Neurology
of the Newborn
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Joseph J. Volpe
Bronson Crothers Distinguished Professor of Neurology
Harvard Medical School
Neurologist-in-Chief Emeritus
Children’s Hospital
Boston, Massachusetts
Neurology
of the Newborn
FIFTH EDITION
1600 John F. Kennedy Boulevard
Suite 1800
Philadelphia, PA 19103-2899
NEUROLOGY OF THE NEWBORN, FIFTH EDITION ISBN: 978-1-4160-3995-2
Copyright ! 2008, 2001 by Saunders, an imprint of Elsevier Inc.
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Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our knowledge, changes in practice, treatment, and drug therapy may
become necessary or appropriate. Readers are advised to check the most current information
provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of
administration, and contraindications. It is the responsibility of practitioners, relying on their
own experience and knowledge of the patient, to make diagnoses, to determine dosages and

the best treatment for each individual patient, and to take all appropriate safety precautions. To
the fullest extent of the law, neither the Publisher nor the Author assumes any liability for any
injury and/or damage to persons or property arising out of or related to any use of the material
contained in this book.
The Publisher
Library of Congress Cataloging-in-Publication Data
Volpe, Joseph J.
Neurology of the newborn/Joseph J. Volpe. – 5th ed.
p.; cm.
Includes bibliographical references and index.
ISBN 978-1-4160-3995-2
1. Newborn infants–Diseases. 2. Pediatric neurology. I. Title.
[DNLM: 1. Nervous System Diseases. 2. Infant, Newborn, Diseases. 3. Infant, Newborn.
WS 340 V899n 2008]
RJ290.V64 2008
618.92’01–dc22
2007044207
Acquisitions Editor: Judy Fletcher
Publishing Services Manager: Frank Polizzano
Project Manager: Lee Ann Draud
Design Direction: Ellen Zanolle
Cover design: Ellen Zanolle
Printed in the United States of America
Last digit is the print number: 9 87654321
To my wife,
Sara,
for her love and understanding,
without which this book would not be possible
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Preface to the Fifth Edition

The nearly 30 years since publication of the first edition
of this book have been a period of extraordinary devel-
opment in the discipline of the neurology of the
newborn. In 1981, at the time of publication of the
first edition, there was a sense of a new frontier to be
pioneered. Currently articles on neonatal neurology are
abundant in the major journals in pediatrics, child neu-
rology, and related disciplines. Current-day annual
meetings of scientific societies of pediatrics and child
neurology are dominated by research and clinical pre-
sentations on the neurology of the newborn. Thus, the
field now has matured fully into a discipline in its own
right.
The fifth edition of this book has been completely
updated and extensively revised. All of the changes
have been incorporated into an organization that is
identical to that of the previous editions. Thus, the
four initial chapters establish the foundation of the
remainder of the book. These four chapters deal with
the development of the nervous system, the disorders
caused by anomalous development, the clinical neuro-
logical examination, and the specialized techniques in
the neurological evaluation. The fifth chapter, con-
cerning neonatal seizures, serves as an effective bridge
between the initial chapters and the later, disease-
focused chapters, because neonatal seizure is a key
manifestation of many of the neurological disorders
dealt with later in the book. The next 19 chapters
focus on the neurological disorders, with a strong clin-
ical emphasis. However, as in the past, the lessons

learned from basic and clinical research are brought
to the bedside in the discussions of the diseases.
This book is intended for a broad audience, that is,
from the most highly specialized neonatal physicians to
those with a more general perspective. I have attempted
to generate a systematic, readable, and comprehensive
synthesis of the neurology of the newborn that will be
of value to all individuals who care for the infant, both
in the critical neonatal period and later. The clinical
discussions are buttressed by information generated
from the most recent diagnostic methodologies, by
the results of promising new therapies, and by insights
gained from basic research in such relevant disciplines
as neuroscience, genetics, and developmental biology.
Attempting to do all this has been stimulating and chal-
lenging, and I apologize if I have oversimplified in some
areas and displayed my ignorance in others. After
five editions I hope that these two problems are few.
Previous readers will recognize that I place great
value on the liberal use of tables to synthesize major
points throughout the book. This edition contains
approximately 550 tables. Many of these are new,
many replace earlier tables, and many of the original
tables contain new information. As with tables,
I value greatly the illustrative power of figures, in the
form of flow diagrams, experimental findings, clinical
and pathological specimens, and all types of brain im-
aging. This edition contains approximately 665 figures,
many of which are new. Moreover, many of the original
figures have been replaced with better examples of the

relevant findings.
The extraordinary progress in the study of the neu-
rology of the newborn is reflected in part by the explo-
sion of new literature in the relevant disciplines. This
edition contains approximately 12,500 references,
nearly 3000 more than in the previous edition. The
enormous increase in the relevant literature between
the last and current edition is a tangible reflection of
the intense interest in this extraordinarily important
field. Every chapter contains many new citations as
part of the updating of the entire book.
I have been extremely fortunate to have the help of
many very talented and dedicated people in the prep-
aration of this book. As she did for the previous two
editions, Irene Miller performed the simply incredible
task of typing and retyping the entire book: text, tables,
legends, and references. She manipulated and renum-
bered the 12,500 references with aplomb; to this day,
I don’t understand how she did it so efficiently and
without losing her mind. Janine Zieg prepared many
new flow diagrams and schematics and updated many
others with great skill and patience, particularly
because I revised them incessantly. Sarah Andiman
ably assisted in this endeavor. My young colleague,
Dr. Omar Khwaja, spent many hours at the computer
helping a computer-naı¨ve author with illustrations; he
contributed important images and helped restore the
value of some originals. Finally, as in previous editions,
I acknowledge the support and patience at Elsevier of
Judy Fletcher, with whom I have worked for almost

20 years since the third edition and who supervised
the overall project. Ellen Zanolle designed the fetching
cover and successfully convinced a stodgy author that
covers should be eye-catching. Lee Ann Draud
superbly led the production efforts. Not only was her
Elsevier group so tolerant of my obsessive pursuit of
perfection, but they allowed me to add new references
until the very end of 2007.
Joseph J. Volpe, MD
vii
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Preface to the First Edition
The neurology of the newborn is a topic of major
importance because of the preeminence of neurological
disorders in neonatology today. The advent of modern
perinatal medicine, accompanied by striking improve-
ments in obstetrical and neonatal care, has changed the
spectrum of neonatal disease drastically. Many pre-
viously dreaded disorders such as respiratory disease
have been controlled to a major degree. At the same
time, certain beneficial results of improved care, for
example, markedly decreased mortality rates for prema-
ture infants, have been accompanied by neurological
disorders that would not have had time to evolve in
past years.
This major importance of neonatal neurological
disease has stimulated efforts by workers in many dis-
ciplines to recognize, understand, treat, and ultimately
prevent such disease. This book is an attempt to bring
together the knowledge gained from these efforts and

to present my current understanding of the neurology
of the newborn. Because of the diversity of knowledge
that I have attempted to bring to bear upon the prob-
lems discussed in this book, I may have oversimplified
in certain areas and displayed my own ignorance in
others. Nevertheless, I have written the material in
the hope that it will be of value to all health profes-
sionals involved in the care and follow-up of the new-
born infant with neurological disease.
The prime focus of the discussions of neonatal neu-
rological disease throughout this book is the clinical
evaluation of the infant, that is, what we can learn
from observation of the setting and mode of presenta-
tion of the disease and the disturbances of neurological
function apparent on careful examination. The theme
that recurs most often is that careful clinical assess-
ment, in the traditional sense, is the prerequisite and
the essential foundation for understanding the neuro-
logical disorders of the newborn. The infant does not
advertise his or her neurological disorder with the
drama that older children and adults exhibit, but with
patience and diligence we can discover a treasure of
important clinical clues when we elicit a complete his-
tory and perform a careful physical examination. It is
this quality of discovery with simple techniques that
has made the neurology of the newborn so stimulating
for me, and I hope that this book can lead the reader to
similar discoveries.
With accomplishment of the essential first step of
definition of the clinical problem, we can turn in a

rational way to the increasingly sophisticated means
of studying the infant’s deranged neural structure and
function. Although my emphasis is, first, on the sim-
plest and least invasive techniques for providing us
with the necessary information, we are in an era
when sophisticated and informative procedures such
as imaging the brain itself can be done in a safe and
effective way.
The final process in our understanding the infant
with a neurological disorder requires an awareness of
a burgeoning corpus of information derived from stu-
dies in human and experimental pathology, physiology,
biochemistry, and related fields. Of necessity, often we
must extrapolate to our newborn patient data obtained
from animals. Such extrapolation must always be made
cautiously, and yet we cannot ignore the many lessons
learned from the laboratory that have proved invaluable
in our understanding of neonatal neurological disease.
In this book, on the one hand, I attempt to synthesize
in a comprehensible manner relevant material from a
diversity of disciplines and, on the other hand, try very
hard not to oversimplify what are clearly very complex
issues.
I believe that the neurology of the newborn has
come of age and, indeed, should be viewed as a disci-
pline in its own right. I hope that in some way this book
will contribute to establishing that status. My most fer-
vent hope is that this discipline excites the interests and
efforts of others concerned with the neonatal patient
and that, through concerted actions, the greatest pos-

sible benefits accrue to the infant with neurological
disease.
ix
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Acknowledgments
It is with pleasure and eagerness that I acknowledge
with gratitude the help of so many over the years.
I am grateful to Dr. Raymond Adams, who introduced
me to neurology and neuropathology and provided
a model of scholarship in medicine that I have
since striven to achieve; to Dr. C. Miller Fisher, who
taught me the inestimable value of looking carefully
at the patient and never denying observations that
did not fit preconceived notions; and to Dr. E. P.
Richardson, Jr., who taught me neuropathology and
provided a framework for study on which I remain
dependent.
I owe enormous gratitude to Dr. Philip Dodge, who
stimulated me to study pediatric neurology and, after
my training, guided me to the neurology of the new-
born. To this day he has been a continual source of
support and inspiration.
I gratefully acknowledge the help and contributions
of many investigators with an interest in the newborn.
Their work is included on many of the pages of this
book, and although acknowledgment is made in those
places, I take this particular opportunity to thank them
again for their generosity. Many other physicians
involved in the care of newborns have shared their
unusual and interesting cases with me; I thank them

for their stimulation and education. Many faculty,
fellows, and house officers at St. Louis Children’s
Hospital and Boston Children’s Hospital have helped
me immeasurably in the study of neonatal patients. My
collaborators in clinical and basic research, especially
Drs. Hannah Kinney, Paul Rosenberg, Frances Jensen,
and Timothy Vartanian, have been wonderful partners
in our pursuit of discovery and creativity in the study of
the newborn brain. Finally, my colleagues in neonatal
neurology at Boston Children’s Hospital, Drs. Adre du
Plessis, Janet Soul, and Omar Khwaja, have been a
constant source of stimulation. I am grateful for all of
these contributions.
Joseph J. Volpe, MD
xi
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CONTENTS
UNIT I HUMAN BRAIN DEVELOPMENT, 1
Chapter 1 Neural Tube Formation and Prosencephalic Development, 3
Chapter 2 Neuronal Proliferation, Migration, Organization, and Myelination, 51
UNIT II NEUROLOGICAL EVALUATION, 119
Chapter 3 Neurological Examination: Normal and Abnormal Features, 121
Chapter 4 Specialized Studies in the Neurological Evaluation, 154
Chapter 5 Neonatal Seizures, 203
UNIT III HYPOXIC-ISCHEMIC ENCEPHALOPATHY, 245
Chapter 6 Hypoxic-Ischemic Encephalopathy: Biochemical and Physiological Aspects, 247
Chapter 7 Hypoxic-Ischemic Encephalopathy: Intrauterine Assessment, 325
Chapter 8 Hypoxic-Ischemic Encephalopathy: Neuropathology and Pathogenesis, 347
Chapter 9 Hypoxic-Ischemic Encephalopathy: Clinical Aspects, 400
UNIT IV INTRACRANIAL HEMORRHAGE, 481

Chapter 10 Intracranial Hemorrhage: Subdural, Primary Subarachnoid, Cerebellar,
Intraventricular (Term Infant), and Miscellaneous, 483
Chapter 11 Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage
of the Premature Infant, 517
UNIT V METABOLIC ENCEPHALOPATHIES, 589
Chapter 12 Hypoglycemia and Brain Injury, 591
Chapter 13 Bilirubin and Brain Injury, 619
Chapter 14 Hyperammonemia and Other Disorders of Amino Acid Metabolism, 652
Chapter 15 Disorders of Organic Acid Metabolism, 686
Chapter 16 Degenerative Diseases of the Newborn, 716
xiii
UNIT VI DISORDERS OF THE MOTOR SYSTEM, 745
Chapter 17 Neuromuscular Disorders: Motor System, Evaluation, and Arthrogryposis
Multiplex Congenita, 747
Chapter 18 Neuromuscular Disorders: Levels above the Lower Motor Neuron to the
Neuromuscular Junction, 767
Chapter 19 Neuromuscular Disorders: Muscle Involvement and Restricted Disorders, 801
UNIT VII INTRACRANIAL INFECTIONS, 849
Chapter 20 Viral, Protozoan, and Related Intracranial Infections, 851
Chapter 21 Bacterial and Fungal Intracranial Infections, 916
UNIT VIII PERINATAL TRAUMA, 957
Chapter 22 Injuries of Extracranial, Cranial, Intracranial, Spinal Cord, and Peripheral
Nervous System Structures, 959
UNIT IX INTRACRANIAL MASS LESIONS, 987
Chapter 23 Brain Tumors and Vein of Galen Malformations, 989
UNIT X DRUGS AND THE DEVELOPING NERVOUS SYSTEM, 1007
Chapter 24 Teratogenic Effects of Drugs and Passive Addiction, 1009
Index, 1055
xiv Contents
UNIT I

HUMAN BRAIN
DEVELOPMENT
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Chapter 1
Neural Tube Formation
and Prosencephalic Development
An understanding of the development of the nervous
system is essential for an understanding of neonatal
neurology. An obvious reason for this contention is
the wide variety of disturbances of neural development
that are flagrantly apparent in the neonatal period. In
addition, all the insults that affect the fetus and new-
born, and that are the subject matter of most of this
book, exert their characteristic effects in part because
the brain is developing in many distinctive ways and
at a very rapid rate. As I discuss further in Chapter 2,
a strong likelihood exists that many of these common
insults exert deleterious and far-reaching effects on cer-
tain aspects of neural development—effects that until
now have escaped detection by available techniques.
In Chapters 1 and 2, I emphasize the aspect of
normal development that has been deranged, the struc-
tural characteristics of the abnormality, and the neuro-
logical consequences. It is least profitable to attempt to
characterize exhaustively all the presumed causes of
these abnormalities of the developmental program.
Although a few examples of environmental agents
that insult the developing human nervous system at
specific time periods and produce a defect are recog-
nized, few of these agents leave an identifying stamp.

This obtains particularly because, in the first two tri-
mesters of gestation, the developing brain is not capa-
ble of generating the glial and other reactions to injury
that serve as useful clues to environmental insults that
occur at later time periods. The occasional example of a
virus, chemical, drug, or other environmental agent
that has been shown to produce a disorder of brain
development is mentioned only in passing. However,
I emphasize genetic considerations whenever possible
because of their importance in parental counseling.
Therefore, the organizational framework is the chro-
nology of normal development of the human nervous
system. A brief review of the major developmental
events that occur most prominently during each time
period is presented, followed by a discussion of the
disorders that result when such development is
deranged.
This chapter is devoted to the first two major pro-
cesses involved in human brain development: forma-
tion of the neural tube and the subsequent formation
of the prosencephalon. These early processes are dis-
cussed separately from later events because, together,
the early processes result in the essential form of the
central nervous system (CNS) and can be considered
the neural components of embryogenesis. The later
developmental events, relating largely to the intrinsic
structure of the CNS, can be considered the neural
components of fetal development.
MAJOR DEVELOPMENTAL EVENTS AND PEAK
TIMES OF OCCURRENCE

The major developmental events and their peak times
of occurrence are shown in Table 1-1. The time peri-
ods are those during which the most rapid progression of
the developmental event occurs. Although some over-
lap exists among these time periods, it is valid and con-
venient to consider the overall maturational process in
terms of a sequence of individual events.
Termination Period
In a discussion of the timing of the disorders, the time
periods shown in Table 1-1 are obviously of major
importance. Nonetheless, it is necessary to recognize
that an aberration of a developmental event need not
be caused by an insult impinging at the time of the event.
Thus, a given malformation may not have its onset after
the developmental event is completed, but the develop-
mental program may be injured at any time before the
event is under way. The concept of a termination period
(i.e., the time in the development of an organ after
which a specific malformation cannot occur by any ter-
atogenic mechanism) was enunciated by Warkany.
1
Thus, in the discussion of timing of malformations, I
state that the onset of a given defect could occur no later
than a given time.
PRIMARY NEURULATION AND CAUDAL
NEURAL TUBE FORMATION (SECONDARY
NEURULATION)
Normal Development
Neurulation refers to the inductive events that occur on
the dorsal aspect of the embryo and result in the for-

mation of the brain and spinal cord. These events can
be divided into those related to the formation of brain
and spinal cord exclusive of those segments caudal to
the lumbar region (i.e., primary neurulation) and those
related to the later formation of the lower sacral seg-
ments of the spinal cord (i.e., caudal neural tube formation
or secondary neurulation). Primary neurulation and sec-
ondary neurulation are discussed separately.
3
Primary Neurulation
Primary neurulation refers to formation of the neural
tube, exclusive of the most caudal aspects (see later).
The time period involved is the third and fourth weeks
of gestation (Table 1-2). The nervous system begins on
the dorsal aspect of the embryo as a plate of tissue
differentiating in the middle of the ectoderm (Fig. 1-1).
The underlying notochord and chordal mesoderm
induce formation of the neural plate, which is formed
at approximately 18 days of gestation.
2,3
Under the con-
tinuing inductive influence of the chordal mesoderm,
the lateral margins of the neural plate invaginate and
close dorsally to form the neural tube. During this clo-
sure, the neural crest cells are formed, and these cells
give rise to dorsal root ganglia, sensory ganglia of the
cranial nerves, autonomic ganglia, Schwann cells, and
cells of the pia and arachnoid (as well as melanocytes,
cells of the adrenal medulla, and certain skeletal ele-
ments of the head and face). The neural tube gives

rise to the CNS. The first fusion of neural folds
occurs in the region of the lower medulla at approxi-
mately 22 days. Closure generally proceeds rostrally and
caudally, although it is not a simple, zipper-like pro-
cess.
4-9
The anterior end of the neural tube closes at
approximately 24 days, and the posterior end closes at
approximately 26 days. This posterior site of closure is
at approximately the upper sacral level, and the most
caudal cord segments are formed by a different devel-
opmental process occurring later (i.e., canalization and
retrogressive differentiation, as discussed later).
10-12
Interaction of the neural tube with the surrounding
mesoderm gives rise to the dura and axial skeleton
(i.e., the skull and the vertebrae).
The deformations of the developing neural plate
required to form the neural folds, and subsequently
the neural tube, depend on a variety of cellular and
molecular mechanisms.
7-9,12-34
The most important
cellular mechanisms involve the function of the cyto-
skeletal network of microtubules and microfilaments.
Under the influence of vertically oriented microtu-
bules, cells of the developing neural plate elongate,
and their basal portions widen. Under the influence
of microfilaments oriented parallel to the apical
surface, the apical portions of the cells constrict.

These deformations produce the stresses that lead to
formation of the neural folds and then the neural tube.
A
A′
Neural plate
Ectoderm
AA′
Neural groove
Somite
Neural tube
Somite
Neural crest
Brain
Spinal cord
Spinal cord
(white matter)
Spinal cord
(gray matter)
Central canal
Somite
Figure 1-1 Primary neurulation. Schematic depiction of the develop-
ing embryo: external view (left) and corresponding cross-sectional view
(right) at about the middle of the future spinal cord. Note the formation
of the neural plate, neural tube, and neural crest cells. (From Cowan WM:
The development of the brain, Sci Am 241:113-133, 1979.)
TABLE 1-1 Major Events in Human Brain
Development and Peak Times of Occurrence
Major Developmental Event Peak Time Of Occurrence
Primary neurulation 3–4 weeks of gestation
Prosencephalic development 2–3 months of gestation

Neuronal proliferation 3–4 months of gestation
Neuronal migration 3–5 months of gestation
Organization 5 months of gestation to
years postnatally
Myelination Birth to years postnatally
TABLE 1-2 Primary Neurulation
Peak Time Period
3–4 weeks of gestation
Major Events
Notochord, chordal mesoderm ! neural plate ! neural
tube, neural crest cells
Neural tube ! brain and spinal cord ! dura, axial skeleton
(cranium, vertebrae), dermal covering
Neural crest ! dorsal root ganglia, sensory ganglia of cra-
nial nerves, autonomic ganglia, and so forth
4
Unit I HUMAN BRAIN DEVELOPMENT
Concerning molecular mechanisms, a particular role of
surface glycoproteins, particularly cell adhesion mole-
cules, involves cell-cell recognition and adhesive inter-
actions with extracellular matrix (i.e., to cause adhesion
of the opposing lips of the neural folds). Other critical
molecular events include action of the products of cer-
tain regional patterning genes (especially bone mor-
phogenetic proteins and sonic hedgehog), homeobox
genes, surface receptors, and transcription factors.
The relative importance of these molecular character-
istics is currently under intensive study.
Caudal Neural Tube Formation (Secondary
Neurulation)

Formation of the caudal neural tube (i.e., the lower
sacral and coccygeal segments) occurs by the sequential
processes of canalization and retrogressive differentia-
tion. These events, sometimes called secondary neurula-
tion, occur later than those of primary neurulation and
result in development of the remainder of the neural
tube (Table 1-3). At approximately 28 to 32 days, an
aggregate of undifferentiated cells at the caudal end of
the neural tube (caudal cell mass) begins to develop
small vacuoles. These vacuoles coalesce, enlarge, and
make contact with the central canal of the portion of
the neural tube previously formed by primary neurula-
tion.
2
Not infrequently, accessory lumens remain and
may be important in the genesis of certain anomalies of
neural tube formation (see later). The process of cana-
lization continues until approximately 7 weeks, when
retrogressive differentiation begins. During this phase,
from 7 weeks to sometime after birth, regression of
much of the caudal cell mass occurs. Remaining struc-
tures are the ventriculus terminalis, primarily located in
the conus medullaris, and the filum terminale.
Disorders
Disturbances of the inductive events involved in primary
neurulation result in various errors of neural tube clo-
sure, which are accompanied by alterations of axial skel-
eton as well as of overlying meningovascular and dermal
coverings. The resulting disorders are considered next,
in order of decreasing severity (Table 1-4). Disorders of

caudal neural tube formation (i.e., occult dysraphic
states) are discussed in the final section.
Craniorachischisis Totalis
Anatomical Abnormality. In craniorachischisis, essen-
tially total failure of neurulation occurs. A neural plate–
like structure is present throughout, and no overlying
axial skeleton or dermal covering exists (Fig. 1-2).
35,36
Timing and Clinical Aspects. Onset of craniora-
chischisis totalis is estimated to be no later than 20 to
22 days of gestation.
2
Because most such cases are
aborted spontaneously in early pregnancy, and only a
few have survived to early fetal stages, the incidence is
unknown.
Anencephaly
Anatomical Abnormality. The essential defect of an-
encephaly is failure of anterior neural tube closure.
Thus, in the most severe cases, the abnormality extends
from the level of the lamina terminalis, the site of final
closure at the most rostral portion of the neural tube, to
the foramen magnum, the approximate site of onset of
anterior neural tube closure.
2,36
When the defect in the
skull extends through the level of the foramen
magnum, the abnormality is termed holoacrania or holo-
anencephaly. If the defect does not extend to the foramen
magnum, the appropriate term is meroacrania or mero-

anencephaly. The most common variety of anencephaly
is involvement of the forebrain and variable amounts of
upper brain stem. The exposed neural tissue is repre-
sented by a hemorrhagic, fibrotic, degenerated mass of
neurons and glia with little definable structure. The
frontal bones above the supraciliary ridge, the parietal
bones, and the squamous part of the occipital bone are
usually absent. This anomaly of the skull imparts a
remarkable, froglike appearance to the patient when
viewed face on (Fig. 1-3).
Timing and Clinical Aspects. Onset of anencephaly is
estimated to be no later than 24 days of gestation.
2
Polyhydramnios is a frequent feature.
37
Approxi-
mately 75% of the infants are stillborn, and the remain-
der die in the neonatal period (see later). The disorder
is not rare, and epidemiological studies reveal striking
variations in prevalence as a function of geographical
location, sex, ethnic group, race, season of the year,
maternal age, social class, and history of affected sib-
lings.
36,38-42
Anencephaly is relatively more common in
whites than in blacks, in the Irish than in most other
ethnic groups, in girls than in boys (especially in pre-
term infants), and in infants of particularly young or
particularly old mothers.
36,39,43

The risk increases
with decreasing social class and with the history of
TABLE 1-3 Caudal Neural Tube Formation
(Secondary Neurulation)
Peak Time Period
Canalization: 4–7 weeks of gestation
Retrogressive differentiation: 7 weeks of gestation to after
birth
Major Events
Canalization: undifferentiated cells (caudal cell mass) !
vacuoles ! coalescence ! contact central canal of ros-
tral neural tube
Retrogressive differentiation: regression of caudal cell mass
! ventriculus terminalis, filum terminale
TABLE 1-4 Disorders of Primary Neurulation:
Neural Tube Defects
Order of Decreasing Severity
Craniorachischisis totalis
Anencephaly
Myeloschisis
Encephalocele
Myelomeningocele, Chiari type II malformation
Chapter 1
Neural Tube Formation and Prosencephalic Development 5
affected siblings in the family. Since the late 1970s,
the incidence of anencephaly, like that of myelomenin-
gocele (see later), has been declining. Rates of occur-
rence of anencephaly decreased from approximately 0.4
to 0.5 per 1000 live births in 1970 to approximately 0.2
per 1000 live births in 1989.

40,44
In the United States
this decline has been more apparent in Hispanic and
non-Hispanic white infants than in black infants,
40,45-47
and this finding is of potential relevance to pathogene-
sis. Both genetic and environmental influences appear
to operate in the genesis of anencephaly (see the
later discussion of myelomeningocele). This defect is
identified readily prenatally by cranial ultrasonography
in the second trimester of gestation (Fig. 1-4).
48
A B
Figure 1-3 Anencephaly. Face-on (A) and dorsal (B) views. (Courtesy of Dr. Ronald Lemire.)
A B
Figure 1-2 Craniorachischisis. Dorsal (A) and dorsolateral (B) views of a human fetus. (Courtesy of Dr. Ronald Lemire.)
6 Unit I HUMAN BRAIN DEVELOPMENT
Systematic prenatal detection and elective termination
of pregnancy of all infants with anencephaly resulted
in no anencephalic births over a 2-year period in one
large university hospital in the eastern United States.
46
Renewed investigation of the neurological function
and survival of anencephalic infants was provoked by
interest in the 1990s in the use of organs of such infants
for transplantation.
49-53
Because lack of function of the
entire brain, including the brain stem, is obligatory for
the diagnosis of brain death in the United States, the

finding of persistent clinical signs of brain stem function
of anencephalic infants supported by neonatal intensive
care in the first week of life is of major importance
(Table 1-5).
54-56
Moreover, with such neonatal inten-
sive care, including intubation, most infants survived
for at least 7 days after extubation (Table 1-6).
54
This
survival with intensive care is strikingly different from
the situation with no intensive care, in which no more
than 2% of liveborn anencephalic infants survive to 7
days (see Table 1-6).
39,57,58
The persistence of brain
stem function and of viability is consistent with the
not uncommon finding at neuropathological study of
a rudimentary brain stem.
36,39
Myeloschisis
Anatomical Abnormality. The essential defect of
myeloschisis is failure of posterior neural tube closure.
A neural plate–like structure involves large portions of
the spinal cord and manifests as a flat, raw, velvety struc-
ture with no overlying vertebrae or dermal covering.
Timing and Clinical Aspects. Onset of myeloschisis
is no later than 24 days of gestation.
2
Most infants with

myeloschisis are stillborn and merge with the category
of more restricted defect of neural tube closure (i.e.,
myelomeningocele). Myeloschisis is often associated
with anomalous formation of the base of skull and
upper cervical region that results in retroflexion of
the head on the cervical spine.
59,60
This constellation
is termed iniencephaly.
Encephalocele
Anatomical Abnormality. Encephalocele may be
envisioned as a restricted disorder of neurulation involving
anterior neural tube closure. This concept, however, must
be understood with the awareness that the precise
pathogenesis of this disorder remains unknown. The
lesion occurs in the occipital region in 70% to 80% of
cases (Fig. 1-5).
61-65
A less common site is the frontal
region, where the encephalocele may protrude into the
nasal cavity. Cases of frontal lesions are relatively more
common in Southeast Asia than in Western Europe or
North America.
66-68
Least common lesion sites are the
temporal and parietal regions.
69
In the typical occipital
encephalocele, the protruding brain is usually derived
from the occipital lobe and may be accompanied by

dysraphic disturbances involving cerebellum and supe-
rior mesencephalon. The neural tissue in an encepha-
locele usually connects to the underlying CNS through
a narrow neck of tissue. The protruding mass, most
often occipital lobe, is represented usually by a closed
neural tube with cerebral cortex, exhibiting a normal
gyral pattern, and subcortical white matter. As many as
50% of cases are complicated by hydrocephalus.
70
Encephaloceles located in the low occipital (below the
inion) or high cervical regions and combined with
deformities of lower brain stem and of base of skull
and upper cervical vertebrae characteristic of the
Chiari type II malformation (associated with myelome-
ningocele [see later]) comprise the Chiari type III mal-
formation.
71
This type of encephalocele contains
O
Figure 1-4 Ultrasonogram of anencephaly at 17 weeks of gesta-
tion. Note the symmetrical absence of normal structures superior to
the orbits (O). (From Goldstein RB, Filly RA: Prenatal diagnosis of anen-
cephaly: Spectrum of sonographic appearances and distinction from
the amniotic band syndrome, AJR Am J Roentgenol 151:547-550,
1988.)
TABLE 1-5 Brain Stem Function in Anencephaly
Clinical Feature Number (Total n = 12)
Reactive pupils 3
Spontaneous eye movements 4
Oculocephalic responses 6

Corneal reflex 6
Auditory response 5
Suck, root, and gag responses 7
Spontaneous respiration 12
Adapted from data in Peabody JL, Emery JR, Ashwal S: Experience with
anencephalic infants as prospective organ donors, N Engl J Med
321:344-350, 1989.
TABLE 1-6 Survival in Anencephaly
No Intensive Care (n = 181)*
40% alive at 24 hours
15% alive at 48 hours
2% alive at 7 days
None alive at 14 days
Intensive Care (n = 6)
{
Birth to 7 days: 5/6 alive at 7 days
After extubation: death at 8 days (2/5), 16 days (1/5),
3 weeks (1/5), and 2 months (1/5)
*Data from Baird PA, Sadovnick AD: Survival in infants with anen-
cephaly, Clin Pediatr 23:268-271, 1984.
{
Data from Peabody JL, Emery JR, Ashwal S: Experience with anen-
cephalic infants as prospective organ donors, N Engl J Med
321:344-350, 1989.
Chapter 1 Neural Tube Formation and Prosencephalic Development 7
cerebellum in virtually all cases and occipital lobes in
approximately one half of cases (Fig. 1-6).
71
Partial or
complete agenesis of the corpus callosum occurs in two

thirds of cases. Anomalies of venous drainage (aberrant
sinuses and deep veins) occur in about one half of
patients and must be considered in surgical approaches
to these lesions.
71
Timing and Clinical Aspects. Onset of the most
severe lesions is probably no later than the approximate
time of anterior neural tube closure (26 days) or shortly
thereafter. Later times of onset are likely for the lesions
that involve primarily or only the overlying meninges or
skull.
36
(Approximately 10% to 20% of the occipital
lesions contain no neural elements and thus are
appropriately referred to as meningoceles.) Infants with
encephaloceles not uncommonly exhibit associated
malformations.
64,72
A frequent CNS anomaly is subep-
endymal nodular heterotopia.
73
The most commonly
recognized syndromes associated with encephalocele
are Meckel syndrome (characterized by occipital ence-
phalocele, microcephaly, microphthalmia, cleft lip and
palate, polydactyly, polycystic kidneys, ambiguous gen-
italia, other deformities
66
) and Walker-Warburg
syndrome (see Chapters 2 and 19). These disorders,

as well as several other less common syndromes asso-
ciated with encephalocele, are inherited in an autoso-
mal recessive manner.
64,72,74
Maternal hyperthermia
A
B
Figure 1-5 Encephalocele. A, Newborn
with a large occipital encephalocele. B,
Newborn with both an occipital encephalo-
cele and a thoracolumbar myelomeningo-
cele. (Courtesy of Dr. Marvin Fishman.)
M
Figure 1-6 Encephalocele. Midline sagittal spin echo 700/20 mag-
netic resonance imaging scan demonstrates a low occipital encepha-
locele containing cerebellar tissue. The cystic portions (asterisk) within
the herniated cerebellum are of uncertain origin. The posterior aspect
of the corpus callosum (straight black arrows) is not clear and is prob-
ably dysgenetic. The third ventricle is not seen, but the massa inter-
media (M) is very prominent. The tectum is deformed and is not readily
identified. The fourth ventricle (arrowhead) is deformed and displaced
posteriorly. A syrinx (curved white arrows) is present in the middle to
lower cervical spinal cord. (From Castillo M, Quencer RM, Dominguez R:
Chiari III malformation: Imaging features, AJNR Am J Neuroradiol
13:107-113, 1992.)
8 Unit I HUMAN BRAIN DEVELOPMENT
between 20 and 28 days of gestation has been associ-
ated with an increased incidence of occipital encepha-
locele,
72

as well as with other neural tube defects (see
later). Diagnosis by intrauterine ultrasonography in the
second trimester has been well documented.
75-79
Diagnosis before fetal viability has been followed by
elective termination; later diagnosis may allow delivery
by cesarean section.
Neurosurgical intervention is indicated in most
patients.
62,64
Exceptions include those with massive
lesions and marked microcephaly. Surgery is necessary
in the neonatal period for ulcerated lesions that are
leaking cerebrospinal fluid (CSF). An operation can
be deferred if adequate skin covering is present.
Preoperative evaluation has been facilitated by the use
of computed tomography (CT) and, especially, mag-
netic resonance imaging (MRI) scans.
71,80,81
Outcome
is difficult to determine precisely because of variability
in selection for surgical treatment. In a combined sur-
gical series of 40 infants,
62,63
15 infants (38%) died,
many of whose complications can be managed more
effectively now in neurosurgical facilities. Of the
25 survivors, 14 (56%) were of normal intelligence,
although often with motor deficits, and 11 (44%)
exhibited both impaired intellect and motor deficits.

Outcome is more favorable for infants with anterior
encephaloceles than those with posterior encephalo-
celes. Thus, in one series of 34 cases, mortality was
45% for infants with posterior defects and 0% for
those with anterior defects. Normal outcome occurred
in 14% of the total group with posterior defects and in
42% of those with anterior defects.
64
Myelomeningocele
Anatomical Abnormality. The essential defect in
myelomeningocele is restricted failure of posterior neural
tube closure. Approximately 80% of lesions occur in
the lumbar (thoracolumbar, lumbar, lumbosacral)
area, presumably because this is the last area of the
neural tube to close.
62
The neural lesion is represented
by a neural plate or abortive neural tube–like structure
in which the ventral half of the cord is relatively less
affected than the dorsal. Most of the lesions are asso-
ciated with dorsal displacement of the neural tissue,
such that a sac is created on the back (Fig. 1-7). This
dorsal protrusion is associated with an enlarged sub-
arachnoid space ventral to the cord. The axial skeleton
is uniformly deficient, and an incomplete although
variable dermal covering is present. The defects of the
spinal column were studied in detail by Barson
82
and
consist of a lack of fusion or an absence of the vertebral

arches, resulting in bilateral broadening of the verte-
brae, lateral displacement of pedicles, and a widened
spinal canal. The caudal extent of the vertebral changes
is usually considerably greater than the extent of the
neural lesion.
Timing. Onset of myelomeningocele is probably no
later than 26 days of gestation.
2
This period in the
fourth week of gestation is the time for normal neural
tube closure. Studies of early human embryos with dys-
raphic states support this conclusion by providing histo-
logical evidence for dysraphism at developmental stages
before completion of neural tube closure.
83
Clinical Aspects. Myelomeningocele and its variants
are the most important examples of faulty neurulation,
because affected infants usually survive. As with anen-
cephaly, earlier studies showed the highest incidences
in certain areas of Ireland, Great Britain, northern
Netherlands, and northern China.
41,42
A large variation
in incidences in the United States is apparent, ranging
in earlier studies from 0.6 per 1000 live births in
Memphis, Tennessee, to 2.5 per 1000 in Providence,
Rhode Island.
40,84
Over approximately the last 2 to
3 decades, the incidence has declined in Great

Britain, the United States, and several other countries,
even before the advent of folic acid supplementation
Figure 1-7 Newborn with a large thoracolumbar myelome-
ningocele. The white material is vernix. Note the neural plate–
like structure in the middle of the lesion. (Courtesy of Dr.
Marvin Fishman.)
Chapter 1 Neural Tube Formation and Prosencephalic Development 9
(see later).
40-42,44,85-95
In the United States, overall
incidences of myelomeningocele were 0.5 to 0.6 per
1000 live births in 1970 and 0.2 to 0.4 per 1000 live
births in 1989.
40
In California, the incidence per 1000
live births in 1994 was 0.47 in non-Hispanic whites,
0.42 in Hispanics, 0.33 in African Americans, and
0.20 in Asians.
41,42
The major clinical features relate primarily to the
nature of the primary lesion, the associated neurologi-
cal features, and hydrocephalus. Approximately 80% of
myelomeningoceles seen at birth occur in the lumbar,
thoracolumbar, or lumbosacral regions (see Fig. 1-7).
Neural tissue of most lesions appears platelike.
Neurological Features. The disturbances of neuro-
logical function, of course, depend on the level of the
lesion. Particular attention should be paid to examina-
tion of motor, sensory, and sphincter function.
Moreover, in the first days of life, motor function sub-

served by segments caudal to the level of the lesion is
common, but then it generally disappears after the first
postnatal week.
96
Table 1-7 lists some of the important
correlations among motor, sensory, and sphincter
function, reflexes, and segmental innervation. Assess-
ment of the functional level of the lesion allows reason-
able estimates of potential future capacities. Thus,
most patients with lesions below S1 ultimately are
able to walk unaided, whereas those with lesions
above L2 usually are wheelchair dependent for at
least a major portion of their activities.
97-102
Approxi-
mately one half of patients with intermediate lesions are
ambulatory (L4, L5) or primarily ambulatory (L3) with
braces or other specialized devices and crutches. Con-
siderable variability exists between subsequent ambu-
latory status and apparent neurological segmental level,
especially in patients with midlumbar lesions.
100,103,104
Good strength of iliopsoas (hip flexion) and of quadri-
ceps (knee extension) muscles is an especially impor-
tant predictor of ambulatory potential rather than
wheelchair dependence.
103,104
Deterioration to a
lower level of ambulatory function than that expected
from segmental level occurs over years, and this

tendency is worse in the absence of careful manage-
ment. In addition, patients with lesions as high as
thoracolumbar levels, at least as young children, can
use standing braces or other specialized devices to be
upright and can be taught to ‘‘swivel walk.’’
98,105
Indeed, continuing improvements in ambulatory aids
and their use are constantly increasing the chances
for ambulation in children with higher lesions (see
‘‘Results of Therapy’’).
Segmental level also is an important determinant of
the likelihood of development of scoliosis. Most
patients with lesions above L2 ultimately exhibit signif-
icant scoliosis, whereas this complication is unusual in
patients with lesions below S1.
Hydrocephalus. Several clinical features are helpful
in evaluating the possibility of hydrocephalus. First, on
examination, the status of the anterior fontanelle and the
cranial sutures should be noted. A full anterior fontanelle
and split cranial sutures are helpful signs for the diag-
nosis of increased intracranial pressure, if the menin-
gomyelocele is not leaking CSF. In the latter case, the
CSF leak at the site of the primary lesion serves as
decompression, and the signs may be absent.
Evaluation of the head size provides useful information.
If the head circumference is more than the 90th per-
centile, approximately a 95% chance exists that appre-
ciable ventricular enlargement is present.
106
If the head

circumference is less than the 90th percentile, an
approximately 65% chance of hydrocephalus still
exists.
106
The site of the lesion is also helpful in predicting
the presence or imminent development of hydroceph-
alus. With occipital, cervical, thoracic, or sacral lesions,
the incidence of hydrocephalus is approximately 60%;
with thoracolumbar, lumbar, or lumbosacral lesions,
the incidence of hydrocephalus is approximately 85%
to 90%.
106-108
Signs of increased intracranial pressure are not pre-
requisites for the diagnosis of hydrocephalus in the
newborn and, indeed, are observed in only approxi-
mately 15% of newborns with myelomeningocele.
109
Serial ultrasound scans are important because progres-
sive ventricular dilation, without rapid head growth or
signs of increased intracranial pressure, occurs in
infants with myelomeningocele,
109,110
in a manner
analogous to the development of hydrocephalus after
TABLE 1-7 Correlations Among Motor, Sensory, and Sphincter Function, Reflexes, and Segmental Innervation
Major
Segmental
Innervation* Motor Function Cutaneous Sensation Sphincter Function Reflex
L1–L2 Hip flexion Groin (L1) — —
Anterior, upper thigh (L2)

L3–L4 Hip adduction Anterior, lower thigh and knee (L3) — Knee jerk
Knee extension Medial leg (L4)
L5–S1 Knee flexion Lateral leg and medial foot (L5) — Ankle jerk
Ankle dorsiflexion Sole of foot (S1)
Ankle plantar flexion
S1–S4 Toe flexion Posterior leg and thigh (S2) Bladder and
rectal function
Anal wink
Middle of buttock (S3)
Medial buttock (S4)
*Segmental innervation for motor and sensory functions overlaps considerably; correlations shown are approximate.
10 Unit I HUMAN BRAIN DEVELOPMENT