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VOLPE’S
Neurology of the
Newborn
This page intentionally left blank
VOLPE’S
Neurology of the
Newborn Sixth Edition

EDITOR-IN-CHIEF
Joseph J. Volpe, MD
Bronson Crothers Professor of Neurology, Emeritus
Harvard Medical School
Neurologist-in-Chief, Emeritus
Boston Children’s Hospital
Boston, Massachusetts

EDITORS
Terrie E. Inder, MBChB, MD Adré J. du Plessis, MBChB, MPH
Mary Ellen Avery Professor of Pediatrics in Division of Fetal and Transitional Medicine
the Field of Newborn Medicine Fetal Medicine Institute
Harvard Medical School Children’s National Medical Center
Chair, Department of Pediatrics/Newborn Medicine Washington, District of Columbia
Brigham and Women’s Hospital
Boston, Massachusetts Jeffrey J. Neil, MD, PhD
Professor of Neurology
Basil T. Darras, MD Department of Neurology
Joseph J. Volpe Chair in Neurology Boston Children’s Hospital
Harvard Medical School Boston, Massachusetts
Associate Neurologist-in-Chief
Chief, Division of Clinical Neurology Jeffrey M. Perlman, MBChB
Boston Children’s Hospital Professor of Pediatrics
Boston, Massachusetts Department of Pediatrics
Weill Cornell Medical College
Linda S. de Vries, MD, PhD Division Chief, Newborn Medicine
Consultant Neonatologist New York Presbyterian Hospital
Wilhelmina Children’s Hospital New York, New York
Professor in Neonatal Neurology
University Medical Center Utrecht
Utrecht, The Netherlands
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

VOLPE’S NEUROLOGY OF THE NEWBORN, SIXTH EDITION ISBN: 978-0-323-42876-7

Copyright © 2018 by Elsevier, Inc. All rights reserved.

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Notices

Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional practices, or
medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein.
In using such information or methods they should be mindful of their own safety and the
safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, 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 their patients, to make diagnoses, to determine
dosages and the best treatment for each individual patient, and to take all appropriate safety
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To the fullest extent of the law, neither the Publisher nor the authors, contributors, or
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Previous editions copyrighted 2008 and 2001.

Library of Congress Cataloging-in-Publication Data

Names: Volpe, Joseph J., editor. | Preceded by (work): Volpe, Joseph J.

Neurology of the newborn.
Title: Volpe’s neurology of the newborn / editors, Joseph J. Volpe [and 6 others].
Other titles: Neurology of the newborn
Description: Sixth edition. | Philadelphia, PA : Elsevier, [2018] | Preceded
by Neurology of the newborn / Joseph J. Volpe. 5th ed. c2008. | Includes
bibliographical references and index.
Identifiers: LCCN 2017036645 | ISBN 9780323428767 (hardcover : alk. paper)
Subjects: | MESH: Nervous System Diseases | Infant, Newborn, Diseases |
Infant, Newborn
Classification: LCC RJ290 | NLM WS 340 | DDC 618.92/01–dc23
LC record available at https://lccn.loc.gov/2017036645

Executive Content Strategist: Kate Dimock

Senior Content Development Specialist: Janice Gaillard
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Claire Kramer
Designer: Bridget Hoette

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 To my wife,
Sara,
for her love and understanding,
without which this book would not be possible
 Contributors

Nicholas S. Abend, MD Partha S. Ghosh, MD

Associate Professor of Neurology Assistant Professor
Children’s Hospital of Philadelphia Department of Neurology
Perelman School of Medicine Harvard Medical School
University of Pennsylvania Director, EMG Laboratory
Philadelphia, Pennsylvnania Boston Children’s Hospital
Boston, Massachsuetts

Stephen A. Back, MD, PhD

Professor of Pediatrics and Neurology Petra S. Hüppi, MD
Clyde and Elda Munson Professor of Pediatric Research Professor of Pediatrics
Director, Neuroscience Section Chief, Division of Development and Growth
Papé Family Pediatric Research Institute Chilren’s Hospital
Oregon Health and Science University University of Geneva
Portland, Oregon Geneva, Switzerland

Basil T. Darras, MD Terrie E. Inder, MBChB, MD

Joseph J. Volpe Chair in Neurology Mary Ellen Avery Professor of Pediatrics in the Field of
Harvard Medical School Newborn Medicine
Associate Neurologist-in-Chief Harvard Medical School
Chief, Division of Clinical Neurology Chair, Department of Pediatrics/Newborn Medicine
Boston Children’s Hospital Brigham and Women’s Hospital
Boston, Massachusetts Boston, Massachusetts

Linda S. de Vries, MD, PhD Frances E. Jensen, MD, FACP

Consultant Neonatologist Professor of Neurology
Wilhelmina Children’s Hospital Department of Neurology
Professor in Neonatal Neurology Hospital of the University of Pennsylvania
University Medical Center Utrecht Perelman School of Medicine
Utrecht, The Netherlands University of Pennsylvania
Philadelphia, Pennsylvania

Adré J. du Plessis, MBChB, MPH

Division of Fetal and Transitional Medicine Hannah C. Kinney, MD
Fetal Medicine Institute Department of Pathology
Children’s National Medical Center Boston Children’s Hospital
Washington, District of Columbia Harvard Medical School
Boston, Massachusetts

Christopher M. Elitt, MD, PhD

Assistant in Neurology Catherine Limperopoulos, PhD
Department of Neurology Director, The Developing Brain Research Program
Fetal-Neonatal Neurology Program Vice-Chair, Radiology Research
Boston Children’s Hospital Diagnostic Imaging and Radiology
Instructor of Neurology Children’s National Health System
Harvard Medical School Washington, District of Columbia
Boston, Massachusetts

vi
 Contributors vii

Christopher C. McPherson, PharmD Shenandoah Robinson, MD, FAAP, FACS

Assistant Professor of Pediatrics and Clinical Pharmacist Professor of Neurosurgery and Neurology - PAR
Departments of Pediatrics and Pharmacy Division of Pediatric Neurosurgery
Washington University School of Medicine and St. Louis Johns Hopkins University School of Medicine
Children’s Hospital Baltimore, Maryland
St. Louis, Missouri

Joseph J. Volpe, MD
Jeffrey J. Neil, MD, PhD Bronson Crothers Professor of Neurology, Emeritus
Professor of Neurology Harvard Medical School
Department of Neurology Neurologist-in-Chief, Emeritus
Boston Children’s Hospital Boston Children’s Hospital
Boston, Massachusetts Boston, Massachusetts

Jeffrey M. Perlman, MBChB Lianne J. Woodward, PhD

Professor of Pediatrics Professor of Pediatrics
Department of Pediatrics Pediatric Newborn Medicine
Weill Cornell Medical College Harvard Medical School
Division Chief, Newborn Medicine Brigham and Women’s Hospital
New York Presbyterian Hospital Boston, Massachsuetts
New York, New York

Annapurna Poduri, MD
Department of Neurology
Harvard Medical School and Epilepsy Genetics Program
Department of Neurology
Boston Children’s Hospital
Boston, Massachusetts
 Preface to the Sixth Edition

In the preface to the first edition of this book, published more increased from four to nine chapters. The principal changes
than 35 years ago, I expressed the view that the neurology involved separation of the discussions of the preterm and term
of the newborn “should be viewed as a discipline in its own infant because the etiologies, neuropathology, pathophysiology,
right.” Over the decades, through four subsequent editions, and clinical features exhibit many differences and unique
the evolution of this discipline has been extraordinary. Work aspects. The chapters on neuropathology, especially, reflect new
relevant to neonatal neurology now is abundant in clinical insights gained by application of advanced neuropathological
journals in the fields of pediatrics, neurology, neonatology, techniques, those on pathophysiology, the impact of many
perinatology, and obstetrics, among others, and in multiple relevant neurobiological and clinical research studies, and
scientific journals of the many neurobiological disciplines. those on clinical features, the knowledge gained from advanced
The explosion of information in the field led me to conclude neuroimaging and the remarkable advances in therapeutic
several years ago that single authorship is no longer feasible, interventions. Unit V, concerned with intracranial hemorrhage,
especially if the quality of the book is to be at the highest level. includes a separate chapter on cerebellar hemorrhage and
With the prompting of Kate Dimock and others of the Elsevier the impact thereof on cognitive and related outcomes. The
team, I decided to embark on a multiauthored effort. Thus chapter on intraventricular hemorrhage and posthemorrhagic
this edition has been updated and revised with remarkable hydrocephalus in the preterm infant expands on previous
efforts from 5 editors and 12 additional authors. The editors discussions, especially of management, that are based on recent
and authors are particularly meaningful to me because they clinical investigations. Unit VI, concerned with metabolic
are former trainees, current colleagues, or both. They are truly encephalopathies, includes insights from clinical and basic
experts and in this edition have tolerated my compulsive editing research into hypoglycemia and hyperbilirubinemia, particularly
and sometimes incessant suggestions for each chapter. In management thereof, as well as important updates on neonatal
addition to their great skills as scholars, they have proven to be amino acid and organic acid disorders. Unit VII is a single
markedly resilient and tolerant of my often intrusive role in each chapter on degenerative disorders, specifically those that
chapter. present clinically in the newborn period. Insights obtained
The organization of the sixth edition is identical to that of from recent studies of molecular genetics, clinical features, and
previous editions. However, in addition to extensive updating, novel interventions are emphasized. Unit VIII, which covers
revising, and rewriting, many original chapters have been split neuromuscular disorders, has been expanded to four chapters,
into multiple chapters. The first eight chapters constitute the with a new chapter on arthrogryposis. These chapters reflect the
unit on human brain development, which were previously enormous advances in this field in delineation of phenotypes,
contained in two chapters. Particular expansion of this diagnosis, and interventions. The roles of molecular genetics
unit reflects new insights into the neurobiology of brain in disease characterization and gene manipulation therapies
development, fetal diagnosis, intrauterine interventions, and in interventions are among the new areas of emphasis in
molecular genetics. A major expansion of the discussion of brain neuromuscular disorders. Unit IX, which covers intracranial
organizational events of the third trimester of gestation was infections, remains as two chapters, but they have been
undertaken to accommodate the explosion of brain information expanded considerably. Important insights provided by modern
from advanced neuroimaging of normal cerebral cortical and neuroimaging and the advent of new therapies are emphasized.
white matter development and derangements thereof in the Unit X, which is on perinatal trauma, remains a single chapter
human premature infant. Unit II, concerning the neurological about injuries of extracranial, cranial, intracranial, spinal
evaluation, was expanded to describe new methodologies, cord, and peripheral nervous system structures, expanded by
especially advanced MRI techniques, to study the newborn insights obtained from modern neuroimaging. Unit XI, which
brain. A new chapter on neurodevelopmental follow-up was is about intracranial mass lesions, includes a chapter on brain
added to this unit. My longstanding devotion to the neurological tumors and vein of Galen malformations that provides new
examination and the importance thereof is reflected in its own insights into molecular characterization of tumors, clinical
dedicated chapter. Unit III, which focuses on neonatal seizures, features, and advances in management. Unit XII, which covers
serves as an effective bridge between the initial chapters and drugs and the developing nervous system, remains a single
the later, diseased-focused chapters because neonatal seizure chapter, with particularly new insights into clinical features
is a key manifestation of many of the neurological disorders and treatment. The impact of recent surges in opioid abuse
dealt with later in the book. The discussion of neonatal and the effects on the newborn are among the areas of special
seizures reflects the impact of new neurobiological insights emphasis.
(e.g., chloride channels, GABA excitation) and their importance Concerning the specific editors and authors who contributed
for understanding the newborn’s propensity to seizures, the to the sixth edition of Volpe’s Neurology of the Newborn, the
impact on subsequent brain development, and the effects of critical first unit, as noted earlier, was expanded from two to
anticonvulsant medications. Unit IV, concerned with hypoxic- eight chapters. The first four of these chapters were updated
ischemic and related disorders, the largest unit of the book, was and revised by one of my first neonatal neurology fellows at

viii
 Preface to the Sixth Edition ix

Washington University in St. Louis and later a faculty member at Washington University in St. Louis) and as a brilliant
in neonatal neurology with me in Boston, Dr. Adré du Plessis, clinician and clinical investigator taught me a great deal about
who has developed especial expertise in disorders of neural tube the critical nonneurological aspects of the sick newborn and
formation, prosencephalic development, fetal ventriculomegaly, the importance thereof in the genesis of neurological illness.
and cerebellar development and the clinical impact of defects Over the years he has been an admired colleague who now
thereof. Dr. Annapurna Poduri, a child neurology resident and leads a major neonatology program at Cornell University in
later member of the faculty in the Department of Neurology that New York.
I led at Boston Children’s Hospital, is an accomplished expert Unit VII was updated with the help of Dr. Christopher Elitt,
in cerebral cortical development, especially proliferative and a fellow in neonatal neurology with me at Boston Children’s
migrational defects, and genetic disorders thereof. Dr. Hannah Hospital and now a junior faculty member here. The final
Kinney, a distinguished neuropathologist and my longtime product in this important area reflects his strong background in
colleague at Boston Children’s Hospital, is a pioneer in the neuroscience and molecular genetics and his ability to tolerate
application of advanced neuropathological techniques to the my incessant critiquing of his generally fine work in updating
study of organizational events and myelination of the brain, this chapter.
especially premature and early infant brain. Unit VIII was updated and revised by Dr. Basil Darras,
Particularly involved in the update/revision of Unit II was my closest colleague at Boston Children’s Hospital during
Dr. Jeffrey Neil, a former child neurology resident and fellow my tenure as Chair of Neurology from 1990–2005. I am
during my years at Washington University in St. Louis. Dr. especially proud that he holds a Neurology Chair in my
Neil, who is now a colleague in Neurology at Boston Children’s name. He remains an esteemed colleague and a trusted
Hospital, is internationally recognized for his expertise and friend. His stature in the neuromuscular field is recognized
innovation in advanced MR methodologies, especially as applied internationally and is reflected in part by his leading role in the
to premature infants. The only new chapter in the book, which outstanding book Neuromuscular Disorders of Infancy, Childhood and
is on neurodevelopmental follow-up, was prepared by Dr. Adolescence.
Petra Huppi, a neonatal neurology fellow with me in Boston Unit IX on intracranial infections, constituting two chapters,
at the turn of the century when she carried out pioneering was updated by Dr. Linda de Vries. She is an admired leader
research on the application of MR methodologies to the study in our field, with whom I have had the privilege of previously
of the premature brain and who is currently a leading figure in coauthoring. Her great expertise in neuroimaging and all aspects
neurodevelopment, and by Dr. Lianne Woodward, an esteemed of clinical research in neonatal neurology is reflected in the
colleague in the Department of Pediatric Newborn Medicine two chapters.
at Harvard Medical School. Unit XI is a single chapter that was greatly enriched by the
Especially involved in the update/revision of Unit III was a work of my former colleague at Boston Children’s Hospital,
former colleague in my Department of Neurology at Boston Dr. Shenandoah (Dody) Robinson. As a leading pediatric
Children’s Hospital, Dr. Frances Jensen (currently Chair of neurosurgeon, she enhanced the chapter with new insights
Neurology at the University of Pennsylvania). Her work on the into surgical approaches and results, as well as molecular aspects
pathophysiology of neonatal seizures has been seminal. Her of tumor classification and clinical characteristics.
colleague, also formerly with us in Boston, Dr. Nicholas Abend, The final unit consists of a single chapter updated by Dr.
contributed importantly to the update. Dr. Terrie Inder (see Lianne Woodward and Dr. Christopher McPherson. The
later) my former trainee and current colleague, also contributed latter, a particular expert on the pharmacology of drugs in
in a major way to this chapter. the developing fetus and newborn, was a colleague during his
Unit IV, the largest unit of the book, now includes nine recent period on the faculty in Pediatric Newborn Medicine
chapters. The update/revisions were led by Dr. Inder (see at the Brigham and Women’s Hospital.
later), Dr. Kinney, Dr. Neil, and Dr. Back. The first three Particular recognition should be accorded to Dr. Terrie
are current colleagues in Boston, and Dr. Stephen Back, Inder who has authored/coauthored multiple chapters and,
currently at Oregon Health Sciences University, was a former importantly, has interacted copiously with Elsevier concerning
child neurology resident and postdoctoral fellow with us at myriad details involved in generating a finished product. After
Boston Children’s Hospital. He is now recognized as a world completing her training in neonatology in New Zealand, Terrie
leader in the pathophysiology of brain injury in the premature trained with me in Boston in the late 1990s as a resident in
infant. Exceptional expertise also is apparent in relation to child neurology and then as a fellow in neonatal neurology.
clinical features (Dr. Inder), neuroimaging (Dr. Neil), and During that period she spearheaded seminal studies of preterm
neuropathology (Dr. Kinney). brain by advanced MR techniques, which she used also in
Unit V includes major efforts by Dr. Terrie Inder (see later), subsequent years with distinguished academic positions in
Dr. Catherine Limperopoulos, and Dr. Jeff Perlman (see later). New Zealand, Australia, and St. Louis and finally as Chair
Dr. Limperopoulos was a fellow in neonatal neurology in my of Pediatric Newborn Medicine here (Brigham and Women’s
Department of Neurology at Boston Children’s Hospital, when Hospital and Harvard Medical School).
I had the privilege of working with her during her initial work My colleagues in this undertaking have been aided
on the developing cerebellum. She has established her own immeasurably by many people. My assistant for the past 25 years,
program at George Washington University and has developed Irene Miller, typed manuscripts, prepared tables, manipulated
greatly her widely recognized research in the study of the thousands of references, checked and double-checked table
cerebellum. and figure numbering, and tolerated my obsessive pursuit
The four-chapter Unit VI was updated by Dr. Jeffrey Perlman. of perfection, as she has over three previous editions of this
Dr. Perlman was my first fellow in neonatal neurology (then book. Shaye Moore, leader of the Medical Writing Team of
x Preface to the Sixth Edition

the Department of Neurology, dealt with such complex issues implementation in bringing this project to fruition. All the
of digital manuscript preparation (multiplied by 38 chapters), editors and authors agree that we could not have had a better
that I cannot begin to understand or explain. No challenge publishing group.
was too great for her to confront and overcome. The Elsevier
team, particularly Kate Dimock and Janice Gaillard, struck Joseph J. Volpe, MD
a remarkable balance of guidance, patience, efficiency, and Boston, Massachusetts
 Preface to the First Edition

The neurology of the newborn is a topic of major importance important clinical clues when we elicit a complete history and
because of the preeminence of neurological disorders in perform a careful physical examination. It is this quality of
neonatology today. The advent of modern perinatal medicine, discovery with simple techniques that has made the neurology
accompanied by striking improvements in obstetrical and of the newborn so stimulating for me, and I hope that this
neonatal care, has changed the spectrum of neonatal disease book can lead the reader to similar discoveries.
drastically. Many previously dreaded disorders such as With accomplishment of the essential first step of definition
respiratory disease have been controlled to a major degree. of the clinical problem, we can turn in a rational way to the
At the same time, certain beneficial results of improved care, increasingly sophisticated means of studying the infant’s
for example, markedly decreased mortality rates for premature deranged neural structure and function. Although my emphasis
infants, have been accompanied by neurological disorders that is, first, on the simplest and least invasive techniques for
would not have had time to evolve in past years. providing us with the necessary information, we are in an
This major importance of neonatal neurological disease has era when sophisticated and informative procedures such as
stimulated efforts by workers in many disciplines to recognize, imaging the brain itself can be done in a safe and effective way.
understand, treat, and ultimately prevent such disease. This The final process in our understanding the infant with a
book is an attempt to bring together the knowledge gained neurological disorder requires an awareness of a burgeoning
from these efforts and to present my current understanding corpus of information derived from studies in human and
of the neurology of the newborn. Because of the diversity of experimental pathology, physiology, biochemistry, and related
knowledge that I have attempted to bring to bear upon the fields. Of necessity, often we must extrapolate to our newborn
problems discussed in this book, I may have oversimplified patient data obtained from animals. Such extrapolation must
in certain areas and displayed my own ignorance in others. always be made cautiously, and yet we cannot ignore the
Nevertheless, I have written the material in the hope that it many lessons learned from the laboratory that have proved
will be of value to all health professionals involved in the invaluable in our understanding of neonatal neurological
care and follow-up of the newborn infant with neurological disease. In this book, on the one hand, I attempt to synthesize
disease. in a comprehensible manner relevant material from a diversity
The prime focus of the discussions of neonatal neurological of disciplines and, on the other hand, try very hard not to
disease throughout this book is the clinical evaluation of the oversimplify what are clearly very complex issues.
infant, that is, what we can learn from observation of the setting I believe that the neurology of the newborn has come of age
and mode of presentation of the disease and the disturbances and, indeed, should be viewed as a discipline in its own right. I
of neurological function apparent on careful examination. The hope that in some way this book will contribute to establishing
theme that recurs most often is that careful clinical assessment, that status. My most fervent hope is that this discipline excites
in the traditional sense, is the prerequisite and the essential the interests and efforts of others concerned with the neonatal
foundation for understanding the neurological disorders of the patient and that, through concerted actions, the greatest possible
newborn. The infant does not advertise his or her neurological benefits accrue to the infant with neurological disease.
disorder with the drama that older children and adults exhibit,
but with patience and diligence we can discover a treasure of Joseph J. Volpe, MD

xi
 Acknowledgments

It is with pleasure and eagerness that I acknowledge with acknowledgment is made in those places, I take this particular
gratitude the help of so many over the years. I am grateful opportunity to thank them again for their generosity. Many
to Dr. Raymond Adams, who introduced me to neurology other physicians involved in the care of newborns have shared
and neuropathology and provided a model of scholarship in their unusual and interesting cases with me; I thank them for
medicine that I have since striven to achieve; to Dr. C. Miller their stimulation and education. Many faculty, fellows, and
Fisher, who taught me the inestimable value of looking carefully house officers at St. Louis Children’s Hospital and Boston
at the patient and never denying observations that did not fit Children’s Hospital have helped me immeasurably in the
preconceived notions; and Dr. E. P. Richardson, Jr., who taught study of neonatal patients. My collaborators in clinical and
me neuropathology and provided a framework for study on basic research have been wonderful partners in our pursuit
which I remain dependent. of discovery and creativity in the study of the newborn brain.
I owe enormous gratitude to Dr. Philip Dodge, who For this edition I acknowledge with great pride and gratitude
stimulated me to study pediatric neurology and, after my the work of my former trainees and current esteemed colleagues
training, guided me to the neurology of the newborn. To this who served as editors and authors. They are distinguished
day he has been a continual source of support and inspiration. and dedicated scholars in their own right, and their efforts in
I gratefully acknowledge the help and contributions of many bringing to fruition this sixth edition were prodigious indeed.
investigators with an interest in the newborn. Their work is
included on many of the pages of this book, and although Joseph J. Volpe, MD

xii
 Contents

UNIT I: HUMAN BRAIN 18. Hypoxic-Ischemic Injury in the Term Infant:

DEVELOPMENT, 1 Neuropathology, 484
Hannah C. Kinney and Joseph J. Volpe
1. Neural Tube Development, 3
19. Hypoxic-Ischemic Injury in the Term Infant:
Adré J. du Plessis and Joseph J. Volpe
Pathophysiology, 500
2. Prosencephalic Development, 34
Joseph J. Volpe
Adré J. du Plessis and Joseph J. Volpe
20. Hypoxic-Ischemic Injury in the Term Infant:
3. Congenital Hydrocephalus, 58
Clinical-Neurological Features, Diagnosis, Imaging,
Adré J. du Plessis, Shenandoah Robinson, and Joseph J. Volpe
Prognosis, Therapy, 510
4. Cerebellar Development, 73
Terrie E. Inder and Joseph J. Volpe
Adré J. du Plessis, Catherine Limperopoulos, and Joseph J. Volpe
21. Stroke in the Newborn, 564
5. Neuronal Proliferation, 100
Terrie E. Inder and Joseph J. Volpe
Annapurna Poduri and Joseph J. Volpe
6. Neuronal Migration, 120
Annapurna Poduri and Joseph J. Volpe UNIT V: INTRACRANIAL
7. Organizational Events, 145 HEMORRHAGE, 591
Hannah C. Kinney and Joseph J. Volpe 22. Intracranial Hemorrhage: Subdural, Subarachnoid,
8. Myelination Events, 176 Intraventricular (Term Infant), Miscellaneous, 593
Hannah C. Kinney and Joseph J. Volpe Terrie E. Inder, Jeffrey M. Perlman, and Joseph J. Volpe
23. Cerebellar Hemorrhage, 623
UNIT II: NEUROLOGICAL Catherine Limperopoulos, Adré J. du Plessis,
EVALUATION, 189 and Joseph J. Volpe
24. Preterm Intraventricular Hemorrhage/
9. Neurological Examination: Normal and
Posthemorrhagic Hydrocephalus, 637
Abnormal Features, 191
Terrie E. Inder, Jeffrey M. Perlman, and Joseph J. Volpe
Joseph J. Volpe
10. Specialized Neurological Studies, 222
Jeffrey J. Neil and Joseph J. Volpe UNIT VI: METABOLIC
11. Neurodevelopmental Follow-Up, 255 ENCEPHALOPATHIES, 699
Lianne J. Woodward and Petra S. Hüppi 25. Glucose, 701
Jeffrey M. Perlman and Joseph J. Volpe
UNIT III: NEONATAL SEIZURES, 273 26. Bilirubin, 730
Jeffrey M. Perlman and Joseph J. Volpe
12. Neonatal Seizures, 275
27. Amino Acids, 763
Nicholas S. Abend, Frances E. Jensen, Terrie E. Inder,
Jeffrey M. Perlman and Joseph J. Volpe
and Joseph J. Volpe
28. Organic Acids, 793
Jeffrey M. Perlman and Joseph J. Volpe
UNIT IV: HYPOXIC-ISCHEMIC AND
RELATED DISORDERS, 323
UNIT VII: DEGENERATIVE
13. Pathophysiology: General Principles, 325 DISORDERS, 821
Terrie E. Inder and Joseph J. Volpe
29. Degenerative Disorders of the Newborn, 823
14. Encephalopathy of Prematurity: Neuropathology, 389
Christopher M. Elitt and Joseph J. Volpe
Hannah C. Kinney and Joseph J. Volpe
15. Encephalopathy of Prematurity: Pathophysiology, 405
Stephen A. Back and Joseph J. Volpe UNIT VIII: NEUROMUSCULAR
16. Encephalopathy of Prematurity: Clinical-Neurological DISORDERS, 859
Features, Diagnosis, Imaging, Prognosis, Therapy, 425 30. Evaluation, Special Studies, 861
Jeffrey J. Neil and Joseph J. Volpe Basil T. Darras and Joseph J. Volpe
17. Intrauterine, Intrapartum Assessments in 31. Arthrogryposis Multiplex Congenita, 874
the Term Infant, 458 Partha S. Ghosh and Joseph J. Volpe
Terrie E. Inder and Joseph J. Volpe

xiii
xiv Contents

32. Levels Above Lower Motor Neuron to UNIT XI: INTRACRANIAL

Neuromuscular Junction, 887 MASS LESIONS, 1125
Basil T. Darras and Joseph J. Volpe
37. Brain Tumors and Vein of Galen Malformations, 1127
33. Muscle Involvement and Restricted Disorders, 922
Shenandoah Robinson and Joseph J. Volpe
Basil T. Darras and Joseph J. Volpe

UNIT XII: DRUGS AND THE DEVELOPING

UNIT IX: INTRACRANIAL NERVOUS SYSTEM, 1147
INFECTIONS, 971
38. Passive Addiction and Teratogenic Effects, 1149
34. Viral, Protozoan, and Related Intracranial Infections, 973
Lianne J. Woodward, Christopher C. McPherson,
Linda S. de Vries and Joseph J. Volpe
and Joseph J. Volpe
35. Bacterial and Fungal Intracranial Infections, 1050
Linda S. de Vries and Joseph J. Volpe

UNIT X: PERINATAL TRAUMA, 1091

36. Injuries of Extracranial, Cranial, Intracranial, Spinal
Cord, and Peripheral Nervous System Structures, 1093
Joseph J. Volpe
 Video Contents

33 Muscle Involvement and Restricted Disorders

33-1 Congenital myotonic dystrophy: infant and mother.
Head lag in a floppy infant with DM1.
33-2 Congenital myotonic dystrophy: infant and mother.
Forearm percussion myotonia.
33-3 Congenital myotonic dystrophy: infant and mother.
Hand grip myotonia.
33-4 Congenital myotonic dystrophy: infant and mother.
Thenar percussion myotonia.

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 UNIT I

HUMAN BRAIN
DEVELOPMENT
This page intentionally left blank
 Chapter

Neural Tube Development

1
Adré J. du Plessis ♦ Joseph J. Volpe

An understanding of the development of the nervous system is NORMAL DEVELOPMENT OF THE

essential for an understanding of fetal and neonatal neurology. FUNDAMENTAL CENTRAL NEUROAXIS
An obvious reason for this contention is the wide variety of
disturbances of neural development that are flagrantly apparent Developments in recent years have required a reevaluation of
in the neonatal period and increasingly diagnosed in the fetal conventional paradigms for developmental disorders of the
period. In addition, all the insults that affect the fetus and central neuroaxis. A variety of traditional classification systems
newborn, and that are the subject matter of most of this book, have been unsatisfactory, and the persistent inconsistent use of
exert their characteristic effects in part because the brain is terminology has compromised the diagnostic and prognostic
developing in many distinctive ways and at a very rapid rate. As accuracy in clinical practice. New insights from animal models,
discussed further in Chapter 14, a strong likelihood exists that advanced fetal imaging, and fetal intervention trials for neural
many of these common insults exert deleterious and far-reaching tube disorders have led to the notion of primary and secondary
effects on certain aspects of neural development—effects that consequences of these conditions. For example, the unifying
until now have escaped detection by available techniques. hypothesis for open neural tube defects proposes that the primary
In Chapters 1, 2, and 4 we emphasize the aspect of normal failure of spinal closure leads to cerebrospinal fluid (CSF)
development that has been deranged, the structural characteristics leakage, which in turn leads to the secondary consequences of
of the abnormality, and the neurological consequences. It is posterior fossa underdevelopment, hindbrain herniation, and
least profitable to attempt to characterize exhaustively all the the development of hydrocephalus.1 More precise diagnostic
presumed causes of these abnormalities of the developmental paradigms consider the germ cell layers involved (i.e., ectodermal,
program. Although a few examples of environmental agents neuroectodermal, or mesodermal) in the primary dysgenetic
that insult the developing human nervous system at specific lesion, as well as the secondary effects of trauma, toxicity, and
time periods and produce a defect are recognized, few of these mechanical disruption of subsequent development. For example,
agents leave an identifying stamp. This obtains particularly it is now proposed that the primary defect in anencephaly is
because, in the first two trimesters of gestation, the developing likely not failure of neurulation but rather failure of normal
brain is not capable of generating the glial and other reactions cutaneous and mesenchymal development (skin, bone and
to injury that serve as useful clues to environmental insults dural coverings), with a secondary degeneration of the exposed
that occur at later time periods. The occasional example of a neural tissue. Similarly, lesions such as meningoceles with no
virus, chemical, drug, or other environmental agent that has neural involvement are often still classified as “closed neural
been shown to produce a disorder of brain development is tube defects,” although their etiology is unrelated to neurulation.
mentioned only in passing. However, we emphasize genetic
considerations whenever possible because of their importance in Milestones of Major Events
parental counseling. Therefore the organizational framework is The major developmental events and their peak times of
the chronology of normal development of the human nervous occurrence are shown in Table 1.1. The time periods are those
system. A brief review of the major developmental events that during which the most rapid progression of the developmental
occur most prominently during each time period is presented, event occurs. Although some overlap exists among these time
followed by a discussion of the disorders that result when such periods, it is valid and convenient to consider the overall
development is deranged. maturational process in terms of a sequence of individual
This chapter is devoted to the first major process in human events. In a discussion of the timing of the disorders, the time
brain development: the formation of the neural tube. These periods shown in Table 1.1 are obviously of major importance.
early events culminate in formation of the fundamental Nonetheless, it is necessary to recognize that an aberration of a
central neuroaxis. Development of the neural tube and the developmental event need not be caused by an insult impinging
subsequent development of the prosencephalon (discussed in at the time of the event. Thus a given malformation may not have
the next chapter) can be considered the neural components its onset after the developmental event is completed, but the
of embryogenesis. In subsequent chapters we discuss later fetal developmental program may be disturbed at any time before the
developmental events that lead to the intrinsic structural event is under way. The concept of a termination stage refers to
development of the central nervous system (CNS). the time in the development of an organ after which a specific

3
4 Unit I Human Brain Development

BOX 1.1 Primary Neurulation

TABLE 1.1 Major Events in Human Brain
Development and Peak Times of Peak Time Period
Occurrence 3–4 weeks of gestation
Major Events
MAJOR DEVELOPMENTAL PEAK TIME OF Notochord, chordal mesoderm → neural plate → neural tube, neural
EVENT OCCURRENCE crest cells
Neural tube → brain and spinal cord → dura, axial skeleton (cranium,
Primary neurulation 3–4 weeks of gestation
vertebrae), dermal covering
Prosencephalic development 2–3 months of gestation
Neural crest → dorsal root ganglia, sensory ganglia of cranial nerves,
Neuronal proliferation 3–4 months of gestation
autonomic ganglia, and so forth
Neuronal migration 3–5 months of gestation
Organization 5 months of gestation to
years postnatally
Myelination Birth to years postnatally
segments of the spinal cord). With fusion of the neural folds,
there is separation of the cutaneous and neural ectoderm, with
the ingrowth of the mesodermal layers between them; the timing
TABLE 1.2 Development of the Fundamental of these events closely follows the progressive closure of the
Craniospinal Axis—Major Phases and neural tube. Primary neurulation and secondary neurulation
Peak Times of Occurrence are discussed separately.

MAJOR DEVELOPMENTAL PEAK TIME OF Primary Neurulation

PHASE OCCURRENCE By the end of gastrulation, the most anterior part of the axial
1. Gastrulation 16–18 days p/c mesoderm is the prechordal plate, a critical ventral patterning
2. Primary neurulation 18–26 days p/c center for the developing forebrain, while the more posterior
Neural plate formed 18 days p/c parts of the axial mesoderm are made up of the notochord.
First fusion of neural folds 22 days p/c Primary neurulation is a series of events in the dorsal neural
Anterior neuropore closes 24 days p/c ectoderm of the embryo culminating in formation of the neural
Posterior neuropore closes 26 days p/c tube—rostral to the upper sacral level—and its separation from
3. Secondary neurulation 26 days p/c—postnatal the other germ cell layers.3,4 The critical events are summarized
Vacuolation-canalization 26 days—7 weeks p/c in Box 1.1. By 18 days p/c the neural plate has been formed by
Retrogressive differentiation 7 weeks p/c—postnatal
differentiation of the dorsal neural ectoderm from the original
4. Disjunction and fusion of Tracks regional neural
mesodermal-cutaneous tube closure ectodermal layer. Next the lateral edges of the neural plate
structures become elevated into neural folds, and the midline of the
neural plate invaginates (Fig. 1.1). The neural folds continue
to elevate in a dorsomedial direction, until the edges meet in
the midline to begin closure of the neural tube. In the human
malformation cannot occur by any teratogenic mechanism.2 embryo, the first fusion of the neural folds is at the level of the
Thus, in the discussion of timing of malformations, we state future hindbrain-cervical junction (foramen magnum), which
that the onset of a given defect could occur no later than a given occurs at 22 p/c days. Closure generally proceeds rostrally to
time. Note that in this text the timing of events is based on form the anterior neural tube (and then the brain) and caudally
the postconceptional (p/c) age, rather than the postmenstrual to form the posterior neural tube (and then the spinal cord),
or gestational age. although it is not a simple, zipper-like process.5-10 The anterior
neuropore of the neural tube closes at approximately 24 days,
Formation of the Neural Tube and the posterior neuropore closes at approximately 26 days, at
Formation of the neural tube and its coverings proceeds which point primary neurulation is complete. During closure
through four phases (Table 1.2)—namely gastrulation, primary of the neural tube, cells from the dorsal-most region become
neurulation, secondary neurulation, and dorsal midline closure separated from the neural tube to form the neural crest, which in
of the mesodermal-cutaneous ectodermal layers. Gastrulation turn gives rise to the future craniofacial bony structures, dorsal
is the fundamental formation of the trilaminar plate between root ganglia, sensory ganglia of the cranial nerves, autonomic
days 16 and 18 p/c during which the endodermal, mesodermal, ganglia, Schwann cells, and cells of the pia and arachnoid (as
and ectodermal layers of the embryo become distinct. The well as melanocytes, cells of the adrenal medulla, and certain
ectodermal layer differentiates into cutaneous and neural skeletal elements of the head and face).11 Finally, the neural
ectoderm. The neural ectoderm develops in the longitudinal tube becomes physically separated from the meso-endoderm
plane along the dorsal surface of the embryo as the neural and cutaneous ectoderm, a process called disjunction (see
plate. Neurulation refers to the inductive events that occur in Table 1.2). Ongoing interaction between the neural tube and
the neural plate that result in formation of the neural tube, surrounding mesoderm gives rise to the dura and axial skeleton
which ultimately gives rise to the entire CNS. Neurulation can (i.e., the skull and the vertebrae). Understanding this sequence
be divided into primary neurulation (i.e., formation of brain and of normal differentiation of the different germ cell layers is
spinal cord down to the sacral level) and secondary neurulation critical to an understanding of the different features of cranial
(i.e., events related to the later formation of the sacrococcygeal and spinal dysraphism.
 Chapter 1 Neural Tube Development 5

Neural plate Ectoderm

A A′

AA′

Neural groove Somite

*
NP

Neural crest SE
Neural tube Somite M
2 E

NF NF
NG

1
MHP
N

Spinal cord
Brain (white matter)
Central 3
canal Spinal cord
(gray matter) SE
Somite
AM
DLHP
Spinal NT
cord MHP

5 4

A B
Figure 1.1 Primary neurulation. Schematic depiction (A) of the developing embryo: external view (left) and
corresponding cross-sectional view407 at about the middle of the future spinal cord. Note the formation of the
neural plate, neural tube, and neural crest cells. (B) Neurulation in the chick embryo. Dorsal view showing cranial-
to-caudal neural plate formation at the level of the line in panel 1. More cranially (arrow), the neural plate is shaping,
and still more cranially, the neural plate is bending (asterisk), and a neural groove and paired neural folds have
formed. Panel 2: Transverse section through the neural plate. Panel 3: Transverse section through neural groove at
the future midbrain level. Panel 4: Dorsal view during closure of the neural groove. groove. Panel 5: Transverse
section through the incipient neural tube. DLHP, Dorsolateral hinge point; E, endoderm; M, mesoderm; MHP, median
hinge point; N, notochord; NF, neural fold; NG, neural groove; NP, neural plate; NT, neural tube; SE, surface ectoderm.
(A, From Cowan WM. The development of the brain. Sci Am. 1979;241:113–133. B, From Schoenwolf GC, PhD,
Larsen’s Human Embryology, Chapter 4, 82–107. Copyright © 2015, 2009 by Churchill Livingstone, an imprint of
Elsevier Inc.)

Cellular and Molecular Mechanisms of Primary Neurulation. cellular and molecular mechanisms,5,6,9,12-33 the most important
Primary neurulation occurs under the induction of the of which involve the cytoskeletal network of microtubules
underlying notochord and chordal mesoderm during the third and microfilaments. Under the influence of vertically oriented
and fourth weeks p/c (see Box 1.1 and Fig. 1.1).11 The neural microtubules, cells of the developing neural plate elongate, while
plate deformations required for development of the neural folds, contraction of actin microfilaments arranged circumferentially
and subsequently the neural tube, are mediated by a variety of around the apical portions of the cells results in cells with a
6 Unit I Human Brain Development

BOX 1.2 Secondary Neurulation (Caudal Neural categorization to be used in this text.40,41 The term dysraphism
Tube Formation) is best understood by considering its root (i.e., raphe), which is
defined as a line of union between two contiguous bilaterally
Peak Time Period symmetric structures. Dysraphism is therefore a failure of this
Canalization: 4–7 weeks of gestation process, and in its broadest sense includes any incomplete
Retrogressive differentiation: 7 weeks of gestation to after birth midline closure of the developing head and spine, and may
Major Events involve the mesenchymal and ectodermal structures individually
Canalization: undifferentiated cells (caudal cell mass) → vacuoles → or in combination. Embryologically, dysraphic states of the
coalescence → contact central canal of rostral neural tube central neuroaxis can be divided into those that occur (1)
Retrogressive differentiation: regression of caudal cell mass →
pre-neurulation (during gastrulation) and involve the neurenteric
ventriculus terminalis, filum terminale
canal; (2) during primary neurulation, forming the vast majority
of open neural tube defects; (3) during secondary neurulation
with disturbed development of the caudal cell mass, which is
broad base and narrow apex. These forces on the neural plate responsible for most closed neural tube defects; or (4) during
result in invagination of its midline, dorsomedial folding of its midline closure of the mesoderm and cutaneous ectoderm. Spina
edges, and closure to form the neural tube (see Fig. 1.1). The bifida refers only to defects of vertebral arch formation (described
process of neural fold bending in a dorsomedial direction also later); subtyping of spina bifida is based on the presence and
appears to involve differential proliferation and translocation nature of associated neuroectodermal malformations. Isolated
of the neuroepithelial cells.34 Surface glycoproteins, especially vertebral arch dysraphism without underlying neural defects
cell adhesion molecules important for cell-cell recognition, as or cystic evagination of the meninges or cord results in true
well as adhesive interactions with extracellular matrix, mediate spina bifida occulta.
fusion of the opposing neural folds. Other critical molecular Neural tube defects refer to a disturbance in neuroectodermal
events include action of the products of certain regional development, defined embryologically as defects of primary or
patterning genes (especially bone morphogenetic proteins secondary neurulation. Anatomically, neural tube defects can be
and sonic hedgehog), homeobox genes, surface receptors, and further categorized by their location relative to the first fusion
transcription factors. point of the neural tube, at the level of the future foramen
magnum. Lesions of the anterior neural tube (rostral to the
Secondary Neurulation (Caudal Neural Tube Formation) foramen magnum) lead to cranial dysraphism, while those of
Secondary neurulation is the process of caudal neural tube the posterior neural tube (caudal to the foramen magnum)
formation, which commences at completion of primary lead to spinal dysraphism. The distinction between open or
neurulation (i.e., on closure of the posterior neuropore around closed dysraphic lesions is important for understanding the
the S2 spinal level, on day 26 p/c; Box 1.2).35,36 Secondary primary lesion and its secondary complications. Open neural
neurulation occurs in the caudal cell mass and, by forming tube defects have at least some continuity between the external
the remaining sacrococcygeal neural tube, completes neural surface of the fetus and the underlying neural tissue and at least
tube formation. Secondary neurulation gives rise to the intermittent CSF leakage. In addition, open neural tube defects
conus medullaris, cauda equina, as well as components of are usually associated with other CNS anomalies, including
the genitourinary tract and hindgut. Starting between 28 hindbrain, callosal, and cerebral cortical malformations. Closed
and 32 days p/c, the caudal cell mass undergoes vacuolation, neural tube defects are skin covered, with no exposed neural
coalescence, and canalization, processes that culminate by tissue and no CSF leak; the defect is confined to the spine,
7 weeks p/c.18,37,38 At this point the vacuoles connect to the and other associated CNS anomalies are rare.42 As a general
central canal of the neural tube previously formed by primary rule, most open neural tube defects result from disturbed
neurulation.3 Not infrequently, accessory lumens remain and primary neurulation, while most closed neural tube defects
may be important in the genesis of certain anomalies of neural result from disturbed secondary neurulation. However, there
tube formation (discussed later). Following canalization, the are exceptions to this rule. For example, higher (thoracic and
caudal cell mass undergoes retrogressive differentiation between cervical) myelomeningoceles may be skin covered (see the
7 weeks p/c and into postnatal life (see Box 1.2). At 8 weeks discussion of cervical myelocystoceles later on in this chapter),
p/c the spinal cord tissue extends the entire length of the and sacral lesions are occasionally open.43
spinal column. Subsequent disproportionate growth of the Disorders of primary neurulation are discussed in order of
spinal column results in relative ascent of the conus medullaris decreasing severity, starting with complete failure of neural tube
(which contains the ventriculus terminalis), leaving the filum formation (craniorachischisis totalis), followed by disorders
terminale in its wake. As a result the conus ascends to the of anterior neural tube formation (cranial dysraphism) and
level of L3 by 40 weeks,39 reaching its final level of L1–L2 by disorders of posterior neural tube formation (spinal dysraphism).
3 months postnatal.
Craniocerebral Dysraphism (Box 1.3)
Craniorachischisis Totalis
DISORDERS OF CRANIOSPINAL
DEVELOPMENT Anatomical Abnormality. Craniorachischisis totalis (see Box
1.3) results from essentially total failure of neurulation at a
The terminology used to describe embryonic anomalies of very early stage, leaving an exposed neural plate–like structure
craniospinal development is inconsistent and often imprecise, (with no overlying axial skeleton or dermal covering) running
which in turn has compromised diagnosis and counseling. down the entire dorsal extent of the central neuroaxis (Fig.
To remedy this situation, we first review the definitions and 1.2).44,45 Because the neural plate is formed by 18 days p/c,