can result in laceration or
thrombosis of the vessel. Arterial cannulation is facilitated by extension of the legs and elevation of the pelvis to straighten the
common femoral artery. Following induction of general anesthesia, systemic blood pressure is often reduced, and manual
palpation of the femoral and pedal pulses may become difficult. Marking the skin over the femoral puncture site as well as the
foot over the dorsalis pedis and posterior tibialis pulses prior to anesthetic induction can facilitate cannulation and
postoperative patient assessment. Proper positioning and padding of pressure points is necessary, particularly in infants and
small children. Use of a Micropuncture set and a 3 or 4 French access sheath–catheter system will help to reduce local trauma
at the puncture site. Analogous to the concept of ALARA in x-ray dose limitation, keeping the caliber of vascular sheaths
placed in the arteries of children as small as possible is key to lowering the risk of arterial injury, access site thrombosis, and
distal arterial embolization. Although rare, and often difficult to attribute to a particular angiographic procedure, the potential
for adult leg length discrepancy as a late complication of transfemoral angiography in very young children whose lower
extremity blood flow could be compromised by femoral artery occlusion or stenosis, should be mentioned to parents during
informed consent discussions prior to angiography. It can also be helpful intraprocedurally to have pulse oximeters placed on
both great toes: reduced flow to the foot on the side of femoral artery access can be followed intraprocedurally and may be
managed with administration of nitropaste, another vasodilating medication, or heparin after access has been achieved.
Systemic heparinization (70 units/kg) during catheterization may also reduce the risk of thrombosis. Assessment of
anticoagulation status in the angiography suite is rapidly performed using the activated clotting time (ACT). Depending upon
the indication for angiography and other mitigating factors, an ACT 2-3X baseline value is considered therapeutic. In the
presence of a recent cerebral hemorrhage or surgical procedure, anticoagulation may be contraindicated. A lower level of
anticoagulation for interventional procedures should be considered, if necessary. Following removal of the femoral sheath,
access for subsequent arteriographic procedures should alternate between the right and left femoral arteries. In special
circumstances, such as neonatal arteriography, the umbilical artery and vein readily provide vascular access for catheter
systems sized up to 5 French. If so requested, the neonatology service will maintain umbilical catheters to permit arterial and
venous access for endovascular procedures. Umbilical artery access is particularly helpful for the treatment of high-flow
intracranial lesions in neonates, as it generally allows multiple embolization sessions with less chance of access site scarring
than femoral artery access (24).
Catheter Choice
The choice of angiographic catheter depends upon the application and patient size. The smallest diameter catheter that readily
permits diagnostic arteriography is a 3 French catheter, which is used in neonates and infants. Smaller diameter catheters do
not generally allow sufficient injection rate for routine arteriography. Slightly larger (4 French) catheters can be used in older
children and provide greatly improved injection rates due to decreased flow resistance. Diagnostic catheters with an intrinsic
hockey-stick tip-shape can often be custom-shaped using steam heating to reduce their angulation and allow them to sit less
traumatically in the relatively straight cervical vessels of small children without high-flow lesions. For children with high-
flow lesions, cervical vessels are often markedly tortuous and more angulation of catheter tips can be advantageous. Although
not angulated, the same distal access catheters that have become widespread as intermediate support catheters during stroke
intervention in the last decade have also gained popularity as access catheters for intracranial interventions in children either
in combination with a short vascular access sheath or as a stand-alone. Manipulation of these catheters without a sheath at the
access site with attendant vasospasm and potential damage at the access site, however, may limit their utility in cases wherein
extensive navigation between multiple arterial pedicles is necessary. The length of distal access catheters may also limit their
utility in small children, as the long segment of these catheters external to the patient needs to be stabilized in order to prevent
extracorporeal torque dissipation during catheter navigation. Standard microcatheters can be advanced either through a 4
French diagnostic catheter platform in the cervical vessels or directly through a 4 French access sheath in the femoral artery
without coaxial passage into the craniocervical region. Older children and adolescents will tolerate the use of the 4 to 6 French
catheter systems commonly used in the adult population. Percutaneous access sheaths are used routinely in our practice to
facilitate catheter exchange and to reduce trauma at the puncture site.
Endovascular Occlusion
The purpose of interventional neuroradiology is the minimally invasive treatment of vascular lesions. The fundamental
principle of this treatment is occlusion of pathological vascular channels to improve the patient’s neurological or
cardiovascular condition. Embolization, or endovascular occlusion, requires placement of the tip of a microcatheter in
proximity to the abnormal vessels so that these channels can be selectively occluded, sparing normal or other needed vessels.
Recent and ongoing developments in catheter technology allow careful and precise placement of embolic materials within the
abnormal vascular channels while avoiding embolization of the normal adjacent vessels. A number of embolic materials are
currently in use, and many more are under development or employed in clinical practice outside the United States. Table 12-1
lists some characteristics of some of the more commonly used embolic materials. A complete review of the specific
applications of these embolic agents is beyond the scope of this text.
Table 12-1 Selected Agents for Neurovascular Embolization
Polyvinyl alcohol Particulate Cordis, Target Preoperative tumor, AVM embolization 45–1000 μm, calibrated ++
sizes
Balloons Latex Balt Fistula (not FDA approved in the USA) Multiple +++
Ethanolamine oleate Sclerosant Questcor Hemangioma, venous, and lymphatic N/A ++++
malformations
Arteriovenous Malformations
Description and Causes
AVMs are compact collections of abnormal, thin-walled vessels (most commonly called the nidus, this is the true
malformation) that connect dilated arteries to veins without an intervening capillary network. These persistent primitive
connections between arteries and veins are formed during the late somite stages of the fourth embryonic week; they develop
from the sinusoidal vascular network that perfuses the early developing telencephalon. The absence of capillaries produces a
low resistance shunt, which results in rapid arteriovenous shunting within the malformation.
Patients with cerebral AVMs most commonly present as a result of spontaneous intracerebral hemorrhage (up to 61% of
cases) during late childhood (43) or as a young adult (44), but affected patients can present at any age or, rarely, with seizures
(29,45,46). Intraparenchymal hemorrhage can cause significant injury at any age, with 30% to 50% neurological morbidity and
10% mortality (47). Consequently, a premium has been placed upon identification and treatment of AVMs at major
neurosurgical centers throughout the world.
The prevalence (total number of cases in a population at a given time) of AVMs has been estimated in autopsy series
between 0.06% and 0.11% (44,48). Symptomatic AVMs were detected in 1 per 100,000 person-years, and prevalence was
inferred from the incidence data to be less than 10 per 100,000 in a US population study (49,50) and 5 per 100,000 in
Australia (51). Thus, although the precise numbers are not known, it seems that a significant percentage of AVMs become
symptomatic during the average human lifetime, usually due to hemorrhage (44,51,52).
The vascular channels of AVMs that develop instead of normal capillaries are characterized by fibrointimal thickening and
elastic tissue disorganization. These features probably take time to develop, and thus, classic brain AVMs (those with the
classic tangle of vessels that compose the nidus) are not typically seen before birth or in early infancy. Flow-related
angioarchitectural features in pediatric AVMs also appear to take time to develop postnatally: there is a paucity of feeding
artery aneurysms and venous outflow stenosis in young children with AVMs (Fig. 12-1) as compared to older children and
adults (39). No classic AVMs have been described prenatally, although several fetal cases with NGAVFs (direct connections
between artery and vein without the tangle of abnormal vessels) have been identified (47). In neonates, AVMs are generally
seen as direct arteriovenous communication without intervening nidus. Thus, AVMs seem to evolve, not becoming fully
developed until later in life (53). De novo development of AVMs has rarely been documented in children or adults (54).
Although most brain AVMs are thought to be congenital, a growing number of case reports of de novo brain AVMs has
challenged this view in the past decade (55–57). In these apparent de novo cases in children and adults, there may well have
been microscopic arteriovenous abnormalities below the detection threshold of MRI since early in development, but only later
in life did the abnormality enlarge enough to be seen on noninvasive imaging.
No definite genetic linkage has been identified with the exception of Rendu-Osler-Weber (58) and Wyburn-Mason
syndromes (59). Dysautoregulation of vascular growth factors has been implicated in the subsequent development and
maturation of the vascular malformation (60).
AVMs often increase in size with age, as a result of increase in size of the nidus and progressive dilation of the feeding
arteries and draining veins. Astrogliosis and atrophy are often seen in surrounding brain tissues. This was at one time thought
to be a consequence of low resistance shunting of blood through the nidus, causing parenchymal hypoperfusion (vascular steal).
Others suggest that edema and subsequent parenchymal injury results from venous stenosis/venous hypertension, caused by high
pressure and shear stresses from turbulent blood flow and consequent stenosis in draining veins. Rapid flow in the feeding
arteries may result in the development of arterial aneurysms, both in the same distribution as classic berry aneurysms (circle of
Willis) and in feeding arteries (pedicle and nidal aneurysms) close to the malformation (Fig. 12-1). In addition, varices
(venous aneurysms) can develop upstream to venous outflow stenosis and cause hemorrhage if they rupture (61). As a result of
all these factors, AVMs are the vascular malformations that most commonly cause neurological defects other than seizures,
despite the fact that they are not the most common form of vascular malformations.
Clinical Manifestations
Patients with AVMs usually present with seizures, recurrent headaches, progressive neurological deficits, hydrocephalus, or
hemorrhage. Approximately 20% become symptomatic before the age of 20 years (43). The mortality associated with the
initial rupture of an AVM is 10%, with morbidity between 30% and 50% (38,62). Morbidity and mortality increase with each
subsequent hemorrhage.
AVMs are the cause of up to 40% of spontaneous intracranial hemorrhages (2,63,64), most of which occur in the cerebral
parenchyma. However, superficial malformations can rupture into the subarachnoid space and deep malformations may cause
intraventricular hemorrhage. Symptomatic vasospasm and rebleeding are relatively rare unless the source of hemorrhage is an
associated aneurysm. The risk of rehemorrhage from an AVM has been estimated to be higher in children than adults (62). In
children less than 15 years of age, AVMs are the most common cause of spontaneous intracranial hemorrhage and account for
20% of all strokes (2).
Figure 12-1 AVM with hemorrhage from a feeding artery aneurysm. A. Coronal reformatted CTA demonstrates dense vascular enhancement
adjacent to the right lateral ventricular intraventricular hemorrhage. There is associated hydrocephalus. B. Axial T2-weighted image shows a
circular structure within the lateral aspect of the intraventricular hemorrhage consistent with an aneurysm associated with a tangle of AVM
nidus vessels in the corpus striatum just lateral to the right lateral ventricle. C. RAO image from a right internal carotid artery DSA shows the
posterior corpus striatum AVM being fed by a medial lenticulostriate artery (recurrent artery of Heubner) that itself harbors the feeding artery
aneurysm (white arrow) that hemorrhaged. D. The feeding artery aneurysm is more easily seen on a surface-rendered reformat of a 3D
rotational angiogram of the right ICA.
Seizures occur in approximately 70% of patients with AVMs, with one-half of the seizures being generalized (65); most
patients are well controlled with anticonvulsants. Seizures are most common in AVMs that are located in the cerebral cortex
and have associated varices. Their cause is probably cortical injury and gliosis from previous hemorrhage (66) or venous
ischemia (67,68).
Chronic recurrent headaches may be the presenting symptoms in some patients with AVMs and are likely caused by
engorged dural vessels. Headaches are most common in cortical/subcortical AVMs and in those that develop stenosis or
occlusion of feeding cerebral vessels. AVMs located in the occipital region are associated with an increased frequency of
migraines, often with visual symptoms during the migrainous episodes.
Progressive neurological deficits occur in a small percentage of children with AVMs, particularly if the malformation is
large and located close to the motor cortex. The probable cause of neurologic deficit is venous hypertension, as increased
venous pressure is transmitted through the AVM, impairing the venous drainage of normal brain, sharing the same venous
drainage pathway; this mechanism has long been understood as a cause for neurologic deficit in the spinal cord but has only
recently been recognized in the brain (69,70). Venous hypertension may be so marked that it impairs the resorption of
cerebrospinal fluid, producing hydrocephalus (see Chapter 8). Chronic venous hypertension related to cerebral venous and
dural sinus outflow obstruction that may occasionally accompany brain AVMs can also cause profound white matter damage
(Fig. 12-2).
Finally, with the advent of CT and MRI, asymptomatic AVMs are more commonly discovered.
Imaging Findings
The diagnostic workup of vascular malformations usually includes x-ray CT, MRI, and MRA. CT evaluation (using a low dose,
see Chapter 1) remains the standard of care as an effective screening technique to study patients with suspected intracranial
hemorrhage in the acute phase (<2 weeks). A noncontrast CT scan may reveal abnormal high density of the associated acute
hematoma or calcifications within the interstices of the AVM. In addition, CT may show acute subarachnoid hemorrhage, which
sometimes accompanies rupture of a superficial AVM or an associated feeding artery aneurysm. During the ensuing 1 to 2
weeks after hemorrhage, the subacute hematoma becomes progressively isointense with the brain and may show a rim of
peripheral enhancement following intravenous contrast administration; this appearance is nonspecific and may be mistaken for
infection, cavernoma, or neoplasm. While MR has largely supplanted CT in the evaluation of AVMs, vascular malformations
may be detected on contrast-enhanced CT as a region of enhancement adjacent to a high-density, acute hematoma. CT
angiography shows detailed resolution of the cerebral vasculature but can be associated with significant radiation exposure. Its
role in the architectural evaluation of AVMs remains undefined. As CTA has difficulty resolving among arteries, nidus, and
veins, our group favors digital subtraction catheter angiography for the assessment of AVM angioarchitecture and risk
stratification for rerupture; risk is based on presence of feeding artery or nidal aneurysms and venous outflow stenosis, which
are all more readily apparent in the high spatial and temporal resolution images generated by DSA. Parenchymal evaluation
can be achieved with an MRI. The combination of DSA and MRI offers the greatest amount of information with the lowest
amount of ionizing radiation as compared to an imaging strategy that includes CTA.
Figure 12-2 AVM with intracranial venous outflow obstruction and white matter damage. A. Axial CT demonstrates punctate calcifications in
the right parietal lobe associated with enlarged vessels of a brain AVM. There are diffuse bilateral subcortical white matter calcifications away
from the AVM itself. B. Axial T2-weighted MR confirms the tangle of vessels in the right parietal AVM nidus as well as better demonstrating the
extent of white matter damage. Of note, left-sided cortical veins are also enlarged, and there is abnormal signal in the superior sagittal sinus.
C–E. Early-, mid-, and late-phase images during an anteroposterior right ICA angiogram demonstrate an AVM nidus in the right parietal lobe
with venous outflow restriction due to bilateral sigmoid sinus occlusions. Chronic intracranial venous hypertension has resulted in severe white
matter damage.
MR is an excellent initial screening modality for the evaluation of intracranial AVMs (71,72). Fast-flowing intraluminal
blood in AVMs appears as regions of decreased signal or “flow void” on spin-echo sequences. A tangle of serpiginous flow
void represents the nidus of the malformation (Fig. 12-2). Rapid flow within draining veins can be difficult to distinguish from
feeding arteries in or around the nidus. The multiplanar capability of MR helps to delineate the location of the malformation in
relation to critical anatomic structures. Parenchymal hematomas evolve through a recognizable and often specific pattern of
signal characteristics (see Chapter 4; (73,74)). The residua of previous hemorrhages adjacent to malformations remain
detectable many years after hemorrhage as areas of very low intensity on T2- or susceptibility-weighted images. In the
subacute and chronic phases of intraparenchymal hemorrhage, MR is more sensitive and specific than CT for the detection of
blood products. Evidence of prior hemorrhage, even subclinical microscopic hemorrhage evident on gradient-recalled echo or
susceptibility-weighted MR images, appears to be correlated with a higher risk for future hemorrhage in brain AVMs (75). In
patients with AVMs, high frame-rate catheter angiography must still be performed to delineate the angioarchitecture, to
distinguish feeding arteries from draining veins, and to identify any associated arterial aneurysms or venous restriction that
would be associated with a poorer natural history. Thus, MRI with susceptibility-weighted images and DSA offer a
comprehensive imaging evaluation of brain AVMs and identify the imaging features that—along with clinical history of
prior AVM rupture—are commonly used to stratify patients’ risk of future AVM hemorrhage and therefore the impetus for
AVM treatment or observation.
Treatment
The increasing rate of discovery of nonruptured brain AVMs has led to controversy in the management of unruptured AVMs in
both adults and children. A recent randomized trial (ARUBA) comparing the interventional (surgery, embolization,
radiosurgery) treatment of asymptomatic brain AVMs to conservative follow-up showed an excess of strokes in the treated
group over the first few years following treatment (76). Given that interventional treatment is aimed at elimination of
hemorrhage risk over the patient’s entire lifetime, the long-life expectancy of children may argue for more aggressive
management of their asymptomatic AVMs as compared to those found in adults.
The decision to undertake treatment for symptomatic AVMs should consider the natural history of the disease and the
projected risks and benefits of the therapy. A complete discussion of the natural history and current therapeutic options is
beyond the scope of this book, and the reader should consult a more complete text for the discussion of management (77,78).
Briefly, the therapeutic options fall into three categories: surgical excision, radiosurgery, and endovascular embolization or
occlusion. Often combinations of these techniques are utilized for the treatment of complex malformations.
With the improvement in microneurosurgical techniques, even large and complex malformations can be excised with
relatively low morbidity and mortality (77,78). The nidus or core of the malformation infrequently contains cerebral
parenchyma, and if the surgical excision is performed along the margins of the malformation with attention to preserving the
surrounding brain, an excellent outcome can often be achieved. Total excision of the malformation is the goal of surgery, as
prior studies have shown that subtotal resection or ligation of feeding vessels is inadequate to prevent subsequent hemorrhage
(79,80).
Radiation therapy produces hyperplasia of the blood vessel walls and apoptosis of vascular tissues (81); the AVM is
completely obliterated in selected cases. To minimize the risk of radiation-induced damage to adjacent normal parenchyma,
only focused techniques are utilized today, such as the Bragg-peak proton beam therapy or intersecting beam techniques using
gamma knife or LINAC (linear accelerator) therapy units. Occlusion rates range from 35% to 92% depending on a number of
variables including AVM size, location, and radiation dose. The results of radiotherapy have been quite encouraging with small
(<3 cm) malformations (82–84). The major disadvantages of radiosurgical techniques include the difficulty in treating larger
lesions, the 1- to 2-year latency before development of significant vascular intimal hyperplasia and fibrosis are produced
(during which interval the patient remains at risk for hemorrhage), and the risk of delayed radiation necrosis in the surrounding
brain tissue.
Endovascular techniques have emerged as a third modality for the treatment of symptomatic intracranial malformations;
complete angiographic obliteration following embolization of large malformations is unusual even using modern embolic
agents such as ethylene vinyl copolymer (85–88); however, complete obliteration can be obtained with smaller AVMs (89).
Endovascular embolization can also be used to eliminate pseudoaneurysms in brain AVMs that have bled, in order to reduce
the risk of rehemorrhage; definitive surgical, endovascular, or radiosurgical elimination of the remainder of the nidus can then
be performed more safely either immediately or after a convalescent period (Fig. 12-3) (90,91). Endovascular embolization
can palliate patients whose symptoms do not warrant more aggressive therapy or where the size or location of the
malformation precludes more traditional forms of therapy. These procedures can now be performed with a low risk of
complications and appear to make craniotomy for surgical resection safer (78). Patients who present with intractable unilateral
headache frequently have recruitment of dural vascular supply to the malformation (89,92). These dural vessels can be
selectively catheterized and embolized, often resulting in alleviation or resolution of headache. Patients with progressive
neurological decline from arterial steal or venous hypertension can demonstrate clinical improvement following partial
embolization of their malformation.
NGAVFs comprise a subset of brain AVMs and are more common in children than in adults (40). We and others (93,94)
have identified a group of patients with solitary arteriovenous connections (“single-hole NGAVFs,” Fig. 12-4) who present in
childhood with hemorrhage or neurologic deficit. All fifteen patients were treated by transvascular embolization techniques
with placement of either platinum coils or balloons at the fistula site. Fourteen of the fifteen patients were completely cured
and the fifteenth patient underwent surgical excision without incident. In contradistinction to these patients with simple single-
hole fistulas, other pediatric patients harbor multihole NGAVFs and are more severely affected clinically, often presenting with
high-output cardiac failure in the neonatal period (Fig. 12-5), with physiology similar to vein of Galen malfromations.
Comparative clinical outcomes from the treatment of NGAVF, VOGM, and DAVF in children are presented in Table 12-2.
Figure 12-3 Ruptured AVM pseudoaneurysm treated with liquid embolization and recurrent nidus treated with radiosurgery. An 18-year-old
woman presents with acute headache and obtundation. A. Axial CTA demonstrates a pseudoaneurysm at the posteromedial aspect of a right
medial temporal lobe intraparenchymal hematoma and lateral ventricular intraventricular hemorrhage. B. Anteroposterior DSA of the left
vertebral artery confirms a pseudoaneurysm of the middle temporal artery. C. Superselective microcatheter angiogram of the right middle
temporal artery demonstrates arterial supply to the pseudoaneurysm without supply to distal normal branches. The pseudoaneurysm was
treated with n-BCA injection. D. Axial CT 1 week after embolization confirms glue in the middle temporal feeding artery and pseudoaneurysm.
The ventricular and parenchymal hematomas have begun to resorb. E. Lateral DSA of the right internal carotid artery before embolization
demonstrates no definite nidus filling across the posterior communicating artery. Nidus may be compressed by acute hematoma. F. Lateral
DSA of the right internal carotid artery 4 years after embolization demonstrates nidus filling across the posterior communicating artery. Nidus
may previously have been compressed by acute hematoma or may be truly de novo given the patient’s young age.
Figure 12-4 Single-hole simple pial NGAVF. A 3-year-old girl presented with headaches. A. Time-of-flight MRA demonstrates an enlarged ACA
branch terminating in a flow jet. B. Coronal contrast-enhanced T1-weighted MRI confirms that the vascular structure is pulsatile, as evidence
by phase-encoding ghosting artifact. The flow jet into this structure is a dark signal void and the slower-flowing blood enhances. C. Lateral DSA
of the right ICA depicts an enlarged ACA orbitofrontal branch supplying a single-hole pial arteriovenous fistula with a massive draining venous
varix that itself drains to the anterior portion of the superior sagittal sinus. D. Following endovascular detachable coil embolization of the fistula
site, no residual arteriovenous shunting is identified.
Table 12-2 Clinical Outcomes in the Treatment of Pediatric Intracranial Arteriovenous Fistulas
Outcome DAVF (41) NGAVF (40) VOGM (42) VOGM (95) VOGM (96)
Complete AVF occlusion 8/21 (38%) 15/23 (65%) 20/32 (63%) 15/23 (65%) 118/216 (55%)
No neuro deficit or developmental delay 7/20 (35%) 11/23 (48%) 7/36 (20%) 11/23 (48%) 143/216 (66%)
Death 6/22 (27%) 2/23 (9%) 9/36 (22%) 2/23 (9%) 23/216 (11%)
Although some series suggest that over ninety percent of the VOGMs fall into the group called “choroidal” malformations
(99), more recent series have underlined a large degree of overlap between choroidal, mural, and mixed-type (with both
choroidal and mural components) VOGMs (42). Choroidal malformations are arteriovenous connections from a plethora of
vessels, usually numerous choroidal, pericallosal, and thalamoperforator vessels, to the anterior wall of the prosencephalic
vein, resulting in a great deal of arteriovenous shunting (100,101); the consequence of the shunting is presentation as neonates
with CHF. Choroidal malformations have the poorest prognosis and are usually fatal without treatment. The second, less
common, category of VOGM is the so-called “mural” malformation (99). Mural malformations are characterized by fewer
(usually one to four) but larger caliber connections with the prosencephalic vein; the posterior choroidal or collicular arteries
are most commonly involved. Patients with mural malformations usually present in infancy with developmental delay,
hydrocephalus, and seizures but mild or no signs of CHF. The treatment approach to these malformations varies although
endovascular therapy has become the method of choice for both and offers a high rate of cure with low morbidity (95,102,103).
If the VOGM is not diagnosed prenatally, postnatal neuroimaging becomes critical to making the proper diagnosis. On
imaging studies, the dominant feature of the VOGM is the varix, which appears as a large mass in the incisural region,
sometimes extending rostrally and anteriorly displacing the third ventricle (Figs. 12-6 and 12-7). On sonography, the varix will
appear mildly echogenic on 2D imaging and show turbulent flow on Doppler; it is important to demonstrate continuity with the
straight sinus or a persistent falcine sinus. Doppler studies may be useful to quantify the rate of flow within the varix for future
reference. On CT, the varix will be iso- to hyperdense to brain prior to contrast administration (Figs. 12-6 and 12-7). Mixed
attenuation may be seen if the varix is partially thrombosed. Areas of low attenuation (encephalomalacia, usually secondary to
ischemia) and high attenuation (hemorrhage or dystrophic calcification) are often present in the brain parenchyma. The extent
of brain injury should be carefully analyzed, and the parents informed of likely neurological and developmental sequelae,
before therapy is begun. On MR, the varix will be hypointense resulting from a loss of phase coherence of the mobile protons;
mismapped signal will often be seen across the image in the plane of the phase-encoding gradient (Figs. 12-6 and 12-7).
Feeding vessels will be identified on axial images as round areas of signal void in the ambient cisterns and on MRA as thin,
curvilinear structures demonstrating flow-related enhancement and connecting to the varix. Areas of acute thrombosis will
usually be isointense to the brain on T1-weighted sequences and hypointense on T2-weighted sequences, whereas subacute
thrombus will have a high intensity on both T1- and T2-weighted sequences. Thrombus of varying age may line the wall of the
varix. Areas of damaged brain will typically appear hyperintense on T1-weighted images and hypointense on T2-weighted
images in the neonate (Figs. 12-6 and 12-7); they may be difficult to see on FLAIR. Diffusion-weighted images will show acute
injury as regions of reduced diffusivity (Figs. 12-7 and 12-8). As the brain begins to myelinate, injured brain is better seen on
T2-weighted images and then FLAIR images (see explanations in Chapter 4). If left untreated, the fistula can continue to grow,
recruiting additional blood supply with formation of new secondary fistulas (Fig. 12-9).
Figure 12-7 Newborn with severe intractable congestive failure. A. Portable chest radiography demonstrates cardiomegaly and increased
pulmonary vascular markings compatible with pulmonary edema due to high-output congestive heart failure apparent on physical examination.
B. Transfontanelle color Doppler ultrasonography, sagittal plane, shows prominent anterior cerebral arteries in continuity with an enlarged deep
central venous structure. C. Nonenhanced CT brain scan confirms the presence of markedly enlarged central venous structures (V), normal
brain development, and the absence of hydrocephalus or hemorrhage. D–H. Complete cerebral arteriography in multiple projections
demonstrates a choroidal-type vein of Galen aneurysmal malformation supplied by every major vascular distribution. Arteriovenous shunting
converges upon a dilated primitive prosencephalic vein of Markowski continuous with a persistent falcine sinus. Presumably due to the high-
flow state, venous drainage includes persistent occipital sinuses (arrows, H). I–K. Following curative endovascular occlusion of the
malformation, MRI brain scan demonstrates the coil mass (C), normal flow through the mature cerebral venous drainage system, the absence
of cerebral infarction, and no hydrocephalus. Maximum intensity projection from 2D time-of-flight MR venogram shows intact superficial venous
drainage. Drainage of the deep venous system is obscured by susceptibility artifact from the coils. L–N. Complete cerebral arteriography
following both transarterial and transvenous embolization confirms complete absence of arteriovenous shunting and durable occlusion of this
malformation. The child is now 4 years old, has a normal neurological exam, and meets all developmental milestones. Endovascular
techniques are now the preferred treatment method for these lesions.
Treatment
Aggressive medical management of the cardiac failure associated with Galenic malformations is an essential adjunct to surgery
or endovascular procedures, but medical management alone can rarely control the failure. Johnston’s review of neonates
presenting with CHF revealed a mortality of 95%, and none were stabilized without surgical intervention (108). Surgical
ligation of the anomalous connections has been described, but the results have been disappointing. In a review of 60 neonates
treated by surgery, there were only 6 survivors; half of the survivors suffered from neurological deficits (108). Several series
have reported the efficacy of endovascular procedures as a palliative or definitive treatment (109–111). In the early 1980s,
these procedures consisted of free particle embolization. While the majority of these emboli would lodge in the fistulous
connections, the risk of an errant embolus occluding a normal cerebral blood vessel was inversely proportional to the flow in
the fistula, and the majority of these procedures were palliative. With the development of newer microcatheter delivery
systems and embolic agents such as detachable platinum coils (112) and liquid adhesives (99), superselective embolization of
the fistula connections alone can be achieved (Fig. 12-10). Mickle et al. developed a technique where the torcular is surgically
exposed, a small catheter is placed transvenously through the straight or falcine sinus into the involved vein of Galen, so metal
coils can be deposited to diminish the arteriovenous shunting (111). Although useful in the presence of bilateral lateral dural
sinus hypoplasia or occlusion, the transtorcular approach is not often necessary, as embolic agents can be placed via
transfemoral venous access particularly with the advent of improved catheters.
Figure 12-8 Damaged brain in a vein of Galen malformation. This newborn presented with congestive heart failure. A. Sagittal T1-weighted
image shows the large curvilinear varix (V) that compresses the aqueduct (white arrowheads), resulting in hydrocephalus, and anteriorly
displaces the posterior wall of the third ventricle (white arrows). B. Parasagittal T1-weighted image shows abnormal subcortical hyperintensity
(white arrows), indicating parenchymal injury. C and D. Axial (C) and coronal (D) T2-weighted images show the varix (V), multiple enlarged
tortuous vessels around the midbrain, and the varix, and abnormal hypointensity of the periventricular white matter (white arrows), indicating
parenchymal injury/necrosis. In addition, the ventricles are enlarged, likely secondary to a combination of hydrocephalus and loss of
periventricular white matter volume. E. Average diffusivity (Dav) image shows reduced diffusivity (low signal intensity, arrows) in the posterior
frontal periventricular and deep white matter. F and G. Partition image from time-of-flight MR angiogram (F) and maximum intensity projection
from MR venogram (G) show the mural type of vein of Galen varix with enlarged anterior cerebral artery (large white arrowhead) and multiple
branches and feeders from the posterior circulation (small white arrowheads) terminating in the varix. Note the enlarged emissary veins (white
arrows in G) helping to shunt blood from the engorged intracranial venous system into extracranial veins.
Between 1980 and 2002, 34 children with VOGMs were treated at our institution; 26 harbored the choroidal variety and
presented with CHF (102,110,113,114). The first 5 patients were treated by craniotomy and attempted clipping of the feeding
vessels. All 5 patients died during or shortly after the surgery. The subsequent 8 patients underwent transvascular embolization
techniques. Six of the eight survived while two died despite treatment (110). Of the survivors, one suffered a severe middle
cerebral infarct resulting from an errant embolus. Another had a partial visual field deficit, presumably a result of ischemic
damage secondary to the underlying disease. The remaining patients are neurologically and developmentally normal with
marked reduction of the fistula flow following treatment. At long-term independent follow-up, 61% of patients who survived
their initial presentation were neurologically normal or demonstrated only minor developmental delay (95). More recently, we
have updated our outcomes to reflect additional patients treated and longer-term follow-up; about 50% of children treated for
VOGM endovascularly had normal or near-normal neurological outcomes (42).
Improvements in technique and embolic materials allow VOGMs to be treated by transarterial or transvenous approaches.
These new materials and approaches have resulted in a high rate of successful therapy; indeed, greater than 50% angiographic
cure and 75% symptomatic improvement has been achieved in our recent patients, even in those with the high-flow choroidal
malformations (113,114). Our cure rate is 100% for the less common mural type of VOGM that most commonly presents later
in infancy with hydrocephalus, seizures, and failure to thrive (102).
The following are the current recommendations for treatment of VOGMs presenting with severe congestive failure. If the
diagnosis is established prenatally, the delivery should be performed at an institution offering endovascular techniques to
palliate the patient should intractable CHF develop. Severe heart failure in utero can result in polyhydramnios and hydrops
fetalis, which can be an indication for induced delivery. Close coordination among the obstetricians, neurointerventionalists,
neonatologists, and neurosurgeons is essential to optimize planning. Baseline ultrasonography with color flow Doppler should
be performed to serve as a baseline for blood flow in evaluating the results of the endovascular techniques. If possible,
umbilical arterial and venous catheters should be placed at the time of delivery to allow repeated vascular access for both
diagnostic and therapeutic procedures. These indwelling catheters obviate the necessity for repeated femoral punctures in the
fragile neonatal femoral artery. A CT or MR should be performed to assess any parenchymal damage already produced by the
congenital fistula, disclose hydrocephalus, which may require ventriculoperitoneal shunting, and serve as a baseline.
If intractable congestive failure persists despite aggressive medical management, angiography is performed to delineate the
vascular anatomy. Palliative arterial embolization can be performed at this time, preferably with superselective catheterization
of each feeding pedicle to reduce the risk of ischemic damage to normal surrounding brain. The embolization procedure may be
repeated if congestive failure persists. If the congestive failure continues and further arterial embolization is considered risky
or technically impossible, transvenous embolization may become necessary. An arteriogram is performed to localize the
draining venous sinuses. If the draining venous sinuses are patent, the transfemoral or transumbilical routes can be used to
access the varix. On rare occasions, when the lateral sinuses are absent or severely hypoplastic, surgical access to the
intracranial venous system is necessary. A small burr hole is made over the draining falcine or straight sinus. A needle puncture
is made into the sinus, a catheter is advanced into the varix, and platinum coils are deposited. These techniques can be curative
or palliative. When palliative, they alleviate the congestive failure and allow the child to develop normally until a definitive
treatment can be performed with further surgical or radiological techniques. MRI scanning is useful in our experience to assess
brain development, the degree of thrombosis in the fistula site, and delayed development of hydrocephalus. MRV may also
demonstrate connections between the draining varix of the VOGM and the deep cerebral venous system; however, this
connection may only become apparent after the VOGM has been largely treated (115). Thus, a point of caution in treating
VOGM has become apparent in recent years: there is a potential to reflux agents like ethylene vinyl copolymer into the
internal cerebral venous system during VOGM embolization. Our institution’s preferred embolization agents in VOGM are
coils—which can be accurately placed—and n-BCA—which flows downstream and is not as prone to reflux as ethylene vinyl
copolymer.
Figure 12-9 A 32-year-old woman with vein of Galen malformation and presenile dementia. A and B. Midsagittal T1-weighted and axial T2-
weighted images show severe calvarial thickening from chronic anticonvulsant use and extensive flow voids along the posterior falx cerebri and
tentorium cerebelli, surrounding the primitive median prosencephalic vein and persistent falcine sinus. The basal ganglia hyperintensity
probably represents injured, calcified tissue from chronic venous hypertension. C. 3D phase-contrast MRA illustrates the dramatic increase in
the size of intracranial blood vessels caused by the congenital vein of Galen malformation and subsequent recruitment of additional blood
supply from all vascular distributions. D–F. Left internal carotid, external carotid, and vertebral injections, lateral projection in the arterial phase,
define the recruitment of blood supply to the fistula from all vascular distributions. Chronic venous hypertension has engendered development
of several independent and noncontiguous fistulas of the superior sagittal sinus (black arrow) and falx cerebri (white arrowhead).
Figure 12-10 Staged embolization of a vein of Galen malformation. A 1-day-old full-term girl presented with cardiac dysfunction treated with
pharmacotherapy. A. Head CT at 1 day of age shows a central varix and marked hydrocephalus. Ventriculoperitoneal shunting was performed.
B. AP midarterial phase DSA via the right vertebral artery at 7 months confirms several large mural feeders from the PCA and a few smaller
choroidal-type thalamoperforating feeders as well as the large outflow from the VOGM varix to the persistent falcine sinus. The extensive
arteriovenous connections and large venous outflow contributed to progressive congestive heart failure symptoms. C. AP midarterial phase
DSA via the right vertebral artery at 7 months immediately following endovascular coil embolization of the largest mural feeders from the right
PCA demonstrates reduction in arteriovenous shunting. D. AP midarterial phase DSA via the right vertebral artery at 3 years following additional
endovascular coil embolization of the largest mural feeders from the left PCA demonstrates further reduction in arteriovenous shunting,
progressive narrowing of the outflow persistent falcine sinus, and improved flow to normal PCA branches bilaterally. E. Axial FLAIR MRI at 4
years demonstrates resolved hydrocephalus as compared to the neonatal period, but with peritrigonal T2 hyperintensity indicative of long-
standing white matter damage, likely the result of perinatal hydrocephalus.
Cavernous Malformations
Definition and Causes
Cavernous malformations, also called cavernomas, are spherical collections of sinusoidal (cavernous) vascular spaces (38).
Multiple cavernous angiomas are common and are associated with a familial predisposition. Three causative genes have been
identified: KRIT1 (CCM1) at chromosome 7q11.2-q21 (116), CCM2/malcavernin at chromosome 7p13 (59,117), and
PDCD10 (CCM3) at chromosome 3q26.1 (59,117). A recent study suggests that CCM formation can result from endothelial
gain of MEKK3-KLF2/3 signaling (118). The proportions of families linked to these loci have been estimated to be close to
40% (CCM1), 20% (CCM2), and 40% (CCM3) (117). The proportion of patients with onset of symptoms before age 15 years
is highest in the CCM3 group (117), but the number of affected individuals per family is lowest in this group. A 50% incidence
of multiplicity is found in familial cases, whereas only a 13% incidence of multiplicity is found in sporadic cases (119–122).
A significantly lower number of lesions are seen in CCM2 patients than in CCM1 patients (117).
Cavernomas are dilated, hypertrophied capillary beds containing dilated pockets of clotted and unclotted blood in various
stages of oxidation. They have very slow circulation and arteriovenous shunting is not present; as a result, the caliber of
feeding arteries and draining veins is normal. Venous malformations and capillary telangiectasias are often found in association
with cavernomas (123,124), giving rise to speculation that venous hypertension from obstructed outflow of venous
malformations initiates a cascade of events resulting in formation of cavernomas (123). Cavernomas often appear to be
associated with the branching radicles of a DVA, like ornaments hung on the branches of a Christmas tree. Giant cavernomas
have been described in children, associated with massively dilated capillaries (125).
Capillary Telangiectasias
Capillary telangiectasias are collections of dilated capillaries separated by normal brain parenchyma likely representing a type
of vascular choristoma. They are most commonly found in the pons, rarely bleed, and are usually discovered incidentally at
autopsy. Occasionally, they may be found incidentally on routine MRI. Noncontrast scans may be normal, may show slight
hypointensity on T1-weighted images, or may show slight hyperintensity on T2-weighted images; no mass effect is present.
After administration of paramagnetic contrast, moderate enhancement with slightly brush-like borders is seen (Fig. 12-13).
Marked hypointensity is typically seen on gradient echo images (Fig. 12-13) (139), presumably secondary to the presence of
slowly flowing, deoxygenated blood within the vessels (140).
Hemangioma
Hemangiomas are benign neoplasms of endothelial proliferation, occurring in up to 10% of children by 1 year of age.
Manifestations appear shortly after birth and consist of development of a reddish lobulated mass on the skin. Growth may be
rapid during the first year of life. The diagnosis is usually made by clinical examination. Management is usually medical and
includes steroids and other immunomodulatory and antiangiogenic agents (142–144). Hemangiomas usually stabilize after the
first year of life; many will involute and even resolve during the subsequent few years. Atrophy of cutaneous tissues with scar
formation may accompany regression of the lesion. Features requiring more aggressive treatment include functional impairment
(impingement on the eyelid, lip, or mouth impairing development of vision, feeding patterns, or language, respectively),
hemorrhage, mass effect upon the airway, platelet sequestration resulting in coagulopathy (Kasabach-Merritt syndrome), or
high-output CHF (145,146).
Figure 12-12 Developmental venous anomaly. A. Axial T1-weighted image shows a tuft of vessels (open arrows) feeding into a curvilinear
vascular channel (solid arrows) that drains into the superior sagittal sinus (not seen on this image). This appearance is characteristic of
developmental venous anomalies. B. Venous phase angiogram, lateral projection, from a right internal carotid artery injection. The tuft of
vessels (white arrows) is seen to form a curvilinear venous channel (black arrows) that drains into the superior sagittal sinus. The findings are
identical to what was seen on the MR study.
Imaging features of hemangiomas are described in Chapter 7. On angiography, hemangiomas are high-flow capillary lesions
with well-circumscribed areas of dense, prolonged opacification. The feeding arteries are dilated and rapidly drain to dilated
veins (147). Intracranial and orbital structures should always be evaluated in patients with hemangiomas of the face or neck, as
a subgroup of patients with hemangiomas have the PHACES syndrome (see Chapter 6), a constellation of posterior fossa brain
malformations, hemangiomas, arterial anomalies, cardiovascular anomalies, eye abnormalities, sometimes sternal clefting, and
anomalies of cerebral arterial supply (148,149) (Fig. 12-14). Interventions for cerebrovascular disease are a work in progress
(150,151) Endovascular treatment is generally reserved for lesions causing thrombocytopenia and bleeding diathesis. Such
lesions often have a more aggressive histology resembling hemangioendothelioma.
Facial AVM
In contrast to hemangiomas, facial AVMs are composed entirely of vascular channels without associated parenchymal
opacification (147). Although these lesions are usually managed conservatively, hemorrhagic complications may prompt
intervention prior to musculoskeletal maturity. Some facial vascular malformations can be resected primarily. Infiltrative
lesions, osseous involvement, or acute hemorrhage may necessitate endovascular treatment. Embolization is sometimes
requested prior to elective surgical procedures such as dental extraction. In order to prevent occlusion of vascular access to
the malformation in the event that embolization will again be required in the future, temporizing embolization using polyvinyl
alcohol particles is our agent of choice (Fig. 12-15).
Figure 12-15 Ulcerated labial arteriovenous malformation, preoperative imaging and embolization. A. Sagittal T1-weighted SE image showing
multiple small signal voids (white arrow) from a soft tissue arteriovenous malformation of the chin and lower lip. B. Coronal CT scan with bone
windows demonstrates mandibular hypertrophy (white arrow) due to long-standing hyperemia associated with the AVM. C. Left external carotid
arteriography in the lateral projection during the arterial phase showing rapid arteriovenous shunting arising from multiple hypertrophic facial
arteries converging on the premental soft tissue arteriovenous malformation (arrow). D. Following preoperative particulate embolization using
polyvinyl alcohol particles, arteriography shows minimal opacification of the arteriovenous malformation (arrow) with preservation of the lingual
branch.
Preoperative embolization may be required before resection of a vascular pediatric neoplasm. Juvenile angiofibroma
(discussed in Chapter 7) is a common nasal tumor of adolescent males, yet comprises only 0.5% of all head and neck tumors.
These vascular tumors are commonly embolized prior to surgery; resection is facilitated by devascularizing the largest feeder
arteries (157). The vascular supply of the tumor usually arises from both external carotid arteries; thus, bilateral arteriography
is required. The sphenopalatine branches of the internal maxillary artery are the most common feeding vessels. Internal carotid
supply is less common. Judicious particle embolization is safe and effective, although there are serious potential complications
including blindness, cranial neuropathy, and stroke (158). Figure 12-16 demonstrates the arteriographic findings before and
following preoperative embolization of a recurrent juvenile angiofibroma. In the hands of an experienced
neurointerventionalist, the risk of complication during internal carotid artery branch embolization is low (159,160).
Arteriovenous Fistulas
Presentation
In our experience, pediatric DAVFs often present in the neonate, suggesting that they are developmental in these particular
cases. They can present much like a VOGM (a special type of arteriovenous fistula), with macrocephaly, heart murmur, cardiac
failure, distended scalp veins, increased ICP, and hemorrhage (41,166,168). The combination of macrocephaly, distended
scalp veins, and cardiac failure should raise suspicion for a vascular intracranial lesion, prompting neuroimaging evaluation.
Occasionally, they are detected prenatally, as a result of an abnormal structure (typically the venous varix) seen on prenatal
sonography (166).
Treatment
Treatments of dural arteriovenous fistulas include transarterial embolization (175,176), transvenous embolization
(174,177,178), or surgical excision (179). In the larger congenital dural malformations, the goal is to reduce shunting
adequately to treat the heart failure. Intravascular therapy is the procedure of choice to reduce the flow, with subsequent
combined intravascular/surgical therapy when the child is older and more stable (180). Most fistulas respond well to
endovascular treatment. Unfortunately, treatment of torcular fistulas is often hampered by the presence of a multitude of feeding
vessels that are large in caliber. This often makes their treatment extremely difficult and the prognosis in such infants is poor
(41,180).
Presentation
Patients with direct carotid-cavernous fistulas typically present with a bruit, headaches, proptosis, chemosis, and diplopia; a
history of recent trauma can often be elicited (181,184,185). Rarely, hydrocephalus, neurological deficits, visual loss,
blindness, or hemorrhage can ensue (181,186). Rapidly progressive visual loss and new intracranial hemorrhage are
indications for urgent treatment.
Neuroimaging Findings
The CT and MR findings in carotid-cavernous fistulas consist of dilatation of the affected cavernous sinus and the venous
structures that normally drain into or from it, most commonly the ipsilateral superior orbital vein and the petrosal sinuses (Fig.
12-20). Not infrequently, both cavernous sinuses and the adjacent venous structures will be enlarged as a result of shunting of
blood through intercavernous connections. Rarely, only the contralateral venous pathways will enlarge because of pressure
gradients within the venous system. Depending upon the pattern of venous drainage, proptosis may be present in the ipsilateral
and/or contralateral orbit (Fig. 12-20).
Figure 12-17 A dural arteriovenous fistula, detected by fetal ventriculomegaly. A. Fetal sonogram shows ventriculomegaly and a large
echolucent region (arrows) in the region of the tentorial incisura. B. Analysis of the echolucent region by Doppler shows rapid, complex flow
suggesting a vascular structure such as a varix. C and D. Sagittal (C) and axial (D) T2-weighted MR image of the fetus shows a large
heterogeneous occipital mass (white arrows in C) with areas of marked hypointensity suggestive of rapid flow. The mass is pushing the
cerebellum anteriorly (white arrows in D) and compressing the brainstem, thus causing hydrocephalus. E. Postnatal sagittal T1-weighted image
shows the mass (large white arrows), the compressed brainstem, and multiple small signal voids (white arrowheads) around the brainstem. F.
Axial T2-weighted image shows the heterogeneity of the signal in the varix (V) and misregistration of the signal from the flowing blood (arrows
point to misregistered signal on left and right sides of the varix). G. Single image from an MR angiogram shows multiple areas of flow-related
enhancement (arrows) around the brainstem, representing multiple small blood vessels. H. Lateral view of a maximum intensity projection of
an MR angiogram showing that the large varix is separate from the vein of Galen and straight sinus, which course above it (white arrows). The
varix is located too far posteriorly and inferiorly for the prosencephalic vein of Markowski; this is, therefore, not a vein of Galen malformation. I.
Lateral view from a common carotid artery injection of a catheter arteriogram shows large meningeal and occipital branches (arrows) feeding
this large fetal dural arteriovenous fistula.
Figure 12-18 Neonate with macrocephaly and heart failure secondary to a large arteriovenous fistula. A. Coronal sonogram with Doppler
vascular analysis through the occipital lobes shows an echolucent area (V) in the region of the torcular, likely a varix. The right cerebral
hemisphere is markedly echodense, suggesting edema. Multiple enlarged arteries (red) and veins (blue) are identified. B. Noncontrast CT
image shows the large hyperdense varix (V) and mixed hypodensity (edema) and hyperdensity (enlarged arteries and veins) in the abnormal
right hemisphere. C. Sagittal reformation of a CT angiogram shows that the varix (V) involves the torcular, distal superior sagittal sinus, and
occipital veins. Carotid arteries and vertebrobasilar arteries are enlarged. D. Lateral view of right common carotid injection, catheter angiogram,
shows rapid filling of the varix (V) via the enlarged middle cerebral (black arrow) and posterior cerebral (black arrowhead) arteries. E. After
coiling of multiple feeders, filling of the feeding vessels and the varix (V) has markedly slowed.
Figure 12-19 Adult-type DAVF in a child with hypercoagulability. A 9-year-old girl with history of bone marrow transplant for treatment of
underlying C1q deficiency syndrome was noted to have too many vessels in the posterior fossa on surveillance neuroimaging. A. Coronal T1-
weighted contrast-enhanced MRI of the posterior fossa confirms supernumerary enlarged vessels in the cerebellum without a discrete
parenchymal nidus, most consistent with cortical veins draining a dural arteriovenous fistula. B and C. AP and lateral DSA of the left ECA
identifies an adult-type high-risk (Borden-Shucart grade III) dural arteriovenous fistula near the torcula supplied by enlarged branches of the left
middle meningeal artery and draining directly to cerebellar hemispheric cortical veins. D. AP DSA of the left ECA following ethylene vinyl
copolymer embolization of the DAVF demonstrates no residual arteriovenous shunting.
Treatment
Surgical techniques of trapping or proximal ligation are usually ineffective at fistula closure and have been largely supplanted
by endovascular techniques. Historically, a detachable balloon mounted on a microcatheter was guided through the carotid
artery and into the fistula (187,188). In 2004, the manufacturer voluntarily discontinued the only FDA-approved detachable
balloon available in the United States for this type of treatment. Latex microballoons remain available from Europe but lack US
FDA approval. More commonly now, transvenous methods are utilized to safely occlude the fistula without traversing or
impinging upon the injured artery (Fig. 12-21) (174,189,190). Covered stents have been experimentally placed transarterially
to occlude direct fistulas, even in children (191). In the rare instances where proximal carotid occlusion has occurred and
venous pathways are unavailable, direct puncture of the carotid (192), superior orbital or other surrounding veins, or surgical
exposure of the cavernous sinus and placement of embolic material into the sinus can be curative (193). With smaller fistulas,
complete cure can sometimes be achieved by intermittently compressing the internal carotid artery and jugular vein to induce
thrombosis within the fistula (194). In some instances, intimal damage occurs as the result of the initial trauma, and carotid
occlusion is performed to eliminate the risk of distal thromboembolic events. After any of these treatments, the clinical
symptoms of bruit, headache, proptosis, and chemosis dramatically improve. Diplopia is often transiently exacerbated due to
mechanical compression of the cranial nerves by embolic materials or ischemia due to acute thrombus in the cavernous sinus
causing “cavernous sinus syndrome”; this exacerbation resolves within 1 or 2 months. In cases with marked cavernous sinus
compressive symptoms from mass effect, oral corticosteroids can help reduce pain and swelling.
Figure 12-20 Carotid-cavernous fistula. A. Axial T1-weighted image shows a large, low-intensity mass in the region of the cavernous sinus
(white arrows). There is misregistration artifact (black arrows) dorsal to this area in the phase-encoding direction, indicating flowing blood within
the structure. The left globe is proptotic (open arrow). B. Axial T1-weighted image shows an enlarged superior orbital vein in the left orbit (black
arrows). C. Coronal T1-weighted image also shows the enlarged superior orbital vein on the left (arrow). The extraocular muscles are also
enlarged on the left side. D. Parasagittal T1-weighted image shows the internal carotid artery (open arrows) emptying into the cavernous sinus
at the site of the fistula (straight arrow). The enlarged cavernous sinus is seen as a large area of mixed signal intensity (curved arrows). E.
Lateral film from an internal carotid angiogram shows the internal carotid artery (open arrows) emptying into the cavernous sinus (small closed
arrows). The venous blood is seen to drain through an enlarged superior orbital vein (arrowheads) and inferior petrosal sinus (flared arrow).
Figure 12-21 A 17-year-old who sustained a basal skull fracture during a motor vehicle accident and developed a loud bruit, proptosis, and
visual loss in the right side. A and B. Right internal carotid angiogram, lateral projection (A) and AP projection (B), demonstrate a large carotid-
cavernous fistula extending into the contralateral cavernous sinus (large black arrowhead in B) with extensively dilated draining veins including
ophthalmic vein (large white arrow) and superior petrosal sinus (white arrowhead). Note large pseudoaneurysm (black arrow in B). C. Right
internal carotid angiogram, lateral projection, shows the platinum coils utilized to produce fistula closure.
Vertebral Fistulas
Vertebral fistulas are usually solitary connections between the vertebral artery and surrounding paravertebral venous plexus.
While the majority are the result of penetrating (195,196) or blunt trauma (197), congenital vertebral fistulae are not uncommon
and can be associated with neurofibromatosis type I (198–200). Paraspinal arteriovenous fistulas may not arise from the
vertebral artery itself but they clinically mimic vertebral fistulas and are successfully treated using similar endovascular
techniques.
Presentation
The most common presenting symptoms of vertebral fistulas are bruit and neck pain. Rarely, neurological deficits (201,202)
can result from vascular steal away from the intracranial vessels into the fistula; the steal is more common with large
congenital fistulas. If the venous drainage is to the epidural or medullary venous system, the patient may present with
radiculopathy or subarachnoid hemorrhage, respectively (198,203). It must be remembered that congenital fistulas can have an
exceptionally loud bruit that is totally unnoticed by the child since they accept the pulse synchronous noise as normal. These
anomalies can only be fully assessed by angiography, a necessity for treatment planning.
Figure 12-22 A 13-year-old female suffered blunt trauma to the upper cervical spine at age 6 years and subsequently developed a loud bruit
and severe headaches. A. Left vertebral injection, lateral projection, demonstrates a vertebral fistula at the C2 level. Note the tremendous
hypertrophy of the vertebral artery proximal to the fistula site. B. Same injection and projection as in (A), postembolization, with a single
detachable balloon (arrows) demonstrates complete closure of the fistula with preservation of the vertebral artery. The patient’s headaches and
bruit abated immediately after closure of the fistula.
Treatment
Many surgical techniques have been described for treatment of vertebral fistulas, including proximal ligation (195), trapping
procedures, and direct surgical repair. As elsewhere in the body, proximal and distal trapping is often ineffective at closing the
fistula; proximal ligation can increase steal away from the cerebral vasculature, exacerbating neurologic deficits. Direct
surgical approach to the fistula is often effective in fistula obliteration, but surgical exposure through the cervical spine and
arterialized vertebral veins may be difficult, as is preserving patency of the parent vertebral artery.
Endovascular treatment of vertebral fistulas is the treatment of choice and can be performed by embolization of the abrupt
transition from artery to vein (199,201,202). Historically, silicone balloons were inflated and, if properly positioned in the
fistula, detached (203). Figure 12-22 is an example of a traumatic vertebral fistula treated with endovascular occlusion using a
detachable balloon. Other embolic materials such as thrombogenic coils, metallic occlusion devices, and liquid polymers are
currently used to accomplish the same goal of eradicating the fistula (204). In some traumatic fistulas, the vertebral artery is
completely transected; these require occlusion on both sides of the injury to ensure fistula closure. Rarely, with long-standing
congenital vertebral fistulas, blood flow away from the brain into the fistula impairs cerebral autoregulation. When such
fistulas are abruptly closed, and normal blood supply is restored to the chronically ischemic brain, hyperperfusion can occur
with resultant neurological deficits or hemorrhage; progressive, staged closure is required to allow for the gradual recovery of
autoregulation (198).
Intracranial Aneurysms
Intracranial aneurysms are rare in children and, thus, relatively poorly understood as compared to those in adults. A recent
review of UCSF’s experience with the treatment of these aneurysms between 1981 and 2008 (205) included 40 females and 37
males ranged in age from 3 months to 18 years (mean 12.5 ± 5 years). Among the 77 patients, 45% presented with headache,
16% with cranial neuropathy, 15% with nausea/vomiting, 13% with vision changes, 13% with trauma, 4% with seizure, and
3% with sensory changes. Overall 25/77 (32%) had subarachnoid hemorrhage at presentation. Of 103 total aneurysms, 11%
were considered giant (>25 mm in diameter). Aneurysms were separated into four groups: (type I) noninfectious nontraumatic
fusiform aneurysms (n = 34), (type II) noninfectious nontraumatic saccular aneurysms (n = 47), (type III) infectious aneurysms
(n = 12), and (type IV) traumatic aneurysms (n = 15). The rate of hemorrhage at presentation was highest for saccular
noninfectious aneurysms and lowest for fusiform aneurysms. However, given the critical illnesses associated with trauma and
infection, aneurysms associated with those conditions may have come to attention relatively earlier in their course. Fifty-nine
patients underwent aneurysm treatment, with 19 undergoing primary endovascular coiling (Fig. 12-23), 1 endovascular stent-
assisted coiling (Fig. 12-24), 11 endovascular parent artery occlusion, 19 surgical clipping, and 10 surgical bypass and
aneurysm trapping. Morbidity included 8% infarction and 4% new-onset seizures; mortality was 1.3%.
Figure 12-23 Coiling of ruptured basilar tip aneurysm in a 12-year-old boy followed by endovascular treatment of cerebral vasospasm. A. AP
DSA via the right vertebral artery on subarachnoid hemorrhage day 5 demonstrates a saccular aneurysm at the basilar artery apex as well as
narrowings in the intradural right vertebral artery and inferior basilar artery trunk consistent with cerebral vasospasm. B. AP DSA via the right
vertebral artery immediately following endovascular coil occlusion of the basilar tip aneurysm demonstrates no residual aneurysm filling. C.
Lateral DSA of the left ICA on subarachnoid hemorrhage day 5 shows severe vasospasm of the supraclinoid ICA. D. Lateral DSA of the left ICA
immediately following angioplasty demonstrates improved caliber of the supraclinoid ICA.
Underlying conditions that may predispose to aneurysm formation are important to recognize in children (Table 12-3), as the
likelihood of developing new or enlarging aneurysms will dictate the clinical and imaging follow-up strategy after index
aneurysm treatment or observation. Whereas in our original study (205) of pediatric aneurysms 34/77 patients had identifiable
comorbidities that may have contributed to formation of their index aneurysms, our follow-up study (206) found that 8/9
children who developed new or enlarging aneurysms within an average of 4.2 years after index aneurysm treatment had such
identifiable comorbid conditions. Patients with index fusiform aneurysms were the most likely to form new aneurysms during
follow-up.
Saccular Aneurysms
Intracranial saccular aneurysms are rare in the pediatric population with a prevalence of 0.6% to 4.6% (220,221,224–226). In
a cooperative study of 6368 patients with intracranial aneurysms and subarachnoid hemorrhage, only 41 patients (0.6%) were
less than 19 years of age (227–230) and only about 20% of pediatric aneurysms are classified in this group (231). Although
intracranial aneurysms in children are associated with a variety of disorders (Table 12-3), no underlying systemic disorder is
detected in many affected children (205). Aneurysms in the pediatric population are more commonly of the large (“giant”) type
and more commonly arise distal to the circle of Willis than those in the adult population. The distribution of aneurysms within
the circle of Willis also differs from that in adults. Most studies indicate that the internal carotid artery bifurcation is the most
common location for aneurysms in children (Fig. 12-25G–I) (225,231–237). In addition, 15% of pediatric aneurysms arise
from the posterior circulation (compared with 5% in adults) (231–235,237). Other studies show a high incidence of
intracavernous internal carotid artery and internal carotid artery termination aneurysms in children (235). Given the long-life
expectancy of children, the development of de novo or enlarging intracranial aneurysms is of particular concern (206) and
warrants noninvasive follow-up such as with MRA at regular intervals.
Figure 12-24 Stent coiling of a growing saccular component of fusiform ICA aneurysm. A. Time-of-flight MRA in a 9-year-old with history of
tricuspid atresia status post Fontan procedure with a recent mechanical fall demonstrates marked ectasia of the right ICA with a superimposed
saccular enlargement in the paraclinoid segment. B. AP DSA of the right ICA performed shortly after the MRA confirms a paraclinoid saccular
aneurysm superimposed on long-segment fusiform ectasia of the ICA. C. AP DSA of the right ICA performed at age 13 confirms marked
enlargement of the paraclinoid aneurysm. D. Surface rendered reformat of a 3D DSA of the right ICA following stent-assisted coiling of the
paraclinoid aneurysm demonstrates preserved parent artery patency and aneurysm occlusion with coils.
Platinum detachable coils can be navigated into the aneurysm and electrolytically detached to occlude the neck and dome. If
the aneurysm has a broad neck, it may be occluded with coils using a neck-remodeling technique whereby a temporary balloon
occludes the lumen of the parent vessel across the aneurysm neck while detachable coils are deployed into the aneurysm (244).
If the balloon-assisted coiling technique is not possible due to the presence of a fusiform aneurysm, then stent-assisted coil
occlusion of the aneurysm or surgical bypass with vessel occlusion or reconstruction can be undertaken. Alternatively, a
balloon test occlusion of the parent vessel in a cooperative patient can be performed. Test occlusion must be performed in an
awake patient to ensure that the patient can tolerate the occlusion. Clinical testing can be supplemented by imaging such as
nuclear medicine SPECT or flat panel CT perfusion, the latter of which can be performed in the modern angiography suite
without moving the patient during an angiogram. If the test occlusion is tolerated, the parent artery and the aneurysm are
permanently occluded with coils or other embolic devices.
Figure 12-25 Pediatric nontraumatic aneurysms. A–F. A 11-year-old male with giant anterior cerebral artery aneurysm. A–C. Sagittal and
coronal T1 (A and B) and axial T2 (C) weighted images show a large aneurysm (arrows) partially filled with subacute thrombus projecting
toward the left, causing significant edema in the inferior left frontal lobe (open arrows). D. Oblique arteriographic projection from a right internal
carotid artery injection, arterial phase, demonstrates to advantage the neck (long arrow) of a partially thrombosed aneurysm (arrows) arising
proximally from right anterior cerebral artery. E and F. Following uncomplicated endovascular coil occlusion, the aneurysm (arrows) is
completely thrombosed. There is no iatrogenic cerebral artery occlusion. The patient made an uneventful recovery. G–I. An 8-year-old male
with acute headache. G. Axial noncontrast CT image shows acute blood (black arrows) in the suprasellar, interhemispheric, and left sylvian
fissures. H. Coronal image from CT angiogram shows a small outpouching (white arrow) at the bifurcation of the internal carotid artery. I. Right
internal carotid arteriogram, AP projection, confirms the small aneurysm (black arrow).
Radiology
CT or MR may help to localize the aneurysm by demonstrating adjacent intraparenchymal hemorrhage or infarct (Fig. 12-26A)
or by directly visualizing the lesion, especially in the case of intracavernous aneurysms. Associated cerebritis, abscess, edema,
or infarction may be identified. Cerebral angiography is necessary for definitive diagnosis (Fig. 12-26). On angiograms,
mycotic aneurysms appear as fusiform dilatations of the affected vessel. They tend to be located peripherally, most frequently
in the distribution of the middle cerebral artery (196,247,248), in contrast to the saccular congenital aneurysms, which tend to
be located on the circle of Willis.
Therapy
If the aneurysms remain following appropriate antimicrobial therapy, endovascular occlusion of the aneurysm can be
considered. The decision regarding when to treat a mycotic aneurysm depends upon the size and location of the aneurysm, the
clinical presentation, and observed changes in the patient and the aneurysm over time. Clinical urgency to replace a failing
infected cardiac valve may also require repair of a mycotic brain aneurysm before a full course of antibiotics can be
completed. Because mycotic aneurysms are typically fusiform, aneurysm treatment often necessitates occlusion of the involved
vessel segment immediately proximal to the aneurysm origin. Collateral flow may preserve perfusion of parenchyma distal to
the aneurysm, especially for distal lesions. Surgical bypass (either entirely intracranial or extracranial to intracranial) with
surgical interruption of the vessel proximal to the aneurysm may be indicated to preserve perfusion of eloquent
cerebrovascular territory (249).
Traumatic Aneurysms
Traumatic aneurysms are common in childhood, representing up to 39% of pediatric intracranial aneurysms (231,250), are
most commonly caused by penetrating injuries (251,252), although blunt trauma (even seemingly mild concussive injury
(251,252)) may also result in damage to the craniocervical vessels (253,254). Traumatic aneurysms can be found intracranially
or extracranially. The latter are typically associated with flexion/extension/rotation injuries such as from motor vehicle
accidents or from projectile injuries causing comminuted fractures at the skull base (255). Many authors classify traumatic
aneurysms as pseudoaneurysms because all layers of the arterial wall are disrupted; flowing blood is confined only by the
integrity of the surrounding tissues.
Figure 12-26 A 10-year-old with infectious aneurysms and MCA infarction secondary to bacterial endocarditis. A. Axial noncontrast CT scan
shows an area of low attenuation (white arrows) in the posterior left middle cerebral artery distribution. B and C. Left internal carotid artery
arteriogram, AP (B) and lateral (C) projections show extensive spasm of the supraclinoid internal carotid artery and proximal MCA. The black
arrows show a fusiform enlargement of the left MCA, while the black arrowhead shows fusiform enlargement of the supraclinoid ICA. The
vessels normalized after therapy with antibiotics.
Figure 12-27 A 5-year-old boy presenting with ophthalmoplegia after automobile accident. A and B. Axial T2-weighted and postcontrast T1-
weighted images show a mass (arrow) with intrinsic T2 shortening that uniformly enhances. C and D. Posterior circulation arteriograms before
(C) and after (D) endovascular occlusion of a fusiform aneurysm of the left PCA with platinum coils (white arrows).
Clinical presentation may be significantly delayed with respect to the traumatic event, and a high index of clinical suspicion
is warranted if these lesions are to be identified prior to catastrophic hemorrhage (252,256). Immediate arteriographic
evaluation has been recommended (257), and arteriographic re-evaluation is suggested if no lesion is identified or after
treatment is completed. Historically, the surgical approach has been difficult because disruption of the tenuous pseudocapsule
may result in massive hemorrhage before vascular control can be established (258,259). More recently, endovascular
occlusion of the feeding vessel or endovascular trapping of inflow and outflow to the aneurysm has proven effective (Figs. 12-
27 and 12-28) (260).
Figure 12-28 A 17-year-old male with massive oropharyngeal hemorrhage during attempted reduction of mandibular fracture following
transfacial gunshot wound. A. Lateral arteriographic projection from a conventional subtraction arteriogram performed at the referring institution
during right carotid artery injection, arterial phase, demonstrates a posttraumatic pseudoaneurysm (large solid arrows) arising from the
proximal internal maxillary artery (open arrow). Note multiple bullet fragments (small solid arrows) traversing the midface and skull base. B.
Lateral arteriographic projection from a digital subtraction arteriogram during right carotid artery injection, arterial phase, following coil occlusion
(small arrows) of the pseudoaneurysm demonstrates complete occlusion of the aneurysm. There was no reconstitution of the aneurysm from
distal or contralateral carotid branches.
The glomus type, where the arteriovenous connections are tightly packed within the spinal cord substance, most often
presents as an intramedullary hemorrhage (70% in a recently reported series) that causes an abrupt neurologic decline (269).
Spinal subarachnoid hemorrhage can also occur from rupture of dysplastic aneurysms that develop in arteries that supply the
AVM. Genetic analysis has identified an autosomal dominant gene mutation in RASA1. Previously, this mutation was reported in
18.5% of the brain, facial, and extremity AVMs. An identical RASA1 mutation has now been found in all five patients with
spinal AVMs recently evaluated (270).
Capillary malformation-arteriovenous malformation syndrome is a recently described hereditary disorder that is
characterized by cutaneous capillary malformation occurring in association with high-flow vascular lesions (AVMs or
arteriovenous fistula). This condition is caused by mutations in the RASA1 gene. This gene encodes for a protein that plays an
important role in the signaling for growth factor receptors involved in the proliferation migration and survival of various cell
types including endothelial cells (as signaling pathway) (271). Phenotypic variability is described. The high-flow lesions may
be located in the skin and subcutaneous tissue, bone, muscle, or brain. Some of these patients have the clinical features of
Parkes Weber syndrome. The CMs are often small pink-red macules that may be widely distributed over the skin surface; a
pale halo may be noted at the periphery of the capillary malformation. Larger solitary capillary malformations are also
reported in this condition (272). Figure 12-29 shows the arteriograms of a 13-year-old girl who presented with subarachnoid
hemorrhage. Initial evaluation at an outside hospital consisted of a CT scan that revealed hemorrhage in the basal cisterns. A
subsequent four-vessel cerebral arteriogram was interpreted as normal. She was discharged and had a second subarachnoid
hemorrhage 1 week later. Repeat evaluation at our institution revealed an intramedullary AVM at the C2 level with a dysplastic
aneurysm arising from the feeding anterior spinal artery. A small microcatheter was navigated through the vertebral artery and
the radicular artery to the aneurysm site. Small-fibered platinum microcoils were delivered into the aneurysm and adjacent
anterior spinal artery. Particulate embolization was also performed, with 80% reduction of the AVM and elimination of the
aneurysm. She had no change in her neurologic status, and subsequent surgery further reduced the malformation. Figure 12-30
shows a cervical AVM in a 3-year-old boy with a cutaneous hemangioma who developed progressively severe headaches and
neck muscle spasms. Preoperative angiography and endovascular embolization with provocative neurological testing and
evoked potentials allowed safe and effective embolization prior to complete surgical resection. The child is neurologically
normal.
Figure 12-29 A 13-year-old girl presented with recurrent subarachnoid hemorrhage. A and B. Left vertebral artery injection, AP (A) and lateral
(B) projections demonstrate an arteriovenous malformation located in the right anterior spinal cord at the C2 vertebral level. A fusiform
pseudoaneurysm arises from the midanterior spinal artery projecting anteriorly from the midanterior spinal artery and projects ventrally (oblique
arrow). Subselective catheterization of the anterior spinal artery was performed with subsequent particulate embolization of the AVM and coil
deposition across the zone of the aneurysm. C. One month later, left vertebral artery injection, lateral projection, demonstrates markedly
diminished vascularity of the AVM and durable obliteration of the anterior spinal artery aneurysm and pseudoaneurysm by small platinum coils
(short straight arrows). The patient remained neurologically intact.
The juvenile type of spinal AVM is an intradural malformation that fills an entire segment of the spinal canal, encompassing
the parenchyma of the spinal cord. It is the most common of the intramedullary spinal malformations. Affected patients may
present with an audible spinal bruit, progressive or sudden motor or sensory symptoms, or parenchymal or subarachnoid
hemorrhage. The initial workup should include MR. Flow within the vessels of the AVM creates signal voids, which are
outlined by the adjacent spinal cord parenchyma. Any associated parenchymal hemorrhage can be identified, with more acute
blood being iso- to hyperintense on T1-weighted images and hypointense on T2-weighted images (see Chapter 4). Selective
spinal arteriography is needed to delineate the feeding medullary arteries and draining veins. The angiogram may show
multiple feeder arteries and ectasia of draining veins. Usually, the anterior spinal artery provides significant flow to the
malformation; it may demonstrate flow-related dysplastic changes including perimedullary aneurysms in up to 20% of affected
patients (269,273,274). Metameric lesions represent a complex form of spinal AVM involving the spinal cord, the surrounding
perimedullary space, the spine itself, and possibly even the surrounding tissues of the thorax or abdomen (Fig. 12-31); this is
often termed Cobb syndrome (275).
Treatment of spinal AVMs depends on the presenting symptoms and the anatomy of the malformation. As spinal AVMs,
especially the juvenile type, may contain normal spinal parenchyma within the vascular interstices, surgical extirpation is
difficult. The glomus-type malformation can be suitable for surgical excision, particularly if located posteriorly and
superficially along the spinal cord. Figure 12-32 shows an example of a glomus-type malformation that presented with spinal
cord hemorrhage and was treated with superselective embolization and surgical resection. Endovascular techniques, in
particular superselective arteriography and preoperative embolization, play an important role in the management of
intramedullary lesions. Particularly in the juvenile type, both the feeding arterial aneurysms and the malformation itself can be
obliterated in selected cases (264,276,277). If complete obliteration cannot be attained, palliative embolization often results in
improvement in symptoms from these difficult lesions, possibly from reduction in edema.
Figure 12-30 Spinal arteriovenous malformation in a 3-year-old boy with complaint of progressively severe headache and episodic paraspinal
muscle spasms. A and B. Sagittal and axial T2-weighted images show a parenchymal arteriovenous malformation of the cervical spinal cord
at C4-C5 level with varicoid and aneurysmal perimedullary venous drainage compressing and distorting the cord (arrows). C and D. Right
vertebral and left subclavian arteriography in the frontal projection show both pial and dural supply to the malformation (arrows). E and F.
Sagittal T2 and T1 postgadolinium images show fluid–fluid levels without contrast enhancement in the malformation (arrows) following
transarterial acrylic embolization with n-BCA. G and H. Right vertebral and left subclavian arteriography after super-selective arteriography,
provocative neurological anesthetic testing with somatosensory and motor-evoked potentials and acrylic embolization with n-BCA show
occlusion of the AVM (arrows).
Figure 12-31 Metameric (juvenile) spinal arteriovenous malformation with subacute biparesis. A and B. Sagittal T1-weighted (A) and T2-
weighted (B) weighted images demonstrate focal hemorrhagic signal (small curved arrows) posteriorly along the midthoracic spinal canal
adjacent to irregular vessels (small open arrows) filling the spinal canal, encompassing the medullary and perimedullary spaces. Note the focal
sclerosis in the T9 and T10 vertebral bodies most compatible with healed infarcts (large solid arrows). C and D. Frontal arteriographic images
from sequential injection of several intercostal artery pedicles, arterial phase, demonstrate an extensive arteriovenous malformation (small
arrows). Multiple additional arterial feeder vessels (not shown) to the malformation were found arising from other intercostal arteries. E and F.
Frontal arteriographic images before and after embolization of the left T6 radiculopial supply (large solid arrow) show focal occlusion of a
portion of the malformation with improved visualization of the anterior spinal artery (small open arrows). The patient’s strength subsequently
improved. Due to extensive medullary involvement, surgical resection of the lesion was not pursued. Embolization in such cases is palliative,
and the natural history remains poor. Conservative management is suggested. Repeated embolization may be undertaken when the patient’s
symptoms progress.
Figure 12-32 A 17-year-old male presented with acute quadriparesis. A. Sagittal T1-wighted images demonstrated hematomyelia (white
arrows) surrounding a lobulated area of signal void (black arrows) consistent with an intramedullary AVM. B. Left T4 intercostal injection
demonstrates a glomus-type arteriovenous malformation (arrows) located in the posterior aspect of the spinal cord. C. Same injection and
projection as in (B), status post embolization, demonstrates complete obliteration of the malformation. Subsequent surgery was performed,
resulting in complete cure of the malformation. The patient made a remarkable recovery with only mild residual arm weakness.
Epidural Fistulas
Epidural fistulas are rare, large-caliber connections that occur outside of the thecal sac. Because of their proximity to the
spinal cord, they can drain into the medullary veins (Fig. 12-35). Subarachnoid hemorrhage and progressive myelopathy are
the most common presentations.
Figure 12-33 A 3-year-old female presents with acute headache, paraparesis, and loss of continence due to a ruptured spinal perimedullary
AV fistula (PMAVF). A. Noncontrast head CT shows fourth ventricular intraventricular hemorrhage and mild hydrocephalus. B. Axial CTA
demonstrates an enlarged intraspinal vascular structure near the cervicothoracic junction. C. Right costocervical angiogram in the arterial
phase demonstrates an arteriovenous fistula from a radiculomedullary branch of the costocervical artery to a dilated intrathecal venous varix.
D. Later-phase image from the costocervical angiogram demonstrates multiple enlarged intrathecal veins that decompress to the epidural
venous plexus. E. Roadmap angiogram demonstrates endovascular coiling of the venous varix, perimedullary arteriovenous fistula site, and
distal feeding artery. F. Completion angiogram of the right subclavian artery confirms no residual filling of the PMAVF.
Figure 12-34 Previously healthy 7-year-old girl developed acute dense paraparesis over a 2-hour period. A and B. Axial T1-weighted images
at the cervical-thoracic junction demonstrate a large signal void (arrows) displacing the spinal cord to the right. At a slightly inferior level (B), a
signal void is noted within the spinal cord substance. C. Right costocervical artery injection, AP projection, demonstrates a large perimedullary
fistula (large arrow) supplied by the anterior spinal artery (small arrows). Open arrows point to the superiorly draining vein. D. Superselective
injection through a microcatheter placed through the anterior spinal artery into the draining varix demonstrates the superiorly draining vein
(arrows). Multiple platinum coils were delivered within the varix and distal anterior spinal artery. E. Right costocervical artery injection
postembolization, AP projection, shows obliteration of the flow to the venous varix. Over the ensuing 3 months, the patient made a dramatic
recovery, regaining full strength in her left leg and sufficient strength in the right leg to ambulate with an ankle orthosis. Her physical examination
was consistent with Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia syndrome (HHT).
Figure 12-35 An 8-year-old girl with subtle paraparesis and a loud paraspinal bruit. A and B. Sagittal and axial T1-weighted images show
prominent left paraspinal and epidural flow voids (arrows). C and D. Digital and subtracted arteriography of the left L2 lumbar artery
demonstrates rapid arteriovenous shunting via a single-hole fistula to the left paraspinal and epidural venous plexus (arrow). E. Microcatheter
arteriography following coil occlusion of the fistula shows complete cessation of flow through the fistula without impairment of the normal
circulation.
Moyamoya Syndrome
Definition and Clinical Features
The moyamoya syndrome is a progressive vasculopathy characterized by slowly progressive stenosis involving the proximal
portions of the major intracranial arteries (295–298). Collateral vessels (most commonly lenticulostriate and
thalamoperforator arteries) hypertrophy to compensate for the slowly progressive stenoses. These hypertrophied collaterals
resemble a “puff of smoke” on angiography, an appearance from which the disease derives its name (299). Many disorders are
associated with the moyamoya syndrome (Table 12-5), and genetic factors have been described (308–311). It is likely to be a
heterogeneous disorder, with many genetic and epigenetic factors involved. Five gene loci have been identified using linkage
analysis (312). A number of cellular growth factors have been identified that may mediate vessel wall hypertrophy
(297,313,314). An infectious etiology has been proposed in some cases based upon the presence of increased Epstein-Barr
virus DNA and antibodies in patients with moyamoya (315). An underlying cause can more often be identified when the
occlusive changes are unilateral. When no cause can be identified, the disorder is classified as moyamoya “disease.”
Although a bimodal age distribution is reported in moyamoya syndrome (316), most affected patients come to medical
attention during childhood. Approximately 70% of the reported cases occur in patients less than 20 years of age, and 50%
occur in children below the age of 10 years (317). In contrast to adults, who typically present in the fourth decade with
subarachnoid or intraparenchymal hemorrhage, children usually have recurrent transient ischemic attacks with progressive
neurological impairment (318). Partial and secondary generalized seizures are common in younger children, whereas recurrent
headache is more frequent in older children.
Radiology
CT and MR are useful for detecting regions of cerebral infarction. Both CT and MR can show focal regions of acute infarction
(Fig. 12-39) or localized or diffuse atrophy, depending upon the site(s) of vascular narrowing and the adequacy of collateral
flow. Sometimes, calvarial thickening may be present as a consequence of chronic anemia. MR is more sensitive than CT in the
demonstration of ischemic and infarcted regions of the brain and will often reveal narrowing of affected intracranial vessels
(Fig. 12-39) or signal voids in the basal ganglia (Figs. 12-40 and 12-41) due to the enlarged moyamoya collaterals. FLAIR
sequences are particularly useful to detect areas of ischemic injury, which may be missed because of their isointensity to
adjacent CSF on T2-weighted images. As discussed in Chapter 4, reduced diffusion, as determined by diffusion-weighted
imaging will help to differentiate acute infarctions (reduced diffusion) from subacute and chronic ones (increased diffusion). If
intravenous contrast has been administered, intense enhancement of the basal ganglia can occur, either as a result of infarction
and breakdown of the blood–brain barrier or from visualization of the collateral vessels as they course through the basal
ganglia region. Curvilinear streaks of enhancement may be seen coursing radially through the centrum semiovale from the
lateral ventricles to the cortex, probably representing dilated deep medullary veins (Fig. 12-41). Branching pial enhancement
may also be seen, likely representing dilated capillaries supplying collateral cortical blood flow (Fig. 12-41). Perfusion
imaging can be performed using SPECT (319) or MR (320). Perfusion imaging is useful to identify regions of relative ischemia
that are at risk for infarction; it is also useful to assess changes in perfusion after therapy. Generally, an increase in mean transit
time within a region of the brain is associated with abnormal blood flow to that region, although it is not specific for the cause.
Increased mean transit time may be the result of stenoses in the anterior circulation or posterior circulation or the development
of moyamoya collateral vessels (321). An increase in mean transit time associated with reduced cerebral blood volume or
with a lack of increase in cerebral blood volume after administration of intravenous acetazolamide is more suggestive of tissue
at risk (322).
The radiologic evaluation nearly always includes angiography, which defines the extent of the disease and, to some extent,
the adequacy of collateral flow. The typical angiographic appearance is that of narrowing of the supraclinoid internal carotid
artery, proximal anterior cerebral artery, and proximal middle cerebral artery (Figs. 12-39 and 12-40). The posterior
circulation is rarely involved until late in the course of the disease. The lenticulostriate and thalamoperforator arteries
hypertrophy to compensate for narrowing of the major vessels. At arteriography, care must be taken to evaluate for associated
vascular abnormalities including saccular aneurysms (323), dissection (324), and AVMs (325). Although catheter angiography
remains the gold standard, CT and MRA show the narrowing of the ICA, MCA, and ACA very well. CTA is useful for
identification of the extracranial vessels that might be used for therapeutic synangiosis (see following paragraph) and identifies
the moyamoya collaterals (326). Use of intravenous contrast or imaging at 3T allows the moyamoya collaterals to be
visualized by MRA (327), which, as mentioned multiple times in this text, has the benefit of no ionizing radiation.
After pial synangiosis (the surgical therapy of choice, in which an external carotid artery branch is placed in apposition to
the pia–arachnoid), the external carotid vessels are seen to slowly enlarge and the branches of the middle cerebral artery
ultimately begin to fill from collaterals, mostly arising from the superficial temporal or middle meningeal branches of the
external carotid artery. These collaterals are best seen by digital subtraction angiography (328), although CT and MRA can
sometimes show them, as well (Fig. 12-40) (326,329).
Figure 12-39 Moyamoya disease. A. Axial CT scan shows low attenuation in the posterior right frontal cortex (arrows). Note some prominent
CSF spaces in the anterior portion of the frontal lobe (arrowhead). B. Axial diffusion-weighted image shows reduced diffusion (arrows) in the
posterior right frontal cortex. Some lesser hyperintensity (arrowhead) possibly T2 effect (“shine through”) is seen more anteriorly. C. Axial T2-
weighted image shows the acute infarction (small arrows), but in addition, areas of T2 prolongation and volume loss in the right middle frontal
gyrus (larger arrows). D. Coronal FLAIR image shows hyperintensity (small arrows) and volume loss in the right middle frontal
gyrus/intervascular boundary zone. A smaller area of hyperintensity (large arrow) is present in the deep left frontal intervascular boundary zone.
These findings suggest subacute to chronic ischemic injury. E. Maximum intensity projection image from a 3D time-of-flight MR angiogram
shows bilateral narrowing of the supraclinoid internal carotid arteries and proximal anterior and middle cerebral arteries.
Neurologic manifestations of sickle cell disease can be divided into three major categories: decreased cognitive function
(also called “silent stroke”), acute onset of focal neurologic deficit (stroke), and severe headache and meningismus from
subarachnoid hemorrhage (330,333,335,336). Stroke and silent stroke are the most common manifestations in children and are
250 times more common in sickle cell patients than the general pediatric population (337). Stroke occurs in 11% of patients
with homozygous sickle cell disease by the age of 20 years, usually due to stenosis or occlusion of the major cerebral vessels
(338).
Radiology
Imaging findings tend to be related to the neurologic manifestations. Patients who present with decreased cognitive function are
often found to have reduced cerebral blood flow as assessed by TCD (339–341). As narrow blood vessels must increase
blood velocity in order to maintain perfusion, the time averaged maximum mean velocity is assessed; if between 170 and 200
cm/s, the result is considered conditional, while values above 200 cm/s is considered definitely abnormal (339–341). Patients
with decreased cognition also have increased evidence of ischemic cerebral damage on MR studies, manifested as
encephalomalacia, with multifocal T2/FLAIR hyperintensity superimposed upon both focal and generalized atrophy (Fig. 12-
42) (336). Often, the calvarium is thickened due to hematopoiesis in the diploic space (Fig. 12-42). Patients who present with
acute onset of focal neurologic deficit will show typical neuroimaging findings of acute cerebral infarction of gray or white
matter, such as reduced diffusion (see more complete discussion of cerebral infarction in Chapter 4) or acute intracerebral
hemorrhage. The acute infarction is often superimposed upon chronic ischemic changes and atrophy; the diffusion findings are
very helpful in separating acute from chronic injury.
Figure 12-40 Moyamoya disease: appearance before and after surgical treatment. A 9-year-old girl with transient ischemic attacks. A. Axial
FLAIR MRI shows bilateral white matter T2 hyperintensities consistent with areas of subacute ACA-MCA watershed infarction. B and C. Time-
of-flight MRA demonstrates apparent occlusion of the bilateral M1 MCAs with lenticulostriate region collateral formation. D. Time-of-flight MRA
following bilateral STA to MCA bypass grafting suggest that the STA to MCA bypass grafts are patent on the basis of flow-related signal
enhancement in distal MCA branches (arrows).
Figure 12-41 Dilated medullary and pial collateral vessels in moyamoya disease. A. Axial FLAIR image shows multiple dilated hyperintense
vessels (arrowheads) in the cerebral white matter. B. Postcontrast axial T1-weighted image shows enhancement of the dilated medullary
vessels (large arrowheads) and of dilated pial vessels (small arrowheads).
CT scans are generally performed without contrast in patients with sickle cell disease, as hypertonic contrast agents may
precipitate sickling. Small doses of paramagnetic contrast are probably safe during MR scanning but use of MR contrast is
rarely necessary; it should only be used if absolutely essential and the patient should be well hydrated before and during the
examination.
MRA is very useful to assess the status of the major cerebral arteries and the circle of Willis (Fig. 12-42) (342). Catheter
angiography should be restricted to those patients who have hemorrhage, should be performed with low-osmolality
contrast, and should be performed only after the patient is transfused and well hydrated (see below). Vascular stenoses,
vascular occlusions, and prominent collateral vessels may be identified; the anterior circulation is much more commonly
involved than the posterior circulation (342,343). In severe cases, a moyamoya pattern (see previous section) may be present.
About 20% of sickle cell–related strokes are hemorrhagic (344). Most of these are probably the result of rupture of dilated
perforating arteries that are acting as collateral vessels. The appearance of the acute hemorrhage, hyperdense on CT, iso- to
hyperintense on T1-weighted spin-echo MR studies, and hypointense on T2 and T2* or susceptibility-weighted MR studies,
has been discussed in Chapter 4.
Figure 12-42 A 13-year-old child with sickle cell disease presenting with altered cognition. A and B. Axial FLAIR images show abnormal
hyperintensity in much of the cerebral white matter. Focal areas of cortical atrophy (arrows) are present. The calvarium is thickened due to
hematopoiesis in the diploic space. C. Collapsed view from time-of-flight MR angiogram shows occlusion of both anterior and middle cerebral
arteries and the right posterior cerebral artery. Multiple dilated external carotid branches and leptomeningeal collateral vessels from the left
posterior cerebral artery supply collateral blood flow.
Figure 12-43 Multiple brain AVMs in HHT. A 23-year-old woman with clinically definite and genetically confirmed HHT underwent screening
MRI. A–C. Axial postcontrast T1-weighted MRI confirms small vascular malformations in the left mesial temporal lobe and left putamen and
also identifies a small vascular malformation in the left superior frontal gyrus. D. Right ICA lateral DSA visualizes two adjacent small nidus
AVMs in the right posterior frontal lobe. These did not have imaging correlates on MRI. E. Left ICA lateral DSA identifies small nidus AVMs in the
left mesial temporal lobe, left basal ganglia, and left superior frontal gyrus—these correspond to the AVMs suggested on contrast-enhanced
MRI. Overall whereas three brain AVMs were suggested on screening MRI, eleven brain AVMs were identified on DSA.
Rarely, patients with sickle cell disease may present with severe headache, meningismus, and photophobia from
subarachnoid hemorrhage (335). Although subarachnoid hemorrhage may result from rupture of dilated collateral vessels, it is
most commonly the result of ruptured aneurysms (335). Aneurysms have an increased incidence in sickle cell disease (Fig. 12-
43) and may be multiple. The mechanism by which these aneurysms develop has not been established, but it is likely related to
damage to the vessel walls by the abnormal red blood cells (345,346). MRA should be the first vascular imaging study
performed in patients with sickle cell disease and subarachnoid hemorrhage, as it is accurate in the detection of aneurysms
greater than 3 mm in size (347). If the source of bleeding is not found or if patients are being considered for surgical or
endovascular therapy, they should undergo catheter angiography to definitively establish the size and location of aneurysms and
their precise relation to parent vessels. Due to the danger of precipitating sickling by injection of hypertonic contrast agents,
catheter angiography should be performed only after hydrating and transfusing the patients (335,346); the osmolality of the
contrast should be as low as possible for a diagnostic study. The goal of transfusion is to reduce the hemoglobin S level below
20%.
These radiological procedures, especially catheter angiography, are often performed in children under general anesthesia.
Proper ventilation is absolutely imperative, and the pCO2 must be maintained at normal levels. If the patient is
overventilated, the pCO2 may decrease, thus reducing cerebral blood flow. These patients are at great risk for ischemic
infarction under such circumstances.
Radiology
The first step in the radiology evaluation for craniocervical dissection is brain imaging. A nonenhanced CT is a good first step
if the patient has any evidence of meningeal inflammation (nuchal rigidity, photophobia), as it is the most sensitive modality for
detection of subarachnoid blood. CT can also detect ischemic injury, which raises the suspicion for presence of vascular
injury. Cross-sectional imaging with CT and MRI may demonstrate crescentic hemorrhage in the vessel wall, which is
diagnostic of dissection. A noncontrast T1-weighted axial sequence with fat suppression through the upper neck and skull base
is most sensitive and, therefore, is the imaging sequence of choice. MRA in the cooperative or sedated patient is increasingly
used to evaluate for the presence and extent of vascular narrowing and flow restriction. Two-dimensional time-of-flight MRA
has been shown to have a sensitivity of 95% in the carotid circulation but only 20% in the vertebral circulation (359).
Conventional arteriography remains the gold standard in the evaluation for detection of intimal irregularities if no intramural
hematoma is present.
Common arteriographic findings in traumatic dissection include pseudoaneurysm, intimal irregularity or flap, stenosis with
limitation of flow, complete vessel occlusion, and distal embolic occlusion (360,361). Great care must be taken during
arteriography not to probe the dissected segment with the catheter or guide wire, as a mild stenosis can be converted into a
complete occlusion. It is important to exercise such caution during evaluation of all the craniocervical blood vessels due to the
risk of additional sites of dissection and the risk of damage to sources of collateral cerebral blood flow should the dissected
vessel require complete occlusion.
The treatment for dissection is systemic anticoagulation in an effort to prevent embolization and consequent stroke.
However, detection of embolic events or subarachnoid hemorrhage may warrant surgical or endovascular intervention.
Endovascular therapy consists of balloon or coil occlusion to trap the dissected segment (362). Pseudoaneurysms can be
occluded with coils while sparing the parent vessel; this treatment reduces the risk of emboli, aneurysmal enlargement, and
subarachnoid hemorrhage (363). Use of endovascular stents to remodel the dissected vessel segment is currently under
evaluation in adults.
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Index
(Note: Page numbers followed by ‘f ’ indicate figures; those followed by ‘t’ indicate tables)
A
AAs. See Anaplastic astrocytomas (AAs)
Abscesses, 711, 713f, 989, 1115
Acetoaspartase, 57
ACG. See Angiocentric glioma (ACG)
Achondroplasia, 1031f
Acoustic neuromas, bilateral, 654f
Acoustic schwannomas, bilateral, 652f
Acquired immune deficiency syndrome (AIDS), 1093–1095, 1095f
ACTH-secreting adenomas, 782
Actin/tubulinopathies, 436, 438, 438f–442f, 439
Acute cerebellitis, 1137f
Acute disseminated encephalomyelitis (ADEM), 144–147, 146f, 713
monophasic, 139, 145
multiphasic, 145
recurrent, 145
Acute hemorrhagic encephalomyelitis, 147
Acute hydrocephalus, 915
Acute necrotizing encephalitis (ANE), 210–211, 213f, 214, 214f
Acute nonobstructive hydrocephalus, 944–945, 947–948, 947f–948f
Acute obstructive hydrocephalus, 935
Acute pancreatitis, 89
Acyl CoA oxidase deficiency, 94, 96–97, 96t, 97f–101f, 98, 100
Adamantinomatous craniopharyngiomas, 767
Adams-Oliver syndrome, 1097
ADC. See Apparent diffusion coefficient (ADC)
ADEM. See Acute disseminated encephalomyelitis (ADEM)
Adenohypophysis, 509
Adenoma
cystic, 770
diffuse, 783
discrete, 782
hemorrhagic, 770
invasive, 786f
pituitary, 782–786, 783f–786f
sebaceum, 656
Adenomata sebaceum, 657
Adenylosuccinate lyase deficiency, 406
Adrenoleukodystrophy (ALD), 97, 97f
Adrenomyeloneuropathy (AMN), 94, 95f, 96–98, 97f–100f, 100
Aedes aegypti, 1092
Agenesis of the corpus callosum with interhemispheric cyst (ACC/IHC), 423, 424, 424t
Agenetic porencephalies, 263
Aggressive tumors, 884–885
juvenile angiofibromas, 888, 889f, 890f
melanotic neuroectodermal tumors of infancy, 888
nasopharyngeal carcinoma, 885–888
rhabdomyosarcoma, 884–885, 884f
Aicardi syndrome, 417, 584, 1096
Aicardi-Goutières syndrome (AGS), 125, 125f, 1096
ALD. See Adrenoleukodystrophy (ALD)
Alexander disease
infantile, 84, 87, 173f
juvenile form, 174f
Allan-Herndon-Dudley syndrome, 131
Alobar holoprosencephaly, 495, 495f–498f
Alorainy syndrome, 526
α-foetoprotein (AFP), 782, 837
Alternating muscle tonus, 91
Amebiasis, 1151
Anaplastic astrocytomas (AAs), 727, 800f
Anaplastic gliomas, 1050
Anaplastic oligodendrogliomas, 803
Aneurysmal bone cysts, 765, 1051, 1052, 1052f
Angiocentric glioma (ACG), 822–823, 823f
Angiofibromas, juvenile, 888, 889f, 890f
Angiomas
cavernous, 715
choroidal, 672
Angiomatosis, 667, 672f
Angiomyolipomas, 667
Anisotropy, 63, 70
Anophthalmia, 516
Anorectal anomalies, 977
Anterior communicating arteries (ACAs), 767
Anterior sacral meningocele, 1008, 1010f
Anteroposterior patterning defects, 525–526, 527f
Antidiuretic hormone (ADH), 778
Anti-N-methyl-D-aspartate receptor encephalitis, 149, 150f
Aplasia cutis congenita, 581, 581f
Apoptosis, 642
Apparent diffusion coefficient (ADC), 10, 63, 359f, 642
Aqueductal forking, 932
Aqueductal stenosis (AS), 711, 932–933, 933f, 934f
extrinsic, 926f
incomplete, 927f
intrinsic, 925f
by tectal mass, 924f
Arachnoid cysts, 771
clinical characteristics, 584, 586
imaging characteristics, 586–587, 587f–591f, 589–590
pathologic characteristics, 584
L-arginine:glycine amidinotransferase (AGAT), 159
Arrhinia/arrhinencephaly, 500, 503–505, 506f–507f
Arterial dissection in childhood, 373, 1233–1234
Arterial infarctions, 1110
Arterial spin labeling (ASL), 12
Arterial thrombosis, 1098
Arteriography, 715, 853, 1178
Arteriopathy, intracranial, 666–667
Arteriovenous fistulas
direct carotid cavernous fistulas, 1203–1204
neuroimaging findings, 1204, 1207, 1208f
symptoms, 1204
treatment, 1207, 1209, 1209f
intracranial dural, 1203, 1204f
vertebral fistulas, 1209–1210, 1210f
Arteriovenous malformations (AVMs)
clinical manifestations
asymptomatic, 1182
chronic recurrent headaches, 1182
hemorrhages, 1181
progressive neurological deficits, 1182
seizures, 1182
de novo, 1181
definition and causes, 1181, 1182f
imaging findings, 1182, 1182f, 1184
symptomatic, 1181
treatment, 1184, 1185f–1186f, 1186
Arthropod-borne viruses
acute flaccid paralysis, 1165f
alphaviruses, 1140
bunyaviruses, 1140
Eastern equine encephalitis, 1130, 1130t, 1140
European tick-borne encephalitis, 1140
flaviviruses, 1140
Japanese encephalitis, 1140
La Crosse encephalitis, 1140
Powassan virus, 1140
reovirus, 1140
St. Louis encephalitis, 1140
West Nile virus (WNV), 1140
Western equine encephalitis, 1140
Aspartoacylase deficiency, 170, 171f, 172, 172f
Aspartylglucosaminuria, 166
Aspergillus fumigatus, 1150
Astroblastoma, 812–813, 813f
Astrocytes, 634
Astrocytic tumors, 794
Astrocytomas, 639, 655, 793
anaplastic, 727, 800f
cerebellar, 726–729, 729f
cystic, 728
diffuse, 728
giant cell, 844
hemispheric, 730f
pilocytic, 639, 640f, 777f
pilomyxoid, 728, 775
spinal cord, 1043–1045, 1044f–1047f
suprasellar pilocytic, 771–777
Ataxia–telangiectasia (AT), 223
clinical manifestations, 675–676
Nijmegen breakage syndrome, 678
pathological and neuroimaging manifestations, 677–678, 677f
Ataxia–telangiectasia mutated (ATM) syndrome, 676
Athabaskan brainstem dysgenesis syndrome, 526
Atretic cephaloceles, 570, 574f–575f, 575, 576f
Atypical teratoid/rhabdoid tumors (ATRTs), 717, 725, 726f, 810–812, 811f, 812f
pineal, 840, 842f
Autoimmune diseases, 81
Autoimmune/infectious disorders
acute disseminated encephalomyelitis (ADEM), 144–147, 146f
acute hemorrhagic encephalomyelitis, 147
anti-Ma2–associated encephalitis, 149
anti-N-methyl-D-aspartate receptor encephalitis, 149, 150f
basal ganglia encephalitis, 149
children with anti-GAD65 encephalitis, 149, 151
differential diagnosis, 151
multiple sclerosis, 139, 140f, 141–142, 141f
neuromyelitis optica spectrum, 142–144, 143f–144f, 143t
systemic lupus erythematosus, 147–149, 148f, 149f
Autoregulation, 283
Autosomal dominant multisystem disorder, 691
Autosomal dominant polycystic kidney disease, 584
Autosomal recessive multisystem disorder, 675
Autosomal recessive spastic ataxia, 225
B
Back pain, 361–362, 1029, 1160
Bacterial abscesses, 1115, 1125f
Bacterial cerebritis, 1119
Bacterial meningitis, 935
Bacterial/spirochetal/rickettsial infections of CNS
bacterial cerebritis, 1119, 1120f
brain abscess, 1119, 1121–1126, 1121f
bacterial meningitis, 1097–1098
cat-scratch disease, 1126–1127
Lyme disease, 1127–1128, 1128f
Rocky mountain spotted fever, 1128–1129
Band heterotopia, 466, 470f
Bannayan-Riley-Ruvalcaba (BRR) syndrome, 691–692
Basal cell nevus syndrome (BCNS), 683, 720
clinical manifestations, 683
neuroimaging manifestations, 683–685, 683f, 684f, 685f
Basal ganglia
congenital cytomegalovirus and, 1076f
germ cell tumors of, 830–831
germinoma of, 832, 833f
and pediatric stroke, 271–272
signal abnormalities, 643f
T1 and T2 prolongation in, 644f
BCNS. See Basal cell nevus syndrome (BCNS)
Benign arachnoid collection, of infancy, 943
Benign enlargement, of subarachnoid spaces in infancy, 943
Benign paroxysmal torticollis of infancy, 360
Benign rhabdomyomas, 667
Benign tumors, 880–881
Benign-appearing lesions, 644
β-ketothiolase deficiency, 160, 161f
β-human chorionic gonadotrophin (β-HCG), 782
Bifocal germinomas, 833–835, 834f, 835f, 836f
Bilateral acoustic neuromas, 654f
Bilateral acoustic schwannomas, 652f
Bilateral C1-C2 spinal neurofibromas, 651f
Bilateral choroid plexus villous hyperplasia, 847, 947
Bilateral colobomas, with cysts, 869f
Bilateral frontoparietal polymicrogyria (BFPP), 477, 479, 481, 481f
Bilateral medial parietal-occipital polymicrogyria, 491f
Bilateral optic gliomas, 776f
Bilateral perisylvian polymicrogyria, 486, 488f
Bilateral polymicrogyria syndromes, 489, 491f
Bilateral retinoblastomas, 861f
Bilateral symmetrical frontal polymicrogyria, 491f
Bilateral thalamic LGGs, 827, 828f, 829, 829f
Bilirubin encephalopathy, 340, 341f, 342
Birth trauma injuries
head trauma
extracranial hemorrhage, 346, 347, 349f
skull fractures, 347, 349, 350, 350f
traumatic intracranial hemorrhage, 350–354, 352f–354f
spinal cord/nerve root, 342, 343f
Biventricular hydrocephalus, 927
Blake’s pouch, 524
Bloch-Sulzberger syndrome. See Incontinentia pigmenti
Bone cyst, aneurysmal, 765
Bone dysplasia, sphenoid, 646
Bone lesions, 667
Bone, membranous development, 976
Borrelia burgdorferi, 1127
Bosma syndrome, 503
Brain abscess
bacterial/spirochetal/rickettsial infections, 1119, 1120f–1121f, 1121–1126, 1122t, 1123f, 1124f
Citrobacter spp., 1119
Cryptococcus neoformans, 1119
E. coli, 1121
Enterobacter spp., 1119
in infants and newborns, 1122
Brain atrophy, 923f
Brain calcification, 126, 126f
Brain development
basic concepts/patterning, pathways, 405–406
cranial fontanelles/sutures and, 50–51
division into stages of, 19
embryology and, 18–19, 20f
fontanelles/sutures/paranasal sinuses development, 50–51
germinal zones, 408
Hensen node, 52, 406
mineralization and, 51–52
myelination changes and, 28
neural folds, 406
neural plate, 406
neural tube, 406
normal postnatal
anatomic MRI, 34
corpus callosum, 47, 48f–49f, 49
maturation, 34
4-month-old infant, 35, 37f
6-month-old infant, 36, 38f–39f
8-month-old infant, 36, 40f–41f
12-month-old infant, 38, 42f
15-month-old infant, 39, 43f
22-month-old infant, 42, 44f
24-month-old infant, 42, 44f
paranasal sinuses and, 51
physiologic MR evaluation
brain region variations, 59, 60f
changes with brain maturation, 30, 34t
magnetization transfer imaging, 71, 72f
metabolites present, 56–59, 58f
normal MR spectrum, 56, 57f
pituitary gland and, 49–50, 51f
primitive streak, 406
protosegment, 408
terminal zones and, 43, 45f, 46
Brain injuries
bilirubin encephalopathy, 340, 342, 343f
birth trauma
extracranial hemorrhage, 346
skull fractures, 347, 349, 350f, 351f
spinal cord/nerve root, 344, 345f–347f
traumatic intracranial hemorrhage, 344, 345f, 346, 346f
CNS injury in multiple pregnancies and, 332, 334
congenital heart disease and, 342, 343f
diffuse ischemic, causes of, 268, 269f, 270, 270t–271t, 271
diffuse ischemic (premature infant), 287, 289t
cerebellar injury, 295
image findings, 290f–294f, 295–298, 296f–297f, 299f–301f, 302–305, 303f–307f, 307
morphological effects, 288
neurologic sequelae of, 288
preterm birth, imaging sequelae of, 287
profound hypotension/circulatory arrest, 304–305, 305f–307f, 307, 310t
diffuse ischemic (term infant)
mild-moderate hypotension, 285, 285f, 286f
parasagittal/watershed injury, 310–312, 310f–315f, 315
parenchymal/intraventricular hemorrhage, 326, 328, 329, 329f, 330f–331f
profound hypotension, 315–317, 318f–327f, 324
diffuse ischemic (older children) imaging choices, 333f–336f
encephalomalacia and, 265–266, 267f–269f
hydranencephaly and, 264, 266f
hypernatremic dehydration, 342
localized hypoxic-ischemic infarctions
manifestations/causes, 268, 270–271, 270t, 271t
radiologic choices, 271–272
secondary to venous occlusion, 277–282, 279f–282f
mild traumatic, 383, 384f–385f
neonatal hypoglycemia, 338–340, 339f–340f
porencephaly and, 263, 264f
postnatal brain/head trauma
abusive trauma, 373–379, 375f–382f, 381, 381t, 383
extraparenchymal hematomas, 362–365, 363f–366f
parenchyma injuries, 367–370, 370f–372f, 372
sequelae of trauma, 373
subarachnoid hemorrhage, 365, 366f–367f, 367
postnatal trauma
imaging choices, 354, 355
spinal, 355–357, 357f
Brain malformations, 406
Brain maturation
full-term normal brain imaging, 19–23, 20f–32f, 28, 30
grading of premature maturation, 30, 34t
imaging of, 20f–32f
sulcation in, 19t
Brain stem tumors 738–751
differential diagnosis of, 747–748
diffuse vs. focal brainstem gliomas, 739–742
general concepts, 738–739
medullary tumors, 739f, 740f, 741f, 742
midbrain tumors, 745, 747f
with neurofibromatosis type 1, 745–747
pontine tumors, 742, 743f, 744f, 745
Brain tumor, 793
anatomic imaging, 5–7, 5t
biology of, 704
cardinal features, 705
clinical features, 704–705
contrast agents and, 3–4
in first year of life, 858–859, 858t
incidence and severity, 703–704
MRS markers of, 710t
Brain tumor identification
anatomical analysis, 707
aqueductal stenosis, 711
differential diagnosis, 710
differentiation from abscess, 711, 713f
differentiation from demyelinating plaques, 714f, 715
differentiation from infarctions, 715
differentiation from inflammatory lesions, 713
differentiation from radionecrosis, 715
differentiation from vascular malformations, 715
diffusion characteristics, 705, 707
hemorrhage, 715
invasion, 715
location of tumor, 709t
mass lesion detection, 707
perfusion characteristics, 707
posttherapeutic follow-up neuroimaging, 716
pretherapeutic assessment, 715
proton MR spectroscopy, 710, 711
structural characteristics, 707–708
Brain tumor stem cells (BTSCs), 704
Brainstem glioma, 641
Brainstem tumor, 639
Branchial cleft cysts, 872–874, 874f, 875f
Bronchogenic cysts. See Enteric cysts
BRR syndrome. See Bannayan-Riley-Ruvalcaba (BRR) syndrome
Bundles of Probst, 421, 422, 422f
Buphthalmos, 520
C
Café au lait spots, 634, 658
Callosal anomalies
anatomic sequelae, 421, 422f, 722–423
diagnosis of, 424–425, 425f
imaging of, 423
interhemispheric cyst, 423, 424, 424f–428f, 424t
Calvarial masses of childhood, 577–578, 579t
Calvarial tumors, 856
Canalization/retrogressive differentiation of neural tube
caudal cell mass, 975
conus medullaris/filum terminale, 976, 976f
formation of distal spinal cord and, 976
tail bud, 975
Cancer, 634t
Capillary hemangiomas, 865
Capillary malformation-arteriovenous malformation syndrome, 1217
Capillary telangiectasias, 1197, 1199f
Caput succedaneum, 346
Carcinoma, 844
choroid plexus, 847
nasopharyngeal, 885–888
Carcinomatous meningitis, 935–936, 938f
Catheter angiography, 674, 1177–1180
Caudal cell mass anomalies
anterior sacral meningocele, 1008, 1010f
fibrolipomas of filum terminale/tight filum terminale, 1002–1004, 1002f–1004f
sacrococcygeal teratoma, 1008–1009, 1010f, 1011, 1011f
syndrome of caudal regression, 1004–1005, 1006f, 1007, 1007f
terminal myelocystocele, 1007–1008, 1008f
ventriculus terminalis, 1001
Caudal regression syndrome, 1004–1005, 1006f, 1007, 1007f
Cavernous angiomas, 715
Cavernous hemangiomas, 865–868
Cavernous lymphatic malformations, 876
Cavernous malformations, 867, 1196–1197, 1198f
Cavernous sinus thrombosis, 1110, 1111f
Central gray matter tumor
bilateral thalamic LGGs, 827, 828f, 829, 829f
ependymomas, 830
germ cell tumors of basal ganglia, 830–831
thalamic oligodendrogliomas, 829
thalamus and basal ganglia
high-grade gliomas of, 827–829
low-grade gliomas of, 824–827
Central nervous system (CNS)
disorders, 634
radiation-induced tumors of, 859
tumors, 703, 704t, 705, 858–859
Central neurocytoma, 849–850, 851f
Central white matter
diffusion imaging of brain maturation, 63
myelination, 102
Cephaloceles/calvarial defects
anterior fontanelle persistence, 581
aplasia cutis congenital, 581, 581f
atretic cephaloceles, 570, 574f–575f, 575, 576f
calvarial masses of childhood, 577–578, 579t
definition/causes/classification, 561–562
fetal imaging, 562
fontanelle dermoids, 577–579, 578f
frontoethmoidal cephaloceles, 565, 566f–567f, 568–570, 571f
nasal dermal sinus, 565, 567f–571f
nasal gliomas, 565, 567f, 573f
nasopharyngeal cephaloceles, 575, 577, 577f
occipital cephaloceles, 563, 563f–566f
parietal cephaloceles, 570, 575, 576f
parietal foramina, 579, 580f
repaired cephaloceles, 563, 563f–564f, 565
Cephalohematoma, 346, 349f
Cerebellar astrocytomas, 726–728
imaging studies, 728–729, 729f
pathology, 728
proton MR spectroscopy, 737
Cerebellar atrophy, 219–220, 220f–221f, 220t, 221t–222t
with adolescent/young adult onset
cerebrotendinous xanthomatosis, 233, 234f
spinocerebellar ataxias, 233
Wolfram syndrome, 233, 234
ataxia with oculomotor apraxia, 223–224
ataxia–telangiectasia, 223
autosomal recessive spastic ataxia, 225
cerebellar degeneration, from kinesin mutations, 231–232, 232f
congenital disorders of glycosylation, 229, 229f
dentatorubral and pallidoluysian atrophy, 230–231, 231f
Friedreich ataxia, 222–223, 223f
GM2 gangliosidosis, 223, 223f
hypomyelination with atrophy, 233
infantile neuroaxonal dystrophy, 226
Langerhans cell histiocytosis, 232–233, 233f
Marinesco-Sjögren syndrome, 224, 224f
mevalonate kinase deficiency, 229
mitochondrial disorders
coenzyme Q10 deficiency, 225, 225f
mitochondrial DNA depletion syndrome 7, 226
POLG1 mutations, 225–226
neuronal ceroid lipofuscinoses, 232
PEHO syndrome, 229–230, 230f
pontocerebellar hypoplasias, 226–228, 227t, 228f
Cerebellar degeneration, from kinesin mutations, 231–232, 232f
Cerebellar gangliocytoma, dysplastic, 817
Cerebellar hamartoma, 668f
Cerebellar hemangioblastomas, 673f, 674
Cerebellar hypoplasia, 234–235, 527, 529f–530f, 538, 539, 540f
Cerebellar injury, premature neonates, 290f, 303–304
Cerebellar lesions, 666
Cerebellar mutism syndrome, 723, 725
Cerebellar polymicrogyria, 545, 548, 548f–549f
Cerebellar tubers, 667
Cerebellitis, 1137f, 1145
Cerebellotrigeminal dermal dysplasia syndrome, 530
Cerebral arteries, 909
Cerebral contusions, 368, 377, 380f
Cerebral cortex
diffusion brain imaging and, 63, 64f–65f, 66, 69f, 70
preterm brain imaging and, 19–23, 20f–32f, 28, 30
Cerebral cortical development
actin/tubulinopathies, 436, 438, 438f–442f, 439
band heterotopia/double cortex, 466, 470f
bilateral frontoparietal polymicrogyria, 477, 479, 481, 481f
bilateral perisylvian polymicrogyria, 486, 488f
bilateral polymicrogyria syndromes, 489, 491f
causes/classification, 432
dysgenesis with abnormal proliferation, 439–540, 543f
dysgyria associated with tubulin mutations, 493–494
dysplasias with abnormal lamination, 442–443, 444f
dysplasias with dysplastic neurons, 443–448, 445f–449f
epilepsy syndromes, 489
FCMD, 475–476, 478f
focal cortical dysplasias, 441–442
focal subcortical heterotopia, 458–460, 459f–462f
hemimegalencephaly, 448–451, 450f–453f
imaging techniques, 432–434, 434f
lissencephaly, 460–464, 462f, 462t, 463t, 464f–473f, 466–471
macrocephaly–polymicrogyria syndromes, 487, 489, 490f
malformations of, 425–428, 433t
microcephalies, 434–436, 436t, 437f–438f
microcephaly-polymicrogyria syndromes, 489
muscle–eye–brain phenotype, 476–477, 479f–480f
occipital cobblestone malformations, 482–483, 482f–483
patients with cobblestone malformations, 472–474
periventricular heterotopia, 452–458, 457f–459f
polymicrogyria, 471, 483–484, 484f–488f, 486
schizencephaly, 489–491, 492f–493f, 493
sublobar dysplasia, 451
too shallow sulci, 460
tuberous sclerosis complex, 441
Walker-Warburg phenotype, 474–475, 474f–477f
Cerebral creatine deficiency syndrome (CCDS1), 159
Cerebral hamartomas, 813
Cerebral hemispheric tumors, 795t
Cerebral malaria, plasmodium falciparum, 1157
Cerebral toxocaral disease, 1153, 1157, 1157f
Toxocara canis, 1153
Cerebral tubers, 662–665, 663f, 664f
Cerebral vasculature, dysplasia of, 644
Cerebral vasculature anomalies
arterial dissection in childhood, 1233–1234
cerebral vasculopathy in childhood
hereditary hemorrhagic telangiectasia, 1233
moyamoya syndrome, 1228, 1231f
sickle cell disease, 1228–1229, 1231, 1231f–1232f, 1233
extradural vascular malformations/neoplasms
epistaxis/juvenile angiofibroma, 1202, 1202f, 1203
facial arteriovenous malformation, 1201, 1201f
hemangiomas, 1198–1199, 1200f
venous and lymphatic malformations, 1199–1201
intracerebral hemorrhage, 1180–1181
intracerebral vascular malformations
arteriovenous, 1181–1182, 1182f, 1183f, 1184, 1185f–1186f, 1186
capillary telangiectasias, 1197, 1199f
cavernous, 1196–1197, 1198f
vein of Galen, 1186, 1188, 1188f–1195f, 1190, 1192–1193, 1195–1196
venous, 1197
intracranial aneurysms
mycotic, 1215, 1215f
saccular, 1211–1213, 1213f–1214f, 1213t
traumatic, 1215–1216, 1216f
spinal cord arteriovenous malformations
classification, 1216, 1217t
epidural fistulas, 1221, 1224f
intramedullary, 1217–1219, 1218f–1220f
perimedullary, 1221, 1222f–1223f
technical considerations in neuroangiography
catheter choice, 1179
endovascular occlusion, 1179–1180, 1180t
fluid and contrast limitations, 1179
indications, 1178
postprocedural patient care, 1180
preprocedural planning, 1178
vascular access, 1179
Cerebral vasculopathy in childhood
hereditary hemorrhagic telangiectasia, 1233
moyamoya syndrome, 1228, 1231f
sickle cell disease
cerebral infarction, 1226f
definition and clinical features, 1228–1229
mechanical devices, 1226
mechanical thrombectomy, 1225f
transient cerebral arteriopathy, 1227f
Cerebral veins, 909
Cerebritis, 1119
Cerebrospinal fluid (CSF), 639. See also Hydrocephalus
absorption, 911
anatomy, 908–909
development, 909–910
dynamics and related disorders, 912–914, 912f, 913f, 913t, 914f
flow, site of obstruction, 641
hydranencephaly and, 373
production, 910–911
secretion and absorption, 910–911
volume, 907–908
Cerebrotendinous xanthomatosis, 233, 234f
Cervical hemangiomas, 872
Cervical kyphosis, 648f
Cervical lymphadenitis, 888
Cervical myelocystocele, 989–991, 992f, 993f
Cervicomedullary tumors, 742
Chédiak-Higashi syndrome, 687–688
Chemical blankets, 2
Chemotherapy, 114
brain injury, 81
Chiari I deformity, 550, 552f–554f, 553–554
Chiari II malformation, 554–555, 555f–561f, 558–560, 561t, 933
neurulation anomalies and, 987
syringohydromyelia and, 1028
Chiari III malformation, 560–561, 562f
Chiasmatic lesion, 636
Childhood ataxia with diffuse central nervous system hypomyelination (CACH), 100
Chloroma, 869
Cholesterol biosynthesis, 229
Chondrosarcomas, 763–764, 764f
Chordomas, 761, 762f, 763f, 1056, 1056f
Choriocarcinomas, 778
Choroid plexus, 671, 909–910
carcinomas, 945
hyperplasia, 947
papillomas, 944, 947f
secretion, 910–911
Choroid plexus carcinoma (CPC), 738, 847, 848f
Choroid plexus papillomas (CPPs), 738, 738f, 844, 845
proton MR spectroscopy, 846
Choroid plexus tumors, 737–738, 844–852, 846f–847f
Choroid plexus villous hyperplasia, 847–849, 850f
Choroidal angioma, 672
Chromosomal anomalies
fragile X syndrome, 606
short arm of chromosome 8, inversion duplication of, 606
trisomy 13, 606, 607f
trisomy 18, 606, 606f
trisomy 21, 600, 602, 603
Wolf-Hirschhorn syndrome, 606, 607
Chronic enteroviral encephalopathy, 1145
Chronic hydrocephalus, 914–915
Chronic nonobstructive hydrocephalus, 941–944, 942f, 944f–947f
Chronic obstructive hydrocephalus, 914
Circulatory arrest
older children, 331
premature infants, 304, 305
term infants, 315
Clivus chordomas, 761, 762f, 763f
Closed spinal dysraphisms, 978, 979
CNM. See Congenital melanotic nevi (CNM)
Coagulopathies and pediatric stroke, 271t
Coats disease, 520, 862, 863f
Cockayne syndrome, 125–126, 126f
Cognitive impairment, 288
Coloboma, 518
with cyst, 868f
Colpocephaly, 423
Commissural malformation, variants, 412
Communicating hydrocephalus, 373
Complex dysraphic state, 979
Complex meningoceles, 1022
Computed tomographic angiography (CTA), 4, 1177
Computed tomography (CT), 4–5
Congenital embryonal cysts
branchial cleft cysts, 872–874, 874f–875f
thymic cysts, 874–875
thyroglossal duct cysts, 872, 873f, 874f
Congenital and perinatal infections of CNS
acquired immune deficiency syndrome (AIDS), 1093–1095, 1095f
cytomegalovirus, 1073–1075, 1074f–1080f, 1077, 1079–1080
general concepts, 1072–1073
herpes simplex virus, 1080–1082, 1081f–1085f
human parvovirus B19 infection, 1096
infection transmission pathway, 1073t
infectious pathogens transmission pathway, 1073
lymphocytic choriomeningitis virus infection (LCVM), 1082, 1083, 1085, 1087f
mimicking congenital infections, 1096–1097, 1097f
parechovirus, 1093, 1094f
rubella, 1085, 1088, 1088f
Toxoplasma gondii, 1089, 1090f, 1091
Treponema pallidum (syphilis), 1089
tuberous sclerosis complex (TSC), differentiation from, 1097
varicella-zoster virus, 1091
zika virus, 1092, 1092f, 1093f
Congenital brain/skull malformations
arachnoid cysts
clinical characteristics, 584, 586
imaging characteristics, 586–587, 587f–591f, 589–590
pathologic characteristics, 584
arrhinia/arrhinencephaly, 500, 503–505, 506f–507f
callosal anomalies
anatomic sequelae, 421, 422f, 722–423
diagnosis of, 424–425, 425f
imaging of, 423
interhemispheric cyst, 423, 424, 424f–428f, 424t
cephaloceles/calvarial defects
aplasia cutis congenital, 581, 581f
atretic cephaloceles, 570, 574f–575f, 575, 576f
calvarial masses of childhood, 577–578, 579t
definition/causes/classification, 561–562
fetal imaging, 562
fontanelle dermoids, 577–579, 578f
frontoethmoidal cephaloceles, 565, 566f–567f, 568–570, 571f
nasal dermal sinus, 565, 567f–571f
nasal gliomas, 565, 567f, 573f
nasopharyngeal cephaloceles, 575, 577, 577f
occipital cephaloceles, 563, 563f–566f
parietal cephaloceles, 570, 575, 576f
parietal foramina, 579, 580f
persistence of anterior fontanelle, 581
repaired cephaloceles, 563, 563f–564f, 565
cerebral cortical development
actin/tubulinopathies, 436, 438, 438f–442f, 439
band heterotopia/double cortex, 466, 470f
bilateral frontoparietal polymicrogyria, 477, 479, 481, 481f
bilateral perisylvian polymicrogyria, 486, 488f
bilateral polymicrogyria syndromes, 489, 491f
causes/classification, 432
dysgenesis with abnormal proliferation, 439–540, 543f
dysgyria associated with tubulin mutations, 493–494
dysplasias with abnormal lamination, 442–443, 444f
dysplasias with dysplastic neurons, 443–448, 445f–449f
epilepsy syndromes, 489
FCMD, 475–476, 478f
focal cortical dysplasias, 441–442
focal subcortical heterotopia, 458–460, 459f–462f
hemimegalencephaly, 448–451, 450f–453f
imaging techniques, 432–434, 434f
lissencephaly, 460–464, 462f, 462t, 463t, 464f–473f, 466–471
macrocephaly–polymicrogyria syndromes, 487, 489, 490f
malformations of, 425–428, 433t
microcephalies, 434–436, 436t, 437f–438f
microcephaly-polymicrogyria syndromes, 489
muscle–eye–brain phenotype, 476–477, 479f–480f
occipital cobblestone malformations, 482–483, 482f–483
patients with cobblestone malformations, 472–474
periventricular heterotopia, 452–458, 457f–459f
polymicrogyria, 471, 483–484, 484f–488f, 486
schizencephaly, 489–491, 492f–493f, 493
sublobar dysplasia, 451
too shallow sulci, 460
tuberous sclerosis complex, 441
Walker-Warburg phenotype, 474–475, 474f–477f
Chiari I deformity, 550, 552f–554f, 553–554
Chiari II malformation, 554–555, 555f–561f, 558–560, 561t
Chiari III malformation, 560–561, 562f
clinical manifestations, 268, 270–271, 270t, 271t
craniosynostosis
abnormal fontanelle closure, 595
face and skull, embyrology of, 590, 592
inherited forms of, 596t–597t
nonsyndromic, 592, 592f–593f, 594
radiology of, 594, 594f, 595
syndromic, 595, 597, 598f–599f, 599, 600
eye anomalies
embryology, 514, 516, 516f
ocular, 516–521, 517f–521f
holoprosencephaly
alobar, 495, 495f–498f
causes, 494
classic, 495
clinical presentation, 494
embryogenesis, 494
familial cases, 494
lobar, 497–498, 502f
in mild cases, 494
semilobar, 495–497, 499f–501f
in severe cases, 494
sonic hedgehog gene, 494
subcategory, 494
syntelencephaly, 498, 500, 503f–505f
hypothalamic–pituitary axis, 508–509
embryology, 509–510, 510f
hypothalamic dysgenesis and adhesions, 513, 514, 515f
Kallmann syndrome, 513, 514f
pituitary absence/hypoplasia/duplication, 510–511, 511f, 512f
pituitary dwarfism, 511, 512f–513f
intracranial lipomas, 581–583, 582f–586f
isolated absence of septum pellucidum, 508
midbrain–hindbrain development
anteroposterior patterning defects, 525–526, 527f
brain and meninges interactions, 524, 525f
cell proliferation and migration, 522–524, 523f
cerebellar connections, 524
cerebellar hemisphere duplication, 548, 550f
cerebellar hypoplasia, 527, 529f–530f, 538, 539, 540f
cerebellar nodular heterotopia with overlying dysgenesis, 545, 547f
cerebellum and brain stem on MRI, 524–525, 525f, 526f
congenital disorders of glycosylation, 550
congenital fibrosis of the extraocular muscle, 542–543
Dandy-Walker complex, 532–535, 536f–538f
diffuse and unilateral cerebellar dysgenesis, 545, 548, 548f–549f
disconnection syndromes, 526, 528f
disproportionately small brainstem, 538
dorsal medullary protuberances, 550, 552f
dorsoventral patterning defects, 527, 528, 530
horizontal gaze palsy with progressive scoliosis, 542, 546f
Joubert syndrome, 540–542, 541t, 543f–545f
Lhermitte-Duclos disease/Cowden syndrome, 535, 537, 538, 538f–540f
malformations, 539, 541t
patterning, 522, 522f
pontine tegmental cap dysplasia, 549, 550, 551f
pontocerebellar hypoplasias, 550
rhombencephalosynapsis, 530, 531f, 532, 533f–535f
tectal enlargement, 543, 545, 547f
septooptic dysplasia, 505–508, 508f, 509f
Congenital disorders of glycosylation, 229, 229f
Congenital fibrosis of the extraocular muscles (CFOEM), 542–543
Congenital hemangiomas, 879–880
Congenital hyperthyroidism, 1096
Congenital lesions, 872
Congenital malformations, 633
Congenital melanotic nevi (CNM), 678
Congenital tumors, 858f–859f, 1025
Contrast agents, 3–4
Conus medullaris, hemangioblastoma of, 675f
Coronal T2-FSE, hydrocephalus, 915, 917
Corpus callosum, 642f
agenesis, interhemispheric cyst, 423, 424, 424f–428f, 424t
normal postnatal MR development of, 47, 48f–49f, 49
Cortical calcifications, 668
Cortical ependymomas, 807f
Cortical hyperechogenicity, 663
Cortical tumors, 815
angiocentric glioma, 822–823, 823f
desmoplastic infantile ganglioglioma (desmoplastic astrocytoma of infancy), 820–822, 821f
dysembryoplastic neuroepithelial tumor, 815–817, 816f, 817f
gangliocytomas, 817–820
gangliogliomas, 817–820, 819f, 820f
meningioangiomatosis, 823–824, 825f
papillary glioneuronal tumor, 823, 824f
Cowden syndrome, 535, 537, 538, 538f–540f, 691, 691f
CPC. See Choroid plexus carcinoma (CPC)
CPPs. See Choroid plexus papillomas (CPPs)
Cranial fontanelles, 50–51
Cranial manifestations, 646
Cranial nerve tumors, 645
Cranial neural crest cells, 633
Craniopharyngioma
differential diagnosis, 768
imaging studies, 768, 768f, 769f, 770f, 771f, 772f, 773f
pathology, 767
symptoms, 767
Craniosynostosis
abnormal fontanelle closure, 595
face and skull, embyrology of, 590, 592
inherited forms of, 596t–597t
nonsyndromic, 592, 592f–593f, 594
primary, 592
radiology of, 594, 594f, 595
syndromic, 595, 597, 598f–599f, 599, 600
CRASH syndrome, 933, 933f, 934f
Creatine deficiency syndromes, 159
Cree encephalitis, 1096
Cree leukoencephalopathy, 102
CSF. See Cerebrospinal fluid (CSF)
CT reversal sign, 332, 335f
Cushing disease, 782
Cutaneous adenomata sebaceum, 657
Cutaneous neurofibromas, 634
Cyanotic congenital heart disease, 1119, 1200f
Cyclic AMP (cAMP), 634
Cystathionine beta synthase deficiency, 109
Cystic adenomas, 770
Cystic astrocytomas, 728
Cystic encephalomalacia, 1086f
Cystic hygroma, 877f
Cystic hypothalamic hamartoma, 790f
Cystic lesions, 666
Cystic leukoencephalopathy without megaloencephaly, 124–125, 124f
Cystic pilocytic astrocytoma, 796f
Cytomegalovirus, 1073–1075, 1077, 1079–1080
D
Dandy-Walker complex, 532–535, 536f–538f
DAs. See Diffuse astrocytomas (DAs)
Default mode network (DMN), 73
Dehiscent septum pellucidum, 949
Dentatorubral atrophy, 230–231, 231f
Depigmented nevi, 657
Dermal sinuses, 751
Dermoids, 751–753, 756f, 757f, 770
and epidermoids, 984, 985f
idiopathic scoliosis imaging, 984, 985f
orbital, 871–872, 871t
pineal, 841
Desmoplastic astrocytoma of infancy. See Desmoplastic infantile ganglioglioma (DIG)
Desmoplastic infantile ganglioglioma (DIG), 820–822, 821f
Desmoplastic medulloblastoma, 721f
Desmoplastic SHH tumors, 720
Devastating metabolic diseases, newborn, 89
Developmental venous anomalies (DVAs), 1180–1181
Diabetes insipidus, 788
Diastematomyelia, 1014–1017, 1017f–1022f, 1019
Diencephalic tumor, 639f
Diencephalon, 408
Diffuse adenomas, 783
Diffuse astrocytomas (DAs), 728, 793, 795–797, 799f–800f
Diffuse cerebellar volume loss, 303
Diffuse intrinsic pontine gliomas (DIPGs), 726, 739, 740, 742, 743f, 744f
Diffuse leptomeningeal gliomatosis, 803, 805f
Diffuse macroadenomas, 784
Diffuse medullary tumors, 742
Diffuse midbrain tumors, 745, 747f
Diffuse necrotizing leukoencephalopathy, 121, 122f
Diffuse neonatal hemangiomatosis, 687
Diffuse neoplasms, 739
Diffuse retinoblastoma, 862, 862f
Diffusion tensor imaging (DTI), 10, 434, 710, 794, 917
Diffusion-weighted imaging (DWI), 5, 86, 705, 708, 713f
Diffusivity images, 63
DIG. See Desmoplastic infantile ganglioglioma (DIG)
Dihydropyrimidine dehydrogenase deficiency (DPD), 136, 138f
DIPGs. See Diffuse intrinsic pontine gliomas (DIPGs)
Diplomyelia. See Diastematomyelia
Direct carotid cavernous fistulas, 1203–1204
neuroimaging findings, 1204, 1207, 1208f
symptoms, 1204
treatment, 1207, 1209, 1209f
Discitis/osteomyelitis, 1160, 1160f–1161f, 1162f
Disconnection syndromes, 526, 528f
Discrete adenomas, 782
Discrete microadenoma, 783f
Disequilibrium syndrome, 471
Disjunction disorders, 977
DNA methylation, 731
DNET. See Dysembryoplastic neuroepithelial tumor (DNET)
Dorsal dermal sinuses, 987–989, 987f–989f
Dorsal medulla, hemangioblastoma of, 750f
Dorsal meningocele
complex, 1023
simple, 1022–1023
Dorsal prosencephalon development
anterior commissure, 408
callosal anomalies
anatomic sequelae, 421, 422f, 722–423
imaging of, 423
interhemispheric cyst, 423, 424, 424f–428f, 424t
cavum septi pellucidi, 411, 411f
cavum Vergae, 412
cerebral commissures
anatomy and embryology, 408–412, 408f–411f
callosal agenesis/dysgenesis in fetus, 424, 425, 429f–431f
hemispheric anomalies and syndromes, 414, 417, 418f–421f, 419, 421, 422t
incidence of, 408
spectrum of abnormalities of, 412, 412f, 413f–417f
corpus callosum, 408, 409
fasciculation, 409
glial sling, 409, 410f, 411f
glial wedge, 411f
hippocampal commissure, 408
indusium griseum glia, 411f
lamina reuniens/commissural plate, 409, 410f
malformations of cerebral cortical development, 425–428, 432f
midline glial zipper, 409, 410f, 411f
Dorsally exophytic medullary glioma, 739f, 742
Double inversion recovery, 142
Down syndrome, 600, 602, 603
Downward brain herniation, 964
Drop metastases, 715
DTI. See Diffusion tensor imaging (DTI)
Dural ectasia, 649, 649f
Dynamic cardiac-gated cine phase-contrast imaging, 917
Dynamic perfusion imaging, 142
Dynamic susceptibility contrast (DSC), 12, 705
Dynamic T1 perfusion, 705
Dysembryoplastic neuroepithelial tumor (DNET), 715, 793, 815–817, 816f, 817f, 818f
Dysembryoplastic tumors, 751–754, 753f, 754f
enteric (enterogenous) cysts, 753–754, 758f
imaging studies, 752–753, 753f–754f
pathology, 751–752
Dysontogenic tumors, 767
Dysplasia
of cerebral vasculature, 644
focal cortical, 711
neuroectodermal, 678
of sphenoid, 646f
sphenoid bone, 646
vascular, 644–645, 645f, 646f
Dysplastic cerebellar gangliocytoma, 817
Dysplastic megalencephaly, 450
Dysplastic neurons, 817
E
Ecchordosis physaliphora, 761, 761f–762f
ECCL. See Encephalocraniocutaneous lipomatosis (ECCL)
Echinococcus, 1151, 1152f
Echo times, 58
Ectasia, dural, 649, 649f
Edema and parenchymal injury, cortex, 379
Edwards syndrome. See Trisomy 18
Effusions/empyemas, meningitis, 1100, 1100f–1102f
Embolization (neurovascular), 1180t
Embryology
brain development, 406, 407f
cerebral cortex
development, 426–428, 430–431, 432f
GABAergic neurons, 428, 431f
ganglionic eminences, 426
glutamatergic neurons, 426, 428
pallial/dorsal germinal zone, 426
radial glial cells, 427
subpallium, 426
subventricular zone, 427
ventricular zone, 426
congenital brain/skull malformations, 405–406
dorsal prosencephalon development, 408–412, 408f–411f
eye anomalies, hypothalamic-pituitary axis, 509–510, 510f
of normal prenatal brain development, 18–19, 20f
spinal formation, anomalies of, 977
split cord malformation (SCM), 1015, 1016
split notochord syndrome, 1011
Embryonal carcinomas, 778
Embryonal tumor, 703, 793, 807
Embryonal tumor with multilayered rosettes (ETMRs), 725–726, 727f, 807
Encephalitis, immune-mediated, 1148
Encephaloclastic porencephalies, 263
Encephalocraniocutaneous lipomatosis (ECCL)
clinical manifestations, 689
neuroimaging manifestations, 689–690, 690f
Encephalomalacia, 265–266, 267f–269f
Encephalomyelitis
acute disseminated, 144–147, 146f
acute hemorrhagic, 147
Encephalopathy
acute necrotizing encephalitis, 210–211, 213f, 214, 214f
bilirubin, 340, 341f, 342
influenza virus, 1141–1142
metabolic disorders, 90
mitochondrial disorders, 127
neurometabolic diseases, 90
Wernicke, 160–161, 161f
Encephalotrigeminal angiomatosis, 667
Endoderm, 52
Endodermal cysts. See Enteric cysts
Endodermal sinus tumors, 778
Endolymphatic sac, papillary cystadenomas of, 674–675, 676f
Endoscopic third ventriculostomy (ETV), 954, 956, 957f, 958f
Enteric cysts, 753–754, 758f
Enterobacter sakazakii, 1097
Enterogenous cysts. See Enteric cysts
Enteroviruses infection, 1131f, 1137f, 1139–1140, 1139f, 1143–1145, 1144f
Enzyme deficiency, homocystinuria, 109
Ependyma, 831, 910
Ependymoblastoma, 731
Ependymomas, 655, 720, 729–730, 830, 849
imaging studies, 734f, 735f, 736f, 737
lateral-type, 735f, 737
midfloor-type, 734f, 737
pathology, 730–732, 735
proton MR spectroscopy, 737
rare roof-type, 736f, 737
spinal cord, 1046f–1047f, 1047
supratentorial, 793, 803–807, 850f
thalamic, 830f
Epiblast, 52
Epidermal nevus syndrome
clinical manifestations, 688–689
neuroimaging findings in, 689t
ocular and brain manifestations, 670f, 689
Epidermoids, 751–753, 753f, 770, 871–872
pineal, 841
Epidural hematomas, 362–365, 363f–365f
Epilepsy, 787
and pediatric stroke, 270
progressive, mental retardation, 166
syndromes, polymicrogyria, 489
Epilepsy-associated tumors. See Primarily cortical tumors
Epileptogenic tubers, 665
Epistaxis/juvenile angiofibroma, 1202, 1202f, 1203
Epithelial cysts. See Enteric cysts
Epstein-Barr virus, 815, 1130, 1136, 1138
Errors affecting cobalamin (vitamin B12) metabolism, 109–110
Escherichia coli, 1097, 1104f, 1106f
Ethmoid sinuses, 51
ETMRs. See Embryonal tumor with multilayered rosettes (ETMRs)
Ewing sarcoma, 765, 1056, 1057f
Exophytic medullary glioma, 739f, 742
Extensive encephalomalacia, 269f
Extra-axial tumors
extramedullary hematopoiesis, 856
infantile myofibromatosis, 853
leukemia and lymphoma, 853–854, 854f, 855f
tumors of meninges, 852–853
Extradural vascular malformations/neoplasms
epistaxis/juvenile angiofibroma, 1202, 1202f, 1203
facial arteriovenous malformation, 1201, 1201f
hemangiomas, 1198–1199, 1200f
venous and lymphatic malformations, 1199–1201
Extramedullary hematopoiesis, 856, 1066, 1068, 1068f
Extramedullary neoplasms, spinal tumor
cerebrospinal fluid dissemination, 1050–1051, 1050f, 1051f
epidural space, tumor invasion
extramedullary hematopoiesis, 1066, 1068, 1068f
ganglioneuroblastoma, 1064
ganglioneuroma, 1063f, 1064
infantile hemangioma, 1065, 1066, 1068f
leukemia and lymphoma, 1064, 1065f, 1066f
neuroblastoma, 1062–1064, 1063f
peripheral primitive neuroectodermal tumors, 1065, 1067f
soft tissue sarcomas, 1065, 1067f
meningeal tumors
meningeal cyst, 1058, 1060, 1060f
meningiomas, 1057, 1058, 1059f
nerve roots and nerve root sheaths, 1061, 1061f
spinal column tumors
aneurysmal bone cysts, 1051, 1052, 1052f
chordomas, 1056, 1056f
Ewing sarcoma, 1056, 1057f
giant cell tumor, 1054, 1055f
Langerhans cell histiocytosis, 1052, 1053f–1054f, 1054, 1054f
osteoblastoma, 1056, 1057, 1058f
osteogenic sarcoma, 1054, 1055
vertebral tumors, 1057
Extraocular orbital masses, 864
hematogenous and neoplastic, 869–871, 870f, 871f
orbital cysts, 868–869
vascular masses, 864
hemangioma, 865
venolymphatic malformations, 865–868, 866f
Extraosseous Ewing sarcomas, 853
Extraparenchymal hematomas, general concepts of, 362–365, 363–365f
Extraparenchymal lesions, 707, 708f
Extraparenchymal tumors
in children, 717t
dysembryoplastic tumors, 751–754, 753f, 754f, 758f
miscellaneous tumors, 757–765
schwannomas, 751, 752f
teratomas, 754–757, 758f–759f
Extraventricular obstructive hydrocephalus, 939, 941f
Eye anomalies
embryology, 514, 516, 516f
ocular, 516–521, 517f–521f
F
Fabry disease, 90
Facial arteriovenous malformation, 1201, 1201f
Facial dysmorphism, 494
Facial hemiatrophy, 688, 688f
Facial nevus flammeus, 667, 668
Facial plexiform neurofibromas, 635
Facial teratoma, 883f
Falx cerebri, 683
Falx laceration, 353, 354
Fasciculation, 409
“Fast” MR scanning, 917
Fast spin-echo (FSE), 5
Fat saturation techniques, 707
Fat-suppression techniques, 637
FCD. See Focal cortical dysplasia (FCD)
FCMD. See Fukuyama congenital muscular dystrophy phenotype (FCMD)
Fetal alcohol syndrome, 417
Fetal brain disruption sequence, 1097
Fetal hydrocephalus
imaging, 949–952, 950f, 951f
myelomeningocele–Chiari II malformation, 952, 952f
pathophysiologic considerations, 948–949
Fetal MRI, 425
Fetal ultrasound, 424
Fibrillary astrocytes, 795
Fibrillary glioma, 641f
Fibrolipomas and cysts, filum terminale, 1002
Fibromatosis colli, 360, 889, 891f
Fibrous dysplasia, of skull base, 889, 891f, 892f
Fistula, 751
Fluid-attenuated inversion recovery (FLAIR), 86, 274, 637
Focal cerebellar injury, 303
Focal cortical dysplasia (FCD), 441–442, 662, 711
Focal lesions, 644
Focal medullary tumors, 741f, 742
Focal midbrain tumors, 745, 748f
Focal neoplasms, 741
Focal pontine tumors, 745, 746f
Focal subcortical heterotopia, 458–460, 459f–462f
Focal tumors, 741, 742
Fontanelle, closure of, 50–51
Fontanelle dermoids, 577–579, 578f
Foregut cysts. See Enteric cysts
Fractional anisotropy (FA), 11
Fragile X syndrome, 606
Friedreich ataxia, 222–223, 223f
Frontal sinuses, 51
Frontal white matter
diffusion imaging of, 63, 65f
proton spectra of, 58f, 60f
Frontoethmoidal cephaloceles, 565, 566f–567f, 568–570, 571f
Fucosidosis, 135–136, 135f
Fukuyama congenital muscular dystrophy phenotype (FCMD), 475–476, 478f
Functional MRI (fMRI), 13–14, 71–74, 73f–74f
Fungal abscesses, 1125, 1148
Fungal infections
of CNS, 1148t
aspergillosis, 1149f, 1150
coccidioidosis, 1150
cryptococcosus, 1151
neonatal candidiasis, 1148–1149, 1150f
Coccidioides immitis, 1148
Cryptococcus neoformans, 1148
Histoplasma capsulatum, 1148
G
Gadolinium-based contrast agents (GBCAs), 705
Gait disorder, 91
Galactosemia, 126–127, 126f
Gangliocytomas, 817–820
Gangliogliomas (GGGs), 793, 816–820, 818f, 819f, 820f
desmoplastic infantile, 820–822, 821f
suprasellar optic, 775
Ganglioneuroblastoma, 1064
Ganglionic eminence, 18, 269
Gastrulation/neurulation
intercalation, 973
neural plate, 973
normal and abnormal, 975f
posterior neuropore, 974
primitive neurenteric canal, 973
primitive streak, 973
GBM. See Glioblastoma multiforme (GBM)
GCTs. See Germ cell tumors (GCTs)
Germ cell tumors (GCTs), 725, 793
of basal ganglia, 830–831
suprasellar, 777–778, 778–782, 779f, 780f, 781f, 782f
Germinal matrix hemorrhage, 289, 289t, 295, 295f
Germinoma, 777, 778, 780, 780f, 781f
Germinoma of basal ganglia, 832, 833f
Germ-line mutation, 634
Gestation, brain development
24 and 30 weeks, 23
20 to 24 weeks, 22, 22f
31 to 32 weeks, 28
34 to 36 weeks, 28
38 to 40 weeks, 30
20 weeks, 20
GGGs. See Gangliogliomas (GGGs)
Giant axonal neuropathy, 103–104, 105f
Giant cell astrocytomas, 844
Giant cell tumor, 1054, 1055f
Giant cystic craniopharyngioma, 772f
Gigantism, 782
Glial fibrillary acidic protein (GFAP) expression, 772
Glial tumor, intraparenchymal, 711f, 712f
Glioblastic elements, tumors with, 807
Glioblastoma multiforme (GBM), 703, 801f–802f
Glioma, 639–642
angiocentric, 822–823, 823f
brainstem, 641
grade 2 (fibrillary), 641f
tectal, 641
unilateral high-grade, 827
Gliomatosis cerebri, 803, 804f
Gliomatosis, diffuse leptomeningeal, 803, 805f
Glioneuronal heterotopia, 813–814, 814f
Glioneuronal tumors, 793
Globoid cell leukodystrophy, 92, 93f, 94, 95f
Glutamate spectra, 58
Glutamine spectra, 57
Glymphatics, 911
Gomez-Lopez-Hernandez syndrome, 532
Gonadotropin-releasing hormone (GnRH), 787
Grade 2 (fibrillary) glioma, 641f
Gradient echo images, 375f
Gradient-recalled echo (GRE), 5
Gram negative bacillus Bartonella henselae, 1126
Granule cell, 677
Granulocytic sarcomas, 869
Granulomas, plasma cell, 814–815
Granulomatosis, larval, 863f
Gray matter metabolic disease/disorders
Aicardi-Goutières syndrome, 125, 125f
aspartylglucosaminuria, 166
β-ketothiolase deficiency, 160, 161f
carbon monoxide poisoning, 169, 169f
chronic liver disease, 164
creatine deficiency syndromes, 159, 160, 160f
cyanide poisoning, 169, 170f
hemolytic–uremic syndrome, 161–162, 162f
hypoplastic basal ganglia, 164
infantile beriberi/Wernicke encephalopathy, 160–161, 161f
infantile neuroaxonal dystrophy/NBIA2A/PLAN, 167, 167f
isovaleric acidemia, 158, 158f
juvenile Huntington disease, 155, 156, 158, 158f
neurodegeneration with brain iron accumulation, 153
neuronal ceroid lipofuscinosis, 164, 164t, 165f–166f, 166
Niemann-Pick disease, 167–168, 168f
pantothenate kinase–associated neuropathy, 154–155, 154f, 155f, 156t, 157t
progressive cerebral poliodystrophy, 169
Rett syndrome, 168, 169f
succinate semialdehyde dehydrogenase deficiency, 159, 159f
Sydenham chorea, 162, 163f, 164
toxins, 169, 169f, 170f
trichopoliodystrophy, 169
Wernicke’s encephalopathy, 160–161, 161f
Growth hormone-secreting adenomas (GRH), 782
Guanidinoacetate methyltransferase (GAMT) deficiency, 157t, 159
Guillain-Barré syndrome, 1092
Gyral development of brain, 19
H
Haemophilus influenzae, 1097, 1098t, 1100f
Hallervorden-Spatz disease, 154–155, 154f, 155f, 156t, 157t
Hamartoma. See also Cerebral tubers
cerebellar, 668f
congenital spine tumor, 1028f, 1029
hypothalamic, 642f, 787–788, 788f, 789f, 790f
neuroglial, 813–814, 814f
retinal, 658, 658f
in tuberous sclerosis complex, 659f
Hamartomatous, 641, 641f
HARD syndrome, 948
Head and neck tumor, 859–860
aggressive tumors, 884–885
juvenile angiofibromas, 888, 889f, 890f
melanotic neuroectodermal tumors of infancy, 888
nasopharyngeal carcinoma, 885–888
rhabdomyosarcoma, 884–885, 884f
cervical lymphadenitis, 888
congenital embryonal cysts
branchial cleft cysts, 872–874, 874f–875f
thymic cysts, 874–875
thyroglossal duct cysts, 872, 873f, 874f
extraocular orbital masses
hematogenous and neoplastic, 869–871, 870f, 871f
orbital cysts, 868–869
vascular masses, 864–868, 866f
fibromatosis colli, 889, 891f
fibrous dysplasia of skull base, 889, 891f
neuroblastoma, 889
ocular tumors
differential diagnosis, 862–864, 863f–865f
retinoblastoma, 860–862, 861f
vascular malformations
infantile and congenital hemangiomas, 881f, 879–880, 880f
venolymphatic malformations, 864, 875–878, 876f–879f
Head injury, 373. See also Brain injuries
Hemangioblastomas, 674, 715, 748–749
cerebellar, 673f, 674
of conus medullaris, 675f
imaging studies, 749, 750f, 751
pathology, 749
Hemangiomas, 865
cavernous, 865–868
congenital, 879–880
dermoids and epidermoids, 871–872
extradural vascular malformations/neoplasms, 1198–1199, 1200f
infantile, 879–880, 880f, 881f
orbital, 866f
orbital cysts, 868–869
plexiform neurofibromas, 869
venolymphatic malformations, 865–868, 866f
Hemangiomatosis, diffuse neonatal, 687
Hematological abnormalities, 89
Hematopoiesis, extramedullary, 856
Hemiatrophy, progressive facial, 688, 688f
Hemimegalencephaly (HME), 448–451, 450f–453f
septum, 419
Hemispheric astrocytoma, 730f
Hemispheric atypical teratoid/rhabdoid tumor, 810–812, 811f, 812f
Hemispheric medulloepithelioma, 809–810, 810f
Hemispheric primitive neuroectodermal tumor, 807–809, 808f, 809f
Hemispheric tumors, 793–794
astroblastoma, 812–813, 813f
cerebral, 795t
central gray matter tumor
bilateral thalamic LGGs, 827, 828f, 829, 829f
ependymomas, 830
germ cell tumors of basal ganglia, 830–831
thalamic oligodendrogliomas, 829
thalamus and basal ganglia, 824–829
diffuse astrocytoma, 795–797
embryonal tumors, 807–813, 808f–813f
gliomatosis cerebri, 803, 804f
hemispheric atypical teratoid/rhabdoid tumor, 810–812, 811f, 812f
hemispheric medulloepithelioma, 809–810, 810f
hemispheric primitive neuroectodermal tumor, 807–809, 808f, 809f
high-grade astrocytomas, 797–803
lymphoproliferative disorders, 815
neuroglial hamartomas (glioneuronal heterotopia), 813–814, 814f
pilocytic astrocytoma, 794–795, 796f–797f, 798f
plasma cell granulomas (inflammatory pseudotumors), 814–815
primarily cortical tumors, 815
angiocentric glioma, 822–823, 823f
desmoplastic infantile ganglioglioma (desmoplastic astrocytoma of infancy), 820–822, 821f
dysembryoplastic neuroepithelial tumor, 815–817, 816f, 817f
gangliocytomas/gangliogliomas, 817–820, 819f, 820f
meningioangiomatosis, 823–824, 825f
papillary glioneuronal tumor, 823, 824f
pleomorphic xanthoastrocytomas, 821–822, 822f
supratentorial ependymomas, 803–807, 806f
Hemolytic–uremic syndrome (HUS), 161–162, 162f
Hemorrhage, 715
subretinal, 862
Hemorrhagic adenomas, 770
Hemorrhagic microadenoma, 784f, 785f
Hemorrhagic vasculopathy, 115
Hensen node, 52, 406, 973–975, 974f, 1011
Hereditary hemorrhagic telangiectasia, 1233
Hereditary spastic paraplegias (HSP), 111, 113, 113f
Herniation, 930
transtentorial, 707
Herpes simplex encephalitis (HSE), 1132f, 1133–1134, 1134f–1135f, 1136
limbic system, 1133
Herpes simplex virus (HSV), 1080–1082, 1081f–1085f, 1081t–1082t
Heterogeneous chiasmatic/hypothalamic PMA, 779f
Heterotopia, 711
band, 466, 470f
focal subcortical, 458–460, 459f–462f
glioneuronal, 813–814, 814f
periventricular, 452–458, 457f–459f
HHs. See Hypothalamic hamartomas (HHs)
Histiocytic disorders, 758–759
Histoplasma capsulatum, 1148
Holoprosencephaly
alobar, 495, 495f–498f
causes, 494
classic, 412, 495
clinical presentation, 494
embryogenesis, 494
familial cases, 494
lobar, 497–498, 502f
middle interhemispheric variant of, 412
in mild cases, 494
semilobar, 495–497, 499f–501f
in severe cases, 494
sonic hedgehog gene, 494
subcategory, 494
syntelencephaly, 498, 500, 503f–505f
Homogeneous chiasmatic/hypothalamic glioma, 778f
Homogeneous primitive neuroectodermal tumor, 808f
Horizontal gaze palsy with progressive scoliosis (HGPPS), 542, 546f
Höyeraal-Hreidarsson syndrome, 235
Human herpes virus-6 (HHV-6), 1138, 1138f
Human immunodeficiency virus (HIV) infection
chronic encephalitis, 1143t
congenital infections, 1093–1095, 1095f
recovery of NAA in, 57
Hydrocephalus, 844, 847
communicating, 907
CSF and CSF spaces
anatomy, 908–909
development, 909–910
dynamics and related disorders, 912–914, 912f, 913f, 913t, 914f
secretion and absorption, 910–911
volume, 907–908
diagnosis
clinical presentation, 914–915, 915t
CT scanning, 919, 920, 920f
etiopathogenic contexts, 931–952
extracerebral spaces, 928–929, 929f
imaging features of, 921–931, 921t, 922f–931f
magnetic resonance imaging (MRI), 915, 916f, 917–919, 918f–920f
parenchymal changes, 929–931, 930f, 931f
ultrasonography (US), 920–921
ventricular system, 921, 922f–929f, 923, 925–927
fetal
imaging, 949–952, 950f, 951f
myelomeningocele–Chiari II malformation, 952, 952f
pathophysiologic considerations, 948–949
hyperacute
hydrocephalus, 915
malformative, 933–934
mild, 949
moderate, 949
nature of, 907
neurocutaneous melanosis with, 680
nonobstructive
acute nonobstructive, 944–945, 947–948, 947f–948f
chronic nonobstructive, 941–944, 942f, 944f–947f
pathophysiologic considerations, 940–941
venous hypertension, 941–944, 942f, 944f–947f
obstructive, 907
acute ventricular, 934–936, 936f–940f, 939
aqueductal stenosis, 932–933, 933f, 934f
extraventricular, 939, 941f
malformative hydrocephalus, 933–934
severe, 949
treatment
clinical data, 952–953
complications of shunts, 958–961, 961f–966f, 963–964, 966
craniocerebral disproportion, 963–964, 965f, 966f
early follow-up, 954, 955f, 956
endoscopic third ventriculostomy (ETV), 954, 956, 957f, 958f
functional assessment, 956–958, 957f–960f
intracranial hypotension, 963–964, 965f, 966f
rare CSF diversion techniques, 954
therapeutic goals and options, 953–954
ventriculoperitoneal shunts, 953–954
Hydromyelia, 983f, 984f, 985
Hygroma, cystic, 877f
Hyperechogenicity, cortical, 663
Hyperhomocysteinemia, 109–110, 109f
Hyperlipoproteinemia, 271t
Hypernatremic dehydration, 342
Hyperplasia, choroid plexus villous, 847–849, 850f
Hypertonia, 91
Hypertrophy, 847
Hypervascular nidus, 751
Hypoblast, 52
Hypoglycemia, 338–340, 339f–340f
Hypomelanosis of Ito, clinical manifestations, 681–682
Hypomyelinating leukodystrophies 2 (HLD2), 130
Hypomyelinating leukoencephalopathy (HLD), 127, 128f–129f, 130
Hypomyelination, 84t, 85t, 88, 131–132
Hypomyelination with atrophy of the basal ganglia/cerebellum (HABC), 84t, 85t, 131–132
Hypophysitis, lymphocytic, 791f, 793
Hypotension-caused brain injury
mild-moderate (premature infant), 310
mild-moderate (term infant), 324
profound, 307
profound (premature infant), 310
profound (term infant), 304
severity, 284–285
Hypothalamic adhesions, 514, 515f
Hypothalamic gliomas, 769
Hypothalamic hamartomas (HHs), 641, 642f, 710, 787–788, 788f, 789f, 790f
Hypothalamic lesions, 766t
Hypothalamic–pituitary dysfunction, 7932
Hypothalamus, 641, 766
Hypotonia, 91
Hypoxic–ischemic–inflammatory injury
localized infarctions
imaging arterial appearance, 272, 272f–273f, 274, 274f–277f, 276, 277
manifestations/causes, 267, 270–271, 270t, 271t
radiologic choices, 271–272
secondary to venous occlusion, 272–282, 279f–282f
older children, imaging choices, 331–332, 332f–336f
patterns of, 315t
premature infants
brain injury, 287, 289t
cerebellar injury, 295
image findings, 290f–294f, 295–298, 296f–297f, 299f–301f, 302–305, 303f–307f, 307
morphological effects, 288
neurologic sequelae of, 288
preterm birth, imaging sequelae of, 287
profound hypotension/circulatory arrest, 304–305, 305f–307f, 307, 310t
term infants
mild-moderate hypotension, 285, 285f, 286f
parasagittal/watershed injury, 310–312, 310f–315f, 315
parenchymal/intraventricular hemorrhage, 326, 328, 329, 329f, 330f–331f
profound hypotension, 315–317, 318f–327f, 324
I
Idiopathic syringomyelia, 1031, 1035
Immature teratomas, 778, 782, 837
Immune-mediated encephalitis, 1148
Inborn errors of metabolism, 81, 82t–83t, 90
Incontinentia pigmenti
clinical manifestations, 681
neurological manifestations, 682
neuropathological and neuroimaging manifestations, 682–683
pathological and neuroimaging manifestations, 681, 682f
Infantile benign idiopathic external hydrocephalus, 943
Infantile ganglioglioma, desmoplastic, 820–822, 821f
Infantile hemangiomas, 879–880, 880f, 881f, 1065, 1066, 1068f
Infantile myofibromatosis, 853
Infantile neuroaxonal dystrophy, 88, 167, 167f, 226
Infarctions, 373
Infections of CNS
bacterial/spirochetal/rickettsial infections
bacterial cerebritis, 1119, 1120f, 1121f
brain abscess, 1119, 1120f–1121f, 1121–1126, 1122t, 1123f, 1124f
bacterial meningitis, 1097–1098
cat-scratch disease, 1126–1127
Lyme disease, 1127–1128, 1128f
Rocky mountain spotted fever, 1128–1129
cerebellitis, 1137f, 1145
congenital and perinatal
acquired immune deficiency syndrome (AIDS), 1093–1095, 1095f
cytomegalovirus, 1073–1075, 1074f–1080f, 1077, 1079–1080
general concepts, 1072–1073
herpes simplex virus, 1080–1082, 1081f–1085f
human parvovirus B19 infection, 1096
infection transmission pathway, 1073t
infectious pathogens transmission pathway, 1073
lymphocytic choriomeningitis virus infection (LCVM), 1082, 1083, 1085, 1087f
mimicking congenital infections, 1096–1097, 1097f
parechovirus, 1093, 1094f
rubella, 1085, 1088, 1088f
Toxoplasma gondii, 1089, 1090f, 1091
Treponema pallidum (syphilis), 1089
tuberous sclerosis complex (TSC), differentiation from, 1097
varicella-zoster virus, 1091
zika virus, 1092, 1092f, 1093f
Dengue virus, 1140
fungal
aspergillosis, 1149f, 1150
coccidioidosis, 1150
cryptococcosus, 1151
neonatal candidiasis, 1148–1149, 1150f
immune-mediated encephalitis, 1148
intracranial empyema, 1103f, 1117, 1119
parainfectious leukoencephalopathies, 1148
protozoan/parasitic
cerebral malaria, 1157
cerebral toxocaral disease, 1153, 1157, 1157f
neurocysticercosis, 1115f, 1116f, 1151–1153, 1154f–1156f
visceral larva migrans, 1157f
Rasmussen encephalitis, 1146, 1146f, 1147f, 1148
sarcoidosis, 1157–1158, 1158t, 1159f
spinal infections/inflammation
cord dysfunction, 1164, 1165f
discitis/osteomyelitis, 1160, 1160f–1161f, 1162f
empyemas, 1160–1162, 1163f, 1164f
viral
arthropod-borne viruses, 1139f, 1140–1141
chronic viral infections, 1131f, 1143–1145, 1143t, 1144f
Epstein-Barr virus, 1136, 1138
general concepts, 1129–1130, 1130t, 1131f, 1132
herpes simplex encephalitis, 1132f, 1133–1134, 1134f–1135f, 1136
herpesvirus, 1132–1138, 1133t, 1134f–1135f, 1137f, 1138f
human herpes virus-6 (HHV-6), 1138, 1138f
influenza virus, 1141–1142, 1142f
Nipah virus, 1129t, 1143
non-polio enteroviruses, 1139–1140, 1139f
rabies, 1142–1143
varicella zoster virus, 1136, 1137f
Infiltrative tumors, 709–710
Inflammatory lesions, 713, 872
Inflammatory pseudotumors, 814–815
Influenza virus, 1142
Infratemporal rhabdomyosarcoma, 886f
Infravermian arachnoid cyst, 755f
Infravermian epidermoid tumor, 754f
Infundibulum, 766
Interhemispheric lipomas, 582
Intermediate zone, 19, 21, 22f, 23f, 70
Interpeduncular cistern, 767
Intersegmental laminar fusion, 1017
Intervertebral disc degeneration, 362
Intervertebral disc herniations, in children, 361–362
Intracerebral vascular malformations
arteriovenous fistulas
direct carotid cavernous fistulas, 1203–1204, 1207, 1208f, 1209, 1209f
intracranial dural, 1203, 1204f
vertebral fistulas, 1209–1210, 1210f
capillary telangiectasias, 1197, 1199f
cavernous malformations, 1196–1197, 1198f
vein of Galen
clinical presentation and imaging findings, 1188, 1188f–1189f, 1190, 1190f–1195f, 1192
definition and causes, 1186, 1188
treatment, 1192–1194, 1195f–1196f, 1196
venous malformations, 1197
Intracranial aneurysms. See also Brain tumors: Cerebellar atrophy
adrenoleukodystrophy (ALD), 97, 97f
agenesis of corpus callosum with interhemispheric cyst (ACC/IHC), 423, 424, 424t
Aicardi syndrome, 417, 584, 1096
Alexander disease
infantile, 84, 87, 173f
juvenile form, 174f
Alpers disease, 169
angiomatosis
encephalotrigeminal, 667
leptomeningeal, 672f
meningofacial, 667
arachnoid cysts, 771
Ataxia–telangiectasia (AT), 223
back pain, 361–362, 1029, 1160
epilepsy, 787
Fabry disease, 90
Guillain-Barré syndrome, 1092
mycotic, 1215, 1215f
saccular, 1211–1213, 1213f–1214f, 1213t
traumatic, 1215–1216, 1216f
Intracranial arteriopathy, 666–667
Intracranial dural arteriovenous fistulas, 1203, 1204f
Intracranial empyemas, 1103f, 1117, 1119
Intracranial ependymomas, 730
Intracranial hemorrhage, newborn, 350–351
Intracranial lipomas, 581–583, 582f–586f
Intracranial subarachnoid tumor, 718
Intracranial teratomas, 754
Intramedullary arteriovenous malformations
glomus type, 1217
juvenile type, 1218
Intramedullary masses, 1043
Intramedullary neoplasms, spinal tumors
clinical presentation, 1043–1044
imaging, 1045, 1045f–1049f, 1047–1048
pathology, 1044–1045
root pain, 1044
spinal pain, 1044
tract pain, 1044
Intramedullary tumors, 647–649
Intraneural form, 636–637
Intraorbital optic nerves, tumors of, 637
Intraparenchymal glial tumor, 711f, 712f
Intraparenchymal masses, 707, 708f
Intrasellar craniopharyngiomas, 768
Intraspinal neurofibromas, 651f
Intraventricular cysticercosis, 1152, 1152t, 1153, 1155f–1156f
Intraventricular hemorrhage, 292f, 295–296, 296f, 350
Intraventricular primitive neuroectodermal tumor, 809f
Intrinsic meningeal tumors, 852
Intrinsic spinal cord tumors, 654
Invasive adenoma, 786f
Ionizing radiation, 634t
IP achromians. See Hypomelanosis of Ito
Ipsilateral cerebral hemisphere, 671
Ischemic perinatal stroke (IPS), 270
Isolated fourth ventricle, 926
Isosexual precocious puberty, 787
Isotretinoin, 1097
Isovaleric acidemia, 158, 158f, 271t
J
Joubert syndrome, 540–542, 541t, 543f–545f
JPAs. See Juvenile pilocytic astrocytomas (JPAs)
Juvenile angiofibromas, 888, 889f, 890f
Juvenile Huntington disease, 155, 156, 158, 158f
Juvenile pilocytic astrocytomas (JPAs), 725–728 729f
with central necrosis, 732f
large cystic, 731f
Juxtaventricular LGGs, 826
K
Kallmann syndrome, 513, 514f, 766
Keratocystic odontogenic tumors (KOTs), 683
Kleeblattshädel, 597
Klippel-Feil anomaly, 1017
Knobloch syndrome, 563
KOTs. See Keratocystic odontogenic tumors (KOTs)
Krabbe disease, 92, 93f, 94, 95f
Kyphoscoliosis, 1017, 1019f–1021f
L
Lactate, 57, 331
Langerhans cell histiocytosis (LCH), 232–233, 233f, 758–759, 788–789, 791f, 854–856, 855f, 856f, 869
bone involvement in face and head, 759, 759f, 760f
involvement of brain, 759–761, 761f
Large perivascular spaces, 45f, 46
Larval granulomatosis, 863f
LCH. See Langerhans cell histiocytosis (LCH)
Learning disability, defined, 635
Lemniscus, lateral, 35
Lemniscus, medial, 35
Leptomeningeal angiomatosis, 672f
Leptomeningeal gliomatosis, diffuse, 803, 805f
Leptomeningeal metastasis, 706
Lesions. See specific types of lesions
Leukemia, 853–854, 854f, 855f, 859, 869
chloromas, 1064
Leukocoria, 863
causes of, 860t
Lhermitte-Duclos disease/Cowden syndrome, 535, 537, 538, 538f–540f
Lhermitte-Duclos syndrome, 817
LH-releasing hormone (LHRH). See Gonadotropin-releasing hormone (GnRH)
Lipoma with dorsal defect
clinical presentation, 996
imaging characteristics
lipomyeloceles, 996, 997f
lipomyelomeningoceles, 996, 999f, 1000f
terminal lipoma, 996, 1001f
malformations, 998
Lipomas
curvilinear, 583
interhemispheric, 582
intracranial, 581–583, 582f–586f
Lisch nodules, 634
Lissencephaly
abnormal neuronal migration, 462t
actins, 461
agyria, 460, 461
with ARX mutations, 467–470, 471f
band heterotopia, 466, 470f
with central predominance, 466, 467, 468f
with cerebellar hypoplasia, 467, 468f
classic, 462, 462f, 463, 463t
imaging studies, 464, 464f, 465f
incomplete, 466
microtubule-associated proteins, 461
microtubules, 461
pachygyria, 460, 461
reelin signaling pathway, 470, 471, 473f
Listeria monocytogenes, 1097, 1098t
Liver disease, 164
Lobar holoprosencephaly, 497–498, 502f
Lowe syndrome, 110–111, 112f
Low grade gliomas (LGGs), thalamic, 827, 827f, 828f
bilateral, 827, 828f, 829, 829f
inferior, 826
juxtaventricular, 826
lateral, 827
unilateral, 825–826
Low grade gliomas of basal ganglia (LGGBG), 825
Low-grade epilepsy-associated neuroepithelial tumors (LEAT), 815
Lumboperitoneal shunts, 953
Lupus erythematosus, 147–149, 148f, 149f
Lyme disease, 1127, 1128
Lymphadenitis, cervical, 888
Lymphangioleiomyomatosis, 667
Lymphangiomas, 865–868, 866f
Lymphatic malformations, 865–868, 866f
Lymphocytic choriomeningitis virus infection (LCVM), 1082, 1083, 1085, 1087f
Lymphocytic hypophysitis, 791f, 793
Lymphoma, 853–854
Lymphoproliferative disorders, 815
Lysosomes
aspartylglucosaminuria and, 166
GM1/GM2 gangliosidosis and, 207
Krabbe disease and, 92, 93f, 94
metabolic disorders, 88–89
mucolipidosis type IV and, 111
mucopolysaccharidoses and, 174
and pediatric stroke, 271t
M
Macroadenomas, 785f
diffuse, 784
invasive, 783
Macrophthalmia, 520, 521f
Magnetic resonance imaging (MRI)
brain, anatomic imaging, 5–7, 5t
fetal hydrocephalic brain, 918, 919
fetal MRI, 9–10
immature hydrocephalic brain, 917–918, 920f
mature hydrocephalic brain, 915, 916f, 917, 918f–919f
microstructural/physiologic/metabolic imaging
CSF, 12
diffusion, 10–11
functional MRI, 13–14
magnetization transfer, 12–13
perfusion, 11–12
spectroscopy, 13
neurography, 10
of normal postnatal corpus callosum, 47, 48f–49f, 50
of normal postnatal 4-month-old infant, 37f
of normal postnatal 6-month-old infant, 36, 38f–39f
of normal postnatal 8-month-old infant, 36, 40f–41f
of normal postnatal 12-month-old infant, 38, 42f
of normal postnatal 15-month-old infant, 39, 43f
of normal postnatal 22-month-old infant, 42, 44f
PROPELLER, 10
spine, anatomic imaging, 8–9
vascular imaging, 7–8
Magnetization transfer (MT)
of acute inflammation, 86
contrast, 12–13
quantify, 71
techniques, 142
Magnetoencephalography (MEG), 362
Malformations of unknown origin (spine)
dorsal meningocele, 1022–1023, 1025f, 1026f
lateral meningocele, 1023, 1025, 1026f
segmental spinal dysgenesis, 1022, 1023f, 1024f
Malignant nerve sheath tumor, 648f
Malignant peripheral nerve sheath tumor (MPNST), 635, 650–651
Malignant tumors, 872
Mammalian target of rapamycin (mTOR), 656
Maple syrup urine disease, 105, 106, 106f–108f, 108
Marfan syndrome, 1023, 1026f
Marinesco-Sjögren syndrome, 224, 224f
Martin-Bell syndrome. See Fragile X syndrome
Mature teratomas, 778, 782
Maxillary sinus, 51
Measles virus
acute encephalomyelitis, 1143–1144
subacute measles encephalopathy, 1143
subacute sclerosing panencephalitis, 1144f
Meckel-Gruber syndrome, 563
Medial lemniscus, 35
Medullary glioma
diffuse, 740f
exophytic, 739f
focal, 741f
Medullary tumors, 739f, 740f, 741f, 742
Medulloblastoma, 717
clinical presentation, 717–718
imaging studies, 719–725, 719f–725f
molecular subgroups, 717, 718t
pathology, 718–719
proton MR spectroscopy, 737
Medulloepithelioma, 807, 863, 865
hemispheric, 809–810, 810f
Megalencephaly with leukoencephalopathy and cysts (MLC)
phenotypes, 121–122
physiology/pathology/imaging, 122, 123f, 124
Melanin-producing cells, 678
Melanocytes, 678
Melanotic neuroectodermal tumors of infancy, 888
Meningeal cyst, 1058, 1060, 1060f
Meningeal tumors, intrinsic, 852
Meningioangiomatosis, 823–824, 825f
Meningiomas, 655, 703, 757–758, 851, 853, 1057, 1058, 1059f
of tela choroidea, 852f
Meningitis
bacterial, causes of, 1097
bacterial meningitis, 1097–1098
complications
arterial infarcts, 1110, 1112f–1114f
effusions/empyemas, 1100, 1100f–1101f
hydrocephalus, 1102, 1105, 1106f
venous thrombosis/infarction, 1105, 1107f–1109, 1109–1110, 1111f
ventriculitis, 1102, 1104f–1105f
contrast agents and, 3
infants, children, and adolescents, 1097–1098, 1098t
neonatal, 1097, 1097t
pathophysiology, 1098–1099
tuberculous, 1110–1111, 1113–1115, 1115f–1118f
uncomplicated purulent, 1099–1100
Meningocele manqué, 1016, 1021f
Meningoencephaloceles, 562
Meningoencephalopathy, 1158t
Meningofacial angiomatosis, 667
Meninx primitiva, 532
Merlin, 651
Metabolic disorders
acyl CoA oxidase deficiency, 94, 96–97, 96t, 97f–101f, 98, 100
ALD (adrenoleukodystrophy), 97, 97f
Alexander disease, 172–174, 173f, 174f
Alpers disease, 169
basal ganglia
anatomic distribution of diseases, 157t
calcification of, 154
diseases involving, 154f
causes/classification, 88–89
Cockayne syndrome, 125–126, 126f
combined methylmalonic aciduria/homocystinuria (MMS/HC), 109
cystathionine beta synthase deficiency, 109
cystic leukoencephalopathy without megaloencephaly, 124–125, 124f
cytomegalovirus disease, 126
dihydropyrimidine dehydrogenase deficiency, 136, 138f
galactosemia, 126–127, 126f
giant axonal neuropathy, 103–104, 105f
globoid cell leukodystrophies, 92, 93f, 94, 95f
gray matter metabolic disease/disorders
Aicardi-Goutières syndrome, 125, 125f
aspartylglucosaminuria, 166
β-ketothiolase deficiency, 160, 161f
carbon monoxide poisoning, 169, 169f
chronic liver disease, 164
creatine deficiency syndromes, 159, 160, 160f
cyanide poisoning, 169, 170f
hemolytic–uremic syndrome, 161–162, 162f
hypoplastic basal ganglia, 164
infantile beriberi/Wernicke encephalopathy, 160–161, 161f
infantile neuroaxonal dystrophy/NBIA2A/PLAN, 167, 167f
isovaleric acidemia, 158, 158f
juvenile Huntington disease, 155, 156, 158, 158f
neurodegeneration with brain iron accumulation, 153
neuronal ceroid lipofuscinosis, 164, 164t, 165f–166f, 166
Niemann-Pick disease, 167–168, 168f
pantothenate kinase–associated neuropathy, 154–155, 154f, 155f, 156t, 157t
progressive cerebral poliodystrophy, 169
Rett syndrome, 168, 169f
succinate semialdehyde dehydrogenase deficiency, 159, 159f
Sydenham chorea, 162, 163f, 164
toxins, 169, 169f, 170f
trichopoliodystrophy, 169
Wernicke’s encephalopathy, 160–161, 161f
hereditary spastic paraplegias, 111, 113, 113f
3-hydrooxy-3-methylglutaryl-coenzyme A lyase deficiency, 136, 138, 139f
hyperhomocysteinemia, 109–110, 109f
hypomyelinating leukoencephalopathies, 127, 128f–129f, 130
Krabbe disease, 92, 93f, 94, 95f
maple syrup urine disease, 105, 106, 106f–108f, 108
megalencephaly with leukoencephalopathy and cysts, 12–122, 123f, 124
mitochondrial disorders, 127, see also Mitochondrial disorders
mucolipidosis type IV, 111, 113f
nonketotic hyperglycinemia, 136, 137f
oculocerebrorenal syndrome (Lowe syndrome), 110–111, 112f
and pediatric stroke, 90–91
Pelizaeus-Merzbacher disease, 127, 128f–129f, 130
phenylketonuria, 104–105, 106f
pseudo-TORCH syndrome, 126
sialic acid storage diseases, 134–135, 135f
Sjögren-Larsson syndrome, 113–114, 114f
thalamus and, 124
toxic/nutritional encephalopathy
lead encephalopathy, 152, 153f
osmotic demyelination syndrome, 151–152, 152f
progressive multifocal leukoencephalitis, 153
solvent abuse, 152–153
subacute sclerosing panencephalitis, 153
toxic heroin ingestion, 151, 151f
trichothiodystrophy, 133–134
vanishing white matter disease, 100, 102–103, 103f–105f
white and gray matter disorders
acute necrotizing encephalitis, 210–212, 213f–215f
aspartoacylase deficiency, 170, 171f, 172, 172f
canavan disease, 170, 171f–172f, 172
Cree leukoencephalopathy, 102
D-bifunctional protein deficiency, 183, 184
familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency, 194t
fibrinoid leukodystrophy, 172–174, 173f–175f
fucosidosis, 135–136, 135f
glutaric aciduria type I, 82t, 85t, 157t, 201, 202f
glutaric aciduria type II, 157t, 201, 202f, 203
GM1/GM2 gangliosidosis and, 87, 207, 208f–209f, 209, 210f, 211f, 223
hypomyelination with atrophy of the basal ganglia/cerebellum, 84t, 85t, 131–132
isolated sulfite oxidase deficiency, 91, 217, 218f, 219
Kearns-Sayre syndrome/ophthalmoplegia plus, 85t, 157t, 196–197, 196f
Leigh’s syndrome, 85t, 187t, 188–190, 189f–193f
L-2-hydroxyglutaric aciduria, 209, 210, 212f
3-methylglutaconic aciduria, 214–216, 216f
methylmalonic acidemia, 90, 109
mitochondrial disorders, 184, 187–189, 187t, 189f–193f, 190, 192–204, 194t, 195f–200f, 202f–204f
molybdenum cofactor deficiency, 216–217, 217f
mucopolysaccharidoses, 174–176, 176t, 177f–178f, 179
nonrhizomelic chondrodysplasia punctata, 184
nonspecific mitochondrial, 203–204, 203f, 204f
peroxisomal disorders, 179–180, 179t
propionic acidemia, 205–206, 208f
pyruvate dehydrogenase deficiency, 204
rhizomelic chondrodysplasia punctata, 184, 185f
toxin ingestions, 219, 219f
trichopoliodystrophy (Menkes disease), 199–201, 200f
urea cycle/ammonia disorders, 204–205, 205t, 206f–208f
Wilson’s disease, 184, 186f
white/gray matter, 87–88
X-linked α-thalassemia/mental retardation, 111, 112f
Metameric lesions, 1218
Metastasis, 703
leptomeningeal, 706
Metastatic medulloblastoma, 723f
Metastatic neuroblastoma, 869
to calvarium, 857f
to calvarium and dura, 857f
to orbit, 870f
Methionine adenosyltransferase (MAT) I/III deficiency, 110, 111f
5-Methylenetetrahydrofolate reductase deficiency (MTHFRD), 109
Metopon, 51
Mevalonate kinase deficiency, 229
Microadenomas, 782, 783f
hemorrhagic, 784f, 785f
Microcephalies, 434–436, 436t, 437f–438f
Microcephaly-polymicrogyria syndromes, 489
Microphthalmia, 517, 863
Midbrain tumors, 745, 747f
Midbrain–hindbrain development anomalies
anteroposterior patterning defects, 525–526, 527f
brain and meninges interactions, 524, 525f
cell proliferation and migration, 522–524, 523f
cerebellar connections, 524
cerebellar hemisphere duplication, 548, 550f
cerebellar hypoplasia, 527, 529f–530f, 538, 539, 540f
cerebellar nodular heterotopia with overlying dysgenesis, 545, 547f
cerebellum and brain stem on MRI, 524–525, 525f, 526f
congenital disorders of glycosylation, 550
congenital fibrosis of the extraocular muscle, 542–543
Dandy-Walker complex, 532–535, 536f–538f
diffuse and unilateral cerebellar dysgenesis, 545, 548, 548f–549f
disconnection syndromes, 526, 528f
disproportionately small brainstem, 538
dorsal medullary protuberances, 550, 552f
dorsoventral patterning defects, 527, 528, 530
horizontal gaze palsy with progressive scoliosis, 542, 546f
Joubert syndrome, 540–542, 541t, 543f–545f
Lhermitte-Duclos disease/Cowden syndrome, 535, 537, 538, 538f–540f
malformations, 539, 541t
patterning, 522, 522f
pontine tegmental cap dysplasia, 549, 550, 551f
pontocerebellar hypoplasias, 550
rhombencephalosynapsis, 530, 531f, 532, 533f–535f
tectal enlargement, 543, 545, 547f
Midline craniofacial dysgenesis, 419
Midline craniofacial dysraphisms, 570
Midline zipper glia (MZG), 409
Mild malformations of cortical development (mMCD), 441
Mild traumatic brain injury, 383, 384f–385f
Missing cortex sign, 274, 274f
Mitochondria, 57
Mitochondrial acetoacetyl-CoA thiolase deficienc, 160
Mitochondrial disorders, cerebellar atrophy
coenzyme Q10 deficiency, 225, 225f
mitochondrial DNA depletion syndrome 7, 226
POLG1 mutations, 225–226
Mitral valve prolapse, 271t
Möbius syndrome, 530
Morning glory syndrome, 518
Moyamoya phenomenon, 645
Moyamoya syndrome, 1228, 1231f
MPNST. See Malignant peripheral nerve sheath tumor (MPNST)
MR neurography (MRN), 10
MR spectroscopic imaging (MRSI), 434
MR-compatible pediatric ventilators, 2
Mucolipidosis type IV, 111, 113f
Multicystic encephalomalacia, 265, 268f–269f, 327f, 336
Multifocal leukoencephalopathy, 1136
Multifocal tumors, 860
Multilayered rosettes, embryonal tumor with, 725–726, 727f
Multiple hamartomas, 633
Multiple meningiomas, 654f
Multiple pregnancies, central nervous system (CNS) injury in, 332, 334
Multiple sclerosis (MS), 139, 140f, 141–142, 141f, 713
Multiple spinal schwannomas, 655f
Muscle–eye–brain phenotype (MEB), 476–477, 479f–480f
Mycobacterium tuberculosis, 1098
Mycotic aneurysms, 1215, 1215f
Myelin vacuolation, 640f
Myelination process
metabolic disorders and, 91
normal postnatal brain development and, 34
T1-/T2-weighted images and, 23, 28
Myelinoclastic disorders
adrenoleukodystrophy as, 97
mucopolysaccharidoses, 174–176, 176t, 177f–178f, 178
osmotic myelinolysis in childhood, 151–152, 152f
van der Knaap disease and, 85t
vanishing white matter disease, 103f
Myelomeningocele–Chiari II malformation, 952, 952f
Myelopathy, 9, 1012, 1094
Myofibroblastic inflammatory tumors, 814
Myofibromatosis, infantile, 853
Myotomes, 52, 52f
N
Nasal dermal sinus, 565, 567f–571f
Nasal gliomas, 565, 567f, 573f
Nasoethmoidal cephaloceles, 568
Nasoorbital cephaloceles, 568
Nasopharyngeal carcinoma, 885–888
Nasopharyngeal cephaloceles, 575, 577, 577f
Nasopharyngeal rhabdomyosarcoma, 885f, 886f
NBS. See Nijmegen breakage syndrome (NBS)
NCC. See Neural crest cell (NCC)
NCM. See Neurocutaneous melanosis (NCM)
Necrosis, 709, 728
Neisseria meningitides, 1097
Neisseria meningitis, 1098t
Neonatal alloimmune thrombocytopenia, 329
Neonatal candidiasis, 1148–1149, 1150f
Neonatal herpes simplex virus, 1080–1082, 1081t–1082t
Neonatal meningitis
Citrobacter, 1097
Escherichia coli, 1097, 1097t
Listeria monocytogenes, 1097, 1097t, 1098
Pseudomonas, 1097, 1098t
Staphylococcus, 1097, 1098t
Streptoccocus, 1097, 1102f
Streptococcus agalactiae, 1097, 1112f
Neoplasia, 714f
Neoplasms, 704
Nerve sheath tumors, 648f, 649–650
Neural crest cell (NCC), 633, 668
cranial, 633
Neural placode, 981, 982f
Neural tube defects (NTDs), 554–555
Neurenteric cysts. See Enteric cysts
Neuroaxonal dystrophy, 226
Neuroblastic elements, tumors with, 807
Neuroblastoma, 764–765, 765f, 889
metastatic, 856, 869
Neurocristopathy, 633
Neurocutaneous disorders, 633
Neurocutaneous melanosis (NCM)
clinical manifestations, 678
neuroimaging manifestations, 679, 679f, 680f, 681
pathological manifestations, 678–679
Neurocysticercosis, 1151, 1153, 1155f–1156f
Neurocytomas, 849–850, 851f
Neurodegeneration with brain iron accumulation, 153
Neuroectodermal dysplasia, 678
Neuroectodermal tumor, hemispheric primitive, 807–809, 808f, 809f
Neurofibromas, 635, 646–648, 880, 882f
bilateral C1-C2 spinal, 651f
cutaneous, 634
intra- or paraspinous, 649
intraspinal, 651f
orbital, 646, 647f
orbital plexiform, 870f
plexiform, 635, 646–648, 646f, 647f, 869, 881, 883f
solitary, 647
spinal, 635
subcutaneous, 635
Neurofibromatosis type 1 (NF1), 634, 739
brain stem tumors with, 745–747
clinical manifestations, 634–636
cranial and intracranial manifestations
calvarial and orbital abnormalities, 646
cranial nerve tumors, 645
gliomas and tumor-like conditions, 639–642
hyperintense T2 lesions, 642–644
neurofibromas and plexiform neurofibromas, 646–648
optic pathway gliomas (OPG), 636–639, 636f, 637f
vascular dysplasia, 644–645, 645f
white matter abnormalities, 642–644, 642f, 643f
criteria for diagnosis of, 634t
incidence of clinical features of, 635t
neuropsychological manifestation of, 635
spinal manifestations
dural dysplasia and meningoceles, 647–649
nerve sheath and soft tissue tumors, 649–650
scoliosis and intramedullary tumors, 647–649
Neurofibromatosis type 2 (NF2)
clinical manifestations, 651–653
criteria for diagnosis of, 654t
intracranial manifestations, 653–654
spinal manifestations, 654–656
schwannomatosis, 656
Neurofibromin, 634
Neurofibrosarcomas. See Malignant peripheral nerve sheath tumor (MPNST)
Neuroglial hamartomas, 813–814, 814f
Neurohypophysis, 509
Neurometabolic disorders, 81, 90–91
Neuronal ceroid lipofuscinosis (NCL), 164, 164t, 165f–166f, 166, 232
congenital form, 164
infantile forms, 164
juvenile forms, 164
late infantile forms, 164
Neuronal–glial tumors, 815
Neurulation anomalies, 977
NF1. See Neurofibromatosis type 1 (NF1)
NF2. See Neurofibromatosis type 2 (NF2)
NF1 gene, 634, 635
NG-GCTs. See Nongerminomatous germ cell tumors (NG-GCTs)
Niemann-Pick disease, 167–168, 168f
Nijmegen breakage syndrome (NBS), 675, 678
Nipah virus, 1143
Nodular leptomeningeal enhancement, 716
Nondisjunction, 981
Nonenhanced CT (NECT), 1092
Nongerminomatous germ cell tumors (NG-GCTs), 777, 782, 782f, 837, 837f
Noninvoluting congenital hemangiomas (NICHs), 879
Nonobstructive hydrocephalus. See also Hydrocephalus
acute nonobstructive, 944–945, 947–948, 947f–948f
chronic nonobstructive, 941–944, 942f, 944f–947f
pathophysiologic considerations, 940–941
venous hypertension, 941–944, 942f, 944f–947f
Non-polio enteroviruses, 1139–1140, 1139f
Nonsecreting tumors, 837
Normal stem cells (NSCs), 704
Normal-pressure hydrocephalus (NPH), in children, 943
Notochordal process, 52
Nuclear medicine techniques, 715
O
Obstructive hydrocephalus, 907. See also Hydrocephalus
acute ventricular, 934–936, 936f–940f, 939
aqueductal stenosis, 932–933, 933f, 934f
clinical classification, 915t
extraventricular, 939, 941f
malformative hydrocephalus, 933–934
Occipital cephaloceles, 563, 563f–566f
Occipital osteodiastasis, 351–353, 352f, 353f
Occlusive vasculopathy, 115, 117, 118f
Occult spinal dysraphisms, 1007
Ocular colobomas, 868
Ocular masses, differential diagnosis of, 862–864
Ocular tumors, retinoblastoma (RB), 860–862, 861f
Oculo–cerebral–cutaneous syndrome, 489
Oculocerebrocutaneous syndrome, 543
Oculocerebrorenal syndrome (Lowe syndrome), 110–111, 112f
Oculodigital dental dysplasia, 85t, 155
Oligodendrocyte myelin glycoprotein gene, 642
Oligodendrocytes, 634
Oligodendrogliomas, 800–803, 802f
anaplastic, 803
thalamic, 829
Open spinal dysraphism (OSD), 977, 978f, 979, 981–987
OPG. See Optic pathway gliomas (OPG)
Optic nerve glioma, 774f, 775f
Optic nerve tumor, 636–637, 638f
Optic pathway gliomas (OPG), 636–639, 636f, 637f
Optic pathway tumor, 636, 638f
Optic–hypothalamic astrocytomas, 777
Optic–hypothalamic gliomas. See Suprasellar pilocytic astrocytomas
Orbital cysts, 868–869
Orbital hemangiomas, 864, 866f
Orbital lymphatic malformations, 865
Orbital neurofibromas, 646, 647f
Orbital plexiform neurofibroma, 870f
Orbital rhabdomyosarcomas, 884
Orbital varices, 868
Orbital venous malformation, 868
Osmotic myelinolysis in childhood, 151–152, 152f
Osteoblastoma, 1056, 1057, 1058f
Osteogenic sarcoma, 1054, 1055
Osteomyelitis, 1215
Overgrowth syndromes, 670f, 688–689, 689t, 690f, 690–692, 691f
P
Pai syndrome, 582
Pallidoluysian atrophy, 230–231, 231f
Panhypopituitarism, 780
Pantothenate kinase-associated neurodegeneration, 154–155, 154f, 155f, 156t, 157t
Pantothenate kinase-associated neuropathy, 154–155
Papillary craniopharyngioma, 767, 773f
Papillary cystadenomas, of endolymphatic sac, 674–675, 676f
Papillary glioneuronal tumor (PGNTs), 823, 824f
Papillary tumors of pineal region (PTPR), 840–842, 843f
Parainfectious leukoencephalopathies, infections of CNS, 1148
Paranasal sinuses, 51
Paraspinous neurofibromas, 649
Parietal cephaloceles, 570, 575, 576f
Parietal foramina, 579, 580f
Parinaud syndrome, 844
Parry-Romberg syndrome, 688, 688f
Pars intermedia cysts, 792
Partial pituitary ectopia, 511
PAs. See Pilocytic astrocytomas (PAs)
Pascual–Castroviejo type II syndrome, 685
Patau syndrome. See Trisomy 13
Pediatric brain tumors
CT scan, 707
MR evaluation, 705
Pedunculated hypothalamic hamartoma, 789f
Pelizaeus-Merzbacher disease (PMD), 127, 130
atrophy in, 129f
connatal from, 128f
evolution of, 128f
Perfusion imaging, 71
Perfusion MR techniques, 11–12
Perinatal/prenatal stroke, 268
Peripheral primitive neuroectodermal tumor, 1065, 1067f. See also Ewing sarcoma
Perivascular spaces, 45f, 46
Periventricular and intraventricular hemorrhage, 289, 295
Periventricular hemorrhagic infarction (PVHI), 296–297
Periventricular heterotopia, 452–458, 457f–459f
Periventricular interstitial edema, 929–930, 930f
Periventricular leukomalacia (PVL), 291, 302
Peroxisomes, 89, 179–180, 179t
Persistent hyperplastic primary vitreous (PHPV), 519, 520f, 862, 864f
PGNTs. See Papillary glioneuronal tumor (PGNTs)
PHACE (Posterior fossa malformations, facial Hemangiomas, Arterial anomalies, Cardiac anomalies and aortic coarctation,
Eye anomalies) syndrome, 865, 878
clinical manifestations, 685–686
neuroimaging manifestations, 686–687, 686f, 687f
Phakomatoses. See Neurocutaneous disorders
Phase-contrast (PC) techniques, 8
Phenylalanine hydroxylase (PAH) deficiency, 104
Phenylketonuria, 104–105, 106f
Phosphatase and tensin homolog (PTEN) gene, 691
Phosphodiester in phosphorus spectroscopy, 59
Phosphomonoester in phosphorus spectroscopy, 59
PHTS. See PTEN hamartoma tumor syndrome (PHTS)
Pilocytic astrocytomas (PAs), 639, 640f, 703, 777f, 794–795, 796f–797f, 798f, 824
histologic examination of, 728
Pilomyxoid astrocytomas (PMAs), 728, 775
Pilomyxoid variant, 728
Pineal and bifocal germinomas, 833–835, 834f, 835f, 836f
Pineal atypical teratoid/rhabdoid tumor, 840, 842f
Pineal cysts, 843–844
Pineal dermoids and epidermoids, 841
Pineal germinomas, 833–835, 834f, 835f, 836f
Pineal parenchymal tumor, 837–839
Pineal parenchymal tumor of intermediate differentiation (PPTID), 837
Pineal region gliomas, 839–840, 842f
Pineal region masses, 831–833, 833t
nongerminomatous germ cell tumors, 837, 837f
papillary tumors of the pineal region, 840–842, 843f
pineal and bifocal germinomas, 833–835, 834f, 835f, 836f
pineal atypical teratoid/rhabdoid tumor, 840, 842f
pineal cysts, 843–844
pineal dermoids and epidermoids, 841
pineal parenchymal tumors, 837–839
pineal region gliomas, 839–840, 842f
teratomas, 837, 838f
Pineoblastomas, 837, 839f, 840f, 841f
Pineocytomas, 837
PISC. See Postoperative intraspinal subdural collections (PISC)
Pituitary adenomas, 782–786, 783f–786f
Pituitary dwarfism, 511, 512f–513f
Pituitary gland, 49–50, 51f
Pituitary lesions, 766t
Pituitary stalk, 766
Pituitary tumors, 703
Placental alkaline phosphatase (PLAP), 837
Plain film radiography, 649
Plasma cell granulomas, 814–815
Pleomorphic xanthoastrocytomas (PXAs), 821–822, 822f
Plexiform neurofibromas (PNs), 635, 646–648, 647f, 650f, 869, 881, 883f
facial, 635
PMAs. See Pilomyxoid astrocytomas (PMAs)
PNET. See Primitive neuroectodermal tumor (PNET)
Pneumococcus, 1117
Pneumocystis jiroveci, 1093
PNs. See Plexiform neurofibromas (PNs)
Point-resolved spectroscopy (PRESS), 713
Pol III–related leukodystrophy, 132–133, 133f
Polymicrogyria (PMG), 668
Pontine tegmental cap dysplasia, 549, 550, 551f
Pontine tumor, 639, 742, 743f, 744f, 745
Pontocerebellar hypoplasias (PCH), 226–228, 227t, 228f, 550
Positron emission tomography (PET), 286f
Posterior fossa tumors, 716, 717t
brainstem tumors, 738–751
extraparenchymal tumors
in children, 717t
dysembryoplastic tumors, 751–754, 753f, 754f, 758f
miscellaneous tumors, 757–765
schwannomas, 751, 752f
teratomas, 754–757, 758f–759f
hemangioblastoma, 748–751, 750f
ventricular tumors
atypical teratoid/rhabdoid tumor, 725, 726f
cerebellar astrocytomas, 726–729, 729f
in children, 717t
choroid plexus tumors, 737–738
embryonal tumor with multilayered rosettes, 725–726, 727f
ependymomas, 729–737, 734f, 735f, 736f
medulloblastoma, 717–725
rosette-forming glioneuronal tumor, 729, 733f
Posterior reversible encephalopathy syndrome, 148
Posthemorrhagic hydrocephalus, 936, 939, 940f
Postnatal trauma, 354–362, 355f–361f
Postoperative intraspinal subdural collections (PISC), 722, 724f
PPTID. See Pineal parenchymal tumor of intermediate differentiation (PPTID)
Prechiasmatic craniopharyngiomas, 768, 771f
Premature infants, imaging problems of, 1–2
Preplate, 19
Presumed perinatal ischemic stroke (PPIS), 270, 270t
Primarily cortical tumors, 815
angiocentric glioma, 822–823, 823f
desmoplastic infantile ganglioglioma (desmoplastic astrocytoma of infancy), 820–822, 821f
dysembryoplastic neuroepithelial tumor, 815–817, 816f, 817f
gangliocytomas, 817–820
gangliogliomas, 817–820, 819f, 820f
meningioangiomatosis, 823–824, 825f
papillary glioneuronal tumor, 823, 824f
Primitive knot, 52
Primitive neuroectodermal tumor (PNET), 717, 807, 1044
Primitive streak, 52, 973, 974f
Probst bundles, 421, 422, 422f
Progenitor cells, 704
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome, 229–230, 230f
Progressive epilepsy, mental retardation, 166
Progressive facial hemiatrophy, 688, 688f
Progressive multifocal leukoencephalopathy (PML), 1143t, 1145
Progressive myoclonic epilepsy syndrome, 230–231
Prolactin-secreting adenomas (PL), 782
Prosencephalon, 406, 408. See also Dorsal prosencephalon development
Proteus syndrome, 690–691, 691f
Proton MR spectroscopy, 89, 103, 710, 711
arterial infarctions, in children, 277
basal ganglia, 160, 161f, 307f, 320f
brain development, 58–60,
canavan disease, 170, 171f
cerebellar astrocytomas, 737
choroid plexus papillomas, 846
craniopharyngiomas, 768
ependymomas, 737
galactosemia, 126
3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency, 138
with MSUD, 108
NAA, 94, 98, 111, 129f, 317, 372
occipital white matter, 114, 114f
parasagittal/watershed injury, 311, 312f
suprasellar astrocytomas, 775
Protozoan/parasitic infections of CNS
cerebral malaria, 1157
cerebral toxocaral disease, 1153, 1157, 1157f
neurocysticercosis, 1151–1153, 1154f–1156f
Pseudocontinuous ASL (pCASL), 917
Pseudomonas aeruginosa, 1098
Pseudo-TORCH syndrome, 126
Pseudotumors, inflammatory, 814–815
PTEN hamartoma tumor syndrome (PHTS), 691
PTPR. See Papillary tumors of the pineal region (PTPR)
Puberty, 50, 50f
isosexual precocious, 787
Purkinje cell, 677
Putamen
juvenile Huntington disease and, 155, 156, 158, 158f
metabolic disorders and, 157t, 158
PXAs. See Pleomorphic xanthoastrocytomas (PXAs)
Pyogenic brain abscesses, MRI features, 1122
Q
18q-syndrome, 134, 134f
Quadriventricular hydrocephalus, 927