To my wife, Sara, for her love and understanding, without which this book would not be possible
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To my wife, Sara, for her love and understanding, without which this book would not be possible
Preface to the Fifth Edition The nearly 30 years since publication of the first edition of this book have been a period of extraordinary development 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 neurology, and related disciplines. Current-day annual meetings of scientific societies of pediatrics and child neurology are dominated by research and clinical presentations 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 neurological examination, and the specialized techniques in the neurological evaluation. The fifth chapter, concerning neonatal seizures, serves as an effective bridge between the initial chapters and the later, diseasefocused 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 clinical 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 challenging, 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 imaging. 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 neurology of the newborn is reflected in part by the explosion 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 preparation 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 renumbered 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
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 improvements in obstetrical and neonatal care, has changed the spectrum of neonatal disease drastically. Many previously 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 premature 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 disciplines 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 problems 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 professionals involved in the care and follow-up of the newborn infant with neurological disease. The prime focus of the discussions of neonatal neurological 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 presentation of the disease and the disturbances of neurological function apparent on careful examination. The theme that recurs most often is that careful clinical assessment, in the traditional sense, is the prerequisite and the essential foundation for understanding the neurological 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 history 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 simplest 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 studies 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 discipline in its own right. I hope that in some way this book will contribute to establishing that status. My most fervent hope is that this discipline excites the interests and efforts of others concerned with the neonatal patient and that, through concerted actions, the greatest possible benefits accrue to the infant with neurological disease.
ix
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 newborn. 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
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 newborn, 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 certain 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 structural characteristics of the abnormality, and the neurological 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 recognized, few of these agents leave an identifying stamp. This obtains particularly because, in the first two trimesters of gestation, the developing brain is not capable 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 chronology 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 processes involved in human brain development: formation of the neural tube and the subsequent formation of the prosencephalon. These early processes are discussed 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 periods are those during which the most rapid progression of the developmental event occurs. Although some overlap exists among these time periods, it is valid and convenient 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 developmental 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 teratogenic 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 formation 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 segments of the spinal cord (i.e., caudal neural tube formation or secondary neurulation). Primary neurulation and secondary neurulation are discussed separately. 3
4
Unit I TABLE 1-1
HUMAN BRAIN DEVELOPMENT
Neural plate
Major Events in Human Brain Development and Peak Times of Occurrence
Ectoderm
Major Developmental Event Peak Time Of Occurrence Primary neurulation Prosencephalic development Neuronal proliferation Neuronal migration Organization Myelination
3–4 weeks of gestation 2–3 months of gestation 3–4 months of gestation 3–5 months of gestation 5 months of gestation to years postnatally Birth to years postnatally
A
A′ AA′
Neural groove Somite
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 continuing inductive influence of the chordal mesoderm, the lateral margins of the neural plate invaginate and close dorsally to form the neural tube. During this closure, 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 elements 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 approximately 22 days. Closure generally proceeds rostrally and caudally, although it is not a simple, zipper-like process.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 developmental 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).
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 cranial nerves, autonomic ganglia, and so forth
Neural tube
Neural crest Somite
Spinal cord (white matter)
Brain
Spinal cord (gray matter)
Central canal Somite
Spinal cord
Figure 1-1 Primary neurulation. Schematic depiction of the developing 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.)
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 cytoskeletal network of microtubules and microfilaments. Under the influence of vertically oriented microtubules, 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.
Chapter 1 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 rostral neural tube Retrogressive differentiation: regression of caudal cell mass ! ventriculus terminalis, filum terminale
Concerning molecular mechanisms, a particular role of surface glycoproteins, particularly cell adhesion molecules, involves cell-cell recognition and adhesive interactions 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 certain regional patterning genes (especially bone morphogenetic proteins and sonic hedgehog), homeobox genes, surface receptors, and transcription factors. The relative importance of these molecular characteristics 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 differentiation. These events, sometimes called secondary neurulation, 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 neurulation.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 canalization 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 structures 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 closure, which are accompanied by alterations of axial skeleton 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.
Neural Tube Formation and Prosencephalic Development TABLE 1-4
5
Disorders of Primary Neurulation: Neural Tube Defects
Order of Decreasing Severity Craniorachischisis totalis Anencephaly Myeloschisis Encephalocele Myelomeningocele, Chiari type II malformation
Craniorachischisis Totalis Anatomical Abnormality. In craniorachischisis, essentially 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 craniorachischisis 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 anencephaly 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 holoanencephaly. If the defect does not extend to the foramen magnum, the appropriate term is meroacrania or meroanencephaly. The most common variety of anencephaly is involvement of the forebrain and variable amounts of upper brain stem. The exposed neural tissue is represented 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 Approximately 75% of the infants are stillborn, and the remainder 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 siblings.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 preterm 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
6
Unit I
HUMAN BRAIN DEVELOPMENT
A Figure 1-2
Craniorachischisis. Dorsal (A) and dorsolateral (B) views of a human fetus. (Courtesy of Dr. Ronald Lemire.)
affected siblings in the family. Since the late 1970s, the incidence of anencephaly, like that of myelomeningocele (see later), has been declining. Rates of occurrence 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
A Figure 1-3
B
non-Hispanic white infants than in black infants,40,45-47 and this finding is of potential relevance to pathogenesis. 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
B
Anencephaly. Face-on (A) and dorsal (B) views. (Courtesy of Dr. Ronald Lemire.)
Chapter 1
Neural Tube Formation and Prosencephalic Development TABLE 1-6
7
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
O
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)
Figure 1-4 Ultrasonogram of anencephaly at 17 weeks of gestation. Note the symmetrical absence of normal structures superior to the orbits (O). (From Goldstein RB, Filly RA: Prenatal diagnosis of anencephaly: Spectrum of sonographic appearances and distinction from the amniotic band syndrome, AJR Am J Roentgenol 151:547-550, 1988.)
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 intensive 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. TABLE 1-5
Brain Stem Function in Anencephaly
Clinical Feature Reactive pupils Spontaneous eye movements Oculocephalic responses Corneal reflex Auditory response Suck, root, and gag responses Spontaneous respiration
Number (Total n = 12) 3 4 6 6 5 7 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.
*Data from Baird PA, Sadovnick AD: Survival in infants with anencephaly, Clin Pediatr 23:268-271, 1984. { Data from Peabody JL, Emery JR, Ashwal S: Experience with anencephalic infants as prospective organ donors, N Engl J Med 321:344-350, 1989.
A neural plate–like structure involves large portions of the spinal cord and manifests as a flat, raw, velvety structure 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 superior mesencephalon. The neural tissue in an encephalocele 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 myelomeningocele [see later]) comprise the Chiari type III malformation.71 This type of encephalocele contains
8
Unit I
HUMAN BRAIN DEVELOPMENT
Figure 1-5 Encephalocele. A, Newborn with a large occipital encephalocele. B, Newborn with both an occipital encephalocele and a thoracolumbar myelomeningocele. (Courtesy of Dr. Marvin Fishman.)
A
B
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 M
Figure 1-6 Encephalocele. Midline sagittal spin echo 700/20 magnetic resonance imaging scan demonstrates a low occipital encephalocele 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 probably dysgenetic. The third ventricle is not seen, but the massa intermedia (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.)
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 subependymal nodular heterotopia.73 The most commonly recognized syndromes associated with encephalocele are Meckel syndrome (characterized by occipital encephalocele, microcephaly, microphthalmia, cleft lip and palate, polydactyly, polycystic kidneys, ambiguous genitalia, other deformities66) and Walker-Warburg syndrome (see Chapters 2 and 19). These disorders, as well as several other less common syndromes associated with encephalocele, are inherited in an autosomal recessive manner.64,72,74 Maternal hyperthermia
Chapter 1
Neural Tube Formation and Prosencephalic Development
9
Figure 1-7 Newborn with a large thoracolumbar myelomeningocele. The white material is vernix. Note the neural plate– like structure in the middle of the lesion. (Courtesy of Dr. Marvin Fishman.)
between 20 and 28 days of gestation has been associated with an increased incidence of occipital encephalocele,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, magnetic resonance imaging (MRI) scans.71,80,81 Outcome is difficult to determine precisely because of variability in selection for surgical treatment. In a combined surgical 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 encephaloceles. 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 associated 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 subarachnoid 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 Barson82 and consist of a lack of fusion or an absence of the vertebral arches, resulting in bilateral broadening of the vertebrae, 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 dysraphic states support this conclusion by providing histological 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 anencephaly, 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
10
Unit I
TABLE 1-7
HUMAN BRAIN DEVELOPMENT
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
—
—
L3–L4
Hip adduction Knee extension Knee flexion Ankle dorsiflexion Ankle plantar flexion Toe flexion
Groin (L1) Anterior, upper thigh (L2) Anterior, lower thigh and knee (L3) Medial leg (L4) Lateral leg and medial foot (L5) Sole of foot (S1)
—
Knee jerk
—
Ankle jerk
Bladder and rectal function
Anal wink
L5–S1 S1–S4
Posterior leg and thigh (S2) Middle of buttock (S3) Medial buttock (S4)
*Segmental innervation for motor and sensory functions overlaps considerably; correlations shown are approximate.
(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 neurological 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 neurological function, of course, depend on the level of the lesion. Particular attention should be paid to examination of motor, sensory, and sphincter function. Moreover, in the first days of life, motor function subserved 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. Assessment of the functional level of the lesion allows reasonable 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 Approximately one half of patients with intermediate lesions are ambulatory (L4, L5) or primarily ambulatory (L3) with braces or other specialized devices and crutches. Considerable variability exists between subsequent ambulatory status and apparent neurological segmental level, especially in patients with midlumbar lesions.100,103,104 Good strength of iliopsoas (hip flexion) and of quadriceps (knee extension) muscles is an especially important 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 management. 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 significant 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 diagnosis of increased intracranial pressure, if the meningomyelocele 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 percentile, approximately a 95% chance exists that appreciable 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 hydrocephalus. 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 prerequisites for the diagnosis of hydrocephalus in the newborn and, indeed, are observed in only approximately 15% of newborns with myelomeningocele.109 Serial ultrasound scans are important because progressive 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
Chapter 1 TABLE 1-8
Hydrocephalus and Myelomeningocele
Temporal Features Most rapid progression occurring in first postnatal month Dilation of ventricles before rapid head growth or before signs of increased intracranial pressure or both Etiological Features Chiari type II hindbrain malformation with obstruction of fourth ventricular outflow or flow of cerebrospinal fluid through posterior fossa Associated aqueductal stenosis Importance Major cause of neurological morbidity, especially if complicated by infection Effective control correlated with ultimate neurological function
intraventricular hemorrhage (see Chapter 11). The most common time for hydrocephalus with myelomeningocele to be accompanied by overt clinical signs is 2 to 3 weeks after birth; more than 80% of infants who have hydrocephalus with myelomeningocele and who do not undergo shunting procedures exhibit such clinical signs by 6 weeks of age (Table 1-8).108,109 Chiari Type II Malformation. The Chiari type II malformation is central for causation of both clinical deficits related to brain stem dysfunction, a serious complication in a minority of patients with myelomeningocele, and hydrocephalus, a serious complication in most patients with myelomeningocele (see earlier). Nearly every case of thoracolumbar, lumbar, and lumbosacral myelomeningocele is accompanied by the Chiari type II malformation. The major features of this lesion include (1) inferior displacement of the medulla and the fourth ventricle into the upper cervical canal, (2) inferior displacement of the lower cerebellum through the foramen magnum into the upper cervical region, (3) elongation and thinning of the upper medulla and lower pons and persistence of the embryonic flexure of these structures,
Neural Tube Formation and Prosencephalic Development
11
and (4) a variety of bony defects of the foramen magnum, occiput, and upper cervical vertebrae. Hydrocephalus associated with the Chiari type II malformation probably results primarily from one or both of two basic causes (see Table 1-8). The first is the hindbrain malformation that blocks either the fourth ventricular CSF outflow or the CSF flow through the posterior fossa. The second is aqueductal stenosis, which may be associated with the Chiari type II malformation in approximately 40% to 75% of the cases.109,111,112 Aqueductal atresia is present in an additional 10%. Studies of human embryos and fetuses with myelomeningocele support the concept that the Chiari type II hindbrain malformation is a primary defect and not a result of hydrocephalus.82 Moreover, studies of a mutant mouse with defective neurulation (‘‘Splotch’’) provide insight into the mechanism by which myelomeningocele may lead to the Chiari type II malformation.18 Thus, in this model it is clear that the Chiari type II malformation results because of growth of hindbrain in a posterior fossa that is too small. The abnormally small posterior fossa is caused by a lack of the normal distention of the developing ventricular system, including the fourth ventricle; the lack of distention occurs largely because of the open neural tube defect. Hydrocephalus then results from the Chiari type II malformation, as described earlier. Additionally supportive of this formulation is the demonstration that closure of the myelomeningocele in the second trimester of fetal life, before the most rapid growth of the cerebellum, results in upward displacement of the inferiorly herniated cerebellar vermis, expansion of the posterior fossa, improvement in CSF flow, and reduced need for ventriculoperitoneal shunting for hydrocephalus (see later) (Fig. 1-8).113,114 Clinical features directly referable to the hindbrain anomaly of the Chiari type II malformation (i.e., not to hydrocephalus) are probably more common than is recognized. In one carefully studied series of 200 infants, one third exhibited feeding disturbances
Figure 1-8 Pathogenetic formulation for the Chiari type II malformation and the effect of treatment. See text for details. In A, Chiari malformation (a) and the open myelomeningocele (b) are shown. The negative pressure generated from drainage of cerebrospinal fluid from the open myelomeningocele (b) results in the inferior displacement of the cerebellum (a) and thereby the Chiari type II malformation. B, After fetal closure, positive back pressure reduces the cerebellar hernia and expands the posterior fossa. (From Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, et al: Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele, JAMA 282:1826-1831, 1999.)
12
Unit I
TABLE 1-9
HUMAN BRAIN DEVELOPMENT
Relation of Brain Stem Dysfunction to Mortality in Myelomeningocele
Clinical Features Stridor Stridor and apnea Stridor, apnea, cyanotic spells, and dysphagia Total
Number
Mortality
10 4 5
0 25% 60%
19
21%
Adapted from Charney EB, Rorke LB, Sutton LN, Schut L: Management of Chiari II complications in infants with myelomeningocele, J Pediatr 111:364-371, 1987.
(associated with reflux and aspiration), laryngeal stridor, or apneic episodes (or all three).115 In one third of these affected infants, death was ‘‘directly or indirectly attributed to these problems.’’ Indeed, in this and similar series, at least one half of the deaths of infants with myelomeningocele can be attributed to the hindbrain anomaly (despite treatment of the back lesion and hydrocephalus).18,115-118 In a cumulative series of 142 infants, the median age at onset of symptoms referable to brain stem compromise was 3.2 months.117 The clinical syndromes of brain stem dysfunction and their relation to mortality are presented in Table 1-9.117,119,120 The 19 affected infants represented 13% of those with myelomeningocele. The principal clinical abnormalities in this and related studies reflect lower brain stem dysfunction and include vocal cord paralysis with stridor, abnormalities of ventilation of both obstructive and central types (especially during sleep), cyanotic spells, and dysphagia.118,119,121-128 The full constellation of stridor, apnea, cyanotic spells, and dysphagia is associated with a high mortality (see Table 1-9). Such sensitive assessments of brain stem function as brain stem auditory-evoked responses, polysomnography, pneumographic ventilatory studies, and somatosensory-evoked responses yield abnormal results in infants with myelomeningocele in approximately 60% of cases and are the neurophysiological analogues of the clinical deficits.118,129-133 The clinical abnormalities of brain stem function have three primary causes. First, they relate in part to the brain stem malformations, which involve cranial nerve and other nuclei, and are present in most cases at autopsy (Table 1-10).112 Second, compression and traction of the anomalous caudal brain stem by hydrocephalus and increased intracranial pressure may play a role, especially in the vagal nerve disturbance that results in the vocal cord paralysis and stridor. Third, ischemic and hemorrhagic necrosis of brain stem is often present and may result from the disturbed arterial architecture of the caudally displaced vertebrobasilar circulation.119 Other Anomalies of the Central Nervous System. Other anomalies of the CNS have been described with myelomeningocele and the Chiari type II malformation. Perhaps most important of these are abnormalities of cerebral cortical development. In earlier studies, the pathological finding of microgyria was described in 55% to 95% of cases.134,135 Whether this finding reflected a true cortical dysgenesis was
TABLE 1-10
Brain Stem Malformations in Myelomeningocele
Total with Brain Stem Malformation Defective myelination Hypoplasia of cranial nerve nuclei Hypoplasia or aplasia of olives Hypoplasia or aplasia of basal pontine nuclei Hypoplasia of tegmentum
76% 44% 20% 20% 16% 4%
Adapted from Gilbert JN, Jones KL, Rorke LB, Chernoff GF, et al: Central nervous system anomalies associated with meningomyelocele, hydrocephalus, and the Arnold-Chiari malformation: Reappraisal of theories regarding the pathogenesis of posterior neural tube closure defects, Neurosurgery 18:559-564, 1986.
not clear, but its presence was of major potential importance because of a relationship with the intellectual deficits that occur in a minority of these patients. Moreover, the occurrence of seizures in approximately 20% to 25% of children with myelomeningocele may be accounted for in part by such cortical dysgenesis.136-138 This issue was clarified considerably by a careful neuropathological study of 25 cases of myelomeningocele (Table 1-11). Fully 92% of the brains showed evidence of cerebral cortical dysplasia, and 40% had overt polymicrogyria.112 Thus, impaired neuronal migration was a common feature. Other anomalous features, such as cranial lacunae, hypoplasia of the falx and tentorium, low placement of the tentorium, anomalies of the septum pellucidum, anterior and inferior ‘‘pointing’’ of the frontal horns, thickened interthalamic connections, and widened foramen magnum, are of uncertain clinical significance. However, they are visualized readily to varying degrees with CT, MRI, and cranial ultrasonography.66,139-141 Anomalies in position of cerebellum are observable in utero by ultrasonography or MRI.142,143 Cerebellar dysplasia, including heterotopias, is definable neuropathologically in 72% of cases.112 Management. Management of the patient with myelomeningocele, or of any patient with a neural tube defect, should begin with the following question: How could this have been prevented? Indeed, prevention must be considered the primary goal for the future. Major advances have been made in this direction (see later).
TABLE 1-11
Cerebral Cortical Malformations in Myelomeningocele
Total with Cerebral Cortex Dysplasia Neuronal heterotopias Polymicrogyria (with disordered lamination) Disordered lamination only Microgyria, normal lamination Profound migrational disturbances
92% 44% 40% 24% 12% 24%
Adapted from Gilbert JN, Jones KL, Rorke LB, Chernoff GF, et al: Central nervous system anomalies associated with meningomyelocele, hydrocephalus, and the Arnold-Chiari malformation: Reappraisal of theories regarding the pathogenesis of posterior neural tube closure defects, Neurosurgery 18:559-564, 1986.
Chapter 1 TABLE 1-12
Incidence of Ventriculoperitoneal Shunt Placement after Fetal Surgery
Upper Level of Lesion
Shunt Placement No. (%)
T10–T12 L1–L3 L4–L5 S1 Total group
5/5 (100%) 33/43 (77%) 19/52 (37%) 6/16 (37%) 63/116 (54%)*
*Historical controls, 85% to 90%. Data from Bruner JP, Tulipan N, Reed G, Davis GH, et al: Intrauterine repair of spina bifida: Preoperative predictors of shunt-dependent hydrocephalus, Am J Obstet Gynecol 190:1305-1312, 2004.
The first issue that must be faced in a newborn with myelomeningocele is whether the newborn should receive anything more than conservative, supportive care (e.g., tender nursing care and oral feedings). A decision for no surgical intervention must be made with a clear understanding of the prognosis of the lesion (see ‘‘Results of Therapy’’). If an infant is to receive more than supportive therapy, the major consideration must be the management of the myelomeningocele and the complicating hydrocephalus. Most neurosurgeons in the United States operate on the back lesion and the associated hydrocephalus in nearly every newborn with myelomeningocele.117,144,145 Although the therapies are best discussed by the appropriate surgical specialists, a brief review is necessary here. Myelomeningocele. The first issue to be addressed in the management of the myelomeningocele is the possibility of antenatal therapy. Experimental and clinical data raise the possibility that exposure of the open neural tube to amniotic fluid and to the intrauterine pressure and mechanical stresses associated with labor and delivery can injure the spinal cord and worsen the neurological outcome.7,146-150 Indeed, because of experimental evidence that prolonged exposure of the dysplastic spinal cord to the intrauterine environment before labor may accentuate the neurological deficits, and that covering the lesion may prevent this deterioration, human fetal surgery in the 20th to 30th weeks of gestation has been performed.113,114,151-155 Although an endoscopic approach was used in initial studies, currently a hysterotomy is performed, and the lesion is covered with
TABLE 1-13
13
Neural Tube Formation and Prosencephalic Development
dura and skin. In one study of 42 infants treated in utero at 20 to 26 weeks of gestation and followed postnatally, 24 (57%) with thoracic or lumbar level defects had lower extremity function better than predicted from the anatomical level of the lesion.114 Particularly striking has been the apparent decrease in need for postnatal shunt placement for hydrocephalus (Table 1-12).114,155 Thus, overall, 54% of 116 infants treated in utero at a mean gestational age of 25 weeks required postnatal shunt placement, compared with approximately 85% to 90% of historical control infants not treated in utero. Notably, reversal of the hindbrain herniation of the Chiari type II malformation was a consistent finding114 and may underlie the decrease in need for shunt placement. This beneficial effect of intrauterine repair on the hindbrain herniation was predicted by experiments in fetal lambs.156 The promising findings with intrauterine surgery has led to a large randomized clinical trial in the United States. Consistent with the possibility of mechanical injury during labor, the results of a retrospective review of 160 carefully studied cases of myelomeningocele suggest that delivery by cesarean section before the onset of labor may result in better subsequent motor function than vaginal delivery or delivery by cesarean section after a period of labor (Table 1-13).157 Overall, infants delivered by cesarean section before the onset of labor had a mean level of paralysis 3.3 segments below the anatomical level of the spinal lesion, compared with 1.1 and 0.9 for infants delivered vaginally or delivered by cesarean section after the onset of labor, respectively. This variance is large enough to make the difference between the child’s being ambulatory or wheelchair bound. Thus, scheduled delivery by cesarean section before the onset of labor should be considered for the fetus with meningomyelocele, particularly if prenatal ultrasonography and karyotyping rule out the presence of severe hydrocephalus, chromosomal abnormality, or multiple systemic anomalies. The prevalent notion is that early closure of the back lesion (within the first 24 to 72 hours) is optimal. The rationale for this approach has been the prevention of infection and the loss of motor function that may occur after the first days of life (see earlier). The prevention of infection is supported by several studies.115,158,159 A study of 110 infants suggests that closure of the back
Level of Motor Paralysis at 2 Years of Age as a Function of Exposure to Labor and Type of Delivery FUNCTIONAL LEVEL OF PARALYSIS (%)
Labor/Delivery No labor: cesarean section Labor: cesarean section Labor: vaginal delivery All exposed to labor
Mean Anatomical Level*
Sacral or No Paralysis
L4 or L5
T12–L3
L1.1 L1.0 L2.5{
45 20 14 16
34 29 55 47
21 51 31 37
*Based on radiographs of the spine. { P < .001 compared with both cesarean section groups; by chance, the newborns in the vaginal delivery group had a significantly more favorable (i.e., lower) anatomical level. Data from Luthy DA, Wardinsky T, Shurtleff DB, Hollenbach KA, et al: Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally, N Engl J Med 324:662-666, 1991; total number, 160.
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Unit I
HUMAN BRAIN DEVELOPMENT
lesion is not indicated so urgently. In infants whose lesions were closed in the first 48 hours, the incidence of ventriculitis was 10% (5/52) versus 12% (4/32) when lesions were closed in 3 to 7 days and 8% (1/12) when lesions were closed after 7 days.160 Moreover, lower extremity paralysis was neither worsened by delay of surgery nor improved by surgical treatment within 48 hours. On balance, it would appear most prudent to close the back as promptly as possible (within the first 24 to 72 hours) but not to feel compelled to proceed so rapidly as to interfere with rational decision making. In addition, value for the use of prophylactic antibiotics from the first 24 hours of life to the time of surgery is suggested by the results of two studies.160,161 In the later and larger study, ventriculitis developed in only 1 of 73 infants (1%) receiving broad-spectrum antibiotic prophylactic therapy, compared with 5 of 27 (19%) who did not receive antibiotics.161 Details of the operative repair of myelomeningocele are discussed in other sources.145,162,163 Techniques to minimize the risk of subsequent development of tethered cord are important. Hydrocephalus. The management of the commonly associated hydrocephalus depends, first, on identification of the condition in the affected child. The findings of rapid head growth, bulging anterior fontanelle, and split cranial sutures are obvious, and an ultrasound scan can define the severity and the pattern of the ventricular dilation. More difficult is identification of lowgrade hydrocephalus, often with no clinical signs, with CSF pressure in the normal range and with ventricles that are moderately dilated but not necessarily increasing disproportionately in size. Often such patients are considered to have ‘‘arrested’’ hydrocephalus. Later observations of similar patients have demonstrated a discrepancy in performance versus verbal intelligence quotient (IQ) scores, with the latter higher than the former. This discrepancy is considered consistent with a hydrocephalic state, which benefits from placement of a shunt.164,165 Improvements in performance scores and decreases in ventricular size have been described in studies of such patients.164 These data suggest that earlier use of shunt placement improves the cognitive outcome of infants with myelomeningocele (see next section). Value for nonsurgical therapy (e.g., isosorbide) to alleviate the need for shunt placement, suggested by earlier studies,166,167 was not demonstrated in a later study.168 This therapy, however, may delay the need for shunt placement; such temporization is useful for the infant too small or too sick to undergo a shunt procedure. When a shunt is considered appropriate in the first weeks of life, a ventriculoperitoneal system is used.115,116,169 Although controlled data are not available, in several studies of apparently comparable series of patients, intelligence appeared to be better preserved if ventriculoperitoneal shunts were performed more liberally.170,171 Such an apparent benefit for the early treatment of hydrocephalus is supported by data suggesting that the degree of ventriculomegaly identified in utero or the size of the cerebral mantle in the first week
of life correlates significantly with subsequent intelligence if the hydrocephalus is treated.172,173 This conclusion must be interpreted with the awareness that the incidence of shunt complications varies depending on the clinical circumstances and that shunt complications have a major deleterious effect on intellectual outcome.106,174,175 The dominant deleterious shunt complication is infection. In a study of 167 infants with myelomeningocele, the mean IQ of infants with shunt placement for hydrocephalus complicated by infection was 73; with shunt placement for hydrocephalus and no infection, the mean IQ was 95.176 The mean IQ in infants with myelomeningocele but no hydrocephalus was 102. The similarity of IQ in infants with and without hydrocephalus suggests that the hydrocephalus per se, if adequately treated and not complicated by infection, does not have a major deleterious effect on intellectual outcome. Brain Stem Dysfunction Associated with the Chiari Type II Malformation. Management of the clinical abnormalities of brain stem dysfunction (see Table 1-9) associated with the Chiari II malformation is difficult. Infants with stridor and obstructive apnea generally respond effectively to improved control of hydrocephalus; any additional benefit for cervical decompression is less clear.119,121 However, infants with severe symptoms, especially cyanotic episodes related to expiratory apnea of central origin, do not respond effectively to current modes of therapy.119,121 With progression of the condition, mortality rates in such infants exceed 50%. In a study of 17 infants who had brain stem signs in the first month of life (swallowing difficulty, 71%; stridor, 59%; apneic spells, 29%; weak cry, 18%; aspiration, 12%), and in whom functioning shunts were in place, decompressive upper cervical laminectomy resulted in complete resolution of signs in 15 (2 infants died).127 Postoperative morbidity was least when surgery was carried out within weeks rather than months after clinical presentation. Orthopedic and Urinary Tract Complications. Of major subsequent importance to outcome of the infant with myelomeningocele are the incidence and severity of orthopedic and urinary tract complications. The latter are the major causes of death after the first year of life. The management of these groups of complications is a major problem after the newborn period and is best discussed in another context.177-182 However, urodynamic evaluation in the newborn with myelomeningocele is of major predictive value concerning the risk of subsequent decompensation of the urinary tract.182,183 Indeed, in a study of 36 infants, 13 of 16 who had subsequent deterioration of the urinary tract had incoordination of the detrusor-external urethral sphincter in the newborn period. This incoordination was followed by such deterioration in 72% of the newborns. Thus, addition of a urodynamic evaluation in the newborn provides critical information about the urinary tract and helps to determine the optimal type and frequency of follow-up management. Subsequent therapies, such as anticholinergic medication and clean, intermittent
Chapter 1 TABLE 1-14
Outcome of Myelomeningocele as a Function of Therapeutic Approach*
‘‘Conservative’’ Therapy: 1950s Mortality: 85%–90% by 10 years Survivors: 70% ambulatory; mean IQ, 89 ‘‘Aggressive’’ Therapy (Unselected Early Closure of Primary Lesion and Treatment of Hydrocephalus): 1960s Mortality: 40%–50% by 16 years Survivors: 45% ambulatory; mean IQ, 77 ‘‘Selective’’ Therapy (Selected Early Closure of Primary Lesion and Treatment of Hydrocephalus): Early 1970s Mortality: 55% (most were selected for no early closure) Survivors: 80% ambulatory; 85% IQ >75 ‘‘Aggressive-Selective’’ Therapy: Late 1970s to Present Mortality: 14% by 3 to 7 years Survivors: 74% ambulatory; 73% IQ >80 *See text for references. IQ, intelligence quotient.
catheterization, have resulted in continence for as many as 85% of patients.18,100,115,177-179,182 Notably, orthopedic and urinary tract difficulties are very important determinants of patient and family perceptions of quality of life in adolescence.184 Results of Therapy. Conservative therapy (i.e., no early surgery), the standard of care in the 1950s, provides an approximate measure of the natural history of the disorder (Table 1-14).185 Approximately 50% of patients managed conservatively were dead by 2 months of age, 80% by 1 year, and 85% to 90% by 10 years. Of the survivors, 70% were ambulatory (with or without aids), and their mean IQ was 89. With the advent of early closure of the myelomeningocele and improved techniques of dealing with the hydrocephalus, aggressive therapy, which included unselective early operation of the primary lesion, was adopted in many medical centers in the 1960s. The results of this approach were, in some ways, disappointing (see Table 1-14).100,185-187 Although mortality decreased markedly (40% to 50% of patients were alive at age 16 years), the quality of life suffered notably. Of the larger number of survivors, 55% were confined to wheelchairs, and most of these children were incontinent, with a mean IQ of 77.185 Approximately 30% of survivors exhibited epilepsy.187 Because the policy of unselective early operation appeared to cause a larger number of severely handicapped children who required an enormous amount of medical supervision and in-hospital therapy, and whose families required a great deal of social support, Lorber186 advocated selective therapy, the use of strict criteria for treatment. The criteria were designed to exclude patients who would die despite therapy or, if they survived, would be very severely handicapped. Adverse prognostic criteria were identified as follows: (1) severe paraplegia (no lower limb function other than hip flexors, adductors, and quadriceps), (2) gross enlargement of the head, (3) kyphosis, (4) associated gross congenital
Neural Tube Formation and Prosencephalic Development
15
anomalies, and (5) major birth injury. Shortly after the published recommendation to use such criteria, Stark and Drummond171 reported their experience with 163 patients with myelomeningocele at a medical center (Edinburgh) that had been using criteria comparable to those recommended by Lorber for 7 years (1965 to 1971) (see Table 1-14). Approximately 50% of the Edinburgh patients were considered to have the most favorable prognosis and were selected for early closure of the back lesion and subsequent vigorous therapy. The more severely affected 50% were given only symptomatic therapy. More than 70% of the treated patients were alive at 6 years of age, whereas more than 80% of the untreated patients were dead by 3 months of age. Of treated patients, approximately 80% were ambulatory with or without aids, and 87% were free of upper urinary tract disease. The level of intelligence was higher in the selectively treated patients than in the previously reported, unselectively treated patients.188 Thus, only 15% of patients selected for therapy exhibited an IQ of less than 75, whereas 33% of patients unselectively treated had an IQ of less than 75. The improvement in intellectual function was associated with a more liberal use of shunting procedures for hydrocephalus, a relationship noted by others.170 In later series of children similarly selected for therapy, treated survivors exhibited a similarly better outcome than with earlier ‘‘aggressive’’ therapy.189-191 The use of selective criteria for the institution of therapy for myelomeningocele in the newborn period presented at least two major problems. First, some infants who could possibly have had a favorable outcome were excluded and were allowed to experience a poor outcome or to die. Second, some infants who were selected for early vigorous therapy had a poor outcome. Perhaps in part because of the problems encountered with the use of selective criteria, as just noted, aggressive therapy has been favored in the last 2 to 3 decades in most centers in North America. Moreover, results of such therapy appear to be superior to those reported previously for selective therapy (see Table 1-14). For example, in one series of 200 consecutive, unselected infants who were treated aggressively, mortality was only 14% after 3 to 7 years of follow-up. Of the survivors, 74% were ambulatory at least a portion of the time, and 87% were continent of urination.115 The apparent improvement in outcome relative to the earlier results of aggressive therapy relates to several factors, including improvements in diagnosis and monitoring of hydrocephalus (e.g., brain imaging), improvements in management of CSF shunts, more effective therapy of infections, and improvements in braces and other aids for ambulation.115-117,192,193 A largely aggressive approach that appears to combine a degree of selection (e.g., advising against early surgery for infants with major cerebral anomalies, hemorrhage, or infection; high cord lesions and ‘‘cord paralysis’’; and advanced hydrocephalus) has yielded results similar to those just recorded for aggressive therapy.116 Indeed, in a study of this ‘‘aggressive-selective’’ approach, fully 71% of infants were selected for early surgery because of the absence of the adverse initial findings
16
Unit I
HUMAN BRAIN DEVELOPMENT
noted. Of these infants, 79% of survivors exhibited ‘‘normal’’ cognitive development, and 72% were ambulatory.116 Conclusions. No easy answers exist to the questions of when and how to treat the newborn infant who has myelomeningocele. The widespread employment of prenatal diagnosis and termination of pregnancy, especially in the presence of associated severe cerebral or systemic anomalies, will continue to alter the spectrum of infants observed in neonatal units. The possibility of intrauterine treatment, as noted earlier, likely will have a major impact on decision making. Currently, concerning the newborn with the lesion in the absence of major irreversible parenchymal injury (e.g., complicating major hypoxic-ischemic encephalopathy or serious associated cerebral anomaly), the likelihood for intellectual impairment seems low, and aggressive therapy directed toward the back lesion and the hydrocephalus seems indicated to me. Indeed, even in the infant with major parenchymal disease, closure of the back lesion and placement of a shunt for hydrocephalus for the purposes of the infant’s comfort and nursing care are reasonable. Although undue delay in onset of therapy is inappropriate, time for rational discussions with the family can be taken and should not compromise outcome. However, little enthusiasm can be marshaled for delaying decisions for management. Not only does delay lead to compromise in outcome for many patients, but it also puts the parents in an uncertain and nearly intolerable position. It is not trite to conclude that management of each patient must be determined individually. Perhaps no other problem in neonatal medicine necessitates as much perception and sensitivity on the part of primary physicians. They must be able to make as precise a prognostic formulation as possible in the context of current medical
TABLE 1-15
knowledge and the facilities available to them and the patient’s family. Of equal importance, physicians must have the sensitivity toward the family and the patient that is needed to estimate the impact of the disease on everyone concerned. Etiology: Genetic and Environmental Considerations. Prevention of myelomeningocele and other neural tube defects necessitates understanding of their causes. Recognized causes of such defects include (1) multifactorial inheritance, (2) single mutant genes (e.g., the autosomal recessively inherited Meckel syndrome), (3) chromosomal abnormalities (e.g., trisomies of chromosomes 2, 7, 9, 13, 14, 15, 16, 18, and 21 and duplications of chromosomes 1, 2, 3, 6, 7, 8, 9, 11, 13, 16, 20, and X), (4) certain rare syndromes of uncertain modes of transmission, (5) specific teratogens (e.g., aminopterin, thalidomide, valproic acid, carbamazepine), and (6) specific phenotypes of unknown causes (e.g., cloacal exstrophy and myelocystocele).42,90,194-197 Of defects resulting from these causes, most cases (80%) are encompassed within the group in which the neural tube defect is the only major congenital abnormality and inheritance is multifactorial (i.e., dependent on a genetic predisposition that is polygenic and influenced by minor additive genetic variation at several gene loci).92,198 Environmental influences may play an important role on this substrate. Factors establishing the combined influence of both genetic and environmental influences are summarized in Tables 1-15 and 1-16. Factors establishing the genetic role include (1) a preponderance in female patients, (2) ethnic differences that persist after geographical migration, (3) increased incidence with parental consanguinity, (4) increased rate of concordance in apparently monozygotic twin pairs, and (5) increased
Factors Influencing Differences in Prevalence of Myelomeningocele
Factor Country England/Wales Finland Norway Northern Netherlands Region of Country Northern China Southern China Time Period Eastern Ireland Eastern Ireland Ethnic/Racial (California) Non-Hispanic White Hispanic African-American Asian Prenatal Diagnosis and Elective Termination (England/Wales) Live and stillbirths Live and stillbirths and terminations
Time Period
Prevalence
1996 1996 1996 1996
0.32 0.41 0.57 0.63
1992–1993 1992–1993
2.92 0.26
1980 1984
2.7 0.6
1990–1994 1990–1994 1990–1994 1990–1994
0.47 0.42 0.33 0.20
1996 1996
0.09 0.31
Data from Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, et al: Spina bifida, Lancet 364:1885-1895, 2004.
Chapter 1 TABLE 1-16
Neural Tube Formation and Prosencephalic Development
Maternal Risk Factors for Myelomeningocele
17
Synthesis in fetal liver
Factor
Relative Risk
Previous affected pregnancy (same partner) Inadequate intake of folic acid Pregestational diabetes Intake of valproic acid or carbamazepine Low vitamin B12 Obesity Hyperthermia
30 2–8 2–10 10–20 3 1.5–3.5 2
Fetal blood
Fetal urine
Amniotic fluid
Data from Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, et al: Spina bifida, Lancet 364:1885-1895, 2004.
incidence in siblings (as well as in second-degree and, to a lesser extent, third-degree relatives) and in children of affected patients.41,84,90,92,194,196,198-204 The possibility of important environmental influences is suggested particularly by large variations in incidence as a function of geographical location and time period of study (see Table 1-15). Particularly potent data to suggest environmental influences relate to long-term trends in incidence. For example, in the northeastern United States, an epidemic period could be defined between approximately 1920 and 1949, with a peak between 1929 and 1932.205 Since the late 1980s, a prominent steady decline in incidence has occurred in both the United States and Great Britain (see earlier).40-42,84,88,90,91,93,95,206 The interaction of environmental and genetic influences has been demonstrated in experimental studies of the curly-tail mouse, in which a neural tube defect is inherited as an autosomal recessive trait.7,207 Among specific environmental influences, a particularly important role for folate deficiency during the period of neural tube formation is suggested by experimental and clinical studies (see later). Other environmental factors, such as prenatal exposure to maternal hyperthermia, maternal diabetes mellitus, valproic acid (see Chapter 24), carbamazepine (see Chapter 24), maternal obesity, and low maternal vitamin B12 concentrations, also are of varying importance (see Table 1-16).41,89,92,195,208-223 The increased incidence of neural tube defects in siblings of index cases (see Table 1-16) has had major importance for genetic counseling. However, precise estimates of risks in subsequent siblings must take into account the population under study (see Table 1-15). A striking relationship between recurrence risk and the level of the myelomeningocele in the index case has been shown.203 Thus, the risk for recurrence in a sibling was 7.8% if the index case had a lesion at T11 or above but only 0.7% if the lesion was below T11. A decline in the risk of neural tube defect as birth order increases also has been defined111,200; for example, in a study in Albany, New York, the risk for subsequent affected siblings (1.4%) was significantly less than for previously affected siblings (3.1%).201 Prenatal Diagnosis: Alpha-Fetoprotein and Ultrasonography. Prenatal suspicion of the presence of a neural tube defect is based primarily on the determination
Open neural tube defect
Swallowed
Catabolized in fetal gastrointestinal tract Figure 1-9 utero.
Physiology and pathophysiology of alpha-fetoprotein in
of levels of alpha-fetoprotein in maternal serum. This protein is the major protein component of human fetal serum and can be detected 30 days after conception. Serum levels of alpha-fetoprotein peak at approximately 10 to 13 weeks of gestation. Increased levels of alpha-fetoprotein in amniotic fluid occur with open neural tube defects; the mechanism for the elevated levels is thought to represent transudation of the protein from the membranes covering the lesion (Fig. 1-9).224 Until the mid-1980s, amniocentesis for detection of elevated levels of alpha-fetoprotein in amniotic fluid was the most common, albeit invasive procedure for suspicion of an open neural tube defect. Several reports in the late 1970s indicated that determination of maternal serum alpha-fetoprotein levels was useful for screening for neural tube defects.225-229 The largest study involved measurements in more than 18,000 pregnant women in the United Kingdom.225 The optimal time for measurement was shown to be 16 to 18 weeks of pregnancy. Subsequent experience in Scotland,226 Sweden,230 Wales,231 and the United States232,233 confirmed the high sensitivity of the analysis of alphafetoprotein in serum, and large-scale screening programs now are well established.92,231,233,234 The diagnosis and anatomical details of the neural tube defect are then elucidated by ultrasonography and perhaps MRI.78,79,92,231,235-239 The earliest ultrasonographic features include changes in the configuration of the posterior fossa, in addition to the lesion itself. Fetal MRI is the most valuable means to identify anatomical details (Fig. 1-10). Primary Prevention. Prenatal diagnosis of neural tube defects and termination of pregnancy involving an affected fetus are effective methods of secondary prevention. However, a method of primary prevention would be more widely acceptable. Evidence now shows that folate supplementation around the time of conception
18
Unit I
HUMAN BRAIN DEVELOPMENT
A
B
Figure 1-10 Fetal magnetic resonance imaging at 20 weeks of gestation. In A, a large thoracolumbosacral myelomeningocele (arrow) is apparent. In B, note the low-lying cerebellum (arrow), characteristic of a Chiari type II malformation; mild ventriculomegaly is also present. (Courtesy of Dr. Omar Khwaja.)
and therefore neural tube closure has a major preventive effect on the occurrence of neural tube defects.7,41,42,92,95,206,240-281 The effect of multivitamin supplementation before and during early pregnancy on recurrence of neural tube defects was first studied definitively by Smithells and colleagues,240-243 in a recruited series of women with histories of births of one or more previously affected children. The multivitamin supplement contained ‘‘physiological’’ quantities of vitamins, such as folate, riboflavin, ascorbic acid, and vitamin A. The results of the study were striking. Of 454 women taking supplements, only 3 (0.7%) had recurrences, whereas of 519 women not taking supplements, 24 (4.7%) had TABLE 1-17
recurrences. Although the study was criticized for several methodological issues,282,283 the data were promising. A subsequent study by Smithells and coworkers248 showed a similarly striking effect. A noncontrolled study in the United States on women identified largely by elevated serum alpha-fetoprotein levels, measured in a single regional laboratory, confirmed the beneficial role of folate-containing multivitamins (Table 1-17).246 Moreover, the beneficial effect of folate was related clearly to the time during pregnancy when neural tube closure occurs. After the aforementioned study, the British Medical Research Council completed an extremely important multicenter study.250 Women were assigned randomly
Effect of Folate-Containing Multivitamins on Prevalence of Neural Tube Defects WEEKS 1–6
Multivitamin
No.
With folate Without folate
10,713 926
WEEKS 7+ ONLY
NTD (per 1,000) 0.9 3.2
No. 7,795
NTD (per 1,000) 3.2
NTD, neural tube defect. Adapted from Milunsky A, Jick H, Jick SS, Bruell CL, et al: Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects, JAMA 262:2847-2852, 1989.
Chapter 1 TABLE 1-18
Neural Tube Formation and Prosencephalic Development
19
Role of Folic Acid in Prevention of Neural Tube Defects: Multicenter, Randomized, Double-Blind Clinical Trial*
RANDOMIZATION GROUP Folic Acid
Other Vitamins
+ + – –
+ – +
OCCURRENCE OF NEURAL TUBE DEFECT No. Affected/Total No. o 9 1/242 3/483 (0.6%) = 2/241 o ; 10/243 17/477 (3.6%) 7/234
Relative Risk: Folic Acid versus Nonfolic Acid 0.17
*Includes women who were not already pregnant at the time of randomization and who completed treatment period (until 12th week of pregnancy). Data from MRC Vitamin Study Research Group: Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study, Lancet 338:131-137, 1991.
to four groups allocated to receive one of the following regimens of supplementation: folate and a multivitamin supplementation of ‘‘other vitamins,’’ folate alone, ‘‘other vitamins’’ alone, or no folate or ‘‘other vitamins’’ (Table 1-18). The results were decisive in demonstrating the preventive effect and the specific role of folate (versus other components of the previously used multivitamin preparations). The overall reduction in neural tube defects was 83%. The findings clearly had major implications for the primary prevention of neural tube defects. On the basis of this study, the U.S. Centers for Disease Control and Prevention recommended an increase in folic acid intake by 0.4 mg/day for women from the time they plan to become pregnant through the first 3 months of pregnancy.284 The folate was not recommended to be administered as a multivitamin preparation because of the potential danger for toxicity from excessive amounts of other vitamins in the multivitamin preparation. Because of the uncertainty of the degree of risk from the folate supplementation, the initial recommendations were directed only to women who had had a previous pregnancy complicated by a neural tube defect, as in the British study. Subsequently, two studies showed a preventive effect of periconceptional folic acid exposure on the occurrence of neural tube defects in populations of women without a prior affected child.253,254 These observations were followed by the recommendation of the U.S. Public Health Service and the American Academy of Pediatrics that ‘‘all women capable of becoming pregnant consume 0.4 mg of folic acid daily to prevent neural tube defects.’’285 The optimal methods of folate supplementation and dose of the supplement are not totally clarified.286,287 Public educational campaigns, albeit useful, have not been entirely successful, especially because as many as 50% of pregnancies are unplanned, and only a few of the ‘‘nonplanners’’ are reached by such campaigns.287,288 In 1998, the U.S. Food and Drug Administration mandated fortification of all enriched grain products with folate. Similar programs have been instituted in many other countries and have resulted in an approximately 50% reduction in prevalence of neural tube defects.95,206,276-278,280,289,289a However, the British Medical Research Council study used a 4 mg (rather than 0.4 mg) daily folate dose and achieved an 83% reduction in prevalence of lesions. Thus, one expert in the field recommended a public
health policy that includes ‘‘both the mandatory fortification of flour and a recommendation that all women planning a pregnancy take 5 mg of folic acid per day.’’279 The mechanism of the beneficial effect of folate is not established. One report raised the possibility that autoantibodies against folate receptors are present in as many as 75% of women who have had a pregnancy complicated by a neural tube defect.290 The autoantibody-mediated block of cellular folate uptake by folate receptors could be bypassed by administered folate because the latter is reduced and methylated in vivo and is transported into cells by the reduced folate carrier. A related possibility is that the beneficial effect of folate could involve the metabolism of homocysteine to methionine, a reaction catalyzed by methionine synthase and necessitating a metabolite of folic acid (5-methyltetrahydrofolate).7,41,269,271-273,291-294 A critical enzyme in synthesis of 5-methyltetrahydrofolate, methylenetetrahydrofolate reductase, is defective in 12% to 20% of cases of neural tube defects.269,294 One biochemical result of this disturbance is an elevation of homocysteine, which has been shown to produce neural tube defects in avian embryos.293 Another potential mechanism of a defect in homocysteine conversion to methionine is a disturbance in methylation reactions, for which methionine is crucial.269,281 Transmethylations of DNA, proteins, and lipids have far-reaching metabolic consequences.269,281 Occult Dysraphic States Anatomical Abnormality. Occult dysraphic states are characterized by overt abnormalities involving vertebral, overlying dermal structures or both and by neural lesions that are often subtle or even nonexistent (Table 1-19). These disorders are distinguished from the disorders of primary neurulation not only by their usual caudal locus but also particularly by the presence of intact skin over the lesions. Often the abnormality is so well concealed that it goes undetected for years, hence the term occult. A basic relation to disorders of primary neurulation is indicated by the finding that 4.1% of siblings of patients with occult dysraphic states exhibit disorders of primary neurulation, most often myelomeningocele or anencephaly.295 The principal developmental abnormality involves the separation of overlying ectoderm from the developing neural tube, a developmental event often termed
20
Unit I
TABLE 1-19
HUMAN BRAIN DEVELOPMENT
Disorders of Caudal Neural Tube Formation: Occult Dysraphic States
Order of Time of Origin during Development Myelocystocele Diastematomyelia-diplomyelia Meningocele-lipomeningocele Lipoma, teratoma, other tumors Dermal sinus with or without ‘‘dermoid’’ or ‘‘epidermoid’’ cyst ‘‘Tethered cord’’ (without any of the above)
disjunction. Failure of this separation impairs the insertion of mesoderm between the ectoderm and neural tube and, as a consequence, results in disturbed development of vertebrae and related mesodermal tissue. Although disturbances in disjunction may occur at any level of the neuraxis, they are most common in the region of the caudal neural tube and are thus often classified, as I do here, among disorders of caudal neural tube formation.296 The disjunctional failure results most conspicuously in ectodermal abnormalities, dermal tracts and sinuses, abnormalities of mesodermally derived tissue (e.g., vertebral defects, lipomatous masses), and caudal neural tube abnormalities. Because caudal neural tube formation by the processes of canalization and retrogressive differentiation results in the conus medullaris and filum terminale, it is not surprising that almost invariable and unifying findings in these disorders are abnormalities of the conus and filum. The conus is usually prolonged, and the filum terminale is thickened. Moreover, these structures frequently are ‘‘tethered’’ or fixed at their caudal end by fibrous bands, lipoma, extension of dermal sinus, or related lesions. This fixation is thought to impair the normal mobility of the lower spinal cord, and as a consequence, movements of the trunk such as flexion and extension transmit tension through the prolonged conus to the spinal cord and cause injury.297-299 This explanation of the neural injury complements the ‘‘traction’’ concept (i.e., because of its tethered caudal end, the cord sustains a traction injury caused by the differential growth of the vertebral column and the neural tissue). This concept of differential growth as the sole cause of the injury is contradicted by the finding that differential growth is slight between approximately the 26th week of gestation, when the cord is at the level of the third lumbar segment, and maturity, when the cord is at the level of the first or second lumbar segment.82,300 Nevertheless, contributory importance for traction associated with tethering in the genesis of the injury is indicated by studies of mitochondrial oxidative metabolism of cord in vivo in affected patients by dual-wavelength reflection spectrophotometry.301 Thus, distinct disturbances observed intraoperatively improved markedly on release of the tethered cord. With the occult dysraphic states, as noted earlier, the neural lesion is often rather subtle, and the major overt abnormality involves mesodermally derived structures
(especially the vertebrae), the overlying dermal structures, or both. Thus, vertebral defects occur in 85% to 90% of cases and consist most commonly of laminar defects over several segments; other skeletal abnormalities include a widened spinal canal and sacral deformities.2,62,81,298,299,302-304 Approximately 80% of affected infants exhibit a dermal lesion in the lumbosacral area, consisting of abnormal collections of hair, cutaneous dimples or tracts, superficial cutaneous abnormalities (e.g., hemangioma), or a subcutaneous mass (see later). Timing. The neural lesions, in approximate order of time of origin during neural development, are myelocystocele, diastematomyelia-diplomyelia, meningocelelipomeningocele, lipoma (other tumors), dermal sinus with or without ‘‘dermoid’’ or ‘‘epidermoid’’ cyst, and ‘‘tethered cord’’ alone (see Table 1-19). Less common (although related) lesions include anterior dysraphic disturbances, such as neurenteric cyst and anterior meningocele, and the caudal regression syndrome. This latter rare disorder is characterized by dysraphic changes primarily of the sacrum and coccyx, with atrophic changes of muscles and bones of the legs; the neural anomalies range from minor fusion of spinal nerves and sensory ganglia to agenesis of the distal spinal cord.305 Approximately 15% to 20% of patients are infants of diabetic mothers, and approximately 0.3% of infants of diabetic mothers exhibit the lesion.306-310 (Infants of diabetic mothers also exhibit a 15- to 20-fold increased risk, relative to infants of nondiabetic mothers, of anencephaly or myelomeningocele.310) Because the lower genitourinary tract and anorectal structures are developing simultaneously and in close proximity to the caudal neural tube, the lesions listed in Table 1-19 are not uncommonly associated with anorectal and genitourinary abnormalities.81 Indeed, the presence of such lesions should be considered in infants with abnormalities of caudal neural tube formation. In myelocystocele, a localized cystic dilation of the central canal of the caudal neural tube is present.2,311 The frequent association with cloacal exstrophy, omphalocele, imperforate anus, severe vertebral defects, and other malformations makes this one of the most severe malformations of the newborn period.2 The onset of this lesion is estimated to be 28 days of gestation. In diastematomyelia, the spinal cord is bifid.2,81,298,303,304,312,313 The lesion is most common in the lumbar region. In some cases, the spinal cord is separated by a bony, cartilaginous, or fibrous septum protruding from the dorsal surface of the vertebral body, whereas in other cases no septum is present (the term diplomyelia is sometimes used for the latter cases). Because many types of duplication of the developing caudal neural tube may occur during canalization, it is postulated that persistence of these tubes could result in diastematomyelia. The duplications may occur because of splitting of the notochord with impaired induction of both the neural tube and the vertebrae. Meningocele over the lower spine is rare as an isolated lesion and is not associated with
Chapter 1
hydrocephalus or neurological deficits, unlike disorders of primary neurulation.2,303 More cases are associated with infiltration of fibrofatty tissue that is contiguous with a subcutaneous lipoma (i.e., lipomeningocele).2,314,315 Subcutaneous lipoma with intradural extension is more common without an accompanying meningocele. Less commonly, other tumors may be observed.316-319 By far the most common of these tumors is teratoma, although neuroblastoma, ganglioneuroma, hemangioblastoma, and related neoplasms, presumably originating from germinative tissue in the primitive caudal cell mass, or arteriovenous malformation, may occur. Congenital dermal sinus consists usually of a dimple in the lumbosacral region from which a small sinus tract proceeds inwardly and rostrally. The tract may enlarge subcutaneously into a cyst that contains predominantly dermal structures (‘‘dermoid’’) or epidermal structures (‘‘epidermoid’’). Extension of the tract into the vertebral canal may cause neurological symptoms as a result of compression, tethering, or infection. These lesions result from an invagination of ectoderm that is carried by the canalized neural tube as it separates from the surface.2 With tethered cord, the conus is prolonged, the filum abnormal, and the caudal end of the cord fixed by fibrous bands.2,81,298,299,303 The relative frequency of the several occult dysraphic states differs somewhat, according to the source of the cases. Thus, in one large surgical series of 73 patients, dermal sinus with or without cyst accounted for approximately 35% of cases; lipoma accounted for approximately 30% of cases. Diastematomyelia and anterior meningocele were much less common.302 Very frequent accompanying features, and sometimes the sole and predominant abnormalities, were the prolongation of the conus and a defective filum terminale. In a series of 144 cases of caudal lesions observed in a children’s hospital, as in the surgical series, lipoma was similarly common (40% of cases), and diastematomyelia was similarly uncommon (4% of cases), but dermal sinus with or without cyst accounted for only 10% of cases.316 Sacrococcygeal teratoma composed 12% and myelocystocele 8% of cases in this less selected series. In another children’s hospital–based series of 104 cases, data were similar except that diastematomyelia accounted for approximately 25% of cases.303 Clinical Aspects. In the newborn period, the clinical features most suggestive of an occult dysraphic state are the dermal stigmata (Table 1-20). Thus, abnormal collections of hair, subcutaneous mass, superficial cutaneous abnormalities (e.g., hemangioma, skin tag, cutis aplasia, pigmented macule), or cutaneous dimples or tracts, should raise suspicion of a disorder of caudal neural tube formation.298,299,303,317,320-327 The incidence of associated spinal dysraphism with various cutaneous stigmata in one large series was as follows: ‘‘hairy patch,’’ 4 of 10; subcutaneous mass, 6 of 6; hemangioma, 2 of 11; skin tag 1 of 7; cutis aplasia, 1 of 1; ‘‘simple dimple’’ (midline, T mutation in families with spina bifida offspring, J Mol Med 74:691-694, 1996. 293. Rosenquist TH, Ratashak SA, Selhub J: Homocysteine induces congenital defects of the heart and neural tube: Effect of folic acid, Proc Natl Acad Sci U S A 93:15227-15232, 1997. 294. Christensen B, Arbour L, Tran P, Leclerc D, et al: Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects, Am J Med Genet 84:151-157, 1999. 295. Carter CO, Evans KA, Till K: Spinal dysraphism: Genetic relation to neural tube malformations, J Med Genet 13:343-350, 1976. 296. Harding BN, Surtees R: Metabolic and neurodegenerative diseases of childhood. In Graham DI, Lantos PL, editors: Greenfield’s Neuropathology, 7, London: 2002, Arnold Publishers. 297. Grant DN: Spinal dysraphism, Postgrad Med J 48:493-495, 1972. 298. McLone DG, La Marca F: The tethered spinal cord: Diagnosis, significance, and management, Semin Pediatr Neurol 4:192-208, 1997.
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299. Cornette L, Verpoorten C, Lagae L, Plets C, et al: Closed spinal dysraphism: A review on diagnosis and treatment in infancy, Eur J Paediatr Neurol 2:179-185, 1998. 300. Sahin F, Selcuki M, Ecin N, Zenciroglu A, et al: Level of conus medullaris in term and preterm neonates, Arch Dis Child 77:F67-F69, 1997. 301. Yamada S, Zinke DE, Sanders D: Pathophysiology of ‘‘tethered cord syndrome,’’ J Neurosurg 54:494-503, 1981. 302. Anderson FM: Occult spinal dysraphism: A series of 73 cases, Pediatrics 55:826-835, 1975. 303. Scatliff JH, Kendall BE, Kingsley DP, Britton J, et al: Closed spinal dysraphism: Analysis of clinical, radiological, and surgical findings in 104 consecutive patients, AJNR Am J Neuroradiol 10:269-277, 1989. 304. Pang D: Split cord malformation. I. A unified theory of embryogenesis for double spinal cord malformations, Neurosurgery 31:451-480, 1992. 305. Towfighi J, Housman C: Spinal cord abnormalities in caudal regression syndrome, Acta Neuropathol 81:458-466, 1991. 306. Kitzmiller JL, Cloherty JP, Younger MD, Tabatabaii A, et al: Diabetic pregnancy and perinatal morbidity, Am J Obstet Gynecol 131:560-580, 1978. 307. Assemany SR, Muzzo S, Gardner LI: Syndrome of phocomelic diabetic embryopathy (caudal dysplasia), Am J Dis Child 123:489-491, 1972. 308. Rusnak SL, Driscoll SG: Congenital spinal anomalies in infants of diabetic mothers, Pediatrics 35:989, 1965. 309. Mills JL: Malformations in infants of diabetic mothers, Teratology 25:385-394, 1982. 310. Becerra JE, Khoury MJ, Cordero JF, Erickson JD: Diabetes mellitus during pregnancy and the risks for specific birth defects: A population-based case-control study, Pediatrics 85:1-9, 1990. 311. Peacock WJ, Murovic JA: Magnetic resonance imaging in myelocystoceles: Report of two cases, J Neurosurg 70:804-807, 1989. 312. Gower DJ, Del Curling O, Kelly DLJ, Alexander EJ: Diastematomyelia: A 40-year experience, Pediatr Neurosci 14:90-96, 1988. 313. Harwood-Nash DC, McHugh K: Diastematomyelia in 172 children: The impact of modern neuroradiology, Pediatr Neurosurg 16:247-251, 1990. 314. Seeds JW, Jones FD: Lipomyelomeningocele: Prenatal diagnosis and management, Obstet Gynecol 67:S34-S37, 1986. 315. Seeds JW, Powers SK: Early prenatal diagnosis of familial lipomyelomeningocele, Obstet Gynecol 72:469-471, 1988. 316. Lemire RJ, Beckwith JB: Pathogenesis of congenital tumors and malformations of the sacrococcygeal region, Teratology 25:201-213, 1982. 317. Baraitser P, Shieff C: Cutaneomeningo-spinal angiomatosis: The syndrome of Cobb. A case report, Neuropediatrics 21:160-161, 1990. 318. Michaud LJ, Jaffe KM, Benjamin DR, Stuntz JT, et al: Hemangioblastoma of the conus medullaris associated with cutaneous hemangioma, Pediatr Neurol 4:309-312, 1988. 319. Langer JC, Harrison MR, Schmidt KG, Silverman NH, et al: Fetal hydrops and death from sacrococcygeal teratoma: Rationale for fetal surgery, Am J Obstet Gynecol 160:1145-1150, 1989. 320. Higginbottom MC, Jones KL, James HE, Bruce DA, et al: Aplasia cutis congenita: A cutaneous marker of occult spinal dysraphism, J Pediatr 96:687-689, 1980. 321. Hall DE, Udvarhelyi GB, Altman J: Lumbosacral skin lesions as markers of occult spinal dysraphism, JAMA 246:2606-2608, 1981. 322. Albright AL, Gartner JC, Wiener ES: Lumbar cutaneous hemangiomas as indicators of tethered spinal cords, Pediatrics 83:977-980, 1989. 323. Pang DL, Hoffman HJ, Rekate HL: Split cord malformation. II. Clinical syndrome, Neurosurgery 31:481-500, 1992. 324. Kriss VM, Desai NS: Occult spinal dysraphism in neonates: Assessment of high-risk cutaneous stigmata on sonography, AJR Am J Roentgenol 171:1687-1692, 1998. 325. Ackerman LL, Menezes AH: Spinal congenital dermal sinuses: A 30year experience, Pediatrics 112:641-647, 2003. 326. Tubbs RS, Wellons JC, 3rd, Iskandar BJ, Oakes WJ: Isolated flat capillary midline lumbosacral hemangiomas as indicators of occult spinal dysraphism, J Neurosurg 100:86-89, 2004. 327. Piatt JH Jr: Skin hemangiomas and occult dysraphism, J Neurosurg 100:81-82; discussion 82, 2004. 328. Scheible W, James HE, Leopold GR, Hilton SV: Occult spinal dysraphism in infants: Screening with high-resolution real-time ultrasound, Radiology 146:743-746, 1983. 329. Naidich TP, Fernbach SK, McLone DG, Shkolnik A: John Caffey Award. Sonography of the caudal spine and back: Congenital anomalies in children, AJR Am J Roentgenol 142:1229-1242, 1984. 329a. Lowe LH, Johanek AJ, Moore CW: Sonography of the neonatal spine: Part 2, spinal disorders, AJR Am J Roentgenol 188:739-744, 2007. 330. Packer RJ, Zimmerman RA, Sutton LN, Bilaniuk LT, et al: Magnetic resonance imaging of spinal cord disease of childhood, Pediatrics 78:251256, 1986. 331. Naidich TP, McLone DG, Mutluer S: A new understanding of dorsal dysraphism with lipoma (lipomyeloschisis): Radiologic evaluation and surgical correction, AJR Am J Roentgenol 140:1065-1078, 1983. 332. Hoffman HJ, Taecholarn C, Hendrick EB, Humphreys RP: Management of lipomyelomeningoceles: Experience at the Hospital for Sick Children, Toronto, J Neurosurg 62:1-8, 1985.
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Shanks DE, Wilson WG: Lobar holoprosencephaly presenting as spastic diplegia, Dev Med Child Neurol 30:383-386, 1988. 388. Biancheri R, Rossi A, Tortori-Donati P, Stringara S, et al: Middle interhemispheric variant of holoprosencephaly: A very mild clinical case, Neurology 63:2194-2196, 2004. 389. Holmes LB, Driscoll S, Atkins L: Genetic heterogeneity of cebocephaly, J Med Genet 11:35-40, 1974. 390. Mu¨nke M: Clinical, cytogenetic, and molecular approaches to the genetic heterogeneity of holoprosencephaly, Am J Med Genet 34:237-245, 1989. 391. Lorch V, Fojaco R, Bauer CR: Cebocephalus associated with trisomy 1315 mosaicism, Arch Neurol 35:163-165, 1978. 392. Uchida IA, McRae KN, Wang HC, Ray M: Familial short arm deficiency of chromosome 18 concomitant with arrhinencephaly and alopecia congenita, Am J Hum Genet 17:410, 1965. 393. 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397. Helmuth RA, Weaver DD, Wills ER: Holoprosencephaly, ear abnormalities, congenital heart defect, and microphallus in a patient with 11qmosaicism, Am J Med Genet 32:178-181, 1989. 398. Lazaro L, Dubourg C, Pasquier L, LeDuff F, et al: Phenotypic and molecular variability of the holoprosencephalic spectrum, Am J Med Genet A 129:21-24, 2004. 399. Pfitzer P, Muntefering H: Cyclopism as a hereditary malformation, Nature 217:1071-1072, 1968. 400. Berry SA, Pierpont ME, Gorlin RJ: Single central incisor in familial holoprosencephaly, J Pediatr 104:877-880, 1984. 401. Hennekam RC, Van Noort G, de la Fuente FA, Norbruis OF: Agenesis of the nasal septal cartilage: Another sign in autosomal dominant holoprosencephaly [letter], Am J Med Genet 39:121-122, 1991. 402. Ardinger HH, Bartley JA: Microcephaly in familial holoprosencephaly, J Craniofac Genet Dev Biol 8:53-61, 1988. 403. Kato M, Nanba E, Akaboshi S, Shiihara T, et al: Sonic hedgehog signal peptide mutation in a patient with holoprosencephaly, Ann Neurol 47:514-516, 2000. 404. Marini M, Cusano R, DeBiasio P, Caroli F, et al: Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability, Am J Med Genet A 117:112115, 2003. 405. Hehr U, Gross C, Diebold U, Wahl D, et al: Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation, Eur J Pediatr 163:347-352, 2004. 406. Barr M Jr, Hanson JW, Currey K, Sharp S, et al: Holoprosencephaly in infants of diabetic mothers, J Pediatr 102:565-568, 1983. 407. Binns W, James LF, Shupe JL, Thacker EJ: Cyclopian-type malformation in lambs, Arch Environ Health 5:106, 1962. 408. Chervenak FA, Isaacson G, Hobbins JC, Chitkara U, et al: Diagnosis and management of fetal holoprosencephaly, Obstet Gynecol 66:322-326, 1985. 409. McGahan JP, Nyberg DA, Mack LA: Sonography of facial features of alobar and semilobar holoprosencephaly, AJR Am J Roentgenol 154:143148, 1990. 410. Nyberg DA, Mack LA, Bronstein A, Hirsch J, et al: Holoprosencephaly: Prenatal sonographic diagnosis, AJR Am J Roentgenol 149:1051-1058, 1987. 411. Verlinsky Y, Rechitsky S, Verlinsky O, Ozen S, et al: Preimplantation diagnosis for sonic hedgehog mutation causing familial holoprosencephaly, N Engl J Med 348:1449-1454, 2003. 412. Barkovich AJ, Norman D: Absence of the septum pellucidum: A useful sign in the diagnosis of congenital brain malformations, AJNR Am J Neuroradiol 9:1107-1114, 1988. 413. Utsunomiya H, Ogasawara T, Hayashi T, Hashimoto T, et al: Dysgenesis of the corpus callosum and associated telencephalic anomalies: MRI, Neuroradiology 39:302-310, 1997. 414. Taylor M, David AS: Agenesis of the corpus callosum: A United Kingdom series of 56 cases, J Neurol Neurosurg Psychiatry 64:131-134, 1998. 415. Nissenkorn A, Michelson M, Ben-Zeev B, Lerman-Sagie T: Inborn errors of metabolism: A cause of abnormal brain development, Neurology 56:1265-1272, 2001. 416. Barkovich AJ, Simon EM, Walsh CA: Callosal agenesis with cyst: A better understanding and new classification, Neurology 56:220-227, 2001. 417. Sztriha L: Spectrum of corpus callosum agenesis, Pediatr Neurol 32:94101, 2005. 418. Bedeschi MF, Bonaglia MC, Grasso R, Pellegri A, et al: Agenesis of the corpus callosum: Clinical and genetic study in 63 young patients, Pediatr Neurol 34:186-193, 2006. 419. Hetts SW, Sherr EH, Chao S, Gobuty S, et al: Anomalies of the corpus callosum: An MR analysis of the phenotypic spectrum of associated malformations, AJR Am J Roentgenol 187:1343-1348, 2006. 419a. Fratelli N, Papageorghiou AT, Prefumo F, Bakalis S, et al: Outcome of prenatally diagnosed agenesis of the corpus callosum, Prenat Diagn 27:512-517, 2007. 420. Hale BR, Rice P: Septo-optic dysplasia: Clinical and embryological aspects, Dev Med Child Neurol 16:812-817, 1974. 421. Barkovich AJ, Kjos BO, Norman D, Edwards MS: Revised classification of posterior fossa cysts and cystlike malformations based on the results of multiplanar MR imaging, AJNR Am J Neuroradiol 10:977-988, 1989. 422. Barkovich AJ, Fram EK, Norman D: Septo-optic dysplasia: MR imaging, Radiology 171:189-192, 1989. 423. Breeding LM, Bodensteiner JB, Cowan L, Higgins WL: The cavum septi pellucidi: A magnetic resonance imaging study of prevalence and clinical associations in a pediatric population, J Neuroimaging 1:115-118, 1991. 424. Bodensteiner JB, Schaefer GB: Wide cavum septum pellucidum: A marker of disturbed brain development, Pediatr Neurol 6:391-394, 1990. 425. Aicardi J, Goutie`res F: The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects, Neuropediatrics 12:319-329, 1981. 426. Shimozawa N, Ohno K, Takashima S, Takakura H, et al: The syndrome of the absence of a septum pellucidum with porencephaly, Brain Dev 8:632-636, 1986.
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Unit I
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Griebel ML, Williams JP, Russell SS, Spence GT, et al: Clinical and developmental findings in children with giant interhemispheric cysts and dysgenesis of the corpus callosum, Pediatr Neurol 13:119-124, 1995. 450. Neidich JA, Nussbaum RL, Packer RJ, Emanuel BS, et al: Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome, J Pediatr 116:911-917, 1990. 451. Nielsen KB, Anvret M, Flodmark O, Furuskog P, et al: Aicardi syndrome: Early neuroradiological manifestations and results of DNA studies in one patient, Am J Med Genet 38:65-68, 1991. 452. Donnenfeld AE, Packer RJ, Zackai EH, Chee CM, et al: Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome, Am J Med Genet 32:461-467, 1989. 453. Molina JA, Mateos F, Merino M, Epifanio JL, et al: Aicardi syndrome in two sisters, J Pediatr 115:282-283, 1989. 454. Roland EH, Flodmark O, Hill A: Neurosonographic features of Aicardi’s syndrome, J Child Neurol 4:307-310, 1989. 455. Hamano S, Yagishita S, Kawakami M, Ito F, et al: Aicardi syndrome: Postmortem findings, Pediatr Neurol 5:259-261, 1989. 456. Tagawa T, Mimaki T, Ono J, Tanaka J, et al: Aicardi syndrome associated with an embryonal carcinoma, Pediatr Neurol 5:45-47, 1989. 457. Bertoni JM, von Loh S, Allen RJ: The Aicardi syndrome: Report of 4 cases and review of the literature, Ann Neurol 5:475-482, 1979. 458. Menezes AV, MacGregor DL, Buncic JR: Aicardi syndrome: Natural history and possible predictors of severity, Pediatr Neurol 11:313-318, 1994.
459. Rosser TL, Acosta MT, Packer RJ: Aicardi syndrome: Spectrum of disease and long-term prognosis in 77 females, Pediatr Neurol 27:343-346, 2002. 460. Aicardi J: Aicardi syndrome, Brain Dev 27:164-171, 2005. 461. Palmer L, Zetterlund B, Hard AL, Steneryd K, et al: Aicardi syndrome: Presentation at onset in Swedish children born in 1975-2002, Neuropediatrics 37:154-158, 2006. 462. Atlas SW, Shkolnik A, Naidich TP: Sonographic recognition of agenesis of the corpus callosum, AJR Am J Roentgenol 145:167-173, 1985. 463. Fawer C-L, Calame A, Anderegg A, Deonna T, et al: Agenesis of the corpus callosum: Real-time ultrasonographic diagnosis and autopsy findings, Helv Paediatr Acta 40:371-380, 1985. 464. Hellstrom A, Wiklund LM, Svensson E, Stromland K, et al: Midline brain lesions in children with hormone insufficiency indicate early prenatal damage, Acta Paediatr 87:528-536, 1998. 465. Friedman JM, Santos-Ramos R: Natural history of X-linked aqueductal stenosis in the second and third trimesters of pregnancy, Am J Obstet Gynecol 150:104-106, 1984. 466. Cochrane DD, Myles ST: Management of intrauterine hydrocephalus, J Neurosurg 57:590-596, 1982. 467. Chervenak FA, Berkowitz RL, Romero R, Tortora M, et al: The diagnosis of fetal hydrocephalus, Am J Obstet Gynecol 147:703-716, 1983. 468. Cochrane DD, Myles ST, Nimrod C, Still DK, et al: Intrauterine hydrocephalus and ventriculomegaly: Associated anomalies and fetal outcome, Can J Neurol Sci 12:51-59, 1985. 469. Bromley B, Frigoletto FD Jr, Benacerraf BR: Mild fetal lateral cerebral ventriculomegaly: Clinical course and outcome, Am J Obstet Gynecol 164:863-867, 1991. 470. Amato M, Hu¨ppi P, Durig P, Kaiser G, et al: Fetal ventriculomegaly due to isolated brain malformations, Neuropediatrics 21:130-132, 1990. 471. Hudgins RJ, Edwards MS, Goldstein R, Callen PW, et al: Natural history of fetal ventriculomegaly, Pediatrics 82:692-697, 1988. 472. Pober BR, Greene MF, Holmes LB: Complexities of intraventricular abnormalities, J Pediatr 108:545-551, 1986. 473. Renier D, Sainte-Rose C, Pierre-Kahn A, Hirsch JF: Prognostic des hydroce´phalies ante´natales, Presse Med 18:168-172, 1989. 474. Pretorius DH, Davis K, Manco-Johnson ML, Manchester D, et al: Clinical course of fetal hydrocephalus: 40 cases, AJR Am J Roentgenol 144:827-831, 1985. 475. Serlo W, Kirkinen P, Jouppila P, Herva R: Prognostic signs in fetal hydrocephalus, Childs Nerv Syst 2:93-97, 1986. 476. Nyberg DA, Mack LA, Hirsch J, Pagon RO, et al: Fetal hydrocephalus: Sonographic detection and clinical significance of associated anomalies, Radiology 163:187-191, 1987. 477. Renier D, Sainte-Rose C, Pierre-Kahn A, Hirsch JF: Prenatal hydrocephalus: Outcome and prognosis, Childs Nerv Syst 4:213-222, 1988. 478. Drugan A, Krause B, Canady A, Zador IE, et al: The natural history of prenatally diagnosed cerebral ventriculomegaly, JAMA 261:1785-1788, 1989. 479. Stirling HF, Hendry M, Brown JK: Prenatal intracranial haemorrhage, Dev Med Child Neurol 31:807-811, 1989. 480. Benacerraf BR: Fetal hydrocephalus: Diagnosis and significance [editorial], Radiology 169:858-859, 1988. 481. Hanigan WC, Gibson J, Kleopoulos NJ, Cusack T, et al: Medical imaging of fetal ventriculomegaly, J Neurosurg 64:575-580, 1986. 482. Leidig E, Dannecker G, Pfeiffer KH, Salinas R, et al: Intrauterine development of posthaemorrhagic hydrocephalus, Eur J Pediatr 147:26-29, 1988. 483. Rosseau GL, McCullough DC, Joseph AL: Current prognosis in fetal ventriculomegaly, J Neurosurg 77:551-555, 1992. 484. Levitsky DB, Mack LA, Nyberg DA, Shurtleff DB, et al: Fetal aqueductal stenosis diagnosed sonographically: How grave is the prognosis? AJR Am J Roentgenol 164:725-730, 1995. 485. Kirkinen P, Serlo W, Jouppila P, Ryynanen M, et al: Long-term outcome of fetal hydrocephaly, J Child Neurol 11:189-192, 1996. 486. Futagi Y, Suzuki Y, Toribe Y, Morimoto K: Neurodevelopmental outcome in children with fetal hydrocephalus, Pediatr Neurol 27:111-116, 2002. 487. Cavalheiro S, Moron AF, Zymberg ST, Dastoli P: Fetal hydrocephalusprenatal treatment, Childs Nerv Syst 19:561-573, 2003. 488. Davis GH: Fetal hydrocephalus, Clin Perinatol 30:531-539, 2003. 489. Mealey J Jr, Gilmor RL, Bubb MP: The prognosis of hydrocephalus overt at birth, J Neurosurg 39:348-355, 1973. 490. McCullough DC, Balzer-Martin LA: Current prognosis in overt neonatal hydrocephalus, J Neurosurg 57:378-383, 1982. 491. Hanigan WC, Morgan A, Shaaban A, Bradle P: Surgical treatment and long-term neurodevelopmental outcome for infants with idiopathic aqueductal stenosis, Childs Nerv Syst 7:386-390, 1991. 492. Fernell E, Uvebrant P, von Wendt L: Overt hydrocephalus at birth: Origin and outcome, Childs Nerv Syst 3:350-353, 1987. 493. Halliday J, Chow CW, Wallace D, Danks DM: X linked hydrocephalus: A survey of a 20 year period in Victoria, Australia, J Med Genet 23:23-31, 1986.
Chapter 1 494. Fernell E, Hagberg B, Hagberg G, von Wendt L: Epidemiology of infantile hydrocephalus in Sweden. II. Origin in infants born at term, Acta Paediatr Scand 76:411-417, 1987. 495. Wong EV, Kenwrick S, Willems P, Lemmon V: Mutations in the cell adhesion molecule LI cause mental retardation, Trends Neurosci 18:168172, 1995. 496. Schrander Stumpel C, Howeler C, Jones M, Sommer A, et al: Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clinical review with six additional families, Am J Med Genet 57:107-116, 1995. 497. Yamasaki M, Thompson P, Lemmon V: CRASH Syndrome: Mutations in L1CAM correlate with severity of the disease, Neuropediatrics 28:175178, 1997. 498. Takahashi S, Makita Y, Okamoto N, Miyamoto A, et al: LICAM mutation in a Japanese family with X-linked hydrocephalus: A study for genetic counseling, Brain Dev 19:559-562, 1997. 499. Sztriha L, Vos YJ, Verlind E, Johansen J, et al: X-linked hydrocephalus: A novel missense mutation in the L1CAM gene, Pediatr Neurol 27:293-296, 2002. 500. Haverkamp F, Wolfle J, Aretz M, Kramer A, et al: Congenital hydrocephalus internus and aqueduct stenosis: Aetiology and implications for genetic counselling, Eur J Pediatr 158:474-478, 1999. 501. McComb JG: Cerebrospinal fluid physiology of the developing fetus, AJNR Am J Neuroradiol 13:595-599, 1992. 502. Catala M: Carbonic anhydrase activity during development of the choroid plexus in the human fetus, Childs Nerv Syst 13:364-368, 1997. 503. Holtzman RN, Garcia L, Koenigsberger R: Hydrocephalus and congenital clasped thumbs: A case report with electromyographic evaluation, Dev Med Child Neurol 18:521-524, 1976. 504. Willems PJ, Vits L, Raeymaekers P, Beuten J, et al: Further localization of X-linked hydrocephalus in the chromosomal region-xq28, Am J Hum Genet 51:307-315, 1992. 505. Serville F, Lyonnet S, Pelet A, Reynaud M, et al: X-linked hydrocephalusclinical heterogeneity at a single gene locus, Eur J Pediatr 151:515-518, 1992. 506. Vintzileos AM, Ingardia CJ, Nochimson DJ: Congenital hydrocephalus: A review and protocol for perinatal management, Obstet Gynecol 62:539-549, 1983. 507. Birnholz J: Fetal neurology. In Sanders RC, Hill M, editors: Ultrasound Annual, New York: 1984, Raven Press. 508. Glick PL, Harrison MR, Nakayama DK, Edwards MS, et al: Management of ventriculomegaly in the fetus, J Pediatr 105:97-105, 1984. 509. Zlotogora J, Sagi M, Cohen T: Familial hydrocephalus of prenatal onset, Am J Med Genet 49:202-204, 1994. 510. Wyldes M, Watkinson M: Isolated mild fetal ventriculomegaly, Arch Dis Child Fetal Neonatal Ed 89:F9-13, 2004. 511. Hart MN, Malamud N, Ellis WG: The Dandy-Walker syndrome: A clinicopathological study based on 28 cases, Neurology 22:771-780, 1972. 512. Tal Y, Freigang B, Dunn HG, Durity FA, et al: Dandy-Walker syndrome: Analysis of 21 cases, Dev Med Child Neurol 22:189-201, 1980. 513. Hirsch JF, Pierre-Kahn A, Renier D, Sainte Rose C, et al: The DandyWalker malformation: A review of 40 cases, J Neurosurg 61:515-522, 1984. 514. Connolly MB, Jan JE, Cochrane DD: Rapid recovery from cortical visual impairment following correction of prolonged shunt malfunction in congenital hydrocephalus, Arch Neurol 48:956-957, 1991. 515. Den Hollander NS, Vinkesteijn A, Schmitz-van Splunder P, CatsmanBerrevoets CE, et al: Prenatally diagnosed fetal ventriculomegaly: Prognosis and outcome, Prenat Diagn 18:557-566, 1998. 516. Michejda M, Hodgen GD: In utero diagnosis and treatment of nonhuman primate fetal skeletal anomalies. I. Hydrocephalus, JAMA 246:1093-1097, 1981. 517. Michejda M, Patronas N, DiChiro G, Hodgen GD: Fetal hydrocephalus. II. Amelioration of fetal porencephaly by in utero therapy in nonhuman primates, JAMA 251:2548-2552, 1984. 518. Michejda M, Queenan JT, McCullough D: Present status of intrauterine treatment of hydrocephalus and its future, Am J Obstet Gynecol 155:873882, 1986. 519. Clewell WH, Johnson ML, Meier PR, Newkirk JB, et al: A surgical approach to the treatment of fetal hydrocephalus, N Engl J Med 306:1320-1325, 1982. 520. Bannister CM: Fetal neurosurgery: A new challenge on the horizon, Dev Med Child Neurol 26:827-830, 1984. 521. Manning FA, Harrison MR, Rodeck C: Catheter shunts for fetal hydronephrosis and hydrocephalus: Report of the International Fetal Surgery Registry, N Engl J Med, 3151986. 522. Oi SZ, Yamada H, Kimura M, Ehara K, et al: Factors affecting prognosis of intrauterine hydrocephalus diagnosed in the third trimester, Neurol Med Chir 30:456-461, 1990. 523. ten-Donkelaar HJ, Lammens M, Wesseling P, Thijssen HOM, et al: Development and developmental disorders of the human cerebellum, J Neurol 250:1025-1036, 2003. 524. Patel S, Barkovich AJ: Analysis and classification of cerebellar malformations, AJNR Am J Neuroradiol 23:1074-1087, 2002.
Neural Tube Formation and Prosencephalic Development
49
525. Boltshauser E: Cerebellum-small brain but large confusion: A review of selected cerebellar malformations and disruptions, Am J Med Genet A 126:376-385, 2004. 526. Sarnat HB, Alcala´ H: Human cerebellar hypoplasia: A syndrome of diverse causes, Arch Neurol 37:300-305, 1980. 527. Tomiwa K, Baraitser M, Wilson J: Dominantly inherited congenital cerebellar ataxia with atrophy of the vermis, Pediatr Neurol 3:360-362, 1987. 528. Fenichel GM, Phillips JA: Familial aplasia of the cerebellar vermis: Possible X-linked dominant inheritance, Arch Neurol 46:582-583, 1989. 529. Mathews KD, Afifi AK, Hanson JW: Autosomal recessive cerebellar hypoplasia, J Child Neurol 4:189-194, 1989. 530. Dooley JM, LaRoche GR, Tremblay F, Riding M: Autosomal recessive cerebellar hypoplasia and tapeto-retinal degeneration: A new syndrome, Pediatr Neurol 8:232-234, 1992. 531. Guzzetta F, Mercuri E, Bonanno S, Longo M, et al: Autosomal recessive congenital cerebellar atrophy: A clinical and neuropsychological study, Brain Dev 15:439-445, 1993. 532. Shevell MI, Majnemer A: Clinical features of developmental disability associated with cerebellar hypoplasia, Pediatr Neurol 15:224-229, 1996. 533. Gardner RJM, Coleman LT, Mitchell LA, Smith LJ, et al: Near-total absence of the cerebellum, Neuropediatrics 32:62-68, 2001. 534. Wassmer E, Davies P, Whitehouse WP, Green SH: Clinical spectrum associated with cerebellar hypoplasia, Pediatr Neurol 28:347-351, 2003. 535. Zafeiriou DI, Vargiami E, Boltshauser E: Cerebellar agenesis and diabetes insipidus, Neuropediatrics 35:364-367, 2004. 536. Yapici Z, Eraksoy M: Non-progressive congenital ataxia with cerebellar hypoplasia in three families, Acta Paediatr 94:248-253, 2005. 537. Glass HC, Boycott KM, Adams C, Barlow K, et al: Autosomal recessive cerebellar hypoplasia in the Hutterite population, Dev Med Child Neurol 47:691-695, 2005. 538. Boycott KM, Flavelle S, Bureau A, Glass HC, et al: Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification, Am J Hum Genet 77:477-483, 2005. 539. Bordarier C, Aicardi J: Dandy-Walker syndrome and agenesis of the cerebellar vermis: Diagnostic problems and genetic counselling, Dev Med Child Neurol 32:285-294, 1990. 540. Russ PD, Pretorius DH, Johnson MJ: Dandy-Walker syndrome: A review of fifteen cases evaluated by prenatal sonography, Am J Obstet Gynecol 161:401-406, 1989. 541. Maria BL, Zinreich SJ, Carson BC, Rosenbaum AE, et al: Dandy-Walker syndrome revisited, Pediatr Neurosci 13:45-51, 1987. 542. Golden JA, Rorke LB, Brucke DA: Dandy-Walker syndrome and associated anomalies, Pediatr Neurosci 38:38-44, 1987. 543. Edwards MS, Raffel C: Discussion of articles by Maria et al and Golden et al, Pediatr Neurosci 13:45-51, 1987. 544. Bindal AK, Storrs BB, McLone DG: Management of the Dandy-Walker syndrome, Pediatr Neurosurg 16:163-169, 1990. 545. Osenbach RK, Menezes AH: Diagnosis and management of the DandyWalker malformation: 30 years of experience, Pediatr Neurosurg 18:179189, 1992. 546. Estroff JA, Scott MR, Benacerraf BR: Dandy-Walker variant-prenatal sonographic features and clinical outcome, Radiology 185:755-758, 1992. 547. Strand RD, Barnes PD, Poussaint TY, Estroff JA, et al: Cystic retrocerebellar malformations: Unification of the Dandy-Walker complex and the Blake’s pouch cyst, Pediatr Radiol 23:258-260, 1994. 548. Tortori Donati P, Fondelli MP, Rossi A, Carini S: Cystic malformations of the posterior cranial fossa originating from a defect of the posterior membranous area. Mega cisterna magna and persisting Blake’s pouch: Two separate entities, Childs Nerv Sys 12:303-308, 1996. 549. Tan E-C, Takagi T, Karasawa K: Posterior fossa cystic lesions-magnetic resonance imaging manifestations, Brain Dev 17:418-424, 1995. 550. Elterman RD, Bodensteiner JB, Barnard JJ: Sudden unexpected death in patients with Dandy-Walker malformation, J Child Neurol 10:382-384, 1995. 551. Ondo WG, Delong GR: Dandy-Walker syndrome presenting as opisthotonus: Proposed pathophysiology, Pediatr Neurol 14:165-168, 1996. 552. Ecker JL, Shipp TD, Bromley B, Benacerraf B: The sonographic diagnosis of Dandy-Walker and Dandy-Walker variant: Associated findings and outcomes, Prenat Diagn 20:328-332, 2000. 553. Joubert M, Eisenring JJ, Robb JP, Andermann F: Familial agenesis of the cerebellar vermis: A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation, Neurology 19:813-825, 1969. 554. Steinlin M, Schmid M, Landau K, Boltshauser E: Follow-up in children with Joubert syndrome, Neuropediatrics 28:204-211, 1997. 555. Maria BL, Hoang KB, Tusa RJ, Mancuso AA, et al: ’’Joubert syndrome’’ revisited: Key ocular motor signs with magnetic resonance imaging correlation, J Child Neurol 12:423-430, 1997. 556. Sztriha L, Al-Gazali LI, Aithala GR, Nork M: Joubert’s syndrome: New cases and review of clinicopathologic correlation, Pediatr Neurol 20:274281, 1999. 557. Anderson JS, Gorey MTP, Pasternak JF, Trommer BL: Joubert’s syndrome and prenatal hydrocephalus, Pediatr Neurol 20:403-405, 1999.
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558. Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, et al: Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria, Am J Hum Genet 75:979-987, 2004. 559. Hodgkins PR, Harris CM, Shawkat FS, Thompson DA, et al: Joubert syndrome: Long-term follow-up, Dev Med Child Neurol 46:694699, 2004. 560. Janecke AR, Muller T, Gassner I, Kreczy A, et al: Joubert-like syndrome unlinked to known candidate loci, J Pediatr 144:264-269, 2004. 561. Morava E, Dinopoulos A, Kroes HY, Rodenburg RJ, et al: Mitochondrial dysfunction in a patient with Joubert syndrome, Neuropediatrics 36:214217, 2005. 562. Valente EM, Marsh SE, Castori M, Dixon-Salazar T, et al: Distinguishing the four genetic causes of Jouberts syndrome-related disorders, Ann Neurol 57:513-519, 2005. 563. Valente EM, Brancati F, Silhavy JL, Castori M, et al: AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders, Ann Neurol 59:527-534, 2006.
564. Toelle SP, Valcinkaya C, Kocer N, Deonna T, et al: Rhombencephalosynapsis: Clinical findings and neuroimaging in 9 children, Neuropediatrics 33:209-214, 2002. 565. Odemis E, Cakir M, Aynaci FM: Rhombencephalosynapsis associated with cutaneous pretibial hemangioma in an infant, J Child Neurol 18:225-228, 2003. 566. Napolitano M, Righini A, Zirpoli S, Rustico M, et al: Prenatal magnetic resonance imaging of rhombencephalosynapsis and associated brain anomalies: Report of 3 cases, J Comput Assist Tomogr 28:762-765, 2004. 567. Demaerel P, Morel C, Lagae L, Wilms G: Partial rhombencephalosynapsis, AJNR Am J Neuroradiol 25:29-31, 2004. 568. Chemli J, Abroug M, Tlili K, Harbi A: Rhombencephalosynapsis diagnosed in childhood: Clinical and MRI findings, Eur J Paediatr Neurol 11:35-38, 2007. 569. Bodensteiner JB, Gay CT, Marks WA, Hamza M, et al: Macro cisterna magna: A marker for maldevelopment of the brain? Pediatr Neurol 4:284286, 1988.
Chapter 2 Neuronal Proliferation, Migration, Organization, and Myelination The awesome complexity of the human brain begins its evolution after the essential external form is established by the events described in Chapter 1. The events that follow are proliferation of the brain’s total complement of neurons, migration of those neurons to specific sites throughout the central nervous system (CNS), the series of organizational events that results in the intricate circuitry characteristic of the human brain, and, finally, the ensheathment of this circuitry with the neural-specific membrane, myelin. These events span a period from the second month of gestation to adult life, including the perinatal period. Aberrations of neural development may be an important consequence of many perinatal insults; this consequence heretofore was not clearly recognized. This chapter reviews the normal aspects of neuronal proliferation, migration, organization, and myelination. A discussion follows regarding the disorders encountered when normal development goes awry. NEURONAL PROLIFERATION Normal Development Major proliferative events occur initially between 2 and 4 months of gestation, with the peak time period quantitatively in the third and fourth months (Table 2-1). All neurons and glia are derived from the ventricular and subventricular zones, present in the subependymal location at every level of the developing nervous system. This highly critical process clearly relates to the ultimate integrity of every system within the neural apparatus. Valuable quantitative information concerning cellular proliferation is derived from studies of the deposition of brain DNA, the chemical correlate of cell number, or from direct counting by optical and stereological methods (Fig. 2-1).1,2 Two phases can be distinguished: the first, occurring from approximately 2 to 4 months of gestation, is associated primarily with generation of radial glia and neuronal proliferation; the second, occurring from approximately 5 months of gestation to 1 year (or more) of life, is associated primarily with glial multiplication (see later discussion concerning organizational events). Similarly, some neuronal formation occurs later than 4 months of gestation, principally in the cerebral subventricular zone and the cerebellar external granule cell layer (see later). Finally, proliferation of the vascular tree, arterial before
venous, is particularly active during the phase of neuronal proliferation.3-6 Initially, a leptomeningeal plexus of vessels appears; this is followed in the third month by radially oriented, primarily unbranched vessels, which in the fourth and later months develop horizontal branching (Fig. 2-2).4,6 The fundamental aspects of cell proliferation in the wall of the neural tube were described first on the basis of morphological observations by Sauer in 1935.7,8 They then were delineated further by the use of radioautography with [3H]thymidine-labeled DNA by Sidman, Rakic, Berry, and others 2 to 3 decades later, still later by Caviness, Rakic, and co-workers with bromodeoxyuridine-labeled DNA,9-20 and most recently by immunocytochemistry, computer-assisted serial electron micrographic reconstruction, and time-lapse multiphoton imaging (Fig. 2-3).21-23b Cells in the periphery of the ventricular zone were shown to replicate their DNA, migrate toward the luminal surface, and divide; the two daughter cells then were noted to migrate back to the periphery of the ventricular zone. This to-and-fro migration, or interkinetic nuclear migration, is repeated each time DNA replication and mitosis occur in the ventricular zone. In some regions of the forebrain, a subventricular zone of proliferating cells can be identified (see Fig. 2-3). In the monkey cerebrum, studied in detail by Rakic and co-workers and by others,13,16,19,21-26 the ventricular zone gives birth to most neurons, and the subventricular zone is the point of origin of some later-appearing neurons (e.g., upper layers of cerebral cortex and later subplate neurons) and most glia. When cells withdraw from the mitotic cycle and cease proliferative activity, they migrate into the intermediate zone on their way to forming the cortical plate (see later discussion). The elegant work of Caviness and co-workers defined
TABLE 2-1
Neuronal Proliferation
Peak Time Period 3–4 months Major Events Ventricular zone and subventricular zone are the sites of proliferation. Proliferative units are produced by symmetrical divisions of progenitor cells. Proliferative units later enlarge by asymmetrical divisions of progenitor cells before neuronal migration.
51
Relative cell number
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3.0 Glial 2.0
1.0
Neuronal and radial glial
0 5 10
20 30 Prenatal
40 10 Birth Age (wk)
20 30 Postnatal
40
50
Figure 2-1 Relative cell number in human forebrain as a function of age. Total content of forebrain DNA is used to estimate relative cell number. Note that the curve has two phases of rapid increase in cell number. See text for details. (Adapted from Dobbing J, Sands J: Quantitative growth and development of human brain, Arch Dis Child 48:757–767, 1973.)
the G1 phase of the cell cycle as the molecular ‘‘control point’’ for these critical proliferative events.20,27 Rakic’s studies of monkey cortical development led him to the conclusion that, in the earliest phases of proliferation, progenitor cells divide symmetrically into two
additional progenitor cells, and that ‘‘proliferative units’’ of neuronal progenitor cells develop in this way (see later and see also Table 2-1).16,25,26,28 This process determines the number of proliferative units in the ventricular-subventricular zones. Later, at a time comparable to the second half of the second month of gestation in the human, the number of these proliferative units becomes stable as the progenitor cells begin to divide asymmetrically (i.e., each division results in dissimilar cells, one of which is a stem cell and the other a postmitotic neuronal cell). These asymmetrical divisions determine the size of each proliferative unit (see Table 2-1). As the proliferative phase progresses, proportionately more postmitotic neuronal cells and fewer stem cells are produced.19 Rakic concluded that the neurons of these proliferative units migrate together in a column to form the neuronal columns of the cerebral cortex (Fig. 2-4).28 Other factors can become operative to determine the complete functional organization of the cerebral cortex (see later discussion of migration), but the general principle is the generation of neuronal units in the ventricular-subventricular zones with subsequent migration
Plexus tentorii
A. cerebelli superior A. cerebri posterior
Plexus posterior
Plexus sagittalis
transve Sinus
rs u s
Sin. rectus A. choroidealis
Sin. petrosus superior Sin
Plexus choroideus
. c a v e r n.
A. occipitalis V. jugularis interna
A. cerebri anterior
A. vertebralis V. ophthalmica Plexus maxillary A. maxillaris interna A. carotis interna
A. et V. cerebri media
A. centralis retinae
A. maxillaris externa
A. lingualis Figure 2-2 Reconstruction of the perineural vascular territory of the brain (intracranial vasculature) of a stage 20 human embryo (51 days, 18 to 22 mm). The dural venous sinuses, the arachnoidal arterial and venous systems, and the pial plexus that characterize the adult brain are already recognizable at this age. The wall of the cerebral cortex (cerebral vesicle) has been opened to demonstrate that, at this age, its intrinsic vascularization has not started, but that of the choroid plexus is already under way. A, artery; cavern, cavernous; sin, sinus; V, vein. (From Streeter GL: Contributions to Embryology, vol. 8. Carnegie Institute of Embryology, 1918.)
Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
53
M CP
Figure 2-3 Cerebral wall during cortical plate development. Schematic drawing of the cerebral wall during development of the mammalian cortical plate (CP) to demonstrate the major zones: ventricular (V), subventricular (S), intermediate (I), and marginal (M). (From Rakic P: Timing of major ontogenetic events in the visual cortex of the rhesus monkey. In Buchwald NA, Brazier MAB, editors: Brain Mechanisms in Mental Retardation, New York: 1975, Academic Press.)
M CP M
I
I
I M V
V
V
S
S
V
V
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Figure 2-4 The relation between a small patch of the proliferative, ventricular zone (VZ) and its corresponding area within the cortical plate (CP) in the developing cerebrum. Although the cerebral surface in primates expands and shifts during prenatal development, ontogenetic columns (outlined by cylinders) may remain attached to the corresponding proliferative units by the grid of radial glial fibers. Neurons produced between E40 and E100 by a given proliferative unit migrate in succession along the same clonally related radial glial guides (RG) and stack up in reverse order of arrival within the same ontogenetic column. Each migrating neuron (MN) first traverses the intermediate zone (IZ) and then the subplate (SP), which contains subplate neurons and ‘‘waiting’’ afferents from the thalamic radiation (TR) and ipsilateral and contralateral corticocortical connections (CC). After entering the cortical plate, each neuron bypasses earlier generated neurons and settles at the interface between the CP and marginal zone (MZ). As a result, proliferative units 1 to 100 produce ontogenetic columns 1 to 100 in the same relative position to each other without a lateral mismatch (e.g., between proliferative unit 3 and ontogenetic column 9, indicated by a dashed line). Thus, the specification of cytoarchitectonic areas and topographic maps depends on the spatial distribution of their ancestors in the proliferative units, whereas the laminar position and phenotype of neurons within ontogenetic columns depend on the time of their origin.
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pia
2' 1
2
2
1
2
vz
A
Early neural progenitor
B
Radial glial progenitor
Figure 2-5 Two types of neuronal progenitors. In A, as occurs especially early in neuronal proliferation, a single neural precursor (1) gives rise to two identical precursors (2), that is, a symmetrical division. In B, as occurs especially later in neuronal proliferation, a radial neuronal progenitor (radial glial progenitor or radial glial cell) (1) divides asymmetrically into dissimilar cells, that is, an identical radial progenitor (2) and a postmitotic neuronal cell (20 ) that migrates along the fiber of its clonally related radial progenitor to ultimately reach the cerebral cortex.
of these groups. Rakic showed that the distinguishing features of the kinetics of neuronal proliferation in primates versus species with smaller neocortices are a longer cell-cycle duration and, particularly, a more prolonged developmental period of neuronal proliferation.19 Because of the latter, the total number of proliferative units of neuronal cells generated is much greater in the primate. At least two types of neuronal progenitors are present in the ventricular zone: (1) a short neural precursor that has a ventricular endfoot and a leading process of variable length and (2) the radial glial cell that spans the entire cortical plate with contacts at both the ventricular and pial surfaces (Fig. 2-5).23 The former progenitor previously was considered the principal neuronal precursor cell. An exciting advance in the understanding of neuronal proliferation was the identification of the radial glial cell as another major neuronal progenitor in the ventricular zone.22,23,23a,23b,29-38 Previously, the major roles of this cell were considered to be, initially, a glial guide for migrating neurons and, later, a source of astrocytes (see later). However, more recent studies based on immunocytochemical and molecular techniques indicate that radial glial cells give rise to many neurons generated in the ventricular zone, particularly radially migrating excitatory projection cortical neurons. Thus, the term radial glial cell (which I continue to use) may ultimately be replaced by ‘‘radial glial progenitor’’ or ‘‘radial progenitor.’’ When the radial glial cell functions as a neuronal progenitor, the clonally related neuron so generated then migrates along the parent radial glial fiber (see Fig. 2-5). These elegant proliferative events involving the radial glial cell as neuronal progenitor are modulated by several key signaling pathways involving the Notch receptor, the ErbB receptor (through the ligand neuregulin), and the fibroblast growth factor receptor.28,38,39 Other critical molecular determinants include beta-catenin, a protein that functions in the decision of progenitors to proliferate or differentiate.40 Finally, of particular importance in the regulation of radial glial production of neurons are calcium waves propagating through connexin channels of the radial
glial cell.35 Calcium entry is critical in the regulation of the cell cycle. Subsequent to neurogenesis, radial cells produce astrocytes and probably other glial cells (e.g., oligodendroglia).36 Additionally, more recent data indicate that radial glial cells also give rise to cells that persist in the subventricular zone of adult brain as stem cells capable of producing neurons.36 The multiple functions of radial glial cells are summarized in Table 2-2. Disorders Disorders of neuronal proliferation would be expected to have a major impact on CNS function. Because of difficulties in quantitating neuronal populations, however, proliferative disorders often are difficult to define by conventional neuropathological examination. Even when the disorder is so extreme that the brain is grossly undersized (i.e., micrencephaly) or oversized (i.e., macrencephaly), defining the nature and severity of the proliferative derangement is also difficult by conventional techniques. (Although theoretically there is the possibility that the disorders relate to alterations in later-occurring normal apoptotic events, I consider these to be disorders of proliferation until evidence of an apoptotic disorder is recorded.) In the following discussion, I focus on these two extremes of apparent proliferative disorders, but I emphasize that conclusions about the nature of the disorders can be made only cautiously. Micrencephaly Disorders apparently related to impaired neuronal proliferation are categorized under the term primary micrencephaly, to distinguish the disorder from micrencephalies secondary to destructive disease (Table 2-3). TABLE 2-2
Functions of Radial Glial Cells
Progenitors for cortical neurons Guides of neuronal migration Progenitors for astrocytes and oligodendrocytes Neural stem cells found in subventricular zone of adult brain
Chapter 2 TABLE 2-3
Disorders of Neuronal Proliferation: Primary Micrencephaly*
Familial Autosomal recessive (micrencephaly vera) Autosomal dominant X-linked recessive Genetics unclear (ocular abnormalities) Teratogenic Irradiation Metabolic-toxic (e.g., fetal alcohol syndrome, related to cocaine, hyperphenylalaninemia) Infection (rubella, cytomegalovirus) Syndromic (Multiple Systemic Anomalies) Chromosomal Familial Sporadic Sporadic (Nonsyndromic) *Excluded are cases of congenital microcephaly secondary principally to destructive disease (hypoxia-ischemia, infection) developing after the conclusion of cerebral neuronal proliferation.
Neuronal Proliferation, Migration, Organization, and Myelination TABLE 2-4
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Radial Microbrain
Term newborns: death, birth–30 days Brain weight 16–50 g (normal, 350 g) No evidence for destructive process Normal residual germinal matrix at term Normal cortical lamination Cortical neurons 30% of normal number Cortical neuronal columns decreased in number Neuronal complement of each column normal Data from Evrard P, de Saint-Georges P, Kadhim HJ, Gadisseux J-F: Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors: Child Neurology and Developmental Disabilities, Baltimore: 1989, Paul H. Brookes.
proliferative events, which generates by symmetrical divisions of neuronal progenitors the total number of proliferative units, is based on the finding of a marked reduction in number of cortical neuronal columns but an apparent normal complement of the neurons per column (i.e., normal size of columns) (Fig. 2-6).5
The latter relates to hypoxic-ischemic, infectious, metabolic, or other destructive events, occurring usually following completion of cerebral neuronal proliferative events near the end of the fourth month of gestation (see Chapters 8, 9, 14, 15, 16, and 20). The primary micrencephalies that have been shown most clearly to be related to impaired neuronal proliferation include the autosomal recessively inherited disorders, often categorized as micrencephaly vera. Thus, in the context of this chapter, I discuss these conditions in most detail. Micrencephaly Vera. Micrencephaly vera refers to a heterogeneous group of disorders that appear to have, as the common denominator, small brain size because of a derangement of proliferation (see Table 2-3). Thus, no evidence of intrauterine destructive disease or of gross derangement of other developmental events (e.g., neurulation, prosencephalic cleavage, neuronal migration) exists, and the abnormal brain size is apparent as early as the third trimester of gestation). The brain is generally well formed, although the gyrification pattern may be simplified to a variable degree. As noted earlier, the clearest examples of micrencephaly vera are the autosomal recessively inherited micrencephalies, and I use this term only for these examples of primary micrencephaly. I first discuss radial microbrain, an informative but rare and particularly severe type of micrencephaly vera, and then the more common varieties of micrencephaly vera. Anatomical Abnormality: Radial Microbrain. Radial microbrain is a rare disorder of particular interest because it appears to provide the first clear example of a disturbance in number of proliferative units.5,41 The major features of the seven cases studied carefully by Evrard and colleagues5,41 are outlined in Table 2-4. The extremely small brain has no marked gyral abnormality, no evidence of a destructive process, and no disturbance of cortical lamination. The conclusion that the disturbance involves the early phase of
Figure 2-6 Radial microbrain. Brain of a full-term newborn with the pathological picture of radial microbrain described in the text. Note the normal cortical lamination (long arrows) and the normal residual germinative zone (both short arrows). From Evrard P, de Saint-Georges P, Kadhim HJ, et al: Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors: Child Neurology and Developmental Disabilities, Baltimore: 1989, Paul H. Brookes.)
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Timing and Clinical Aspects: Radial Microbrain. The presumed timing of radial microbrain is no later than the earliest phase of proliferative events in the second month of gestation. The essential abnormality involves the symmetrical divisions of progenitors to form additional progenitors and thereby the number of proliferative units. Later proliferative events that determine the size of each column proceed normally, as evidenced not only by the normal neuronal complement of each column but also by the presence of a normal residual amount of germinal matrix at term (see Fig. 2-6). The clinical features are not entirely clear, because this anomaly is rare. The reported cases have been fullterm newborns who died in the first month of life. The distinction from anencephaly and aprosencephaly-atelencephaly is based on the presence of an intact skull and dermal covering, in contrast to anencephaly, and of a normal external appearance of cerebrum and ventricles, observable by ultrasonography, in contrast to aprosencephaly-atelencephaly. The disorder is notably familial, probably of autosomal recessive inheritance. Anatomical Abnormality: Micrencephaly Vera. As noted earlier, the designation micrencephaly vera refers to a heterogeneous group of autosomal recessive disorders that appear to have, as the common denominator, small brain size because of a derangement of proliferation (see Table 2-3). In recent years, remarkable insights into the genetics and molecular bases of these disorders have been gained (see later). The anatomical studies of Evrard and colleagues5,41 provide insight into the fundamental disturbance in micrencephaly vera, at least in a prototypical autosomal recessive variety (Table 2-5). The brain is small (clearly more than several standard deviations below the mean) but not so strikingly as in the tiny radial microbrain. Simplification of gyral pattern exists with no other external abnormality and no evidence of a destructive process. The number of cortical neuronal columns appears normal, but the neuronal complement of each column, especially the superficial cortical layers, is decreased markedly. Additional evidence of disturbance of the later proliferative events that determine size of cortical neuronal
TABLE 2-5
Micrencephaly Vera: Autosomal Recessive Type
No evidence for destructive process No evidence for migrational defect No apparent defect in number of cortical neuronal columns Cortical neuronal columns with marked decrease in neurons of layers II and III No residual germinal matrix at 26 weeks of gestation (‘‘premature exhaustion’’ of matrix) From Evrard P, de Saint-Georges P, Kadhim HJ, Gadisseux J-F: Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors: Child Neurology and Developmental Disabilities, Baltimore: 1989, Paul H. Brookes.
columns is the absence of residual germinal matrix in the 26-week fetal brain studied by Evrard and colleagues (Fig. 2-7). The deficiency in neurons of the superficial cortical layers may explain the simplification of gyral pattern (see the later discussion of gyral development in migrational disorders). Timing and Clinical Aspects: Micrencephaly Vera. The presumed timing of the micrencephaly vera group of disorders involves the period of later proliferative events by asymmetrical divisions of neuronal progenitors, that is, onset at approximately 6 weeks in the human, with later rapid progression until approximately 18 weeks (see earlier). The most severely undersized brains are expected to have the earliest onsets and the most marked deficiency of neurons in each cortical column. The clinical presentation of infants with the prototypical autosomal recessive forms of micrencephaly vera is interesting in that, as newborns, most affected infants do not show striking neurological deficits or seizures. This presentation is in contrast to that of other varieties of micrencephaly, that is, intrauterine destructive disease or other developmental derangement (e.g., migrational defect). Rare autosomal recessive forms of micrencephaly with severe neuronal migrational defects (i.e., microlissencephaly) are more likely to be accompanied by neurological deficits and seizures (see the later discussion of disorders of neuronal migration). Magnetic resonance imaging (MRI) has been invaluable in the assessment of micrencephaly vera, especially for evaluation of gyral development and the presence of associated migrational abnormalities.42 Most commonly, gyral formation is variably simplified (Fig. 2-8), and the term microcephaly with simplified gyri is often used.42-50 Simplification of the gyral pattern often is not obvious. Rare cases are associated with severe migrational disturbances, such as lissencephaly, periventricular heterotopia, or posterior fossa deficits, especially cerebellar hypoplasia.45,47,48,51-53 Etiology: Autosomal Recessive Micrencephaly. At least six gene loci have been identified for autosomal recessive primary micrencephaly, or micrencephaly vera. Four of the genes have been identified (Table 2-6).46,54-59 Perhaps not unexpectedly, the genes play key roles in mitosis. Microcephalin is crucial for cell cycle control, chromosome condensation, and DNA repair. CDK5RAP2 is a centrosomal protein involved in microtubular function necessary for formation of the mitotic spindle. ASPM also is necessary for microtubular function at the poles of the mitotic spindle, and CENPT similarly is involved in formation of the mitotic spindle. Etiology: Other Disorders. The four major etiological categories for primary micrencephaly, in addition to the autosomal recessive group just discussed, are familial, teratogenic, syndromic, and sporadic (see Table 2-3). Familial syndromes are most critical to detect because of implications for genetic counseling. In addition to the autosomal recessive group (see earlier), these inherited varieties include autosomal dominant and X-linked recessive types, as well as familial types with ocular
A
B
Figure 2-7 Premature exhaustion of the germinal layer in microcephaly vera. A, Microcephaly vera, human fetal forebrain, 26 weeks of gestation. B, Normal human fetal forebrain, 26 weeks, same cortical region for comparison. The germinal layer (arrowheads), cerebral cortex (arrows), and intervening cerebral white matter are visible. In microcephaly vera (A), the germinal layer is exhausted at this age, and the white matter is almost devoid of late migrating glial and neuronal cells. Cortical layers VI to IV are normal, whereas the two superficial layers are almost missing. (From Evrard P, de Saint-Georges P, Kadhim HJ, et al: Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors: Child Neurology and Developmental Disabilities, Baltimore: 1989, Paul H. Brookes.)
A
B
Figure 2-8 Microcephaly with simplified gyri. In A, the sagittal T1-weighted magnetic resonance imaging (MRI) scan shows marked microcephaly. In B, the axial T2-weighted MRI scan shows simplification of the gyral pattern. No other dysgenetic abnormalities are present, nor is any evidence of destructive disease manifest. (Courtesy of Dr. Omar Khwaja.)
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Autosomal Recessive Primary Micrencephaly (Micrencephaly Vera): Molecular Genetics
Locus
Gene/Protein
Function
MCPH 1 MCPH 3
Microcephalin CDK5RAP2 (cyclin-dependent kinase-5 regulatory associated protein-2) ASPM (abnormal spindle in microcephaly) CENPJ (centromere-associated protein J)
Cell cycle control Mitotic spindle formation
MCPH 5 MCPH 6
Mitotic spindle formation Mitotic spindle formation
MCPH, Autosomal recessive primary micrencephaly.
abnormalities and variable genetics.60-74 These ocular abnormalities may include chorioretinopathy that can be confused with the chorioretinitis of intrauterine infection (see Chapter 20). One such disorder is Cohen syndrome, which is inherited in an autosomal recessive manner. Of the unusual cases of micrencephaly with autosomal dominant inheritance, intellect subsequently is usually either spared or only mildly defective; patients generally have no facial dysmorphism, although digital anomalies and rare syndromic varieties have been reported.71,74 X-linked recessive inheritance of micrencephaly has been described, albeit less commonly than autosomal recessive inheritance. The best-documented teratogenic agent producing micrencephaly is irradiation, such as by atomic bomb or radiation therapy for tumor or ankylosing spondylitis, particularly before 18 weeks of gestation (see Table 2-3).75-77 The most critical period in the Nagasaki-Hiroshima experience was 8 to 15 weeks.77 Maternal alcoholism or cocaine abuse (see Chapter 24) and maternal hyperphenylalaninemia have been associated with micrencephaly. Micrencephaly, usually with mental retardation, occurs in as many as 75% to 90% of (nonphenylketonuric) children of women with phenylketonuria; the risk for the fetus correlates with the severity of the maternal hyperphenylalaninemia.78-88 With dietary treatment, the risk declines to as low as 8% when phenylalanine levels are controlled before conception and to 18% when control is achieved by 10 weeks of pregnancy.89 When control is not achieved until 20 to 30 weeks, the incidence of microcephaly increases to 40%. Rarer intrauterine teratogens for micrencephaly include anticonvulsant drugs (see Chapter 24), organic mercurials, and excessive ingestion of vitamin A or vitamin A analogues (see Chapter 24).90 Finally, among intrauterine infections that may cause micrencephaly (see Chapter 20), rubella is the best candidate for an agent that may produce micrencephaly through an impairment of proliferation rather than principally through a destructive process. Cytomegalovirus infection may also act in this way, although disturbances of neuronal migration and destructive lesions contribute to the condition. Human immunodeficiency virus characteristically produces micrencephaly (without major destructive lesions) after the neonatal period, although neonatal cases have been reported (see Chapter 20). Syndromic cases, that is, those with multiple associated systemic anomalies, may be related to chromosomal disorders or monogenic (familial) defects, or they may occur sporadically (see Table 2-3). In one consecutive sample of congenital microcephaly, syndromic
disorders accounted for only 6% of cases.91 The nature of the proliferative disorder in this diverse group is generally not known and is not discussed further. Clinical details are available in standard sources.73 Sporadic nonsyndromic cases, that is, those with no related family history, identifiable teratogen, or recognizable syndrome, are the most common varieties of micrencephaly vera (see Table 2-3).91,92 No associated systemic or other neural malformations can be identified. The nature of the proliferative disturbance is generally unknown. Macrencephaly Anatomical Abnormality. The designation macrencephaly signifies a large brain and is a feature of a heterogeneous group of disorders that have not been well defined from the neuropathological standpoint. Nevertheless, several entities clearly exist in which the brain is generally well formed but is unusually large (see Table 2-5). Genetic varieties, suggestive of a derangement in the developmental program for neuronal proliferation, have been defined (see following discussion). As with micrencephaly, however, the conclusion that we are dealing with proliferative disorders can be made only tenuously until central neuronal populations can be quantified more accurately. This discussion excludes other rare disorders of macrocephaly, such as enlargement of the skull (craniometaphyseal dysplasia, hemoglobinopathy), subdural hematoma or effusion (see Chapters 10, 21, 22), hydrocephalus (see Chapters 1, 11, 21), metabolic disorders (see Chapter 15), or degenerative disorders (Alexander disease, Canavan disease [see Chapter 16]). Timing and Clinical Aspects. Although neuronal proliferation in the cerebrum is an event that occurs principally during the third and fourth months of gestation, this time period may be prolonged in disorders of excessive proliferation. Alternatively, abnormal proliferation may occur at the appropriate time during development but at an excessive rate. Additionally, a later-occurring defect of normal apoptosis or programmed cell death (see later section on organization) perhaps could lead to macrencephaly. The issues of mechanism are unresolved and await development of suitable experimental models for elucidation. The clinical syndrome in the several types of macrencephaly (Table 2-7) varies from no apparent neurological deficit (e.g., autosomal dominant, isolated macrencephaly) to severe recalcitrant seizures and mental retardation (e.g., autosomal recessive, isolated
Chapter 2 TABLE 2-7
Disorders of Neuronal Proliferation: Macrencephaly
Isolated Macrencephaly Familial Autosomal dominant (relation to ‘‘benign enlargement of extracerebral spaces’’ or ‘‘external hydrocephalus’’) Autosomal recessive Sporadic Associated Disturbance of Growth Achondroplasia Beckwith syndrome Cerebral gigantism Fragile X syndrome (see ‘‘Chromosomal Disorders’’ below) Marshall-Smith syndrome Thanatophoric dysplasia Weaver syndrome Neurocutaneous Syndromes Multiple hemangiomatosis Lipomas, hemangiomas, lymphangiomas, pseudopapilledema (Bannayan-Riley-Ruvalcaba) Asymmetrical hypertrophy, hemangiomata, varicosities (Klippel-Trenaunay-Weber) Asymmetrical hypertrophy, telangiectatic lesions, flame nevus of the face (cutis marmorata telangiectatica congenita) Neurofibromatosis,* tuberous sclerosis,{ Sturge-Weber syndrome{ Epidermal nevus syndrome (see ‘‘Unilateral Macrencephaly’’ below) Chromosomal Disorders Fragile X syndrome (relative macrencephaly) Klinefelter syndrome Unilateral Macrencephaly (Hemimegalencephaly) Isolated Syndromic: epidermal nevus syndrome, Proteus syndrome (most common) *Neurocutaneous disorder of cellular proliferation causing macrencephaly and affecting primarily nonneuronal elements (i.e., glia). { Neurocutaneous disorders of cellular proliferation but not usually associated with neonatal macrencephaly.
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macrencephaly, or unilateral macrencephaly). In other types of the disorder, extraneural features may dominate the clinical presentation (e.g., associated growth disorders and certain neurocutaneous syndromes). Some of these individual clinical aspects are mentioned briefly in the following discussion. Familial, Isolated Macrencephaly. Perhaps the most common variety of macrencephaly occurs in the familial setting and in the absence of any other extraneural findings. For this group, I use the term familial, isolated macrencephaly. Two genetic types can be recognized: autosomal dominant and autosomal recessive; the former is much more common. In familial, isolated macrencephaly of the autosomal dominant type, the head is usually large at birth (>90th percentile in 50%) and continues to grow postnatally at a relatively rapid rate.93,94 Neurological deficits are rarely striking, and development and ultimate level of intelligence are in the normal range in approximately 50% to 60% of cases. Mental retardation is present in only approximately 10%. The genetic component of this syndrome is overlooked frequently until the head circumference of the parents is measured. The diagnosis of fetal macrocephaly of this type was made in the 34th week of pregnancy in a woman with benign macrocephaly.95 Related to autosomal dominant macrencephaly is a syndrome of macrocephaly, categorized under several names: benign enlargement of extracerebral spaces, benign subdural effusions of infancy, and idiopathic external hydrocephalus.94,96-102 The clinical features described in the previous paragraph are present, and brain imaging studies show prominent extracerebral subarachnoid spaces and a large brain (Fig. 2-9). The cisterna magna especially may be prominent. In some cases, subdural and subarachnoid fluid appears to be present; the distinction is best made by MRI scan.96 Head growth in the first year is rapid, and infants not overtly macrocephalic at birth attain rates of head growth at the 97th percentile or slightly higher. Accelerating
B
Figure 2-9 ‘‘Benign’’ macrocephaly. A, Coronal sonogram demonstrates mild ventricular enlargement and moderate extra-axial fluid over the convexities (arrowheads). B, Axial computed tomography scan shows similar findings. (From Babcock DS, Han BK, Dine MS: Sonographic findings in infants with macrocrania, AJNR Am J Neuroradiol 9:307-313, 1988.)
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head growth ceases by approximately 1 year, and over the next several years extracerebral spaces become smaller, although the brain is clearly larger than average. Because of the large brain size, if the infant is first evaluated after the second year of life, isolated macrencephaly will be observed. Because as many as 90% of these infants have a parent with a large head, the genetic features are similar to those of autosomal dominant isolated macrencephaly. The similarity of the clinical features and genetics suggests that these may represent different forms of the same fundamental disorder. Those unusual patients with isolated macrencephaly that conforms to autosomal recessive inheritance are more likely to exhibit definite mental retardation, epilepsy, and motor deficits.90 Sporadic, Isolated Macrencephaly. Isolated macrencephaly with no evidence of a familial disorder by history and after measurement of parental head circumference occurs only slightly less often than the autosomal dominant disorder described previously.93,103,104 The clinical course is similar. Associated Disturbance of Growth. Macrencephaly may be associated with generalized disorders of growth, such as achondroplasia, Beckwith syndrome, cerebral gigantism (Sotos syndrome), fragile X syndrome, Marshall-Smith syndrome, thanatophoric dysplasia, and Weaver syndrome (see Table 2-7).73,93,105-108 Except in Beckwith syndrome, which is complicated by neonatal hypoglycemia, neurological features in the neonatal period are unusual. The precise neuropathological correlates for the macrencephaly in these disorders remain to be defined. The gene mutated or deleted in Sotos syndrome, NSD1, encodes a nuclear receptor binding protein that may be involved in proliferative events. Neurocutaneous Syndromes. Several of the neurocutaneous disorders are associated with evidence of excessive cellular proliferation within the CNS, sometimes with overt macrencephaly, and evidence of excessive proliferation of mesodermal structures (see Table 2-7). Macrencephaly occurs most consistently in this context in the multiple hemangiomatosis syndromes.73,109-115 In neurofibromatosis, an autosomal dominant disorder, the principal proliferative abnormality involves glia, particularly astrocytes. (Thus, the onset of the proliferative disorder in this disease primarily occurs after the time period of neuronal proliferative events.) Approximately 40% of infants exhibit more than five cafe´-au-lait spots larger than 5 mm at birth.116-122 Approximately 40% to 50% of such infants have macrocephaly, usually after the neonatal period.123,124 Consistent with the predominantly glial rather than neuronal involvement in the disorder, the megalencephaly relates primarily to increases in cerebral white matter volume, primarily in frontal and parietal areas.125 Relative macrocephaly with generalized glial tumors has been documented by prenatal ultrasound.126 Hemimegalencephaly with neonatal seizures and
associated neuronal migrational defects also have been observed.127,128 Of the glial tumors that are the hallmark of this disease, optic nerve glioma and plexiform neuroma of the eyelid have been observed in the newborn, albeit rarely.117,122 The gene for this disorder, located on chromosome 17, NF1, has been shown to encode a protein involved in the negative regulation of a key signal transduction pathway, the Ras pathway, which transmits mitogenic signals to the nucleus.120-122,129,130 Thus, loss of the neurofibromatosis protein, neurofibromin, leads to increased mitogenic signaling and thereby to the proliferative abnormalities characteristic of the disorder. In Sturge-Weber disease, a sporadic disorder, the principal abnormality affects leptomeningeal blood vessels. Thus, the time of onset is probably coincident with that for neuronal proliferation. Data suggest that the fundamental defect in this disorder is a failure of development of superficial cortical veins that diverts blood to the developing leptomeninges, with the formation of abnormal vascular channels as a consequence.131 Abnormalities of fibronectin in cerebral vessels may play a role in the genesis of the vascular abnormality.132 The characteristic facial port-wine stain is described in Chapter 3; the overall incidence of clinical manifestations of SturgeWeber disease (glaucoma or seizures) is 2% to 8% in patients with unilateral facial lesions and 24% in patients with bilateral facial lesions.131,133,134 Identification of the newborn with intracranial involvement is difficult. Seizures and cerebral calcification (identified by computed tomography [CT]) have been noted only occasionally in newborns (Fig. 2-10).42,135-138 Cerebral calcifications most commonly appear after 6 months of age and often considerably later.114,131,139-141 MRI appears to be the most useful imaging study in the first year42,114,131,134,140-143; the principal findings are cerebral cortical and white matter changes in the region of the leptomeningeal angiomatosis, angiomatous alteration of overlying calvaria, and atypically located, congested deep cerebral veins.114,140,142 Gadolinium-enhanced MRI is the gold standard for demonstration of the leptomeningeal vascular lesion (Fig. 2-11).42,114,131,140-142 The choroid plexus is enlarged on the side of the leptomeningeal lesion, presumably because of the diversion of venous blood into the deep venous system, as a consequence of the lack of superficial cortical venous drainage (see earlier discussion). On single photon emission tomographic studies, decreased cortical perfusion may be observed in the region of the vascular lesion.131,141,144,145 MRI perfusion studies also may be useful in detecting perfusion deficits.146 Infants with Sturge-Weber syndrome who have bilateral cerebral disease have a much poorer outcome (8% with average intelligence) than those with unilateral cerebral disease (45% with average intelligence).134,138,144,145,147,148 In tuberous sclerosis, the principal proliferative abnormality affects both neurons and glia. The neuropathological and molecular aspects of these disorders indicate that tuberous sclerosis also reflects abnormal migration and differentiation (see later).149-151 The critical neonatal cutaneous feature is a depigmented, ash
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Figure 2-10 Sturge-Weber disease, computed tomography (CT) scan. This infant exhibited seizures on the fifth day of life. The CT scan was obtained at the age of 4 months. Left, Conventional CT scan. Right, Contrast-enhanced CT scan. Note marked atrophy and calcification in the left frontal region and, to a lesser extent, in the left parietal region. Only scant contrast enhancement is apparent. (From Kitihara T, Maki U: A case of Sturge-Weber disease with epilepsy and intracranial calcification at the neonatal period, Eur Neurol 17:8-12, 1978.)
leaf–shaped macule. Seizures may occur in the neonatal period.149,152-155 Cardiac tumors (rhabdomyomata) are characteristic and uncommonly may lead to neurological features by causing cardiac failure, arrhythmias, or cerebral emboli (personal cases). Cardiac rhabdomyomata have been identified in affected fetuses and are usually the first clue to prenatal diagnosis.156,157 The diagnosis
A
of tuberous sclerosis is established in 80% to 95% of fetuses with cardiac rhabdomyomata.158,159 The natural history of these tumors is favorable—virtually all regress at least partially.159 Subependymal nodules, the most common cerebral lesion detected in utero, have been identified as early as 21 weeks.160 Indeed, I consider the most useful constellation of features for
B
Figure 2-11 Sturge-Weber disease, gadolinium-enhanced magnetic resonance imaging (MRI) scan. A, Axial MRI scan before administration of gadolinium in an infant with a port-wine stain shows no definite abnormality. B, The scan after gadolinium enhancement shows diffuse leptomeningeal enhancement in the right occipital and temporal regions. The findings are characteristic of Sturge-Weber disease. (Courtesy of Dr. Omar Khwaja.)
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Figure 2-12 Tuberous sclerosis, computed tomography scan. This infant exhibited generalized seizures and depigmented macules at 4 weeks of age. Note, A, the striking cortical tuberous change in the left occipital region and, B, the small subependymal nodules (arrowheads) near the heads of both caudate nuclei.
A
B
the diagnosis of tuberous sclerosis in the neonatal period to consist of the depigmented macule, cardiac rhabdomyoma, subependymal nodule, and cortical tuber. In one large series, approximately 90% of newborns studied by MRI exhibited the latter two cerebral lesions.157 Neuropathological features include both the characteristic subependymal and cerebral corticalsubcortical collections of abnormal neurons and glia (i.e., subependymal nodules and cortical tubers) and heterotopic collections of similar cells in the cerebral white matter, often arranged in radial bands.161-166 The cells are often bizarre, large, and poorly differentiated, exhibiting features of both neurons and astrocytes. Subependymal giant cell astrocytoma has been reported in newborns with tuberous sclerosis157,167-169 but more typically it appears in older children. Both CT scanning and ultrasonography can be useful in diagnosis (Figs. 2-12 and 2-13).42,152,153,170,171 However, MRI has proven of particular value in the neonatal period and demonstrates the subependymal collections, the cortical tubers, and
Figure 2-13 Tuberous sclerosis, ultrasound scan. This infant exhibited depigmented macules with myoclonic seizures at 3 weeks of age. The parasagittal ultrasound scan shows an echogenic subependymal nodule (arrowhead) that was also seen on a computed tomography scan.
the white matter lesions especially well (Fig. 2-14).42,157,165,166,168,172-174 Because of the unmyelinated cerebral white matter in the newborn, the cortical tubers (hypointense on T1-weighted images, hyperintense on T2-weighted images) have signal characteristics opposite those exhibited by older children with the disorder.42,166 The tuberous sclerosis phenotype is associated with dysfunction of genes on either chromosome 9 or chromosome 16.130,175-177 The disorder, although autosomal dominant, is associated with a high spontaneous mutation rate. Overall, approximately 80% of cases are sporadic.150,151 The genes, TSC1 on chromosome 9 and TSC2 on chromosome 16, encode the respective
Figure 2-14 Tuberous sclerosis, magnetic resonance imaging (MRI) scan. This 11-day-old infant was identified in utero with a cardiac rhabdomyoma. On this axial T1-weighted MRI, note the multiple cortical tubers (thick arrow), subependymal nodules (thin arrow), and radial cerebral white matter lesion (double arrow). (Courtesy of Dr. Omar Khwaja.)
Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
63
proteins, hamartin and tuberin.150,151 Hamartin and tuberin interact to form a complex, and this complex is involved in molecular signaling critical for cell proliferation, cell growth, and cell adhesion/migration.150,151 Disturbance of these processes underlies the proliferative abnormalities (subependymal nodules, astrocytomas, and cardiac, renal, and other tumors), the abnormalities of cell size (large, bizarre cells in nodules and tubers) and the radial white matter disturbances (apparent disturbances in radial migration and release of migrating cells from the radial glial progenitor). The TSC2 mutations result in the most severe phenotypes and account for the majority of neonatal cases. Chromosomal Disorders. The possibility that the fragile X syndrome may include a proliferative abnormality is raised by the finding of absolute or relative macrocephaly in approximately 40% of infants.178,179 However, a disturbance of cerebral organizational events appears to be the dominant neural abnormality in fragile X syndrome (see later). Rarer chromosomal disorders with macrencephaly are Klinefelter syndrome and partial trisomy of chromosome 7.90,180,181 Unilateral Macrencephaly (Hemimegalencephaly). Unilateral macrencephaly represents, at least in part, a localized disorder of cell proliferation within the CNS. The anatomical data suggest excessive proliferation of both neurons and astrocytes, but also defects in subsequent migration of neurons and in cortical organization. In this disorder, enlargement of one hemisphere, or a portion thereof, occurs, often accompanied by abnormal cortical gyration, a disordered and unusually thick cortex, large and sometimes bizarre neurons, heterotopic neurons in subcortical white matter, and increased number and often size of astrocytes.95,182-196 The clinical syndrome in isolated and syndromic cases consistently has included severe seizures from early infancy, usually in the neonatal period, with subsequent severely disturbed neurological development.95,193-210 The cranial asymmetry in unilateral macrencephaly may be overlooked in the newborn if the skull is not examined carefully, especially from above. CT scanning demonstrates a degree of enlargement of the hemisphere or a portion thereof that initially may be suggestive of a congenital neoplasm. MRI scanning is the best imaging method to demonstrate the neuronal heterotopias and abnormalities of cerebral cortical gyration (Fig. 2-15). Electroencephalography (EEG) in the infants with earliest onset of seizures may demonstrate a characteristic pattern of larger-amplitude triphasic complexes. Seizures are usually recalcitrant to therapy. Hemispherectomy, as early as the first months of life, has been followed by improved outcome.195,200202,208,211 Prognosis after hemispherectomy depends primarily on the functional status of the contralateral hemisphere. Positron emission tomographic studies of cerebral glucose utilization showed cortical hypometabolism in the contralateral hemisphere in four of eight infants, and this abnormality correlated with a poorer outcome after hemispherectomy.211 Related
Figure 2-15 Hemimegalencephaly, magnetic resonance imaging (MRI) scan. This T2-weighted axial MRI shows an enlarged right hemisphere with right frontal pachygyria. Note also the enlarged right lateral ventricle and anomalous configuration of the right frontal horn. The left hemisphere is normal. (From Flores-Sarnat L: Hemimegalencephaly. I. Genetic, clinical, and imaging aspects, J Child Neurol 16:373-384, 2002.)
physiological studies showed that the nonmalformed hemisphere is secondarily impaired with persistent clinical and electrical seizures as early as the first months of life, and early hemispherectomy is beneficial.212 Indeed, bilateral neuropathological changes, albeit with less severe changes in the contralateral hemisphere, have been described.191 Syndromic varieties of hemimegalencephaly are multiple but most commonly include epidermal nevus syndrome, Proteus syndrome, and hypomelanosis of Ito.195 A relatively rare neurocutaneous disorder, epidermal nevus syndrome, is associated with hemimegalencephaly in approximately one half of cases.195,205,213-215 The clinical neurological and neuropathological features are essentially similar to those just described for sporadic cases of hemimegalencephaly.205,213,216-224 The characteristic cutaneous feature is illustrated in Figure 2-16. Many infants exhibit facial hemihypertrophy as a result of lipomatous-hamartomatous lesions of the lower half of the cheek. In Proteus syndrome, unilateral or generalized hypertrophy of the body; thickened, hyperpigmented skin; lipomata; lymphangiomata; and hemangiomata, macrodactyly, and a curious gyriform appearance of the plantar surface of the feet may accompany the hemimegalencephaly. MIGRATION Normal Development Neuronal migration refers to the remarkable series of events whereby millions of nerve cells move from their sites of origin in the ventricular and subventricular zones to the loci within the CNS, where they will reside for life. The peak time period for this occurrence is
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HUMAN BRAIN DEVELOPMENT TABLE 2-8
Neuronal Migration
Peak Time Period 3–5 months Major Events Cerebrum Radial migration: cerebral cortex (projection neurons), deep nuclei Tangential migration: cerebral cortex (interneurons) Cerebellum Radial migration: Purkinje cells, dentate nuclei Tangential migration: external ! internal granule cells
Figure 2-16 Epidermal nevus syndrome. This infant was 48 hours old. Note the midline linear nevus (arrows). (From Chalhub EG, Volpe JJ, Gado MH: Linear nevus sebaceous syndrome associated with porencephaly and nonfunctioning major cerebral venous sinuses, Neurology 25:857-860, 1975.)
the third to fifth months of gestation, although neuronal migration can be detected in certain areas of the cerebrum as early as the second month and slightly after the fifth month (Table 2-8). Regulation of the timing and direction of these many simultaneous migrations must be highly ordered, but only recently has insight been gained into these control mechanisms (see later). Two Basic Varieties of Neuronal Migration The major features of cell migration in the primate were defined initially, particularly by the classic studies of Sidman and Rakic,24-26,225-228 who used primarily autoradiographic, electron microscopic, and Golgi techniques. Later work used immunocytochemical and retroviral methods and the study of genetically manipulated animals to elaborate earlier observations.23a,25,26,31,41,228-261 Two basic varieties of cell migration have been delineated: radial and tangential (see Table 2-8). In the cerebrum, radial migration of cells from their origin in the ventricular and subventricular zones is the primary mechanism for formation of the cortex and deep nuclear structures. Radial migration gives rise to the projection neurons of the cortex. These neurons emanate primarily from the dorsal region of the subependymal germinative zones. Tangential migration of neurons generated in the ventral aspect of the subependymal germinative zones results in the gamma-aminobutyric acid (GABA)–expressing interneurons of the cerebral cortex.23a,249,250,253,254,258,259,262 These neuronal precursors migrate parallel to the surface of the cortex and proceed in one of three streams (i.e., through the subventricular zone, the intermediate zone, or the marginal zone) before terminal radial movement to arrive in the cortical plate. In the cerebellum, radial migration causes
the genesis of Purkinje cells, the dentate nucleus, and other roof nuclei. Tangential migration of cells that originate in the germinal zones in the region of the rhombic lip and migrate over the surface of the cerebellum forms the well-known external granular layer. These cells then migrate radially inward to form the internal granule cell layer of the cerebellar cortex. Thus, during their journey from their point of origin in the ventricular zone, the granule cells exhibit both radial and tangential migration. Migration to Cerebral Cortex The basic pattern of cell migration for formation of the cerebral cortex is shown in Figures 2-17 and 2-18. Two basic modes of cell migration are apparent (see Fig. 2-18). The first and earlier mechanism is movement by translocation of the cell body (i.e., somal translocation) (Table 2-9).258,263 This mode of migration probably results in the formation of the preplate (see Fig. 2-17). This layer of neurons later is split by the arrival of the cortical plate neurons into a superficial layer nearest the pial surface, which produces the Cajal-Retzius and related neurons of the marginal zone, and a deeper layer, which becomes the subplate neurons. The preplate neurons and the subsequently formed Cajal-Retzius and subplate neurons are critical for the progression of neuronal migration (see later). The second mode of migration, leading to the formation of most of the cerebral cortex, occurs by radial migration (see Figs 2-17 and 2-18). These cells are generated by the radial glial progenitors discussed earlier (see the discussion of proliferation). The clonally related neuron migrates along the parental radial glial fiber, which extends to the pial surface. Initially, cells are generated in the ventricular zone, and then they migrate relatively rapidly and synchronously through the intermediate zone in waves to the developing cortical plate. At later stages, as shown by Rakic24-26,226-228 in studies of the monkey visual cortex, the neurons are generated especially in the subventricular zone (see Fig. 2-17). By labeling dividing cells with [3H]thymidine at various times during development and then determining where the labeled cells appear in the cortical plate, Rakic showed that cells that migrate first take the deepest positions in the cortex, whereas those migrating later take more superficial positions. By 20 to 24 weeks of gestation, the human cerebral cortex essentially has its full complement of neurons.
Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
65
M
CP M CP
SPN
SPN I PP I
SV
SV
V
V
V
7 wk
10 wk
13 wk
Figure 2-17 Schematic diagram of the developing human cerebral cortex at the gestational ages indicated. The pial surface is at the top and the ventricular surface at the bottom of each depiction of the cerebral wall. CP, cortical plate; I, intermediate zone; M, marginal zone; PP, preplate zone; SPN, subplate neurons; SV, subventricular zone; V, ventricular zone. A radial glial fiber is shown traversing the cerebral mantle in the two right schematics and is not labeled.
How do the migrating cells know how to reach where they are going? In the major process of radial migration, radial glial cells serve as the guides for migration of young neurons from their sites of origin in the ventricular and, later, subventricular zones across a distance that can be many times greater than the length of their leading processes to their ultimate position in the cortical plate (see Table 2-9; Fig. 2-19).* The elaboration of the structure of the *See references 25,26,31,41,227-231,239,245,248,249,251-253,255, 256,258-260,264-266.
radial glial fiber system has been clarified by immunocytochemical and ultramicroscopic studies, especially by Caviness and others.229-231,239,255,256,258 Initially, the system is uniformly radial in alignment, and in the ventricular zone the fibers appear to separate columns of germinative cells, the proliferative units described by Rakic in the primate (see earlier). The radial glial system in the developing cerebral wall forms fascicles of fibers rather than isolated fibers. With the rapid growth of the cerebral wall, and particularly the intermediate zone, the fiber fascicles develop distinct curves with definite region-specific changes in
Cortical plate
Intermediate zone
Ventricular zone
A
B
Figure 2-18 Two modes of radial neuronal migration. In A, an early mechanism is somal translocation in which the cell body is translocated from the point of origin in the ventricular zone to the cortical plate. In B, a later and predominant mechanism is radial migration, in which cells are generated by radial glial progenitors, and the clonally related neuron migrates along the parent radial glial fiber. Tangential migration differs from radial migration (see text).
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TABLE 2-9
HUMAN BRAIN DEVELOPMENT
Migration to Cerebral Cortex
Initially, neurons migrate by translocation of the cell body (somal translocation). Later and predominantly, neurons migrate by following radial glial guides (i.e., the fibers of their clonally related radial progenitors). Simultaneous with this radial migration, tangential migration parallel to the surface of the cortex (followed by radial migration to the cortex) results in the GABA-expressing interneurons of the cortex. Proliferative units of the ventricular zone migrate through the radial glial scaffolding to become the ontogenetic neuronal columns of cerebral cortex. Migration through subplate neurons and ‘‘waiting’’ thalamocortical and corticocortical afferents is likely important for later neuronal development (e.g., synaptogenesis). Early-arriving neurons take deep positions in cortex, and later-arriving neurons take superficial positions (i.e., ‘‘inside-out’’ pattern).
LP
A
GABA, gamma-aminobutyric acid.
trajectory (Fig. 2-20). Nevertheless, the dominant feature remains the migration of apparent clonally related columns of cells among the same radial glial fascicles, again likely related to the proliferative units described earlier.237 As the migrating neurons approach the cortical plate, the radial glial fascicles begin to defasciculate, and radial fibers tend to penetrate the cortex more as single fibers.230 This occurrence develops at the junction of the upper intermediate zone and the subplate zone, an important site for neuronal heterotopias in disorders of neuronal migration (see later). Insights into the key molecular determinants of neuronal migration have been gained in recent years (Table 2-10). I present a brief discussion here of some of the best-studied molecules; further review of molecular determinants is provided later in the discussions of the molecular aspects of individual disorders of migration. Roles for molecules on preplate neurons (and the later CajalRetzius and subplate neurons), radial glia, and migrating neurons have been established. From preplate neurons and the Cajal-Retzius cells of the marginal zone, such extracellular matrix molecules as fibronectin and chondroitin and heparan sulfate proteoglycans clearly are crucial.232,249,258,267-269 The secreted glycoprotein, reelin, lacking in the mutant mouse ‘‘reeler’’ with a neuronal migrational disorder, is an important product of the Cajal-Retzius cells.251,253,257,258,266,270-274 Platelet-activating factor acetylhydrolase, lacking in one form of human lissencephaly (see later), suggests an important role for a molecule related to platelet-activating factor, a notion further supported by in vitro studies.249,275-277 Neurons with GABA receptors in the preplate, CajalRetzius cells, and perhaps migrating neurons also now appear to be involved in migrational events.266,278 Important molecular determinants of migration on radial glia include three signaling pathways, involving erb B4 receptors, Notch receptors and brain lipid-binding protein (BLBP) (see Table 2-10).249,251,253,279,280 The first of these are the surface ligands for neuregulin located on migrating neurons (see Table 2-10). An additional and well-characterized surface molecule of importance on migrating neurons is the surface
RF2
TP
RF1
RF3
RF4 RF5 RF6
Figure 2-19 Three-dimensional reconstruction of migrating neurons, based on electron micrographs of semiserial sections. Note the apposition of the migrating neuron (A), with its leading process (LP) and attenuated trailing process (TP), to the guiding radial glial fiber (RF). As discussed in the text, the migrating neuron and the radial glial progenitor are clonally related. (From Sidman RL, Rakic P: Neuronal migration, with special reference to developing human brain: A review, Brain Res 62:1-35, 1973.)
glycoprotein, astrotactin.281,282 Doublecortin is the product of a gene on the X chromosome and is involved in double cortex (band) heterotopia in female patients and lissencephaly in male patients, important human neuronal migration disorders (see later).252,253,257,258,283-287 This protein, expressed in migrating neurons at the growing end, is involved in an intracellular signaling pathway important for neuronal migration. Doublecortin is a microtubule-associated protein, which plays a role in microtubule polymerization and thereby may be involved in neuronal migration by mediating the cytoskeletal changes required for such movement.252,253,258 The gene
Chapter 2
CP
SP
IZ
SVZ
VZ
Figure 2-20 Glial fiber alignment at E15 in the developing rat. The glial fibers ascend almost radially through the ventricular (VZ) and subventricular zone (SVZ). Within the intermediate zone (IZ), the fiber fascicles become arced medially to laterally. At the level of the IZ-subplate (SP) interface, they again become inflected to a radial alignment, orthogonal to the pial surface, which is maintained across the cortical strata. This coronal 6-mm plastic section was immunostained with RC2 antibody for radial glial fibers. Bar = 20 mm; CP, cortical plate. (From Gadisseux JF, Evrard P, Misson JP, Caviness VS: Dynamic structure of the radial glial fiber system of the developing murine cerebral wall: An immunocytochemical analysis, Dev Brain Res 50:55-67, 1989.)
TABLE 2-10
Neuronal Proliferation, Migration, Organization, and Myelination
responsible for the human neuronal migration disorder, periventricular heterotopia, filamin 1, encodes a neuronal actin cross-linking protein that transduces ligand-receptor binding into actin reorganization, critical for locomotion of many cell types.258,288 Involvement of neuronal calcium channels, glutamate, and N-methyl-D-aspartate (NMDA) receptors is supported by the work particularly of Rakic and coworkers, but also of others.243,244,251,252,289-294 Thus, selective blockage of N-type, but not of L-and T-type, calcium channels inhibits neuronal migration. N-type calcium channels are involved primarily in release of neurotransmitters. That the neurotransmitter involved is glutamate, which acts on the NMDA receptor, is suggested by the demonstration that blockers of NMDA receptors, but not of non-NMDA receptors, inhibit neuronal migration (Fig. 2-21). Axonal release of glutamate may be the source of the glutamate that acts on the migrating neuron. Radial glial cells have additional functions, aside from guidance of neuronal migration (see Table 2-2 and earlier discussion). Thus, the initial role of these cells is as neuronal progenitors. Generation of neurons is followed by the role as radial glial guides. Still later, these cells give rise to astrocytes and oligodendroglia, and the cellular progeny of the radial glial cell will then serve as a source of neural stem cells in the subventricular zone of the mature brain. Disorders Disorders of neuronal migration usually cause overt disturbances of neurological function with clinical deficits often apparent from the first days of life. Seizures are most often the dominant early neurological sign with the more severe migrational disturbances. The advent of MRI scanning markedly increased the ability to identify these disorders in vivo, demonstrated the relatively high prevalence of these disorders, and
Selected Key Molecular Determinants of Neuronal Migration
Preplate neurons (also marginal [Cajal-Retzius] zone and subplate neurons) and extracellular matrix
Radial glia Migrating neurons
GABA, gamma-aminobutyric acid.
67
Fibronectin, chondroitin, and heparan sulfate Fukutin proteoglycans GABA receptors Integrins Laminin Reelin erb B4 receptors Brain lipid binding protein (BLBP) Notch receptors Neuregulin Astrotactin Doublecortin Platelet-activating factor acetylhydrolase (subunit 1) Filamin 1 Cyclin-dependent kinase-5 (cdk-5) Neural cell adhesion molecule (NCAM) N-methyl-D-aspartate (NMDA) receptors Calcium channels GABA receptors
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TABLE 2-11
HUMAN BRAIN DEVELOPMENT
25 days
Disorders of Neuronal Migration
Order of Decreasing Severity Schizencephaly Lissencephaly: pachygyria Polymicrogyria Heterotopia Focal cerebrocortical dysgenesis
5 months
35 days
40 days
50 days
6 months
100 days
7 months
Possible Concomitant Abnormalities of Corpus Callosum
showed their broad clinical expression (see later discussion). The major disorders are listed in Table 2-11 in order of decreasing severity. Gyral Abnormality in Migrational Disorders The hallmark of the migrational disorders is an aberration of gyral development. Formation of the many secondary and tertiary gyri of the human brain occurs after neuronal migration has ceased (Fig. 2-22).3,295-298
8 months
9 months
Distance (m)
30
20 **
0
Figure 2-22 Schematic depiction of gyral development in human brain. Note the particularly prominent changes in the last 3 months of gestation. (From Cowan WM: The development of the brain, Sci Am 241:113-133, 1979.)
**
10
CM
D-AP5 MK-801 CNQX
BICU
PHACL
BICU
PHACL
40
Distance (m)
30
20
** **
10
0
CM
D-AP5 MK-801 CNQX
Figure 2-21 The effect of antagonists to inotropic receptors on the migration of cerebellar granule cells. All preparations were obtained from 10-day-old mice. Each column shows the mean length of the migration route for at least 100 labeled cells. The small bar is the standard error of the mean. Each antagonist to specific N-methyld-aspartate (NMDA) (D-AP5, MK-801), non-NMDA (CNQX), gamma-aminobutyric acid A (GABAA) (bicuculline [BICU]), or GABAB (phaclofen [PHACL]) receptors was added to the tissue culture medium in separate experiments 2 hours after staining, and preparations were maintained for an additional 2 hours (A) to 4 hours (B). The mean distance of cell displacement after the addition of 10 mm CNQX, 10 mm BICU, or 500 mm PHACL was not significantly different from values obtained in control slice preparations (CM) at each time point. However, addition of 100 mm D-AP5 or 10 mm MK-801 (NMDA antagonists) inhibited cell movement. Mean migratory distance was obtained by subtracting the mean displacement of the cell soma at 2 hours in culture from the total length of the migratory pathway. The double asterisks indicate statistical significance (P < .01). (From Komuro H, Rakic P: Modulation of neuronal migration by NMDA receptors, Science 260:95-97, 1993.)
The fastest increase in number of the major gyri occurs between 26 and 28 weeks of gestation.295 Further elaboration of these gyri continues during the third trimester and shortly after birth.295 The stimulus for gyral formation appears to be the remarkable increase in surface area of cerebral cortex that occurs during this period, particularly the difference in increase in surface area of the outer versus the inner cortical layers.299 In the normal cortex, the surface area of the outer cortical layers is greater than the inner layers, and this discrepancy leads to compressive stresses that may lead to gyral formation. These relative increases in cortical surface area require the complement of neurons provided by migrational events. In lissencephaly, in which all cortical layers fail to receive their full complement of neurons, no gyri develop. In polymicrogyria, the surface area of outer cortical regions is much greater than that of inner cortical regions, and the result is an excess of gyri.299 In addition, gyral development may be stimulated by the forces produced by growth of cerebral white matter axons originating in the cortex, the concept of tension-based morphogenesis.300 Corpus Callosum Defect in Migrational Disorders In addition to gyral abnormality, a common feature of migrational disorders is hypoplasia or agenesis of the corpus callosum; occasionally, absence of the septum pellucidum also accompanies these disorders. Development of the corpus callosum (the major interhemispheric commissure) and of the septum is associated temporally and causally with the migrational
Chapter 2
events in the cerebrum (see Chapter 1). Thus, the timing of these aspects of midline prosencephalic development occurs almost coincidentally with the major neuronal migrational events for formation of cerebral cortex. Moreover, normal elaboration of cortical-cortical callosal fibers requires normal progression of neuronal migration to cerebral cortex. The frequent concurrence of hypoplasia or agenesis of the callosum with the migrational disorders discussed is therefore understandable. Schizencephaly Anatomical Abnormality. Schizencephaly is the most severe, yet restricted, of the cortical malformations (see Table 2-11).301-309 A complete agenesis of a portion of the germinative zones and thereby the cerebral wall is believed to exist, leaving seams or clefts. The pial-ependymal seam is characteristic (Fig. 2-23). In the walls of the clefts, the cortical plate exhibits the hallmarks of migrational disturbance (e.g., a thick, microgyric cortex and large neuronal heterotopias). In bilateral lesions, schizencephaly in one hemisphere may be accompanied by polymicrogyria or focal cortical dysplasia in the other. The lips of the clefts may become widely separated, and dilation of the lateral ventricles may occur. Hydrocephalus often complicates such open-lipped lesions, especially when bilateral (see later). These open-lipped lesions, when bilateral, may be referred to incorrectly as hydranencephaly, a later destructive lesion of the cerebral hemispheres; when they are unilateral, they may be referred to incorrectly as porencephaly, a destructive lesion of one
hemisphere. Indeed, it is now clear that unilateral and bilateral schizencephalies can be familial and probably account for previous reports of ‘‘familial porencephaly.’’148,310-317 Gray matter (often polymicrogyric), lining the lesion and demonstrable on brain imaging, especially MRI, is the key finding indicative of schizencephaly. The advent of MRI expanded greatly the understanding of anatomical and clinical aspects of schizencephaly. Indeed, several previous notions that were based almost exclusively on study of autopsy cases (i.e., that schizencephaly is rare, bilateral, and associated invariably with severe neurological deficits) were shown to be incorrect. Thus, in two large series, 67 cases were collected, and schizencephaly was unilateral in 63% (Table 2-12).318 The clefts tended to be in the regions of the rolandic and sylvian fissures and involved predominantly frontal areas. Subsequent series confirmed these observations.306 Timing and Clinical Aspects. Onset of the developmental disturbance that leads to schizencephaly is considered to be no later than the beginning of migrational events in the cerebrum in the third month of gestation. The possibility that destructive lesions operate in the third or fourth month of gestation, perhaps injuring both the germinative zones and migrating
TABLE 2-12
Schizencephaly: Anatomical (Magnetic Resonance Imaging) and Clinical Features
Feature Anatomical Unilateral Bilateral Closed clefts Open clefts Frontal Frontoparietal Parietal, temporal, or occipital Associated septo-optic dysplasia
pes
ve
pes
ve
he
Figure 2-23 Schizencephaly. Horizontal section of the cerebrum, stained for myelin. Note the symmetrical clefts in the axis of the central fissures, pial-ependymal seams (pes), portion of lateral ventricles (ve), polymicrogyric cortex in margins of clefts, and neuronal heterotopias, especially on the left (he). (From Yakovlev PI, Wadsworth RC: Schizencephalies: A study of the congenital clefts in the cerebral mantle. I. Clefts with fused lips, J Neuropathol Exp Neurol 5:116, 1946.)
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Neuronal Proliferation, Migration, Organization, and Myelination
Anatomical-Clinical Correlates Cognitive Disturbances (Prominent) Bilateral Unilateral Motor Disturbances Bilateral Unilateral Frontal Not frontal Open lip Closed lip Seizure Disorder Bilateral Unilateral Hydrocephalus Open lip Closed lip
Percentage 63% 37% 42% 58% 44% 30% 26% 39%
100% 24% 86% 77% 84% 29% 94% 22% 72% 60% 52% 0%
Data from Barkovich AJ, Kjos BO: Schizencephaly: Correlation of clinical findings with MR characteristics, AJNR Am J Neuroradiol 13:85-94, 1992 and Packard AM, Miller VS, Delgado MR: Schizencephaly: Correlations of clinical and radiologic features, Neurology 48:14271434, 1997 and based on a cumulative series of 67 cases.
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HUMAN BRAIN DEVELOPMENT
A
B
Figure 2-24 Unilateral schizencephaly with separated lips. A, Contrast-enhanced axial computed tomography scan shows deep infolding of the cortex in the right frontal region, apparently pressing on the right lateral ventricle (arrowheads). (This cortical gray matter lining of the cleft is important in distinction from a destructive lesion, such as porencephaly.) B, Coronal SE 600/20 magnetic resonance imaging scan shows the infolding to be a large cleft in apparent continuity with lateral ventricle. (The pial-ependymal seam may not be demonstrable or may be disrupted.) Continuity of gray matter through the cleft is clearly shown (arrowheads), as is the focus of heterotopic gray matter along the roof of the right lateral ventricle (open arrow). The septum pellucidum is absent, consistent with the diagnosis of septo-optic dysplasia. (From Barkovich AJ, Norman D: MR imaging of schizencephaly, AJNR Am J Neuroradiol 9:297-302, 1988.)
neurons on radial glial fibers, is raised by multiple reports.304,309,319-321 However, the demonstration, at least in certain rare familial cases, of a defect in the homeobox gene, EMX2, supports the notion that schizencephaly most often is a disorder of the developmental program.252,315,322-324 This gene, specifically expressed in neuroblasts of the ventricular zone, is involved in the structural patterning of the developing forebrain, including neuronal migration. Nevertheless, a multifactorial origin of schizencephaly is supported by the association with fetal cytomegalovirus infection (which can cause both dysgenetic and destructive effects) and systemic abnormalities secondary to vascular disruption.309,325 The clinical features of schizencephaly have begun to be clarified by the study of patients identified by MRI. The lesion may be suspected because of the appearance of a focal ventricular dilation on ultrasonogram or CT scan or occasionally because of visualization of a gray matter–lined cleft on CT scan (Fig. 2-24A).306,307,326,327 However, far more sensitive for identification of schizencephaly is MRI (Fig. 2-24B).42,307,308,318,326,328,329 The salient feature is the lining of the cleft by cerebral cortex, often thickened by pachygyric or polymicrogyric cortex with heterotopias. The clinical spectrum is clearly broader than was previously expected. Severity relates to extent and TABLE 2-13
distribution of cerebral involvement (see Table 2-11).306,307,318,330 In two series, prominent cognitive disturbances were present with all bilateral lesions but only 24% of unilateral lesions.316,318 (I have seen one patient who had bilateral clefts with average intelligence.) Motor disturbances are nearly invariable with frontal and with open-lipped lesions (see Table 2-12).306,307,316,318 Seizures may begin as late as adult life in patients with schizencephaly.307,316,331,332 Hydrocephalus complicates approximately 50% of open-lipped lesions (see Table 2-12), although the mechanism for the impaired cerebrospinal fluid dynamics is unclear.316 Agenesis of the septum pellucidum occurs in 70% of cases, and accompanying septo-optic dysplasia occurs in 10% to 25% (see Chapter 1).307 Agenesis or hypoplasia of the corpus callosum occurs in 30% of cases of schizencephaly.307 Lissencephaly and Pachygyria Anatomical Abnormality. In lissencephaly (i.e., ‘‘smooth brain’’), the brain has few or no gyri.* Two basic anatomical types of lissencephaly can be distinguished (Tables 2-13 and 2-14). In type I lissencephaly, the cerebral wall is similar to that of an approximately *See references 5,41,90,248,252,253,257,258,261,262,303,333-347.
Major Varieties of Type I Lissencephaly: Etiology/Genetics
Disorders
Gene Locus
Protein
Function
Isolated lissencephaly (LIS1) Miller-Dieker syndrome (LIS1)
17p13.3 17p13.3
Cytoskeleton (microtubules/dynein) Cytoskeleton(microtubules/dynein)
Isolated lissencephaly (XLIS) XLAG LCHb
Xq22.3 Xp22 7q22
PAFAH PAFAH 14-3-3e Doublecortin ARX Reelin
Cytoskeleton (microtubules) Homeobox Neuron/radial glial cell interactions
ARX, an Aristaless-related homeobox transcription factor encoded by the gene ARX; LCHb, lissencephaly with cerebellar hypoplasia b; PAFAH, platelet-activating factor acetylhydrolase; XLAG, X-linked lissencephaly with abnormal genitalia.
Chapter 2 TABLE 2-14
Neuronal Proliferation, Migration, Organization, and Myelination
71
Major Varieties of Type II (‘‘Cobblestone’’) Lissencephaly: Etiology/Genetics
Disorder
Gene Locus
Protein
Function
Fukuyama congenital muscular dystrophy Walker-Warburg syndrome Muscle-eye-brain disease
9q31-32 9q34.1 1p34
Fukutin POMT1 POMGnT1
Glycosylation Glycosylation Glycosylation
POMGnT1, protein O-mannose N-acetylglucosaminyltransferase; POMT1, protein O-mannosyltransferase 1.
lissencephaly syndromes may be characterized principally by pachygyria rather than by lissencephaly (see later).
12-week-old fetus (Fig. 2-25A and B). The layers consist, from the pial surface, of an outermost relatively cellpoor marginal layer, a diffuse cellular layer containing primarily pyramidal and other neurons characteristic of lower layers of cortex, a zone of heterotopic neurons in columns, and an innermost band of white matter. The pathological features indicate that the diffuse cellular layer contains neurons that were destined to constitute the deep layers of cortex but were never displaced by subsequent migrations, the neurons of which constitute the heterotopic layer. In type II lissencephaly the appearance is quite different (Fig. 2-25C). The cortex is represented by clusters and circular arrays of neurons, with no recognizable organization or lamination, separated by glial and vascular septa. Large heterotopic collections of neurons are prominent. Notable, however, are the protrusions over the cortical surface where neurons have migrated through the pia. These protrusions cause the cortical surface to be irregular or ‘‘pebbly’’ in appearance. In pachygyria, the features are similar to those described for lissencephaly but are less marked.* The gyri are relatively few, are unusually broad, and are associated with an abnormally thick cortical plate (Fig. 226, parasagittal region). The microscopic features are similar to those of lissencephaly, although the abnormalities are less marked (Fig. 2-27). Pachygyria should be considered on a continuum with lissencephaly, because, depending on the nature of the genetic disturbance,
Clinical Aspects: Type I Lissencephaly. The clinical aspects of lissencephaly-pachygyria are considered best in terms of those disorders characterized by type I and type II disease (see Tables 2-13 and 2-14). Thus, eight genetic disorders are recognized, five resulting in type I lissencephaly. Approximately 60% of cases of type I lissencephaly are caused by defects of the chromosome 17p13.3 gene (LIS1), and approximately one half of the remaining cases are caused by defects of the Xq22.3 gene XLIS or DCX (see Table 2-12). (The XLIS cases account for nearly all the male infants in the non-LIS1 group.) Both lissencephaly with cerebellar hypoplasia b (reelin deficiency) and X-linked lissencephaly with abnormal genitalia (XLAG) are much less common. The clinical features of the major form of type I lissencephaly (LIS1, isolated lissencephaly related to the chromosome 17p13.3 locus), are summarized in Table 2-15.* Despite the major brain anomaly,
*See references 348-353.
*See references 248,252,253,257,258,261,262,341,344,346,355-369.
Timing. The onset of lissencephaly-pachygyria is considered to be no later than the third and fourth months of gestation. This conclusion is based on the anatomical features of the lesions, as well as cases in which putative teratogenic exposures could be documented.5,303,341,354
5,41,252,253,257,258,261,303,339-341,343,345,
Figure 2-25 Lissencephaly, types I and II. A, Cerebral hemisphere wall of a normal 14-week human fetus. The undifferential cortical plate is bordered inferiorly by migrating neurons. In the lower part of the figure, migrating cells are seen arranged in vertical columns. The subventricular zone is seen in the lowest part (hematoxylin and eosin [H&E], bar = 0.1 mm). B, Type I (classic) lissencephaly in a newborn. The neocortex is represented by a narrow band of (pyramidal) cells, separated by a cell-sparse zone from vertically arranged columns of neurons arrested during migration. Compare with A (H&E, bar = 1 mm). C, Type II (Walker-Warburg) lissencephaly in a newborn. The neocortex is disorganized into ectopic clusters of neurons. Note the radial projection of white matter, with associated fibrovascular tissue, into the cortex between the clusters. This arrangement results in the ‘‘cobblestone’’ appearance on magnetic resonance imaging (H&E, bar = 1 mm). Note also the protrusion of migrating neurons through the glia limitans, leading to the uneven or ‘‘pebbly’’ cortical surface. (From Barth PG: Disorders of neuronal migration, Can J Neurol Sci 14:1-16, 1987.)
A
B
C
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Major Neurological Features of Type I Isolated Lissencephaly
Normal head size at birth ! microcephaly in the first year Hypotonia ! hypertonia later in infancy Paucity of movement, feeding disturbance Seizures (common evolution to infantile spasms or LennoxGastaut syndrome in early infancy) Electroencephalogram severely disordered with high amplitude and rapid frequency
Figure 2-26 Pachygyria and polymicrogyria. Coronal section of the parietal lobe, parasagittal region, and lateral convexity from an infant with Zellweger cerebrohepatorenal syndrome (Nissl stain for cell bodies). Note the pachygyric cortex in the parasagittal region and the polymicrogyric cortex over the lateral convexity. (From Volpe JJ, Adams RD: Cerebro-hepato-renal syndrome of Zellweger: An inherited disorder of neuronal migration, Acta Neuropathol [Berl] 20:175-198, 1972.)
microcephaly usually is not present at birth, but characteristically develops in the first year. The craniofacial appearance is generally unremarkable, except for bitemporal hollowing of the skull and a small jaw. Marked hypotonia and paucity of movement are characteristic. Spasticity does not develop until later in the first year or even after that. Neonatal seizures can occur, but characteristically seizures develop in the first 6 months as infantile spasms or as akinetic-myoclonic seizures with grossly disordered findings on the EEG (Lennox-Gastaut syndrome). The EEG is always abnormal; particularly characteristic is high-amplitude, fast activity, occurring in approximately 75% of patients with type I lissencephaly. Bursts of sharp and slow-wave complexes, interspersed with periods of voltage depression, are also common features of the EEG. Infants with primarily pachygyria rather than lissencephaly have less severe clinical deficits, including occasionally only mild subsequent impairment of
Figure 2-27 Pachygyric cortex in the specimen shown in Figure 2-26 (Nissl stain for cell bodies). The pial surface is at the upper left-hand corner, and the subcortical white matter is at the lower right-hand corner. Note the broad layer of heterotopic neurons arranged in columns and nests, separated from the pachygyric cortex by a sparsely cellular region. The neurons of the pachygyric cortex, at higher magnification, had the characteristics of pyramidal neurons of deeper cortical layers, not displaced by subsequent migrations. (From Volpe JJ, Adams RD: Cerebro-hepatorenal syndrome of Zellweger: An inherited disorder of neuronal migration, Acta Neuropathol [Berl]) 20:175-198, 1972.)
Chapter 2
A
B
C
D
E
F
Figure 2-28 Miller-Dieker syndrome. A to C, Frontal and, D to F, lateral views of three infants. See text for details. (From Dobyns WB: The neurogenetics of lissencephaly, Neurol Clin 7:89-105, 1989.)
intellect. In general, however, neurological outcome in LIS1 isolated lissencephaly is characterized ultimately by mental retardation, spastic quadriparesis, and seizures. The clinical features of the second major form of type I lissencephaly related to the chromosome 17p13.3 locus, the Miller-Dieker syndrome, are different from those of isolated lissencephaly because of the additional presence of craniofacial abnormalities.73,248,257,258,261,364,370,371 Thus, in addition to the bitemporal hollowing and small jaw observed with isolated lissencephaly, patients have a characteristic facial appearance with a short nose with upturned nares, a long and protuberant upper lip with a thin vermilion border, and a relatively flattened midface (Fig. 2-28). Additional characteristic features of Miller-Dieker syndrome include cardiac malformations (20% to 25%), genital anomalies in male infants (70%), a sacral dimple (70%), deep palmar creases (65% to 70%), and clinodactyly (40% to 45%). Neurological features are similar to those described for isolated lissencephaly, although generally the disturbances are even more marked, consistent with the uniformly severe degree of the lissencephaly. The clinical aspects of the major X-linked form of type I lissencephaly (i.e., those related to a defect in the DCX [or XLIS] gene), are similar to those described for isolated lissencephaly caused by LIS1. The clinical features, of course, occur in hemizygous male infants, whereas heterozygous female infants exhibit subcortical band heterotopia (see later). The clinical aspects of the rarer form of X-linked lissencephaly (i.e., XLAG) are somewhat distinctive.372-376 Particularly characteristic features include severe neonatal seizures (onset in >50% in the first hour of life and in utero in 20%), hypothermia, severe diarrhea, and ambiguous genitalia (micropenis, cryptorchidism). The epileptic syndrome is especially severe and relates to the particular involvement of GABAergic interneurons (see later). The lissencephaly is accompanied also
Neuronal Proliferation, Migration, Organization, and Myelination
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Figure 2-29 Lissencephaly, type I, computed tomography scan. Note the smooth cortical surface and colpocephaly (dilation of trigone and occipital horns of lateral ventricles). (From Dobyns WB: The neurogenetics of lissencephaly, Neurol Clin 7:89-105, 1989.)
by complete agenesis of the corpus callosum. The full syndrome occurs in hemizygous male infants, although less severe phenotypes occur as a function of the severity of the genetic abnormality. Heterozygous female infants often exhibit agenesis of the corpus callosum and epilepsy. The clinical aspects of lissencephaly with cerebellar hypoplasia b, related to a defect in RELN, which encodes reelin, are difficult to define decisively because of the paucity of careful clinical descriptions.257,377-379 Perhaps most notable is the presence of microcephaly at birth, rather than the postnatal development of microcephaly, as in other varieties of type I lissencephaly. The term lissencephaly with cerebellar hypoplasia b is used to distinguish these cases from lissencephaly with cerebellar hypoplasia a. The latter are examples of type I lissencephaly secondary to either LIS1 or DCX gene defects (see earlier) that may be accompanied by prominent hypoplasia of the cerebellar vermis and mild hypoplasia of the cerebellar hemispheres. By contrast, the reelin-related cases exhibit severe hypoplasia of the entire cerebellum, which also lacks folia. The radiological features of type I lissencephaly may include a distinctive appearance on CT scan (Fig. 2-29). However, MRI provides superior definition of the parenchymal lesion (Figs. 2-30 and 2-31). Indeed, insight into the likely genetic lesion can be gained by evaluating the degree of lissencephaly and pachygyria, any anteroposterior gradient, agenesis of the corpus callosum, and the degree of cerebellar hypoplasia (see Fig. 2-31).257 Thus, of LIS1 cases, the cortex is very thick, posterior more than anterior involvement is apparent, and Miller-Dieker cases have even more severe lissencephaly than do isolated cases. DCX cases have anterior more than posterior involvement. XLAG cases have only a moderately thick cortex and prominent agenesis of the corpus callosum. Reelin cases have a moderately thick, pachygyric cortex with striking cerebellar hypoplasia. A uniform accompanying feature
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in all genetic types is colpocephaly (i.e., dilation of the trigone, occipital horns, and temporal horns of the lateral ventricles). The ventricular dilation of colpocephaly occurs in the trigone and occipital horns because of underdevelopment of the corpus callosum and calcarine sulci and in the temporal horns because of failure of inversion of the hippocampus.363
Figure 2-30 Lissencephaly, type I, magnetic resonance imaging (MRI) scan. Note the smooth cortical surface and colpocephaly, as described in the Figure 2-29 legend. The cerebral parenchymal features are visualized better by MRI than by computed tomography.
ILS, grade 1 (DCX)
Etiology/Genetics: Type 1 Lissencephaly. The five major genetic varieties of type I lissencephaly appear to involve three different mechanisms of migrational failure (see Table 2-13). The LIS1 cases, both isolated lissencephaly and Miller-Dieker syndrome, and the DCX (XLIS) cases have a defect in the pace of migration. XLAG appears to involve a defect in tangential more than radial migration. The RELN cases appear to be related to a defect in migrating neuron and radial glial interactions. Isolated lissencephaly (LIS1) secondary to a deficiency in PAFAH1B1 (LIS1) involves a disturbance in migration because of abnormal function of the cytoskeleton.257,258,260,262,380,381 This protein is the
ILS, grade 4 (DCX)
LCHb, grade 4 (RELN?)
SBH, grade 6 (DCX)
a>p
A
B
C
D
E
F
G
H
p>a
MDS, grade 1 (LIS1 and 14-3-3e)
ILS, grade 3 (LIS1)
XLAG, grade 3 (ARX)
Normal control
Figure 2-31 Lissencephaly, type I, magnetic resonance imaging scans. In contrast to a normal control (H), all types of lissencephaly (A to G) have absent or broad gyri and an abnormally thick cortex, except for subcortical band heterotopia (SBH), resulting from DCX mutation in heterozygous female infants (SBH is discussed in the text with heterotopias rather than with lissencephaly-pachygyria). The anteroposterior or rostrocaudal gradient of lissencephaly is strictly correlated with the causative gene. Specifically, mutations of DCX or RELN result in a more severe anterior than posterior (a>p) gradient (A to D), whereas mutations of LISI with or without 14-3-3e or ARX lead to a more severe posterior than anterior (p>a) gradient (E to G). The absolute thickness of the cortex and the presence of a cell-sparse zone also differ based on the causative gene. In patients with mutations of DCX (A and B) or LISI (E and F), the cortex is very thick, typically 10 to 20 mm, and prominent cell-sparse zones are seen in areas of agyria (arrowheads in A, E, and F). In patients with lissencephaly with cerebellar hypoplasia group b (C, which resembles patients with known RELN mutations, although a mutation has not been demonstrated in this patient) or ARX (G) mutations, the cortex is only moderately thick, typically 5 to 10 mm, and cell-sparse zones are never seen, even in areas of agyria (G). In lissencephaly with cerebellar hypoplasia group b (LCHb) with or without proven RELN mutations, other images show an abnormal hippocampus and severe cerebellar hypoplasia (not shown). In male infants with X-linked lissencephaly with abnormal genitalia (XLAG) caused by ARX mutations, other images demonstrate poorly demarcated basal ganglia often with small cysts, immature white matter, and agenesis of the corpus callosum (not shown). In heterozygous female infants, mutations of DCX result in SBH (D), whereas mutations of ARX often result in agenesis of the corpus callosum (not shown). ILS, isolated lissencephaly; MDS, Miller-Dieker syndrome; XLAG, X-linked lissencephaly with abnormal genitalia. (From Kato M, Dobyns WB: Lissencephaly and the molecular basis of neuronal migration, Hum Mol Genet 12:R89-R96, 2003.)
Chapter 2
noncatalytic alpha subunit of the isoform Ib of plateletactivating factor acetylhydrolase. This LIS1-encoded protein interacts with microtubules and cytoplasmic dynein motors, crucial for both somal translocation and cell motility. Miller-Dieker syndrome, of course, shares the PAFAH defect but because the disorder relates to a deletion, other genes are disturbed.253,257,258,364,370,382 The protein, 14-3-3e, appears to be the key additional defect in this more severe lissencephaly syndrome.371 Deficiency of 14-3-3e results in mislocalization of the LIS1 protein and accentuates the dynein motor disturbance and thereby neuronal migration. Isolated lissencephaly, secondary to the X-linked DCX (XLIS) gene and deficiency of doublecortin, appears also to be mediated at the level of the cytoskeleton.248,257,258,283,383-385 Doublecortin is a microtubuleassociated protein that binds to tubulin and is necessary for microtubule polymerization. Thus, as with the two LIS1 disorders, a defect in the cytoskeleton and thereby in cell motility results. XLAG involves a second mechanism of migration disturbance.257,258,373,375,376 The gene involved, ARX, is a homeobox gene that encodes a protein critical for tangential migration. The result of the mutation is a marked deficiency of GABAergic interneurons, because, as noted earlier, tangential rather than radial migration is the mechanism for movement of neurons destined to be interneurons from the ventricular zone to the cortex. The severe deficiency of GABAergic neurons likely underlies the striking clinical feature of prenatal and early neonatal seizures and intractable infantile seizures (see the earlier discussion of clinical aspects). Lissencephaly with cerebellar hypoplasia b, related to the RELN gene, involves a third mechanism of disturbed migration. RELN encodes a glycoprotein, reelin, secreted by horizontally oriented Cajal-Retzius cells in the preplate and marginal zones and is crucial for signaling to migrating neurons on radial glial cells.257,258,261 Reelin appears to function as a stop signal and in neuronal and radial glial cell interactions. The result of reelin deficiency is a cortex that is abnormally cellular in its most superficial zone and is inverted (i.e., early migrating pyramidal cells are the uppermost layer). Preplate-like cells accumulate in the marginal zone, a finding suggesting that the preplate has not been split by the migrating cortical neurons. Related phenomena occur in cerebellum to cause the severe cerebellar hypoplasia. Other causes of type I lissencephaly, albeit rare, are worthy of note. A role for vascular insult during the third to fourth months of gestation has been suggested.357,364,365,386 Moreover, lissencephalypachygyria has been documented with fetal cytomegalovirus infection (see Chapter 20) and with a variety of inborn errors of metabolism (e.g., pyruvate dehydrogenase deficiency, Zellweger syndrome, glutaric acidemia [type 2, nonketotic hyperglycinemia]; see Chapters 14, 15 and 16). Rare autosomal recessive forms with marked neonatal microcephaly and lissencephaly, the most severe form of microcephaly with simplified gyri
Neuronal Proliferation, Migration, Organization, and Myelination
75
discussed among proliferative disorders, have been reported (see earlier).42,345,387-389 Recurrence risks for type 1 lissencephaly depend on the genetic type.261 Thus, LIS1 isolated lissencephaly, which is caused by de novo mutations, has a recurrence risk of approximately 1% (because of the theoretical risk of germline mosaicism in either parent). MillerDieker syndrome is related to de novo deletions in approximately 80% (recurrence risk of 1%), and in 20%, to inheritance of a deletion from a parent carrying a balanced chromosomal rearrangement. In the latter, recurrence risk is higher and depends on the nature of the rearrangement. With XLIS lissencephaly, the mother may be a carrier even if the brain MRI does not show subcortical band heterotopia.385 Even if the mother is not a carrier, the risk of harboring germline mosaicism places a recurrence risk at about 5%. With XLAG, the carrier status of the mother should be evaluated because the phenotype in girls and women can be very mild. Thus far, the few families reported with reelin deficiency lissencephaly have exhibited autosomal recessive inheritance. Clinical Aspects: Type II Lissencephaly. The three disorders consistently associated with type II lissencephaly are Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease (see Table 2-14).252,253,390-403 As noted earlier, these disorders are characterized by lissencephaly in which protrusions of neurons are found over the surface of the brain and thereby render a ‘‘bumpy’’ or ‘‘pebbly’’ configuration to the cortical surface. In type II lissencephaly, the ectopic clusters of neurons within the cortex, separated by fibroglial vascular tissue that extends radially from the cerebral white matter, result in a typical MRI appearance, termed ‘‘cobblestone’’ lissencephaly (see later). The migrational defect is unique and is similar for the three disorders (see later). In addition to type II lissencephaly, these disorders also share congenital muscular dystrophy as a prominent clinical feature. Fukuyama congenital muscular dystrophy and muscle-eye-brain disease are discussed most appropriately with diseases of muscle (see Chapter 19). The clinical aspects of Walker-Warburg syndrome are described here. The major clinical features of Walker-Warburg syndrome in many respects are different from those for the type I lissencephalic disorders (Table 2-16). Macrocephaly (84%), either apparent at birth (58%) or developing postnatally (26%), retinal malformations (100%), congenital muscular dystrophy (100%), cerebellar malformation (100%), and type II lissencephaly (100%) are characteristic.390-393,401-403 Type II lissencephaly and the retinal, cerebellar, and muscular abnormalities are necessary for the diagnosis. The neurological features (e.g., severe seizure disorders and mental retardation) are similar to those identified for type I lissencephaly. However, the severe muscle disease, accompanied by elevated serum creatine kinase, accentuates the marked hypotonia and weakness observed with lissencephaly. Death in the first year is common.
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TABLE 2-16
HUMAN BRAIN DEVELOPMENT
Major Clinical Features of WalkerWarburg Syndrome
Macrocephaly Present at birth Develops postnatal Type II lissencephaly Cerebellar malformation Ventricular dilation/hydrocephalus Retinal malformation Anterior chamber abnormality Congenital muscular dystrophy
o
84% 58% 26% 100%* 100%* 95% 100%* 76% 100%*
3
*Necessary for diagnosis. Data from Dobyns WB: The neurogenetics of lissencephaly, Neurol Clin 7:89-105, 1989.
The radiological features are similar to those for type I lissencephaly in terms of the agyric brain and the concurrence of agenesis or hypoplasia of the corpus callosum or septum pellucidum. However, because of the different cerebral cortical microscopic pathological features (see earlier discussion), a slightly uneven cortex is apparent. Moreover, as noted earlier, irregular projections of the underlying white matter into the cortex lead to the term ‘‘cobblestone’’ lissencephaly (Fig. 2-32). The latter appearance is more clearly apparent after the neonatal period. The most characteristic distinguishing features of Walker-Warburg syndrome include the presence of cerebellar malformation and, invariably, vermian agenesis or hypoplasia, as well as complete Dandy-Walker malformation (50%) and posterior encephalocele (25% to 35%) (see Fig. 2-32; Fig. 2-33). The ventricular dilation (95%) can be
A
C
Figure 2-32 Magnetic resonance imaging scan, type II lissencephaly in Walker-Warburg syndrome. At the level of the third ventricle, a smooth cortical surface, open and shallow sylvian fissures (open arrow), a Dandy-Walker cyst (C), and enlargement of the lateral and third (3) ventricles are demonstrated. A lack of cerebral gray-white matter interdigitation is seen (o, arrowhead) adjacent to a thickened cortical mantle. The ‘‘cobblestone’’ appearance of the cortex is faintly visible in the right frontal region and will become more apparent after the neonatal period. The anterior interhemispheric fissure is obliterated as a result of leptomeningeal thickening and proliferation (arrow). The ventricular dilation and cerebellar malformation are characteristic of the syndrome (see text). (From Rhodes RE: WalkerWarburg syndrome, AJNR Am J Neuroradiol 13:123-126, 1992.)
distinguished from the colpocephaly of type I lissencephaly by involvement of the third and fourth ventricles and by the presence of the macrocephaly of hydrocephalus. Some of these distinguishing features are recalled by the eponymic designation for this
B
Figure 2-33 Magnetic resonance imaging scan, type II lissencephaly, Walker-Warburg syndrome. Note in A the hydrocephalus, smooth cortical surface anteriorly and pachygyric cortex posteriorly, and, barely observable, the interdigitations of white matter into the cortex with a resulting ‘‘cobblestone’’ appearance (arrows). In B, note the dysgenetic corpus callosum, cerebellar hypoplasia, and anomalous kinking of the lower brain stem (arrow), all characteristic of Walker-Warburg syndrome. (Courtesy of Dr. Omar Khwaja.)
Chapter 2
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77
Figure 2-34 Lateral view of the cerebrum from an infant with Zellweger syndrome. Note the area of polymicrogyria, anterior to the sylvian fissure, involving the convexity of the frontal lobe. (From Volpe JJ, Adams RD: Cerebro-hepato-renal syndrome of Zellweger: An inherited disorder of neuronal migration, Acta Neuropathol [Berl] 20:175-198, 1972.)
syndrome: HARD ± E, hydrocephalus, agyria, retinal dysplasia, encephalocele. I suggest an alternative, CHARM ± E, to add cerebellar and muscle. Etiology/Genetics: Type II Lissencephaly. The three autosomal recessive disorders that result in cobblestone lissencephaly occur because of a failure of neurons to terminate their radial migration to the cerebral cortex. Indeed, these neurons migrate through the glia limitans at the pial surface of the cortex and into the subarachnoid space.258,398,399,403,404 The fundamental disturbance involves glycosylation of alpha-dystroglycan, a protein secreted particularly by astrocytes but also by neurons. Secreted alpha-dystroglycan interacts with beta-dystroglycan in the glial plasma membrane and with laminin of the extracellular matrix. The glia limitans consists of the apposed astrocytic end feet and the overlying extracellular matrix. Because the interactions of alpha-dystroglycan require correct glycosylation of the protein, failure of glycosylation is associated with gaps in the glia limitans, protrusion of neurons through these gaps, and failure of neurons to organize themselves within the cortical plate. The three mutant genes are involved in glycosylation, especially by encoding glycosyl transferases, as shown in Table 2-14. The molecular details require further delineation because the precise role of fukutin in glycosylation remains to be clarified, and only 10% to 20% of Walker-Warburg cases exhibit the protein O-mannosyl transferase defect.399,402 In muscle, correctly glycosylated alpha-dystroglycan is required to interact with extracellular laminin and sarcolemmal betadystroglycan, which is bound to dystrophin. In the three disorders, failure of this interaction leads to degeneration of the muscle fiber and ‘‘dystrophy’’ (see Chapter 19). Polymicrogyria Anatomical Abnormality. Polymicrogyria is characterized by a great number of small plications in the
cortical surface, rendering to the external aspect of the cerebrum the appearance of a wrinkled chestnut (Fig. 2-34). The multitude of small gyri are arranged in complicated festoon-like or glandular formations, appearing to result from fusion of their molecular layers (see Fig. 2-26, lateral convexity).261,405-407 Two basic varieties of polymicrogyria, layered and unlayered, can be distinguished from the microscopic appearance (Table 2-17 and Fig. 2-35; see Fig. 2-26).5,41,261,303,408,409 In the ‘‘classic,’’ layered variety, the cerebral cortex has four distinct layers. Thus, a relatively intact outermost molecular layer, a richly cellular second layer consisting of normal superficial cortical neurons, a cell-poor, gliotic layer in place of normal deeper cortical neurons, and a fourth layer of relatively preserved neurons arranged in columns are noted (see Fig. 2-35A). The cerebral white matter is much more abundant than in lissencephaly-pachygyria. This type of polymicrogyria often coexists in the margins of more severe ischemic destructive lesions (hydranencephaly) or in association with destructive infectious processes (e.g., toxoplasmosis or cytomegalovirus infection).5,303,409–413 In the nonlayered variety of polymicrogyria, the neurons destined primarily (although not exclusively) for the outer cortical layers appear to have been impeded in their migrations. The result is a poorly laminated or nonlaminated cortex, which, after the outermost cell-poor molecular layer, consists of an ill-defined zone of larger pyramidal cells (appropriate for deeper cortex) followed by a stream of heterotopic neurons; many of these neurons are smaller pyramidal and granular cells (appropriate TABLE 2-17
Major Varieties of Polymicrogyria
Layered: ‘‘classic’’ four-layered, probably postmigrational and related to destructive process Unlayered: ‘‘nonclassic,’’ not four-layered, migrational defect, accompanied by heterotopias and other consequences of migrational disorder
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A
B
Figure 2-35 Microgyria. A, ‘‘Classic,’’ layered microgyria, with transition between the microgyric and normal cortex. The aneuronal band (arrow) of the microgyric segment is continuous with layers III and IV of the normal cortex (arrowhead). Layer II of the microgyric cortex and layer II of the normal cortex are continuous (Nissl stain 30). B, Unlayered microgyria in a microencephalic newborn with convulsions and general hypertonia. Note the heterotopic neurons in the subcortical white matter (hematoxylin and eosin, 87). (A, From Dias MJM, Rijckevorsel GH, Landrieu P, Lyon LG: Prenatal cytomegalovirus disease and cerebral microgyria: Evidence for perfusion failure, not disturbance of histogenesis, as the major cause of fetal cytomegalovirus encephalopathy, Neuropediatrics 15:18-24, 1984; B, from Barth PG: Disorders of neuronal migration, Can J Neurol Sci 14:1-16, 1987.)
for superficial cortical layers) (see Figs. 2-26 and 235B). The heterotopic neurons in cerebral white matter are arranged in columns, apparently ‘‘glued’’ to the radial glial fibers.5 This type of polymicrogyria is characteristic of that seen in Zellweger syndrome (see later discussion). Timing. The two varieties of polymicrogyria appear to have differing times of onset. The nonlayered variety represents a disorder of neuronal migration, and the classic four-layered variety is a postmigrational disorder. The first type includes cases, such as patients with Zellweger syndrome (see Fig. 2-26), with concomitant migrational defects present in the cerebrum as well as in the brain stem or cerebellum. In these instances, the deepest collection of neurons appears to represent heterotopic neurons arrested during migration. Disturbance of neuronal migration as one basic cause of polymicrogyria is supported further by the occurrence of polymicrogyria in index patients and siblings of infants with Miller-Dieker lissencephaly syndrome and in the cerebral hemisphere contralateral to unilateral schizencephaly (see earlier discussion).414 The time of onset of this nonlayered variety of polymicrogyria appears to be generally no later than the fourth to fifth months of gestation. The second variety of polymicrogyria includes those cases with evidence of laminar neuronal necrosis in the cortex after the apparent completion of migration. Such examples of this postmigrational polymicrogyria include those cases associated with carbon monoxide exposure at approximately 20 to 24 weeks,415,416 as well as with other, less well-defined intrauterine insults.303,411,417-422 In these patients, the sparsely cellular gliotic third layer represents an area of laminar cortical necrosis, and the fourth layer is composed not of heterotopic neurons but of neurons of the deeper layers of previously formed cortex. The postnatal evolution of polymicrogyria and periventricular leukomalacia has been documented in a premature infant
from 31 weeks’ postconceptional age, thereby documenting the postmigrational development of encephaloclastic polymicrogyria.413 Some examples of polymicrogyria associated with cytomegalovirus infection, vascular anomalies, ischemic events, or metabolic abnormalities (mitochondrial disorders) could reside in the maldevelopmental categories, encephaloclastic categories, or both.413,423-427 Indeed, the demonstration of lissencephaly-pachygyria in some infants with cytomegalovirus infection (see earlier discussion) documents clearly the potential for this viral infection to impair migratory events directly. A few observations suggest that some cases of polymicrogyria are caused by an encephaloclastic process during neuronal migration that interfered with the migrational events and produced polymicrogyria, that is, a combination of encephaloclastic and maldevelopmental varieties.319,407,428,429 An experimental model that supports such a pathogenesis has been described.430,431 Clinical Aspects. The best example of a clinically welldefined, autosomal recessive disorder of neuronal migration with polymicrogyria and pachygyria is Zellweger cerebrohepatorenal syndrome.5,190,432-437 The neurological syndrome in these infants is startling and is characterized by marked generalized weakness with severe hypotonia, severe recurrent seizures, and absence or marked impairment of high-level responses to visual, auditory, or somesthetic stimuli. Other features of the syndrome include a distinctive craniofacial appearance, hepatomegaly, multiple renal cortical cysts, and stippled calcification of the patellae. A disturbance of peroxisomal biogenesis is indicated by the demonstrations of absence of peroxisomes in the liver and other tissues and certain metabolic abnormalities (e.g., elevated levels of pipecolic acid and very-long-chain fatty acids and decreased levels of plasmalogens; see Chapter 16). Very-long-chain fatty acids are important constituents of plasma
Chapter 2 TABLE 2-18
Neuronal Proliferation, Migration, Organization, and Myelination
79
Potential Importance of Very-Long-Chain Fatty Acids in Neuronal Migration
Disease
Very-Long-Chain Fatty Acids
Plasmalogens
Neuronal Migration
Zellweger syndrome Neonatal adrenoleukodystrophy Bifunctional enzyme Rhizomelic chondrodysplasia punctata
" " " Normal
# # Normal #
Abnormal Abnormal Abnormal Normal
Data from Moser HW: The peroxisome: Nervous system role of a previously underrated organelle. The 1987 Robert Wartenberg lecture, Neurology 38:1617-1627, 1988 and Kaufmann WE, Theda C, Naidu S, et al: Neuronal migration abnormality in peroxisomal bifunctional enzyme defect, Ann Neurol 39:268-271, 1996.
membranes in the brain; the possibility that the accumulation of these compounds may interfere with normal membrane properties crucial for neuronal migration along radial glial fibers is suggested by the consistent relationship among generalized peroxisomal disorders between this abnormality (rather than others) and abnormal neuronal migration (Table 2-18).438 This notion is supported further by the occurrence of polymicrogyria in an infant with deficiency of peroxisomal bifunctional enzyme, in which the impairment of peroxisomal function was confined to very-long-chain fatty acids (and bile acid intermediates).425,439 The clinical features of sporadic cases of generalized polymicrogyria are not well defined, although seizures are often recorded. In general, a broad range of clinical features has been reported, from severely impaired neurological development and intractable epilepsy to only selective disturbances of neurological function.261 Unilateral polymicrogyria is a well-documented substrate for congenital hemiplegia.440 Polymicrogyria may accompany other dysgenetic disorders, which have distinctive clinical features (e.g., a form of Joubert syndrome, Aicardi syndrome, Smith-Lemli-Opitz syndrome, periventricular nodular heterotopia; see Chapter 1).261,441-443 The postnatal and postmigrational development of bilateral perisylvian polymicrogyria was documented by MRI in a premature infant with periventricular leukomalacia.413 Focal polymicrogyria is a prominent feature of focal cerebrocortical dysgenesis, the clinical aspects of which are discussed separately later. Growing numbers of bilateral symmetrical polymicrogyria syndromes, some familial, have been recognized (Table 2-19).444-458a The clinical features in most of these disorders occur after the neonatal period. A prominent exception is the bilateral perisylvian polymicrogyric syndromes, many of which are characterized by pseudobulbar palsy with oral-buccal-lingual deficits, TABLE 2-19
feeding disturbances, and facial diparesis, as well as seizures from early infancy. The radiological diagnosis of polymicrogyria in the neonatal period is often difficult, even with MRI (Fig. 2-36).42,459 This difficulty relates in part to the lack of myelination and the less prominent gray-white matter junction in the newborn than at later ages. Neuronal Heterotopias Anatomical Abnormality. The least severe of the migrational disturbances, neuronal heterotopias, are collections of nerve cells in the periventricular region or in subcortical white matter, apparently arrested during radial migration from the subependymal germinative zones. Such collections are constant accompaniments of the more severe migrational disorders. At the other end of the spectrum, small collections of neurons in cerebral white matter are not unusual as incidental findings at autopsy. Two major varieties of cerebral neuronal heterotopias are recognized (Table 2-20). The heterotopic collections in the periventricular (subependymal) region occur near the site of origin of neuroblasts in
Bilateral Symmetrical Polymicrogyria Syndromes
Topography
Genetics
Frontal Frontoparietal
Sporadic GPR56 (a G-protein–coupled receptor) Heterogeneous (includes Xq28 locus) Sporadic
Perisylvian Parasagittal (Parieto-occipital) Generalized
16q locus
Figure 2-36 Magnetic resonance imaging (MRI) scan, polymicrogyria. This axial T2-weighted MRI scan from an infant with seizures shows bilateral symmetrical frontal polymicrogyria (arrows). Note the multiple but very small sulcal indentations of the cerebral cortex. The cortical surface thus appears somewhat smooth. The distinction from lissencephaly is aided by noting that the cortex is not thick. Also notable are underopercularization of the sylvian fissure and colpocephaly (dilation of occipital horns). (Courtesy of Dr. Omar Khwaja.)
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TABLE 2-20
HUMAN BRAIN DEVELOPMENT
Major Varieties of Cerebral Neuronal Heterotopias
Periventricular (subependymal) Cerebral white matter Laminar: subcortical band or double cortex Nodular: focal or diffuse
the germinative ventricular and subventricular zones (Fig. 2-37). In the cerebral white matter, heterotopias may occur in a subcortical laminar distribution or as focal or diffuse nodular collections in the white matter. Those in the periventricular region are usually nodular and are termed periventricular nodular heterotopia, periventricular heterotopia, or subependymal heterotopia (see later). Those in the cerebral white matter that occur as a diffuse laminar band below the cerebral cortex are termed band heterotopia or double cortex (see later discussion). Timing and clinical aspects. The onset of neuronal heterotopias is presumed to be no later than the last weeks of migrational events (i.e., no later than 20 weeks of gestation). The clinical features of disorders associated with cerebral neuronal heterotopias were clarified considerably by the advent of MRI scanning.252,253,284,303,366,460-489 The clinical manifestations of nearly all cases of cerebral neuronal heterotopias begin after the neonatal period. Thus, a detailed discussion is not presented here. Periventricular heterotopia and band heterotopia (or double cortex) provide insights into mechanisms of neuronal migration and are described briefly. Focal or nodular cerebral white matter heterotopias exhibit clinical features related to the size and location of the heterotopias and are most likely to be encountered in the newborn as a feature of disorders discussed elsewhere in this book.42,303,425,467-472,474-477,490-494 This latter diverse group is summarized in Table 2-21. The two most common heterotopic lesions, periventricular heterotopia and band heterotopia of the double cortex syndrome, are of particular interest. (Table 2-22).52,252,253,284,288,349,366,383,462,464,467-480,484489,495-502 The most common genetic forms of these two lesions are X linked. An unusual autosomal recessive type of periventricular heterotopia (with microcephaly) is also recognized (see Table 2-22). In X-linked TABLE 2-21
Figure 2-37 Periventricular heterotopic nodular masses. The patient is a newborn (hematoxylin and eosin, 12.7). (From Barth PG: Disorders of neuronal migration, Can J Neurol Sci 14:1-16, 1987.)
periventricular heterotopia, the anatomical defect is caused by a failure of initiation of migration.258 The gene involved is filamin which encodes filamin-1, an actin-binding protein expressed at high levels in the ventricular zone of the developing cerebrum and crucial for the initial cytoskeletal rearrangement for initiation of migration. Because of random X inactivation, neurons with the mutant gene active do not initiate migration and remain in the periventricular region, whereas neurons with the normal gene migrate normally. In the autosomal recessive variety of the disorder, related to a mutation of the ARGEF gene (ADP ribosylation factor, GEF-2), critical for vesicle trafficking, the mechanism for failure of some neuroblasts to initiate migration is less clear. Importantly, in this disorder, a derangement of neuronal proliferation also occurs, and severe congenital microcephaly results. In the double cortex syndrome, the diffuse laminar heterotopia appears to occur because, as a consequence of random X inactivation, one population of neurons contains only the abnormal gene and thus fails to migrate fully to the cortical plate (see Table 2-22). The characteristic locus of this laminar heterotopia beneath the cerebral cortex is at the site of the critical interface of the intermediate zone and subplate neurons (Fig. 2-38). Presumably the mutated doublecortin is unable to effect the critical interaction between the migrating neurons and the subplate neurons required to penetrate this region and form the cortical plate.248,252,253,257,258,261,285 As discussed earlier,
Disorders Associated with Neuronal Heterotopias as the Major Manifestation of Migrational Disturbance*
Metabolic disorders: neonatal adrenoleukodystrophy, glutaric aciduria type II, nonketotic hyperglycinemia, Leigh disease, Menkes disease, GM2-gangliosidosis, Hurler disease, Zellweger syndrome, bifunctional enzyme deficiency, carnitine palmitoyltransferase deficiency Myotonic dystrophy Neurocutaneous syndromes: neurofibromatosis, tuberous sclerosis, incontinentia pigmenti, Ito hypomelanosis, linear nevus sebaceus, encephalocraniocutaneous lipomatosis, Ehlers-Danlos syndrome Multiple congenital anomaly syndromes: Smith-Lemli-Opitz, Potter, de Lange, orofacial-digital, Meckel-Gruber, Coffin-Siris Chromosomal syndromes: trisomy 18, trisomy 13, deletion 4p, trisomy 21 Fetal toxic exposures: carbon monoxide, isotretinoic acid, ethanol, organic mercurial *See text for references. This excludes disorders commonly associated with prominent gyral abnormalities (i.e., schizencephaly, lissencephaly, pachygyria, polymicrogyria). Uncommonly, some of the disorders listed here may also have migrational defects severe enough to have accompanying gyral abnormalities. The genetic disorders summarized in Table 2-22 are not repeated here.
Chapter 2 TABLE 2-22
Neuronal Proliferation, Migration, Organization, and Myelination
81
Major Genetic Syndromes with Cerebral Heterotopias*
Type of Heterotopia Periventricular heterotopia Periventricular heterotopia (and microcephaly) Double cortex (band or laminar)
Seizures
Major Cognitive Deficits
Common
Uncommon
Common
Common
Common
Common
Mode of Inheritance
Manifestation in Males
Location of Gene
Gene or Gene Product
X-linked dominant Autosomal recessive
Lethal(?)*
Xq28
Filamin 1
As in females
20q11
ARGEF
X-linked dominant
Lissencephaly
Xq23
Doublecortin
*Occasional male patients exhibit periventricular heterotopia.
hemizygous male infants with the doublecortin defect develop lissencephaly, and the fundamental role of doublecortin involves microtubule dynein motor function. Focal Cerebral Cortical Dysgenesis (Dysplasia) With the advent of MRI scanning and removal of cortical anomalies for intractable epilepsy, focal disorders of the final stages of neuronal migration to cerebral cortex have been increasingly recognized. The lesions have been described as focal cerebral cortical dysgeneses or dysplasias.252,253,464,503-541 The anatomical descriptions have not varied appreciably and consist of aberrations of gyral formation (polymicrogyric or pachygyric in appearance), a cerebral cortical plate without normal lamination, and heterotopic neurons in subcortical white matter. The lesions studied most often in specimens obtained at epilepsy surgery may exhibit impaired lamination with normal appearing neurons or large, dysmorphic (misshapen) neurons. Large cells with immunocytochemical properties of neurons, glia, and multipotent neuroepithelial cells, termed balloon cells, may also be present. Those cases with dysmorphic large neurons, with or without the balloon cells, are
Figure 2-38 Magnetic resonance imaging (MRI) scan, band heterotopia or double cortex syndrome. This T1-weighted MRI scan shows a symmetrical band of heterotopic subcortical gray matter (arrowheads) underlying a cerebral cortex with a normal convolutional pattern. (From Miura K, Watanabe K, Maeda N, et al: Magnetic resonance imaging and positron emission tomography of band heterotopia, Brain Dev 15:288-290, 1993.)
categorized as cortical dysplasia of Taylor. Because MRI has been the basis of the anatomical diagnosis in most cases, and the finding of a ‘‘thick’’ cortical plate with heterotopic gray matter is the prominent feature, it has not been clear whether all the lesions are related more to focal polymicrogyria than to pachygyria. Indeed, the descriptive term macrogyria is sometimes used to describe the MRI appearance. Based on the cytological features, these lesions appear to represent not only disturbances of late neuronal migration but also abnormalities of proliferative and organizational events. The clinical syndromes have been dominated by seizure disorders (Table 2-23) and relate in considerable part to the topography of the lesions. The seizure disorders usually begin after the neonatal period. However, in two large series, neonatal seizures occurred in approximately 35% of cases of Taylor-type focal cortical dysplasia. Notably, among the 19 patients without balloon cells, approximately 60% had neonatal onset, whereas only 15% of the 15 patients with balloon cells exhibited neonatal seizures.538,541 Agenesis of the Corpus Callosum, Abnormality of Septum Pellucidum, and Colpocephaly Agenesis of the corpus callosum is a common accompaniment of the major disorders of neuronal migration, as noted in the previous discussions of the specific disorders. The reasons for the relationship are at least twofold. First, the timing of callosal formation and that of neuronal migration are nearly coincident (see discussion of midline prosencephalic development in Chapter 1). Second, the disturbance of neocortical development caused by the migrational failure is followed by a deficiency in corticocortical fibers destined for the callosum. The first of these reasons may explain the additional frequent accompaniment of neuronal migrational disorder with absence or hypoplasia of the septum pellucidum or persistently wide cavum of the septum pellucidum. Colpocephaly, the disproportionate enlargement of trigones, occipital horns, and usually temporal horns of the lateral ventricles, also is a frequent accompaniment of neuronal migrational disorders. As discussed previously (see lissencephaly), the enlargement of the trigones and occipital horns stems from failure of development of the splenium of the corpus callosum and the calcarine fissure, and the enlargement of the temporal horns results from failure of inversion of the
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TABLE 2-23
HUMAN BRAIN DEVELOPMENT
Major Clinical Syndromes Associated with Focal Cerebral Cortical Dysplasia*
Site of Dysgenesis
Clinical Syndromes
Frontal, temporal, or parietal Temporal (hippocampus) Left frontotemporal Frontal (rolandic) Bilateral perisylvian Occipital
Complex or simple partial seizures, hemiparesis (frontal lesions) Neonatal (subtle) seizures, later multiple seizures, mental retardation Developmental dyslexia Focal myoclonus, focal clonic seizures, hemiparesis Facial diplegia, dysarthria-dysphagia, generalized seizures, mental retardation Congenital hemianopia
*See text for references.
hippocampus, normally provoked by full neocortical development.42,363,542 Disproportionate enlargement of the trigone and occipital horns of the lateral ventricles can be observed in any destructive disorder with particular involvement of periventricular white matter, such as periventricular leukomalacia, other encephaloclastic processes, or any developmental disorder associated with impairment of myelination (see later discussion of myelination).543-547 Because the ventricular dilation associated with these diverse processes is also often characterized as colpocephaly, the term has lost distinctive meaning. ORGANIZATION Normal Development Organizational events occur in a peak time period from approximately the fifth month of gestation to several years after birth. However, these complex processes may continue for many more years in human cerebrum. The major developmental features include the following: (1) establishment and differentiation of the subplate neurons; (2) attainment of proper alignment, orientation, and layering of cortical neurons; (3) elaboration of dendritic and axonal ramifications; (4) establishment of synaptic contacts; (5) cell death and selective elimination of neuronal processes and synapses; and (6) proliferation and differentiation of glia (Table 2-24). These events are of particular importance because they establish the elaborate circuitry that distinguishes the human brain, and they set the stage for the final developmental event, myelination. Subplate Neurons The importance of the subplate neurons in cerebral organizational events was defined by an elegant series
TABLE 2-24
Organization
Peak Time Period 5 months’ gestation–years postnatal Major Events Subplate neurons: establishment and differentiation Lamination: alignment, orientation, and layering of cortical plate neurons Neurite outgrowth: dendritic and axonal ramifications Synaptogenesis Cell death and selective elimination of neuronal processes and of synapses Glial proliferation and differentiation
of studies both in experimental animals and human brain.266,548-565 Cells destined to be subplate neurons are generated in the germinative zones and migrate both radially and tangentially to the primitive marginal zone at approximately 7 weeks of gestation before generation and migration of neurons of the cortical plate (Fig. 2-39 and Table 2-25). Initially, these cells are part of the preplate that is split by approximately 10 weeks of gestation by the developing cortical plate into the subplate neurons below and the Cajal-Retzius neurons of the marginal zone above. (The cortical plate neurons give rise to layers II through VI of the cerebral cortex.) The subplate neurons rapidly exhibit morphological differentiation and express a variety of receptors for neurotransmitters (GABA, excitatory amino acids), neuropeptides, and growth factors (nerve growth factor, neuropeptide gamma, somatostatin, calbindin). The subplate neurons elaborate a dendritic arbor with spines, receive synaptic inputs from ascending afferents from thalamus and distant cortical sites, and extend axonal collaterals to overlying cerebral cortex and to other cortical and subcortical sites (thalamus, other cortical regions, corpus callosum). The functions of the subplate neurons now appear to be particularly far-reaching (see Table 2-25).548-556,559561,563-565 Thus, they provide a site for synaptic contact for axons ascending from thalamus and other cortical sites, termed waiting thalamocortical and corticocortical afferents because their neuronal targets in the cortical plate have not yet arrived or differentiated. These afferents presumably would undergo degeneration if they did not have the subplate neurons as transient targets. Moreover, the subplate neurons have been shown to establish a functional synaptic link between these waiting afferents and their cortical targets. This link could exert a trophic influence on the cortical neuronal targets by the release of neuropeptides or excitatory amino acid neurotransmitter by the subplate axon terminals. A third function appears to be the guidance by subplate axons entering cerebral cortex of the ascending axons to their targets. Indeed, if the subplate neurons are eliminated, thalamocortical afferents destined for the overlying cortex fail to move superiorly into the cortex at the appropriate site and continue to grow aimlessly in the subcortical region. A fourth function of subplate neurons is involvement in cerebral cortical organization; for example, ocular dominance columns in visual cortex fail to develop if underlying subplate neurons are eliminated during development. Related to this role is the importance for subplate neurons in cortical synaptic development and function. A fifth
Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
83
I II I III
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MZ CP
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SPP
IZ
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SV V 10.5 wk
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Figure 2-39 Schematic summary of development of the human prefrontal cortex. At the earliest age studied (10.5 weeks), the preplate zone has been split by the early-arriving neurons of the cortical plate into neurons of the marginal zone (MZ) above and of the subplate zone (SP) below. Note the exuberant neuronal development of the subplate zone into the third trimester of gestation. CP, cortical plate; IZ, intermediate zone; SPL, subplate zone (lower); SPP, subplate-preplate zone; SPU; subplate zone (upper); SV, subventricular zone; V, ventricular zone; WM, white matter. (From Mrzljak L, Uylings HBM, Kostovic I, et al: Prenatal development of neurons in the human prefrontal cortex. I. A qualitative Golgi study, J Comp Neurol 271:355-386, 1988.)
function appears to be mediated by the descending axon collaterals from the subplate neurons; these collaterals appear to ‘‘pioneer’’ or guide the initial projections from cerebral cortex toward subcortical targets (e.g., thalamus, corpus callosum, and other cortical sites). TABLE 2-25
Importance of Subplate Neurons in Development of Cerebral Cortex
Natural History SPNs are generated and migrate beneath the pial surface as part of the preplate before generation and migration of neurons of the cortical plate. Early-arriving cortical plate neurons split the preplate into the overlying marginal zone and the subplate. SPNs rapidly exhibit morphological differentiation and transiently express a variety of receptors for neurotransmitters and growth factors. SPNs elaborate a dendritic tree, receive synaptic inputs, and extend axonal projections to cortical and subcortical sites. The zone of SPNs is most prominent between approximately 22 and 34 weeks of gestation. Approximately 90% of SPNs undergo programmed cell death postnatally. Functions Site of synaptic contact for ‘‘waiting’’ thalamocortical and corticocortical afferents before formation of cortical plate Functional link between ‘‘waiting’’ afferents and cortical targets Axonal guidance into cerebral cortex for ascending afferents Involvement in cerebral cortical organization and synaptic development ‘‘Pioneering’’ axonal guidance for projections from cortex to subcortical targets SPN, subplate neuron.
Concomitant studies of subplate neurons of developing human cerebral cortex provide a crucial link with the experimental studies (see Fig. 2-39; Fig. 2-40).559,561-563,565-569 The subplate neuron layer in human cortex reaches a peak between approximately 24 and 32 weeks of gestation. At this peak time, the width of the subplate is approximately four times that of the cortical plate. Programmed cell death (apoptosis) of this layer appears to begin generally late in the third trimester, and approximately 90% of subplate neurons have disappeared after approximately the sixth month of postnatal life. Slightly different time courses for peak development and regression of the subplate neurons exist for somatosensory and visual cortices. Clearly, the time periods when the functions of the subplate neurons must be operative in the developing human brain correspond closely to the times of occurrence of a variety of periventricular hemorrhagic and ischemic lesions (see Chapters 9 and 11). If these lesions disrupt the subplate neurons or their axonal collaterals to subcortical or cortical sites, the functions described earlier would be impaired, and the impact on cortical neuronal development and on a variety of crucial projection systems could be enormous. Indeed, the major portion of the striking increase in cerebral cortical volume in the last trimester of gestation consists of the extensive elaboration of the afferent fibers, previously ‘‘waiting’’ in contact with subplate neurons, as they enter the cerebral cortex.559 As noted later, this increase in cerebral cortical volume is blunted by injury to cerebral white matter in the premature infant. Lamination and Neurite Outgrowth Attainment of the proper alignment, orientation, and layering of cortical neurons (i.e., lamination) occur as neuronal migration ceases. These events are among
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MZ
MZ
CP CP
SP
SP
WM
WM
A
B
Figure 2-40 Cytoarchitectonics of the subplate zone in the visual area. Shown are, A, an 18-week old human and, B, a E78 monkey fetus displayed in plastic sections 1 mm thick. The subplate zone (SP) is characterized by low cell density and presence of mature neurons. The border between the subplate zone and the white matter (WM) is relatively sharp because of the presence of well-delineated fiber bundles (arrows) in the white matter. External limit of fibers is marked by the arrowhead. Note remarkable similarities between the lamination pattern and the cortical plate (CP)–subplate thickness ratio in man and monkey. The bar (= 100 mm) applies to both illustrations. MZ, marginal zone. (From Kostovic I, Rakic P: Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain, J Comp Neurol 297:441-454, 1990.)
the earliest in cortical organization.5,570-572 Neurite outgrowth (i.e., the elaboration of dendritic and axonal ramifications) next becomes the dominant developmental activity in the cerebral cortex. The most significant early studies of neurite outgrowth in human cerebral cortex were made in 1939 by Conel,573 whose Golgi-Cox preparations of cerebral cortex from birth to 2 years of age demonstrated progressive enrichment of the dendritic and axonal plexus, with much smaller increases in size and no proportionate increases in number of individual neurons. The remarkable elaboration of dendritic branching that results can be seen in the cerebrum of a normal child, shown in Figure 2-41. The studies of Mrzljak and coworkers566 showed similar events in frontal cortex before birth (see Fig. 2-39). Accompanying the elaboration of dendritic and axonal ramifications are the appearance of synaptic elements, the development of neurofibrils, and an increase in size of endoplasmic reticulum within the cytoplasm of cells. The biochemical correlates of these changes are increasing cerebral content of RNA and protein relative to DNA. Immunocytochemical studies document parallel expression of a variety of neurotrophins, neurotransmitters (NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]/kainate, GABA, and glycine receptors), surface glycoconjugates, and cytoskeletal components.574-587 The maturational changes occur relatively rapidly in the hippocampus, whereas
they occur over a more protracted period in the supralimbic region; the latter, of course, is of great significance, because it is the locus of the major association areas. Dendritic development in the human occurs earlier in thalamus and brain stem than in cerebral cortical regions.588,589 These findings were amplified by studies by Purpura, Huttenlocher, Marin-Padilla, Rakic, and other investigators, who used electron microscopic and immunocytochemical methods as well as Golgi techniques.566,569,582-586,590-601 One study of developing human brain demonstrated the strikingly active axonal development in the cerebrum over the last trimester of gestation and in the early postnatal period (Fig. 2-42).586 Thus, immunostaining with GAP-43, a protein expressed on growing axons, shows exuberant expression in the cerebral white matter to approximately the subplate region at 20 weeks, to the cortical plate at 27 weeks, within the cortex at 37 weeks, and into the first year of life. This differential pattern may reflect, at 20 weeks, growth of axons from thalamus to subplate neurons, and at 27 weeks, from subplate neurons to cerebral cortex. At 37 weeks, the increase in cerebral cortical expression of GAP-43 may reflect the increase in cortical penetration of thalamic ascending fibers no longer waiting at the subplate layer, in corticocortical fibers, and in descending cortical fibers, initially pioneered by subplate axons (see earlier). These findings are consistent with more recent studies with different techniques by
Chapter 2
Figure 2-41 Golgi preparation (80) of the middle frontal gyrus from a 6-year-old child without known neurological disease. Note the abundant and complex horizontal and tangential dendritic branches. (From Buchwald NA, Brazier MAB, editors: Brain Mechanisms in Mental Retardation, New York: 1975, Academic Press.)
Kostovic and co-workers.565 Although more data are needed on these issues, it is clear that the last trimester of human gestation is a period of rapid axonal development. The relationship between neurite outgrowth in cortex and development of functional capacity can be illustrated in human visual cortex during the third trimester (Fig. 2-43). Most impressive are the appearance and elaboration of basilar dendrites and the tangential spread of apical dendrites. This dendritic development is accompanied by the appearance of dendritic spines, that is, sites of synaptic contact (see the discussion of synaptic development). These anatomical expressions of differentiation are paralleled by the neurophysiological expression of maturation of the visual evoked potential (see Fig. 2-43). Such detailed relationships between dendritic structural development and specific details of neurophysiological development have been studied in depth in developing animals.602 The progress of dendritic differentiation depends on the establishment of afferent input and presumably synaptic activity.294,566,574,580,581,590,603-608 In certain developing neural systems, the importance of receiving and making proper connections has been emphasized as highly critical for further organization. At least part of the influence of these connections is mediated by the functional activity generated through them (see the earlier discussion of subplate neurons).609-612 This role of functional activity has implications for the effects of a variety of environmental stimuli on the postnatal
Neuronal Proliferation, Migration, Organization, and Myelination
85
progress of organizational development.574,580 Neuronal activity initiates its effects on dendritic development by inducing calcium influx, both through activation of glutamate receptors, principally the NMDA receptor, but likely also GluR2-deficient AMPA receptors (see Chapter 6), and by opening of voltage-dependent calcium channels.606,607 The calciummediated effects include both a direct impact on the actin and microtubular components of the cytoskeleton and on several adhesion molecules and major indirect effects by activating multiple signaling pathways that target nuclear transcription factors and thereby many genes involved in dendritic development. Studies of developing human cerebral cortex show transient exuberant expression of calcium-permeable glutamate receptors in cortical neurons during this perinatal period.613,614 A striking increase in cerebral cortical volume accompanies these developmental changes in cortical neurons. That this phenomenon is particularly rapid in the human infant from approximately 28 to 40 weeks after conception has been shown by quantitative MRI measurements of cortical gray matter volumes.615 Thus, a fourfold increase in cerebral cortical gray matter volume could be documented (Fig. 2-44). The changes in cortical gyral development and cortical surface area that accompany and presumably are caused by the increase in cortical volume can be seen by MRI (Fig. 2-45).616 Advanced diffusion-based MRI imaging known as tractography provides further insight into the changes in fiber tract development in the living premature infant.617 Synaptic Development Synaptic formation differs appreciably among regions in the human brain. The number of dendritic spines, the sites of synaptic contacts, in the medullary reticular formation reaches a peak at 34 to 36 weeks of gestation and declines rapidly after birth (see the later discussion of disorders of organizational events).618 In the cerebrum, synapses are observed initially on neurons of the subplate and of the marginal zone (i.e., neurons of the primitive preplate). For example, in the hippocampus, synapses in these regions are abundant as early as 15 and 16.5 weeks of gestation (Table 226).619 With Golgi preparations, Purpura and co-workers595-598,620 defined the subsequent progression of dendritic spine development in the human cortex from the fifth month of gestation (Fig. 2-46). Initially, dendrites appear as thick processes with only a few fine spicules. As development progresses, a great number and variety of dendritic spines appear. In the visual cortex, synaptogenesis is fastest between 2 and 4 months after term, a time also critical for the development of function in the visual cortex, and maximal synaptic density is attained at 8 months (Fig. 2-47).598,620 Synapse elimination then begins, and by age 11 months, approximately 40% of synapses have been lost. In the frontal cortex, the time course of synaptic formation and of elimination differs somewhat from that in the visual cortex; maximal synaptic density is reached at approximately 15 to 24 months, and
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A
B
C
D
Figure 2-42 GAP-43 expression in developing human parietal white matter and cortex. The cortex is indicated by an asterisk. A, Note, at 20 postconceptional (PC) weeks, evidence for strong expression in the subcortical white matter to a region below the cortical plate, possibly the concentration of subplate neurons. B, At 27 PC weeks, the expression begins to enter the cerebral cortex. C, By 37 PC weeks, diffuse expression in cortex and decreased expression in white matter are apparent. D, At 144 PC weeks (i.e., 2 years of age), expression is prominent in cortex but not in white matter (sections (40; bars = 200 mm). See text for interpretations. (From Haynes RL, Borenstein NS, DeSilva TM, Folkerth RD, et al: Axonal development in the cerebral white matter of the human fetus and infant, J Comp Neurol 484:156-167, 2005.)
synapse elimination, although reaching the same loss of 40%, is more gradual.620,621 In the prefrontal cortex, synapse elimination extends into midadolescence.621 Elegant studies in the monkey exhibit more uniformity in the temporal features of synaptogenesis among cortical regions, but the basic principles are formation of earliest synapses in the marginal and subplate zones, an increase in synapses in cortical plate to a peak in excess of the adult number, and a subsequent period of synaptic elimination.622-625 The factors that stimulate synaptic formation and development in developing brain initially include activity-independent events (i.e., molecular mechanisms involved in targeting), followed by activity-dependent events occurring after the development of receptors on target neurons and the generation of electrical activity (see the previous discussion on neurite outgrowth).574,580,603,626-629 Many molecules and signaling pathways are involved in dendritic spine development and remodeling. The two principal themes are modulation of the following: (1) ion channels, especially calcium-permeable channels, by neurotransmitters, especially glutamate; and (2) cell surface receptors by a variety of ligands. The intracellular events lead ultimately to effects on actin-binding proteins and the actin cytoskeleton, with resulting changes in spine shape, size, and motility.629 The importance of synaptogenesis and synapse elimination in the plasticity of the developing nervous system and in the potential
effect of experiential factors on developing neural function, including cognitive function, could be enormous. Cell Death and Selective Elimination of Neuronal Processes and Synapses Cell death and selective elimination of neuronal processes and synapses, or ‘‘regressive events’’ in brain development, are now recognized to be highly critical (see Table 2-24).572,598,630-644 Results of studies in a variety of developing neuronal systems showed that after formation of neuronal collections by the ‘‘progressive’’ processes of proliferation and migration, cell death occurs.572,634,638-645 Although variable in degree among neuronal regions, typically about half of the neurons in a given collection die before final maturation. This process of cell death is initiated and sustained by the expression of specific genes and their transcription products that actively kill the neuron.634,638,641,643 Critical in the final phases of the sequence to cell death is the activation of a family of cysteine proteases, known as caspases.643 The term programmed cell death has been used to emphasize that this is an active developmental process, although more commonly the term apoptosis, a Greek-rooted word referring to the naturally occurring seasonal loss or falling of flowers, is used to refer to this developmentally determined cell death.572,634,638,639,641-644 The factors that activate this death system appear to relate to competition of neurons for limited amounts of
Chapter 2
O2
Neuronal Proliferation, Migration, Organization, and Myelination
Vi 25 wk 580 g +
Co 27 wk 710 g +
Sb 32 wk 1330 g +
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Figure 2-43 Camera lucida composite drawings of neurons in the visual (calcarine) cortex of human infants of indicated gestational ages. Note the appearance and elaboration of basilar dendrites and the tangential spread of apical dendrites, as well as the accompanying maturation of the visual evoked response (top). (Courtesy of Dr. Dominick Purpura.)
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Figure 2-44 Cerebral cortical gray matter volume as a function of postconceptional age. Quantitative volumetric magnetic resonance imaging determinations of absolute cerebral cortical gray matter volume as a function of postconceptional age in a series (n = 35) of preterm and full-term infants. (From Huppi PS, Warfield S, Kikinis R, et al: Quantitative magnetic resonance imaging of brain development in premature and mature newborns, Ann Neurol 43:224-235, 1998.)
trophic factors, generated by the target, afferent input, or associated glia. This loss of neurons appears to serve two major functions in development: quantitative adjustments (numerical matching) of interconnecting populations of neurons and elimination of projections that are aberrant or otherwise incorrect (refinement of synaptic connections or error correction).633,634,638,640,641,646 Failure of cell death or overactivation of this process clearly could have major deleterious implications for brain development and subsequent function. Neural organization is refined further by a second regressive event, selective elimination of neuronal processes and synapses. This event primarily causes the removal of terminal axonal branches and their synapses, although even larger-scale elimination of a total pathway also occurs. Vivid demonstrations of synapse elimination are apparent in the developing brain stem and cortex of the human infant (see earlier). The determinants of selective elimination of neuronal processes and synapses are similar to those described for cell death. Activation of the NMDA type of glutamate receptor appears to be an important step in synapse elimination during development.637 An additional crucial role of the specific region of cerebral cortex in determining the pattern of selective elimination of its terminal axons was shown by studies with cortical transplants in developing rats.647 Thus, cortical neurons transplanted
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Figure 2-45 Measurements of cortical surface area and volume by advanced magnetic resonance imaging (MRI) (upper) and conventional MRI images of gyral development (lower) during the last 14 weeks of gestation. Data were derived from study of 113 preterm infants. (From Kapellou O, Counsell SJ, Kennea NL, Dvet L, et al: Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth, PLoS Med 3:e265, 2006.)
to another region of cortex (as explants) eliminated their distal axon collaterals in the same way as did neurons of the host cortical region (into which they were transplanted), rather than in the way neurons of the donor region eliminated their distal collaterals. The observations that cell death and elimination of neuronal processes and synapses occur during the organizational period of development have implications for the frequent demonstration that the plasticity of developing brain decreases as this period is completed.630,634,638,639,648-657 It is likely that the regressive events described in this section are modified when the brain is injured and that neuronal processes and synapses destined for elimination can be retained if needed to preserve function. In addition, new projections may develop in response to injury during the TABLE 2-26
Synaptic Formation and Elimination in Human Cerebral Cortex
First synapses involve the subplate neurons (e.g., 15–16week fetal hippocampus). Synaptogenesis in the cortical plate is most active postnatally. Approximately 40% of synapses are eliminated subsequently.
period in which the brain has the capacity to carry out organizational events. In favor of one or both of these predictions is the demonstration in both human infants and experimental models that, after neonatal cerebral lesions, ipsilateral corticospinal tract projections can be demonstrated and presumably can ameliorate the functional deficit.652-654,658-671 The demonstration of an ipsilateral corticospinal projection until early childhood in humans suggests that retention of a normally occurring ipsilateral corticospinal tract, which otherwise is eliminated during development, is the crucial event in this form of plasticity.654,662,672,673 The possible additional role of assumption of motor functions by ipsilateral cerebrum adjacent to the lesion is suggested by other studies.662,665,674 Glial Proliferation and Differentiation Astrocytes, oligodendrocytes, and microglia are the major glial cells of the CNS. Glial proliferation and differentiation are of major importance in developing brain; glial cells clearly outnumber neurons in the CNS. In fact, in human cerebral cortex, glial cells outnumber neurons by approximately 1.25 to 1 and are almost the exclusive cell type in white matter.675 Astrocytic and oligodendrocytic lineage, proliferation, and differentiation have been the topics of intense
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Glial Lineage and Differentiation in Forebrain
Astrocytes and Oligodendrocytes Astrocytes are generated primarily before oligodendrocytes. Astrocytic and oligodendroglial progenitors are principally subventricular cells and radial glia. Proliferation of these progenitors occurs at their sites of origin and locally (during and after migration). Microglia Microglia originate from bone marrow-derived monocytes. Sites of entry from the circulation include the ventricular and subventricular zones. Migration proceeds through the cerebral white matter during middle to late gestation and then to cortex near term.
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10 µm Figure 2-46 Camera lucida drawings of proximal apical dendritic segments of motor cortex pyramidal neurons during development. A, 18-week-old fetus; B, 26-week-old fetus; C, 33-week-old preterm infant; D, 6-month-old infant; E, 7-year-old child. The early phase of dendritic spine differentiation in proximal apical segments is associated with the development of long, thin spines and relatively few stubby and mushroom-shaped spines. The latter two types are prominent in the postnatal period and early childhood. (Courtesy of Dr. Dominick Purpura.)
investigation in experimental systems in recent years,237,676-711 and initial data also are emerging from studies of human brain.577,676,700,712-725 The observations are not entirely consistent, but my best attempt at a synthesis is shown in Table 2-27. In general, astrocytes are generated primarily before oligodendrocytes. The progenitors of both astrocytes and oligodendrocytes initially are cells of the subventricular 8
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Figure 2-47 Synaptic density in layer I and layer II/III of the striate cortex. Open circles represent layer I; closed circles represent layer II/ III. Note the striking increase in the first postnatal year and the subsequent decline. (From Huttenlocher PR, de Courten C: The development of synapses in striate cortex of man, Hum Neurobiol 6:1-9, 1987.)
zone and probably radial glia (see the earlier discussion of proliferation). Radial glial progenitors may give rise to a glial restricted progenitor that then generates astrocytes or oligodendrocytes. Proliferation of glia, unlike that of neurons, also may occur locally, during and after migration. Astrocytes play a variety of complex nutritive and supportive roles in relation to neuronal homeostasis and in the reaction to metabolic and structural insults. For example, astrocytes avidly take up glutamate and convert it to glutamine by the action of the astrocyte-specific enzyme glutamine synthetase; this removal of glutamate from the extracellular space is crucial for protection against excitotoxic injury with ischemia, seizures, or hypoglycemia (see Chapters 5, 6, 8, and 12). Other functions include a wide variety of roles in inflammation, immune responses, production of trophic and neuroprotective factors (e.g., antioxidants), and tissue remodeling after injury.572 Oligodendroglial proliferation and differentiation are crucial for myelination and thus are discussed later in relation to that major developmental event. Microglia comprise the resident and immune cells of the brain and originate principally if not entirely from bone marrow–derived monocytes.572 These cells enter the CNS (especially brain stem and spinal cord) in the first trimester, and in the cerebrum microglia become apparent in the second trimester within the marginal zone, the boundary of the cortical plate and subplate, and the ventricular-subventricular zones (see Table 227).726-732a A study of developing human cerebrum from 20 weeks of gestation made the striking observation that microglial cells during the second and third trimesters were primarily in the active (ameboid morphology) state and could be seen to migrate progressively from ventricular-subventricular zones to the cerebral white matter (20 to 35 weeks) and then to the cerebral cortex.733 Migration may occur along white matter tracts, radially oriented vasculature, and residual radial glial cells.729,733 Although the prevailing notion is that these cells enter the ventricular-subventricular zones through the circulation, whether any of these cells may originate in the ventricular-subventricular zones is unresolved. The critical point is that the cerebral white matter is heavily populated with activated microglia during a period when developmental events are active and a
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variety of insults can lead to white matter injury (see Chapters 6 and 8). Microglial cells play key roles during brain development, involving vascularization,729 apoptosis,644 axonal development,586 and later myelination.734 In addition to these key beneficial roles, these cells, when activated by such insults as hypoxia-ischemia or infectioninflammation, can release such substances as cytokines and reactive oxygen and nitrogen species, which could injure, as ‘‘innocent bystanders,’’ differentiating oligodendrocytes of the premature infant or neurons of the term infant (see Chapter 6). DISORDERS The normative data just reviewed define a critical period in brain development that includes the perinatal period. Unfortunately, little is known about disorders of this phase of neural maturation. This ignorance is caused primarily by the inadequacy of standard neuropathological techniques to evaluate the complex circuitry and synaptic connections of human brain. Earlier, only a few studies using appropriate techniques, such as the Golgi method for staining neuronal processes, were available, and it was often not clear whether the changes observed were primary or secondary, or specific or nonspecific. Although the latter uncertainties often persist, in recent years the advent of advanced immunocytochemical methodologies, the delineation of molecular genetic defects, and the use of genetically manipulated animals provided new insights into the identity and the basis of organizational disorders. Moreover, MRI techniques (e.g., quantitative volumetric MRI, diffusion tensor MRI, and functional MRI) are clarifying these issues in the living infant (see later discussions and Chapter 4). In Table 2-28, disorders are classified according to whether deficits in organizational events appear to be the most significant TABLE 2-28
neuropathological lesion (primary disturbance), a likely but not entirely proven lesion (potential disturbance), or an associated lesion (associated disturbance). Primary Disturbance Mental Retardation with or without Seizures. Several studies in which the Golgi technique was used showed abnormalities of development of dendritic branching and spines in children with idiopathic mental retardation with or without seizures.594,595,735739 The children in these studies had no anatomical evidence for destructive disease, metabolic disorder, or other developmental aberration (see Table 2-28). Huttenlocher,594,738 using the Golgi technique and quantitative estimation of dendritic branching, initially studied 11 brains from individuals with severe mental retardation of unknown cause. In six of these brains, severe defects in the number, length, and spatial arrangement of dendritic branching and in dendritic spines, the sites of synaptic contacts, were demonstrated. The relative sparsity of horizontal and tangential dendritic branches is shown clearly in Figure 2-48. Four of the six affected children with marked dendritic abnormalities had, in addition to severe mental retardation, histories of infantile myoclonic seizures and hypsarrhythmic EEGs.594,738,739 Moreover, Purpura595,735 demonstrated, in a cerebral biopsy specimen of a severely retarded infant, marked abnormalities of dendritic spines, characterized principally by a marked
Disorders of Organization
Primary Disturbance Mental retardation (idiopathic), with or without seizures Fragile X syndrome Rett syndrome Infantile autism Down syndrome Angelman syndrome Duchenne muscular dystrophy Other rare disorders Potential Disturbance Premature infants Periventricular leukomalacia Postnatal dexamethasone Hypothyroxinemia Ventilator dependence Nutrition and breast-feeding: long-chain polyunsaturated fatty acids Experiential effects Other perinatal and postnatal insults Associated Disturbance Diverse (see text)
Figure 2-48 Golgi preparation (80) of the middle frontal gyrus from a 10-year-old child with severe mental retardation of unknown origin. Note the relative sparsity of horizontal and tangential dendritic branches (compare with Fig. 2-41). (From Buchwald NA, Brazier MAB, editors: Brain Mechanisms in Mental Retardation, New York: 1975, Academic Press.)
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10 m Figure 2-49 Camera lucida drawings of dendritic segments of motor cortex neurons, rapid Golgi preparations, from a normal infant and a mentally retarded infant. A, From a normal 6-month-old infant: 1 and 2, proximal apical dendritic segments with a predominance of stubby and mushroom-shaped spines; 3 and 4, distal apical dendritic segment and basilar dendritic segment with many more thin spines. B, From a 10-monthold infant with mental retardation of unknown origin: 1, 2, 3, proximal apical and, 4, basilar dendritic segments. Note the presence in the proximal segments (1, 2, 3) of many long, thin spines, comparable to the appearance of the cortex in normal preterm infants (see Fig. 2-39). (Courtesy of Dr. Dominick Purpura.)
reduction in short, thick-necked spines (Fig. 2-49). This finding was the only detectable defect in the biopsy specimen and after extensive clinical and laboratory studies yielded negative results. Insight into a major mechanism in the production of such defects was provided first by the work of Purpura and co-workers.736,737 Golgi studies of cerebral cortex from five children with mental retardation and seizures (two in one family) demonstrated striking dendritic abnormalities, the most prominent of which was the formation of distinct varicosities along the dendritic
Figure 2-50 Camera lucida drawings of distal dendritic segments from an infant with mental retardation and seizures. Note the irregular varicosities of the dendritic segments. (From Purpura DP, Bodick N, Suzuki K, et al: Microtubule disarray in cortical dendrites and neurobehavioral failure. I. Golgi and electron microscopic studies, Brain Res 281:287-297, 1982.)
processes (Fig. 2-50). Ultrastructural studies showed an aberration of microtubules with loss of the usual parallel array of these structures. These findings indicated that a disturbance of cytoskeletal structures, so critical for maintenance of cell shape and for outgrowth of dendrites and axons, can cause a severe dendritic abnormality and marked neurological disturbance.737 More recent work has begun to delineate the molecular bases for at least some of these cases.629 X-linked genes have been shown to be particularly important, perhaps accounting in part for the higher incidence of mental retardation in male than in female patients.740,741 The greatest insight into X-linked mental retardation disorders involves fragile X syndrome and Rett syndrome (discussed subsequently). However, many other genes have been identified. Prominent among these are four X-linked genes found mutated in families with mental retardation that encode proteins known as Rho guanine nucleotide exchange factor 6 (ARHGEF6), oligophrenin-1, p21-activated kinase, and guanine dissociation inhibitor 1.741,742 These proteins are involved in signaling pathways that regulate the actin cytoskeleton, so critical for neurite outgrowth, dendritic spine formation and morphology, and neurotransmitter release. This rapidly evolving field may lead to insights into potential therapies. Rett Syndrome. Rett syndrome, a remarkable disorder observed in full form only in female patients, constitutes one of the most common causes of mental retardation in girls and women.743,744 The disorder is characterized clinically by onset of deceleration of rate of head growth in the first months of life, loss of purposeful hand movement near the end of the first year, and development of stereotypical hand movements, autism,
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ataxia, microcephaly, seizures, and mental retardation before the age of 5 years.745 The course is progressive until early childhood, when it becomes essentially static. The neuropathology consists of a small brain with an apparent disturbance of neuronal development, characterized by dendritic spine abnormalities (decreased spine density, simplified branching) and small, densely packed neurons.746-748 Disturbed synaptogenesis has been identified.749,750 The gene involved encodes an X-linked methyl-CpG-binding protein 2 (MeCP2) that selectively binds CpG dinucleotides and mediates transcriptional repression.744,750-752 The specific genes apparently not repressed in Rett syndrome and causing the neuropathological features remain to be determined. Initial data indicate a critical role of MeCP2 in regulation of activity-dependent dendritic growth and synaptic maturation.753 The disorder in its full form occurs only in female patients because of the predilection for the responsible mutations to occur in the paternal germline; thus, male children receive the paternal Y chromosome.752 (A rare male disorder secondary to MeCP2 defects is described in Chapter 16.) Infantile Autism. Infantile autism is a dramatic syndrome characterized by deficits in language and cognitive spheres and by behavioral abnormalities, particularly involving social interactions. Multiple causes are recognized, and indeed several of the organizational disorders delineated in this section cause pronounced autistic phenomena (e.g., fragile X syndrome, Rett syndrome). The neuropathology in infantile autism is characterized by microscopic neuronal abnormalities consistent with an organizational defect. Thus, the regions particularly affected are the frontal cerebral cortex (impaired columnar structure), limbic cortex (small neurons, increased density), cerebellum (reduced numbers of Purkinje cells), and cerebellar relay nuclei, such as the inferior olive (enlarged neurons in young patients and small neurons in adult patients).754-757a Additionally, evidence indicates brain overgrowth of postnatal onset that is most apparent in the first 2 years of life and is accompanied by relative macrocephaly.758-761 The basis of the latter is unclear, although the possibility of enhanced, albeit anomalous axonal growth has been raised.761 Overall, available data suggest a complex disturbance of principally neuronal organizational events. Down Syndrome. Striking abnormalities of dendritic and axonal development have been described in infants with Down syndrome.595,629,741,762-770 Significant aberrations of other aspects of brain development previously have not been consistently described in Down syndrome, and thus these well-defined organizational defects may represent the essential neuropathology of this common cause of mental retardation. The abnormalities in Down syndrome are alterations in cortical lamination, reduced dendritic branching, diminished dendritic spines and synapses, giant spines, and abnormal spine shape.595,741,762,764-770 Abnormalities are not apparent before 22 weeks of gestation (i.e., before the rapid progression of
organizational events). In the first months of postnatal life, an excess in dendritic branching precedes the consistent decrease observed after approximately 6 months of age. This sequence of excessive initial branching followed by deficits is similar to that seen in certain animal models of impaired dendritic development. Notably, neurons of layers II and IV, which use GABA as a neurotransmitter, are deficient in number, and this disturbance would be expected to result in decreased inhibitory activity (i.e., hyperexcitability) in the cerebral cortex in Down syndrome. Two additional factors favor hyperexcitability in the cortex in Down syndrome: the specific nature of the disturbances of ion channels and the shape of dendrite spines. Together with decreased inhibitory activity, these three factors may explain the 5% to 10% incidence of seizures in these patients.771,772 The demonstration of a defect in antioxidant capacity in Down syndrome neurons, with resulting free radical–mediated cell death, provides another important possible cause for the neuronal disturbance in Down syndrome.773 Fragile X Syndrome. Fragile X syndrome is the most common form of inherited mental retardation and is a disorder of male patients.774-778a The diagnosis was formerly based on the cytogenetic finding of a fragile site on the X chromosome, which is induced when cells are grown in medium with low folic acid and thymidine. Highly accurate direct DNA diagnostic testing is now widely available for identification of the fragile X syndrome.777 The molecular defect involves the presence of a large amplification of a trinucleotide repeat sequence in the fragile X gene (a similar genetic amplification involves the abnormal gene in myotonic dystrophy; see Chapter 19). The neuropathology is notable for abnormal dendritic spine morphology (Fig. 2-51) by Golgi analysis of neocortical neurons.741,776,778-780 The principal findings are an increase in long dendritic spines, fewer short spines, more immature-appearing spines, and fewer mature-appearing spines. The brain otherwise has no overt abnormalities. That the dendritic abnormality is related to the genetic defect is supported by the finding of similarly abnormal dendritic spines in fragile X gene (FMR1) knockout mice.778a,781-783 Thus, these observations may indicate that the crucial morphological disturbance in this common form of mental retardation involves cortical dendritic development. The mechanism of this disturbed development appears to relate to the obligatory role played by the fragile X mental retardation protein (FMRP) in controlling cytoskeletal organization during neuronal development.778a,784 Angelman Syndrome. Angelman syndrome, or happy puppet syndrome, is identified usually after the first 6 months of life, when the prominent findings are developmental delay, ataxia, seizures, hypotonia, paroxysms of laughter, postnatally developing microbrachycephaly, and a characteristic facial appearance with macrostomia and prognathia.785-797 The disorder is associated with a microdeletion of chromosome 15q11-13 (identifiable in 70% of cases), which is
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Figure 2-51 Composite camera lucida drawing of Golgi-stained, neocortical, apical dendrite in patients with fragile X syndrome. Note the long, tortuous spines with prominent terminal heads (a) and irregular dilations (b) admixed with an apparent decrease of normal short, stubby spines (c). (From Hinton VJ, Brown WT, Wisniewski K, Rudelli RD: Analysis of neocortex in three males with the fragile X syndrome, Am J Med Genet 41:289-294, 1991.)
the same site as the chromosomal defect in PraderWilli syndrome. The source of the abnormal chromosome in Angelman syndrome is the mother, and in the Prader-Willi syndrome, it is the father. The critical gene affected in Angelman syndrome appears to be UBE3A, the product of which functions in protein ubiquitination; the latter targets proteins for proteolysis and is crucial in brain development.798,799 This gene is imprinted in brain; only the maternal copy normally is expressed.799 A Golgi analysis of an affected woman showed a prominent decrease in dendritic arborization of pyramidal neurons in layers III and V and a significant decrease in the numbers of dendritic spines in apical layer III dendrites and basal layer V dendrites.800 No other definite neuropathological abnormalities were present in the cerebrum; thus, the morphological substrate for the mental retardation and, perhaps, seizures in this disorder may involve a defect in dendritic development. A second case showed an irregular distribution of cortical neurons of layer III, but Golgi analysis was not performed.801 More data are needed. Duchenne Muscular Dystrophy. A consistent feature of Duchenne muscular dystrophy is mild impairment of intellect. The neuropathological substrate for this disturbance is unclear. In careful studies of more than 30 patients by conventional neuropathology,802,803 no abnormality was recognized. However, Golgi study of cortical neurons in three patients revealed reduced length and branching of apical and basal dendrites of pyramidal neurons.803 This observation suggests that abnormal dendritic development and arborization may underlie the intellectual abnormality in this
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disease. The findings may be explainable by the demonstration that the absent protein in this disorder, dystrophin, is present normally not only in muscle but also in neurons.804,805 Because dystrophin is associated with the cytoskeletal network, which is crucial for dendritic outgrowth, the abnormalities defined by Golgi analysis may be related directly to the absence of dystrophin in neurons. Dystrophin has been shown to be absent in neurons in Duchenne muscular dystrophy,806 and initial data suggest that the absence of the brain isoforms of the gene are correlated with the severity of cerebral dysfunction.807 Other Disorders. Disorders that initial data suggest may be related to a primary disturbance of organizational events were the topic of two reports. Lyon and co-workers808 described three infants, including two sisters, with a severe congenital encephalopathy manifested by an absent or minimal response to sensory stimuli and profound weakness and hypotonia. At autopsy, the predominant finding was a marked deficiency of cerebral axons with an associated marked decrease in size of corpus callosum and cerebral white matter. Multiple axonal swellings were present in the remaining axons. These authors postulated a primary disorder of axonal development and suggested that ‘‘the anomaly may be due to extension of the normal phenomenon of axonal elimination, related to a primary defect of the cytoskeleton.’’ Disorders with somewhat similar findings have been reported.809,810 More data are clearly needed. Roessmann and co-workers described two infants with impaired motor development, with involvement of both bulbar and peripheral muscles and accompanying spasticity from the first days of life.811 The most prominent finding at postmortem examination was the absence of corticospinal tract fibers below the level of the internal capsule. The possibility exists that absent or disturbed signals from the targets of these axons during development result in failure of innervation and, as a consequence, secondary axonal elimination. A similar phenomenon may underlie the absence of pyramidal tracts in X-linked aqueductal stenosis, the genetic disorder in which this finding has been recorded most consistently.812 Potential Disturbance A growing body of data suggests that organizational events may be altered by a variety of common perinatal and postnatal events. Because morphological studies have been few, the possibility of an organizational disturbance currently can be regarded as potential, albeit likely. Premature Infants. Premature infants with cerebral white matter injury (i.e., periventricular leukomalacia), later exhibit diminished volume of cerebral cortex, a finding made by advanced volumetric MRI and suggesting a disturbance in cerebral cortical development (see Chapter 8).813 The cerebral cortical disturbance is also accompanied by diminished volume of thalamus and basal ganglia. The cortical disturbance does not
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Figure 2-52 Cerebral cortical gray matter volume. Cerebral cortical gray matter volume, determined by three-dimensional volumetric magnetic resonance imaging at term age, in 21 term infants, 98 premature infants without moderate to severe white matter injury (WMI), and 21 premature infants with moderate to severe WMI (nearly exclusively noncystic WMI). See text for details. (Redrawn from Inder TE, Warfield SK, Wang H, Huppi PS, et al: Abnormal cerebral structure is present at term in premature infants, Pediatrics 115:286294, 2005.)
Figure 2- 53 Cerebral cortical gray matter volume. Cerebral cortical gray matter volume, determined by three-dimensional volumetric magnetic resonance imaging at term age, in 14 term infants, 11 premature infants not treated with dexamethasone, and 7 premature infants treated with dexamethasone. See text for details. (Redrawn from Murphy BP, Inder TE, Huppi PS, Warfield S, et al: Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease, Pediatrics 107:217-221, 2001.)
require the relatively uncommon overtly cystic type of periventricular leukomalacia, but rather it occurs after the more common noncystic disease (Fig. 2-52) (see Chapters 8 and 9). The decreased cerebral cortical volumes have been noted by MRI volumetric studies performed as early as term equivalent,615,814-817a as well as later in childhood.818-824 The neuropathological substrate of the disturbed cerebral cortical volumetric development is unknown. Indeed, whether the volumetric changes reflect underdevelopment or atrophy after injury or a combination of dysgenetic and destructive influences remains to be elucidated. The cellular elements of concern are cerebral cortical neurons, underlying subplate neurons, descending and ascending axons in white matter, and neurons of deep nuclear structures, especially thalamus. These components constitute an interconnected interactive neuronal-axonal unit, and disturbance of one of the elements could lead to disturbance in cortical development, particularly at the levels of dendritic development and axonal ramification into the cortex, the two developmental events most responsible for the normal increase in volume of cerebral cortex over the third trimester (see earlier). The anatomical, mechanistic, and clinical issues related to this neuronal-axonal abnormality of prematurity are examined in detail in Chapters 8 and 9. Postnatal dexamethasone treatment of preterm infants may cause a disturbance in cerebral cortical neuronal organizational events (see Table 2-28).813 Glucocorticoids administered postnatally to premature infants are recognized widely to lead to a decreased incidence of bronchopulmonary dysplasia and to be associated with numerous short-term adverse systemic effects.825,826 Still more concerning, long-term adverse neurological effects have been identified.827-830 These observations led the American Academy of Pediatrics and the
Canadian Pediatric Society to recommend that systemic dexamethasone not be used routinely for prevention or treatment of chronic lung disease and that the use of corticosteroids in general be limited to ‘‘exceptional’’ clinical circumstances.827 Consistent with the neurological sequelae, a report of a small group of premature infants treated with high-dose dexamethasone showed, at term, a significant reduction in cerebral cortical gray matter volume quantitated by three-dimensional volumetric MRI (Fig. 2-53).831 These observations, reminiscent of those just discussed in relation to premature infants with periventricular white matter injury, raise the possibility of a disturbance in cerebral cortical development. Disturbances of dendritic and axonal development have been identified in nonhuman primates treated with dexamethasone early in development.832 Because nearly all studies of the adverse neurological effects of postnatal glucocorticoids have involved dexamethasone, a compound shown experimentally to impair neuronal development and potentially to enhance neuronal injury,826 the possibility of less or no neurotoxicity with the administration of other glucocorticoids has been raised. Four recent reports818,833,833a,833b suggested that hydrocortisone could be such an agent. In one large study, 60 preterm infants were evaluated at a mean age of 8 years by quantitative MRI. Twenty-five had been treated with hydrocortisone as newborns (mean age at onset, 18 days; dose, 5 mg/kg/day for 1 week; total duration after taper, 26 days), and 35 were not treated. At 8 years of age, cerebral cortical gray matter, white matter, and hippocampal volumes did not differ between the two groups, and scores on the Wechsler Intelligence Scale for Children also were similar. In a later report, hydrocortisone therapy had no subsequent adverse effect at school age on hippocampal metabolism (assessed by proton MRI spectroscopy) or short-term memory.833
Why may hydrocortisone therapy not be associated with long-term neurological deficits when dexamethasone is associated with such deficits? One possible contributing factor is that hydrocortisone in brain binds preferably to the mineralocorticoid receptor, whereas dexamethasone binds preferably to the glucocorticoid receptor.834,835 Activation of the glucocorticoid receptor leads to adverse neuronal effects.836,837 A possible contributory deleterious role related to the excitotoxic effects of sulfites contained in the dexamethasone preparation is suggested by in vitro studies.838 However, despite these interesting observations, the mechanisms of the neurological effects of dexamethasone in the premature newborn are likely still more complex and remain to be clarified. Although it is possible that the pharmacological doses of hydrocortisone used in the two studies showing no adverse effect818,833 may be preferable to dexamethasone, it will require a larger experience to ensure that the former steroid regimen is completely free of any adverse effects of cerebral cortical neuronal organizational events. Some studies suggested that the common transient hypothyroxinemia of premature infants is associated with subsequent cognitive disturbances and cerebral palsy.839-847 The neonatal thyroid deficit is more severe and prolonged and the adverse outcome is more pronounced in the most preterm infants.847 The value of neonatal therapy with thyroid hormone is unresolved. The anatomical substrate for these deficits is unknown, but abundant experimental data show that thyroid hormone is crucial for both neuronal and glial differentiation.848-852 The possibility that the cumulative effect of the adverse events associated with ventilator dependence in premature infants could play a role in a disturbance of organizational events was suggested by a careful anatomical study.618 Thus, in this Golgi study of the medulla oblongata of ventilator-dependent infants, decreased numbers of dendritic spines, abnormally thin dendrites, and long, thin dendritic spines were documented (Fig. 2-54).618 These abnormalities were not observed in premature infants who did not require mechanical ventilation. The potential causes of these disturbances of dendritic development were not clear. Nutrition, Long-Chain Polyunsaturated Fatty Acids and Breast-Feeding. The deleterious effects of infant undernutrition and the apparent beneficial effects of breast-feeding on cognitive development together suggest that nutritional factors can have an impact on organizational events (see Table 2-28).853-866 Longer-chain polyunsaturated fatty acids, which are especially abundant in neuronal and retinal membranes, are critical for neurological and retinal development, can have beneficial effects on neurological and visual function in infants, and are present in considerable amounts in breast milk relative to at least certain formula milks.860,867-880 Therefore, it is possible that one key determinant of these effects of breastfeeding on neuronal development is the level of such fatty acids in the infant’s diet.
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Experiential Effects. The potential impact of experiential factors in regulation of cortical organization is suggested by the demonstration that variations in maternal care or related alterations in the environment in experimental animals result in an increase in synaptogenesis.860,881,882 Particularly elegant experiments in normal and preterm monkeys showed that premature visual stimulation results in increases in size and proportions of various synapses, presumably by alterations in normal synaptic modification or elimination.883 Visual experience of premature infants is associated with an accentuation of the development of visual evoked potentials, a finding consistent with enhancement of dendritic and axonal development and synaptogenesis (see earlier).884 Additionally, a randomized clinical trial of an individualized developmental care program showed, at 9 months’ corrected age, improved neurobehavorial function, quantitative EEG evidence of enhanced maturation, and diffusion-tensor MRI evidence of more advanced cerebral fiber tract development.885 More data clearly are needed in these promising areas. Other Perinatal and Postnatal Insults. Because its time of rapid developmental progression coincides with the perinatal period, it is most reasonable to ask whether the very frequent specific insults that affect the human brain in the perinatal period (e.g., hypoxiaischemia, acidosis, intracranial hemorrhage, posthemorrhagic hydrocephalus, infection, and specific sensory deprivations or excesses) may exert serious consequences on these aspects of brain development. Considerable precedent for deleterious effects of various perinatal insults on organizational events is provided by studies with experimental animals.832,881,883,886-906 Initial studies of later cortical neuronal development in ‘‘undamaged’’ areas adjacent to ischemic cortical injury in human infants showed dendritic aberrations that could contribute importantly to subsequent cognitive deficits and epilepsy.907 It is a clinical truism
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Myelination
Peak Time Period Birth–years postnatally Major Events Oligodendroglial proliferation, migration, differentiation, and alignment ! myelin sheaths
that some children affected by one or more perinatal insults may exhibit neurological sequelae that are more severe than would be predicted from the extent of injury recognized by the usual brain imaging or neuropathological techniques. To what extent such sequelae are related to deficits in organizational development is a major topic for further research. Associated Disturbance In several carefully executed studies, defects in organizational events were demonstrated in such diverse disorders as congenital rubella,908 phenylketonuria,909 Rubinstein-Taybi syndrome,910 trisomy 13-15,911 trisomy 18,912 Zellweger syndrome,190 and maternal phenylketonuria syndrome (i.e., microcephalic child of a mother with phenylketonuria).913 It appears unlikely that the defects represent the major or primary developmental disturbance in these disorders. In two patients with congenital rubella, heterotopic neurons (i.e., a migrational defect) and significant retardation of myelination were also noted. In patients with phenylketonuria and Rubinstein-Taybi syndrome, a similar disturbance of myelination accompanied the cytoarchitectural disturbances of cerebral cortex. The most dramatic neuropathological disturbance in trisomy 13-15 involves prosencephalic cleavage (see Chapter 1).
OL Progenitor
Pre OL
A common feature of trisomy 18 is periventricular heterotopias, and a consistent feature of Zellweger syndrome is major disturbance of neuronal migration (see earlier). Maternal phenylketonuria syndrome is associated most commonly with microcephaly. Nevertheless, a contributory role for defects in cortical organization in the genesis of the neurological deficits in these and other disorders is suggested by the studies cited. MYELINATION Normal Development Myelination is characterized by the acquisition of the highly specialized myelin membrane around axons. The time period of myelination in the human is long, beginning in the second trimester of pregnancy and continuing into adult life.572,914-917 Myelination within the CNS, particularly the forebrain, generally progresses most rapidly after birth (Table 2-29). The process of myelination begins with proliferation of oligodendroglia, which align along axons. The plasma membranes of the oligodendroglia become elaborated as the myelin membrane of the CNS.572,701,710,915,918,919 Thus, myelination is considered best in two phases: first, oligodendroglial proliferation and differentiation, and second, myelin deposition around axons. Oligodendroglial Development The progression of the oligodendroglial lineage proceeds through four basic stages, beginning with the oligodendroglial progenitor and continuing successively with the preoligodendrocyte, the immature oligodendrocyte, and the mature oligodendrocyte (Fig. 2-55).699-701,708-710,718,721,722,920 Oligodendrocytes originate from progenitors in the subventricular zone
Myelinating
Premyelinating Migration
Proliferation A2B5 NG2
Mature OL
Immature OL
GalC (O1)
MBP
Sulfatide (O4)
GalC (O1) Sulfatide (O4)
Sulfatide (O4)
Figure 2-55 Progression of the oligodendroglial lineage (OL) through the four major stages. The predominant forms in the premature infant are the O4+O1 and O4+O1+ forms. See text for details. (From Back SA, Volpe JJ: Cellular and molecular pathogenesis of periventricular white matter injury, Ment Retard Dev Disabil Res Rev 3:96-107, 1997.)
Chapter 2
and also from radial glial progenitors (see earlier). The early phase in oligodendroglial lineage arising from progenitors is a mitotically active migratory cell recognized by the monoclonal antibodies A2B5 and NG2. This cell is generated from midgestation to the early postnatal period.699-701,718,721,722,921 As this cell migrates into the cerebral white matter, oligodendroglial differentiation proceeds to the preoligodendrocyte, a multipolar cell that retains proliferative capacity and is recognized by a monoclonal antibody to sulfatide (O4). The waves of migration of these cells may be the anatomical correlate of the periventricular bands visualized on MRI scans of the premature infant.922,923 The O4-positive preoligodendrocyte is the predominant oligodendroglial phase before term and accounts for 90% of the total oligodendroglial population until 28 weeks of gestation.721 The O4 cell differentiates into the postmitotic immature oligodendrocyte, a richly multipolar cell recognized by a monoclonal antibody to galactocerebroside (O1).699-701,718 The proportion of O1 cells among the entire oligodendroglial population rises from 5% to 10% before 28 weeks of gestation to 30% to 40% during the premature period and to approximately 50% at term. In the third trimester of gestation, the O1 cells can be observed to develop striking linear extensions as they wrap around axons in preparation for myelination. This premyelination encasement of axons contributes to an important MRI correlate, the increase in directionality of water diffusion measured as relative anisotropy (Fig. 2-56).707,924,925 This process is followed by differentiation to the mature 40
RA (%)
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0 26
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Figure 2-56 Diffusion tensor magnetic resonance imaging determination of relative anisotropy (RA) in the cerebral white matter of normal preterm (PT) and term (FT) infants (open circles) as a function of postconceptional age. Note the striking increase in RA, indicative of increasing directionality of diffusion, perhaps related at least in part to oligodendroglial ensheathment of axons, with maturation. The lower values of the preterm infants studied at term (closed circles) suggest a deleterious effect of prematurity on this process (see text for details). (From Huppi PA, Maier SE, Peled S, et al: Microstructural development of human newborn cerebral white matter assessed in vivo by diffusion tensor magnetic resonance imaging, Pediatr Res 44:584-590, 1998.)
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oligodendrocyte, a strikingly multipolar cell with membrane sheets and recognition by antibodies to myelin basic protein and proteolipid protein. This cell becomes the predominant oligodendroglial stage in the months following term and gives rise to myelination. The molecular determinants of this process include a variety of growth factors, hormones, cytokines, surface receptors, and secreted ligands.699-701,710,920,926-931a These molecules include basic fibroblast growth factor, neurotrophin-3, platelet-derived growth factor, insulin-like growth factors, nerve growth factor, transferrin, iron, members of the interleukin-6 family, thyroid hormone, neuregulin, erbB receptors, semaphorins, neuropilin receptors, ephrin, Eph receptors, Nogo, and Nogo receptors. Programmed cell death is an important feature of oligodendroglial development, as it is for neurons (see earlier). Data show that approximately 50% of oligodendroglia will undergo apoptosis during development.695,696 Myelination in Human Brain Regions The most informative of the anatomical descriptions of the progress of myelination in the human brain are those by Yakovlev and Lecours932 and Gilles, Kinney, and coworkers.916,917,933 Using the Loyez method for staining myelin, Yakovlev and Lecours defined the development of myelin in 25 areas of the human nervous system (Fig. 2-57). Because approximately 7 to 10 myelin lamellae are necessary for resolution by light microscopy, it is not surprising that electron microscopic data demonstrated that the onset of myelination in various brain areas occurs several weeks or more before the onset indicated in Figure 2-57. Nevertheless, the data shown from Yakovlev and Lecours932 provide important information. Several general points can be made on the basis of current knowledge. First, myelination begins in the peripheral nervous system, where motor roots myelinate before sensory roots. Second, shortly thereafter and before birth, myelin appears in the CNS in the brain stem and cerebellum in components of some major sensory systems (e.g., medial lemniscus for somesthetic stimuli; lateral lemniscus, trapezoid body, and brachium of the inferior colliculus for auditory stimuli) and in components of some major motor systems (e.g., corticospinal tract in the midbrain and pons and superior cerebellar peduncle). In general, however, and in contrast to the peripheral nervous system, myelination in central sensory systems tends to precede that in central motor systems.932 Third, myelination within the cerebral hemispheres, particularly those regions involved in higher level associative functions and sensory discriminations (e.g., association areas, intracortical neuropil, and cerebral commissures), occurs well after birth and progresses over decades. A study of 162 cases at a single children’s hospital provided further insight into the progress of myelination from prenatal life through childhood.572,916,917 General agreement exists between these data and those obtained by Yakovlev and Lecours932 with a smaller sample size. The median post-term age at
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2 yr 3 yr 4 yr
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IAK Inner div inf cereb ped AAK Outer div inf cereb ped Sup cerebellar ped Mid cerebellar ped Reticular formation
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3rd 10 yr 2nd Decade Decade
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8 9 10
7 yr
Frontopontine tract Fornix
?
Cingulum Great cerebral commissures Intracortic. neuropil., assoc. areas
?
Figure 2-57 Myelogenetic cycles in the human brain. The width and length of the graphs indicate progression in the intensity of staining and the density of myelinated fibers. The vertical strips at the end of the graphs indicate the approximate age range of termination of myelination. (Courtesy of Dr. Paul Yakovlev.)
which mature myelin was observed in selected brain areas in this study is depicted in Table 2-30. The similarity between these data and the findings made in vivo by MRI (see Chapter 4) is striking, although MRI showed myelin somewhat earlier, especially in the preterm infant (e.g., myelin in the posterior limb of the internal capsule at 36 postconceptional weeks versus 44 weeks in the anatomical study).934 This difference may relate to the ability of MRI to detect very early myelin wrapping. Five major general rules concerning cerebral myelination in the human can be derived from the elegant anatomical study of Kinney and co-workers: (1) proximal pathways myelinate before distal pathways, (2) sensory pathways myelinate TABLE 2-30
before motor pathways, (3) projection pathways myelinate before cerebral associative pathways, (4) central cerebral sites myelinate before cerebral poles, and (5) occipital poles myelinate before frontotemporal poles.572,917 The latter two points are illustrated in Figure 2-58. Overall, the fastest changes in myelination occurred within the first 8 postnatal months.917 Disorders Unequivocal documentation of developmental disturbances of myelin formation in the human has been hindered considerably by the inadequacy of standard neuropathological techniques in quantifying the
Median Age When Mature Myelin Is Reached
Brain Region
Posterior Frontoparieto-occipital Sites
Internal capsule Sensory radiation Corpus callosum
Posterior limb, 4 weeks* Optic radiation, 12 weeks Body, 20 weeks Splenium, 25 weeks Precentral gyrus, 30 weeks Posterior frontal, 40 weeks Posterior parietal, 59 weeks Occipital pole, 47 weeks
Central white matter
Anterior Frontotemporal Sites Anterior limb, 47 weeks Heschl gyrus, 48 weeks Rostrum, 47 weeks Temporal lobe, 79 weeks Temporal pole, 82 weeks Frontal pole, 79 weeks
*Age shown is post-term age at which 50% of infants attain mature myelin; for postconceptional age, add 40 weeks. Data from Brody BA, Kinney HC, Kloman AS, Gilles FH: Sequence of central nervous system myelination in human infancy. I. An autopsy study of myelination, J Neuropathol Exp Neurol 46:283-301, 1987.
Chapter 2 Central sulcus
I. Posterior frontoparieto-occipital sites
II. Anterior frontal sites
II. Temporal sites
Figure 2-58 Progression of myelination. This drawing of the cerebrum depicts the progression of myelination in telencephalic sites from the central sulcus outward to the poles, with the posterior sites preceding the anterior frontotemporal sites.
degree of myelination in brain. Moreover, the most commonly used brain imaging technique in the past, CT, provides little information concerning myelination in the human infant. The advent of MRI provided considerable capability for monitoring of myelination (see Chapter 4), and MRI is invaluable in defining disturbances of human myelination (see later). Of particular importance are quantitative volumetric MRI determinations and diffusion tensor MRI studies of relative anisotropy (see later). At least one series of cases does appear to qualify as representative of an inherited disorder of deficient myelination in the human cerebrum (see the following discussion). Moreover, the hypomyelination after cerebral white matter injury in the premature infant also is a clear example of hypomyelination. Additionally, amino acid and organic acid disturbances, hypothyroidism, and undernutrition in early infancy appear to impair brain development principally at the level of myelination. These several disorders are categorized in Table 2-31 as primary disturbances of myelination, that is, those in which the most significant neuropathological
TABLE 2-31
Disorders of Myelination
Primary Disturbance Cerebral white matter hypoplasia Prematurity Periventricular leukomalacia Other Amino and organic acidopathies Hypothyroidism Postnatal undernutrition 18q–syndrome Potential Disturbance Perinatal/early infancy insults Iron deficiency Associated Disturbance Diverse (see text)
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disturbance involves myelination. Disorders in which a derangement of myelination is an associated defect or is a likely but unproved lesion are categorized as associated or potential disturbances, respectively (see Table 2-28). (Leukodystrophies and degenerative disorders caused by aberrations of myelin or glial metabolism are described in Chapter 16.) Primary Disturbance Cerebral white matter hypoplasia. Chattha and Richardson935 reported the clinical and neuropathological features of 12 patients with severe intellectual impairment and spastic quadriparesis that were present from the first weeks of life but were nonprogressive. Pregnancy, labor, and delivery were essentially uneventful. Neurological deficits, particularly seizures, were apparent in the neonatal period. Subsequent neurological development was severely impaired. The unifying and outstanding neuropathological feature was a marked deficiency in cerebral white matter, most conspicuous in the centrum ovale (Fig. 2-59). Neurons were normal in appearance, and no gliosis, sign of inflammation, or other indication of a destructive process was present. An inherited developmental aberration in myelin formation was supported by the finding that the series included a set of three affected siblings, and in two other cases a family history of affected siblings was elicited. The biochemical basis of the disorder in myelin formation awaits elucidation. The use of MRI in evaluation of similar patients may lead to further delineation of this disorder. The cases are reminiscent of the murine mutants (e.g., ‘‘quaking’’ and ‘‘jimpy’’ mice) with deficient myelin formation.936,937 Recently, an autosomal recessive disorder with hypomyelination of the central and peripheral nervous systems, as well as congenital cataract, has been defined.937a The central nervous system hypomyelination was principally supratentorial. Definition of the molecular genetics of this disorder will be important. The decrease in cerebral white matter without evidence of destructive disease in the patients just described is similar to that recorded in the familial disorders of ‘‘axonal development’’ by Lyon and co-workers808 and others.809,810 In the latter cases, axonal abnormalities were identifiable, and this finding may be the crucial distinction from the cases of cerebral white matter hypoplasia. Prematurity. Premature birth may lead to subsequent impairment of developmental events related to myelination, especially as a sequel to periventricular leukomalacia (see Chapters 8 and 9). Periventricular leukomalacia results in injury to cerebral white matter, characterized most commonly (80% to 90% of cases) by a diffuse abnormality consisting of astrogliosis and injury to premyelinating oligodendrocytes.938-940 Fewer patients (10% to 20% of cases) also exhibit focal necrosis with loss of all cellular elements and with subsequent cyst formation (see Chapter 8). Either variety leads to hypomyelination documented by neuropathological study, the results of conventional brain imaging, including ultrasonography and MRI, and
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matter abnormality by term equivalent (see Chapters 8 and 9 for more details). Moreover, the finding of markedly lower relative anisotropy in cerebral white matter of premature infants at term when compared with white matter of term infants further suggests a disturbance of oligodendroglial development and subsequent myelination (see Fig. 2-56) (see earlier). Thus, currently available data indicate that subsequent hypomyelination of premature infants is a sequel to diffuse injury to cerebral white matter, specifically to premyelinating oligodendrocytes. Amino and organic acidopathies. A disturbance in myelination has been well documented in several amino acidopathies, such as maple syrup urine disease,954 phenylketonuria,909,955 homocystinuria,956 and nonketotic hyperglycinemia,956 as well as in organic acidopathies (ketotic hyperglycinemia) (see Chapters 14 and 15) (see Table 2-31).956 The earliest change is vacuolation of myelin, which then evolves to deficient myelination. The microscopic sequence is similar to that observed in mutant mice with deficient myelin formation (see earlier). The disturbance of myelination has been documented by MRI (see Chapters 14 and 15). The mechanisms by which an amino acid disturbance leads to impaired myelination are not clear, but one explanation could be a disturbance in synthesis of myelin proteins.957 The possibility that concomitant or preceding deficits in organizational events (e.g., elaboration of axonal ramifications, glial proliferation, or differentiation) are involved in the genesis of the myelin abnormality is raised by the organizational defects observed in phenylketonuria.909 On balance, however, current data suggest that the primary disturbance of brain development in these patients involves myelination. Figure 2-59 Cerebral white matter hypoplasia. Coronal sections of the cerebrum are stained for myelin (black). Note the marked diminution in cerebral myelin, including the corpus callosum. As a consequence of the myelin disturbance, ventricular size increases. (From Chattha AS, Richardson EP Jr: Cerebral white-matter hypoplasia, Arch Neurol 34:137-141, 1977.)
measurements of cerebral myelinated white matter volume, as early as term and later in childhood (see also Chapter 9).814,817,941-953 The myelination defect relates to a presumed loss of premyelinating oligodendrocytes that therefore do not differentiate to myelinproducing mature oligodendrocytes. Whether factors associated with prematurity, other than cerebral white matter injury, result in impaired myelination is unclear. Imaging studies of premature infants without signs of cystic periventricular leukomalacia demonstrate apparent disturbances in subsequent myelination.817,818 However, as noted earlier, cystic disease accounts for the minority of cases of cerebral white matter injury, and most available studies with later MRI in the neonatal period did not use imaging methodology or timing capable of identifying the more common noncystic disease. Indeed, when careful diffusion-based MRI was used in large cohorts of premature infants, nearly 80% exhibited signs of cerebral white
Hypothyroidism. A disturbance in myelination may be the principal neuropathological abnormality in congenital hypothyroidism (see Table 2-31). A substantial experimental literature documented impaired myelination with hypothyroidism, studied either in the intact animal or in cultured glial cells.958-961 The report of a hypothyroid infant who was carefully studied by MRI also suggests that the principal deleterious effect of congenital hypothyroidism and the beneficial effect of therapy thereof are on the progress of myelination.962 Moreover, data concerning the relation between timing of therapy and intellectual outcome suggest that the crucial period begins perhaps late in fetal life or in the first weeks of postnatal life.963-967 In addition, however, the amount of thyroxine in the first 2 years is correlated with intellectual outcome, a finding further implicating the time period of myelination or oligodendroglial proliferation-differentiation or both.968 Further data, particularly with quantitative MRI assessments of myelination, will be of interest. Finally, a disturbance of myelination is not likely to be the only important disturbance in congenital hypothyroidism, because experimental thyroid deficiency is known to impair neuronal differentiation (see earlier),969,970 also an active process during the time period of importance
Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
in congenital hypothyroidism. Moreover, the adverse effect of maternal hypothyroxinemia during early pregnancy on neonatal neurological function raises this possibility in the human.971 However, to my knowledge, no data are available on neuronal differentiation (e.g., Golgi analyses) in human infants dying with congenital hypothyroidism. The earlier discussion in the section on the deleterious effects of the transient hypothyroxinemia of the premature infant on organizational events and on subsequent cognitive and motor development is relevant here. Whether a defect in myelination occurs in that context remains to be established but is plausible in view of the crucial role of thyroid hormone in oligodendroglial differentiation, as noted earlier. Undernutrition. The effect of undernutrition in early infancy on brain development was discussed earlier in relation to disorders of organizational events. Relevant data in the context of myelination include the demonstration of a 20% to 30% reduction in cerebrosides and a 15% to 20% reduction in plasmalogens (important myelin lipids) in the cerebral white matter of malnourished infants.972 The composition of the myelin from these infants was found to be normal, and thus decreased formation of chemically normal myelin was postulated to occur in malnutrition.973 Results of a later study confirmed these findings.974 The observation of Chase and Martin975 that severe undernutrition to 4 months of age results in a permanent reduction in intelligence quotient may also be relevant in this context. Long-term follow-up studies of children undernourished in infancy generally confirm the deleterious effects on intelligence and school performance, although the roles of other factors related to deficient environmental stimulation, ‘‘social deprivation,’’ and confounding deleterious biological factors remain to be defined clearly.860,865,976-984 Nevertheless, the important effects of undernutrition in infancy on organizational events in the human suggest an important role for impaired neuronal differentiation or synaptogenesis as well. The developmental events particularly affected could relate principally to the timing of the insult. Deletion 18q Syndrome. A well-recognized syndrome caused by partial deletion of the long arm of chromosome 18 (18q) may include a primary disturbance of myelination (see Table 2-31). This disorder is characterized by postnatal microcephaly, dysmorphisms of the craniofacial region, limbs, and genitalia, and a neurological syndrome manifested by mental retardation, hypotonia, deafness, and aberrant behavior.73 Approximately 95% of affected patients exhibit disturbances of myelination, characterized by delayed onset of myelination, low rate of the process, and diminished final levels of myelin.985-987 The myelin disturbance, readily detected by MRI, apparently results because the deletion includes the gene for myelin basic protein.988 Myelin basic protein is a key structural protein of mature myelin and plays a major role in myelin accretion and compaction.
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Potential Disturbance Perinatal/Early Infantile Insults. As indicated for organizational events, the time of rapid developmental progression of myelination in human cerebrum includes the neonatal period, and indeed it proceeds most rapidly during a potentially ‘‘vulnerable’’ or ‘‘critical’’ period of the first 8 months of life (see Table 2-31) (see earlier). It is reasonable to ask whether perinatal insults, such as hypoxia-ischemia, metabolic disturbances, intracranial hemorrhage, posthemorrhagic hydrocephalus, and administration of various drugs, may exert serious consequences on this specific aspect of brain development. The initial positive MRI findings in premature infants discussed earlier are relevant in this context. Considerable precedent is available from studies in animals and cultured systems.989-998 Iron Deficiency. Iron deficiency in infancy, a very common disorder, is associated with cognitive, motor, and behavioral deficits that may be related to impaired myelination (see Table 2-31). Iron deficiency in this context is usually related to dietary deficiency but also to breast-feeding and prematurity.879,999,1000 Indeed, as many as 10% of infants 1 to 2 years of age in the United States and 15% of breast-fed Canadian infants exhibit iron deficiency. Because premature birth deprives the infant of the primary period of fetal iron deposition (i.e., the third trimester), the risks are still higher in these infants. Although the data are not entirely consistent, most studies show impaired motor, cognitive, and behavioral development in irondeficient infants.879,999-1003 Although the deleterious effects are generally modest, they may be irreversible if treatment is not prompt. Supportive of an effect on central myelination is the finding on studies of auditory and visual evoked potentials of prolonged latencies, without impairment of amplitudes.1001,1004,1005 The maturational decline in latencies relate to acquisition of myelin, whereas changes in amplitude relate more to neuronal development (see Chapter 4). Additionally supportive of an effect on myelination is the recognition of the crucial role of iron in myelination.710,879,999,1006 Moreover, transferrin concentrations in oligodendrocytes increase during myelination and reach a peak at the height of myelination. Finally, transferrin is involved in the regulation of the transcription of the myelin basic protein gene and has a synergistic enhancing effect on myelination with insulin-like growth factor I.710 Because iron plays a critical role in neurotransmitter metabolism, the neural effects of iron deficiency may extend beyond an impairment of myelination. Associated Disturbance Defects in myelination have been recorded in congenital rubella,908 Rubinstein-Taybi syndrome,910 and Down syndrome.1007 As reviewed previously, however, when careful studies of other aspects of brain development were performed, associated defects in such features as cortical organization were present. Whether the deficits
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Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
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HUMAN BRAIN DEVELOPMENT
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Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
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Unit I
HUMAN BRAIN DEVELOPMENT
634. Oppenheim RW: Cell death during development of the nervous system, Annu Rev Neurosci 14:453-501, 1991. 635. Koester SE, O’Leary DM: Functional classes of cortical projection neurons develop dendritic distinctions by class-specific sculpting of an early common pattern, J Neurosci 12:1382-1393, 1992. 636. Campbell G, Shatz CJ: Synapses formed by identified retinogeniculate axons during the segregation of eye input, J Neurosci 12:18471858, 1992. 637. Rabacchi S, Bailly Y, Delhayebouchaud N, Mariani J: Involvement of the N-methyl d-aspartate (NMDA) receptor in synapse elimination during cerebellar development, Science 256:1823-1825, 1992. 638. Ferrer I, Soriano E, Delrio JA, Alcantara S, et al: Cell death and removal in the cerebral cortex during development, Prog Neurobiol 39:1-43, 1992. 639. Oppenheim RW, Schwartz LM, Shatz CJ: Neuronal death, A tradition of dying i:1111-1115, 1992. 640. Janec E, Burke RE: Naturally occurring cell death during postnatal development of the substantia nigra pars compacta of rat. In Conn PM, editor: Molecular and Cellular Neurosciences, San Diego: 1993, Academic Press. 641. Allsopp T: Life and death in the nervous system, Trends Neurosci 16:1-4, 1993. 642. Narayanan V: Apoptosis in development and disease of the nervous system. I. Naturally occurring cell death in the developing nervous system, Pediatr Neurol 16:9-13, 1997. 643. Bergeron L, Yuan J: Sealing one’s fate: Control of cell death in neurons, Curr Opin Neurobiol 8:55-63, 1998. 644. Rakic S, Zecevic N: Programmed cell death in the developing human telencephalon, Eur J Neurosci 12:2721-2734, 2000. 645. Driscoll M, Chalfie M: Developmental and abnormal cell death in C. elegans, Trends Neurosci 15:15-19, 1992. 646. Catsicas S, Thanos S, Clarke PG: Major role for neuronal death during brain development: Refinement of topographical connections, Proc Natl Acad Sci U S A 84:8165-8168, 1987. 647. O’Leary DD, Stanfield BB: Selective elimination of axons extended by developing cortical neurons is dependent on regional locale: Experiments utilizing fetal cortical transplants, J Neurosci 9:2230-2246, 1989. 648. Kolb B, Whishaw IQ: Plasticity in the neocortex: Mechanisms underlying recovery from early brain damage, Prog Neurobiol 32:235-276, 1989. 649. Chugani HT, Muller R-A, Chugani DC: Functional brain reorganization in children, Brain Dev 18:347-356, 1996. 650. Nieman G, Grodd W, Schoning M: Late remission of congenital hemiparesis: The value of MRI, Neuropediatrics 27:197-201, 1996. 651. Lebeer J: How much brain does a mind need? Scientific, clinical and educational implications of ecological plasticity, Dev Med Child Neurol 40:352-357, 1998. 652. Staudt M, Gerloff C, Grodd W, Holthausen H, et al: Reorganization in congenital hemiparesis acquired at different gestational ages, Ann Neurol 56:854-863, 2004. 653. Johnston MV: Clinical disorders of brain plasticity, Brain Dev 26:73-80, 2004. 654. Krageloh-Mann I: Imaging of early brain injury and cortical plasticity, Exp Neurol 190(Suppl):S84-S90, 2004. 655. Staudt M, Erb M, Braun C, Gerloff C, et al: Extensive peri-lesional connectivity in congenital hemiparesis, Neurology 66:771, 2006. 656. Staudt M, Braun C, Gerloff C, Erb M, et al: Developing somatosensory projections bypass periventricular brain lesions, Neurology 67:522-525, 2006. 657. Jacola LM, Schapiro MB, Schmithorst VJ, Byars AW, et al: Functional magnetic resonance imaging reveals atypical language organization in children following perinatal left middle cerebral artery stroke, Neuropediatrics 37:46-52, 2006. 658. Ono K, Shimada M, Yamano T: Reorganization of the corticospinal tract following neonatal unilateral cortical ablation in rats, Brain Dev 12:226236, 1990. 659. Ono K, Yamano T, Shimada M: Formation of an ipsilateral corticospinal tract after ablation of cerebral cortex in neonatal rat, Brain Dev 13:348351, 1991. 660. Barth TM, Stanfield BB: The recovery of forelimb-placing behavior in rats with neonatal unilateral cortical damage involves the remaining hemisphere, J Neurosci 10:3449-3459, 1990. 661. Farmer SF, Harrison LM, Ingram DA, Stephens JA: Plasticity of central motor pathways in children with hemiplegic cerebral palsy, Neurology 41:1505-1510, 1991. 662. Lewine JD, Astur RS, Davis LE, Knight JE, et al: Cortical organization in adulthood is modified by neonatal infarct: A case study, Radiology 190:9396, 1994. 663. Maegaki Y, Yamamoto T, Takeshita K: Plasticity of central motor and sensory pathways in a case of unilateral extensive cortical dysplasia: Investigation of magnetic resonance imaging, transcranial magnetic stimulation, and short-latency somatosensory evoked potentials, Neurology 45:2255-2261, 1995. 664. Uematsu J, Ono K, Yamano T, Shimada M: Development of corticospinal tract fibers and their plasticity. II. Neonatal unilateral cortical damage and subsequent development of the corticospinal tract in mice, Brain Dev 18:173-178, 1996.
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Chapter 2
Neuronal Proliferation, Migration, Organization, and Myelination
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HUMAN BRAIN DEVELOPMENT
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Neuronal Proliferation, Migration, Organization, and Myelination
930. Cohen RI: Visions and reflections: Exploring oligodendrocyte guidance ‘‘to boldly go where no cell has gone before,’’ Cell Mol Life Sci 62:505510, 2005. 931. Chen S, Velardez MO, Warot X, Yu ZX, et al: Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function, J Neurosci 26:3079-3086, 2006. 931a. Zeger M, Popken G, Zhang J, Xuan S, et al: Insulin-like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination, Glia 55:400-411, 2007. 932. Yakovlev PI, Lecours AR: The myelogenetic cycles of regional maturation of the brain. In Minkowski A, editor: Regional Development of the Brain in Early Life, Philadelphia: 1967, FA Davis. 933. Gilles FH: Myelination in the neonatal brain, Hum Pathol 7:244-248, 1976. 934. Counsell SJ, Maalouf EF, Fletcher AM, Duggan PJ, et al: MR imaging assessment of myelination in the very preterm brain, AJNR Am J Neuroradiol 23:872-881, 2002. 935. Chattha AS, Richardson EP Jr: Cerebral white-matter hypoplasia, Arch Neurol 34:137-141, 1977. 936. Samorajski T, Friede RL, Reimer PR: Hypomyelination in the quaking mouse: A model for the analysis of disturbed myelin formation, J Neuropathol Exp Neurol 29:507-523, 1970. 937. Torii J, Adachi M, Volk BW: Histochemical and ultrastructural studies of inherited leukodystrophy in mice, J Neuropathol Exp Neurol 30:278289, 1971. 937a. Biancheri R, Zara F, Bruno C, Rossi A, et al: Phenotypic characterization of hypomyelination and congenital cataract, Ann Neurol 62:121-127, 2007. 938. Volpe JJ: Cerebral white matter injury of the premature infant: More common than you think, Pediatrics 112:176-179, 2003. 939. Haynes RL, Folkerth RD, Keefe R, Sung I, et al: Nitrosative and oxidative injury to premyelinating oligodendrocytes is accompanied by microglial activation in periventricular leukomalacia in the human premature infant, J Neuropath Exp Neurol 62:441-450, 2003. 940. Back SA, Luo NL, Mallinson RA, O’Malley JP, et al: Selective vulnerability of preterm white matter to oxidative damage defined by F(2)-isoprostanes, Ann Neurol 58:108-120, 2005. 941. Cioni G, Bartalena L, Biagioni E, Boldrini A: Neuroimaging and functional outcome of neonatal leukomalacia, Behav Brain Res 49:7-19, 1992. 942. Fedrizzi E, Inverno M, Bruzzone MG, Botteon G, et al: MRI features of cerebral lesions and cognitive functions in preterm spastic diplegic children, Pediatr Neurol 15:207-212, 1996. 943. Iida K, Takashima S, Takeuchi Y, Ohno T, et al: Neuropathologic study of newborns with prenatal-onset leukomalacia, Pediatr Neurol 9:45-48, 1993. 944. Iida K, Takashima S, Ueda K: Immunohistochemical study of myelination and oligodendrocyte in infants with periventricular leukomalacia, Pediatr Neurol 13:296-304, 1995. 945. Leviton A, Gilles F: Ventriculomegaly, delayed myelination, white matter hypoplasia, and ‘‘periventricular’’ leukomalacia: How are they related? Pediatr Neurol 15:127-136, 1996. 946. Olsen P, Paakko E, Vainionpaa L, Pyhtinen J, et al: Magnetic resonance imaging of periventricular leukomalacia and its clinical correlation in children, Ann Neurol 41:754-761, 1997. 947. Paneth N, Rudelli R, Monte W, Rodriguez E, et al: White matter necrosis in very low birth weight infants: Neuropathologic and ultrasonographic findings in infants surviving six days or longer, J Pediatr 116:975-984, 1990. 948. Pellicer A, Cabanas F, Garcia-Alix A, Rodriguez JP, et al: Natural history of ventricular dilatation in preterm infants: Prognostic significance, Pediatr Neurol 9:108-114, 1993. 949. Rorke LB: Pathology of Perinatal Brain Injury, New York: 1982, Raven Press. 950. Skranes JS, Vik T, Nilsen G, Smevik O, et al: Cerebral magnetic resonance imaging and mental and motor function of very low birth weight children at six years of age, Neuropediatrics 28:149-154, 1997. 951. Weisglas-Kuperus N, Baerts W, Fetter W, Sauer P: Neonatal cerebral ultrasound, neonatal neurology and perinatal conditions as predictors of neurodevelopmental outcome in very low birthweight infants, Early Hum Dev 31:131-148, 1992. 952. Argyropoulou MI, Xydis V, Drougia A, Argyropoulou PI, et al: MRI measurements of the pons and cerebellum in children born preterm: Associations with the severity of periventricular leukomalacia and perinatal risk factors, Neuroradiology 45:730-734, 2003. 953. Carmody DP, Dunn SM, Boddie-Willis AS, DeMarco JK, et al: A quantitative measure of myelination development in infants, using MR images, Neuroradiology 46:781-786, 2004. 954. Silberman J, Dancis J, Feigin T: Neuropathological observations in maple syrup urine disease, Arch Neurol 5:351-363, 1961. 955. Malamud N: Neuropathology of phenylketonuria, J Neuropathol Exp Neurol 25:254-268, 1966. 956. Shuman RM, Leech RW, Scott CR: The neuropathology of the nonketotic and ketotic hyperglycinemias: Three cases, Neurology 28:139146, 1978. 957. Prensky AL, Moser HW: Brain lipids, proteolipids, and free amino acids in maple syrup urine disease, J Neurochem 13:863-874, 1966.
117
958. Patel AJ, Hunt A, Kiss J: Neonatal thyroid deficiency has differential effects on cell specific markers for astrocytes and oligodendrocytes in the rat brain, Neurochem Int 15:239-248, 1989. 959. Shanker G, Amur SG, Pieringer RA: Investigations on myelinogenesis in vitro: A study of the critical period at which thyroid hormone exerts its maximum regulatory effect on the developmental expression of two myelin associated markers in cultured brain cells from embryonic mice, Neurochem Res 10:617-625, 1985. 960. King RA, Smith RM, Dreosti IE: Regional effects of hypothyroidism on 50 -nucleotidase and cyclic nucleotide phosphohydrolase activities in developing rat brain, Dev Brain Res 7:287-294, 1983. 961. Rosman NP, Malone MJ, Helfenstein M, Kraft E: The effect of thyroid deficiency on myelination of brain: A morphological and biochemical study, Neurology 22:99-106, 1972. 962. Alves C, Eidson M, Engle H, Sheldon J, et al: Changes in brain maturation detected by magnetic resonance imaging in congenital hypothyroidism, J Pediatr 115:600-603, 1989. 963. Rovet J, Ehrlich R, Sorbara D: Intellectual outcome in children with fetal hypothyroidism, J Pediatr 110:700-704, 1987. 964. Komianou F, Makaronis G, Lambadaridis J, Sarafidou E, et al: Psychomotor development in congenital hypothyroidism: The Greek screening programme, Eur J Pediatr 147:275-278, 1988. 965. Glorieux J, Dussault J, Van Vliet G: Intellectual development at age 12 years of children with congenital hypothyroidism diagnosed by neonatal screening, J Pediatr 121:581-584, 1992. 966. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, et al: Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism, J Pediatr 136:292-297, 2000. 967. Selva KA, Harper A, Downs A, Blasco PA, et al: Neurodevelopmental outcomes in congenital hypothyroidism: Comparison of initial T4 dose and time to reach target T4 and TSH, J Pediatr 147:775-780, 2005. 968. Heyerdahl S, Kase BF, Lie SO: Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment, J Pediatr 118:850-857, 1991. 969. Patel AJ, Hayashi M, Hunt A: Selective persistent reduction in choline acetyltransferase activity in basal forebrain of the rat after thyroid deficiency during early life, Brain Res 422:182-185, 1987. 970. Patel AJ, Hayashi M, Hunt A: Role of thyroid hormone and nerve growth factor in the development of choline acetyltransferase and other cell-specific marker enzymes in the basal forebrain of the rat, J Neurochem 50:803811, 1988. 971. Kooistra L, Crawford S, van Baar AL, Brouwers EP, et al: Neonatal effects of maternal hypothyroxinemia during early pregnancy, Pediatrics 117:161167, 2006. 972. Fishman MA, Prensky AL, Dodge PR: Low content of cerebral lipids in infants suffering from malnutrition, Nature 221:552-553, 1969. 973. Fox JH, Fishman MA, Dodge PR, Prensky AL: The effect of malnutrition on human central nervous system myelin, Neurology 22:1213-1216, 1972. 974. Martinez M: Myelin lipids in the developing cerebrum, cerebellum, and brain stem of normal and undernourished children, J Neurochem 39:16841692, 1982. 975. Chase HP, Martin HP: Undernutrition and child development, N Engl J Med 282:933-939, 1970. 976. Stoch MB, Smythe PM, Moodie AD, Bradshaw D: Psychosocial outcome and CT findings after gross undernourishment during infancy: A 20-year developmental study, Dev Med Child Neurol 24:419-436, 1982. 977. Galler JR, Ramsey F, Solimano G: The influence of early malnutrition on subsequent behavioral development. III. Learning disabilities as a sequel to malnutrition, Pediatr Res 18:309-313, 1984. 978. Rosso P: Morbidity and mortality in intrauterine growth retardation. In Senterre J, editor: Intrauterine Growth Retardation, New York: 1989, Raven Press. 979. Ballabriga A: Some aspects of clinical and biochemical changes related to nutrition during brain development in humans. In Evrard P, Minkowski A, editors: Developmental Neurobiology, New York: 1989, Raven Press. 980. Galler JR, Ramsey FC, Morley DS, Archer E, et al: The long-term effects of early kwashiorkor compared with marasmus. IV. Performance on the national high school entrance examination, Pediatr Res 28:235-239, 1990. 981. Rosso P: Maternal nutrition and fetal growth: Implications for subsequent mental competence, Current Topics in Nutrition and Disease, vol. 16: Basic and Clinical Aspects of Nutrition and Brain Development, New York: 1987, Alan R. Liss. 982. Dobbing J: Maternal nutrition in pregnancy and later achievement of offspring: A personal interpretation, Early Hum Dev 12:1-8, 1985. 983. Dobbing J: Infant nutrition and later achievement, Am J Clin Nutr 41:477484, 1985. 984. Stein Z, Susser M: Early nutrition, fetal growth, and mental function: Observations in our species, Current Topics in Nutrition and Disease, vol. 16: Basic and Clinical Aspects of Nutrition and Brain Development, New York: 1987, Alan R. Liss. 985. Gay CT, Hardies LJ, Rauch RA, Lancaster JL, et al: Magnetic resonance imaging demonstrates incomplete myelination in, 18q- syndrome: Evidence for myelin basic protein haploinsufficiency, Am J Med Genet 74:422-431, 1997.
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986. Loevner LA, Shapiro RM, Grossman RI, Overhauser J, et al: White matter changes associated with deletions of the long arm of chromosome 18 (18q- syndrome): A dysmyelinating disorder? AJNR Am J Neuroradiol 17:1843-1848, 1996. 987. Lancaster JL, Cody JD, Andrews T, Hardies LJ, et al: Myelination in children with partial deletions of chromosome 18q, AJNR Am J Neuroradiol 26:447-454, 2005. 988. Kamholz J, Spielman R, Gogolin K, Modi W, et al: The human myelinbasic-protein gene: Chromosomal localization and RFLP analysis, Am J Hum Genet 40:365-373, 1987. 989. Winick M: Malnutrition and brain development, J Pediatr 74:667-679, 1969. 990. Dobbing J: Undernutrition and the developing brain: The relevance of animal models to the human problem, Am J Dis Child 120:411-415, 1970. 991. Chase HP, Dorsey J, McKhann GM: The effect of malnutrition on the synthesis of a myelin lipid, Pediatrics 40:551-559, 1967. 992. Benton JW, Moser HW, Dodge PR, Carr S: Modification of the schedule of myelination in the rat by early nutritional deprivation, Pediatrics 38:801807, 1966. 993. Wiggins RC, Fuller GN: Early postnatal starvation causes lasting brain hypomyelination, J Neurochem 30:1231-1237, 1978. 994. Krigman MR, Hogan EL: Undernutrition in the developing rat: Effect upon myelination, Brain Res 107:239-255, 1976. 995. Fuller GN, Wiggins RC: A possible effect of the methylxanthines caffeine, theophylline and aminophylline on postnatal myelination of the rat brain, Brain Res 213:476-480, 1981. 996. Allan WC, Volpe JJ: Reduction of cholesterol synthesis by methylxanthines in cultured glial cells, Pediatr Res 13:1121-1124, 1979. 997. Volpe JJ: Effects of methylxanthines on lipid synthesis in developing neural systems, Semin Perinatol 5:395-405, 1981.
998. Royland J, Klinkhachorn P, Konat G, Wiggins S: How much undernourishment is required to retard brain myelin development, Neurochem Int 21:269-274, 1992. 999. Yager JY, Hartfield DS: Neurologic manifestations of iron deficiency in childhood, Pediatr Neurol 27:85-92, 2002. 1000. Gordon N: Iron deficiency and the intellect, Brain Dev 25:3-8, 2003. 1001. Roncagliolo M, Garrido M, Walter T, Peirano P, et al: Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: Delayed maturation of auditory brainstem responses, Am J Clin Nutr 68:683-690, 1998. 1002. Friel JK, Aziz K, Andrews WL, Harding SV, et al: A double-masked randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants, J Pediatr 143:582-586, 2003. 1003. Lozoff B, De Andraca I, Castillo M, Smith JB, et al: Behavioral and developmental effects of preventing iron-deficiency anemia in health full-term infants, Pediatrics 112:846-854, 2003. 1004. Algarin C, Peirano P, Garrido M, Pizarro F, et al: Iron deficiency anemia in infancy: Long-lasting effects on auditory and visual system functioning, Pediatr Res 53:217-223, 2003. 1005. Sarici SU, Serdar MA, Dundaroz MR, Unay B, et al: Brainstem auditoryevoked potentials in iron-deficiency anemia, Pediatr Neurol 24:205-208, 2001. 1006. Connor JR, Benkovic SA: Iron regulation in the brain: Histochemical, biochemical, and molecular considerations, Ann Neurol 32(Suppl):S51S61, 1992. 1007. Koo BK, Blaser S, Harwood-Nash D, Becker LE, et al: Magnetic resonance imaging evaluation of delayed myelination in Down syndrome: A case report and review of the literature, J Child Neurol 7:417421, 1992.
Chapter 3 Neurological Examination: Normal and Abnormal Features The neurological evaluation of the newborn comprises, as it does at other ages in pediatric medicine, the history, physical examination, and appropriate specialized studies. Relevant aspects of these three basic parts of the evaluation are illustrated in essentially every chapter of this book. Thus, enumerating all these aspects here would serve little purpose. In this chapter, the neonatal neurological examination is emphasized, because an organized approach to the infant is so critical and, in fact, is the cornerstone of the neurological evaluation. My approach is organized on the framework of the neurological examination of older infants and children, but it is supplemented and modified significantly for adaptation to the newborn. Too often, an organized, systematic approach to the infant is omitted because of the morass of catheters, tubes, monitors, blindfolds, intravenous accoutrements, and the like surrounding the child. It is curiously paradoxical that these outward manifestations of our attempts to provide optimal therapy may interfere significantly with the careful clinical examination that is necessary for rational judgments regarding diagnosis, prognosis, and management. Conversely, the examiner should remember that the sick newborn, especially the premature infant, often has only tenuous control of such critical functions as respiration and cardiovascular status, and overly vigorous manipulation of the baby may have adverse consequences. The purpose of the following discussion is to describe the normal and abnormal features of the neonatal neurological examination and to illustrate the importance of these features in our understanding of neurological development and disease. NORMAL NEUROLOGICAL EXAMINATION In the following section, the normal features of the neonatal neurological examination are outlined (Table 3-1). Before addressing the formal neurological examination, brief discussions of determination of gestational age and evaluation of the head are necessary. Estimation of Gestational Age Estimation of gestational age is particularly important for several reasons. First, various aspects of the neonatal neurological evaluation change with maturation, and recognition of these changes is critical in assessing the observations. Second, certain disorders are particularly characteristic of infants who are born prematurely but
who are of average weight for gestational age, those born at term but are small for gestational age, and so forth. Third, the same insult (e.g., hypoxia-ischemia) will have a different impact on various regions of the central nervous system, in large part as a function of the gestational age of the infant. The most helpful information for estimating gestational age is the date of the mother’s last menstrual period, particularly in the smallest infants.1,2 It is unfortunate that, too often, this information is not known precisely. Thus, various other measures have been used to estimate gestational age, including the following: anthropometric measurements, such as birth weight and head circumference; certain external characteristics; neurological evaluation; radiological study of bone maturation; certain neurophysiological parameters, especially measurement of motor nerve conduction velocity or the electroencephalogram; and cranial ultrasonographic determinations of sulcal development. All these approaches have certain merit, as well as significant limitations. Of the techniques evaluated, examination of certain external characteristics has been at least as effective as other methods.2-4 I find four selected external characteristics to be particularly useful: the ear cartilage and its reflection in ear position, the amount of breast tissue, the characteristics of the external genitalia, and the creases of the plantar surface of the foot (Table 3-2).3,5-10 In the first hours of life, I do not use the measurements of tone and posture for this purpose,9,10 because in my experience these measurements are variable and are sensitive to exogenous factors, including the process of birth. However, for infants after the first hours of life, some clinicians find these evaluations useful for assessing maturation.2,11,12 These comments are not to deny the value of recognizing the temporal characteristics of neurological maturation, as discussed in detail subsequently, but rather to emphasize that, in my experience, such characteristics are not optimal for the purposes of estimating gestational age, particularly in the immediate neonatal period.
Head: External Characteristics and Rate of Growth External Characteristics The external characteristics of the head to be evaluated include the size and shape (see later discussion) and the skin. 121
122 TABLE 3-1
Unit II
NEUROLOGICAL EVALUATION
Neonatal Neurological Examination: Basic Elements
Level of Alertness Cranial Nerves Olfaction (I) Vision (II) Optic fundi (II) Pupils (III) Extraocular movements (III, IV, VI) Facial sensation and masticatory power (V) Facial motility (VII) Audition (VIII) Sucking and swallowing (V, VII, IX, X, XII) Sternocleidomastoid function (XI) Tongue function (XII) Taste (VII, IX)
V1
V2
V3
Motor Examination Tone and posture Motility and power Tendon reflexes and plantar response Primary Neonatal Reflexes Moro reflex Palmar grasp Tonic neck response
Figure 3-1 Dermatomal distribution of the face. Note the delineation of the three branches of the trigeminal nerve: ophthalmic (V1), maxillary (V2), and mandibular (V3). (From Enjolras O, Riche MC, Merland JJ: Facial port-wine stains and Sturge-Weber syndrome, Pediatrics 76:4851, 1985.)
Sensory Examination
Skin. The skin of the head should be examined carefully for the presence of dimples or tracts, subcutaneous masses (e.g., encephalocele, tumor), or cutaneous lesions, all generally discussed elsewhere in this book. In this setting, I discuss only the significance of portwine stains, congenital vascular abnormalities that are present at birth and persist into adulthood. At birth, these lesions are most often pale pink, macular lesions that subsequently become dark red to purple and often nodular.13 Port-wine stains are categorized according to their dermatomal distribution (Fig. 3-1). Their importance, apart from the significant cosmetic issue, relates principally to their association with abnormalities of choroidal vessels in the eye, which may result
TABLE 3-2
in glaucoma, and of meningeal and superficial cerebral vessels, which may result in cortical lesions with seizures and other neurological deficits (i.e., SturgeWeber syndrome). The relationships between the location of the port-wine stain and the incidence of glaucoma or intracranial vascular lesion are shown in Table 3-3. In one large series, the intracranial vascular lesion of Sturge-Weber syndrome occurred in 40% to 50% of children with total involvement of V1.14,15 Notably, with partial involvement of V1, the risk was markedly lower (1 of 17 children affected), and none of the 64 children with involvement of V2 or V3, or both, developed either the intracranial lesion or glaucoma.14,15 The particular prognostic importance of involvement of V1 was confirmed in
External Characteristics Useful for Estimation of Gestational Age GESTATIONAL AGE
External Characteristic
28 Weeks
32 Weeks
36 Weeks
40 Weeks
Ear cartilage
Pinna soft, remains folded
Pinna harder, springs back
Pinna firm, stands erect from head
Breast tissue External genitalia: male
None Testes undescended, smooth scrotum
1–2-mm nodule Testes high in scrotum, more scrotal rugae
External genitalia: female
Prominent clitoris, small, widely separated labia Smooth
Pinna slightly harder but remains folded None Testes in inguinal canal, few scrotal rugae Prominent clitoris, larger separated labia One or two anterior creases
6–7-mm nodule Testes descended, pendulous scrotum covered with rugae Clitoris covered by labia majora
Plantar surface
Adapted from references 3, 5, and 7 to 10.
Clitoris less prominent, labia majora cover labia minora Two or three anterior creases
Creases cover sole
Chapter 3 TABLE 3-3
Neurological Examination: Normal and Abnormal Features
123
Relation between Location of Port-Wine Stain and Subsequent Incidence of Glaucoma or SturgeWeber Syndrome
Location of Port-Wine Stain (Dermatomal Distribution)
Total Number
V1 (total) alone V1 (total) with other dermatomes V1 (partial) with or without other dermatomes V2 alone V3 alone V2 and V3 (unilateral or bilateral)
Intracranial Vascular Lesion with or without Glaucoma
Glaucoma Alone
Port-Wine Stain Only
4 21
2 9
1 3
1 9
17
1
0
16
29 13 22
0 0 0
0 0 0
29 13 22
Data from Enjolras O, Riche MC, Merland JJ: Facial port-wine stains and Sturge-Weber syndrome, Pediatrics 76:48-51, 1985.
more selected series.16,17 The optimal timing of therapy has been the subject of debate; a large prospective study did not report treatment early in infancy and childhood to be superior to later treatment.18-21 Head Size and Shape. Head circumference is a useful measure of intracranial volume and therefore also of volume of brain and cerebrospinal fluid. Less commonly, head circumference is significantly affected by the size of extracerebral spaces, subdural and subarachnoid, or by the intracranial blood volume. Scalp edema, subcutaneous infiltration of fluid from intravenous infusion, and cephalhematoma also have obvious effects. Nevertheless, measurement of head circumference remains one of the most readily available and useful means for evaluating the status of the central nervous system in the newborn period. Longitudinal measurements in particular provide valuable information. Head circumference is influenced by head shape: the more circular the head shape, the smaller the circumference needs to be to contain the same area and the same intracranial volume. Infants with relatively large occipital-frontal diameters have larger measured head
circumferences than infants with relatively large biparietal diameters. This finding has important implications for evaluating the head circumference of an infant with a skull deformity such as craniosynostosis (see next paragraph). In premature infants, over the first 2 to 3 months of life, an impressive change in head shape is characterized by an increase in occipital-frontal diameter relative to biparietal diameter (Fig. 3-2). Because this alteration occurs over a matter of weeks, it usually does not cause major difficulties in the interpretation of head circumference, but it does need to be considered, especially in infants with unusually marked dolichocephalic change. Craniosynostosis, defined as premature cranial suture closure, may affect one or more cranial sutures (Table 3-4).22 Simple sagittal synostosis is most common.22,23 The diagnosis can be suspected by the shape of the head; with synostosis of a suture, growth of the skull can occur parallel to the affected suture but not at right angles (Fig. 3-3). The ‘‘keel-shaped’’ head of sagittal synostosis is termed dolichocephaly or scaphocephaly, the wide head of coronal synostosis is brachycephaly, and the tower-shaped head of combined coronal, sagittal, and lambdoid synostosis is acrocephaly. A few cases of
AP/BP ratio 1.3
AP/BP ratio 1.48
AP/BP ratio 1.54
Figure 3-2 Change in head shape in premature infants. Measurements of AP/BP ratio (anterior-posterior [AP] and biparietal [BP] diameters) and drawings of head shape (vertex view) of an infant, born at 28 weeks of gestation, made at, A, 1 week, B, 5 weeks, and, C, 111=2 weeks. (From Baum JD, Searls D: Head shape and size of pre-term low-birthweight infants, Med Child Neurol 13:576-581, 1971.)
A
B
C
124 TABLE 3-4
Unit II
NEUROLOGICAL EVALUATION
Coronal
Distribution of Suture Involvement in Craniosynostosis
Sutures Sagittal only Coronal only One Both Metopic only Lambdoid only (one or both) Various combinations
Percentage of Cases*
Lambdoid
56 25 13 12 4 2 13
*Total of 519 patients. Data from Matson D: Neurosurgery of Infancy and Childhood, Springfield, IL: 1969, Charles C Thomas.
cranial synostosis represent complex syndromes, the major features, genetics, and neurological outcome of which are summarized in Table 3-5.24-30 The importance of early correction of synostosis for optimal cosmetic appearance and the other aspects of management are discussed in standard textbooks of neurosurgery. Positional or deformational plagiocephaly has become a frequent clinical issue. The term plagiocephaly (‘‘oblique head,’’ from the Greek) refers to a head appearance in which the occipital region is flattened and the ipsilateral frontal area is prominent (i.e., anteriorly displaced) (Fig. 3-4). In positional or deformational plagiocephaly, caused by external molding forces, the ipsilateral ear is also displaced anteriorly, and the contralateral side of the face may appear flattened.31,32 Torticollis may be associated and may cause a head tilt. Deformation plagiocephaly may be present at birth, secondary to intrauterine restriction to head movement as occurs with multiple gestation, abnormal uterine lie, or neck abnormality (e.g., torticollis), or it may evolve over the first weeks to months of life, usually secondary to supine sleeping position as part of the ‘‘Back to Sleep’’ program.31,33 Differentiation of deformational plagiocephaly from the rare unilateral lambdoid synostosis, which can also cause occipital flattening, is usually readily made clinically. In unilateral lambdoid synostosis, the anterior displacement of the frontal area is usually less pronounced, the ear is posterior, not anterior, and is displaced inferiorly, and facial deformity is rare. Management of deformational plagiocephaly consists of parental counseling regarding head positioning with the infant supine, supervised time in the prone position, various exercises, and skull-molding helmets if necessary (see Fig. 3-4).31,34-36 Rate of Head Growth Interpretation of the rate of head growth in premature infants is often difficult, in part because ‘‘normal’’ postnatal rates have been difficult to define conclusively (in contrast to normal rates of intrauterine growth, as plotted on most standard charts) and in part because commonly occurring systemic diseases and caloric deprivation in the neonatal period may interfere with brain and head growth.
Metopic Coronal Sagittal Lambdoid
A
Metopic
B
C Figure 3-3 Changes related to premature closure of cranial sutures. Schematic diagram of, A, cranial sutures and changes in cranial shape with premature closure of, B, sagittal or, C, coronal sutures.
The rate of head growth in premature infants has been the subject of numerous reports.37-50 In the healthy premature infant, change in the head circumference in the first days of life is minimal; indeed, a small amount of head shrinkage with suture overriding has been documented.39,51 Head shrinkage reaches a peak at approximately 3 days of life, usually averages 2% to 3% of the head circumference at birth, and correlates closely with postnatal weight and urinary sodium losses. In view of these findings and the overriding of
Chapter 3 TABLE 3-5
125
Craniosynostosis Syndromes
Syndrome Name Crouzon
Carpenter
Apert
SaethreChotzen Pfeiffer
Antley-Bixler
Greig Baller-Gerold
Opitz
Neurological Examination: Normal and Abnormal Features
Cranium
Other Major Features
Acrocephaly (tower-shaped) Ocular proptosis (shallow with synostosis of orbits) and maxillary coronal, sagittal, and hypoplasia lambdoid sutures Acrobrachycephaly with Lateral displacement of synostosis of coronal, inner canthi, polydactyly sagittal, and lambdoid and syndactyly of feet sutures Brachycephaly with irregu- Midfacial hypoplasia, lar synostosis, espesyndactyly of fingers and cially of coronal suture toes, broad distal phalanx of thumb and big toe Brachycephaly with synos- Prominent ear crus, maxiltosis of coronal suture lary hypoplasia, partial syndactyly of fingers and toes Brachycephaly with synos- Hypertelorism, broad tosis of coronal and/or thumbs and toes, partial sagittal sutures syndactyly of fingers and toes Brachycephaly with multiple Maxillary hypoplasia, radiosynostosis, especially of humeral synostosis, coronal suture choanal atresia, arthrogryposis High forehead with variable Hypertelorism, polydactyly synostosis and syndactyly of fingers and toes Synostosis of variable Radial dysplasia with sutures, including absent thumbs metopic with trigonocephaly Trigonocephaly with Upward slant of palpebral synostosis of metopic fissures, epicanthal suture folds, narrow palate, anomalies of external ear, loose skin, variable polydactyly or syndactyly of fingers
sutures, investigators have suggested that the head shrinkage relates to water loss from the intracranial compartment.39 A longitudinal study of 41 premature infants ( distal Areflexia Characteristic posture Collapsed chest Weak cry Difficulty sucking and swallowing Relatively preserved facial movement Normal extraocular movements Normal sensory function Normal sphincter function
Unlike the situation with disorders of the cerebrum and other central causes of hypotonia, weakness is similarly severe. Most infants exhibit generalized weakness, but when it is possible to make a distinction between proximal and distal muscles, a proximal
A
B Figure 18-1 Type 1 spinal muscular atrophy (Werdnig-Hoffmann disease): clinical manifestations of weakness of limb and axial musculature in a 6-week-old infant with severe weakness and hypotonia from birth. Note the marked weakness of, A, the limbs and trunk on ventral suspension and, B, the neck on pull to sit. (From Dubowitz V: Muscle Disorders in Childhood, 2nd ed, Philadelphia: 1978, Saunders.)
more than distal distribution is discernible. Only minimal movements at hips and shoulders may be elicited in the presence of active movements of hands and feet. The lower extremities are affected more severely than the upper extremities. Involvement of the axial musculature of the trunk and neck is particularly severe, and the resulting deficits are obvious with ventral suspension and pull-to-sit maneuvers (Fig. 18-1). Muscle atrophy is also severe and generalized, although the severity may be difficult to appreciate fully in the newborn. Indeed, the replacement of atrophied muscle by connective tissue may further hinder the appreciation of atrophy. Fasciculations of limbs are observed rarely, but an analogous phenomenon may be the characteristic fine rhythmic ‘‘tremor’’ of the extended fingers (polyminimyoclonus) most commonly observed in less severe cases.42 Total areflexia is the rule, although rarely some reflex response, albeit depressed, can be elicited. The pattern of weakness of limbs leads to a characteristic posture, characterized particularly by a frog-leg posture with the upper extremities abducted and either externally rotated or internally rotated (‘‘jug handle’’) at the shoulders (Fig. 18-2). The chest is almost always anteriorly collapsed and bell shaped, with an associated distention of the abdomen and intercostal recession with breathing (see Fig. 18-2). These features relate to weakness of the intercostal muscles and the relatively preserved diaphragmatic function. Contractures of the limbs, usually only at wrists and ankles, are evident in 10% to 20% of infants with onset in utero or in the first month of life.41,56,58-60 Involvement of cranial nerve nuclei is less striking than of anterior horn cells, at least early in the clinical course. Thus, extraocular movements are normal, and facial motility is relatively well preserved. Indeed, the pathetic picture of a bright-eyed, nearly totally paralyzed infant is characteristic of Werdnig-Hoffmann disease. Sucking and swallowing are affected early in the course in approximately half of cases. Fasciculations and atrophy of the tongue, clinical signs in anterior horn cell disorders of slightly later onset, are apparent in only about one third to one half of patients with the disease occurring at birth or in the first month.49,56 Particularly noteworthy differential diagnostic features in the neurological examination include the presence of normal sphincter and sensory functions. Both these functions would be expected to be affected with major spinal cord disease, and sensory function with peripheral nerve disease. The patient’s alert state with normal visual and auditory responses rules against a central disorder. Total areflexia and absence of ptosis, ophthalmoplegia, and facial weakness rule against a variety of primary diseases of muscle. Distinction from type II glycogen storage disease (Pompe disease) can be most difficult, but this much less common disease is usually accompanied by prominent involvement of the heart and enlargement of the tongue. Several rare genetic variants of infantile SMA should be distinguished from type 1 SMA just described. These SMA variants and their mode of inheritance include the association of SMA with (1) primary
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Figure 18-2 Type 1 spinal muscular atrophy (WerdnigHoffmann disease): characteristic postures. A, 6-week-old and, B, 1-year-old infants with severe weakness and hypotonia from birth. Note in A the frog-leg posture of the lower limbs and internal rotation (‘‘jug handle’’) or, B, external rotation at shoulders. Note also intercostal recession, especially evident in B, and normal facial expressions. (From Dubowitz V: Muscle Disorders in Childhood, 2nd ed, Philadelphia: 1978, Saunders.)
A
B
respiratory insufficiency secondary to diaphragmatic involvement (autosomal recessive), (2) pontocerebellar atrophy (type 1 pontocerebellar atrophy; see Chapter 17) (autosomal recessive), and (3) congenital arthrogryposis, both with and without bone fractures (autosomal recessive and X-linked, respectively).24,52,61-64 None of these disorders is linked to the genetic region on chromosome 5 involved in type 1 SMA (see later discussion). Course. The course of type 1 SMA is a close function of the age of onset (Table 18-5).* Infants with clear prenatal onset of very severe disease with respiratory failure at birth, marked diffuse weakness, and early deficits of facial movement (i.e., type 0 SMA) usually die by 3 months of age.38-40 Those infants with clinical onset in the first 2 months of life have a range of median age at death of 4 to 8 months, with maximum survival rarely exceeding 12 to 18 months. Infants with clinical onsets after 2 months of age have clearly longer median and maximum survival times (see Table 18-5). Recent work suggests even longer survival times.66a Moreover, although infants who ultimately prove to have type 2 SMA have a peak age at onset between 8 and 14 months,50 an occasional infant exhibits onset before 6 months and has a chronic course, including attainment of sitting or even walking, with prolonged survival.24,42,48,49,55-57,66-69 This portion of the type 2 SMA cases usually can be distinguished from type 1 SMA in the early stages of the disease because of a more insidious onset and slower initial deterioration. Death in type 1 SMA usually relates to intercurrent
respiratory complications. These complications are caused by aspiration because of defective swallowing, hypoventilation because of impaired intercostal muscle function, and impaired clearing of tracheal secretions secondary to weak or absent cough because of weak abdominal muscles. Laboratory Studies Serum Enzymes. The creatine kinase (CK) level is normal in type 1 SMA.24 Electromyography. The electromyogram (EMG) may be difficult to perform in the young infant, but with patience the major features of anterior horn cell disease are usually observed (see Table 17-7). Thus, at rest, fasciculations and fibrillations are apparent. With muscle contraction, one sees a reduced number of TABLE 18-5
Survival as a Function of Age of Onset in Type 1 Spinal Muscular Atrophy* AGE AT DEATH (MO)
Age at Onset (mo)
Median
Maximum
Birth 0–1 1–2 2–3 3–6
4–6 6–7 7–8 14–20 18–20
10–12 10–18 10–12 20–25{ 24–30
*Based on cumulative series of 100 infants from two separate studies: Thomas NH, Dubowitz V: The natural history of type 1 (severe) spinal muscular atrophy, Neuromuscul Disord 4:497–502, 1994; and Ignatius J: The natural history of severe spinal muscular atrophy: Further evidence for clinical subtypes, Neuromuscul Disord 4:527–528, 1994. {Excludes 3 of 18 infants with survival to 8, 10, and 18 years.
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Figure 18-3 Type 1 spinal muscular atrophy (Werdnig-Hoffmann disease): muscle biopsy showing diffuse, panfascicular atrophy in an affected infant. The large muscle fibers are type I. The atrophy is so marked that a grouped pattern cannot be defined readily (adenosine triphosphatase stain, pH 9.4, 172). (From Banker BQ: Hum Pathol 17:656, 1986.)
motor unit potentials that are of increased amplitude and duration. In general, although no simple relationship exists between features on the EMG and outcome,24,70,71 one study showed a strong correlation between the degree of depression of the compound muscle action potential and functional outcome.44 Nerve Conduction Velocity. Motor nerve conduction velocities are usually normal, although in particularly severe disease, a slight reduction may be observed.72 This finding suggests a disproportionate loss of anterior horn cells that give rise to the largest, fastest conducting fibers. Some patients with particularly severe cases of type 1 SMA have exhibited signs of severe neuropathy.73-75 Muscle Biopsy. The muscle biopsy of a patient with Werdnig-Hoffmann disease with clinically apparent findings at birth or in the first month usually exhibits advanced changes of denervation (see Chapter 17). Characteristically, pronounced atrophy of all fibers of both types within entire fascicles of muscle (i.e., panfascicular atrophy) occurs (Fig. 18-3). The early signs of denervation (i.e., loss of checkerboard appearance, type grouping, or even grouped atrophy; see Chapter 17), features of anterior horn cell disease later in infancy (Fig. 18-4), are nearly absent. This virtual absence of signs of terminal axonal sprouting and reinnervation (see Chapter 17) is probably indicative of the severe, fulminating process involving anterior horn cells that causes widespread elimination before such compensatory attempts can occur. A consistent increase in connective tissue is associated with the marked atrophy of muscle (see Fig. 18-4). Hypertrophy of predominantly type I fibers, often in clusters, is an additional characteristic feature. The finding that these hypertrophic fibers often occur in clusters suggests the possibility of reinnervation. The distribution of the histopathological findings parallels the generalized pattern of muscle weakness; the diaphragm is conspicuously less affected.56 Diagnosis by genetic testing may obviate the need for muscle biopsy in the typical case (see later).
Figure 18-4 Type 1 spinal muscular atrophy (Werdnig-Hoffmann disease): muscle biopsy showing grouped atrophy at the age of 6 months in an infant with later onset and less severe disease than in the infant whose biopsy is illustrated in Figure 18-3. Note the presence of groups of atrophic fibers, interspersed with groups of presumed larger fibers (Verhoeff–van Gieson stain, 95). (From Dubowitz V: Muscle Disorders in Childhood, 2nd ed, Philadelphia: 1978, Saunders.)
Other Studies. The identification of the q11.2-13.3 region of chromosome 5 as the site of the genetic defect in Werdnig-Hoffmann disease led to the development of molecular diagnostic techniques (see ‘‘Pathogenesis and Etiology’’ later). Radiographs of the chest are useful in demonstrating the chest deformity, the thin ribs characteristic of severe congenital neuromuscular disease,76-78 and the marked atrophy of muscle. In the rare, very severe type 0 disease, long bone fractures may be observed.40 Studies with real-time ultrasonography of limbs have demonstrated several types of changes (i.e., an increase in the intensity of echoes from muscle and the degree of muscle atrophy).24,79 The echogenicity of muscle correlates well with the severity of histopathological changes observed in biopsy specimens. Neuropathology Essential Cellular Changes. The major neuropathological changes are confined to the anterior horn cells of the spinal cord and the motor nuclei of cranial nerves (Table 18-6).24,53,56,80-83 The essential cellular changes in infantile cases are (1) depletion of the TABLE 18-6
Type 1 Spinal Muscular Atrophy (Werdnig-Hoffmann Disease): Neuropathology
Anterior Horn Cells Decreased number Degenerative changes Neuronophagia Gliosis Cranial Nerve Nuclei Cellular changes as for anterior horn cells Usually affected: V (motor), VII, IX, X, XI, and XII Occasionally affected: VI
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
Figure 18-5 Type 1 spinal muscular atrophy (Werdnig-Hoffmann disease): neuronal degeneration in the hypoglossal nucleus. Note the distended neuronal cell bodies, with chromatolytic change as well as pyknotic shrunken cells. Infiltration with pleomorphic microglia and astrocytes is also evident. (From Dubowitz V: Muscle Disorders in Childhood, 2nd ed, Philadelphia: 1978, Saunders.)
number of neurons, (2) degenerative changes of neurons, (3) neuronophagia, and (4) infiltration with microglia and astrocytes (Fig. 18-5). Enhanced apoptosis of anterior horn cell neurons is the most prominent feature during fetal life.53 Some workers also described cytological findings indicative of immaturity of neurons and suggested impaired development, as well as degeneration, of neurons.80 The depletion of neurons may be so marked that few, if any, remain in an anterior horn or cranial nerve nucleus. The degenerative changes consist particularly of central chromatolysis, characterized by rounded and distended neuronal cell bodies with eccentric nuclei and Nissl substance displaced to the periphery. Neuronophagia is not prominent, although it is readily demonstrated. The glial response consists of both microglia and astrocytes and is particularly prominent in the ventral aspect of the anterior horns.
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Topography. In severe Werdnig-Hoffmann disease, anterior horn cells are affected diffusely, with a particularly prominent affection of the ventromedial group. Cranial nerve nuclei involved invariably and markedly are of cranial nerves VII, IX, X, XI, and XII. The motor nucleus of nerve V is affected in approximately 70% of cases, and the abducens nucleus is involved in fewer than 50% of cases.56 Other areas of the motor system are not consistently involved. Hypoxic changes are occasionally observed in hippocampal neurons and Purkinje cells of cerebellum.56 As noted later, associated degenerative changes in pontocerebellar structures are a feature of an SMA variant that is genetically distinct from type 1 SMA. The motor nerves exhibit the changes expected from a loss of anterior horn cells (i.e., a decrease in number of myelinated fibers particularly and an increase in connective tissue).56 Striking atrophy with glial proliferation may be apparent in the proximal anterior roots. Indeed, the glial proliferation may be so conspicuous that some workers have attributed to it a pathogenetic role.84 The view that the glial infiltration is a secondary event is more widely accepted.43,80,83,85 Perhaps of greater interest is the demonstration of changes typical of axonal neuropathy in some severe cases.73-75,83,86 Such changes have led to the suggestion that the anterior horn cell degeneration is a secondary phenomenon, although the most prevalent view is that the neuropathic abnormalities are secondary. Pathogenesis and Etiology. It is now clear that the acute, early-onset, type 1 form of SMA (WerdnigHoffmann disease), as well as the rare, very severe type 0 form and the later-onset, chronic forms (types 2 and 3), are all related to a genetic defect that involves the q13 region of chromosome 5.24,43,52,65,83,87-97 The SMA region consists of a large inverted duplication containing two copies of the gene deleted (or mutated) in SMA (i.e., the survival motor neuron [SMN] gene; Fig. 18-6). Thus, on each chromosome 5 are two copies of SMN: telomeric (SMN1) and centromeric (SMN2) copies. The deletions involve the telomeric copy. Homozygous deletions of the SMN1 gene
Figure 18-6 The region on chromosome 5q13 involved in spinal muscular atrophy (SMA) type 1. In the normal state, two copies of SMN1 are present (i.e., a telomeric copy that produces 100% normal protein and a centromeric copy that produces approximately 10% normal protein). With SMA type 1, the telomeric copy contains a deletion (or much less commonly a mutation) and the centromeric copy (*) may increase or decrease in copy number. See text for details.
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occur in approximately 95% of cases of SMA, and the remainder are related to mutations in the gene.43,44,52,98-100b The nearly identical SMN2 gene, which contains a single nucleotide change in exon 7 that profoundly influences splicing, produces primarily 90% of a truncated protein lacking exon 7 and having a short half-life and only approximately 10% of the normal protein. Because of the genomic instability of this duplicated region of chromosome 5, SMN2 copy number may increase or decrease in the presence of the deleted SMN1 gene. The importance of this phenomenon in this context is that abundant evidence in animal models and now in humans shows that the copy number of SMN2 is the most critical determinant of the severity of the SMA phenotype.38,39,43,44,99-100b Thus, approximately 90% of SMA type 1 cases have only one (65%) or two (25%) copies of SMN2, whereas SMA types 2 and 3 cases have two or more copies in 85% and 100%, respectively.100 The biological functions of SMN1 and its relationship with SMA are beginning to be elucidated.43,99, 101-105a The SMN protein interacts with other proteins in a multimolecular complex and appears to be involved principally in RNA metabolism. The most critical function of SMN is in the assembly of the ribonucleoproteins of the so-called spliceosome, which is critically involved in the removal of introns from preRNA and splicing together of exons in mature RNA, for many proteins. The biological functions potentially affected are many, but most recent work suggests that axonal growth and maintenance are key roles. Impairment thereof perhaps could result in the subsequent neuronal apoptosis and degeneration observed in neuropathological studies (see earlier). More data are needed. Management. Type 1 SMA that is apparent at birth or in the first month of life is usually accompanied by serious disturbances of sucking and swallowing early in infancy. Frequent aspiration of the oropharynx is needed, and usually cessation of oral feedings and institution of tube feeding are required before long to ensure adequate nutrition. Indeed, when dysphagia becomes severe enough to preclude reasonable nutrition and is complicated by frequent aspirations, many clinicians recommend gastrostomy or gastrojejunostomy feeding. This maneuver is carried out not to prolong life but to improve the patient’s quality of life and particularly to reduce parental anxiety associated with attempts at oral feeding. Surveillance for respiratory infection must be diligent, because this complication is the usual mode of demise for these unfortunate babies. The intensity of therapy (e.g., antibiotics, chest physical therapy, postural drainage, noninvasive positive pressure ventilation, and even tracheostomy and long-term mechanical ventilation) sometimes is difficult to determine decisively.106-111b Tracheostomy and mechanical ventilation have been associated with survival into childhood,51,66,66a although longer survival occurs, albeit rarely, without such invasive intervention.24 The quality of life in such bed-ridden infants and children is a grave concern. More important,
range-of-motion exercises are used to prevent contractures and, I feel, to help the parents ‘‘do something’’ for their infant. In severe Werdnig-Hoffmann disease, my approach is foremost to provide emotional support to the parents and to ensure as much comfort as possible for the infant. I indicate to the family our current understanding of the dire outcome and recommend careful attention to oral-pharyngeal secretions, measures to ensure adequate nutrition, and diligent therapy of respiratory infections. I discuss the complex issues related to long-term mechanical ventilation. Recent insights into the molecular genetic aspects of SMA have led to some potentially promising interventions. Thus, because of the presence of one or more copies of SMN2, the possibility of enhancing production by SMN2 of full-length messenger RNA and SMN protein has been raised. Currently, the most promising approach is the use of histone deacetylase inhibitors.99,112-114 Histone deacetylases deacetylate and thereby change the conformation of DNA-associated histone proteins, thus altering access of genes to messenger RNA. Histone deacetylase inhibitors have been shown to up-regulate full-length SMN protein from the SMN2 gene. Studies in cultured cells and animal models and, more recently, in human carriers and patients showed increased production of full-length SMN. Currently, the most promising agents are sodium phenylbutyrate, hydroxyurea, and valproate. Clinical trials in SMA type 1 will be of great interest. The first such trial did not show benefit for phenylbutyrate in children with SMA type 2.115 Spinal Muscular Atrophy Variants At least four disorders with primary involvement of anterior horn cells, clinical presentation at birth, and subsequent course of progressive deterioration (or severe static disability) mimic SMA in the neonatal period. However, these disorders are not linked to chromosome 5q and do not involve SMN. Thus, the term SMA variants seems most appropriate until the molecular bases are further clarified. At least four disorders should be distinguished (Table 18-7). SMA with respiratory distress type 1 (SMARD1) is a striking disorder.64,116-120 From the first days of life, intrauterine growth retardation, mild hypotonia, weak cry, and mild distal contractures are noted. Between 1 and 6 months of age, respiratory distress secondary to diaphragmatic paralysis becomes obvious, and progressive primary distal lower limb weakness ensues. Motor, sensory, and autonomic disturbances develop. Most infants die in infancy or childhood. The responsible gene (IGHMBP2) encodes immunoglobulin mu-binding protein 2, the function of which is unclear. Pontocerebellar hypoplasia type 1 manifests clinically at birth with arthrogryposis, hypotonia, weakness, and bulbar deficits (swallowing difficulty, stridor).121-124 Subsequent features include progressive bulbar deficits, nystagmus, microcephaly, and cognitive deficits. Brain imaging shows pontocerebellar hypoplasia and cerebral atrophy. Although the disorder is likely autosomal recessive, the molecular defect is unknown.
Chapter 18 TABLE 18-7
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
775
Spinal Muscular Atrophy Variants: Progressive or Severe Neonatal Anterior Horn Cell Disease Not Linked to SMN*
Variant
Major Features
SMA with respiratory distress type 1 (SMARD1)
Mild hypotonia, weak cry, distal contractures initially; respiratory distress from diaphragmatic paralysis 1–6 mo, progressive distal weakness; autosomal recessive, locus 11q13.2, gene: immunoglobulin mu-binding protein 2 (IGHMBP2) Arthrogryposis, hypotonia, weakness, bulbar deficits early; later, microcephaly, extraocular defects, cognitive deficits: pontocerebellar hypoplasia; molecular defect unknown; likely autosomal recessive Arthrogryposis, hypotonia, weakness, congenital bone fractures, respiratory failure, lethal course as in severe type 1 SMA: most cases X-linked (X9/11.3q11.2); a few cases likely autosomal recessive Arthrogryposis, hypotonia, weakness, especially distal lower limbs early; nonprogressive but severe disability; autosomal dominant or sporadic; locus 12q23-24
Pontocerebellar hypoplasia type 1 X-linked infantile SMA with bone fractures Congenital SMA with predominant lower limb involvement *See text for references. SMA, spinal muscular atrophy.
X-linked infantile SMA with congenital bone fractures manifests clinically in the neonatal period with arthrogryposis, hypotonia, and weakness.43,99,125-127 Congenital fractures of long bones and ribs are common. Respiratory failure and progressive weakness lead to death in the first days to weeks in most infants. Anterior horn cell loss is marked. Approximately 80% of cases have been in male infants, and linkage to Xp11.3-q11.2 has been shown. However, some cases likely are autosomal recessive. Congenital SMA predominantly affecting the lower limbs is the only autosomal dominant disorder of this group.43,99,128 Presentation at birth is with talipes equinovarus and lower limb hypotonia. EMG and muscle biopsy show signs of anterior horn cell disease. The subsequent course is marked by severe weakness of the lower extremities, although it is generally nonprogressive. The disorder is linked to chromosome 12q23q24, but the molecular defect is unknown. Neurogenic Arthrogryposis Multiplex Congenita Generalized and Localized Types The term neurogenic has been applied to cases of arthrogryposis multiplex congenita secondary to involvement of either anterior horn cell or peripheral nerve (see Chapter 17). Obvious overlap exists with type 0 SMA and with the SMA variants just discussed. I prefer to use the term neurogenic arthrogryposis multiplex congenita for the clearly nonprogressive forms of arthrogryposis related to anterior horn cell or peripheral nerve disease. By far the most common variety is amyoplasia congenita related to a dysgenetic disturbance of anterior horn cells, described in Chapter 17. Thus, because this generalized form of arthrogryposis multiplex congenita secondary to anterior horn cell has been discussed, I consider in this section only the localized forms. Cervical Form. A group of infants with a cervical form of anterior horn cell disease and arthrogryposis was described.129-132 The striking findings in the neonatal
period were signs of severe symmetrical lower motor neuron deficit in the upper extremities in the absence of a history suggestive of traumatic injury of spinal cord or brachial plexus. Atrophy and flaccid weakness of upper extremities and the proximal and distal muscle groups were marked, and flexor contractures at the elbow and interphalangeal joints were apparent. Bulbar muscles were not affected. Lower extremities were normal. The course was nonprogressive. Onset in utero was suggested by the presence of flexion contractures, and onset in the first trimester was suggested by the presence of poorly formed palmar creases. The nature of the intrauterine insult to cervical anterior horn cells was not clear. One patient with a clinically similar case had intramedullary telangiectasia.133 Caudal Form. A caudal form of anterior horn cell disease with arthrogryposis was described as an apparently sporadic disorder with involvement localized to the lower extremities.134,135 Weakness, hypotonia, areflexia, and multiple joint contractures were the major features. A few patients later developed signs in the upper extremities and fasciculations of the tongue after several years.134 Whether these cases represent a different disorder from the SMA variant with predominant lower limb weakness described earlier (see Table 18-7) is unknown. Laboratory Studies. EMG and muscle biopsy in both the generalized and local forms of neurogenic arthrogryposis multiplex congenita usually demonstrate signs of denervation (see Chapter 17). In the localized forms, the possibility of a correctable structural lesion of the cervical cord or the lumbosacral cord and cauda equina should be ruled out by appropriate studies. Type II Glycogen Storage Disease (Pompe Disease) Type II glycogen storage disease, Pompe disease, is an inherited disorder, transmitted in an autosomal recessive manner. The disease is associated with glycogen deposition in anterior horn cells (as well as in skeletal and
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cardiac muscle, liver, and brain) and with striking weakness and hypotonia in early infancy. Clinical Features Onset. Onset of the Pompe disease may be apparent in the first days of life, although the median age at symptom onset in the largest series (n = 168) was 2.0 months.24,136-141 Neurological Features. Initially, the weakness and hypotonia may be so severe that type 1 SMA is considered the probable diagnosis. The concurrence of fasciculations of tongue and difficulty sucking, crying, and swallowing further mimics this primary anterior horn cell degeneration. However, several clinical features help to distinguish Pompe disease from WerdnigHoffmann disease. First, cardiac involvement, resulting from accumulation of glycogen, is prominent in Pompe disease; radiographs demonstrate an enlarged globular heart, and electrocardiograms demonstrate evidence of myocardiopathy with shortened PR interval, elevated R waves, and inverted T waves. Second, the tongue, although weak and perhaps even fasciculating, is usually large in Pompe disease because of the glycogen accumulation, unlike the small, atrophic tongue of Werdnig-Hoffmann disease. Third, the skeletal muscles, although weak, are usually prominent in Pompe disease, because of glycogen accumulation (i.e., a true hypertrophy), and they have a characteristic rubbery feel. This finding is unlike the atrophy of WerdnigHoffmann disease. Fourth, the liver usually is enlarged and readily palpable in Pompe disease. Tendon reflexes are variable in glycogen storage disease. Most patients have preserved tendon reflexes early in the clinical course and later have total areflexia. A recent report described a delay in myelination, determined by MRI, in five patients with infantileonset Pompe disease.142 The clinical correlates of this disturbance remain to be clarified. Deposition of glycogen is a feature of human oligodendroglial development. Clinical Course. The clinical course is malignant. Infants require ventilatory support at a median age of 6 months, and death in one large series (n = 168) occurred at a median age of approximately 9 months.141 In another series (n = 153), the median age at death was 6 months.140 Survival rates at 12 months of age are approximately 25%, with only 17% ventilator free; at 18 months, the respective values are 12% and 7%.141 Death is related usually to a combination of cardiac involvement and respiratory complications caused by thoracic muscle weakness and bulbar paralysis. Laboratory Studies. The serum CK level is elevated because of cardiac and skeletal muscle involvement, and the serum transaminases also are usually elevated because of the combination of muscle and hepatic disease, with the former predominating.136,140 Muscle biopsy reveals large amounts of periodic acid–Schiff– positive material. Large vacuoles are apparent when
standard fixation procedures are used, although some periodic acid–Schiff–positive material usually remains.143 The EMG reveals fibrillations but often also signs of myopathic disorder because of prominent muscle involvement (see Chapter 19). An additional characteristic feature is ‘‘irritability’’ of muscle with the occurrence of pseudomyotonic bursts of discharges. The large R waves on electrocardiography are particularly helpful signs in diagnosis. Neuropathology. The neuropathology of Pompe disease is characterized by a striking increase in glycogen throughout the central and peripheral nervous systems (including the myenteric plexus of rectal mucosa). The accumulation of glycogen in the anterior horn cells is the most striking change.144 Pathogenesis and Etiology. The biochemical defect involves alpha-glucosidase (acid maltase) activity (Fig. 18-7).138,145,146 This enzyme catalyzes the lysosomal pathway of glycogen degradation, presumably used during normal turnover of cellular constituents. (The major pathway of glycogen degradation, used for glucose-6-phosphate production, occurs in the cytosol and is catalyzed by phosphorylase.) Thus, in Pompe disease, the largest accumulation of glycogen is apparent in lysosomal structures. The enzymatic defect is demonstrable in muscle or cultured fibroblasts.146,147 Moreover, the enzyme is also present in fibroblasts grown from amniotic fluid cells, and this procedure can be used for prenatal diagnosis.139,148 Management. Attempts to replenish alpha-glucosidase by bone marrow transplantation have been unsuccessful.149 However, very promising preliminary results are available for the use of enzyme replacement therapy, involving recombinant human alpha-glucosidase, at least for survival and cardiac and skeletal muscle function.150-152 Additionally, a recent study of five infants treated from a median age of 6 months showed improvement in myelination by MRI in four of the patients.142 Neonatal Poliomyelitis Neonatal poliomyelitis in this section refers to infection with poliovirus acquired either in utero or in the first 4 weeks of life. Only one case has been reported in the United States in the approximately 40 years since the widespread use of live oral poliovirus vaccine (Sabin vaccine).153 An additional infantile case with onset at 3 months of age occurred 1 month after administration of live oral polio vaccine.154 However, poliomyelitis at later ages is still observed, not only in other parts of the world but in the United States among certain religious groups that prohibit vaccination of children. In addition, approximately nine cases per year of poliomyelitis caused by vaccine-related poliovirus still occur in the United States. Indeed, the single neonatal case reported in the past 3 decades in this country acquired the infection by contact with a recently vaccinated infant with diarrhea.153 Moreover, other enteroviruses rarely cause
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
777
GLYCOGEN Phosphorylase V, VI
Brancher enzyme IV
α-Glucosidase II
α-1,4-Glucosan
Limit dextrin
Glycogen synthetase IX UDP-glucose
Phosphorylase V, VI Debrancher enzyme III
Glucose-1-phosphate Glucose Phosphoglucomutase Glucose-6-phosphate
Glucose-6-phosphatase I
Figure 18-7 Major steps in glycogen metabolism. The enzymatic sites of disease are as follows: I, glucose-6phosphatase (von Gierke disease); II, alpha-glucosidase or acid maltase (Pompe disease); III, debrancher enzyme; IV, brancher enzyme; V, muscle phosphorylase; VI, liver phosphorylase; VII, phosphofructokinase; VIII, phosphohexose isomerase; IX, glycogen synthetase; and (no numerical designation) phosphoglucomutase. UDP-glucose, uridine diphosphoglucose.
Phosphohexose isomerase VIII Fructose-6-phosphate Phosphofructokinase VII Fructose-1,6-diphosphate
PYRUVATE
a paralytic syndrome in older patients and, theoretically at least, could cause a neonatal disorder comparable to poliomyelitis. For these reasons, brief attention to neonatal poliomyelitis is warranted here.
neuronophagia, and perivascular cuffing with inflammatory cells involve neurons of the anterior horns, motor nuclei of the brain stem, roof nuclei of the cerebellum, diencephalon, and motor cortex of the cerebrum.
Clinical Features Onset. The disorder may be apparent at birth or may develop in the first weeks of life.153,155–159 Because the incubation period of the disease is approximately 10 days, infants affected at birth or in the first week presumably were affected in utero.
Pathogenesis and Etiology. Neonatal poliomyelitis is caused by infection of neurons by poliovirus, a classic neurotropic virus. The acquisition of virus may occur prenatally or early postnatally. The demonstration of maternal viremia and placental infection and the recovery of virus from meconium of stillborn infants of diseased mothers support the concept of intrauterine infection by transplacental mechanisms. Because of the incubation period for poliomyelitis, infants affected after approximately 10 days of age presumably were infected during delivery by contamination with infected stool or by postnatal exposure.
Neurological Features. Most patients present with diffuse flaccid paralysis that is usually asymmetrical.56 Apnea may be the initial clinical feature.153 Not uncommonly, encephalitic involvement results in cerebral signs, including seizures. Respiratory failure may ensue promptly. Moreover, contractures can evolve rapidly, and care must be taken to avoid the postnatal development of arthrogryposis multiplex. Asymmetrical paresis is a common sequel. Laboratory Studies. The diagnosis is established by viral isolation from the stool. CSF pleocytosis with elevated protein content occurs. Neuropathology. The neuropathological features in the newborn are often more severe than in the adult. The qualitative features are similar. Neuronal necrosis,
Management. Management is entirely supportive. LEVEL OF THE PERIPHERAL NERVE Disorders affecting the peripheral nerve are the least defined of those leading to hypotonia and weakness in the neonatal period. However, the more frequent consideration of disorders of peripheral nerve as the cause of motor deficits in neonatal patients, the more frequent use of refined techniques for studying nerve histology, such as electron microscopy, and the
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TABLE 18-8
DISORDERS OF THE MOTOR SYSTEM
Hypotonia and Weakness: Level of the Peripheral Nerve
Chronic Motor-Sensory Polyneuropathy Myelin Hypomyelination* Autosomal recessive Sporadic Hypomyelination and demyelination-remyelination (onion bulbs) Autosomal recessive* Autosomal dominant* Sporadic Other (associated with axonal disease or focal hypermyelination) Chronic inflammatory demyelinating polyneuropathy Neuronal-Axonal (Rare) Autosomal recessive Autosomal dominant Sporadic Subcellular Mitochondrial: disorders of electron transport, pyruvate dehydrogenase Cytoskeletal structures: intermediate filaments (i.e., giant axonal neuropathy), neurofilaments (i.e., infantile neuroaxonal dystrophy) Lysosomal: Krabbe disease Congenital Sensory Neuropathies Familial dysautonomia, congenital sensory neuropathy with or without anhidrosis and mental retardation Acute Polyneuropathy Guillain-Barre´ syndrome *Each accounts for approximately 25% of all chronic infantile motorsensory polyneuropathies.
explosion in application of molecular genetics lead to the conclusion that disease at this level is probably considerably more common than was previously suspected. The major disorders to be considered in the neonatal period are shown in Table 18-8. The categorization is somewhat arbitrary because available reports suggest some overlap, as well as the need for more definitive means of study. Chronic Motor-Sensory Polyneuropathy: Myelin Disease In chronic motor-sensory polyneuropathies (see Table 18-8) we include several groups of cases, somewhat heterogeneous in basic type but readily identified as affected with a disorder of peripheral nerve myelin. The disorders are categorized best as those that appear to involve a failure of the Schwann cell’s role of synthesis and maintenance of myelin (i.e., characterized by hypomyelination). In many cases, an additional feature, related to proliferation of Schwann cells and fibroblasts, is ‘‘onion bulb’’ formation, with evidence of demyelination-remyelination. In a rare third group, the disturbance of myelin is inflammatory. I discuss the two most commonly recognized of these three categories, the hypomyelinative and the hypomyelinative-demyelinating-remyelinating polyneuropathies, together, because their clinical features overlap, and in many respects the disorders are interrelated.
TABLE 18-9
Congenital Polyneuropathy with Hypomyelination and Clinical Onset at Birth*
Clinical Features
Percentage of Total
Neurological Deficits Severe weakness and hypotonia (at birth) Arthrogryposis multiplex congenita
70% 17%
Age of Walking None (most died; see below) With help (11=2–5 yr) Unassisted (2–6 yr)
70% 19% 11%
Outcome Dead (1 hr–41=2 yr) Alive (14 mo–26 yr)
40% 60%
Motor Nerve Conduction Velocity 5 m/sec or unrecordable
96%
Onion Bulbs Absent{ Present{
33% 67%
Major Genes Involved Myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), early growth response element 2 (EGR2), myotubularin-related protein 2 (MTMR2), ganglioside-induced differentiation-associated protein 1 (GDAP1), periaxin (PRX). *See text for references; values shown are percentages of total number of cases for which data are available. All infants had neonatal clinical features and congenital neuropathy with hypomyelination, with or without onion bulbs, on nerve biopsy. {Approximately 85% died (ages 1 hr–41=2 yr). {Of these, 81% survived (14 mo–21 yr).
Congenital Polyneuropathies with Hypomyelination, with or without Demyelination and Remyelination In this group I include those neuropathies associated with hypomyelination alone and those with hypomyelination and evidence of demyelination-remyelination (i.e., onion bulb formation). Those disorders with onion bulb formation were previously termed Dejerine-Sottas disease or hereditary motor sensory neuropathy (HMSN) type III. The principal overall features of the entire group are summarized in Table 18-9.160-215 Clinical Features In most cases, the disorder has its onset in utero and manifests at birth. The dominant neurological features in the neonatal period are hypotonia and weakness. Involvement usually is generalized, and the distal more than proximal involvement characteristic of peripheral nerve disease has been difficult to demonstrate in the newborn period. This pattern of weakness, however, usually becomes obvious after several months. Muscle atrophy is usually marked. Tendon reflexes are very hypoactive or, more often, absent. Arthrogryposis multiplex congenita has been a feature in a number of cases and may be very prominent (see Table 18-9).
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
The involvement of musculature innervated by cranial nerves has been variable. Impairment of feeding is common, but the nature of the disturbance is not usually characterized. Clear involvement of facial movement is not common, and extraocular abnormalities have not been reported. Involvement of the sensory system is a valuable feature to elicit for identification of neuropathy. Elicitation of sensory deficits in the neonatal patient requires very careful examination (see Chapter 3). Definitive evaluation of the sensory system usually also requires electrophysiological data (see later discussion). Most patients (70%) never walk, and only 11% eventually do so unassisted (see Table 18-9). Approximately 40% of infants die, and a clear relation to severity of disease, as reflected in the presence or absence of evidence for demyelination-remyelination (i.e., onion bulbs on nerve biopsy), is apparent. Thus, approximately 85% of infants with absence of onion bulbs have died, whereas 81% of those with onion bulbs survive (see Table 18-9). Three reports of infants with the clinical electrophysiological and pathological features of congenital hypomyelinating polyneuropathy who improved spontaneously after months and were normal or markedly improved at 18 or 19 months and 9 years, respectively, raised the possibility of a transient, reversible form of this disorder.199,200,203 These observations suggest the need for some caution in rendering a dismal prognosis with the neonatal diagnosis of this form of neuropathy.
779
always elevated, even in the first weeks of life. The elevation usually becomes more marked with age, and occasionally a CSF protein concentration that is only marginally elevated in the first weeks of life becomes markedly elevated later in infancy. Neuropathology The diagnosis of peripheral nerve disease is established by examination of a nerve biopsy specimen. The sural nerve, which has a limited distribution over the skin of the foot, is usually chosen for biopsy. The major abnormalities are hypomyelination and onion bulb formation. Hypomyelination. In the congenital hypomyelinative neuropathies, the essential feature has been the virtual absence of myelin sheaths (Fig. 18-8). If any myelin is present, large-diameter nerve fibers, which normally
Laboratory Studies Serum Enzymes. The CK level is normal. Electromyography. The EMG indicates changes of denervation, as outlined in Table 17-7. Nerve Conduction Velocity. Determination of nerve conduction velocity is critical and is too frequently overlooked in the evaluation of the hypotonic and weak newborn. In most severely affected infants, a drastic reduction in motor nerve conduction velocity has been demonstrated, and values of approximately 5 m/second or less are recorded in nearly all (see Table 18-9). In many infants (including several of my patients), impulse transmission could not be detected. The absence of sensory nerve action potentials is also common.216 Muscle Biopsy. Muscle biopsy usually shows evidence of denervation (see Table 17-8), but the muscle histology occasionally may appear remarkably preserved in the presence of severe disease of nerve. The correct diagnosis may be suggested by examination of intramuscular nerves within the biopsy specimen of muscle. Changes seen in full form on nerve biopsy (see later discussion) may be suggested from such examination. Other Studies. The CSF protein concentration is a valuable adjunct to the diagnosis of infantile polyneuropathy. The CSF protein concentration is almost
Figure 18-8 Hypomyelination polyneuropathy. This infant had severe, generalized hypotonia and weakness of facial movement, sucking, swallowing, and limb movement from the first days of life. The cerebrospinal fluid protein level was slightly elevated on several occasions, and motor nerve conduction velocities were markedly reduced to 2 to 3 m/second. The infant died at 91=2 months of age. The electron micrograph shows several axons (arrows), each surrounded by a Schwann cell, one of which is sectioned through its nucleus (N). Note the marked paucity of myelin lamellae. No onion bulb formation is present. (Courtesy of Dr. Andrew W. Zimmerman.)
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are heavily myelinated, are conspicuous by the paucity of myelination. The normal proportion between diameter size and thickness of myelin sheath thus is lost. No signs of myelin destruction can be discerned; the lack of a demyelinating process is supported by biochemical studies, which showed no accumulation of cholesterol ester, the chemical hallmark of demyelination. Accompanying these changes may be a modest proliferation of Schwann cells and endoneurial fibroblasts. Onion Bulb Formation. In many cases, so-called onion bulb formation has been detected. This morphological change is associated with the proliferation of Schwann cells and, to a lesser extent, endoneurial fibroblasts. Individual axons become invested by multiple Schwann cells. The multiple concentric lamellae of Schwann cell processes and, to a lesser extent, collagen fibers render the onion bulb appearance (Fig. 18-9). In the youngest and most severely affected patients, the concentric lamellae consist principally of basement membrane of Schwann cells, there remaining little of Schwann cell plasma membrane.175 In older and usually less severely affected patients, the proliferative changes cause considerable separation of nerve fibers and an increase in the transverse diameter of the nerve, hence the term interstitial hypertrophy. In such patients, nerves may be palpable, particularly the posterior auricular in the neck, the ulnar at the elbow, and the peroneal at the fibular head. Pathogenesis and Etiology The pathogenesis of congenital hypomyelinative neuropathies is diverse but in general involves a disturbance of myelin formation or maintenance. The major genes involved, myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), early growth response element 2 (EGR2), myotubularin-related protein 2 (MTMR2), ganglioside-induced differentiationassociated protein 1 (GADP1), and periaxin (PRX), are either structural myelin or Schwann cell proteins or transcription factors.195,197,201-215,217,218 Congenital hypomyelinative neuropathies overall have occurred sporadically and by autosomal recessive, autosomal dominant, or X-linked recessive inheritance. The last of these is related to a connexin-32 defect and nearly always presents clinically in childhood. The purely hypomyelinative cases have occurred sporadically or by autosomal recessive inheritance. Among the hypomyelinative group with onion bulb formation (Dejerine-Sottas disease or HMSN III), autosomal recessive inheritance is most common, but autosomal dominant inheritance has been defined (often categorized as a subtype of HMSN I or Charcot-Marie-Tooth disease). Autosomal dominant inheritance may be more common than suspected. Thus, when nerve conduction velocity determinations have been performed in apparently unaffected parents of some affected infants, clear evidence of disease has been detected. Indeed, in the series of 20 patients with congenital polyneuropathy described by Hagberg and Lyon,160,192 5 had clear evidence of autosomal dominant inheritance and
appeared to represent the HMSN I or Charcot-MarieTooth disease. The most common genetic defect for the latter phenotype is a duplication of the chromosomal 17p region that contains PMP22.196,212 Although neonatal electrophysiological abnormalities have been identified in 17p duplication cases, clinical neonatal onset is unusual, but it does occur.207 Autosomal dominant point mutations of both PMP22 and P0 have been shown to lead to congenital hypomyelinating neuropathy and could have accounted for the earlier observations of Hagberg and Lyon.195,197,198,201-205 Less commonly, hypomyelinative-demyelinatingremyelinating forms are associated with axonal disease or with focal areas of hypermyelination, in addition to onion bulbs.212,219 These focal myelin thickenings or tomacula, presumably reflect a separate defect in the Schwann cell that differs from those seen in the more typical cases described in Table 18-9. Management Supportive measures (see the earlier discussion of Werdnig-Hoffmann disease) are important, particularly because many patients live for years. It is critical to prevent contractures, scoliosis, and recurrent pulmonary infection and to optimize the motor function that is retained. Chronic Inflammatory Demyelinating Neuropathy Chronic inflammatory demyelinating neuropathy is a relatively common acquired neuropathy of older children and adults. The disorder is important to recognize because it is treatable. It may be apparent in the neonatal period.220–224 Decrease in fetal movement and the occurrence of contractures indicate that prenatal onset may occur. The newborn exhibits a poor suck and is hypotonic and weak. Weakness is either in a distal more than proximal or distal equal to proximal distribution. Areflexia is common. The diagnosis is suggested by the finding of elevated CSF protein level, delayed motor nerve conduction velocities ( autosomal dominant Early ocular involvement: ptosis > ophthalmoparesis Early facial and bulbar involvement Response to anticholinesterase drugs* Diagnosis often requires the following: single-fiber electromyogram; single-nerve stimulation; specific staining for acetylcholine receptors, receptor subunits, acetylcholinesterase; electron microscopy of motor endplate; in vitro electrophysiological studies; molecular genetic analyses *Except for acetylcholinesterase deficiency syndrome and slow-channel and fast-channel syndromes.
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
Pathogenesis and Etiology. Two major types of molecular defect underlying endplate acetylcholine receptor deficiency have been described, and both are inherited in an autosomal recessive manner.* Thus, occurrence in siblings in approximately 50% of families and with consanguineous parents has been documented. Earlier studies indicated that the inherited defects at the neuromuscular junction involved the endplate acetylcholine receptor (see Table 18-13).355,356,380,381 Thus, a deficiency of the number or function of acetylcholine receptors, measured by alpha-bungarotoxin binding studies and electrophysiologically, was defined. The two molecular forms underlying this defect involve a mutation in a subunit protein or in rapsyn, active in receptor clustering. Of the four subunits of the acetylcholine receptor, the epsilon subunit of the receptor is involved in most cases.24,348,349,351-353,364,367,370,382,383 The disorder is usually related to a mutation in the gene for the epsilon subunit and less commonly in the promoter for this subunit. Rapsyn deficiency is only slightly less common than the subunit deficiency. Management. The essential aspects of management involve the use of anticholinesterase medications, as discussed for neonatal transient myasthenia gravis. Anticholinesterase medication is not invariably beneficial.352,353,355,356,370,384 3,4-Diaminopyridine, which increases nerve terminal acetylcholine release, may be beneficial alone or in combination with anticholinesterase medication.385 Steroid therapy and thymectomy have not been useful, in accordance with the nonimmune basis of the disorder. The nonimmune basis is evidenced by the lack of circulating acetylcholine receptor antibodies.304,380 Congenital Myasthenic Syndromes: Congenital Choline Acetyltransferase Deficiency (Familial Infantile Myasthenia or Congenital Myasthenic Syndrome with Episodic Apnea) Congenital choline acetyltransferase deficiency, formerly referred to as familial infantile myasthenia or, more recently, congenital myasthenic syndrome with episodic apnea, is a presynaptic defect and the second most common type of congenital myasthenic syndrome with onset in the neonatal period (see Table 18-13). In contrast to endplate acetylcholine receptor deficiency, this disorder is based on a presynaptic defect. Like endplate acetylcholine receptor deficiency, the disorder is inherited in an autosomal recessive manner and has its onset in the neonatal period.{ However, several features, readily delineated at the patient’s bedside, help to distinguish this form of myasthenia from the transient form and from acetylcholine receptor deficiency (see later discussion).
* {
See references 24,304,348,351-353,355,356,364,367,370,373,378,380.
See references 24,304,352,353,355,356,360,369,372,380,386-392.
789
2 mV
A
1 mV
B
2 msec
Figure 18-14 Electromyogram in familial infantile myasthenia. In this repetitive nerve stimulation study, recordings were obtained from the left abductor digiti minimi using surface stimulating and recording electrodes. A, A 3-Hz stimulation at rest shows no decrement. B, At 4 minutes after 2 minutes of continuous stimulation of ulnar nerve at 10 Hz, a decrement of 54% (fifth/first response) occurred. (From Matthes JW, Kenna AP, Fawcett PRW: Familial infantile myasthenia: A diagnostic problem, Dev Med Child Neurol 33:912–929, 1991.)
Clinical Features. At birth, infants are hypotonic and cyanotic and require resuscitative efforts. Episodes of apnea occur, and prominent feeding difficulties result from deficits of sucking and swallowing. Facial weakness is prominent, but eye movements are normal and usually remain so. Ptosis may be present but is not striking. Generalized weakness is common. After the serious neonatal course, appropriately treated infants (anticholinesterase medication) improve, and spontaneous remission often ensues in the first months of life. However, the disease may recur later in infancy and, indeed, develop so abruptly with respiratory infection that apnea and death result. A family history of sudden infant death syndrome in previously born siblings is not uncommon. In general, despite the episodic course, improvement with age is the rule. Diagnosis at the Bedside. Diagnosis is suspected by observation of a beneficial response to parenteral anticholinesterase medication. A decremental response of the muscle to repetitive nerve stimulation requires more prolonged stimulation (several minutes) and more rapid rates (10 Hz) than required for other neonatal myasthenias (Fig. 18-14). This electrophysiological aspect relates to the fundamental presynaptic defect, which involves acetylcholine synthesis or release (see later discussion). Laboratory Studies. Although decremental responses to repetitive stimulation are present in this disorder, as in the other myasthenic disorders, elicitation of the abnormality may require more prolonged stimulation in familial infantile myasthenia.380,388
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Pathology. No morphological abnormality is demonstrable at the neuromuscular junction. Pathogenesis and Etiology. The inherited defect at the neuromuscular junction is presynaptic in location and in the gene that codes for choline acetyltransferase (CHAT), the rate-limiting enzyme in resynthesis of acetylcholine from acetyl–coenzyme A and choline within the nerve terminal (see Table 18-13).351-353 Management. Anticholinesterase drugs form the cornerstone of therapy. Moreover, therapy should be continued despite improvement or apparent remission, to avoid the occurrence of apnea and sudden death. 3,4-Diaminopyridine may produce transient benefit but then may worsen symptoms as acetylcholine stores are depleted and are not replenished sufficiently quickly. Close surveillance is necessary indefinitely, because serious respiratory exacerbations have been reported, even in adults with this disorder.390 Toxic-Metabolic Defects of the Neuromuscular Junction Various exogenous and endogenous toxins and metabolites may disturb the function of the neuromuscular junction. Of these, the most important for neonatal patients are magnesium and certain antibiotics (see Table 18-11). Hypermagnesemia Neonatal hypermagnesemia may result in a striking paralytic syndrome. The disorder most often is secondary to administration to the mother of large quantities of intravenous magnesium sulfate for the treatment of eclampsia before delivery. Clinical Features. The clinical syndrome is usually apparent at birth with hypoventilation or apnea, severe weakness and hypotonia, and hyporeflexia or areflexia.393-395 In addition to manifestations relating to skeletal muscular involvement, evidence of depression of the central nervous system (e.g., stupor or coma) and disturbed function of smooth muscle (e.g., abdominal distention and absent bowel sounds) may occur. The smooth muscle dysfunction may be so severe that meconium plug syndrome develops.395 Infants provided supportive therapy recover within approximately 3 days, although serum magnesium levels may remain elevated longer. Laboratory Studies. The diagnosis is confirmed by the observation of elevated serum magnesium levels (usually >4.5 mEq/L). Electrophysiological studies with repetitive stimulation demonstrate impaired neuromuscular function.395 Prolonged post-tetanic facilitation and absent post-tetanic exhaustion are characteristic findings.396 Pathogenesis and Etiology. The pathogenesis of weakness and hypotonia with hypermagnesemia relates
to the effect of magnesium at the presynaptic side of the neuromuscular junction, in contrast to the postsynaptic disturbance in neonatal transient myasthenia or endplate acetylcholine receptor deficiency. Hypermagnesemia results in an impairment of release of acetylcholine from the presynaptic nerve ending. This effect is a result of antagonism of the releasing effect of calcium, and, indeed, calcium counteracts the toxic effects of magnesium to a variable degree. Management. Management of hypermagnesemia is based on vigorous support. A clearly beneficial role for calcium supplementation was not supported by the few clinical trials available.394 Hypocalcemia, however, should be particularly avoided. Exchange transfusion has been useful in the management of the very severely affected infant who is not responsive to supportive therapy.397 Antibiotics Certain antibiotics, particularly the aminoglycosides, may disturb neuromuscular function. The drugs reported to have toxic effects include kanamycin, gentamicin, neomycin, colimycin, streptomycin, and polymyxin.398-400 Drug-induced cases have been recorded in the neonatal period.398,401 Although this disorder has not been recognized in infants with myasthenia, the particular sensitivity of older patients with myasthenia to these drugs399,402 makes it imperative in infants with myasthenia to avoid their use or, when necessary, to use such drugs under carefully controlled conditions. A similar conclusion applies to infants with botulism (see subsequent discussion). Clinical Features. The clinical syndrome in otherwise neurologically normal infants has occurred most commonly with the administration of large quantities of drug, such as at the time of abdominal surgery (intraperitoneal lavage) or pulmonary surgery (intrapleural lavage), retrograde pyelography, and intravenous therapy. Postoperative occurrence has been associated with the combined use of a curare-type drug during anesthesia and an aminoglycoside antibiotic following surgery. Evolution to apnea, bulbar paralysis, and generalized flaccid paralysis occurs within 2 hours.398 Additional diagnostic signs, when present, include pupillary dilation, atonic bladder, and paralytic ileus. Laboratory Studies. The diagnosis is based usually on clinical evidence, although electrophysiological studies demonstrate impaired neuromuscular transmission.399 Pathogenesis and Etiology. The pathogenesis of the neuromuscular disturbance is impairment of presynaptic mobilization of acetylcholine caused by the antibiotic per se.400 Management. Management principally consists of recognition of the syndrome and elimination of the source of the excessive amount of drug. Support of respiration is critical. Neostigmine has been used
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
with benefit.398 Calcium may play an adjunct role, and, at the least, hypocalcemia should be corrected promptly.
TABLE 18-15
Infantile Botulism versus Congenital Myasthenic Syndrome Infantile Botulism
Congenital Myasthenic Syndrome
+
±
+ + +
+
Infantile Botulism Clearly recognized for the first time in 1976,403 infantile botulism is a relatively common disorder. The infantile disease is the result of intestinal infection by Clostridium botulinum, rather than ingestion of preformed toxin, as in the more common form of botulism observed in older patients. Previously reported infants with ‘‘acute polyneuropathy’’ probably include those with botulism.404 More than 1000 cases have been identified in the United States, and currently approximately 70 to 100 cases per year are reported. The disorder has been identified in countries around the world.43,405420 Many other infants with transient hypotonia and weakness may represent unidentified cases of infantile botulism. Clinical Features Onset. Infantile botulism has a characteristic time of onset, between approximately 2 weeks and 6 months of age, with a median age of 10 weeks.43,403407,409,410,416,417,419-428 Thus, although most cases have occurred after the neonatal period, approximately 15% manifest in the first month, and infants as young as 54 hours and 6 days of age have been symptomatic with the disease.411-415,418,419 The patient’s presenting problems are usually constipation, poor feeding, hypotonia, and weakness. Neurological Features. A striking neurological syndrome evolves over days, usually within a week after initial constipation, floppiness, and feeding problems. Almost invariable features include facial diplegia, weak suck, weak cry (‘‘mewlike’’ or ‘‘sheeplike’’), impaired swallowing and gag, peripheral weakness, and hypotonia. The resulting paucity of facial expression and minimal limb movement also gives the appearance of ‘‘lethargy.’’ The paralytic process usually progresses in a descending direction (in contrast to the ascending direction in Guillain-Barre´ syndrome) and is generally symmetrical (in contrast to the asymmetrical flaccid paralysis in poliomyelitis). Ptosis is relatively common, but disturbances of extraocular function occur only in the minority of patients. Particularly helpful in diagnosis are the nearly invariable abnormalities of pupillary function. Pupillary size is most often midposition or dilated, and reaction to light is absent or is recognizably impaired. The pupillary abnormality is accentuated readily (or made apparent when not clear) by repetitive elicitation of the pupillary light reflex. Thus, an initially nearly normal response fatigues rapidly. Pupillary abnormality is the most helpful clinical feature distinguishing this disorder from congenital myasthenic syndromes (Table 18-15). Clinical Course. The course of the disorder is variable, and, with increasing recognition of the illness, less severely affected cases have been
Generalized hypotonia and weakness Facial weakness, ptosis Pupillary abnormality Constipation Response to anticholinesterase Electromyogram +, Present;
791
+ Incremental response
Decremental response
, absent; ±, variable.
recognized.43,405,406,408-410,412,419,420Evolution usually occurs over several or more days, except in rare cases in which evolution to a nadir in hours or a day or so can occur (see botulinum serotype F, later). In most cases, tube feeding is required. Ventilatory support is needed in approximately 70% of cases, from a few days to months.410,412,421 The duration of the illness has been as long as 4 months, but 1 to 2 months is more common.43,412,419,421,428 In earlier reports, among approximately 200 confirmed cases, the fatality rate was approximately 2%.407,410 A later study of 57 infants found no fatalities.412 Approximately 5% of infants experience a relapse within 1 to 2 weeks,429,430 but in general the disorder is self-limiting. A role for this disorder in the genesis of sudden infant death syndrome was suggested by epidemiological and microbiological data. Thus, Arnon and coworkers,423 in 280 autopsy studies in infants, isolated C. botulinum from 10. Of these infants, 9 suffered sudden infant death syndrome and represented 4.3% of all cases of the syndrome in the series. Subsequent observations added support for a relationship between infantile botulism and sudden infant death syndrome,419,431,432 although the possibility that the relationship does not hold for all regions was suggested by other data.43,419,433,434 More importantly, these observations emphasize the suddenness and rapidity with which the disease may evolve.419,423,431,432 The abrupt onset of apnea or need for mechanical ventilation near the onset of this disease, or both, is common in neonatal cases.43,414-416,419 Laboratory Studies. With few exceptions, serum enzyme levels, CSF protein concentration, nerve conduction velocities, and muscle biopsy have been normal. The diagnosis is established by observing, in this clinical setting, three consistent EMG findings. The first, observed in more than 90% of cases, is an incremental response in the muscle action potential produced by high rates (20 and 50 Hz) of repetitive nerve stimulation, a finding characteristic of a presynaptic neuromuscular blockade (Fig. 18-15).43,396,427 This so-called tetanic facilitation results from enhanced acetylcholine release as a consequence of increased intracellular calcium concentration at the presynaptic terminal. The
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5 Hz
10 Hz
20 Hz
A 50 Hz
100 µV
3 msec
Figure 18-15 Electromyogram in infantile botulism: incremental response obtained with repetitive stimulation of the left median nerve from the innervated abductor pollicis brevis at the rates shown. A striking incremental response is observable at the higher rates of stimulation, especially at 50 Hz. (From Cornblath DR, Sladky JT, Sumner AJ: Clinical electrophysiology of infantile botulism, Muscle Nerve 6:448, 1983.)
related post-tetanic facilitation is also a feature of the disorder. The second consistent finding consists of the presence of prolonged post-tetanic facilitation (>120 seconds) and the absence of posttetanic exhaustion.396 The third consistent finding is the brief-duration, smallamplitude, overly abundant motor unit potentials (BSAP) pattern (Fig. 18-16).43,396,427 This pattern is caused by presynaptic block of many motor units but not of all the axonal terminals in the units.435 (Additional findings include abnormal spontaneous activity [e.g., fibrillations], observed in approximately 50% of cases and caused by functional denervation of the muscle fibers.216,427) The EMG may be normal initially,412,413 but usually a repeat study shows the characteristic findings. Indeed, if all three of the consistent EMG findings are present, and hypermagnesemia is excluded, the diagnosis of infantile botulism is considered the only possibility.396 Isolation of C. botulinum from the stool is an important diagnostic adjunct. Pathology. Muscle biopsy is normal.421 This observation is to be expected in view of the nature of the defect (see following discussion). Pathogenesis and Etiology. The defect at the neuromuscular junction is presynaptic in location. The botulinum toxin impairs acetylcholine release from cholinergic nerve terminals.43,419,436-440 The neurotoxin is composed of a heavy chain (100 kDa) and a light chain (50 kDa). The heavy chain binds to specific gangliosides on the nerve terminal, the toxin then enters the nerve ending, and the light chain separates and carries
B Figure 18-16 Electromyogram in infantile botulism: brief-duration, small-amplitude, overly abundant motor unit potentials (BSAP). A, Normal pattern of infant muscle. B, Brief-duration, small-amplitude, overly abundant (for the amount of power exerted) motor unit potentials (i.e., BSAP pattern) from an infant with botulism. (From Johnson RO, Clay SA, Arnon SS: Diagnosis and management of infant botulism, Am J Dis Child 133:586–593, 1979.)
out proteolytic attack on specific proteins involved in synaptic vesicle docking and exocytosis. Botulinum neurotoxin types A and B, produced by C. botulinum, account for nearly all cases of infantile botulism, whereas neurotoxin types E and F, produced by Clostridium butyricum and Clostridium barati, respectively, account for isolated cases. The cases caused by types E and F evolve more rapidly and recover more promptly than do the cases caused by types A and B. In the United States, cases caused by type A neurotoxin are most prevalent west of the Mississippi River, and those caused by type B neurotoxin are more common east of the Mississippi River. As just noted, the source of the toxin is C. botulinum (or rarely C. barati or C. butyricum) infection in the gastrointestinal tract.43,403,419,421-423,425 Thus, this disorder is a toxic infection, in contrast to the more widely recognized type of botulism observed in older patients (i.e., ingestion of preformed toxin, or toxic ingestion). The source of the organism has been difficult to establish, in part because of its wide distribution in soil and dust. After the initial recognition of infantile botulism, epidemiological and laboratory investigations, particularly of hospitalized patients with infantile botulism in California, led to the conclusion that 35% of the cases were caused by ingestion of honey.425 The honey was
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
found to harbor C. botulinum spores. Subsequent data confirmed the initial observation.405 These findings led to the recommendation that infants less than 1 year of age not be given honey. Later work implicated honey as the source of the organism in only approximately 16% of all cases, and, more important, in infants less than 2 months of age, honey was not a statistically significant factor.43,411 A more recent study of 122 infants reported honey exposure in only 5% to 7%.428 Other patients have had similar Clostridium strains isolated from both their stool and dust in their immediate environment (vacuum cleaners and soil). Indeed, in careful studies in Pennsylvania, honey was not an important source of the organism, but contact with soil and dust was critical.410 Residence near an active residential construction site occurred in 87% of cases in a recent series of 34 cases.420 In two series of infants less than 2 months of age, living in a rural area or on a farm was the only significant predisposing factor, a finding further supporting environmental contact with soil and dust as crucial.43,411,415,419 My most recent patient was a 2-week old infant whose father was a landscaper. An interesting recent report described an infant presenting at 54 hours of life with C. barati infection and type F botulinum neurotoxin who was born to parents in a rural setting.418 Remaining to be determined are the host factors (e.g., intestinal flora and immunological status) that allow the infection to become established in the young infant and not in the similarly exposed older child. Early data attributed particular importance to the first few weeks of exposure to food after a diet of only human breast milk.43,409,410 The combination of loss of immunological factors of a human breast milk diet and the dramatic perturbation of gut flora caused by the change to other food may make the infant particularly vulnerable, for the first several weeks after this change, to colonization by the botulinum organism. Clinical and experimental data support this formulation.409,410 However, more important in the youngest infants is poorly developed anaerobic fecal flora, which is important in protection from colonization by C. botulinum.411 Management. The most critical aspects of management are early recognition of infantile botulism, careful surveillance, particularly of respiratory status, and intervention at the early signs of ventilatory compromise. The disease can evolve exceedingly rapidly. Tube feeding and ventilatory support may be required for many days or weeks. Aminoglycosides should be avoided particularly; these antibiotics have been shown to potentiate muscular weakness and to precipitate respiratory failure in infantile botulism because of their effect on acetylcholine release at the neuromuscular junction.43,419,441 A major advance in therapy has been the use of human botulism immune globulin for use in infant botulism.419,420,428,428a This preparation is derived from pooled plasma of adults immunized with pentavalent botulinum toxoid and selected for high titers of antibodies versus type A and B toxin. When this preparation is administered early in the course of the disease,
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Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
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Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
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Papazian O: Transient neonatal myasthenia gravis, J Child Neurol 7:135141, 1992. 310. Batocchi AP, Majolini L, Evoli A, Lino MM, et al: Course and treatment of myasthenia gravis during pregnancy, Neurology 52:447-452, 1999. 311. Tellez-Zenteno JF, Hernandez-Ronquillo L, Salinas V, Estanol B, et al: Myasthenia gravis and pregnancy: Clinical implications and neonatal outcome, BMC Musculoskelet Disord 5:42, 2004.
312. Podciechowski L, Brocka-Nitecka U, Dabrowska K, Bielak A, et al: Pregnancy complicated by myasthenia gravis: Twelve years experience, Neuro Endocrinol Lett 26:603-608, 2005. 313. Hoff JM, Daltveit AK, Gilhus NE: Myasthenia gravis: Consequences for pregnancy, delivery, and the newborn, Neurology 61:1362-1366, 2003. 314. Morel E, Eymard B, Vernet-der Garabedian B, Pannier C, et al: Neonatal myasthenia gravis: A new clinical and immunologic appraisal on 30 cases, Neurology 38:138-142, 1988. 315. Heckmatt JZ, Placzek M, Thompson AH, Dubowitz V, et al: An unusual case of neonatal myasthenia, J Child Neurol 2:63-66, 1987. 316. Vial C, Charles N, Chauplannaz G, Bady B: Myasthenia gravis in childhood and infancy: Usefulness of electrophysiologic studies, Arch Neurol 48:847-849, 1991. 317. Hays RM, Michaud LJ: Neonatal myasthenia gravis: Specific advantages of repetitive stimulation over edrophonium testing, Pediatr Neurol 4:245-247, 1988. 318. Gardnerova M, Eymard B, Morel E, Faltin M, et al: The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn, Neurology 48:50-54, 1997. 319. Bassan H, Muhlbaur B, Tomer A, Spirer Z: High-dose intravenous immunoglobin in transient neonatal myasthenia gravis, Pediatr Neurol 18:181-183, 1998. 320. Andrews PI, Sanders DB: Juvenile myasthenia gravis. In Jones HR Jr, DeVivo DC, Darras BT, editors: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach, Philadelphia: 2003, Butterworth Heinemann. 321. Carr SR, Gilchrist JM, Abuelo DN, Clark D: Treatment of antenatal myasthenia gravis, Obstet Gynecol 78:485-489, 1991. 322. Moutard-Codou ML, Delleur MM, Doulac O, Morel E, et al: Myasthenie ne´o-natale se´ve`re avec arthrogrypose, Presse Med 16:615-618, 1987. 323. Dulitzky F, Sirota L, Landman J, Homburg R: An infant with multiple deformations born to a myasthenic mother, Helv Paediatr Acta 42:173-176, 1987. 324. Shepard MK: Arthrogryposis multiplex congenita in sibs, Birth Defects Orig Artic Ser 7:127, 1971. 325. Holmes LB, Driscoll SG, Bradley WG: Contractures in a newborn infant of a mother with myasthenia gravis, J Pediatr 96:1067-1069, 1980. 326. Wise GA, McQuillen MP: Transient neonatal myasthenia, Arch Neurol 22:556-565, 1970. 327. Koenigsberger MR, Patten B, Lovelace RE: Studies of neuromuscular function in the newborn. I. A comparison of myoneural function in full term and premature infants, Neuropaediatrie 4:350-361, 1973. 328. Drachman DB: The biology of myasthenia gravis, Annu Rev Neurosci 4:195-225, 1981. 329. Almon RR, Andrew CG, Appel SH: Serum globulin in myasthenia gravis: Inhibition of alpha-bungarotoxin binding to acetylcholine receptors, Science 186:55-57, 1974. 330. Toyka KB, Drachman DB, Pestronk A: Myasthenia gravis: Passive transfer from man to mouse, Science 190:397, 1975. 331. Appel SH, Anwyl R, McAdams MW, Elias S: Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins, Proc Natl Acad Sci U S A 74:2130-2134, 1977. 332. Heinemann S, Merlie J, Lindstrom J: Modulation of acetylcholine receptors in rat diaphragm by anti-receptors sera, Nature 274:65-68, 1978. 333. Reiness CG, Weinberg CB, Hall ZW: Antibody to acetylcholine receptor increases degradation of junctional and extrajunctional receptors in adult muscle, Nature 274:68-70, 1978. 334. Lennon VA, Lambert EH: Myasthenia gravis induced by monoclonal antibodies to acetylcholine receptors, Nature 285:238-240, 1980. 335. Kao I, Drachman DB: Myasthenic immunoglobulin accelerates acetylcholine receptor degradation, Science 196:527-529, 1977. 336. Engel AG, Lambert EA, Howard FM: Immune complexes (IgG and C3) at the motor endplate in myasthenia gravis, Mayo Clin Proc 52:267-280, 1977. 337. Keesey J, Lindstrom J, Cokely H: Anti-acetylcholine receptor antibody in neonatal myasthenia gravis, N Engl J Med 296:55, 1977. 338. Nakao K, Nishitani H, Suzuki M, Ohta M, et al: Anti-acetylcholine receptor IgG in neonatal myasthenia gravis, N Engl J Med 297:169-170, 1977. 339. Donaldson JO, Penn AS, Lisak RP, Abramsky O, et al: Anti-acetylcholine receptor antibody in neonatal myasthenia gravis, Am J Dis Child 125:222226, 1981. 340. Ohta M, Matsubara F, Hayashi K, Nakao K, et al: Acetylcholine receptor antibodies in infants of mothers with myasthenia gravis, Neurology 31:1019-1022, 1981. 341. Olanow CW, Lane RJ, Hull KL, Roses AD: Neonatal myasthenia gravis in the infant of an asymptomatic thymectomized mother, Can J Neurol Sci 9:85-87, 1982. 342. Lefvert AK, Osterman PO: Newborn infants to myasthenic mothers: A clinical study and an investigation of acetylcholine receptor antibodies in 17 children, Neurology 33:133-138, 1983. 343. Donat JF, Donat JR, Lennon VA: Exchange transfusion in neonatal myasthenia gravis, Neurology 31:911-912, 1981. 344. Rider LG, Sherry DD, Glass ST: Neonatal lupus erythematosus simulating transient myasthenia gravis at presentation, J Pediatr 118:417-419, 1991.
Chapter 18
Neuromuscular Disorders: Levels above the Lower Motor Neuron to the Neuromuscular Junction
345. Lefvert AK, Bergstrom K, Matell G, Osterman PO, et al: Determination of acetylcholine receptor antibody in myasthenia gravis: Clinical usefulness and pathogenic implications, J Neurol Neurosurg Psychiatry 41:394-403, 1978. 346. Elias SB, Butler I, Appel SH: Neonatal myasthenia gravis in the infant of a myasthenic mother in remission, Ann Neurol 6:72-75, 1979. 347. Tagber RJ, Baumann R, Desai N: Failure of intravenously administered immunoglobulin in the treatment of neonatal myasthenia gravis, J Pediatr 134:233-235, 1999. 348. Engel AG, Ohno K, Milone M, Sine SM: Congenital myasthenic syndromes caused by mutations in acetylcholine receptor genes, Neurology 48:S28-S35, 1997. 349. Engel AG, Ohno K, Sine SM: Congenital myasthenic syndromes, Arch Neurol 56:163-167, 1999. 350. Ohno K, Engel AG: Congenital myasthenic syndromes, Eur J Paediatr Neurol 7:227-228, 2003. 351. Engel AG, Ohno K, Harper CM: Congenital myasthenic syndromes. In Jones HR Jr, DeVivo DC, Darras BT, editors: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach, Philadelphia: 2003, Butterworth Heinemann. 352. Engel AG, Ohno K, Sine SM: Congenital myasthenic syndromes: Progress over the past decade, Muscle Nerve 27:4-25, 2003. 353. Harper CM: Congenital myasthenic syndromes, Semin Neurol 24:111-123, 2004. 354. Cornblath DR: Disorders of neuromuscular transmission in infants and children, Muscle Nerve 9:606-611, 1986. 355. Engel AG: Congenital myasthenic syndromes, J Child Neurol 3:233-246, 1988. 356. Misulis KE, Fenichel GM: Genetic forms of myasthenia gravis, Pediatr Neurol 5:205-210, 1989. 357. Lecky BR, Morgan-Hughes JA, Murray NM, Landon DN, et al: Congenital myasthenia: Further evidence of disease heterogeneity, Muscle Nerve 9:233-242, 1986. 358. Vajsar J, Sloane A, MacGregor DL, Ronen GM, et al: Arthrogryposis multiplex congenita due to congenital myasthenic syndrome, Pediatr Neurol 12:237-241, 1995. 359. Anlar B, Ozdirim E, Renda Y, Yalaz K, et al: Myasthenia gravis in childhood, Acta Paediatr 85:838-842, 1996. 360. Zammarchi E, Donati MA, Masi S, Sarti A, et al: Familial infantile myasthenia: A neuromuscular cause of respiratory failure, Child Nerv Syst 10:347-349, 1994. 361. Ohno K, Hutchinson DO, Milone M, Brengman JM, et al: Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the e subunit, Proc Natl Acad Sci U S A 92:758-762, 1995. 362. Sieb JP, Dorfler P, Tzartos S, Wewer UM, et al: Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency, Neurology 50:54-61, 1998. 363. Harper CM, Engel AG: Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome, Ann Neurol 43:480-484, 1998. 364. Ohno K, Anlar B, Ozdirim E, Brengman JM, et al: Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor, Ann Neurol 44:234-241, 1998. 365. Shen XM, Ohno K, Fukudome T, Tsujino A, et al: Congenital myasthenic syndrome caused by low-expressor fast-channel AChR delta subunit mutation, Neurology 59:1881-1888, 2002. 366. Zafeiriou DI, Pitt M, de Sousa C: Clinical and neurophysiological characteristics of congenital myasthenic syndromes presenting in early infancy, Brain Dev 26:47-52, 2004. 367. Gurnett CA, Bodnar JA, Neil J, Connolly AM: Congenital myasthenic syndrome: Presentation, electrodiagnosis, and muscle biopsy, J Child Neurol 19:175-182, 2004. 368. Webster R, Brydson M, Croxen R, Newsom-Davis J, et al: Mutation in the AChR ion channel gate underlies a fast channel congenital myasthenic syndrome, Neurology 62:1090-1096, 2004. 369. Barisic N, Muller JS, Paucic-Kirincic E, Gazdik M, et al: Clinical variability of CMS-EA (congenital myasthenic syndrome with episodic apnea) due to identical CHAT mutations in two infants, Eur J Paediatr Neurol 9:7-12, 2005. 370. Burke G, Cossins J, Maxwell S, Robb S, et al: Distinct phenotypes of congenital acetylcholine receptor deficiency, Neuromuscul Disord 14:356364, 2004. 371. Bowman JR: Myasthenia gravis in young children, Pediatrics 1:472, 1948. 372. Fenichel GM: Clinical syndromes of myasthenia in infancy and childhood, Arch Neurol 35:97-103, 1978. 373. Simpson JF, Westerberg MR, Magee KR: Myasthenia gravis: An analysis of 295 cases, Acta Neurol Scand Suppl 42:1-27, 1966. 374. Barisic N, Schmidt C, Sidorova OP, Herczegfalvi A, et al: Congenital myasthenic syndrome (CMS) in three European kinships due to a novel splice mutation (IVS7-2A/G) in the epsilon acetylcholine receptor (AChR) subunit gene, Neuropediatrics 33:249-254, 2002. 375. Sieb JP, Kraner MS, Schrank B, Reitter B, et al: Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation, Ann Neurol 48:379383, 2000.
799
376. Burke G, Cossins J, Maxwell S, Owens G, et al: Rapsyn mutations in hereditary myasthenia: Distinct early- and late-onset phenotypes, Neurology 61:826-828, 2003. 377. Ioos C, Barois A, Richard P, Eymard B, et al: Congenital myasthenic syndrome due to rapsyn deficiency: Three cases with arthrogryposis and bulbar symptoms, Neuropediatrics 35:246-249, 2004. 378. Muller JS, Baumeister SK, Rasic VM, Krause S, et al: Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations, Neurology 67:1159-1164, 2006. 379. Namba T, Brunner NG, Brown SB, Muguruma M, et al: Familial myasthenia gravis: Report of 27 patients in 12 families and review of 164 patients in 73 families, Arch Neurol 25:49-60, 1971. 380. Engel AG: Myasthenia gravis and myasthenic syndromes, Ann Neurol 16:519-534, 1984. 381. Vincent A, Cull-Candy SG, Newsom-Davis J, Trautmann A, et al: Congenital myasthenia: Endplate acetylcholine receptors and electrophysiology in five cases, Muscle Nerve 4:306-318, 1981. 382. Nichols P, Croxen R, Vincent A, Rutter R, et al: Mutation of the acetylcholine receptor e-subunit promotor in congenital myasthenic syndrome, Ann Neurol 45:439-443, 1999. 383. Ohno K, Anlar B, Engel AG: Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene, Neuromuscul Disord 9:131-135, 1999. 384. Triggs WJ, Beric A, Butler IJ, Roongta SM: A congenital myasthenic syndrome refractory to acetylcholinesterase inhibitors, Muscle Nerve 15:267272, 1992. 385. Palace J, Wiles CM, Newsom-Davis J: 3,4-Diaminopyridine in the treatment of congenital (hereditary) myasthenia, J Neurol Neurosurg Psychiatry 54:1069-1072, 1991. 386. Greer M, Schotland M: Myasthenia gravis in the newborn, Pediatrics 26:101-108, 1960. 387. Conomy JP, Levinsohn M, Fanaroff A: Familial infantile myasthenia gravis: A cause of sudden death in young children, J Pediatr 87:428430, 1975. 388. Robertson WC, Chun RW, Kornguth SE: Familial infantile myasthenia, Arch Neurol 37:117-119, 1980. 389. Albers JW, Faulkner JA, Dorovini-Zis K, Barald KF, et al: Abnormal neuromuscular transmission in an infantile myasthenic syndrome, Ann Neurol 16:28-34, 1984. 390. Gieron MA, Korthals JK: Familial infantile myasthenia gravis: Report of three cases with follow-up until adult life, Arch Neurol 42:143-144, 1985. 391. Matthes JW, Kenna AP, Fawcett PRW: Familial infantile myasthenia: A diagnostic problem, Dev Med Child Neurol 33:912-929, 1991. 392. Mora M, Lambert E, Engel AG: Synaptic vesicle abnormality in familial infantile myasthenia, Neurology 37:206-214, 1987. 393. Lipsitz PJ: The clinical and biochemical effects of excess magnesium in the newborn, Pediatrics 47:501-509, 1971. 394. Lipsitz PJ, English IC: Hypermagnesemia in the newborn infant, Pediatrics 40:856-862, 1967. 395. Sokal MM, Koenigsberger MR, Rose JS, Berdon WE, et al: Neonatal hypermagnesemia and the meconium-plug syndrome, N Engl J Med 286:823-825, 1972. 396. Gutierrez AR, Bodensteiner J, Gutmann L: Electrodiagnosis of infantile botulism, J Child Neurol 9:362-366, 1994. 397. Brady JP, Williams HC: Magnesium intoxication in a premature infant, Pediatrics 40:100-103, 1967. 398. Percy AK, Saef EC: An unusual complication of retrograde pyelography: Neuromuscular blockade, Pediatrics 39:603-606, 1967. 399. McQuillen MP, Cantor HE, O’Rourke JF: Myasthenic syndrome associated with antibiotics, Arch Neurol 18:402-415, 1968. 400. Wright EA, McQuillen MP: Antibiotic-induced neuromuscular blockade, Ann N Y Acad Sci 183:358-368, 1971. 401. Jones WP: Calcium treatment for ineffective respiration resulting from administration of neomycin, JAMA 170:943-944, 1959. 402. Hokkanen E: The aggravating effect of some antibiotics on the neuromuscular blockade in myasthenia gravis, Acta Neurol Scand 40:346-352, 1964. 403. Pickett J, Berg B, Chaplin E, Brunstetter-Shafer M: Syndrome of botulism in infancy: Clinical and electrophysiologic study, N Engl J Med 295:770772, 1976. 404. Grover WD, Peckman GJ, Berman PH: Recovery following cranial nerve dysfunction and muscle weakness in infancy, Dev Med Child Neurol 16:163-171, 1974. 405. Arnon SS: Infant botulism, Annu Rev Med 31:541-560, 1980. 406. Arnon SS, Damus K, Chin J: Infant botulism: Epidemiology and relation to sudden infant death syndrome, Epidemiol Rev 3:45-66, 1981. 407. Arnon SS, Chin J: Infant botulism. In Wehrle PF, Top F, editors: Communicable and Infectious Diseases, St. Louis, MO: 1981, Mosby. 408. Arnon SS: Infant botulism: A Pan-Pacific perspective, Med J Aust 8:404405, 1983. 409. Long SS: Epidemiologic study of infant botulism in Pennsylvania: Report of the infant botulism study group, Pediatrics 75:928-934, 1985. 410. Long SS, Gajewski JL, Brown LW, Gilligan PH: Clinical, laboratory, and environmental features of infant botulism in southeastern Pennsylvania, Pediatrics 75:935-941, 1985.
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411. Spika JS, Shaffer N, Hargrett-Bean N: Risk factors for infant botulism in the United States, Am J Dis Child 143:828-832, 1989. 412. Schreiner MS, Field E, Ruffy R: Infant botulism: A review of 12 years’ experience at the Children’s Hospital of Philadelphia: Pediatrics 87:159165, 1991. 413. Graf WD, Hays RM, Astley SJ, Mendelman PM: Electrodiagnosis reliability in the diagnosis of infant botulism, J Pediatr 120:747-749, 1992. 414. Hurst DL, Marsh WW: Early severe infantile botulism, J Pediatr 122:909911, 1993. 415. Thilo EH, Townsend SF: Infant botulism at 1 week of age: Report of two cases, Pediatrics 92:151-153, 1993. 416. Cochran DP, Appleton RE: Infant botulism: Is it that rare? Dev Med Child Neurol 37:274-278, 1995. 417. Sheth RD, Lotz BP, Hecox KE, Waclawik AJ: Infantile botulism: Pitfalls in electrodiagnosis, J Child Neurol 14:156-158, 1999. 418. Keet CA, Fox CK, Margeta M, Marco E, et al: Infant botulism, type F, presenting at 54 hours of life, Pediatr Neurol 32:193-196, 2005. 419. Fox CK, Keet CA, Strober JB: Recent advances in infant botulism, Pediatr Neurol 32:149-154, 2005. 420. Thompson JA, Filloux FM, Van Orman CB, Swoboda K, et al: Infant botulism in the age of botulism immune globulin, Neurology 64:2029-2032, 2005. 421. Clay SA, Ramseyer JC, Fishman LS, Sedgwick RP: Acute infantile motor unit disorder, Arch Neurol 34:236-243, 1977. 422. Arnon SS, Midura TF, Clay SA, Wood RM, et al: Infant botulism: Epidemiological, clinical and laboratory aspects, JAMA 237:1946-1951, 1977. 423. Arnon SS, Damus K, Midura TF, Wood RM, et al: Intestinal infection and toxin production by Clostridium botulinum as one cause of sudden infant death syndrome, Lancet 1:1273-1277, 1978. 424. Turner HD, Brett EM, Gilbert RJ, Ghosh AC, et al: Infant botulism in England, Lancet 1:1277-1278, 1978. 425. Arnon SS, Midura TJ, Damus K, Thompson B, et al: Honey and other environmental risk factors for infant botulism, J Pediatr 94:331-336, 1979. 426. Johnson RO, Clay SA, Arnon SS: Diagnosis and management of infant botulism, Am J Dis Child 133:586-593, 1979. 427. Cornblath DR, Sladky JT, Sumner AJ: Clinical electrophysiology of infantile botulism, Muscle Nerve 6:448, 1983.
428. Arnon SS, Schechter R, Maslanka SE, Jewell NP, et al: Human botulism immune globulin for the treatment of infant botulism, N Engl J Med 354:462-471, 2006. 428a. Arnon SS: Creation and development of the public service orphan drug human botulism immune globulin, Pediatrics 119:785-789, 2007. 429. Glauser TA, Maguire HC, Sladky JT: Relapse of infant botulism, Ann Neurol 28:187-189, 1990. 430. Ravid S, Maytal J, Eviatar L: Biphasic course of infant botulism, Pediatr Neurol 23:338-340, 2000. 431. Peterson DR, Eklund MW, Chinn NM: The sudden infant death syndrome and infant botulism, Rev Infect Dis 1:630-636, 1979. 432. Sonnabend O, Sonnabend W: Different types of Clostridium botulinum (A, D and G) found at autopsy in humans. II. Pathological and epidemiological findings in 12 sudden and unexpected deaths. In Lewis GE, editor: Biomedical Aspects of Botulism: Proceedings of an International Conference, New York: 1981, Academic Press. 433. Brown LW: Infant botulism, Adv Pediatr 28:141-157, 1981. 434. Gurwith MJ, Langston C, Citron DM: Toxin-producing bacteria in infants: Lack of association with sudden infant death syndrome, Am J Dis Child 135:1104-1106, 1981. 435. Engel WK: Brief, small, abundant motor unit action potentials: A further critique of electromyographic interpretation, Neurology 25:173-176, 1975. 436. Ambache N: The peripheral action of Clostridium botulinum toxin, J Physiol 108:127-141, 1949. 437. Brooks VB: The action of botulinum toxin on motor-nerve filaments, J Physiol 134:264-277, 1956. 438. Thesleff S: Neurophysiologic aspects of botulism poisoning. In Lewis GE, editor: Biomedical Aspects of Botulism: Proceedings of an International Conference, New York: 1981, Academic Press. 439. Montecucco C: How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem Sci 11:314-317, 1986. 440. Dressler D, Saberi FA: Botulinum toxin: Mechanisms of action, Eur Neurol 53:3-9, 2005. 441. L’Hommedieu C, Stough R, Brown L, Kettrick R, et al: Potentiation of neuromuscular weakness in infant botulism by aminoglycosides, J Pediatr 95:1065-1070, 1979.
Chapter 19 Neuromuscular Disorders: Muscle Involvement and Restricted Disorders Muscle, the final component of the motor system, is the site of abnormalities with those essential clinical manifestations of hypotonia and weakness that unify the other disorders of the motor system (see Chapter 18). In this chapter, I deal with important myopathic disorders in the neonatal patient. In addition, certain restricted disorders of the motor system are reviewed. LEVEL OF THE MUSCLE Disorders of muscle account for a substantial proportion of infants affected with hypotonia and weakness. Although a relatively large number of myopathic disorders may cause manifestations in the neonatal period, only a few disorders account for most of the cases observed. Myotonic dystrophy is the most frequent (see subsequent sections). However, more of the myopathic disorders can be detected in the neonatal period if the physician’s index of suspicion is appropriately high. Detection is valuable for purposes of genetic counseling, determination of prognosis, and institution of therapy. The major myopathic disorders of interest in newborns may be categorized into two broad groups: those in which the histology, although sometimes impressive, is not distinctive enough to be diagnostic, and those in which the histology is distinctive enough to be diagnostic (with some qualifications) (Table 19-1). In the following discussions, major emphasis is placed on the most common disorders. Myopathic Disorders with Nondiagnostic Histology Several disorders are characterized by neonatal hypotonia and weakness and by muscle histological findings that are sometimes impressive, although not distinctive enough to be diagnostic. This category includes the most frequently encountered examples of myopathic disease with clinical manifestations evident in the neonatal period. Myotonic dystrophy is the most common of all, although congenital muscular dystrophy (CMD) is not rare (see Table 19-1). Facioscapulohumeral dystrophy (FSHD) rarely manifests in the neonatal period but is important to recognize. Polymyositis is a rare but treatable muscle disorder in the newborn. Congenital myopathy with minimal or no change as determined by
current laboratory investigation (i.e., minimal change myopathy) represents a shrinking group as diagnostic techniques improve. Congenital Myotonic Dystrophy Congenital myotonic dystrophy is an inherited disorder of muscle that exhibits numerous distinctive differences from myotonic dystrophy of adult patients. The disorder may be associated with muscle weakness so severe that death results in the newborn period. The hallmark of congenital myotonic dystrophy is hypotonia, rather than myotonia, as observed in adult patients. The congenital form of myotonic dystrophy was first described clearly by Vanier in 1960.1 Clinical Features. The disorder is usually apparent in the first hours and days of life. Certain characteristics of the pregnancy often precede the neonatal disorder (Table 19-2) and tend to be prominent in the most severely affected cases. Thus, spontaneous abortion or premature birth occurs in the most severely affected infants.2-7 Polyhydramnios is a common characteristic of the pregnancy (see Table 19-2). Indeed, this sign is almost invariable in the most severely affected infants and is thought to be caused by the disturbance in swallowing.3,8-12 Polyhydramnios in a mother with myotonic dystrophy is a fairly reliable indicator of serious involvement of the fetus. Abnormalities of labor, which may be either prolonged or abbreviated, have been attributed to maternal uterine muscle involvement.2,9 The clinical features in the neonatal period are usually marked and characteristic (see Table 19-2).1,3-5,8,12-26 In the well-established case, the most striking clinical features are facial diplegia, respiratory and feeding difficulties, arthrogryposis (especially of the lower extremities), and hypotonia. The facial diplegia imparts the characteristic tent-shaped appearance to the upper lip (Fig. 19-1). The respiratory difficulties relate to weakness of respiratory muscles, impaired swallowing and handling of secretions, and occasionally diaphragmatic disturbance (Fig. 19-2). At least 80% of patients require mechanical ventilation. The respiratory impairment may be so severe that the newborn infant fails to establish adequate ventilation and suffers an asphyxial episode that so dominates the clinical syndrome that the myopathic origin of the respiratory failure is overlooked. The feeding difficulties involve both sucking and swallowing and are related particularly to weakness 801
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TABLE 19-1
DISORDERS OF THE MOTOR SYSTEM
Hypotonia and Weakness: Level of the Muscle
Histology Not Diagnostic Congenital myotonic dystrophy Congenital muscular dystrophy Facioscapulohumeral dystrophy Polymyositis Minimal change myopathy
Clinical Features of Congenital Myotonic Dystrophy
Clinical Feature
Cases Exhibiting Feature*
Reduced fetal movements Polyhydramnios Premature birth (< 36 wk) Facial diplegia Feeding difficulties Hypotonia Atrophy Hyporeflexia or areflexia Respiratory distress Arthrogryposis Edema Elevated right hemidiaphragm Transmission by mother Neonatal mortality Mental retardation in survivors
Histology Diagnostic Central core disease Nemaline (rod body) myopathy Myotubular (centronuclear) myopathy Congenital fiber type disproportion Multi-minicore disease Mitochondrial myopathies Cytochrome c oxidase deficiency Mitochondrial DNA depletion Metabolic myopathies Glycogen disorders Lipid disorders
68% 80% 52% 100% 92% 100% 100% 87% 88% 82% 54% 49% 100%{ 41% 100%
*See text for references. {Paternal transmission has been documented, albeit very rarely.
of the facial, masticatory, and pharyngeal musculature. (A role for myotonia of pharyngeal muscles is possible.11) A disturbance of gastric motility, a manifestation of the smooth muscle involvement in this disorder, may contribute in a major way to the feeding difficulties in some infants.27 Arthrogryposis (Fig. 19-3) is almost invariable and usually involves at least the ankles. Indeed, in one large series of arthrogryposis multiplex congenita, 50% of the patients with cases related to muscle disease had congenital myotonic dystrophy.28 Hypotonia also is essentially invariable, accompanied by weakness and, in approximately 90% of the cases, by areflexia or marked hyporeflexia. Atrophy is usually obvious, especially after the first days of life, when edema, which is often excessive in these infants, subsides.3 Clinical myotonia, elicited by percussion of such muscles as the deltoid, has been detected as early as 3 hours of age,14 but it usually is not readily elicited until much later in infancy.
A
TABLE 19-2
B
Less severely affected infants may go undetected in the newborn period. Facial weakness and hypotonia are the two most common manifestations in such patients. The clinical course relates clearly to the severity of the disease. Neonatal mortality is generally approximately 15% to 20%, but it is as high as approximately 40% in severely affected patients. Feeding difficulties, which initially may require institution of tube feedings, usually improve, at least in reported survivors.4,5,8,11,12,25,26 However, approximately 20% of infants surviving to adolescence and young adulthood have major gastrointestinal symptoms (e.g., diarrhea and abdominal pain), presumably reflecting smooth muscle involvement.2,17,29 Moreover, the persistence of some degree of pharyngeal and palatal weakness leads to recurrent otitis media in approximately 25%, occasionally with accompanying hearing loss.17 Like the neonatal feeding difficulties, the respiratory difficulties subside over the ensuing weeks. However, approximately one third of
C
Figure 19-1 Congenital myotonic dystrophy: facial appearance in the neonatal period. A, Note the bilateral ptosis and facial diplegia with tentshaped appearance of upper lip. B, Note retrognathia caused by muscle weakness but often mistakenly attributed to a structural anomaly. C, Another affected infant; note the facial diplegia, tented upper lip, and retrognathia. (A and B, From Dodge PR, Gamstorp I, Byers RK, Russell P: Myotonic dystrophy in infancy and childhood, Pediatrics 35:3–19, 1965; C, from Swift TR, Ignacio OJ, Dyken PR: Neonatal dystrophia myotonica, Am J Dis Child 129:734-737, 1975.)
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
803
A
Figure 19-2 Congenital myotonic dystrophy: diaphragmatic involvement. This radiograph of the chest is from a newborn with congenital myotonic dystrophy. The right hemidiaphragm is elevated and paralyzed. Note also the thin ribs, characteristic of severe congenital neuromuscular disease. (From Sarnat HB: Neuromuscular disorders in the neonatal period. In Korobkin R, Guilleminault C, editors: Advances in Perinatal Neurology, vol 1, New York: 1978, Spectrum Publications.)
patients require mechanical ventilation for longer than 30 days.26 Even after cessation of mechanical ventilation, ventilatory reserve may be compromised in severely affected infants, and death secondary to respiratory complications in association with anesthesia or aspiration may occur later in infancy.5,17,26 Unlike the general improvement in neonatal feeding and in respiratory difficulties, facial diplegia usually becomes more obvious as ‘‘baby fat’’ disappears; ptosis often becomes apparent as well. Muscle weakness, which initially is generalized or more marked proximally, begins to assume the distal preponderance characteristic of the adult disease. Clinical myotonia becomes elicitable later in infancy (Fig. 19-4) and is present in the majority of patients after the age of 5 years.15 Cardiac muscle involvement, manifested by electrocardiographic
B Figure 19-4 Clinical myotonia in an 11-month-old infant. A, Blinking was precipitated by a bright flash of light. B, This photograph was taken approximately 15 seconds later. Note the persisting partial closure of the eyelids caused by myotonia of the orbicularis oculi muscles and also the temporal hollowing, suggesting atrophy. (From Dodge PR, Gamstorp I, Byers RK, Russell P: Myotonic dystrophy in infancy and childhood, Pediatrics 35:3-19, 1965.)
abnormalities, also becomes more prominent later in infancy. However, in very severely affected newborns, cardiomyopathy may be apparent in the newborn period and may contribute to neonatal demise.30,31 (Cataracts, baldness, gonadal atrophy, and marked facial atrophy develop later in adult life.)
Figure 19-3 Congenital myotonic dystrophy: arthrogryposis. This affected newborn exhibits contractures at the hips, knees, and ankles. Note also the facial diplegia with a tented upper lip. (From Sarnat HB, O’Connor T, Byrne PA: Clinical effects of myotonic dystrophy on pregnancy and the neonate, Arch Neurol 33:459-465, 1976.)
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Impairment of motor and intellectual development is apparent in the first weeks of life (see Table 19-2). Mental retardation is essentially invariable in infants with congenital myotonic dystrophy who survive the neonatal period.4,5,12,32 Intelligence quotient (IQ) scores in the 50 to 65 range have been generally observed. The disturbance of intellectual development is nonprogressive. The only available data on relatively long-term follow-up (i.e., 10 to 30 years) indicated that only 2 of 42 patients managed ‘‘normal education,’’ and only one was ‘‘gainfully employed.’’17 Some improvement in motor function occurs in late infancy and childhood.26 Transmission of myotonic dystrophy in patients with the neonatal form of the disease is essentially always through the mother (see Table 19-2). Only approximately seven cases of congenital myotonic dystrophy transmitted through an affected father have been reported.33-38 At any rate, it is critical for the physician to be cognizant of the disorder as it appears in adults. Indeed, it is common for the mother with an affected infant to be unaware that she has the disease.3-5,25,39 Most helpful in recognition of the disease in the mother is the typical facies of myotonic dystrophy (Fig. 19-5), characterized by atrophy of the masseter and temporalis muscles, ptosis, and a straight, stiff smile. Myotonia is prominent and readily elicited. Thus, active myotonia is seen in the affected woman
Figure 19-5 Congenital myotonic dystrophy: infant and mother. The mother exhibits the typical facial features of myotonic dystrophy, as described in the text. Note also in the affected infant the facial diparesis with a tent-shaped upper lip. (From Dubowitz V: Muscle Disorders in Childhood, Philadelphia: 1978, Saunders.)
when she closes her eyes tightly and then is unable to open them fully for several seconds or more, or when she clenches her fist tightly and then cannot extend her fingers immediately on command. Passive myotonia is demonstrable by percussion of such muscles as the deltoid, thenar eminence, and tongue, and by observation of the prolonged dimpling caused by sustained muscle contraction. Other characteristics (e.g., cataracts, disturbance of intellect, and cardiac abnormality) may also be present. The essential point is that the physician should examine the mother when this diagnosis is considered in a newborn. Laboratory Studies. Serum creatine kinase (CK) level, cerebrospinal fluid (CSF) protein concentration, and nerve conduction velocities are normal. Slender ribs are observed commonly on chest radiographs (see Fig. 19-2) and may suggest the diagnosis in an infant thought initially to have primary asphyxia.40,41 This finding can be observed with other congenital myopathic disorders, as well as with Werdnig-Hoffmann disease.41 The diagnosis is supported particularly by demonstrating myotonic discharges on the electromyogram (EMG). These discharges are difficult to elicit in the neonatal period, although they have been observed as early as 5 days of age.14,39 Electrical myotonia is elicited by movement of the recording needle or by direct percussion of the recorded muscle; this procedure results in repetitive electrical potentials of up to 100/second that wax and wane in frequency and amplitude (Fig. 19-6).4,14,25 These potentials produce the characteristic ‘‘dive bomber’’ sound. Later in infancy, particularly after the age of 2 to 3 years, myotonia is elicited more easily, and small-amplitude, short-duration, and polyphasic potentials, typical of myopathic disease, also can be demonstrated.16 Fibrillation potentials also may be observed.25
Figure 19-6 Electromyogram from an infant with congenital myotonic dystrophy at 5 days of age. The movement of the needle produces a burst of electrical discharges that then subside over several seconds. Calibration: 200 mV, 1 second. (From Swift TR, Ignacio OJ, Dyken PR: Neonatal dystrophia myotonica, Am J Dis Child 129:734737, 1975.)
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
Ventricular dilation has been observed in approximately 80% of newborns studied by ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI).4,5,42-44 In one study, macrocephaly was present in approximately 70% of the infants in the presence or absence of ventricular dilation.43 However, head circumference within the upper one half of the normal range is more common than is overt macrocephaly.5 The ventricular dilation is nonprogressive and is not accompanied by rapid head growth or signs of increased intracranial pressure. The occasional occurrence of periventricular echodensities on ultrasound scans or hyperintensity on subsequent T2-weighted MRI scans may reflect periventricular leukomalacia occurring in association with neonatal respiratory disturbance.42-46 However, this white matter change also could reflect an abnormality of myelination. A small corpus callosum was documented in four of seven infants studied by MRI in another study.44 The possibility of an abnormality in neuronal development was raised by the demonstration by MR spectroscopy of decreased levels of N-acetylaspartic acid, a neuronal marker (see Chapter 4), in five infants and children with congenital myotonic dystrophy.47 Pathology. Muscle pathology in congenital myotonic dystrophy is different from that observed in the adult with the disease and consists particularly of features of immaturity.4,25,30,48,49 In a detailed postmortem analysis of three infants, Sarnat and Silbert and others48,50-52 demonstrated particular involvement of limb muscles around arthrogrypotic joints, pharyngeal muscles, and the diaphragm. The features indicative of a disturbance of maturation included small round muscle fibers with large internal nuclei and sparse myofibrils, reminiscent of fetal myotubes (Fig. 19-7). Moreover, differentiation of fibers into distinct histochemical types was incomplete. Similarly, electron microscopy showed dilated transverse
A
805
tubules that were aligned longitudinally, as in fetal myotubes, as well as poorly formed Z-bands, simple mitochondria, peripheral halo of absent mitochondria, and many satellite cells, which are also features of immature muscle. Investigators have suggested that these changes principally represent an arrest in fetal muscle maturation.48,51 Others have viewed these changes as signs of abnormal development.30 Pathological findings in pancreas (nesidioblastosis), kidney (persistent renal blastemia), and other organs (cryptorchidism and patent ductus arteriosus) support the concept of a disturbance of maturation.53 The neuropathological substrate for the intellectual failure is unclear. A study of three adult patients with subnormal IQ scores by Rosman and Rebeiz54 revealed pachygyria in two and disordered cortical architectonics with neuronal heterotopias in all three. These findings were not observed in a later study of four infants from the same institution.53 However, another report from a different institution also described cerebral cortical neuronal heterotopias in four infants and neuronal heterotopias in two studied post mortem.43 Thus, the neuropathological basis for the consistent impairment of intellect currently is not established conclusively. It seems reasonable to postulate that an aberration of maturation, as in muscle and other organs, is present. A study of the organizational aspects of brain development (see Chapter 2) would be of interest. Pathogenesis and Etiology. The disorder is inherited as an autosomal dominant trait, in virtually every case through the mother. Additionally, the risk of congenital myotonic dystrophy bears a distinct relationship with the disease in the mother.55 The earlier the onset and the more severe the maternal disease, the greater is the risk for the severe congenital form of myotonic dystrophy in the child. This phenomenon is consistent with
B
Figure 19-7 Congenital myotonic dystrophy: muscle pathology. These specimens were obtained at autopsy from an affected infant who never established spontaneous respiration and who died at 14 days of age. Many of the histological features are those of immature muscle. A, Cross section of rectus abdominis. The muscle fibers are small, round, and loosely arranged, and most contain a single, large internal nucleus or a central pale space (hematoxylin and eosin [H & E] stain, 400). B, Longitudinal section of diaphragm. The large vesicular internal nuclei are aligned in rows within the muscle fibers, with clear vacuolated spaces between them. The sarcomeric striations are poorly distinguished (H & E stain, 400). (From Sarnat HB, Silbert SW: Maturational arrest of fetal muscle in neonatal myotonic dystrophy, Arch Neurol 33:466-474, 1976.)
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TABLE 19-3
DISORDERS OF THE MOTOR SYSTEM
Molecular Genetics of Congenital Myotonic Dystrophy*
The disease is associated with an abnormally high number of CTG trinucleotide reports in the 30 -untranslated region of the myotonic dystrophy protein kinase gene (MDPK) on chromosome 19q13.3. The increased number of repeats correlates approximately with earlier onset and more severe disease. The mutation is ‘‘dynamic’’ (i.e., does not remain of constant size within a pedigree or across generations). Maternal transmission is associated with expansion (i.e., increased number) of the repeat region and with more severe disease in the infant (i.e., ‘‘anticipation’’). The extent of repeat expansion varies among tissues (i.e., ‘‘somatic mosaicism’’); thus, determination of the number of repeats in DNA in blood or chorionic villus cannot predict severity of disease in muscle or other tissues with absolute accuracy. The function of MDPK is unknown, but the gene likely affects the function of ion channels; multiple biologic effects may relate to sequestration of multiple RNA and DNA binding proteins by the region of multiple repeats. *See text for references.
anticipation (i.e., the occurrence of progressively earlier onset and more severe disease in successive generations).55,56 Molecular genetic studies have provided major insight into the reasons for anticipation and related aspects of congenital myotonic dystrophy (Table 19-3).4,23-25,55-69 Thus, myotonic dystrophy has been shown to be associated with an increase in the number of specific (CTG) trinucleotide repeats in an unstable DNA region of the 30 untranslated region of the myotonic dystrophy gene, which is located at chromosome 19q13.3. Moreover, the number of repeats increases with maternal transmission of the gene and a correlation of the number of repeats (i.e., the extent of the so-called expansion of the triplet repeat region on chromosome 19) exists with severity and early onset of the disease in the infant. This molecular genetic phenomenon underlies anticipation. Current data suggest that paternal transmission of the unstable trinucleotide repeat is associated with reduced amplification or even contraction of the region of repeats, in contrast to the situation with maternal transmission.36,70 This feature of paternal transmission may be related to negative selection of sperm with large repeat numbers and may explain the exclusively maternal transmission of congenital myotonic dystrophy. At any rate, determination of the number of repeats from a DNA sample of a woman can be used to estimate the likelihood of transmitting severe congenital myotonic dystrophy, and, in an affected infant, such a determination can be used to estimate the likely severity of the disorder. However, correlations are not perfect, in part because of somatic mosaicism (i.e., the extent of repeat expansion varies from tissue to tissue). Somatic mosaicism has been documented in congenital myotonic dystrophy,30,71 although it is less pronounced than in the adult form of the disease.
The gene affected in myotonic dystrophy (MDPK) encodes a protein kinase that appears to result in altered function of sodium, chloride and potassium channels.24,66,68 Sodium channel defects underlie such later-onset pediatric myotonic syndromes as paramyotonia congenita and hyperkalemic periodic paralysis with myotonia.24,25 Recent data suggest that MDPK does not lead directly to disturbance of channel function. The features of congenital myotonic dystrophy appear to be related to a toxic RNA gain of function.69 Thus, the trinucleotide repeats appear to bind and sequester multiple RNA and DNA-binding proteins and thereby to lead to multiple deleterious effects (see Table 19-3). Management. Management of the affected infant is, in considerable part, an ethical decision. For optimal development, adequate nutrition and ventilation must be ensured, and respiratory support and tube feedings may be needed for days to weeks.4,12,26 Survivors usually are able to suck and swallow adequately for oral nutrition by 8 to 12 weeks of age.4,12 When ventilatory support is required for more than 3 to 4 weeks, the mortality rate exceeds 25%.12,18,26,72 However, the use of nasal continuous positive airway pressure has facilitated weaning in affected infants after such prolonged mechanical ventilation.73 In infants with particularly poor gastric motility, metoclopramide, which decreases the smooth muscle threshold for the action of acetylcholine, may be especially useful.27 Subsequent problems relate to both the muscle and central nervous system (CNS). Supportive measures for the myopathy are required. Most of the joint deformities often can be managed with a nonsurgical approach, although more aggressive management of the foot and ankle deformities may prevent gait disturbances.17 Congenital Muscular Dystrophy The term congenital muscular dystrophy (CMD) refers to a group of disorders that share clinical and myopathological features. In older patients, the term muscular dystrophy has been used for a group of progressive, inherited disorders of muscle that share a striking myopathology. Although some of the reported cases of CMD do not exhibit definite progression, and a familial nature cannot always be established, the disorder indeed does conform generally to an inherited (autosomal recessive) involvement of muscle, progressing prenatally (and ultimately also postnatally) and sharing a myopathology similar to that of later onset dystrophies. Classification of CMDs has become particularly difficult, because in the past few years, largely through molecular genetic studies, increasing numbers of clinical phenotypes and responsible genes have been recognized.74,75 I have elected to use a fundamentally clinical categorization, and I focus on those disorders that may manifest in the neonatal period (Table 19-4). I find it most useful to distinguish those CMD disorders that involve primarily muscle (i.e., without overt CNS abnormalities, e.g., manifested by major neurological deficits) from those CMD disorders that are
Chapter 19 TABLE 19-4
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
807
Congenital Muscular Dystrophy: Major Neonatal Types
Disease CMD without Overt CNS Abnormalities Merosin-deficient CMD Primary merosin-deficiency Secondary merosin deficiency Merosin-positive CMD Classic (pure) CMD Ullrich CMD Rigid spine syndrome CMD with Overt CNS Abnormalities Fukuyama CMD Walker-Warburg syndrome Muscle-Eye-Brain disease CMD with FKRP mutations
Gene Symbol
Protein
LAMA2 ?
Laminin alpha-2 chain ?
? COL6A SEPN1
? Collagen VI Selenoprotein N, 1
FCMD POMT1 POMGnT1 FKRP
Fukutin (protein glycosylation) Protein-O-mannosyl-transferase Protein-O-mannosyl-N-acetylglucosaminyl-transferase Fukutin-related protein (protein-glycosylation)
CMD, congenital muscular dystrophy; CNS, central nervous system.
accompanied by overt CNS abnormalities (with such associated deficits as mental retardation; see Table 19-4). I focus on those disorders that are most likely to be associated with a clear neonatal presentation (i.e., primary, merosin-deficient CMD, classic merosinpositive CMD, and the four CMDs with overt CNS abnormalities; see Table 19-4). I describe only briefly those disorders that are particularly unusual or that do not generally result in marked neonatal features (i.e., Ullrich syndrome and rigid spine syndrome). Congenital Muscular Dystrophy without Overt Central Nervous System Abnormalities. CMD caused by a primary deficiency of merosin (i.e., laminin TABLE 19-5
Distinguishing Features: MerosinDeficient and Merosin-Positive (‘‘Classic’’) Congenital Muscular Dystrophy*
Distinguishing Features
MerosinDeficient
Merosin-Positive
Clinical severity Ambulation Creatine kinase elevation Myopathology Nerve conduction velocity White matter abnormality Cerebral visual evoked and somatosensory evoked responses Epilepsy Chromosomal locus Laminin alpha-2 (merosin)
Marked Rare Marked
Moderate Usual Mild or None
Severe Slow
Moderate Normal
Marked
None
Abnormal
Normal
20% 6q2 Absent{
None Unknown (likely heterogenous) Present
*See text for references. {Partial but not total deficiency of laminin alpha-2 chain is associated with less severe phenotype (see text).
alpha-2 chain; see later), accounts for approximately 40% to 50% of cases of CMD (see Table 19-4). In 1979, an initial series of five infants with CMD was reported with no clinical sign of CNS disease (except for one with seizures) but with marked hypodensity of cerebral white matter on CT.76 Over the next decade, subsequent reports of a similar relationship between CMD and abnormal cerebral white matter, primarily on CT scans, were published.77-88 With the discovery that this disorder is associated with a deficiency of a critical basement membrane component (i.e., the laminin alpha-2 chain), recognition of the relative frequency of this disorder increased dramatically.74,75,89-108 The disorder differs considerably from ‘‘classic’’ or ‘‘pure’’ merosin-positive CMD, as discussed later (Tables 19-5 and 19-6). The clinical presentation with weakness and hypotonia in merosindeficient CMD is more severe than in classic or pure merosin–positive CMD. Indeed, motor function usually does not evolve past sitting or standing with orthotic support; ambulation is hardly ever achieved. Contractures are common, although severe neonatal arthrogryposis is rare. Nevertheless, in my experience, merosin-deficient CMD and congenital myotonic dystrophy are the two most common muscle disorders leading to multiple congenital contractures. Facial weakness is often prominent. Disturbance of chewing and swallowing, with a tendency for aspiration, is very TABLE 19-6
Clinical Features of Congenital Muscular Dystrophy (Merosin-Positive)
Common Facial weakness Hypotonia Axial weakness, neck and trunk Limb weakness, proximal > distal Contractures Nonprogressive or slowly progressive course Less Common Dysphagia Respiratory difficulty
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common. As many as 20% to 30% die of cardiopulmonary complications in the first year or so of life. A less severe phenotype, associated with partial deficiency of merosin, has been reported more recently.96,99,100,107-113 Despite the uniform occurrence of diffusely abnormal cerebral white matter by brain imaging in merosin-deficient CMD (see later discussion), clinical neurological abnormalities are unusual. Approximately 20% to 30% of patients develop seizure disorders, usually later in childhood, and approximately 5% to 10% of patients exhibit cognitive deficits. CMD with secondary deficiency of merosin is rare in the neonatal period and likely represents a heterogenous disorder (see Table 19-4). Formerly, the best characterized of this group was CMD related to FKRP mutations (see later). However, the more recent recognition that this disorder is associated with overt CNS abnormalities makes it more appropriate to discuss later. Merosin-positive CMD encompasses multiple clinical phenotypes, but the three most likely to be encountered in the neonatal period are classic (pure) CMD, Ullrich syndrome, and rigid spine syndrome (see Table 19-4). Classic merosin-positive CMD is a heterogenous disorder that is shrinking in number as molecular genetic studies characterize distinct disorders. In general, the illness is apparent at birth and usually manifests neonatally as a typical myopathic disorder (see Table 19-6).4,76,87,91,94,96,97,114-136 The most common features are facial weakness, variable in severity, and diffuse hypotonia and weakness. The weakness particularly involves the neck, and defective head control, especially of flexion, is a very consistent feature. Limb weakness often exhibits the pattern typical of muscle disease (i.e., proximal more than distal affection). Contractures often are present at birth, and severe arthrogryposis multiplex congenita has been described, albeit uncommonly.28,123,137 Less common features have included disturbances of swallowing and ventilatory function. Extraocular muscle function is spared. The clinical course in classic CMD has ranged from slow improvement to inexorable progression to death.* However, it is likely that many earlier studies, before molecular testing, included merosin-deficient cases among those with classic CMD. Improvement of function during infancy and early childhood may be greater than would have been predicted from the neonatal clinical (or myopathological) findings (Fig. 19-8). However, in one large study (24 patients) with a long follow-up (most between 8 and 16 years), the disease was reported to be ultimately progressive in all.122 Thus, of 15 infants who eventually walked independently (mean age, 2.6 years), only 6 remained ambulant.122 Involvement of the diaphragm and intercostal muscles developed later in infancy and childhood, and approximately one third of these patients ultimately died of respiratory failure. In another large series, 10% of patients died of
*See references 4,76,87,94,96,97,116,117,120-124,128,130134,138,139.
respiratory failure between the ages of 3 months and 12 years, 32% developed spine deformities, and all patients older than 20 years exhibited clearly progressive muscle weakness.128 CNS phenomena (e.g., seizures and impaired intellectual development) are generally absent. Such phenomena would suggest one of the syndromes of CMD with CNS involvement (see later). Indeed, in the series of McMenamin and coworkers122 of cases of CMD without CNS involvement, intellectual development was normal in all patients. Classic merosin-positive CMD exhibits marked differences from merosin-deficient CMD (see Table 19-5). Ullrich CMD is a type of merosin-positive CMD with a characteristic clinical phenotype (see Table 19-4).74,75,140-147a Neonatal presentation with hypotonia, weakness, proximal joint contractures, torticollis, hip dislocation, spine kyphosis, and marked distal hyperlaxity is characteristic. Subsequent motor development is severely delayed, and walking independently occurs in the minority. The defect involves the gene (COL6A) for collagen VI, an extracellular matrix protein. Most neonatal onset cases are autosomal recessive. Rigid spine syndrome is a third merosin-positive CMD that usually presents clinically after the neonatal period with hypotonia and axial weakness.74,75 Neonatal onset has been reported. Subsequently, the characteristic spinal extensor contractures become apparent, with resulting spinal rigidity, scoliosis, and restrictive respiratory disease. The defect involves the gene (SEPN1) for an endoplasmic reticulum protein, selenoprotein N, the function of which is unknown. Congenital Muscular Dystrophy with Overt Central Nervous System Abnormalities. CMD may be accompanied by prominent involvement of the CNS, manifested by severe neurological deficits (e.g., mental retardation; see Table 19-4). Although primary merosin deficiency is associated with a morphological disturbance of cerebral white matter (see later), no clinical neurological abnormalities occur in most cases. The four entities in this category are associated with disorders of neuronal migration, cerebral white matter abnormalities, hindbrain anomalies, and marked clinical neurological abnormalities and are termed Fukuyama CMD, Walker-Warburg syndrome, muscle-eye-brain disease, and CMD with FKRP mutations (see Table 19-4). Because these disorders are related to abnormalities of glycosylation of alphadystroglycan, they are often grouped as dystroglycanopathies. (A fifth such CMD disorder, related to a deficit in the LARGE gene, another putative glycosyltransferase, was reported in a single case with presentation beyond the neonatal period and is not discussed here).148 Fukuyama CMD (see Table 19-4) has been described in several hundred Japanese children and in a much smaller number of children in North America, Europe, and Australia.74,75,96,123,124,149-165 The disorder exhibits the same basic clinical features referable to muscle involvement as the CMDs without CNS involvement: (1) onset in the neonatal period, (2) marked diffuse weakness and hypotonia, (3) facial weakness, and (4)
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
809
A
A
B
C
Figure 19-8 Clinical improvement in congenital muscular dystrophy. A, A 9-month-old boy with weakness and hypotonia from birth. Note the marked head lag with pull to sit. The infant cannot sit without support or support his body weight on his legs. B and C, The same child at 2 years of age. He can sit without support and can bear considerable weight when standing with support. (From Dubowitz V: Muscle Disorders in Childhood, Philadelphia: 1978, Saunders.)
joint contractures that develop particularly in infancy after the neonatal period. The clinical course of the motor function is characterized generally by slow acquisition of skills, usually the ability to crawl or to stand with support, until approximately the age of 8 years, when motor functions begin to deteriorate, ultimately to a lower level. The progression relates both to
worsening of contractures and to apparent increasing weakness. Most patients become bedridden by the age of 10 years, and life expectancy is usually approximately 20 years.96 The hallmark of Fukuyama CMD is the evidence of major CNS disease. Mental retardation is essentially constant, and the usual IQ level is between 30 and
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50.74,75,123,149,161,162,165 Moreover, febrile and afebrile seizures occur in approximately 60% of the cases. CT and, especially, MRI scanning and neuropathological studies (see subsequent discussions of diagnosis and pathology) establish the causes of these neural phenomena, i.e., major neuronal migrational and other abnormalities. Walker-Warburg syndrome is the more severe of the two CMDs with prominent ocular as well as CNS abnormalities (see Chapter 2).74,75,166 Indeed, the life expectancy in this disorder is less than 3 years. In the newborn, the muscle disorder is often overshadowed by the severe CNS (cobblestone lissencephaly, pontocerebellar hypoplasia, severe white matter abnormality) and ocular (microphthalmia, hypoplastic optic nerves, colobomata, retinal detachment) abnormalities. Severe disturbances of feeding and tube or gastrostomy feeding are nearly invariable. Muscle-eye-brain disease is a similar CMD, with ocular and CNS abnormalities, although it is milder than Walker-Warburg syndrome (see Table 19-4). Thus, an initial report from Finland described 18 affected patients with the clinical features referable to CMD, mental retardation of variable severity in 15 of the 18 reported patients, ‘‘occasional’’ seizures, and, distinctively, a wide variety of ocular abnormalities.167 These ocular defects included high myopia, congenital or infantile glaucoma, hypoplasia of the retina and optic nerve, coloboma of the optic nerve, and cataracts.167,168 Many subsequent reports further delineated this type of CMD.74,75,96,123,166,169-190 Although patients with muscle-eye-brain disease that is overt at birth may exhibit severe abnormalities, in general the features of this disorder are milder than those observed with Walker-Warburg syndrome, and both these cerebro-ocular types of CMD exhibit differences from Fukuyama CMD (Table 19-7). The most recently described CMD with overt CNS abnormalities is related to defects in the FKRP gene, which encodes a fukutin-related protein (see Table 19-4). Although this disorder usually manifests beyond the TABLE 19-7
neonatal period and is not considered in detail, neonatal onset is well documented.74,75,108,191,192,192a Weakness and hypotonia are apparent in the first weeks or months of life, although a phenotype as severe as primary deficiency of merosin has been observed. Subsequent motor development is markedly impaired, and respiratory muscle weakness leading to ventilatory failure occurs in the first or second decade of life. In neonatal-onset cases, severe cognitive deficits are common. Muscle biopsy shows a partial deficiency of laminin alpha-2 protein, and thus this disorder previously was classified as CMD with secondary deficiency of merosin. However, the principal defect involves fukutin-related protein, presumed to be a phosphosugar transferase, with alpha-dystroglycan the likely substrate. More recently, more than half of 25 reported cases with FKRP mutations have had prominent CNS abnormalities and thus should be included with the CMD group shown in Table 19-4 with overt CNS abnormalities.193,194 The neurological abnormalities have included mental retardation, and the CNS structural deficits have included subependymal heterotopias, focal pachygyria, white matter abnormalities, cerebellar cysts, marked cerebellar dysplasia, and pontine hypoplasia. These CNS deficits are consistent, at least in part, with neuronal migrational disturbance and overlap with those observed in Fukuyama CMD, Walker-Warburg syndrome, and muscle-eye-brain disease. This similarity is noteworthy because, as discussed earlier, the latter three types of CMD with overt CNS abnormalities all also involve disturbances of glycosylation of alpha-dystroglycan. More data will be of great interest. Laboratory Studies. When all types of CMD (see Table 19-4) are considered, the serum CK level is elevated in most cases, particularly early in the course of the disease. However, the presence and degree of elevation vary with the type of disorder. In the largest series of cases (n = 50) of merosin-positive classic (pure) CMD, 54% of infants had elevated CK level, and the
Distinguishing Features among Major Syndromes of Congenital Muscular Dystrophy with Overt Central Nervous System Abnormalities TYPE OF CMD
Clinical Feature
Fukuyama
Walker-Warburg
Muscle-Eye-Brain
Neurological deficits Microcephaly Macrocephaly Hypotonia Ocular abnormalities (severe) White matter abnormality on neuroimaging (persistent or progressive) Lissencephaly-pachygyria Cortical mantle thin Corpus callosum absent Hydrocephalus Encephalocele Cerebellar malformation
+ + – + – +
+ – + + + +
+ – + + + –
+ ± ± – – –
+ + + + +* +
+ – – ± – ±
*Characteristic when present, but described in less than 50% of cases. +, prominent feature; –, not a prominent feature; ±, variable feature; CMD, congenital muscular dystrophy.
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
average elevation was approximately three times the upper limit of normal.128 In another series of 24 cases, CK elevation was 2.5-fold above the normal upper limit.122 The important clinical point is that a normal CK level does not exclude the diagnosis. By contrast, in merosin-negative CMD, the CK levels are consistently and markedly elevated to approximately 10-fold to 20-fold higher than the upper limit of normal.89-93,95,96,123,138 In Fukuyama CMD, CK levels generally range from 10-fold to 50-fold higher than the normal upper limit. Levels are similarly very high in muscle-eye-brain disease and in WalkerWarburg syndrome. In all cases, CK levels tend to decline with the patient’s age. The EMG reveals the changes of myopathy (see Table 17-7), including small-amplitude, brief-duration, and polyphasic motor unit potentials. CT and MRI scans of the head are useful in identification of the cerebral white matter abnormality characteristic of primary merosin-deficient CMD (Fig. 19-9). The appearance on CT is decreased attenuation of cerebral white matter and on MRI is increased signal on T2-weighted images. The cerebral white matter is affected diffusely, and the cerebellar white matter is unaffected. The cerebral white matter abnormality generally is not apparent in the first weeks of life and becomes apparent by approximately 6 months of life (see Fig. 19-9).74,75,95,195 However, utilization of T2weighted images with a fast spin-echo sequence has demonstrated the white matter abnormality at 5 days of age.196 The abnormal white matter signal is most prominent in structures myelinated after birth (e.g., cerebral white matter), rather than in those structures myelinated before birth (e.g., brain stem and cerebellar white matter).197 Thus, the abnormality may reflect a delay or arrest in myelination, and the finding in the affected white matter of abnormally increased apparent diffusion coefficients, characteristic of immature white matter, is perhaps consistent with this notion.198 Although the cerebral white matter abnormality is the unifying feature of the primary merosin-negative cases, several reports documented the occurrence of cortical gyral dysplasia, especially in the occipital region, in isolated cases.105,186,199-203 Hypoplasia of the cerebellum was observed by MRI to varying degrees in 6 of 14 wellstudied cases103 and associated cerebellar cysts have also been described.204 In Fukuyama CMD, the most striking abnormality is the gyral disturbance (Fig. 19-10). The two major findings detectable by MRI are as follows: (1) a thick cortex with shallow sulci in the frontal regions, consistent with polymicrogyria; and (2) a thick cortex with a smooth surface in the temporo-occipital regions, consistent with lissencephaly-pachygyria.163 These findings correlate well with the neuropathology (see later discussion). Additional consistent features are white matter changes similar to those described earlier for merosin-deficient CMD. However, distinction of these two entities by MRI is straightforward because of the marked gyral abnormalities in Fukuyama CMD. Moreover, the white matter abnormality in the latter diminishes with age. The corpus
811
callosum is slightly hypoplastic in most of the Fukuyama cases.162 In Walker-Warburg syndrome and muscle-eye-brain disease, the dominant finding is the gyral abnormality. In its full form, as in Walker-Warburg syndrome, the appearance of type II lissencephaly (‘‘cobblestone’’ lissencephaly) and pachygyria is striking and is associated with diffuse white matter abnormality of the type observed in merosin-deficient CMD. Again, the distinction by MRI from the latter disorder is straightforward because of the presence of the gyral disturbance, as well as marked dysgenesis of cerebellum and hypoplasia of the pons, especially in Walker-Warburg syndrome. Additional laboratory studies of interest include measurements of cerebral visual and somatosensory evoked responses and of peripheral nerve conduction velocities in merosin-deficient CMD (see Table 19-5). Thus, for somatosensory evoked responses, latencies have been delayed in all patients studied, and for visual evoked responses, latencies have been delayed in approximately 90% of patients.74,75,195,205,206 Nerve conduction velocity studies showed moderately slow values in more than 80% of merosin-deficient cases studied thus far.195,207,208 One infant studied in the newborn period had normal values but exhibited slowed conduction when studied again at 6 months of age.195 No abnormalities in cerebral evoked responses or motor nerve conduction velocities have been observed in merosin-positive CMD. The demonstration of laminin alpha-2 deficiency in skin biopsy and in cultured fibroblasts in primary merosin-deficient cases indicates the potential value of this approach for the diagnosis of merosin-deficient CMD. Additionally, the prenatal demonstration of merosin deficiency in trophoblastic tissue obtained from chorionic villus samples indicates the value of this approach (with simultaneous linkage analysis) in prenatal diagnosis.209-211 Pathology. Muscle biopsy in all types of CMD shows striking changes, consistent with a dystrophic process.4,16,123 Notable are marked variation in fiber size in a nongrouped distribution, internal nuclei, and marked replacement of muscle by fat and connective tissue (Fig. 19-11).4,74,75,94,122-124,138,149,212,213 Necrosis of fibers and evidence of regeneration are common. Striking changes not apparent on initial biopsies may appear on subsequent biopsies. The fiber type pattern is retained (see Fig. 19-11); the muscle does not exhibit the prominent signs of maturational disturbance observed in myotonic dystrophy (see earlier discussion). Although comparisons are difficult, the myopathic changes reported in primary merosindeficient CMD are more striking than those in merosin-positive CMD.4,93,94,127,214 Several reports have emphasized the presence of inflammatory cellular infiltrates, especially early in the disease and perhaps related to necrosis215-217; this finding should not lead to the mistaken diagnosis of infantile polymyositis, a treatable and self-limited disorder (see later discussion). The diagnostic feature critical for merosin-deficient
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A
B
C Figure 19-9 Evolution of cerebral white matter abnormality in merosin-deficient congenital muscular dystrophy, as demonstrated by magnetic resonance imaging (T2-weighted images). A, At 3 weeks of age, the appearance of cerebral white matter was within normal limits. B, At 6 months of age, abnormal signal intensity in cerebral white matter was clearly apparent. C, At 12 months of age, the white matter was extremely abnormal. (From Mercuri E, Pennock J, Goodwin F, Sewry C, et al: Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy, Neuromuscul Disord 6:425-429, 1996.)
CMD is the lack of staining for this molecule on immunocytochemical study (Fig. 19-12). Partial absence is observed in the infants with the less severe, partial type of merosin-deficient CMD or in secondary merosin deficiencies.74,75,97,99,100,109-111 The neuropathology in infants with the merosin-deficient CMD with cerebral white matter abnormalities is not clearly known. The little neuropathological information
available is inconclusive.78,79 The findings that the white matter abnormality becomes most apparent later in infancy and is associated with disturbances of visual and somatosensory evoked potentials and the MRI findings suggesting a defect in postnatal myelin development (see earlier discussions) suggest that myelination is altered in some way. Laminin alpha-2 chain is expressed in the basement membrane of blood
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
Figure 19-10 Computed tomography scan of a 3-year-old-child with Fukuyama congenital muscular dystrophy. Note the following: the paucity of the cortical gyri, most marked in the temporal, parietal, and occipital lobes; hypodensity of the cerebral white matter, especially in the frontal region; prominent sylvian fissures; and asymmetrical dilation of the occipital horns. (From McMenamin JB, Becker LE, Murphy EG: Fukuyama-type congenital muscular dystrophy, J Pediatr 101:580582, 1982.)
vessels that form the blood-brain barrier and also along developing axonal tracts where interaction with oligodendrocytes may occur.75 Disturbances at either or both loci could lead to disturbed myelin development and the abnormal signal with increased water diffusion on MRI or the ‘‘edema’’ by MR spectroscopy.75a
A
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The neuropathology in infants with Fukuyama CMD is striking.123,149,151-154,159,178-180,218-226 The dominant finding is cerebral gyral abnormality, most consistently polymicrogyria (Fig. 19-13A), pachygyria, or agyria (type II lissencephaly). The disorder indicates a disturbance of neuronal migration, as described in Chapter 2. Other neuropathological abnormalities include subpial neuronal-glial heterotopias, cerebellar polymicrogyria (Fig. 19-13B), aberrant myelinated fascicles over the surface of the cerebellum, hypoplasia and aberrant course of the pyramidal tracts, leptomeningeal thickening, and occasional hydrocephalus. No distinct changes have been described in cerebral white matter, except for a delay in myelination, and hence the basis for the white matter abnormality detected by CT or MRI is unclear (see earlier discussion). The neuropathology in the two CMDs with prominent ocular and brain abnormalities has been described.74,75,169,170,174,175,178-180,185 The findings bear similarities to those described in Fukuyama CMD, including the following: type II lissencephaly; polymicrogyria, pachygyria, and heterotopias in the basal meninges; hypoplasia of the pyramidal tracts; and aqueductal stenosis. Distinguishing features in the more severe form of cerebro-ocular CMD, Walker-Warburg syndrome, include more severe cortical migrational disturbances, hydrocephalus, cerebellar dysplasia-hypoplasia (including absence of vermis), and encephalocele (see Table 19-7). In general, the findings in muscle-eye-brain disease are milder than in Walker-Warburg syndrome. Pathogenesis and Etiology. The pathogenesis and etiology of this group of disorders focus on the sarcolemma membrane and the related proteins that link the extracellular matrix to the actin filaments of the myocytic cytoskeleton.74,75,96,97,227,228 The key
B
Figure 19-11 Congenital muscular dystrophy: muscle pathology. These biopsy specimens are from the child shown in Figure 19-8. A, Note nongrouped changes with marked variation in fiber size and extensive replacement of muscle by connective tissue (gray areas) and fat (clear areas) (Verhoeff–van Gieson stain, 250). B, Histochemical preparation shows retention of fiber type pattern (adenosine triphopsphatase stain, pH 4.6, 250). (From Dubowitz V: Muscle Disorders in Childhood, Philadelphia: 1978, Saunders.)
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A
B
C Figure 19-12 Immunofluorescence analysis for merosin. A, Normal muscle. B and C, Muscle from two infants with congenital muscular dystrophy. A, Normal muscle shows strong, continuous staining around the periphery of the myofibers. B, Similar staining is evident in one of the infants with congenital muscular dystrophy, despite the marked variation in fiber size and increased connective tissue. Thus, this infant has classic merosin-positive congenital muscular dystrophy. In C, however, minimal staining for merosin is apparent. This infant has merosin-deficient congenital muscular dystrophy. (From North KN, Specht LA, Sethi RK, Shapiro F, et al: Congenital muscular dystrophy associated with merosin deficiency, J Child Neurol 11:291-295, 1996.)
sarcolemma protein involved in linking to the extracellular matrix is alpha-dystroglycan; the latter interacts with the key extracellular matrix protein, laminin, which, in turn, interacts with collagen type VI. The intracellular connection is mediated by the interaction
of alpha-dystroglycan with the sarcolemma proteins, sarcoglycans, which are linked to dystrophin and thereby to the actin cytoskeleton. In the CMDs, the key proteins affected are alpha-dystroglycan, laminin, and collagen type VI, defects of which interrupt the vital relationship between the extracellular matrix and the muscle cytoskeleton and result in the muscle degeneration of CMD. The molecular basis of primary merosin-deficient CMD is well established.74,75,95-97,138,227-229 Laminin2 or merosin is the critical alpha-dystroglycan-binding, basement membrane protein of the muscle extracellular matrix. The critical laminin alpha-2 chain of laminin 2 is encoded by the LAMA2 gene on chromosome 6q2, and this is the gene defective in merosindeficient CMD. Laminin alpha-2 chain is also present in basement membrane of Schwann cells, and thus its lack may underlie the defect of peripheral nerve described earlier. Moreover, as noted earlier, laminin alpha-2 is present in blood vessels and along developing axons in human brain (see earlier). How these observations relate to the cerebral white matter abnormality remains to be clearly elucidated. Demonstration of the deficient protein in muscle and skin facilitates diagnosis in the infant, and demonstration of the defect in chorionic villus samples facilitates prenatal diagnosis. The molecular basis of classic (pure) merosin-positive CMD is unclear and is likely to be heterogeneous. As the spectrum of phenotypes associated with the known genetic types of CMD expands further, this group will be better clarified. Moreover, the not infrequent autosomal recessive inheritance supports this notion as well as the likelihood that continued molecular genetic studies will elucidate new disorders with this myopathic phenotype. Isolated cases of male infants with CMD with dystrophin deficiency, as in Duchenne-Becker muscular dystrophy, have been reported.94,230-232 The molecular basis of Ullrich CMD involves the gene (COL6A) for collagen VI (see earlier). This defect results in a prominent loss of the basal lamina of muscle fibers and interrupts the vital link between the extracellular space and the intracellular cytoskeleton, as described earlier. The molecular basis of rigid spine syndrome involves a deficiency of the gene (SEPN1) selenoprotein N, an endoplasmic reticulum protein (see earlier). The function of this protein is unknown. The molecular bases for the four CMDs with overt CNS abnormalities (i.e., Fukuyama CMD, WalkerWarburg syndrome, muscle-eye-brain disease and CMD with FKRP mutations), the dystroglycanopathies, all involve defects in genes involved in the O-linked glycosylation of alpha-dystroglycan (see Table 19-4).74,75,138,189,224,225,233 In Walker-Warburg syndrome, the defective gene (POMT1) encodes the protein O-mannosyl transferase and in muscle-eye-brain disease, POMGnT1 encodes the protein O-mannosylN-acetylglucosaminyl transferase. Multiple O-linked glycosylation sites are present in certain serine-threonine rich domains of alpha-dystroglycan. Fukuyama CMD is caused by a defect in a gene (FCMD) that
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
A
815
B
Figure 19-13 Fukuyama congenital muscular dystrophy, with associated encephalopathy (migrational disturbance). This cerebrum and cerebellum are from a child with severe hypotonia and weakness from birth and severe mental retardation. The child died at 6 years, 5 months of age; the muscle pathology was consistent with congenital muscular dystrophy. A, Coronal section of cerebrum. Note the polymicrogyric cortex involving the superomedial and lateral convexity, the pachygyric cortex involving the lateral convexity, and the agyric cortex involving the temporal lobes. B, Horizontal section of cerebellum and brain stem. Note the marked and diffuse polymicrogyria involving the cerebellar cortex. (From Kamoshita S, Konishi Y, Segawa M, Fukuyama Y: Congenital muscular dystrophy as a disease of the central nervous system, Arch Neurol 33:513-516, 1976.)
encodes fukutin, a putative glycosyltransferase, the exact function of which is yet unclear. Disturbances in glycosylation of alpha-dystroglycan impair its interaction with laminin and with sarcolemmal proteins, especially beta-dystroglycan. Muscle degeneration is the result. Because alpha-dystroglycan also is present in the basement membrane of the glia limitans in the developing cerebral cortex, defective glycosylation results in the disturbances in neuronal migration that underlie the occurrence of cobblestone lissencephaly (see Chapter 2). As noted earlier, more than one half of cases of CMD related to FKRP mutations and fukutin-related protein deficiency, which exhibit CNS abnormalities milder but mechanistically similar to those of the three disorders discussed here, are relevant in this context, because the fukutin-related protein also appears to be a glycosyltransferase for alphadystroglycan.193 Management. Because the course in most patients with any of the types of CMD is nonprogressive for many months to years, it is important to attempt to correct existing contractures by physical therapy (i.e., passive stretching or serial splints) and to prevent the development of contractures by active and passive exercises. The development of fixed deformities is often more deleterious to future motor abilities than is muscle weakness. Although no specific therapies are available, more details concerning supportive management are available in specialized sources.138 Facioscapulohumeral Dystrophy FSHD is usually recognized as an autosomal dominantly inherited myopathy with prominent
involvement of the face and upper extremities, onset in adolescence or early adulthood, and a slowly progressive or apparently static course.4,234 A rare type of FSHD with onset in early infancy and a more severe course has been delineated.234-246 Clinical Features. The clinical syndrome is characterized by onset in early infancy of facial weakness.234-246 The weakness is distinctive, in that most patients are unable to move the upper lip and later have a peculiar horizontal smile. Difficulty in closing the eyes is prominent, and the infant may sleep with the eyes open. The whole face tends to be smooth and expressionless. Difficulty in sucking is common. However, motor milestones usually are not significantly delayed, and 8 of 11 patients in the largest series walked alone by 15 months of age.235 Later in infancy and early childhood, progressive weakness and wasting of axial and limb muscles supervene, particularly in the proximal upper extremities, but then also in the lower extremities. Of 5 patients who had reached 15 years of age or more, 4 were no longer walking, and the remaining patient was walking with difficulty. A similarly progressive disease course has been documented by other investigators.237,239,242,243 In a report of 7 infantile-onset cases, the mean duration between onset of first symptoms and wheelchair dependency was 9.9 years.246 The other clinical accompaniment, observed in the series of Carroll and Brooke,235 was sensorineural hearing loss in 6 of 11 children; this loss was severe in 2 children. Approximately 50% of subsequently reported cases have exhibited sensorineural hearing loss.234,239-244 Later in childhood, some patients have developed retinal telangiectasia, exudation, and detachment (in addition to sensorineural hearing loss).238,239,241,243,247 Mental retardation
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DISORDERS OF THE MOTOR SYSTEM
was observed in 30% of cases in one series,239 and it was also documented in other cases.244 Laboratory Studies. The serum CK level is moderately elevated in nearly all patients.235-239,242,244 The EMG reveals low-amplitude and short-duration potentials, indicative of myopathy. Nerve conduction velocities are normal. Pathology. Muscle pathology was striking in six of the nine patients studied in detail by Carroll and Brooke,235 and it exhibited an inflammatory response suggestive of polymyositis (Fig. 19-14). Inflammatory changes in FSHD have been noted by others.235,238,241,244,248,249 This finding may lead to treatment with steroids, which results in no objective benefit. Indeed, it is clear from the relative frequencies of infantile FSHD and of polymyositis (see later) that inflammatory changes in muscle in an infant should raise the question of FSHD rather than polymyositis, especially if the face is particularly involved.
A
Pathogenesis and Etiology. The genetic abnormality in this dominantly inherited disease is located at chromosome 4q35.239,240,242,243,246 The frequency of new mutations is high. However, as many as one half of apparently sporadic cases were found to have an affected parent on careful examination. The defect is particularly interesting and involves a reduction in the number of repeats of a 3.3-kb repeat sequence at the 4q35 locus. Normal individuals carry 11 or more repeats; patients with FSHD have 10 copies or fewer.234 The mechanism by which this genetic change causes FSHD and the genes involved is unclear. A deleterious gain of function of genes located close to the site of the reduced repeats is likely.234,243 Molecular diagnosis is possible by examination of leukocyte DNA. Management. Management is similar to that of progressive myopathy in late childhood and adolescence.4 Of importance for the physician evaluating the newborn with facial weakness is the recognition that FSHD may be present; family members must be examined and perhaps have their leukocyte DNA evaluated. The parents should be counseled that, although the disorder in the affected parent is mild, a distinct possibility exists of a more severe form in their children (i.e., the phenomenon of anticipation).234,235,238,240,243,245 Polymyositis Previously reported in infants no younger than 3 months of age, polymyositis was described in two newborns in 1982.250 The newborns exhibited marked hypotonia and weakness, weak cry, and poor sucking and feeding ability. Neck flexors were affected markedly, as in older patients with polymyositis. Particularly striking were markedly elevated levels of creatine phosphokinase (CK; 2500 and 3600 mU/mL) and muscle biopsy findings that included lymphocytic infiltration as well as myopathic changes. Improvement in overall strength and decrease in CK levels followed treatment with steroids at 6 and 15 months of age. The observations
B Figure 19-14 Infantile facioscapulohumeral dystrophy: muscle pathology. A and B, Striking inflammatory response in muscle from two affected children. In addition, random fiber loss and an increase in connective tissue are evident (A, hematoxylin and eosin stain, 74; B, Gomori trichrome stain, 74). (Courtesy of Dr. James E. Carroll.)
suggested that polymyositis may occur in the newborn, that the diagnosis should be suspected with the findings of markedly elevated CK levels and inflammatory cells in the muscle biopsy specimens, and that treatment with steroids may be beneficial.
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
817
polyphasic potentials) and abnormal muscle biopsy (e.g., modest variation in fiber size). The clinical features are not as prominent as those observed in more common myopathies (e.g., congenital myotonic dystrophy) and in most cases of CMD. Many of these infants have good prognoses and improve over time. With continuing improvements in delineation of genetic myopathies, this category is becoming less common. Myopathic Disorders with Diagnostic Histology
A
B Figure 19-15 Congenital polymyositis: muscle pathology. A, Muscle biopsy shows focal inflammation. B, Immunofluorescence microscopy for immunoglobulin G documents immune complex deposition in a ringlike pattern around individual atrophic muscle fibers. (From Roddy SM, Ashwal S, Peckham N: Infantile myositis: A case diagnosed in the neonatal period, Pediatr Neurol 2:241-244, 1986.)
Subsequent reports supported these general conclusions.251-256 The myopathic changes are consistent with an inflammatory myopathy with an immunological basis (Fig. 19-15). The finding of perifascicular myopathy, generally considered a feature of such autoimmune myopathies as dermatomyositis, is particularly characteristic.254-256 It is important to rule out other neonatal myopathic disorders with inflammatory changes (e.g., FSHD or merosin-deficient CMD), but other features of these latter disorders should make this distinction possible (see earlier discussions). Minimal Change Myopathy Minimal change myopathy, or nonspecific congenital myopathy, is the designation used for those infants with congenital hypotonia and weakness who exhibit minor (or even no) abnormalities of serum enzyme levels, EMG, or muscle biopsy.4,257,258 Myopathic illness is inferred from the clinical features (e.g., proximal more than distal weakness, preserved tendon reflexes, normal sensation, and absence of fasciculations), as well as from the occasional myopathic changes observed on the EMG (e.g., small amplitude, brief duration, and
The histology diagnostic myopathic disorders are characterized by histological changes so striking and distinctive that a specific diagnosis usually can be made. An enormous literature has developed in this area since the 1970s, and several books and reviews deal with the details and complexities of the problem.4,121,247,259-269 Because most of the designations for these disorders are derived from histological and not clinical criteria, the clinical syndromes associated with each histological change vary. Moreover, considerable overlap exists among the disorders on both clinical and histological grounds. Nevertheless, certain specific congenital myopathies are well defined clinically, morphologically, and genetically, and several conclusions relevant to the neonatal patient can be drawn. In the following discussion, I emphasize the most common features of each disorder, particularly those disorders with prominent clinical manifestations in the neonatal period. Of the seven categories listed in Table 19-1, the first five refer to the disorders with morphologically distinctive changes by standard histological and histochemical techniques (i.e., specific congenital myopathies). Certain features are commonly observed among these disorders (Table 19-8). Central core disease, nemaline myopathy, myotubular myopathy, and congenital fiber type disproportion are emphasized because, albeit uncommon, they are the most common in this category (Table 19-9). Multi-minicore myopathy is rare in the newborn and is described only briefly. The mitochondrial myopathies may be suspected by standard histological techniques, but electron microscopic studies are needed to define the distinctive mitochondrial abnormalities. Biochemical studies may identify a specific abnormality of a mitochondrial enzyme. The metabolic myopathies may show no TABLE 19-8
Specific Congenital Myopathies: Certain Common Features
Inheritance: autosomal dominant > recessive > X-linked recessive Onset in neonatal period Recognition often after the neonatal period Hypotonia Weakness: proximal > distal Tendon reflexes decreased in proportion to weakness Muscle enzymes: normal Electromyogram: myopathic Muscle biopsy: diagnostic
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TABLE 19-9
DISORDERS OF THE MOTOR SYSTEM
Specific Congenital Myopathies: Major Neonatal Types
Disease
Gene Symbols Proteins
Central core disease* RYR1 Nemaline myopathy* NEM2 ACTA1 TPM3 TPM2 TNNT1 Myotubular MTM1 myopathy* Congenital ACTA1 fiber type disproportion{ Multi-minicore SEPN1 disease RYR1
Ryanodine receptor Nebulin alpha-Actin alpha-Tropomyosin beta-Tropomyosin Troponin T, slow Myotubularin alpha-Actin Selenoprotein N Ryanodine receptor
*Most common in the neonatal period. {Genetically heterogeneous.
Congenital hip dislocation is also common. Mild facial weakness is not unusual. Ptosis, extraocular muscle weakness, dysphagia, and respiratory difficulties have not been features. The course of the disease is usually nonprogressive, and infants attain motor milestones, albeit at a slow rate. Slow progression of weakness may occur, but even without this progression, contractures and kyphoscoliosis may result. In a series of 11 patients followed to the age of 4 to 20 years, 2 were unable to walk alone, and 2 had difficulty climbing stairs.265 An increased risk of malignant hyperthermia (e.g., during anesthesia) must be recognized to avoid unexpected death. Laboratory Studies. Laboratory investigations, aside from muscle biopsy, are not particularly helpful. The serum CK level is usually normal, and the EMG shows myopathic changes, although frequently minor.
Central Core Disease Central core disease, originally described in 1956,270 was the first of the specific congenital myopathies to be defined. Subsequent reports further delineated a fairly discrete clinical syndrome.4,121,259,262-269,271-278
Pathology. Muscle pathology is distinctive and diagnostic in the presence of the clinical findings.4,121,266 Many muscle fibers (20% to 100%) exhibit cores that are central or somewhat eccentric in location (Fig. 1916). Single or multiple cores may be observed in a given fiber and are well demonstrated with the histochemical stains for oxidative enzymes (e.g., reduced nicotinamide adenine dinucleotide-tetrazolium reductase [NADH-TR]), which are absent in the core region. Indeed, electron microscopy shows an absence of mitochondria in the core region. The cores have a particular predilection for type I fibers and, in some cases, type I fibers predominate or are the only fiber type observable.
Clinical Features. The clinical syndrome consists of hypotonia and weakness, apparent usually in the neonatal period. However, many infants are not recognized as exhibiting muscle disease until months later. Muscle weakness is usually more prominent in the proximal extremities, and tendon reflexes are usually preserved, although diminished in proportion to the weakness.
Pathogenesis and Etiology. The pathogenesis relates to a genetic defect that is usually inherited in an autosomal dominant manner, although rarely autosomal recessive inheritance has been documented.266-269, 278-280 The gene involved is RYR1, which is located on chromosome 19q13.1 and encodes the skeletal muscle ryanodine receptor. The latter is a ligand-related release
distinctive morphological change, and thus one could argue that these myopathies should be classified as histology not diagnostic. However, they are included here because the biopsy specimen indicates glycogen or lipid deposition in muscle, which is usually the critical initial finding in the definition of the specific biochemical lesion.
A
B
Figure 19-16 Central core disease. A, Photograph of twins, one of whom has the disease. Note the weakness of the proximal upper extremities. B, Muscle biopsy from the affected twin. Note the numerous central cores with decreased oxidative enzyme activity (reduced nicotinamide adenine dinucleotide-tetrazolium reductase [NADH-TR] stain, 200). (From Cohen ME, Duffner PK, Heffner R: Central core disease in one of identical twins, J Neurol Neurosurg Psychiatry 41:659-663, 1978.)
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
channel for internally stored calcium and thereby plays a crucial role in excitation-contraction coupling. Management. Management is the same as that of nonprogressive or slowly progressive myopathy. The prevention of contractures is important. Nemaline Myopathy Nemaline (rod body) myopathy, described initially by Shy and colleagues in 1963,281 was the second of the specific congenital myopathies to be defined. The term nemaline is derived from the Greek word nema, meaning ‘‘thread.’’ Numerous subsequent reports emphasized a considerable variation in clinical expression.4,121,259,262-264,266,267,269,282-325a Clinical Features. The clinical presentation in infants with manifestations from the neonatal period can be divided into three syndromes. First, as in typical central core disease, hypotonia and weakness are relatively mild and are sometimes even overlooked in the newborn period. This variety is termed typical congenital nemaline myopathy. Second, marked neonatal hypotonia and weakness occur with no spontaneous movements or respiration at birth. Severe contractures and sometimes fractures complete this syndrome of severe congenital nemaline myopathy. Third, marked neonatal hypotonia and weakness occur, but with some movement and respiratory effort and no severe contractures. This serious disorder, although not so marked as the ‘‘severe’’ cases, is termed intermediate congenital nemaline myopathy. In one large series of nemaline myopathy (n = 143), approximately 50% of patients presented in the neonatal period, and of these, 35% had the severe congenital form, 45% had the intermediate congenital form, and 20% had the typical congenital form.320 Accompanying the severe and intermediate forms were marked facial diplegia and feeding disturbances. The milder, typical form is associated with varying degrees of facial diparesis. Various skeletal anomalies, including high-arched palate, long dysmorphic face, prognathism malocclusion, pectus excavatum, and ‘‘pigeon chest,’’ may be seen. In surviving infants, pes cavus, kyphoscoliosis, and lumbar lordosis evolve. The course of the typical, milder nemaline myopathy is considered generally to be nonprogressive or slowly progressive.266 However, in a study with a 5- to 25-year follow-up, 10 of 12 patients exhibited clinical deterioration, and only 8 of 12 were walking unsupported.294 Ten of 12 patients had developed scoliosis. Similar findings with 3- to 24-year follow-up were reported in a later study.265 The course in those infants with the two more severe forms of the disease (i.e., the severe and intermediate forms) is generally unfavorable.269,320-325 Thus, in one series, 74% of patients with severe congenital cases died, generally before 1 year of age, and 28% of patients with intermediate congenital cases died.320 Among the infants with the severe form, a requirement for ventilation at birth or in the first month was followed by death in more than 90% of cases. Such infants fail to establish adequate ventilation after birth because of
819
weakness of respiratory muscles. This weakness results in failure of full expansion of lungs and, secondary to difficulty with secretions, aspiration often is added. Infants usually die in the neonatal period or in the first months of life. However, longterm survival in these patients, who are usually bedridden and are receiving mechanical ventilation, has been observed.290,293,299 Moreover, rare affected infants with the need for mechanical ventilation at birth, severe weakness, and markedly impaired feeding have improved over the ensuing 2 to 3 years to become independent of mechanical ventilation and to achieve the ability to stand or even walk.297,309 Laboratory Studies. Laboratory investigations have included either normal or slightly elevated values for the serum CK level. The EMG often exhibits shortduration and small-amplitude potentials of myopathy, but signs of denervation have also been observed, particularly late in the disease.4,121,266,288,291,300,307,315 Nerve conduction velocities are normal. Pathology. Muscle pathology is distinctive and diagnostic in the presence of the clinical features.4,121,264,266,315 Although the rod bodies are readily overlooked on routine hematoxylin and eosin staining, Gomori trichrome, toluidine blue, and other selected stains demonstrate them well (Fig. 19-17). Predominance of type I fibers, which also are small, is consistent.16,121,262,263,266,290,292,299,315 The rod body is derived from lateral expansion of the Z-disk, the band found normally at either end of the sarcomere.262,263,266,283,299,315,322,326-329 Thus, the rod bodies have been shown by electron microscopy to be in structural continuity with the Z-disk. The rod’s major protein component is alpha-actin, the main protein of the Z-disk, and the bodies are penetrated by actin filaments, which normally penetrate the Z-disk. The rods are surrounded by desmin, the structural component of muscle-specific intermediate filaments.315 Intranuclear rods have been detected in
Figure 19-17 Nemaline myopathy: muscle biopsy from an affected twin. Note the rod bodies, principally subsarcolemmal in location and occurring in the smaller, atrophic fibers (Gomori trichrome stain, 580). (From Dubowitz V: Muscle Disorders in Childhood, Philadelphia: 1978, Saunders.)
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TABLE 19-10
DISORDERS OF THE MOTOR SYSTEM
Specific Congenital Myopathies: Distinguishing Clinical Features Neonatal Hypotonia and Weakness
Central core disease Nemaline myopathy Myotubular myopathy Congenital fiber type disproportion
Severe Form with Neonatal Death Facial Weakness Ptosis
+ + + +
0 + + ±
± + + ±
0 0 + 0
Extraocular Muscular Weakness 0 0 + +
+, often a prominent feature; ±, variably a prominent feature; 0, not a prominent feature.
some severe fatal neonatal cases.266,308,322,330,331 In general, the severity of the myopathological features correlate only imperfectly with the clinical course.322 Pathogenesis and Etiology. The pathogenesis of nemaline myopathy relates to defects in one of five genes encoding proteins of skeletal muscle thin filaments (see Table 19-9).315,316,318,319,321-325 Approximately 60% to 75% of cases of severe congenital nemaline myopathy are related to defects of ACTA1, the gene for alpha-actin.323,324,325a Most of the remaining cases are related to nebulin defects and are principally autosomal recessive. Mutations in the genes for alpha-tropomyosin, beta-tropomyosin, and troponin are rare causes of severe disease. Management. Management of the typical, nonprogressive, or slowly progressive form of nemaline myopathy depends principally on physical therapy and related techniques. However, respiratory failure may occur during infancy, rapidly and unexpectedly, with a fatal outcome, even in apparently stable or improving patients.266,289,292,293,302,303,312 Thus, careful follow-up is necessary. Infants with the severe neonatal form require prompt recognition and vigorous ventilatory and nutritional support if they are to survive. However, on the basis of the data available, appreciable improvement, despite diligent supportive care, is unlikely. Myotubular Myopathy Myotubular myopathy, described initially in 1966 by Spiro and co-workers,332 was the third specific congenital myopathy to be described. The name is derived from the morphological appearance of the affected muscle fibers, which resemble fetal myotubes. Subsequent reports described considerable variation in clinical expression.4,121,259,263-267,269,316,333-363 Clinical Features. The clinical features of myotubular myopathy can be divided roughly into two syndromes. Less commonly, hypotonia and weakness are relatively mild and are sometimes overlooked in the newborn period. These autosomal varieties generally do not manifest in the neonatal period. The more common disorder affects male infants and is characterized by marked hypotonia and weakness with respiratory failure. Many examples of this severe, malignant, X-linked neonatal form of myotubular myopathy have been described.265-267,269,316,333,336,338-350,352,354-361,363 Polyhydramnios and decreased fetal movement are noted in 50% to 60% during the pregnancy, failure to
breathe effectively at birth often leads to asphyxia (and the mistaken diagnosis of hypoxic-ischemic encephalopathy for the subsequent motor deficits), and striking impairments of neonatal axial, appendicular, and facial movement, sucking, and breathing are apparent. Ptosis is common, and extraocular muscle weakness also is often present. Indeed, the constellation of marked facial weakness, ptosis, and ophthalmoplegia with generalized hypotonia and weakness is highly suggestive of myotubular myopathy, rather than other congenital myopathies (Table 19-10) of either the mild or severe varieties. The course in the severely affected male infants with the X-linked syndrome has been considered to be nearly uniform evolution to a fatal outcome. However, a more recent series of 55 affected male infants showed that 64% survived beyond 1 year of age, although 60% of these long-term survivors were entirely ventilator dependent.360 Only 13% of the longterm survivors did not require at least intermittent mechanical ventilation. Similar data have been reported in other series.363 In the severely affected infant, because of the failure of lung expansion and the superimposed aspiration secondary to swallowing difficulties, atelectasis and pneumonia are the usual causes of death in the first days or weeks of life. Motor outcome in long-term survivors is very unfavorable in most, who often are bedridden or in wheelchairs. However, in a series of 36 patients, 3 were said to exhibit ‘‘no significant disability at 6 months, 5 years, and 7 years, respectively,’’356 and in another group of 55 cases, 7 had only slightly delayed motor milestones.360 Laboratory Studies. Laboratory investigations have included only an occasionally elevated serum CK level. The EMG is usually myopathic, although not impressively so; as with nemaline myopathy, fibrillation potentials are occasionally observed.266,342,347 Chest radiographs often show very thin ribs.41,348,349 Pathology. The muscle pathology is distinctive and diagnostic in the presence of the clinical findings.* Muscle fibers contain one or more centrally placed nuclei, usually surrounded by an area devoid of myofibrils. With adenosine triphosphatase staining, the region around the nucleus appears as a clear zone or halo (Fig. 19-18). Ultrastructurally, the muscle fibers
*See references 4,52,121,266,346,348,351,356-359,363,364
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resemblance of the abnormal fibers to fetal myotubes and the persistence of other features of fetal myotubes, as noted in the previous section. Insight into the potential mechanism of this maturational defect has been gained by identification of the gene at Xq28 (MTM1). MTM1 encodes a protein, myotubularin, that is a phosphatidylinositol phosphatase.363,365,366 Phosphoinositides, the products of the phosphatase, are involved in diverse cellular functions, including survival, differentiation, vesicle trafficking, and actin rearrangement. Which of these functions is altered and how the disturbance leads to the disease remain unclear. Management. Management of the severe X-linked form of myotubular myopathy is as discussed for the severe congenital forms of nemaline myopathy (see previous section). The ethical issues concerning ventilatory support of the severely affected infants are obvious. Figure 19-18 Myotubular myopathy. This muscle biopsy is from a child with deficits from birth. The central nuclei occur in both fiber types (difficult to see in the light, type I fibers) and leave a clear zone with adenosine triphosphatase (ATPase) reactions (ATPase stain, pH 9.4, 250). (From Dubowitz V: Muscle Disorders in Childhood, Philadelphia: 1978, Saunders.)
bear some resemblance to fetal myotubes, with each fiber containing a longitudinal chain of central nuclei (Fig. 19-19). Consistent with these findings suggestive of a disturbance of maturation are other features characteristic of fetal but not mature muscle (i.e., abundant vimentin and desmin [filamentous proteins], neural cell adhesion molecules, and intracytoplasmic distribution of dystrophin).357-359 Type I fibers tend to be small, and this type I fiber hypotrophy usually is a very prominent feature.262,263,333,346,348,363,364 Pathogenesis and Etiology. The pathogenesis of myotubular myopathy is not entirely understood; a maturational arrest has been suggested because of the
Figure 19-19 Myotubular myopathy. This electron micrograph is from a muscle biopsy of a term infant with myotubular myopathy. A central nucleus surrounded by mitochondria is shown. Z-bands are in register (arrowheads), unlike fetal myotubes. (From Sarnat HB: Myotubular myopathy: Arrest of morphogenesis of myofibres associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle, Can J Neurol Sci 17:109-123, 1990.)
Congenital Fiber Type Disproportion Congenital fiber type disproportion, initially described by Brooke in 1973,367 was the fourth identified among the relatively common specific congenital myopathies. Subsequent reports confirmed and amplified the original observations of Brooke.4,248,263-265,368-392 Indeed, variability of the clinical spectrum has been demonstrated conclusively. Clinical Features. The clinical syndrome of the more than 70 reported cases has included particularly hypotonia and weakness of limbs, neck, and respiratory, trunk, facial, bulbar, and extraocular muscles. The last feature, ophthalmoparesis, is present in more than half of the patients who are overtly symptomatic in the neonatal period but in fewer than 10% of those who present later.389 In most cases, the deficits in the early neonatal-onset cases are severe. Other musculoskeletal abnormalities are common, such as limb contractures, congenital hip dislocations, foot deformities, torticollis, and, later, scoliosis. These abnormalities represent primarily postural deformities, generated either prenatally or postnatally. The course is variable, but in general, varies according to the time of onset. Thus, among the infants with overt neonatal-onset disease, fully 40% have died because of the combination of bulbar and respiratory muscle weakness. Most surviving infants have had a static course, with generally severe weakness. Infants with slightly later onset are more likely to have the static and then improving course, often considered characteristic of the disorder, or more precisely, group of disorders. Laboratory Studies. The serum CK level is usually normal. The EMG usually exhibits myopathic changes, albeit often not severe. Pathology. Muscle pathology establishes the diagnosis. The essential features are the predominance of type I fibers (i.e., type I fibers account for more than 55% of the total [normally, type I fibers account for 30% to
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A
B
Figure 19-20 Congenital fiber type disproportion. This muscle biopsy is from an affected child. A, Note the striking disparity in size of fibers (hematoxylin and eosin stain, 150). B, Histochemical preparation shows that the small fibers give a strong reaction for oxidative enzymes (i.e, type I fibers) (reduced nicotinamide adenine dinucleotide-tetrazolium reductase [NADH-TR] stain, 150). (From Dubowitz V: Muscle Disorders in Childhood, Philadelphia: 1978, Saunders.)
55% of the total]) and the small size of type I fibers (i.e., a disparity of 12% or more in the mean diameters of type I and II fibers [normally, the diameters are approximately equal]; Fig. 19-20). Subsequently, hypertrophy of type II fibers appears to occur, and the discrepancy between the size of the fibers may become marked. (In several cases, type II fibers were hypotrophic.379,380,383,384) Fiber type disproportion of the variety observed with congenital fiber type disproportion may be observed with other congenital myopathies, particular nemaline myopathy, myotubular myopathy, and congenital myotonic dystrophy. However, in these disorders, additional changes in muscle coexist and serve to emphasize the nosological status of the disorders, as well as to lead to the correct diagnosis. Moreover, fiber type disproportion has been observed with CNS disorders; in one series, cerebellar hypoplasia was the most common CNS abnormality.377 Pathogenesis and Etiology. The pathogenesis of congenital fiber type disproportion is likely heterogeneous. A functional abnormality in maturation of the motor unit has been suggested for several reasons: (1) similar myopathology can be produced by denervation or cross innervation; (2) type IIc fibers, the fetal precursor of types IIa and IIb fibers, often are present in increased numbers; and (3) fiber type disproportions of various types may occur with developmental disturbances of brain.375,377 The nature of the postulated disturbance in motor unit development is unclear. Numerous documentations of normal anterior horn cells and peripheral nerves in congenital fiber type disproportion are available.372,377 Approximately 45% of cases have a positive family history; approximately two thirds of these suggest autosomal dominant inheritance, and one third suggest autosomal recessive.389,392 In a recent series of
neonatal-onset cases (n = 3), mutations in the ACTA1 gene (different from those for nemaline myopathy) were detected (see Table 19-9).390,390a The clinical features were similar to the severely affected cases noted earlier, except for the absence of ophthalmoparesis. A report of eight cases with onset in the first year or later in infancy and childhood noted defects in the SEPN1 gene (see the description of multi-minicore disease next).393 Management. The most essential aspect of management is recognition that this disorder may be associated with improvement. Thus, even severely affected infants should receive vigorous supportive care, and every effort should be expended to prevent contractures. Multi-Minicore Disease Multi-minicore disease should be discussed briefly in this context of specific congenital myopathies. Although other rare distinctive myopathies have been described (e.g., desmin-related [myofibrillar] myopathies, Bethlem myopathy), presentation in the neonatal period is not typical. However, the classic form of multi-minicore disease typically has its clinical onset in the neonatal period or early infancy.266,267,269,394-396 Neonatal hypotonia and weakness, although generalized, tend to predominate in the axial muscles. Mild facial weakness is common. Respiratory difficulties generally appear later, as do spinal abnormalities, especially scoliosis. Motor development is prominently delayed. The clinical course is static in most patients, although approximately 20% of patients exhibit mild progression. The pathology is distinctive and consists of the occurrence of multifocal corelike areas, seen best as areas of reduced activity on oxidative enzyme stains. Pathogenesis is likely heterogeneous with primarily sporadic and autosomal recessive cases reported. In separate cohorts, defects in the SEPN1 gene, the gene
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
mutated in rigid spine syndrome (see discussion of CMD earlier) and in some later-onset forms of congenital fiber type disproportion, and in the RYR1 gene, the gene mutated in central core disease, have been identified (see Table 19-9). The clinical overlap with CMD with rigid spine syndrome and the histological overlap with central core disease are consistent with these initial genetic findings. Mitochondrial Myopathies Mitochondrial myopathy, in this context, refers to a disorder with prominent involvement of muscle and a primary (not secondary) abnormality of mitochondrial structure and function. Abnormalities of mitochondrial structure sometimes can be demonstrated initially on muscle biopsy by the modified Gomori trichrome stain, which reveals accumulations of red staining material within the fibers (i.e., ‘‘ragged red fibers’’).4,397,398 Further definition of the structural disturbance in mitochondrial number, configuration, or both, is made by electron microscopy.398-402 Of additional importance is documentation of the abnormalities in mitochondrial biochemical function that occur in mitochondrial myopathies.398,402-407 Finally, as discussed later, study of the ratio of mitochondrial to nuclear DNA is important in identification of the mitochondrial DNA depletion syndrome. Classification of mitochondrial myopathies according to biochemical defects is valuable, and clear definition of such defects has progressed rapidly. The major metabolic functions of mitochondria in muscle can be categorized relatively simply as follows: (1) substrate transport, (2) TABLE 19-11
Mitochondrial Disorders Characterized by Presentation with Hypotonia or Weakness in the Neonatal Period CLINICAL FEATURES
Biochemical Disorder Substrate Transport Carnitine deficiency
Primarily Myopathy
Primarily Encephalopathy
+
–
Substrate Utilization Pyruvate carboxylase Pyruvate dehydrogenase complex Fatty acid oxidation
– –
+ +
–
+
Krebs Cycle Fumarase deficiency
–
+
+ + + +
+ + + +
+
+
+
+
Respiratory Chain Complex I Complex II Complex III Complex IV (cytochrome c oxidase) Complex V (adenosine triphosphate synthase) Multiple defects (mitochondrial DNA depletion)
823
substrate utilization, (3) function of the Krebs cycle, and (4) function of the respiratory (electron transport) chain (Table 19-11).398,400,402-410 Of these, only myopathic disease related to defects in the respiratory chain is clearly relevant to the newborn (see subsequent discussion). Substrate Transport. Of particular importance is transport into mitochondria of the two major substrates for energy production through acetyl-coenzyme A (i.e., pyruvate from glucose metabolism and fatty acids). Disturbance of fatty acid transport occurs with carnitine deficiency but is discussed later with lipid myopathies because the lipid deposition dominates the myopathology. Substrate Utilization. Pyruvate dehydrogenase deficiency usually results in a disorder with prominent CNS phenomena, rather than myopathic features (see Chapter 15). However, the enzymatic defect is demonstrable in muscle.411 A major disorder of fatty acid utilization with occasional clinical presentation in the newborn period is medium-chain acyl-coenzyme A dehydrogenase. Because encephalopathic features also are usually present, in addition to hypotonia, this disorder is discussed in Chapter 15. Krebs Cycle. No such disease primarily of muscle has yet been described in the newborn. Respiratory Chain. Disturbances of the mitochondrial respiratory chain may lead to a striking neonatal myopathy syndrome with hypotonia and weakness. Defects primarily of complex IV (cytochrome oxidase), but also of complexes I, II, III, and V, sometimes in combination, and mitochondrial DNA depletion with impairment of multiple enzymes of the respiratory chain have been associated with this syndrome.4,401,403,404-407,412-456 Disturbance of cytochrome c oxidase is the most common cause of this serious neonatal syndrome. The clinical features have been striking (Table 19-12): onset in the first days or weeks of life of severe hypotonia and weakness, with involvement of limbs, trunk, face, and sucking, but only rarely of eye movements. Tendon reflexes are usually absent. Hepatomegaly is common. Additional features have included de Toni-Fanconi-Debre´ renal syndrome in approximately two thirds and, occasionally, myocardiopathy.
TABLE 19-12
Major Features of Infantile Cytochrome c Oxidase Deficiency
Onset, first days or weeks Hypotonia and weakness: axial, appendicular, and facial Hyporeflexia, areflexia Respiratory failure, death in early infancy Hepatomegaly de Toni-Fanconi-Debre´ syndrome Lactic acidosis ‘‘Ragged red’’ fibers, mitochondrial abnormalities, and absent staining for cytochrome c oxidase
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Macroglossia has been noted occasionally. The course has been progressive, with death in the first year. A remarkable benign form of cytochrome c oxidase deficiency has been delineated.403-407,417,426-428,444,457 The newborns present clinically as in the fatal form of the disease but then, over the ensuing weeks and months, exhibit clinical, myopathological, and biochemical improvement. By 2 to 4 years of age, the infants are normal. Distinction of this benign form from the fatal form of cytochrome c oxidase deficiency in the newborn period, crucial for determining prognosis and formulating therapy, requires muscle immunohistochemistry (see discussion of muscle biopsy). Laboratory studies have demonstrated lactic acidosis consistently (see Table 19-12). This finding is an important clue to the diagnosis. When evaluated, the serum pyruvate level also has been elevated. The serum CK level is only slightly elevated, and the EMG is usually normal. In those patients with the Fanconi renal abnormality, glycosuria, proteinuria, phosphaturia, and generalized aminoaciduria are present. Muscle biopsy reveals abnormal accumulations of red staining material on modified Gomori trichrome stain and abnormalities of mitochondrial structure on electron microscopy. Accumulations of lipid and glycogen also are detected readily by appropriate stains (these secondary metabolic changes separate this disorder from the primary abnormalities of lipid and glycogen metabolism, described later). Histochemical staining for cytochrome c oxidase demonstrates the enzymatic deficiency (Figs. 19-21 and 19-22). In infants with the benign form of cytochrome c oxidase deficiency, the deficiency of staining, instead of worsening, resolves (Fig. 19-23 to 19-25).
A
B
Immunohistochemistry with antibodies directed against individual subunits of cytochrome c oxidase differentiates the two disorders: the fatal infantile myopathy is characterized by absence of the nuclear DNA-encoded subunit VIIa,b of the enzyme, whereas in the benign myopathy, both the VIIa,b subunit and the mitochondrial DNA-encoded subunit II are absent (see Figs. 19-21 to 19-24).407,428 The pathogenesis of the myopathic disturbance relates to the impairment of energy production caused by the defect in cytochrome c oxidase. DiMauro and co-workers423 used immunochemical techniques to demonstrate that the deficiency of enzymatic activity results from a decrease in the quantity of enzyme protein, rather than a disturbance in catalytic efficiency. The defect in the respiratory chain results in the lactic acidosis because of decreased utilization of pyruvate (which is converted to lactate by lactate dehydrogenase) and in the accumulation of lipid and glycogen because of decreased utilization of fatty acids and glycogen. The enzymatic defect in the infantile form of cytochrome c oxidase deficiency appears to be inherited as an autosomal recessive disorder. Thus, children of both sexes have been affected, parents have been asymptomatic, and siblings with the disorder have been identified in several families. Management requires intensive supportive therapy, particularly because of the possibility of the reversible form of cytochrome c oxidase deficiency. Infants afflicted with the latter disorder in early infancy are severely affected clinically, morphologically, and biochemically. Muscle immunohistochemistry is needed to distinguish the reversible and fatal forms in the neonatal period.
C
Figure 19-21 Cytochrome c oxidase–deficient myopathies: cytochrome c oxidase (COX) in control human muscle. A, COX histochemistry shows type I (arrow) and type II fibers. B, COX-II and, C, COX-VIIa,b immunostains show particulate immunoreaction of muscle mitochondria ( 350). (From Tritschler HJ, Bonilla E, Lombes A, Andreetta F, et al: Differential diagnosis of fatal and benign cytochrome c oxidase–deficient myopathies of infancy, Neurology 41:300-305, 1991.)
Chapter 19
A
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
B
825
C
Figure 19-22 Cytochrome c oxidase (COX)–deficient myopathies, severe form: muscle biopsies, fatal myopathy. A, COX histochemistry shows lack of enzymatic activity in all fibers. B, COX-II shows particulate immunostain of mitochondria. C, COX-VIIa,b shows lack of immunostain in all fibers ( 350). (From Tritschler HJ, Bonilla E, Lombes A, Andreetta F, et al: Differential diagnosis of fatal and benign cytochrome c oxidase–deficient myopathies of infancy, Neurology 41:300-305, 1991.)
Mitochondrial DNA depletion is a disorder with features similar to those just described for cytochrome c oxidase deficiency.416,438,439,445,446,456,458-463 Thus, approximately 65% of infants with the reported cases have presented in the neonatal period with weakness (limbs and face), hypotonia, and hyporeflexia. Occasional features have been ophthalmoplegia, liver failure, Fanconi syndrome, and seizures. Lactic acidosis has been noted in approximately 50% of cases. Approximately 60% have had elevated values for CK, ranging from 2 to as high as 30 times the upper limit of normal. Of patients with neonatal onset, most have
A
B
died in the first year of life. Muscle biopsy shows ragged red fibers in the minority of cases, but consistent features are a decrease in the content of mitochondrial DNA and a deficiency of multiple mitochondrial enzymes, especially cytochrome c oxidase (complex IV) and combinations of complexes I, II, or III. In infantileonset cases, the disorder appears to be autosomal recessive. The molecular genetic disturbances are likely multiple. At least one recognized gene is involved in DNA metabolism (i.e., thymidine kinase 2 [TK2]).405,456 Other examples will likely be delineated. Recall that Alpers syndrome can be caused by
C
Figure 19-23 Cytochrome c oxidase (COX)–deficient myopathies, benign form at early stage: muscle biopsies. A, COX histochemistry shows lack of activity in all fibers. Enzymatic activity (arrow) is present in the arterial wall. B, COX-II and, C, COX VIIa,b show lack of immunostain in all fibers ( 350 before 14% reduction). (From Tritschler HJ, Bonilla E, Lombes A, Andreetta F, et al: Differential diagnosis of fatal and benign cytochrome c oxidase–deficient myopathies of infancy, Neurology 41:300-305, 1991.)
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DISORDERS OF THE MOTOR SYSTEM
B
C
Figure 19-24 Cytochrome c oxidase (COX)–deficient myopathies, benign form during recovery: muscle biopsies. A, COX histochemistry shows activity in scattered fibers. B, COX-II and, C, COX-VIIa,b immunostains show particulate mitochondrial stain in scattered fibers ( 350 before 14% reduction). (From Tritschler HJ, Bonilla E, Lombes A, Andreetta F, et al: Differential diagnosis of fatal and benign cytochrome c oxidase–deficient myopathies of infancy, Neurology 41:300-305, 1991.)
mitochondrial DNA depletion resulting from a mitochondrial DNA-specific polymerase gamma gene (POLG1; see Chapter 16). Metabolic Myopathies Metabolic myopathy, in this context, refers to a disorder with prominent involvement of muscle and a primary abnormality of glycogen or lipid metabolism. Because glycogen and lipid metabolism also are affected secondarily by mitochondrial abnormalities (see previous section), a certain overlap of clinical and morphological features is to be expected. Glycogen (through glucose) and lipid (through fatty acids) are important for energy production and for structural maintenance and growth in muscle (see Chapter 17). Disorders of glycogen and lipid metabolism are classified here among myopathies that have diagnostic histology because appropriate fixation and staining (e.g., periodic
A
B
acid-Schiff [PAS] for glycogen and oil red O for lipid) usually demonstrate accumulation of the appropriate material and stimulate the search for the specific metabolic defect. Disorders of Glycogen Metabolism. Disorders of glycogen metabolism are shown in Figure 18-7.464-467 Disorders known to exhibit neuromuscular disease in early infancy are alpha-glucosidase (acid maltase) deficiency or Pompe disease (type II), debrancher deficiency (type III), brancher deficiency (type IV), muscle phosphorylase (type V) and phosphorylase kinase (type VIII) deficiencies, and phosphofructokinase deficiency (type VII; Table 19-13). Other glycogenoses may be associated with hypotonia secondary to hypoglycemia (e.g., glucose-6-phosphatase deficiency, Von Gierke disease type I, glycogen synthetase deficiency).
C
Figure 19-25 Cytochrome c oxidase (COX)–deficient myopathies, benign form after recovery: muscle biopsies. A, COX histochemistry shows activity in all fibers. B, COX-II and, C, COX-VIIa,b immunostains show particulate mitochondrial stain in all fibers ( 350 before 14% reduction). (From Tritschler HJ, Bonilla E, Lombes A, Andreetta F, et al: Differential diagnosis of fatal and benign cytochrome c oxidase–deficient myopathies of infancy, Neurology 41:300-305, 1991.)
Chapter 19 TABLE 19-13
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
Neonatal Neuromuscular Disease and Disordered Glycogen Metabolism
Acid maltase deficiency (type II, Pompe disease) Debrancher deficiency (type III) Brancher deficiency (type IV) Muscle phosphorylase deficiency (type V) Muscle phosphorylase kinase deficiency (type VIII) Phosphofructokinase deficiency (type VII)
Type II Glycogen Storage Disease (Pompe Disease). This disease is the prototype of the glycogenoses with onset in the first weeks of life and is discussed in detail in Chapter 18 regarding disorders at the level of the lower motor neuron. The disorder involves skeletal muscle, but involvement of anterior horn cells tends to dominate the clinical syndrome. Type III Glycogen Storage Disease (Debrancher Deficiency). This disorder affects liver as well as muscle. Because debrancher enzyme is involved in the major metabolic pathway for the degradation of glycogen to glucose, hypoglycemia may occur and may be a prominent aspect of the clinical syndrome. Hepatomegaly is impressive, and, indeed, hepatic disease may be severe. Hypotonia and weakness from the neonatal period have been reported, albeit rarely.4,468 Type IV Glycogen Storage Disease (Brancher Deficiency). This disorder classically presents in infancy as progressive cirrhosis of the liver. However, several cases of glycogen storage disease type IV, brancher enzyme deficiency, have been associated with lethal myopathy, sometimes with cardiomyopathy and anterior horn cell glycogen accumulation.469-471 Type V Glycogen Storage Disease (Muscle Phosphorylase Deficiency). This disorder, better known as McArdle disease, usually manifests around the time of puberty with exercise intolerance, muscle cramps,
A
827
fatigue, and myoglobinuria. However, three patients with a fatal infantile form were reported.472-474 The infants exhibited severe, generalized weakness and hypotonia from the neonatal period. Two infants had evidence of prenatal onset because of congenital contractures at the elbows, hips, and knees.473,474 In all three infants, the disorder progressed rapidly to death by respiratory failure at 16 days, 12 weeks, and 13 weeks.472,473 The diagnosis of glycogen myopathy was suggested by the finding of subsarcolemmal vacuoles on muscle biopsy (Fig. 19-26), which were PAS positive. Electron microscopy demonstrated large subsarcolemmal deposits of glycogen that were not membrane bound (unlike the lysosomal-bound deposits of Pompe disease). No phosphorylase staining was apparent on histochemical reaction of muscle. In two cases studied biochemically, the glycogen content of muscle was found to be increased threefold.472,474 Other enzymes of glycogen metabolism were normal, and immunochemical techniques demonstrated absence of phosphorylase protein. The occurrence of parental consanguinity in one of the two cases suggests that the disorder is autosomal recessive.473 Type VIII Glycogen Storage Disease (Muscle Phosphorylase Kinase Deficiency). A different defect at the phosphorylase step has been described in two infants. One had moderate hypotonia and weakness and delayed motor development from birth (sitting but not walking at 19 months of age).475 Although total phosphorylase activity was normal in vitro in both cases, the proportion of the active (‘‘a’’) form was markedly depressed, thus indicating that in vivo most of muscle phosphorylase was present as the inactive (‘‘b’’) form. A defect in the phosphorylase kinase necessary for activation of phosphorylase caused the disorder. A second infant exhibited more severe weakness and hypotonia and died at 7 months of age.476 Type VII Glycogen Storage Disease (Phosphofructokinase Deficiency). This disorder, like McArdle disease, is associated characteristically with later onset of
B
Figure 19-26 Infantile muscle phosphorylase deficiency: muscle biopsy from an affected infant who died at 13 weeks of age. A, Transverse section shows many fibers containing subsarcolemmal vacuoles (arrowheads) (modified Gomori trichrome stain, 500). B, Electron micrograph of longitudinal section shows granular, subsarcolemmal glycogen deposit ( 7500). (From DiMauro S, Hartlage PL: Fatal infantile form of muscle phosphorylase deficiency, Neurology 28:1124-1129, 1978.)
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exercise intolerance, muscle cramps, fatigue, and myoglobinuria. However, several examples of a severe infantile form of phosphofructokinase deficiency were reported.477-481 In the initial report, two siblings, born to related parents, were described with hypotonia and weakness, worse in the upper extremities, from the first days of life. Muscle contractures developed rapidly. One infant died at 6 months of age with respiratory complications, and the other, alive at 14 months at the time of report, could not sit without support. In subsequent reports, three infants were described with progressive weakness and hypotonia, with death at 7, 21, and 21 months, respectively.479,480 One infant exhibited cortical blindness and seizures, and another had mental retardation.478,479 The third infant was treated with a ketogenic diet from 4 months of age and was alive and improving at 2 years of age.481 Muscle specimens showed subsarcolemmal vacuoles that were PAS positive. Glycogen accumulation was demonstrated by biochemical techniques, and muscle phosphofructokinase activity was severely depressed. Disorders of Lipid Metabolism. Defects in the utilization of fatty acids, the steps for which are outlined in Table 19-14, result in several disorders with hypotonia and weakness in the neonatal period or early infancy.4,398,466,482-494 Most of the patients reported with all the defects listed in Table 19-14 exhibit clinical features long after the neonatal period. Even those with neonatal onset manifest, in addition to hypotonia, more prominent features such as stupor or coma, cardiac failure, or congenital malformations (see Chapter 15). Moreover, all but one of the disorders include features more characteristic of a metabolic disorder (hypoketotic hypoglycemia, hyperammonemia) and are discussed as such in Chapter 15. However, the defect of the carnitine transporter (i.e., primary carnitine deficiency) manifests clinically primarily as myopathy involving skeletal and cardiac muscle and thus is discussed here.
TABLE 19-14
Metabolic Defects in Fatty Acid Oxidation
Carnitine transporter* Carnitine palmitoyltransferase I Carnitine-acylcarnitine translocase Carnitine palmitoyltransferase II Very-long-chain acyl-CoA dehydrogenase* Long-chain acyl-CoA dehydrogenase Medium-chain acyl-CoA dehydrogenase* Short-chain acyl-CoA dehydrogenase* Multiple acyl-CoA dehydrogenase* Long-chain 3-hydroxy acyl-CoA dehydrogenase Short-chain 3-hydroxy acyl-CoA dehydrogenase Acetoacetyl-CoA thiolase (beta-ketothiolase)* 3-Oxoacid: CoA transferase Hydroxymethylglutaryl-CoA lyase* See text for references. *Prominent hypotonia and weakness may occur in the neonatal period. CoA, coenzyme A.
Primary Carnitine Deficiency (Carnitine Transporter Deficiency). This disorder is usually characterized by the onset of cardiomyopathy in late infancy or early childhood, but onset in the first 2 months of life is well documented.398,484,485,493,495,496 The major features of this disorder are weakness, hypotonia, and cardiomyopathy. Decreasing fasting ketosis or hypoketotic hypoglycemia may develop. Progression to death may occur if treatment with carnitine is not instituted. Muscle histology demonstrates subsarcolemmal and intermyofibrillar vacuoles that contain lipid (Fig. 19-27). Carnitine levels in muscle and serum are depressed. The nature of the defect in primary carnitine deficiency involves impairment of transport of carnitine into muscle.483 Studies of cultured fibroblasts showed a defect in the specific high-affinity, carrier-mediated carnitine uptake mechanism (i.e., the carnitine transporter).398,484,486,493,496 Management of primary carnitine deficiency is based particularly on treatment with oral carnitine.398,484,487 Prolonged duration of therapy is necessary. RESTRICTED NEUROMUSCULAR DISORDERS Several disorders of the neuromuscular apparatus are restricted to a small portion of the motor system. Some restricted disorders are clearly related to traumatic insults and are discussed in Chapter 22. Restricted disorders that are not established as caused principally by trauma are considered next. Congenital Ptosis Clinical Features. Ptosis is the most common of the congenital nonprogressive neuromuscular syndromes restricted to the ocular region that are likely to manifest in the newborn period (Table 19-15). The disorder is usually familial and is transmitted in an autosomal dominant or an X-linked dominant manner. In both cases, male and female infants are affected equally. Involvement is unilateral in approximately 75% of cases. Patterns of weakness are consistent within families; thus, in one pedigree, left unilateral predominance was striking.497 In a large pedigree of 96 people, 49 had congenital ptosis, and 92% of those had bilateral involvement.498 Superior rectus weakness also may be present; when this weakness accompanies the ptosis, it is on the same side as the levator palpebrae weakness. Pathology. The anatomical locus of the defect generally is considered to be in the muscle of the levator palpebrae, rather than in the third nerve or nucleus thereof. In support of the myogenic theory are the histological abnormalities in the levator muscle and the lack of abnormalities in other structures (e.g., pupil499) innervated by the third nerve.499,500 However, the possibility that the primary abnormality involves an impairment of the caudal central subnucleus of the third nerve with secondary changes in muscle has not been clarified.
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
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D
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Figure 19–27 Muscle carnitine deficiency with lipid myopathy: muscle biopsy from an affected infant who died at 28 months of age. A, Histochemical preparation shows that vacuoles are predominantly in type I fibers (II, type II fibers; V, blood vessels) (adenosine triphosphatase stain, pH 9.3, 200). B, Vacuoles stain positively for lipid (oil red O stain, 200). C, Electron micrograph shows numerous fat vacuoles in the subsarcolemmal area (F, fat; m, mitochondria) ( 14,600). D, Electron micrograph shows rows of lipid vacuoles (F) in intermyofibrillar spaces. Multiple electron-dense granules (D) are visible in some of the mitochondria ( 45,000). (From Hart ZH, Chang CH, DiMauro S, Farooki Q, et al: Muscle carnitine deficiency and fatal cardiomyopathy, Neurology 28:147-151, 1978.)
Pathogenesis and Etiology. The pathogenesis of the disorder in the typical autosomal dominant case involves a gene on chromosome 1 (PTOS1).501,502 The X-linked locus is at chromosome Xq24-q27.1 (PTOS2).501,502 Management. No specific therapy exists. In examples of severe congenital ptosis with the risk of secondary amblyopia, a surgical corrective procedure for the lid is carried out between 6 months and 5 years of age.501 Congenital Unilateral Third Nerve Palsy Clinical Features. The designation congenital unilateral third nerve palsy refers to those cases of unilateral and isolated third nerve palsies apparent from birth. This lesion is not common, although it is frequently not recognized until after the neonatal period. In contrast to congenital ptosis, only uncommonly is congenital third nerve palsy familial (2 of 16 cases in one series). TABLE 19-15
Congenital Nonprogressive Ocular Syndromes
Ptosis Unilateral third nerve palsy Congenital fibrosis of the extraocular muscles Duane retraction syndrome Other ocular disorders (see text)
A very small proportion of cases can be related to orbital trauma (1 of 16 cases in one series).503 The lateral deviation of the affected eye may be confused with comitant exotropia. The usual position of the eye, however, is downward as well as outward. The oculomotor deficits involve medial and upward gaze particularly, and, in addition, ptosis and pupillary dilation are present in the majority of cases. Later in infancy, signs of aberrant reinnervation of third nerve structures are apparent (e.g., constriction of pupil on attempted upward gaze or widening of the palpebral fissure on attempted medial gaze). Pathology. The anatomical locus of the lesion in the common unilateral case often is considered to be outside the brain stem because of the general absence of other signs of brain stem involvement (e.g., contralateral hemiparesis) and the presence of aberrant regeneration.503 However, a disturbance of development of the neurons of the nucleus, as in the congenital fibrosis syndromes (see later), is certainly possible. The usual involvement of the entire third nerve complex excludes a lesion after the bifurcation within the orbit, and the absence of concomitant involvement of the fourth and sixth nerves also suggests that the portion within the cavernous sinus is not the site. Thus, the lesion probably involves the third nerve nucleus or nerve between its exit from the brain stem and its entrance into the cavernous sinus. The pathological substrate is unclear.
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Rarely, a prenatal mesencephalic infarct produces a congenital nuclear syndrome of the oculomotor nerve, with contralateral hemiparesis and aberrant regeneration.504 In addition, a rare bilateral case of congenital partial third nerve palsy secondary to a mesencephalic malformation was reported.505 Pathogenesis and Etiology. The pathogenesis of the usual case is unknown, but the possibility has been raised that the nerve is injured by cranial deformations during labor and delivery, perhaps at the site of its course over the tentorial edge.503 As just noted, a prenatal ischemic lesion of the brain stem or mesencephalic anomaly rarely is responsible.504,505 Management. Management may include surgical correction of the ptosis, which can be severe, and of the lateral eye deviation. It is critical in the neonatal period to be sure that an intracranial process, such as a supratentorial lesion (e.g., hematoma) leading to herniation of temporal lobe through the tentorial notch and compression of the third nerve, is not present. Congenital Fibrosis of the Extraocular Muscles Clinical Features. Congenital fibrosis of the extraocular muscles (CFEOM) syndromes are characterized by congenital, bilateral ptosis, and a restrictive external ophthalmoplegia, with eyes partially or completely fixed in a strabismic position.501,502,506-508 Limitation of extraocular movement in both eyes is pronounced, and forced duction tests reveal marked restriction of globe movement in all directions. The limitations are nonprogressive. When affected infants develop consistent visual fixation and following, the head is held in an extended position to compensate for the marked ptosis. Two clinical phenotypes are most common, designated CFEOM1 and CFEOM2. CFEOM1 is characterized by congenital bilateral ptosis and external ophthalmoplegia, (with pupillary sparing, i.e., not internal ophthalmoplegia). The primary position of the eyes is downward, and patients have a restricted upward gaze and a variably restricted horizontal gaze. In CFEOM2, in addition to the bilateral ptosis, marked exotropia occurs, with severely limited horizontal and vertical eye movements. The only normally functioning extraocular muscle is the abducens-innervated lateral rectus that allows outward movement of each eye. Pathology. Because of the marked fibrosis of the extraocular muscles, it was assumed until the past 10 years that these disorders were basically myopathic. In CFEOM1, careful neuropathological study showed an absence of the superior divisions of the third cranial nerves and corresponding alpha motor neurons in midbrain, with presumably secondary abnormalities of the superior rectus and levator palpebrae superioris muscles, normally innvervated by this branch and responsible for elevation of the eye and eyelid.506,508 In CFEOM2, it appears likely that abnormal development
of both the oculomotor and trochlear nuclei is responsible for all eye movements except abduction.508 Pathogenesis and Etiology. The pathological defects suggest that these disorders reflect abnormality in the development of the extraocular muscle lower motor neuron system.506,508 CFEOM1, an autosomal dominant disorder, is related to heterozygous mutations in K1F21A, a developmental kinesin.508 Kinesins are molecular motors that transport molecules along microtubules. The CFEOM1 defect appears to be in axonal targeting to the extraocular muscles. CFEOM2, an autosomal recessive disorder, is caused by mutations in PHOX2A, which encodes a homeodomain transcription factor necessary for development of the oculomotor and trochlear nerves. Management. Management is difficult and primarily involves surgical attempts to improve the bilateral ptosis. Duane Retraction Syndrome Clinical Features. Duane syndrome is an uncommon congenital disorder of ocular motility with the following characteristics: (1) limitation of abduction of the eye and (2) retraction of the eye into the orbit and consequent narrowing of the palpebral fissure on adduction.500,501,509 Thus, this disorder is another type of congenital restrictive ophthalmoparesis, akin to CFEOM. Additional oculomotor findings may include protrusion of the globe and widening of the palpebral fissure on attempted abduction and downward or upward deviation of the eyes with adduction. Approximately 80% of cases are unilateral. The left eye is involved approximately twice as commonly as the right.500 Approximately 5% to 10% of cases are familial, and inheritance in such cases is autosomal dominant.510,511 At least one other congenital malformation accompanies approximately 33% of cases, and 8% of patients have three or more additional anomalies.511 The anomalies are principally skeletal, auricular, or ocular.511-513 Major skeletal anomalies include vertebral, palatal, and upper extremity defects (e.g., Klippel-Feil anomaly, cervical spina bifida, cleft palate, and anomalies of thumb, radius, and ulna). Auricular anomalies include malformed pinna, auricular appendages, and malformed inner ear with accompanying deafness. Ocular defects include microphthalmia, coloboma, heterochromia iridis, and congenital cataract. Several syndromes are recognized with varying combinations of these anomalies in association with Duane syndrome.501,502,508,508a Pathology. Analogous to the abnormality in CFEOM (see earlier discussion), Duane syndrome is associated with an absence of the abducens nerve and its corresponding abducens nucleus in the pons, with presumably secondary abnormalities in the lateral rectus muscle, the abductor of the eye.508,514,515 The fibrosis of the lateral rectus has been thought to cause the
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retraction of the globe on attempted adduction. The Chiari I malformation was reported in two episodic cases of Duane retraction syndrome, perhaps through involvement of the abducens nerve.508,516,517 Pathogenesis and Etiology. As in CFEOM, the pathological defect suggests that Duane retraction syndrome and its several variants are related to an abnormality in the development of the extraocular muscle lower motor neuron system. The occasional familial occurrence and the not infrequent association with anomalies of certain skeletal, auricular, and ocular structures also are consistent with a defect in embryogenesis. Cross and Pfaffenbach512 emphasized that the sixth nerves and nuclei are developing between the fourth and eighth weeks of gestation, during a period when the eyes, auditory structures, palate, vertebrae, and distal upper extremities are also evolving. Identification of the genes responsible for several of the syndromic variants of Duane syndrome suggests that the disorders relate to disturbances of nuclear development and axonal targeting.508,518 Management. Management should include a careful evaluation of skeletal, auditory, and ocular structures to detect accompanying abnormalities. Other Ocular Disorders Other ocular disorders may be observed in the neonatal period but are generally rare. Congenital Horner syndrome, unassociated with brachial plexus palsy (see Chapter 22), may occur519; association with cervical neuroblastoma has been reported.520,521 Congenital abducens (lateral rectus palsy) may be observed as an isolated finding, although association with Duane retraction syndrome or Mo¨bius syndrome is common.522 Congenital fourth nerve palsy usually escapes detection in the neonatal period (the eye is deviated vertically and medially); anomaly of the brain stem may be present.523 ¨ bius Syndrome Mo Clinical Features. Mo¨bius syndrome, or congenital facial diplegia syndrome, described in 1888 by Mo¨bius,524 consists of facial diplegia and abducens palsies, which are usually bilateral (Table 19-16). Although the essential features of the syndrome are rather restricted, the disorder is accompanied by a variety of neuromuscular and other abnormalities. At first glance, confusion may exist with other disorders of the motor unit with prominent facial weakness (e.g., myasthenias, congenital myotonic dystrophy, CMD, FSHD, nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, and cytochrome c oxidase deficiency [mitochondrial myopathy]). However, associated features usually allow clinical distinction in the newborn period. The clinical findings are striking (see Table 19-16).525-547 The facial weakness is essentially always bilateral and severe. In approximately one third of patients, the face
TABLE 19-16
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Clinical Features of Mo¨bius Syndrome*
Clinical Feature
Percentage of Total
Congenital facial diplegia Upper = lower{ Upper > lower Lower > upper Abducens palsy Total external ophthalmoplegia Oculomotor palsy Ptosis (bilateral) Tongue weakness Talipes equinovarus Hand or arm malformation Pectoralis hypoplasia
100% 35% 63% 2% 100% 10% 20% 10% 75% 30% 40% 10%
*See text for references. { Usually complete or near-complete facial paralysis.
is essentially immobile. In at least 60% of patients, the upper part of the face is affected more severely than the lower. The eyes cannot be closed, and the face is smooth and expressionless. The severe involvement of the face prevents formation of a proper seal around the nipple, and feeding difficulty in the newborn period is a major problem. Abducens palsy, present essentially invariably, is almost always bilateral. In a smaller percentage of cases, total external ophthalmoplegia is present, and, in some patients, lateral gaze palsies (i.e., conjugate weakness) appear to be present. Oculomotor nerve involvement is apparent in 20% and bilateral ptosis in 10% of patients. Involvement of tongue is relatively common, associated with atrophy and bilateral in approximately half of patients. Other neuromuscular abnormalities are frequent. Thus, talipes equinovarus occurs in approximately one third; in a few patients, more widespread arthrogryposis may be present. Hypoplasia of the pectoralis muscle, always unilateral, occurs in approximately 10% to 15% of patients, and when it is associated with syndactyly of the hand, it constitutes Poland syndrome. Hand and arm malformations (e.g., brachydactyly and syndactyly) are present in approximately 40% of patients. Rarer patients with Mo¨bius syndrome have the marked micrognathia of the Robin sequence, congenital myopathy, developmental delay, and other features of CareyFineman-Ziter syndrome.548-551 Central respiratory dysfunction requiring mechanical ventilation was observed in 13 patients with Mo¨bius syndrome, 7 of whom died because of respiratory failure.542 Mental retardation has been reported in 10% to 30% of infants. Autistic spectrum disorders have been observed in 25% to 40%.546 This finding is of particular note because brain stem disturbance has been postulated as a pathogenic mechanism in autism.546 Pathology. The anatomical sites of the pathological features are diverse and may include cranial nerve nuclei, roots, nerves, or muscle. Involvements of cranial nerve nuclei have included apparent developmental hypoplasia or aplasia and
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Figure 19-28 Mo¨bius syndrome. This computed tomography scan shows symmetric dorsal pontine calcifications (arrow). (From D’Cruz OF, Swisher CN, Jaradeh S, Tang T, et al: Mobius syndrome: Evidence for a vascular etiology, J Child Neurol 8:260-265, 1993.)
destructive lesions.526,527,529,532-534,538-540,543,545,547, 552-562 By far the leading abnormalities have been aplasia or hypoplasia of cranial nerve nuclei, sometimes in combination with brain stem hypoplasia, or focal necroses, usually with calcification, involving cranial nerve nuclei. Primary involvement of peripheral nerve or muscle is very uncommon. Abnormalities of brain stem conduction times with testing of brain stem auditory evoked responses, and other electrophysiological measures, have provided in vivo functional correlates of the neuropathology.526,540,563 CT may show calcification at the site of ischemic necrosis in brain stem, usually in the region of the dorsal pons (Fig. 19-28). MRI provides details of brain stem morphology, including hypoplasia or necroses. Involvement of cranial nerves has included apparent developmental hypoplasia or aplasia (with normal cranial nerve nuclei) and possible demyelinative neuropathy.564,565 Involvement of muscle has included apparent primary hypoplasia or aplasia.566 Pathogenesis and Etiology. The pathogenesis of the syndrome is undoubtedly heterogenous, understandable in view of the multiple sites of pathology. Both developmental aberrations and destructive processes appear to be operative. The latter appear to be more common and include intrauterine ischemic brain stem injury, for which neuropathological and brain
imaging data are abundant (see earlier discussion). An ischemic event at approximately 5 to 6 weeks of gestation appears to be very important. Thus, one case occurred after a maternal overdose of ergotamine on day 39 of gestation. Exposure to a similar agent in the first 2 months of gestation was associated with Mo¨bius syndrome or limb reduction deficits, or both, in seven other cases.567 Also supportive of an insult during the fourth to eighth weeks, especially at 5 to 6 weeks of gestation, is the presence of muscle, limb defects, and heart anomalies. It is relevant in this context that the brain stem forms and differentiates rapidly during weeks 5 and 6 and that blood flow changes from the primitive trigeminal circulation to the vertebral arteries. Investigators have hypothesized that, during this period, the pontomesencephalic and pontomedullary tegmental areas, the sites of the affected cranial nerve nuclei, become watershed areas and are thereby vulnerable to ischemic insult.540 It is quite possible that most cases are related to vascular disturbance, with hypoplasias and aplasias the response early in utero and necrosis and calcification later, when fetal inflammatory mechanisms develop. A few cases have been familial, including autosomal dominant and, perhaps, autosomal recessive inheritance.502,568,569 A pedigree described with seven affected members and a reciprocal translocation between chromosomes 1 and 13, demonstrable by banding techniques, suggested that cytogenetic investigation should be considered in the evaluation of affected patients.570 Several other loci have been identified, but responsible genes have not been identified.571 A disturbance of rhombencephalic development is suggested by some of the neuropathological features, and such lesions represent good candidates for defects in homeobox genes. This notion received support by the description of a rare, Mo¨bius-like syndrome characterized by bilateral Duane syndrome, facial weakness, sensorineural hearing loss, hypoventilation, mental retardation, and autism spectrum disorder in association with aberrant hindbrain segmentation. The gene involved was HOXA1, which functions in hindbrain patterning.508,508a,572 As postulated in Mo¨bius syndrome, abnormalities of vascular development were demonstrated.572 Management. Management requires particular attention to feeding techniques. In addition, poor eye closure may result in conjunctival irritation, and thus appropriate eye drops are needed. Later, surgical correction for the severe facial paralysis may be beneficial.501,573 Congenital Hypoplasia of Depressor Anguli Oris Muscle Clinical Features. Congenital hypoplasia of the depressor anguli oris muscle is characterized by an asymmetrical crying facies (Fig. 19-29). The defect is present in approximately 0.5% to 1.0% of newborn infants.574-576a The essential clinical finding is a failure of one corner of the mouth to move downward and outward,
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
A
833
B
Figure 19-29 Asymmetrical crying facies. A, At rest, the infant’s face is symmetrical. B, During crying, left corner of the mouth fails to move down and laterally. (From Pape KE, Pickering D: Asymmetric crying facies: An index of other congenital anomalies, J Pediatr 81:21-30, 1972.)
particularly during cry or grimace.576-580 Other functions of the facial muscles, such as frowning, eye closure, and nasolabial fold depth, are normal. The left side of the face is affected in nearly 80% of cases.580 The appearance of the face during cry or grimace may lead to the mistaken notion that the patient has facial palsy on the side opposite the defect, because the normally functioning muscles, in pulling the corner of the mouth downward and outward, may cause the appearance of lower facial drooping on that normal side. On follow-up, the defect may be less obvious as smiling and other aspects of facial expression become more prominent. A very broad smile or grimace is necessary to elicit the defect in the older child or adult. The major clinical significance relates to an association of the lesion with major congenital anomalies, especially in the cardiovascular system.566,574,576,576a,580-588 Although the reported incidence of the facial defect and the associated anomalies have varied according to the selection of patients, a prospective study of 6487 newborn infants resulted in 44 cases.575 Of these, 3 (6.8%) had cardiac defects (versus 0.45% of controls). The total number with congenital anomalies was 9 (20%), compared with 2.7% of controls. In a hospital-based population, the incidence of anomalies was 70%, and the most common of these were generally minor anomalies of ear and face.580 The proportion with cardiac anomalies in this more selected population was 44%. The cardiac anomalies have been diverse; approximately 50% have consisted of ventricular septal defect (15% to 25%), tetralogy of Fallot, patent ductus arteriosus, and coarctation of the aorta.576a,580,583 Most of the remaining 50% have been atrial septal defects. Other reported anomalies
include genitourinary, musculoskeletal (especially vertebral), and, rarely, CNS defects. The latter include agenesis of the corpus callosum, mega cisterna magna, and cerebral and cerebellar atrophy.576,576a,585,588 The occurrence of the defect in 5% to 10% of infants with congenital heart disease led to the designation cardiofacial syndrome.566 Cayler cardiofacial syndrome is one of a group of conditions linked to a microdeletion in the long arm of chromosome 22.586,587 These syndromes are grouped by the term CATCH22 (Cardiac defects, Abnormal facies, Thymic hyperplasia, Cleft palate, and Hypocalcemia) and include DiGeorge velocardiofacial and Takas syndromes.586 Pathology. The anatomical locus of the defect is the depressor anguli oris muscle and probably represents hypoplasia, although no pathological documentation is available. The EMG reveals paucity of motor units but no fibrillations or other signs of disease of nerve or anterior horn cell. The likelihood of muscle hypoplasia or aplasia is supported further by the occurrence in one family of a mother with aplasia of the left tensor fasciae latae muscle, a child with right hemidiaphragmatic hypoplasia, and another child with aplasia of left depressor anguli oris muscle.579 Pathogenesis and Etiology. The pathogenesis is unclear. The possibility of an inherited defect was suggested by reports of familial occurrence with autosomal dominant characteristics.575 This defect is readily overlooked unless family members are specifically examined for the lesion. Moreover, the occurrence in one family of a mother and two children with aplasia or hypoplasia of different muscles (including the depressor anguli
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oris; see previous section) further supports the possibility of autosomal dominant inheritance with variable expression. In Cayler syndrome, 94% of probands have a de novo deletion of 22q11.2, and 6% have inherited the deletion from a parent.586 Thus, fluorescent in situ hybridization analysis should be carried out on patients with asymmetric crying facies and cardiac anomalies, and the parents’ karyotypes should be evaluated if a deletion is found in the infant. Management. Management essentially is based on ensuring that no other major congenital anomaly is present. An abdominal ultrasound scan to look for visceral anomaly or a neuroblastoma also may be appropriate. Vocal Cord Paralysis Vocal cord paralysis, or so-called laryngeal paralysis, is a relatively common neonatal disorder.589-593 Most descriptions of clinical features, etiology, natural history, and therapy are contained in the otolaryngological literature, and surprisingly few descriptions are contained in the pediatric literature. Data for newborn patients, distinct from older patients, are difficult to obtain, but a reasonable synthesis of current information follows. Clinical Features. The major presenting sign is stridor, which is inspiratory and crowing and is present in approximately 70% of cases. Severe airway obstruction with a need for immediate intubation occurs in approximately 45% of affected infants. Dysphonia, notable with crying, dysphagia, and aspiration are less common. Approximately 40% to 50% of cases are unilateral, and, when unilateral, the left side is affected in 80% to 90% of cases. The course of the disorder relates largely to cause (see ‘‘Pathogenesis and Etiology’’). The diagnosis is established by laryngoscopy. Pathology. The anatomical locus of the pathology is diverse, although few precise data are available. Consideration of probable causes (Table 19-17) suggests that disease at several levels of the neuraxis may be responsible, and levels vary from bilateral upper motor neuron, cranial nuclear (nucleus ambiguus), cranial nerve root (vagal nerve roots), and peripheral nerve (vagus nerve and laryngeal branches). Pathogenesis and Etiology. The major causes of vocal cord paralysis in the newborn are shown in Table 19-17. Most commonly, no clear cause is apparent. Most such cases resolve spontaneously over a period of weeks or months.589 Chiari type 2 malformation associated with myelomeningocele accounts for approximately 20% of cases. In these patients, the syndrome most often evolves several weeks after birth, after correction of the myelomeningocele, in association with the development of hydrocephalus with intracranial hypertension. Vocal cord paralysis often improves after placement of ventriculoperitoneal
TABLE 19-17
Etiology of Vocal Cord Paralysis in the Newborn*
Cause Unknown Chiari type 2 malformation with myelomeningocele Associated with miscellaneous neurological disorders Associated with laryngeal anomalies Birth trauma Other
Percentage of Total 35% 20% 20% 10% 10% 5%
*Based on 208 cases. Data from Holinger LD, Holinger PC, Holinger PH: Etiology of bilateral abductor vocal cord paralysis: A review of 389 cases, Ann Otol Rhinol Laryngol 85:428–436, 1976; and Cohen SR, Birns JW, Geller KA, Thompson JW: Laryngeal paralysis in children: A longterm retrospective study, Ann Otol Rhinol Laryngol 91:417-424, 1982.
shunt and is presumably related to the deformation of the lower brain stem (see Chapter 1). Approximately 20% of infants with vocal cord paralysis have miscellaneous neurological disorders (e.g., cerebral developmental anomalies and Mo¨bius syndrome), which appear to account for the paralysis (see Table 19-17). The 10% of affected infants with associated laryngeal anomalies presumably have a developmental disturbance of the peripheral neuromuscular apparatus in the larynx. The infants with birth trauma usually exhibit signs earliest (i.e., in the first days of life).590 The likelihood of recovery is good (see Chapter 22). Among other causes worthy of note are the association of unilateral vocal cord paralysis with congenital heart defects complicated by pulmonary hypertension and presumed compression of the recurrent laryngeal nerve by the enlarged, tense pulmonary artery (cardiovocal syndrome).594 Injury to the recurrent laryngeal nerve or vagus nerve, or both, in association with the neck dissection required for the institution of extracorporeal membrane oxygenation has been reported in approximately 3% of infants undergoing this procedure.591 In this circumstance, the paralysis is on the right side (i.e., the side of the dissection), unlike the predominantly left-sided paralysis in most cases of unilateral vocal cord paralysis (see earlier discussion). Familial cases are rare, but autosomal dominant, X-linked recessive, and autosomal recessive examples have been observed.593 Management. Unilateral paralysis generally requires no treatment, and, even when recovery does not occur, compensation by the normal vocal cord allows adequate phonation. Bilateral paralysis requires very close surveillance. An artificial airway should be placed if ventilatory compromise appears imminent. Infants with bilateral vocal cord paralysis may die unexpectedly, particularly if the lesion is taken lightly. A need for long-term tracheostomy is not unusual.
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
Congenital Isolated Pharyngeal Dysfunction Clinical Features. Severe impairment of swallowing in a newborn is a life-threatening event. Causes of such impairment include structural malformations of the nasal-oral cavity (e.g., choanal atresia, cleft palate), esophageal or tracheal-esophageal anomalies (e.g., tracheoesophageal fistula, esophageal stenosis, aberrant vessels related to the aortic arch), and a variety of neurological disorders (e.g., bilateral cerebral disorder, Chiari type II malformation, Mo¨bius syndrome, myasthenia, merosindeficient CMD, myotonic dystrophy, nemaline myopathy, myotubular myopathy). However, nearly all the neurological disorders are characterized by other, generally obvious neurological abnormalities. However, one striking defect (i.e., congenital isolated pharyngeal dysfunction) is confined to the pharyngeal musculature. Approximately 30 cases have been reported,584,595-598 but the disorder may be overlooked frequently. Approximately half of all reported cases have been in premature infants. Because the disorder is transient, with spontaneous recovery reported in 2 to 40 months, it is crucial to recognize its presence and to institute measures to prevent aspiration and pneumonia, which have resulted in the death of several of the reported infants. The usual presentation is the development of cyanosis and respiratory distress at the first attempts at feeding. The neurological examination is entirely unremarkable except for the total lack of spontaneous or elicited movements of the pharyngeal muscles and soft palate. Video fluoroscopy of swallowing demonstrates a normal oral propulsive phase but no pharyngeal movement and passive aspiration of contrast medium into the trachea. MRI has revealed no abnormality. The EMG of pharyngeal muscles has been normal. Pathology. Careful study of the brain stem nuclei crucial for swallowing (e.g., nucleus ambiguus, dorsal nucleus of the vagus, nuclei of cranial nerves V, X, and XII, nucleus of the tractus solitarius, and adjacent ventromedian reticular formation in the medulla) has revealed no abnormality. Moreover, no abnormality of other central structures, cranial nerves, or muscles has been detected. Pathogenesis and Etiology. The basic nature of congenital isolated pharyngeal dysfunction is unclear. An abnormality in the functioning of the nucleus ambiguus appears most likely. The abnormality may be at the receptor level, as shown by Kinney and co-workers in the arcuate nucleus of the ventral medulla in sudden infant death syndrome.599 Management. Cessation of attempts at oral feeding and institution of nasogastric tube feedings are crucial. I recommend a period of observation of at least 3 to 6 months with a nasogastric tube before placement of a gastrostomy or jejunostomy tube because more than one half of all affected infants, especially premature infants, recover within 6 months. Clinical improvement precedes radiological improvement,
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and thus follow-up studies with barium swallow or video fluoroscopy may not provide an early indication of recovery.598 Congenital Torticollis Clinical Features. Congenital torticollis is characterized by contracture of the sternocleidomastoid muscle, with resultant lateral flexion of the neck toward the lesion and slight rotation of the neck with the chin away from the side of the lesion.4,600-607 The prominent feature of the syndrome is the head tilt. In association with the tilt of the head, asymmetries of the face and skull usually evolve and include flattening of the face and ear on the side of the lesion and flattening of the occiput on the opposite side (the side of contact of the skull with the bed; see Chapter 3). The rhomboidal skull (i.e., plagiocephaly) usually improves spontaneously with rapid brain and skull growth in the first 5 to 6 months of life if active motility and physical therapy supervene. Most infants can hold the head in the midline position after several weeks.608 Only occasionally do patients have localized swelling of the sternocleidomastoid muscle in the neonatal period, but, when present, this fusiform mass may be quite prominent after 2 to 4 weeks. Although the mass is not usually apparent in the newborn, ultrasonography reveals findings consistent with fibrosis.606 The mass usually disappears gradually by approximately 6 to 8 months of age. In the neonatal period, the muscle often appears shortened, may feel fibrous, and may resist stretch. Pathology. The anatomical locus of the disease is usually confined to the sternocleidomastoid muscle, although occasionally the deep cervical muscles and trapezius appear to be involved (manifested by retraction of the head and elevation of the shoulder). The pathological features consist of fibrotic replacement of muscle tissue, but the remaining muscle appears normal. Pathogenesis and Etiology. The pathogenesis of the disorder in previous years was considered most often to be hemorrhage within the muscle with subsequent fibrosis, but no histological proof of hemorrhage exists. The cause of such hemorrhage is not clear, although birth trauma is often cited. In a study of 311 infants, among those who presented within the first 6 weeks of life with a sternomastoid mass (n = 195), 52% had a history of breech presentation, forceps delivery, or vacuum extraction.607 In another study of 510 infants, the infants with the most severe degree of torticollis had been born after breech presentation in 25% and after ‘‘vacuum extraction/forceps delivery’’ in 41%.605 However, trauma is often difficult to document, and Eng601 suggested that any difficulties observed with delivery relate to the already established intrauterine deformity secondarily disturbing engagement of the head during labor. This possibility could underlie the high frequency of breech presentations reported. In a careful study of 34 patients with congenital torticollis, good evidence indicated that the
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DISORDERS OF THE MOTOR SYSTEM
deformity resulted from aberrant intrauterine positioning in 29%, and evidence was suggestive in an additional 41%.608 Further support for intrauterine constraint as the major cause of congenital torticollis is derived from a well-studied infant born to a mother with a large uterine leiomyoma.609 Hemorrhage into the sternocleidomastoid from vascular anomaly may account for the 18% of infants with congenital torticollis with cavernous hemangioma of face and neck in one series.608 Management. Management consists of physical therapy, with emphasis on two basic exercises: (1) stretching of the clavicular portion of the sternocleidomastoid muscle by lateral flexion of the head to the opposite side and (2) stretching of the sternal portion of the muscle by rotation of the chin toward the affected side. Performance of the exercises in the prone position is easier than in the supine position and is preferable.4 Active stretching exercises may be tolerated more readily than the passive stretching exercises just described; the former exercises involve encouraging the infant to rotate the neck to bottle or breast (when the infant’s shoulders are stabilized) through visual cues of the nipple or bottle and rooting reflex.608 Faithful physical therapy is successful in preventing facial and skull deformities and in relieving the contracture in most cases. In one large series (n = 311), 95% of infants experienced total resolution by 6.5 months.607 Early onset of physical therapy is important. Rarely, botulinum toxin (Botox) injections may be considered. Neglected patients may require tenotomy and develop deformities. Plagiocephaly that persists after 5 to 6 months can be improved markedly by fitting the infant with an individualized plastic helmet to use the remaining brain growth to redirect head growth over approximately the next 6 months (see Chapter 3).608 Isolated Diaphragmatic Myopathy Although most examples of isolated diaphragmatic paralysis in the newborn are related to trauma (see Chapter 22) or to aplasia, at least one case has been described in which a disorder of muscle appeared to be restricted to the diaphragm.610 The infant exhibited respiratory distress with excessive movement of ribs but no movement of diaphragm. The EMG and the serum CK level were normal. Plication of the diaphragm was attempted at 2 months of age, but the infant died at 3 months. At postmortem examination, no abnormality of anterior horn cells, spinal nerve roots, or phrenic nerves could be found. Histological examination of a variety of peripheral muscles was normal. However, the diaphragm, which was very atrophic, exhibited marked random variation in fiber size and degenerating and necrotic muscle fibers. The findings were compatible with a myopathic process. Seven similar cases have been described recently.610a The possibility of myopathy restricted to the diaphragm should thus be considered in infants with respiratory distress secondary to diaphragmatic dysfunction.
Congenital Central Hypoventilation Syndrome Congenital central hypoventilation syndrome (CCHS), or Ondine’s curse, is a disorder of ventilation, particularly during sleep, and is categorized here because the syndrome is manifested as a restricted defect of a motor function. However, the essential defect involves a critical afferent component of the ventilatory system, rather than of the neuromuscular apparatus per se. Many cases have been recorded in the literature.611-637 Clinical Features. The essential clinical features are as follows: (1) decreased ventilatory drive during sleep, with impaired response to hypercarbia and hypoxemia, and (2) no recognizable disease of brain stem (e.g., myelomeningocele), spinal cord (e.g., traumatic transection), or cardiopulmonary system to account for the ventilatory defect. Most patients present in the first days of life with the respiratory disturbance (i.e., hypoventilation), apnea with cyanosis, or both, particularly during sleep. Blood gas studies confirm the presence of hypoxemia and hypercarbia. The respiratory disturbance is most apparent during quiet (non-rapid eye movement [REM]) sleep when the ventilatory drive is most dependent on the response of medullary chemoreceptors to carbon dioxide. This basic defect of unresponsiveness of medullary chemoreceptors to carbon dioxide, however, is also often apparent in these infants during REM sleep. Indeed, some patients also hypoventilate during wakefulness. Associated abnormalities have included Hirschsprung disease in at least 20% of cases and ganglioneuroblastoma or neuroblastoma in approximately 5%. Indeed CCHS, Hirschsprung disease, and neural crest-derived tumors constitute the major neurocristopathies (see later). Associated disturbances of swallowing, sometimes preceded by polyhydramnios, sensorineural hearing loss, and various ocular abnormalities (e.g., ptosis, pupillary dilation) occur in a distinct minority of infants. Additionally, careful studies of heart rate variability delineated abnormalities in all 12 cases in a series.631 These findings enhance the notion of a disturbance in derivatives of the neural crest (i.e., autonomic neurons, sensory neurons, adrenal medullary neurons). Not only is the relationship of the ventilatory syndrome with Hirschsprung disease an excellent example of this common pathogenesis, but also the combination probably accounts for more cases than previously suspected.633 Indeed, CCHS complicates 1.5% of all cases of Hirschsprung disease and fully 10% of severe cases with total colonic aganglionosis. Approximately 15% to 20% of patients with CCHS and Hirschsprung disease have an associated neuroblastoma or ganglioneuroblastoma.633 Diagnosis. The diagnosis is established by the characteristic clinical features and by documentation of the ventilatory abnormalities and resulting blood gas derangements. In contrast to the lack of responsiveness of medullary chemoreceptors to carbon dioxide, the ventilatory response to oxygen through peripheral chemoreceptors is normal. Detailed evaluation to rule out
Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
structural disease of brain stem, spinal cord, phrenic nerves, diaphragm, intercostal muscles, and cardiopulmonary system is important. A search for neuroblastoma or ganglioneuroblastoma also is appropriate. Any suggestion of gastrointestinal dysfunction should lead to rectal biopsy to evaluate the possibility of Hirschsprung disease. Functional MRI studies have shown deficits in pontomedullary regions.638 Etiology. Pathological studies, in general, have demonstrated no consistent abnormalities. In a few cases, an ill-defined decrease in the number of medullary neurons or medullary gliosis has been noted. Molecular genetic studies have clarified the etiology of the disorder. Thus, the gene involved is PHOX2B (a homeobox gene), which is crucial in the development of all autonomic neural crest derivatives. Although most cases are related to sporadic de novo mutations, the heterozygous genetic defect behaves as an autosomal dominant. PHOX2B is involved in Hirschsprung disease and in neuroblastoma. Management. Management must begin with prompt detection and careful surveillance. It is important to correct both the hypoxemia and the hypercarbia to prevent the development of pulmonary hypertension and cor pulmonale. Treatment commonly has consisted of mechanical ventilation, particularly during sleep. Diaphragmatic pacing by stimulation of phrenic nerves has improved treatment while allowing the patient normal mobility and the parents convenient management at home. The apparatus consists of an external radio frequency transmitter, a subcutaneously implanted receiver to convert the radio frequency signal to an electrical current, and a stimulatory electrode on the phrenic nerve.621,628,639 The effectiveness of this approach has been improved by using bilateral rather than unilateral pacing, by minimizing electrical injury to the phrenic nerve, and by using pacing only when necessary (e.g., during sleep) rather than continuously.614,616,619,621,623,628 In the largest experience with diaphragmatic pacing, emphasis was placed on the complementary roles of phrenic nerve pacing and intermittent positive pressure ventilation, and the latter was used in patients with superimposed respiratory illness or inadequate ventilation while awake as well as asleep. DISTINGUISHING FEATURES OF DISORDERS OF THE MOTOR SYSTEM Definition of the anatomical level of the abnormality and of the likely pathology in neonatal disorders of the motor system is possible when one keeps in mind the relatively few distinguishing features (Table 19-18). Thus, the levels to be defined include those above the lower motor neuron (i.e., central), the anterior horn cell, the peripheral nerve, the neuromuscular junction, and the muscle. Distinguishing clinical features include the pattern of weakness, the activity of tendon reflexes, the presence of fasciculations or sensory loss, CSF findings, the level of
837
muscle enzymes in serum, the pattern on the EMG, nerve conduction velocities, and the histological appearance of the muscle biopsy (or, less commonly, nerve biopsy). Disorders related to central causes (e.g., hypoxicischemic encephalopathy) are characterized by weakness of limbs (degree of weakness usually less striking than degree of hypotonia), relatively preserved tendon reflexes (which become hyperactive after the first months of life), and absence of fasciculations or abnormalities on examination of CSF, serum enzymes, EMG, nerve conduction velocities, and muscle biopsy. Other indicators of central disease (e.g., seizures, hemiparesis, and developmental failure) are important to identify. Disease of the anterior horn cell (especially spinal muscular atrophy type I or Werdnig-Hoffmann disease) is characterized by generalized weakness, absent reflexes, and fasciculations (especially of tongue) but normal sensory function, CSF examination, and serum enzyme levels. The EMG shows fasciculations, fibrillations, and other signs of denervation, and muscle biopsy demonstrates marked panfascicular atrophy (only uncommonly type grouping or grouped atrophy). Disease of peripheral nerve is characterized by weakness that often has a distal preponderance, depressed reflexes, abnormal sensory examination, elevated CSF protein concentration, and depressed nerve conduction velocities. Muscle biopsy demonstrates signs of denervation, and nerve biopsy shows usually hypomyelinative changes, with or without onion bulb formation. Disease of neuromuscular junction (e.g., myasthenia gravis) is characterized by weakness that involves the face and, perhaps, extraocular muscles, but normal reflexes (usually), sensory function, CSF examination, and serum enzyme levels are present. The EMG reveals the characteristic decremental response to repetitive stimulation. In botulism, the absence of pupillary reactions and the presence of an incremental response, the brief-duration, small-amplitude, overly abundant motor unit potentials pattern, or both, on the EMG are characteristic. Disease of muscle is characterized by weakness that often is greater in proximal limbs. Involvement of the face is prominent in several such disorders (e.g., myotonic dystrophy, CMD, FSHD, central core disease, nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, and cytochrome c oxidase deficiency [mitochondrial myopathy]). Tendon reflexes are depressed in proportion to the weakness; no fasciculations or sensory or CSF abnormalities are present. Muscle enzyme concentrations in serum may be elevated, although in the slowly progressive disorders, this often is not detectable. The EMG exhibits myopathic changes and, perhaps, more distinctive abnormalities (e.g., myotonia). Muscle biopsy demonstrates myopathic changes and, in certain disorders, abnormalities that are diagnostic (e.g., central cores, rod bodies, myotubular fibers, disproportionate distribution and size of muscle fiber types, multi-minicores, abnormal mitochondria, or accumulation of glycogen or lipid). Thus, with the aforementioned distinguishing features in mind, the clinician should be able to define
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TABLE 19-18
DISORDERS OF THE MOTOR SYSTEM
Distinguishing Features of Disorders of the Motor System WEAKNESS
Locus of Lesion
Face
Arms
Legs
ProximalDistal
Deep Tendon Reflexes
Central
0
+
+
> or =
Normal or increased
Anterior horn cell
Late
++++
++++
> or =
0
Peripheral nerve
0
+++
+++
Decreased
EMG
Muscle Biopsy
Normal
Normal
Other
Seizures, hemiparesis, and delayed development Fasciculations Denervation Fasciculations and pattern (tongue) fibrillations Fibrillations Denervation Sensory deficit, pattern elevated cerebrospinal fluid protein, depressed nerve conduction velocity, abnormal nerve biopsy Decremental Normal Response to response neostigmine (myasor edrophothenia); nium incremental (myasthenia); response constipation and BSAP and fixed (botulism) pupils (botulism) Short duration, Myopathic Elevated muscle small amplipattern* enzyme tude motor levels unit poten(variable) tials and myopathic polyphasic potentials
+ to ++++, varying degrees of severity; EMG, electromyography. *May also show unique features, such as in central core disease, nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, and multi-minicore disease.
the level of the lesion in the neuromuscular apparatus that accounts for the hypotonia and weakness in the infant. This critical initial accomplishment usually leads rapidly to the correct pathological and etiological diagnosis. Appropriate therapeutic intervention, specific or nonspecific, then becomes a relatively straightforward next step.
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Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
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Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
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Matsumoto H, Hayashi YK, Kim DS, Ogawa M, et al: Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan, Neuromuscul Disord 15:342-348, 2005. 166. Cormand B, Pihko H, Mayes M, Valanne L, et al: Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease, Neurology 56:1059-1069, 2001. 167. Raitta C, Lamminen M, Santavuori P, Leisti J: Ophthalmological findings in a new syndrome with muscle, eye and brain involvement, Acta Ophthalmol 56:465-472, 1978. 168. Santavuori P, Leisti J, Kruus S, Raitta C: Muscle, eye and brain disease: A new syndrome, Doc Ophthalmol 17:393, 1978.
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Haltia M, Leivo I, Somer H, Pihko H, et al: Muscle-eye-brain disease: A neuropathological study, Ann Neurol 41:173-180, 1997. 186. van der, Knaap MS, Smit LM, Barth PG, Catsman-Berrevoets CE, et al: Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities, Ann Neurol 42:50-59, 1997. 187. Santavuori P, Valanne L, Autti T, Haltia M, et al: Muscle-eye-brain disease: Clinical features, visual evoked potentials and brain imaging in 20 patients, Eur J Paediatr Neurol 1:41-47, 1998. 188. Kanoff RJ, Curless RG, Petito C, Siatkowski RM, et al: Walker-Warburg syndrome: Neurologic features and muscle membrane structure, Pediatr Neurol 18:76-80, 1998. 189. Vervoort VS, Holden KR, Ukadike KC, Collins JS, et al: POMGnT1 gene alterations in a family with neurological abnormalities, Ann Neurol 56:143-148, 2004. 190. 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UNIT VI
DISORDERS OF THE MOTOR SYSTEM
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Heiman-Patterson TD, Bonilla E, DiMauro S, Foreman J, et al: Cytochromec-oxidase deficiency in a floppy infant, Neurology 32:898-901, 1982. 415. Rimoldi M, Bottacchi E, Rossi L, Cornelio F, et al: Cytochrome-c-oxidase deficiency in muscles of a floppy infant without mitochondrial myopathy, J Neurol 227:201-207, 1982. 416. Boustany RN, Aprille JR, Halperin J: Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and a fatal hepatopathy in a second cousin, Ann Neurol 14:462-470, 1983. 417. DiMauro S, Nicholson JF, Hays AP, Eastwood AB, et al: Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency, Ann Neurol 14:226-234, 1983. 418. 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Roodhooft AM, Van Acker KJ, Martin JJ, Ceuterick C, et al: Benign mitochondrial myopathy with deficiency of NADH-CoQ reductase and cytochrome c oxidase, Neuropediatrics 17:221-226, 1986. 426. Salo MK, Rapola J, Somer H, Pihko H, et al: Reversible mitochondrial myopathy with cytochrome c oxidase deficiency, Arch Dis Child 67:10331035, 1992. 427. Zeviani M, Peterson P, Servidei S, Bonilla E, et al: Benign reversible muscle cytochrome c oxidase deficiency: A second case, Neurology 37:64-67, 1987. 428. Tritschler HJ, Bonilla E, Lombes A, Andreetta F, et al: Differential diagnosis of fatal and benign cytochrome c oxidase–deficient myopathies of infancy, Neurology 41:300-305, 1991. 429. Griebel V, Krageloh-Mann I, Ruitenbeek W, Trijbels JM, et al: A mitochondrial myopathy in an infant with lactic acidosis, Dev Med Child Neurol 32:528-548, 1990. 430. 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Darin N, Moslemi AR, Lebon S, Rustin P, et al: Genotypes and clinical phenotypes in children with cytochrome-c oxidase deficiency, Neuropediatrics 34:311-317, 2003. 448. Sacconi S, Salviati L, Sue CM, Shanske S, et al: Mutation screening in patients with isolated cytochrome c oxidase deficiency, Pediatr Res 53:224230, 2003. 449. Von Kleist-Retzow JC, Cormeir-Dare V, Viot G, Goldenberg A, et al: Antenatal manifestations of mitochondrial respiratory chain deficiency, J Pediatr 143:208-212, 2003.
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DISORDERS OF THE MOTOR SYSTEM
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Chapter 19
Neuromuscular Disorders: Muscle Involvement and Restricted Disorders
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Verzijl HT, van der Zwaag B, Cruysberg JR, Padberg GW: Mobius syndrome redefined: A syndrome of rhombencephalic maldevelopment, Neurology 61:327-333, 2003. 546. Johansson M, Wentz E, Fernell E, Stromland K, et al: Autistic spectrum disorders in Mobius sequence: A comprehensive study of 25 individuals, Dev Med Child Neurol 43:338-345, 2001. 547. Verzijl HT, Valk J, de Vries R, Padberg GW: Radiologic evidence for absence of the facial nerve in Mobius syndrome, Neurology 64:849-855, 2005.
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548. Maheshwari A, Calhoun DA, Lacson A, Pereda L, et al: Pontine hypoplasia in Carey-Fineman-Ziter (CFZ) syndrome, Am J Med Genet Part A 127A:288-290, 2004. 549. Carey JC: The Carey-Fineman-Ziter syndrome: Follow-up of the original siblings and comments on pathogenesis, Am J Med Part A 127A:294297, 2004. 550. Dufke A, Riethmuller J, Enders H: Severe congenital myopathy with Mobius, Robin, and Poland sequences: New aspects of the CareyFineman-Ziter syndrome, Am J Med Genet Part A 127A:291-293, 2004. 551. Verloes A, Bitoun P, Heuskin A, Amrom D, et al: Mobius sequence, Robin complex, and hypotonia: Severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome, Am J Med Genet A 127:277-287, 2004. 552. Richter RB: Congenital hypoplasia of the facial nucleus, J Neuropathol Exp Neurol 17:520, 1958. 553. Thakkar N, O’Neil W, Duvally J, Liu C, et al: Mobius syndrome due to brain stem tegmental necrosis, Arch Neurol 34:124-126, 1977. 554. Towfighi J, Marks K, Palmer E, Vannucci R: Mobius syndrome: Neuropathologic observations, Acta Neuropathol (Berl) 48:11-17, 1979. 555. Wilson ER, Mirra SS, Schwartz JF: Congenital diencephalic and brain stem damage: Neuropathologic study of three cases, Acta Neuropathol (Berl) 57:70-74, 1982. 556. Pedraza S, Gamez J, Rovira A, Zamora A, et al: MRI findings in Mobius syndrome: Correlation with clinical features, Neurology 55:1058-1060, 2000. 557. Peleg D, Nelson GM, Williamson RA, Widness JA: Expanded Mobius syndrome, Pediatr Neurol 24:306-309, 2001. 558. Verzijl HT, van der Zwaag B, Lammens M, ten Donkelaar HJ, et al: The neuropathology of hereditary congenital facial palsy vs Mobius syndrome, Neurology 64:649-653, 2005. 559. Ouanounou S, Saigal G, Birchansky S: Mobius syndrome, AJNR Am J Neuroradiol 26:430-432, 2005. 560. Rerecich A, Alfonso I: Brain calcification in Mobius syndrome, Pediatr Neurol 31:236-237, 2004. 561. Dooley JM, Stewart WA, Hayden JD, Therrien A: Brainstem calcification in Mobius syndrome, Pediatr Neurol 30:39-41, 2004. 562. Sarnat HB: Watershed infarcts in the fetal and neonatal brainstem: An aetiology of central hypoventilation, dysphagia, Mobius syndrome and micrognathia, Eur J Pediatr Neurol 8:71-87, 2004. 563. Verzijl HT, Padberg GW, Zwarts MJ: The spectrum of Mobius syndrome: An electrophysiological study, Brain 128:1728-1736, 2005. 564. Hanissian AS, Fuste F, Hayes WT, Duncan JM: Mobius syndrome in twins, Am J Dis Child 120:472-475, 1970. 565. Rubinstein AE, Lovelace RE, Behrens MM, Weisberg LA: Moebius syndrome in Kallmann syndrome, Arch Neurol 32:480-482, 1975. 566. Cayler GG, Blumenfeld CM, Anderson RL: Further studies of patients with cardiofacial syndrome, Chest 60:161-165, 1971. 567. Gonzalez CH, Vargas FR, Perez AB: Limb deficiency with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy, Am J Med Genet 47:59-64, 1993. 568. McKusick VA: Mendelian Inheritance in Man, Baltimore: 1975, Johns Hopkins University Press. 569. Becker-Christensen F, Lund HT: A family with Mobius syndrome, J Pediatr 84:115-117, 1974. 570. Ziter FA, Wiser WC, Robinson A: Three-generation pedigree of a Mobius syndrome variant with chromosome translocation, Arch Neurol 34:437-442, 1977. 571. Van der Zwaag B, Verzijl HT, Wichers KH, Beltran-Valero de Bernabe D, et al: Sequence analysis of the PLEXIN-D1 gene in Mobius syndrome patients, Pediatr Neurol 31:114-118, 2004. 572. Tischfield MA, Bosley TM, Salih MA, Alorainy IA, et al: Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development, Nat Genet 37:1035-1037, 2005. 573. Puckett CL, Beg SA: Facial reanimation in Mobius syndrome, South Med J 71:1498-1501, 1978. 574. Alexiou D, Manolidis C, Papaevangellou G, Nicopoulos D, et al: Frequency of other malformations in congenital hypoplasia of depressor anguli oris muscle syndrome, Arch Dis Child 51:891-893, 1976. 575. Papadatos C, Alexiou D, Nicolopoulos D, Mikropoulos H, et al: Congenital hypoplasia of depressor anguli oris muscle: A genetically determined condition? Arch Dis Child 49:927-931, 1974. 576. Sapin SO, Miller AA, Bass HN: Neonatal asymmetric crying facies: A new look at an old problem, Clin Pediatr (Phila) 44:109-119, 2005. 576a. Dubnov-Raz G, Merlob P, Geva-Dayan K, Blumenthal D, et al: Increased rate of major birth malformations in infants with neonatal ‘‘asymmetric crying face’’: A hospital-based cohort study, Am J Med Genet A 143A:305-310, 2007. 577. Nelson KB, Eng G: Congenital hypoplasia of the depressor anguli oris muscle: Differentiation from congenital facial palsy, J Pediatr 81:16-20, 1972. 578. Lenarsky C, Shewmon DA, Shaw A, Feig SA: Occurrence of neuroblastoma and asymmetric crying facies: Case report and review of the literature, J Pediatr 107:268-270, 1985. 579. Meberg A, Skogen P: Three different manifestations of congenital muscular aplasia in a family, Acta Paediatr Scand 76:375-377, 1987.
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580. Lin DS, Huang FY, Lin SP, Chen MR, et al: Frequency of associated anomalies in congenital hypoplasia of depressor anguli oris muscle: A study of 50 patients, Am J Med Genet 71:215-218, 1997. 581. Cayler GG: Cardiofacial syndrome: Congenital heart disease and facial weakness, a hitherto unrecognized association, Arch Dis Child 44:69-75, 1969. 582. Pape KE, Pickering D: Asymmetric crying facies: An index of other congenital anomalies, J Pediatr 81:21-30, 1972. 583. Levin SE, Silverman NH, Milner S: Hypoplasia or absence of the depressor anguli oris muscle and congenital abnormalities, with special reference to the cardiofacial syndrome, S Afr Med J 61:227-231, 1982. 584. Renault F, Quijano-Roy S: Congenital and acquired facial palsies. In Jones HR Jr, DeVivo DC, Darras BT, editors: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach, Philadelphia: 2003, Butterworth Heinemann. 585. Voudris KA, Skardoutsou A, Vagiakou EA: Congenital asymmetric crying facies and agenesis of corpus callosum, Brain Dev 25:133-136, 2003. 586. Rioja-Mazza D, Lieber E, Kamath V, Kalpatthi R: Asymmetric crying facies: A possible marker for congenital malformations, J Matern Fetal Neonatal Med 18:275-277, 2005. 587. Akcakus M, Ozkul Y, Gunes T, Kurtoglu S, et al: Associated anomalies in asymmetric crying facies and 22q11 deletion, Genet Couns 14:325-330, 2003. 588. Caksen H, Odabas D, Tuncer O, Kirimi E, et al: A review of 35 cases of asymmetric crying facies, Genet Couns 15:159-165, 2004. 589. Holinger LD, Holinger PC, Holinger PH: Etiology of bilateral abductor vocal cord paralysis: A review of 389 cases, Ann Otol Rhinol Laryngol 85:428-436, 1976. 590. Cohen SR, Birns JW, Geller KA, Thompson JW: Laryngeal paralysis in children: A long-term retrospective study, Ann Otol Rhinol Laryngol 91:417-424, 1982. 591. Schumacher RE, Weinfeld IJ, Bartlett RH: Neonatal vocal cord paralysis following extracorporeal membrane oxygenation, Pediatrics 84:793-796, 1989. 592. Chaten FC, Lucking SE, Young ES, Mickell JJ: Stridor: Intracranial pathology causing postextubation vocal cord paralysis, Pediatrics 87:3943, 1991. 593. Koppel R, Friedman S, Fallet S: Congenital vocal cord paralysis with possible autosomal recessive inheritance: Case report and review of the literature, Am J Med Genet 64:485-487, 1996. 594. Condon LM, Katkov H, Singh A, Helseth HK: Cardiovocal syndrome in infancy, Pediatrics 76:22-25, 1985. 595. Ardran GM, Benson PF, Butler NR, Ellis HL, et al: Congenital dysphagia resulting from dysfunction of the pharyngeal musculature, Dev Med Child Neurol 7:157-166, 1965. 596. Bellmaine SP, McCredie J, Storey B: Pharyngeal incoordination from birth to three years, with recurrent bronchopneumonia and ultimate recovery, Aust Paediatr J 8:137-139, 1972. 597. Mbonda E, Claus D, Bonnier C, Evrard P, et al: Prolonged dysphagia caused by congenital pharyngeal dysfunction, J Pediatr 126:923-927, 1995. 598. Inder TE, Volpe JJ: Recovery of congenital isolated pharyngeal dysfunction: Implications for early management, Pediatr Neurol 19:222-224, 1998. 599. Kinney HC, Filiano JJ, Sleeper LA, Mandell F, et al: Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome, Science 269:1446-1450, 1995. 600. Ford FR: Diseases of the Nervous System in Infancy, Childhood, and Adolescence, Springfield, IL: 1960, Charles C Thomas. 601. Eng GD: Neuromuscular diseases. In Avery GB, editor: Neonatology, Pathophysiology and Management of the Newborn, Philadelphia: 1994, JB Lippincott. 602. Davids JR, Wenger DR, Mubarak SJ: Congenital muscular torticollis: Sequela of intrauterine or perinatal compartment syndrome, J Pediatr Orthop 13:141-147, 1993. 603. Cheng JC, Au AW: Infantile torticollis: A review of 624 cases, J Pediatr Orthop 14:802-808, 1994. 604. Entel RJ, Carolan FJ: Congenital muscular torticollis: Magnetic resonance imaging and ultrasound diagnosis, J Neuroimaging 17:128-130, 1997. 605. Cheng JC, Tang SP, Chen TM: Sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: A prospective study of 510 cases, J Pediatr 134:712-716, 1999. 606. Chen MM, Chang HC, Hsieh CF, Yen MF, et al: Predictive model for congenital muscular torticollis: Analysis of 1201 infants with sonography, Arch Phys Med Rehabil 86:2199-2203, 2005. 607. Tatli B, Aydinli N, Caliskan M, Ozmen M, et al: Congenital muscular torticollis: Evaluation and classification, Pediatr Neurol 34:41-44, 2006. 608. Clarren SK: Plagiocephaly and torticollis: Etiology, natural history, and helmet treatment, J Pediatr 98:92-95, 1981. 609. Romero R, Chervenak FA, DeVore G: Fetal head deformations and congenital torticollis associated with a uterine tumor, Am J Obstet Gynecol 141:839-840, 1981. 610. Bergen BJ, Sangalang VE, Aterman K: Isolated myopathic involvement of the diaphragmatic musculature in a neonate, Ann Neurol 1:403-407, 1977.
610a. Hartley L, Kinali M, Knight R, Mercuri E, et al: A congenital myopathy with diaphragmatic weakness not linked to the SMARD1 locus, Neuromuscul Disord 17:174-179, 2007. 611. Mellins RB, Balfour HH, Turino GM, Winters RW: Failure of automatic control of ventilation (Ondine’s curse): Report of an infant born with this syndrome and review of the literature, Medicine (Baltimore) 49:487-504, 1970. 612. Deonna T, Arczynska W, Torrado A: Congenital failure of autonomic ventilation (Ondine’s curse): A case report, J Pediatr 84:710-714, 1974. 613. Shannon DC, Marsland DW, Gould JB, Callahan B, et al: Central hypoventilation during quiet sleep in two infants, Pediatrics 57:342-346, 1976. 614. Hunt CE, Matalon SV, Thompson TR, Demuth S, et al: Central hypoventilation syndrome: Experience with bilateral phrenic nerve pacing in three neonates, Am Rev Respir Dis 118:23-28, 1978. 615. Phillipson EA: Control of breathing during sleep, Am Rev Respir Dis 118:909-939, 1978. 616. Coleman M, Boros SJ, Huseby TL, Brennom WS: Congenital central hypoventilation syndrome: A report of successful experience with bilateral diaphragmatic pacing, Am J Dis Child 55:901-903, 1980. 617. Fleming PJ, Cade D, Bryan MH, Bryan AC: Congenital central hypoventilation and sleep states, Pediatrics 66:425-428, 1980. 618. Wells HH, Kattwinkel J, Morrow JD: Control of ventilation in Ondine’s curse, J Pediatr 96:865-867, 1980. 619. Ilbawi MN, Hunt CE, DeLeon SY, Idriss FS: Diaphragm pacing in infants and children: Report of a simplified technique and review of experience, Ann Thorac Surg 31:61-65, 1981. 620. Guilleminault C, McQuitty J, Ariagno RL, Challamel MJ, et al: Congenital central alveolar hypoventilation syndrome in six infants, Pediatrics 70:684-694, 1982. 621. Brouillette RT, Ilbawi MN, Hunt CE: Phrenic nerve pacing in infants and children: A review of experience and report on the usefulness of phrenic nerve stimulation studies, J Pediatr 102:32-39, 1983. 622. Guilleminault C, Challamel MJ: Congenital central hypoventilation syndrome (CCHS): Independent syndrome or generalized impairment of the autonomic nervous system? In Korobkin R, Guilleminault C, editors: Progress in Perinatal Neurology, Baltimore: 1981, Williams & Wilkins. 623. Ruth V, Pesonen E, Raivio KO: Congenital central hypoventilation syndrome treated with diaphragm pacing, Acta Paediatr Scand 72:295-297, 1983. 624. Poceta JS, Strandjord T, Badura R, Milstein JM: Ondine curse and neurocristopathy, Pediatr Neurol 3:370-372, 1987. 625. Khalifa MM, Flavin MA, Wherrett BA: Congenital central hypoventilation syndrome in monozygotic twins, J Pediatr 113:853-855, 1988. 626. Alvord EC, Shaw CM: Congenital difficulties with swallowing and breathing associated with maternal polyhydramnios: Neurocristopathy or medullary infarction? J Child Neurol 4:299-306, 1989. 627. Marcus CL, Jansen MT, Poulsen MK, Keens SE, et al: Medical and psychosocial outcome of children with congenital central hypoventilation syndrome, J Pediatr 119:888-895, 1991. 628. Weese-Mayer DE, Hunt CE, Brouillette RT, Silvestri JM: Diaphragm pacing in infants and children, J Pediatr 120:1-8, 1992. 629. Weese-Mayer DE, Silvestri JM, Menzies LJ, Morrowkenny AS, et al: Congenital central hypoventilation syndrome: Diagnosis, management, and long-term outcome in 32 children, J Pediatr 120:381-387, 1992. 630. Silvestri JM, Weesemayer DE, Nelson MN: Neuropsychologic abnormalities in children with congenital central hypoventilation syndrome, J Pediatr 120:388-393, 1992. 631. Woo MS, Woo MA, Gozal D, Jansen MT, et al: Heart rate variability in congenital central hypoventilation syndrome, Pediatr Res 31:291-296, 1992. 632. Weese-Mayer DE, Silvestri JM, Marazita ML, Hoo JJ: Congenital central hypoventilation syndrome: Inheritance and relation to sudden infant death syndrome, Am J Med Genet 47:360-367, 1993. 633. Croaker GD, Shi E, Simpson E, Cartmill T, et al: Congenital central hypoventilation syndrome and Hirschsprung’s disease, Arch Dis Child 78:316-322, 1998. 634. Todd ES, Weinberg SM, Berry-Kravis EM, Silvestri JM, et al: Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: Quantitative pattern of dysmorphology, Pediatr Res 59:39-45, 2006. 635. Gaultier C, Trang H, Dauger S, Gallego J: Pediatric disorders with autonomic dysfunction: What role for PHOX2B? Pediatr Res 58:1-6, 2005. 636. Gaultier C: Functional brain deficits in congenital central hypoventilation syndrome, Pediatr Res 57:471-472, 2005. 637. Chiaretti A, Zorzi G, Di Rocco C, Genovese O, et al: Neurotrophic factor expression in three infants with Ondine’s curse, Pediatr Neurol 33:331-336, 2005. 638. Woo MA, Macey PM, Macey KE, Keen TG, et al: FMRI responses to hyperoxia in congenital central hypoventilation syndrome, Pediatr Res 57:510-518, 2005. 639. Chen ML, Tablizo MA, Kun S, Keens TG: Diaphragm pacers as a treatment for congenital central hypoventilation syndrome, Expert Rev Med Devices 2:577-585, 2005.
Chapter 20 Viral, Protozoan, and Related Intracranial Infections The central nervous system (CNS) and its covering membranes may become involved in a variety of infectious processes, with devastating effects on structure and function. Infections may occur during intrauterine development, in association with the birth process, or in the first postnatal days or weeks. Microbial organisms implicated include several viruses, a protozoan (Toxoplasma gondii), a spirochete (Treponema pallidum), and numerous bacteria and fungi. In this and the following chapter, I review the major features of infections caused by these agents. Because some excellent sources review the microbiological aspects of these infections,1,2 the emphasis of the following discussion is principally on the neurological and neuropathological features. In this chapter, infections of the CNS by viruses, Toxoplasma, and Treponema are reviewed. The major infections in this group are frequently designated by the term TORCH syndrome, in which T stands for toxoplasmosis, O is for others (i.e., syphilis and human immunodeficiency virus [HIV] infection), R is for rubella, C is for cytomegalovirus (CMV) infection, and H represents herpes simplex. I prefer the term SCRATCHES, in which S stands for syphilis, C is for CMV infection, R is for rubella, A is for acquired immunodeficiency syndrome (AIDS) or HIV infection, T is for toxoplasmosis, C is for chickenpox or varicella, H stands for herpes simplex, and ES is for enterovirus infections. Some of the essential features of this group are described in Table 20-1. Most are examples of infection by transplacental passage of the microorganism, usually consequent to infection within the maternal bloodstream. Serious illness resulting from herpes simplex virus (HSV) infection is an exception to this rule because most such cases are contracted around the time of birth, either as an ascending infection just before birth or during passage through an infected birth canal. HIV is transmitted to the fetus by both mechanisms; the relative importance is not entirely clear. With most infections within each group, patients are asymptomatic in the neonatal period, although the neonatal neurological syndromes that do occur are quite dramatic. An exception to this rule, again, is HSV infection, which is rarely accompanied by an asymptomatic neonatal period. In addition to the TORCH group of microbes, enterovirus infections, varicella, and lymphocytic choriomeningitis may cause fetal or neonatal illness, with significant neurological consequences. The neonatal
disorders caused by these organisms are reviewed after the discussion of the TORCH syndromes. DESTRUCTIVE VERSUS TERATOGENIC EFFECTS Although the mechanisms involved in the production of the neuropathological processes associated with these nonbacterial disorders are discussed in more detail in relation to specific infections, two different types of lesions can be distinguished. The first relates to inflammatory, destructive effects and the second relates to developmental derangements (i.e., teratogenic effects). It may be difficult to separate these two types of effects, because destructive processes affecting the developing brain often cause coincident tissue loss and subsequent anomalous development. The distinction is made still more difficult by the relatively limited capacity of early fetal brain to respond to injury; thus, the neuropathologist, evaluating the brain later, finds it difficult to identify signs of parenchymal inflammation and destruction. In contrast, conventional means of identifying intrauterine viral infection (e.g., neonatal virus isolation or antibody response) may not be adequate to detect an infection during early brain development that is completed before the fetus is capable of mounting a humoral antibody response (20 weeks of gestation) or is subjected to viral isolation procedures.3 Such early viral infection has been shown to cause serious brain anomalies in animals. That a similar phenomenon may occur in human infants is suggested by studies in which investigators used a sensitive immunological indicator of early fetal virus exposure (i.e., detection of increased cell-mediated immune response [lymphocyte blastogenesis]).3 Employing this approach, Thompson and Glasgow3 demonstrated early intrauterine exposure to virus in 8 of 23 human infants with several congenital anomalies of the CNS. No elevation of humoral antibody to the viruses involved (mumps and HSV) could be demonstrated. Mumps accounted for seven of the eight cases. These observations require confirmation and elaboration but suggest the possibility that early fetal viral infection may be a more important cause of developmental aberration of the human nervous system than is currently recognized. Although destructive and teratogenic effects overlap, and the precise quantitative contributions of each effect 851
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TABLE 20-1
INTRACRANIAL INFECTIONS
Central Nervous System Involvement by the TORCH Group NEONATAL NEUROLOGICAL ILLNESS
Organism or Disease
Major Route of Infection
Usual Time of Infection*
Symptomatic
Asymptomatic
Cytomegalovirus Herpes simplex Rubella Toxoplasmosis Syphilis Human immunodeficiency virus
Transplacental Ascending and/or parturitional Transplacental Transplacental Transplacental Transplacental/parturitional
T1, T2 Birth T1 T1, T2 T2, T3 T2, T3, Birth
+ ++++ ++ + + +
++++ + +++ ++++ ++++ ++++
*For occurrence of neonatal neurological disease; T1, T2, and T3 refer to the first, second, and third trimesters of gestation, respectively. +, 0% to 25%; ++, 26% to 50%; +++, 51% to 75%; ++++, 76% to 100%; TORCH: T, toxoplasmosis; O, others (i.e., syphilis and human immunodeficiency virus); R, rubella; C, cytomegalovirus; H, herpes simplex.
are not always clear, I attempt to retain a separation of these two basic concepts. The recurring theme regarding destructive effects is varying degrees of inflammation, often with tissue injury (i.e., meningoencephalitis). Regarding teratogenic effects, the theme is more varied, although aberrations of neuronal proliferation and migration have been recognized. Defects in organizational events may be significant but require further study for documentation. TORCH INFECTIONS Cytomegalovirus Infection CMV infection of the infant occurs in utero by transplacental mechanisms (congenital infection). CMV infection is the most common and serious congenital infection. In the United States, approximately 35,000 to 45,000 infants with CMV infection are born yearly.4-7 This number could increase in societies similar to the United States, where mothers with young children work and have their children in day care. Approximately 25% to 75% of such children acquire CMV infection, and 50% of all family members then acquire the infection from them.4,5,7,8 A minority of infants infected in utero exhibit overt neurological or systemic signs in the neonatal period. A majority of infants with congenital infection are asymptomatic, but many of these infants exhibit important sequelae. Still larger numbers of infants acquire CMV infection at the time of birth, during passage through an infected birth canal, or in the first weeks of life, through breast milk or, less commonly, through blood transfusion or other sources.2,5,7,9-16 These infants appear to escape without serious neurological injury. Pathogenesis Fetal Infection. Clinically significant infection with CMV occurs during intrauterine life by transplacental passage of the virus.2,7,9,14,17,18 The organism is transmitted to the fetus usually during a primary maternal infection (less commonly during recurrent infection) with viremia and subsequent placentitis.7,19 The maternal infection is usually asymptomatic but may be manifested by a mononucleosis-like illness (10%) or a more serious systemic illness.7,9 Maternal infection is
very common; cytomegaloviruria occurs in 3% to 6% of unselected pregnant women.7,9,20 Cervical CMV infection is several times more common than cytomegaloviruria but tends to occur late in pregnancy and is probably less likely to result in significant fetal infection. Clinically significant fetal CMV infection probably occurs principally in the first or second trimesters, particularly if CNS disease is the outcome measure.7,14,17,21 The possibility of CNS involvement after CMV infection in the third trimester was suggested by a study of seven children, but the exact timing of the fetal infection was established in only one case (at 27 weeks of gestation).22 Moreover, the nature of the neuropathological features in some infected infants is also consistent with CNS involvement secondary to infection relatively late in pregnancy (see later discussion).23,24 Approximately 30% to 40% of infants whose mothers experience primary infection during pregnancy develop congenital infection.2,7,18,20,25-27 Cytomegaloviruria has been observed in approximately 0.5% to 2% of infants in the neonatal period.3,6,7,10,28-31 Because a period of approximately 4 to 8 weeks is required between the time of infection and the viruria,32 these neonatal examples reflect intrauterine infection and not perinatal acquisition from parturitional or postnatal exposure. In these cases of congenital CMV infection, involvement of the CNS may be overt in the neonatal period or may not become apparent for months or years thereafter (see later discussion). In a prospective series of more than 12,000 pregnant women, primary CMV infection was complicated by congenital infection in 41% of infants, and only 12% of the affected infants were overtly symptomatic at birth.20 Severe, clinically apparent congenital infection rarely occurs following recurrent (nonprimary) infection (i.e., infection in women with preexisting seroimmunity).2,5,7,21,33-35 However, this generally very low risk is increased if the recurrent maternal infection involves a strain of CMV different from that resulting in the preexisting seroimmunity.36 Parturitional and Postnatal Infections. Parturitional and postnatal exposures cause an additional 10% to 15% of infants to acquire CMV infection in the first 4 to 8 weeks of life.7,10-13,17 Breast milk is probably the
Chapter 20 TABLE 20-2
Neuropathology of Congenital Cytomegalovirus Infection Symptomatic in the Neonatal Period
Meningoencephalitis Germinal matrix necrosis/cysts Periventricular cerebral calcification Cerebral white matter cysts/calcification with atrophy and ventriculomegaly Cerebral cortical atrophy Microcephaly Migrational disturbances: polymicrogyria, lissencephaly/ pachygyria, schizencephaly Cerebellar hypoplasia
single most important source of CMV exposure in premature infants.7,37-41 Blood transfusion has been a particularly important source in low-birth-weight infants.15 Although the results of one study raised the possibility of an increased risk of neurological sequelae in premature infants who acquire CMV infection during the first 8 weeks of life,13 most data have indicated that CNS involvement does not occur with parturitional or early postnatal infection.2,7,10-13,16,17,41 The reasons for the difference in propensity to affect the CNS between early prenatal versus natal or postnatal acquisitions of CMV remain to be determined. Neuropathology Congenital CMV infection may be associated with asymptomatic or symptomatic neurological presentations in the neonatal period (see subsequent discussion). The symptomatic presentation is uncommon but serves as the prototype for the neuropathology produced by primary infection of the developing CNS by this virus. Evidence both for inflammation and destruction and for teratogenicity can be observed TABLE 20-3
Neuropathological Features of Congenital Cytomegalovirus Infection in 15 Preterm Infants*
Neuropathological Feature Microcephaly Meningoencephalitis Calcifications Periventricular Cortical Both Polymicrogyria Lissencephaly Ventriculomegaly Cerebellar hypoplasia Periventricular leukomalacia or porencephaly
Percentage of Infants Affected 87% 75% 80% 73% 40% 40% 33% 7% 27% 33% 20%
*Nine infants (mean birth weight, 2350 g; mean gestational age, 33 weeks) died in the neonatal period; 6 infants (mean birth weight, 1145 g; mean gestational age, 33 wks) were stillborn. Data from Perlman JM, Argyle C: Lethal cytomegalovirus infection in preterm infants: Clinical, radiological, and neuropathological findings, Ann Neurol 31:64-68, 1992.
Viral, Protozoan, and Related Intracranial Infections
853
(Table 20-2). The spectrum of the neuropathology was well illustrated by a large neuropathological study of 15 premature infants who died with congenital CMV infection (Table 20-3). Meningoencephalitis. Meningoencephalitis is characterized by the following features: (1) inflammatory cells in the meninges; (2) perivascular infiltrates with inflammatory cells; (3) necrosis of brain parenchyma, with all cellular elements affected, especially in the periventricular region, and often associated with calcification; (4) reactive microglial and astroglial proliferation; and (5) occurrence of enlarged cells (neuronal and glial elements) with intranuclear inclusions (Fig. 20-1).25,32,42-45 Electron microscopic studies have revealed virions in brain tissue, a finding attesting to the primary infection of the CNS by the organism.46 Recovery of virus from brain confirmed this conclusion.9 A role for the inflammatory response itself in causing tissue destruction is suggested by the disparity between the detection of cytomegaloviral DNA by in situ hybridization and the extent of the tissue necrosis.47 The cellular and regional targets of the meningoencephalitis include especially the germinal matrix, cerebral white matter, and cerebral cortex.24,25,32,42-45,48-54 Germinal matrix necrosis and cysts are prominent. Subsequent matrix calcification is important in determining the periventricular distribution of calcifications. Periventricular cerebral white matter also is a site of injury, sometimes with cyst formation and subsequent calcification. A predilection for the parietal white matter may mimic periventricular leukomalacia. In addition, a predilection for anterior temporal white matter is particularly suggestive of CMV infection. Cerebral cortical atrophy is a later feature. Microcephaly. Microcephaly is a common feature in the neonatal period and is still more prominent later in infancy. The small size of the brain appears to relate to the encephaloclastic effects of the virus and probably also to a disturbance of cell proliferation in the developing brain. The latter disturbance relates to the propensity of the virus to affect the subependymal germinal matrix (see earlier). A predilection for involvement of proliferative cells is also suggested by the frequency of intrauterine growth retardation in congenital CMV infection and by the observation in a variety of tissues of a decrease in absolute number of cells.55-58 Disturbances of Neuronal Migration. Disturbances of neuronal migration have been described repeatedly in congenital CMV infection.23,24,42-45,48,50-52,54,59-72 Indeed, polymicrogyria has been documented in approximately 65% of well-studied cases. The polymicrogyria may involve cerebellar (Fig. 20-2) as well as cerebral cortex. Although polymicrogyria has been observed most commonly, lissencephaly, pachygyria, schizencephaly, and neuronal heterotopias have also been reported.23,24,45,64,65,69-72 These observations demonstrate the teratogenic potential of CMV and suggest the occurrence of infection in the latter part of the first trimester and in the second trimester, when
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A A
B B Figure 20-2 Congenital cytomegalovirus infection: neuronal migrational disturbance. A, Microgyric cerebellar cortex from a preterm infant with congenital cytomegalovirus infection. B, Section of the same microgyric cerebellar cortex shown in A, illustrating the distribution of calcification within the malformed cerebellar cortex and suggesting the coexistence of destructive and teratogenic effects. (From Perlman JM, Argyle C: Lethal cytomegalovirus infection in preterm infants: Clinical, radiological, and neuropathological findings, Ann Neurol 31:64-68, 1992.)
C Figure 20-1 Congenital cytomegalovirus infection: encephalitis, from an infant who died at 10 weeks of age. A, Region of necrosis in the subependymal germinal matrix (ependyma is at the upper right). Note enlargement of cells, many with intranuclear inclusions. B, Higherpower view of the same region showing the enlarged cells with prominent intranuclear inclusions. C, A closer view of the inclusions; note the clear halo around the inclusions and the nuclear chromatin displaced to the periphery (Cowdry type A inclusions). (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
neuronal migration begins and then becomes active (see Chapter 2). The usual coexistence of inflammatory, destructive lesions indicates persistent infection by the organism. These cases also may be relevant to the notion that cerebral cortical neuronal injury late in the second trimester may underlie other examples of
polymicrogyria (see Chapter 2). One careful study of four affected brains from infants with congenital CMV infection provided evidence of neuronal destruction in the lower cortical layers within areas of polymicrogyria and suggested that the cortical neuronal injury led ultimately to the gyral abnormality.44 At any rate, CMV infection is the only one of the congenital infections that is associated with overt disturbances of gyral development, and the pathogenesis thereof may include a combination of teratogenic and encephaloclastic mechanisms. Cerebellar Hypoplasia. Cerebellar hypoplasia, best detected by magnetic resonance imaging (MRI), is a feature in at least 50% of symptomatic cases. This finding likely is primarily a proliferative disturbance, although, as noted earlier, migrational disturbances may also be seen in the cerebellum. The finding of cerebellar hypoplasia in the clinical setting of an intrauterine infection is highly suggestive of congenital CMV.
Chapter 20
Other Findings. Porencephaly, hydranencephaly, hydrocephalus, focal subcortical cysts, impaired myelination, and more diffuse cerebral calcifications also have been described to variable extents in congenital CMV infection. Clinical Aspects Incidence of Clinically Apparent Infection. Although congenital CMV infection occurs frequently, clinical manifestations thereof do not. Indeed, available data indicate that approximately 90% of affected infants are asymptomatic in the newborn period.2,7,20,28,31,56,57,73-78 Clinical Features. The most frequent clinical features of symptomatic congenital CMV infection are shown in Table 20-4.2,7,9,14,17-19,56,57,79-84 The most common findings relate to disturbance of the reticuloendothelial system. Hepatosplenomegaly and a petechial rash, usually related to thrombocytopenia, are encountered very frequently. Infants are often small for gestational age; moreover, approximately one third of affected infants have a gestational age of 37 weeks or less. Inguinal hernia is a helpful clinical sign when present (25% of cases). The neurological syndrome is variable in presentation. Seizures may be prominent, although only approximately 10% of symptomatic patients exhibit overt neonatal seizures. Microcephaly is a most consistent manifestation in patients with severe disease and appears in approximately 50% of all symptomatic patients. Cerebral calcification, usually periventricular in location, occurs in 50% to 60% of cases. Cerebrospinal fluid (CSF) findings of encephalitis (e.g., pleocytosis, elevated protein content) are found in the majority of patients, but precise data are not available.
TABLE 20-4
Clinical Features of Symptomatic Congenital Cytomegalovirus Infection*
Clinical Feature
Approximate Frequency
Pregnancy Intrauterine growth retardation Premature birth
21%–50% 21%–50%
Central Nervous System Meningoencephalitis Microcephaly Cerebral calcification
51%–75% 21%–50% 51%–75%
Eye Chorioretinitis
0%–20%
Reticuloendothelial System Hepatosplenomegaly Hyperbilirubinemia Hemolytic and other anemias Thrombocytopenia Petechiae or ecchymoses
51%–75% 51%–75% 21%–50% 51%–75% 51%–75%
Other Inguinal hernias Pneumonitis
21%–50% 0%–20%
*See text for references.
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855
The clinical course is most commonly that of a static process. However, evidence of progressive encephaloclastic disease, documented by computed tomography (CT) scan, was provided by a report of two such cases.85 Similarly, postnatal evolution of cerebral calcification and of subependymal necrosis has been documented.45,86 Moreover, progression of hearing loss during infancy and early childhood has been described clearly (see later).7,18,20,78,83,84,87-90 The observation that virus is still recoverable in urine in 50% of cases at 5 years of age91 demonstrates persistence of infection and further raises the possibility of progressive disease. Clinical Diagnosis. The diagnosis of congenital CMV infection may be suspected with a high degree of accuracy on the basis of certain clinical features. These features include the periventricular locus of the cerebral calcification, microcephaly, CSF pleocytosis, and intrauterine growth retardation. Cerebellar hypoplasia and neuronal migrational abnormality are also distinctive features. The absence of the ‘‘salt-and-pepper’’ chorioretinitis of congenital rubella and the relative infrequency of the grossly scarring chorioretinitis of congenital toxoplasmosis are also helpful. Laboratory Evaluation Virus Isolation. Identification of the microbial agent is based principally on viral cultures and detection of viral genetic material.2,7,9,14,17,18,92 The organism is cultured most readily from the urine but also can be grown from the throat and occasionally from the CSF. The detection of virus in urine remains a highly specific and sensitive test for the diagnosis of congenital CMV infection. Infectivity of urine is retained after storage at 48 C (not at room temperature and not frozen) for as long as 7 days.93 A period of 2 to 4 weeks is required to detect the characteristic cytopathic effects in tissue culture. The detection of DNA of CMV in urine by the polymerase chain reaction (PCR) allows for diagnosis of infection in 1 day.7,94 The increase in sensitivity of this test to virtually 100% by the removal of inhibitory materials in urine by glass filter paper absorption helped make this technique the ideal test for detection of infection.92 PCR has also been shown to detect the virus in CSF, serum, and specimens of umbilical cord, although the sensitivity and specificity in these sites remain to be established.95-98 Immunofluorescent procedures that permit demonstration of specific CMV antigens in the nuclei of tissue culture cells inoculated with infected urine are positive in 90% to 100% of cases.93,99,100 This approach provides diagnostic information in 1 to 3 days. Serological Studies. Many serological tests have been used, but the complement fixation test, enzyme-linked immunosorbent assay (ELISA), and fluorescent antibody test are used most commonly.7,9,56,57 The commonly used complement fixation test depends on immunoglobulin G (IgG), and because this fraction is primarily derived by passive transfer from the infected mother, titers are high in the neonatal period. Persistence of an
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A
Figure 20-3 Congenital cytomegalovirus infection: periventricular calcification. This skull radiograph is from an affected 5-day-old infant with microcephaly. (From Bell WE, McCormick WF: Neurologic Infections in Children, 2nd ed, Philadelphia: 1981, Saunders.)
elevated titer in the neonate suggests infection of the infant, because passively transferred maternal antibody is degraded with an approximate half-life of 23 days.9 A faster and more useful test depends on the detection of CMV-specific immunoglobulin M (IgM), which is primarily derived from the infected fetus and infant.7 This specific IgM fraction is detected best by ELISA or a solid-phase radioimmunoassay that has improved the sensitivity and specificity of detection of CMV-specific IgM.7,17 Diagnostic Studies. CSF characteristically exhibits the findings of meningoencephalitis. In a study of 18 infants with neurological manifestations, the mean white blood cell count was 42, including predominantly lymphocytes, and the mean protein content was 192 mg/dL.101 In a later series of nine newborns with neurological involvement, all had elevated cell counts and protein levels.102 In a later study of 56 infants (which included 30% with no CT abnormalities), CSF protein exceeded 120 mg/dL in 50%.82 Skull radiographs formerly were used to demonstrate the periventricular calcifications (Fig. 20-3). However, CT scanning is more sensitive than skull radiography for detection of calcifications (Fig. 20-4), and CT also provides information on the extent and severity of the cerebral injury.69-71,82,101,103,104 In a series of 41 infants
B Figure 20-4 Congenital cytomegalovirus infection: computed tomography scans. These scans are from a 5-day-old infant with congenital cytomegalovirus infection. A, Periventricular and diffuse cerebral calcifications and ventriculomegaly are apparent. B, In addition to calcifications and ventriculomegaly, note the cerebellar hypoplasia and large cisterna magna (arrows).
with symptomatic congenital CMV infection, a CTdetected abnormality was present in 78%. Of those with abnormalities, periventricular calcifications occurred in 75%, varying degrees of cortical and white matter abnormalities were seen in 30%, and ventriculomegaly was reported in 40%.104 In a smaller series (n = 15), similar findings were reported.101 Occasionally, lissencephaly-pachygyria or diffuse polymicrogyria may be apparent by CT scan (Fig. 20-5). Cranial ultrasound scans frequently demonstrate abnormalities.45,48,101,103,105-115 These findings consist of periventricular cysts, especially in the region of the subependymal germinal matrix (see Fig. 20-5), ventriculomegaly, periventricular (and more diffuse) calcifications, and periventricular echolucencies (consistent with cerebral white matter cysts) (Figs. 20-6 and 20-7). The correlations with neuropathological
Chapter 20
Viral, Protozoan, and Related Intracranial Infections
857
A
Figure 20-5 Congenital cytomegalovirus infection: computed tomography scan. This scan was performed on the first postnatal day shows smooth cerebral cortex, characteristic of lissencephaly, in addition to periventricular and more diffuse calcifications, ventriculomegaly, and cerebellar hypoplasia.
findings (see previous discussion) are obvious. An additional ultrasonographic finding, overt in approximately one third of cases, is the presence of branched echodensities in basal ganglia and thalamus (Fig. 20-8).103,110-114 That the echodensities represent arteries has been shown by Doppler ultrasound examination.111,112,114 In two series, 15% to 40% of infants with such echodensities had CMV infection. (Other diagnoses included congenital rubella, congenital syphilis, trisomy 13, trisomy 21, fetal alcohol syndrome, and ‘‘neonatal asphyxia.’’) One pathological study defined hypercellular vessel walls and a mineralizing vasculopathy, probably secondary to perivascular inflammation (Fig. 20-9).110 MRI is of particular value for detection of the disorders of neuronal migration, cerebral parenchymal destruction, delays in myelination, and cerebellar
A
B Figure 20-6 Congenital cytomegalovirus infection: periventricular cyst in subependymal germinal matrix demonstrated by cranial ultrasound scan. A, This scan performed at 1 day of age demonstrates the bilateral cysts (small arrowheads). The ventricles are indicated by the large arrowheads. B, Coronal section of brain shows both cysts in the subependymal regions. (Courtesy of Dr. Gary Shackelford.)
hypoplasia observed with congenital CMV (Figs. 20-10 to 20-12).23,24,48,52-54,69-72 In a carefully studied series of 11 infants with congenital CMV infection, polymicrogyria was present in 5 and lissencephaly in 4.23 In a series of MRI-documented lissencephaly-pachygyria, CMV infection was present in 6 of 23 cases.69 In a related study of 10 infants with MRI-identified migrational disorders, especially polymicrogyria, 4 were found to have
B
Figure 20-7 Congenital cytomegalovirus infection: cranial ultrasound scan. A and B, Coronal scans in a 1-day-old infant show periventricular echodensities with associated echolucencies, consistent with calcification and white matter injury, dilation of lateral and third ventricles, and a subependymal cyst (arrow in A).
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A
B
Figure 20-8 Congenital cytomegalovirus infection: cranial ultrasound scan. A, Coronal and, B, sagittal scans of newborn known to have cytomegalovirus infection demonstrate bright vessels (arrows) in the region of the basal ganglia and thalami. (From Teele RL, HernanzSchulman M, Sotrel A: Echogenic vasculature in the basal ganglia of neonates: A sonographic sign of vasculopathy, Radiology 169:423-427, 1988.)
CMV.52 Delays in myelination and increased signal on T2-weighted images (see Figs. 20-11 and 20-12) have been observed in approximately one half of infants with CMV studied by MRI.23,24,48,53,54,69-71 Indeed, the predilection of abnormal cerebral white matter signal, including cystic change, for posterior parietal
Figure 20-9 Congenital cytomegalovirus infection: photomicrograph of small vessel. Note the thickened wall, focal globular subendothelial deposits of mineralized material, mononuclear infiltrates in adventitia, and perivascular reactive astrocytosis (hematoxylin and eosin, Luxol fast blue, 250). (From Teele RL, Hernanz-Schulman M, Sotrel A: Echogenic vasculature in the basal ganglia of neonates: A sonographic sign of vasculopathy, Radiology 169:423-427, 1988.)
regions may mimic periventricular leukomalacia. Thus, in an MRI series of 152 infants (mean age, 22 months) with ‘‘static leukoencephalopathy of unknown etiology,’’ 10% were found to have congenital CMV, based on retrospective PCR testing of neonatal blood spots.53 Cerebellar hypoplasia, a finding in 40% to 70% of infants, is detected best by MRI scanning. Notably, MRI is less sensitive than CT for detection of cerebral calcifications. Testing of brain stem auditory evoked responses in the neonatal period and subsequently demonstrates the high likelihood of sensorineural hearing loss, including the delayed onset and the postnatal progression of this loss. In 4 series of 281 infants with symptomatic congenital CMV infections, 50% to 75% exhibited hearing loss on
Figure 20-10 Congenital cytomegalovirus infection: magnetic resonance imaging scan. Note the striking cerebellar hypoplasia on this sagittal view (arrows). (Courtesy of Dr. Klaus Sartor.)
Chapter 20
Viral, Protozoan, and Related Intracranial Infections
859
(‘‘other’’) neurological phenomena had slightly better prognoses. Approximately 70% of these infants with neonatal neurological signs also experienced systemic phenomena. In the large series (n = 80) of MacDonald and Tobin,27 of the group of infants with systemic signs but no neonatal neurological deficits, approximately 50% were normal, and only 16% exhibited major neurological sequelae or died (see Table 20-5). Data from a later series (34 infants) are approximately similar, except the lack of neurological abnormalities in the newborn period was not clearly associated with more favorable outcomes.117 The major neurological deficits include pronounced cognitive deficits, most commonly with intelligence quotient (IQ) scores lower than 70, spastic motor deficits, seizure disorders, and bilateral hearing loss.17,27,78,81,82,87,89,104,117-119 In 2 series of 97 infants with symptomatic congenital CMV infection, mental retardation (IQ < 70) developed in 45% (IQ < 50 in 36%), cerebral palsy in 45%, seizures in 11%, and sensorineural hearing loss in 60%.82,104 Figure 20-11 Congenital cytomegalovirus infection: magnetic resonance imaging scan. This axial T2-weighted image shows markedly high signal intensity in cerebral white matter and diffusely thickened cerebral cortex with undulating appearance of the cortical–white matter junction, (arrow); the latter finding is characteristic of polymicrogyria. (From Titelbaum DS, Hayward JC, Zimmerman RA: Pachygyriclike changes: Topographic appearance at MR imaging and CT and correlation with neurologic status, Radiology 173:663-667, 1989.)
follow-up.84,89,104,116 Although approximately 60% of those with hearing loss had hearing loss at birth or in the neonatal period, fully 40% had delayed-onset loss (i.e., not apparent until months after the neonatal period). Additionally, progressive hearing loss was noted in approximately 60% of the infants with hearing loss.89 Progression of hearing loss has also been observed in infants with asymptomatic CMV infection. Thus, in one series, 3% of such patients had hearing loss detected in the neonatal period, but by the age of 6 years, 11% of the previously asymptomatic patients had hearing loss.83 The value and importance of serial studies throughout infancy are obvious. Prognosis Relation to Neonatal Clinical Syndrome. The outcome relates to the severity of the neuropathological findings, and these findings correlate with the neonatal clinical syndrome (Table 20-5).* Although the data depicted in Table 20-5 are based on a sample that was selected to a certain degree, the observations are useful regarding the relationship between the neonatal clinical signs and the neurological outcome in congenital CMV infection. Thus, of those infants with the overt neurological syndrome (i.e., microcephaly, intracranial calcifications, or chorioretinitis), approximately 95% had major neurological sequelae (e.g., mental retardation, seizures, deafness, and motor deficits) or died. Infants with less obvious
*See references 7,14,17,18,27,78,81,82,87,89,104,117-120.
Outcome with Asymptomatic Congenital Infection. The asymptomatic group has been the particular focus of several investigators.7,35,78,83,84,90,120-127 In these studies, the most consistent sequela was sensorineural hearing loss (Table 20-6). Approximately 11% of the infants developed bilateral hearing loss, with moderate to profound loss in 6%. Often, hearing deficits were not detected until serious impairment of language development occurred. Indeed, as noted with symptomatic disease, with more frequent serial measurements, it became clear that hearing impairment often did not become clearly apparent until, and progressed during, infancy and early childhood (see earlier discussion). In a large longitudinal study of 307 infants, 7.2% exhibited sensorineural hearing loss, and among these infants, 50% exhibited progression (median age at onset of progression, 18 months), and 18% exhibited delayed onset (median age of detection, 27 months).127 In a later study of 388 infants, as noted earlier, 3% of asymptomatic infants had sensorineural hearing loss in the first month, and 11% had hearing loss by 6 years of age.83 In a more recent series of 300 affected infants born after nonprimary (n = 124) or primary (n = 176) infection, although bilateral hearing loss occurred equally in both groups (10% to 11%), infants born after primary maternal infection were more likely to have severe or profound hearing loss (63% versus 15%).90 The diagnosis of hearing loss was made earlier in the infants born after primary maternal infection (mean age, 13 months versus 39 months). Histopathological and immunofluorescent studies of the inner ear in two affected infants revealed destruction of cells of the organ of Corti and the neurons of the eighth nerve, as well as the presence of viral antigen.122 Thus, involvement of cochlear structures with congenital CMV infection and the consequent disturbance of hearing may be an enormous public health problem, in view of the prevalence of the infection. The possibility of subtle disturbances of intellectual function was initially suggested by studies conducted by Hanshaw and co-workers,121 who demonstrated a
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A
INTRACRANIAL INFECTIONS
B
C Figure 20-12 Congenital cytomegalovirus infection, magnetic resonance imaging (MRI) scans. This 16-day-old infant was born after a 31-week gestation with congenital cytomegalovirus infection identified in utero. The axial T1-weighted MRI scan shows in A, increased signal in the periventricular regions (short arrows), consistent with calcification, and diffuse polymicrogyria (long arrow); in B, note the striking cerebellar hypoplasia (arrows). At 6 months of age, the axial T2-weighted MRI scan (C) shows diffuse frontal polymicrogyria (long arrows), abnormal high signal intensity in cerebral white matter (short black arrows), and marked paucity of parieto-occipital cerebral white matter (double white arrows). (Courtesy of Dr. Omar Khwaja.)
Chapter 20 TABLE 20-5
NEUROLOGICAL SEQUELAE{ Normal
Neurological Microcephaly, intracranial calcifications, or chorioretinitis Other Systemic Jaundice, hepatosplenomegaly,or purpura, but no neurological signs No Neurological or Systemic Signs
Major
Minor Death
7%
79%
0%
14%
40%
50%
0%
10%
48%
12%
36%
4%
81%
3%
16%
0%
*Based on 80 infants. { Expressed as percentage of those with designated neonatal clinical signs. Data from MacDonald H, Tobin HO: Congenital cytomegalovirus infection: A collaborative study on epidemiological, clinical and laboratory findings, Dev Med Child Neurol 20:471-478, 1978.
statistically significant lower mean IQ score in asymptomatic patients versus matched controls (102 versus 112). Subsequent large-scale studies did not document definite impairment of intellectual function in asymptomatic infants,123,124,128 particularly when hearingimpaired children were excluded.120,125 Intellectual outcome in hearing impaired children has not yet been studied in detail; outcome in this setting is important to define separately because the virus clearly has entered the CNS in this subgroup of infected infants. Nevertheless, several reports suggest that an asymptomatic neonatal period may be followed by varying combinations of developmental delay, microcephaly, ataxia, sensorineural hearing loss, and seizures, usually recognized in the first year of life.22,23,52-54 CT or MRI may show cerebral calcification, abnormal cerebral white matter signal, delayed myelination, polymicrogyria, focal subcortical areas of abnormality, or cerebellar TABLE 20-6
Subsequent Hearing Loss in Infants with Asymptomatic Congenital Cytomegalovirus Infection HEARING LOSS
Type
Severity*
Bilateral
Affected
Mild Moderate to profound
11% 5% 6%
Mild Moderate to profound
8% 4% 4%
Unilateral
861
hypoplasia. The possibility of late intrauterine acquisition of infection has been suggested in some of these infants. The important clinical point is that CMV infection should be considered later in infancy in the presence of such neurological or neuroradiological features, or both, even if the neonatal period was unremarkable. More data are needed on these issues.
Relationship between Neonatal Clinical Signs and Neurological Outcome in Congenital Cytomegalovirus Infection*
Neonatal Signs
Viral, Protozoan, and Related Intracranial Infections
*Mild hearing loss, 22 to 55 dB; moderate to profound, 55 dB. Data from references 121 to 124.
Management Prevention. Congenital CMV infection is related to primary infection of the pregnant woman, presumably early in pregnancy. Two preventive approaches may be used: one to prevent or treat the primary infection and the other to terminate the pregnancy. Prevention of the primary maternal infection by vaccination has received initial investigation, with variable results.5,7,129,130 However, more information is needed about the effectiveness, hazards, and feasibility of this approach.5,7,9,131-133a Treatment of the primary maternal infection with hyperimmune gamma globulin is a possibility, but the difficulty in detecting most maternal infections has been a major problem with this approach. Termination of a pregnancy complicated by a primary maternal infection has been difficult for a similar reason and also because the exact risks of fetal infection are not entirely known. Detection of the infected fetus by amniocentesis and identification of the virus or DNA by culture or PCR, respectively, comprise the principal approach.7,49,130,134-138 The sensitivity for detection of fetal infection increases markedly after 21 weeks of gestation. The fetal condition then can be assessed further by ultrasonography, which may show intracranial calcification or other evidence of parenchymal disease, and, if desired, by cordocentesis, with evaluation of fetal blood for abnormal liver function tests, CMV-specific IgM, anemia, or thrombocytopenia. In one series, the risk of identification of neonatal neurological abnormality by neurological examination, cranial ultrasonography, or hearing assessment was only 19% when no prenatal ultrasonographic abnormalities were present.49 Ultrasonographic abnormalities were detected prenatally in 21%, and nearly all these pregnancies were terminated. Supportive Therapy. From the neonatal neurological standpoint, supportive therapy consists principally of control of seizures. Antimicrobial Therapy. Several antiviral agents, including adenine arabinoside (Ara-A), 5-iodo-20 deoxyuridine (IDU), cytosine arabinoside (Ara-C), and acyclovir, have been studied because of their effectiveness in vitro.9,132,133 Ara-A and acyclovir are the least toxic of these agents, but early trials did not provide reason for optimism. Ganciclovir, an acyclovir derivative, has been shown to be effective in prophylaxis and treatment of CMV infections in immunocompromised adults and children.7,139-142 Initial data with infants are promising.143 An earlier study of 12 infants with congenital CMV infection suggested distinct clinical benefit (e.g., loss of hepatosplenomegaly, improvement in
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TABLE 20-7
INTRACRANIAL INFECTIONS
Effect of Ganciclovir Therapy on Hearing in Symptomatic Cytomegalovirus Disease*
Hearing from Neonatal Period to 1 Year
Ganciclovir
No Treatment
No deficit: both periods Deficit: improved Deficit: unchanged Deficit: worsened
23% 25% 31% 21%
22% 0% 17% 61%
*Total number of infants, 43; 24 received ganciclovir and 19 had no treatment. Values are percentages of all ears tested in each group. Data from Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, et al: Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: A randomized, controlled trial, J Pediatr 143:16-25, 2003.
tone) with a 3-month course of therapy.102 The most impressive data with ganciclovir involved a randomized controlled trial of the effect of the agent on hearing in symptomatic congenital CMV disease involving the CNS (Table 20-7).116 The treated infants received ganciclovir, 6 mg/kg per dose administered intravenously every 12 hours for 6 weeks. Hearing deficits either improved or remained static in 56% of the ears of treated infants versus only 17% of those of the control infants (see Table 20-7). Progression of deficits occurred in only 21% in the ganciclovir group versus 61% in the control group. The beneficial effect of ganciclovir was accompanied by significant neutropenia in approximately 65% of treated infants. The need for an agent that has less toxicity and can be administered orally is apparent. Valganciclovir, shown to be effective in adults with CMV retinitis, may prove to be such an agent. A recent case report described an effective systemic response in symptomatic neonatal CMV infection to a 6-week course of this drug.144 Ultimately, treatment of asymptomatic infants would be ideal, if the risk-to-benefit ratio of the agent could be favorable. It is perhaps unlikely, although not proven, that postnatal therapy would benefit the CNS, because the injury appears to occur principally in utero. However, more data are needed on this issue.
parasitemia, (3) placentitis, and (4) hematogenous spread to the fetus.145,148 The organism can be cultured consistently from the placenta when the fetus is infected.149 As with CMV, the mother infected with toxoplasmosis is usually asymptomatic.150-152 The most common clinical presentation of the mother is localized or generalized lymphadenopathy, sometimes with fever and other features suggestive of infectious mononucleosis.150 The incidence of primary maternal infection during pregnancy varies around the world. In Paris, when consumption of undercooked meat was relatively common, the value was as high as 5 per 100 pregnancies.148-150 At a comparable time, the rate in the United States was approximately 1.1 per 1000 pregnancies.151 More recent incidences are 0.5 to 2.0 per 1000 pregnancies in Western Australia, Europe, and the United States.145,146,153-155 These rates should be contrasted with the approximately tenfold-higher rates for CMV infection during pregnancy (see earlier discussion). A study of congenital infection, based on a serological study of filter paper blood specimens for neonatal metabolic screening in Massachusetts, yielded an incidence of only approximately 1 per 10,000.156-158 The unusual susceptibility of the human fetus and newborn to severe infection with T. gondii appears to relate, in large part, to inadequate cellular defenses.145,159 Mononuclear phagocytes are the principal defense against such infection, and a decreased generation of macrophage-activating material by fetal lymphocytes has been demonstrated. Moreover, the response to this activating material by macrophages in the neonate is also deficient. Unchecked replication of the organism is the expected result. Importance of Time of Maternal Infection. The likelihood and severity of congenital toxoplasmosis bear a distinct relation to the time of maternal infection (Table 20-8). Only approximately 20% to 25% of infants will be infected if the maternal infection occurs in the first or second trimester, especially the TABLE 20-8
Toxoplasmosis Intrauterine infection with T. gondii, a protozoan parasite, causes congenital toxoplasmosis. This congenital infection is second only to congenital CMV infection in terms of frequency and clinical importance. As with infection with CMV, congenital toxoplasmosis is acquired in utero by transplacental mechanisms, and most affected newborn infants are asymptomatic. However, with careful clinical evaluation and a high index of suspicion, this infection is more readily identified in the infected newborn than is CMV infection. Pathogenesis Fetal Infection. Clinically significant infection with toxoplasmosis occurs during intrauterine life by transplacental passage of the parasite.2,145-147 The sequence of events is (1) primary infection of the mother, (2)
Relationship between the Incidence and Severity of Congenital Toxoplasmosis and the Time of Maternal Infection* CONGENITAL TOXOPLASMOSIS{
Maternal Infection: Trimester of Pregnancy First Second Third
Infants Infected
Severe
Asymptomatic or Mild
17% 25% 65%
60% 30% 0%
40% 70% 100%
*Based on 145 pregnancies. { Percentage of infected infants with severe disease (central nervous system and ocular involvement) or those with asymptomatic disease or isolated ocular involvement (mild). Data from Desmonts G, Couvreur J: Toxoplasmosis in pregnancy and its transmission to the fetus, Bull N Y Acad Med 50:146-159, 1974.
Chapter 20
second to sixth months of gestation, versus approximately 65% if maternal infection occurs in the third trimester.145,150,160 In a large series of 603 women with confirmed maternal toxoplasmosis, the maternalfetal transmission rate was only 6% with infection at 13 weeks but increased to 72% with infection at 36 weeks.160 However, although fetal infection is less likely earlier in pregnancy, the severity of the disease is greater. Indeed, most infants infected in the first trimester exhibit severe disease, manifested by CNS and ocular involvement (see Table 20-8). As a result of these counterbalancing effects, in one large series the highest risk of bearing an infected infant with early clinical manifestations (10%) occurred in women who seroconverted at 24 to 30 weeks of gestation.160 A CT study of 31 infants further documented the severity of the CNS lesions as a function of the time of intrauterine infection.161 Therefore, it appears that although a fetal-maternal barrier to infection may be operative early in pregnancy, once fetal infection is established at that time, it is a potentially devastating disease. Treatment of the infected mother alters both the likelihood of fetal transmission and the severity of the disease (see later discussion). Neuropathology As with CMV infection, congenital toxoplasmosis may be associated with asymptomatic or symptomatic neurological presentations in the newborn period (see later discussion). Although the symptomatic neurological presentation is relatively uncommon, I describe it here because it serves as the prototype for the neuropathology produced by infection with this organism. Toxoplasmosis does not appear to possess the teratogenic potential of CMV infection, and essentially all the neuropathological features are related to tissue inflammation and destruction (Table 20-9).42,43,145,162-164 Meningoencephalitis. The meningoencephalitis of toxoplasmosis has a striking multifocal, necrotizing, granulomatous quality and is characterized by the following: (1) inflammatory cells in the meninges, especially over focal lesions; (2) perivascular infiltrates with inflammatory cells, the latter often including eosinophils; (3) multifocal and diffuse necroses of brain parenchyma, with all cellular elements affected, involving cerebrum, brain stem and spinal cord, and often associated with calcification; (4) reactive microglial and
TABLE 20-9
Neuropathology of Congenital Toxoplasmosis Overtly Symptomatic in the Neonatal Period
Meningoencephalitis, granulomatous Diffuse cerebral necrosis, sometimes with porencephaly and hydranencephaly Diffuse cerebral calcifications Periventricular inflammation and necrosis, especially periaqueductal Hydrocephalus
Viral, Protozoan, and Related Intracranial Infections
863
Figure 20-13 Congenital toxoplasmosis: encephalitis. Photomicrograph of a region of necrosis containing many free Toxoplasma organisms (note small, darkly stained nuclei to the left of larger, preserved neurons). Although this lesion was from an older child with Toxoplasma encephalitis who was receiving immunosuppressive therapy, the organisms are identical in appearance to those of the congenital form. (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
astroglial proliferation; and (5) miliary granulomas, containing large epithelioid cells and free, intracellular, or encysted organisms (Fig. 20-13). Porencephaly and Hydranencephaly. With particularly severe, diffuse, cerebral destructive disease, porencephalic cysts or hydranencephaly may develop.67,165 Of the 33 fetuses with congenital toxoplasmosis studied by Hohlfeld and co-workers,163 all exhibited areas of brain necrosis, the initial lesions that evolve to porencephaly and hydranencephaly. The development of these large areas of tissue dissolution is particularly likely if aqueductal block and increased intraventricular pressure are associated. Hydrocephalus. Two processes appear to be operative in the periventricular region with toxoplasmosis and may underlie the propensity for aqueductal block and consequent hydrocephalus in this disorder. First, the inflammation with toxoplasmosis has a predilection for the periventricular region, as with CMV infection (although in toxoplasmosis more severe diffuse disease is present elsewhere, and calcified areas of necrosis are present throughout the cerebrum). Second, it is believed that Toxoplasma organisms enter the ventricular system from the parenchymal lesions and disseminate there. This highly antigenic ventricular fluid then seeps through the damaged ependyma to periventricular blood vessels, where an antigen-antibody reaction may occur at the vessel wall, thereby causing thrombosis and periventricular infarction.162 This additional necrosis apparently causes the serious aqueductal block that results in the common complication, hydrocephalus. Among 33 infected fetuses identified in utero by Hohlfeld and co-workers,163 19 (58%) had ventricular dilation at autopsy after elective termination of pregnancy.
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Microcephaly. Although hydrocephalus is a more common result of congenital infection with T. gondii and is more frequent in this variety of congenital infection than in any other, microcephaly does occur in a significant percentage of patients, approximately 15% (see subsequent discussion). The microcephaly relates to the multifocal necrotizing encephalitis, particularly of the cerebral hemispheres. Indeed, even in those patients with hydrocephalus, it is clear that a serious loss of brain substance, in addition to the effects of the hydrocephalus, invariably has occurred. Clinical Aspects Incidence of Clinically Apparent Infection. As with CMV, clinically asymptomatic cases of congenital toxoplasmosis outnumber symptomatic cases. However, a larger proportion of infants with congenital toxoplasmosis than with congenital CMV infection can be detected clinically in the newborn period. Of 156 children with congenital toxoplasmosis who were monitored prospectively from the time of maternal infection, approximately 18% had CNS and ocular involvement, 2% had CNS involvement without ocular involvement, 12% had ocular involvement only, and 68% were asymptomatic.145 Thus, 20% of infants with congenital toxoplasmosis had observable CNS involvement in the newborn period in this study. The incidence of subclinical infection is higher in infants of women treated during pregnancy than in infants of women not treated (see later discussion). Clinical Features. Symptomatic patients (not treated in utero) often can be divided into those with predominantly neurological syndromes and those with predominantly systemic syndromes (Table 20-10 shows combined data for both syndromes).2,145,146,164,166,167 The neurological syndrome accounts for approximately two thirds of the cases and consists principally of abnormal CSF and other signs of meningoencephalitis, seizures, diffuse intracranial calcification, hydrocephalus, or, less commonly, microcephaly (see Table 20-10). At least 90% of these patients exhibit chorioretinitis. In congenital toxoplasmosis, chorioretinitis is typically bilateral and prominent in the macular regions (Fig. 20-14) and is of major diagnostic importance.145 Initially, the lesion appears in the fundus as yellowish white, cotton-like patches with indistinct margins. These patches evolve over the ensuing months into sharply demarcated, ‘‘punched-out,’’ pigmented lesions, often accompanied by optic atrophy. Although the chorioretinopathy is most commonly apparent in the newborn period, particularly by indirect ophthalmoscopy, it may not develop for months.145,146,163,168 The systemic syndrome of congenital toxoplasmosis is dominated by signs referable to the reticuloendothelial system, especially hepatosplenomegaly, hyperbilirubinemia, and anemia (see Table 20-10). A petechial rash may occur but is less common than with CMV infection. Overt clinical evidence of neurological involvement is often lacking in these patients, but CSF abnormalities, frequently with a disproportionately elevated protein
TABLE 20-10
Clinical Features of Symptomatic Congenital Toxoplasmosis
Clinical Feature Pregnancy Prematurity, intrauterine growth retardation, or both Central Nervous System Seizures Meningoencephalitis Intracranial calcification Hydrocephalus Microcephaly Eye Chorioretinitis Reticuloendothelial System Hepatosplenomegaly Hyperbilirubinemia Anemia Petechiae Other Pneumonitis
Approximate Frequency 0%–20%
21%–50% 51%–75% 51%–75% 21%–50% 0%–20% 76%–100% 21%–50% 21%–50% 51%–75% 0%–20% 0%–20%
Data from Remington JS, McLeod R, Thulliez P, Desmonts G: Toxoplasmosis. In Remington JS, Klein JO, Wilson CB, et al, editors: Infectious Diseases of the Fetus and Newborn Infant, 6th ed, Philadelphia: 2006, Elsevier Saunders; and Eichenwald H: A study of congenital toxoplasmosis. In Siim JC, editor: Human Toxoplasmosis, Copenhagen, 1970, Munksgaard.
content for the degree of pleocytosis, occur in approximately 85% and reflect concomitant meningoencephalitis.56,57 Chorioretinitis is observed in at least two thirds of patients with systemic cases, and this finding underscores the importance of careful evaluation of the fundus, especially by indirect ophthalmoscopy, when congenital toxoplasmosis is possible.
Figure 20-14 Congenital toxoplasmosis: chorioretinitis. Note the striking lesion at the macula (right), as well as optic atrophy (left). (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
Chapter 20
An unknown but probably very considerable number of infants with no neurological or systemic signs of congenital toxoplasmosis (i.e., asymptomatic disease) will exhibit chorioretinitis, detectable in the newborn period by indirect ophthalmoscopy. Although most of the retinal lesions observed later probably develop in the weeks and months after delivery (see subsequent discussion), further data are needed regarding the proportion detectable in the newborn period. In a series of 48 asymptomatic infants in whom infection was detected by newborn blood screening, 2 had active chorioretinitis, and 7 others had retinal scars; thus, 19% had retinal disease.158 Moreover, approximately 20% had cerebral calcifications detectable by CT, and 25% had CSF findings consistent with encephalitis. The later development of neurological deficits and visual loss is appreciable and is discussed in the ‘‘Prognosis’’ section. The clinical course of the disease is not readily predicted, and indeed, evidence of progression of retinal and cerebral disease has been presented.146,163,168-171 Because many patients with symptomatic congenital toxoplasmosis exhibit very severe neurological deficits from the neonatal period, the frequency of progression is difficult to quantitate. Clinical Diagnosis. Certain clinical features are helpful in suggesting the diagnosis of congenital toxoplasmosis. A particularly noteworthy constellation of features includes evidence of meningoencephalitis, focal and multifocal cerebral necroses, diffuse cerebral calcification, hydrocephalus, and scarring chorioretinopathy in the macular regions. Intrauterine growth retardation or prematurity is generally not a prominent feature, as in infants with congenital CMV or rubella infections, and microcephaly is less common than in congenital CMV infection. The systemic syndrome may cause confusion when differentiating toxoplasmosis from other congenital infections, but a petechial rash is relatively less common in congenital toxoplasmosis. Laboratory Evaluation Toxoplasma Isolation. Determination of T. gondii as the responsible microbe in the newborn with congenital toxoplasmosis depends principally on serological tests, rather than isolation of the organism per se. Nevertheless, the organism or associated DNA can be isolated from placental tissue, ventricular or lumbar CSF, and blood.145 The tissue extracts or fluids can be injected into either mice or tissue culture preparations.145,172,173 Parasitemia is more readily demonstrated in the first week after birth (71%) than in the second to fourth weeks (33%), and it is detected most easily in generalized rather than in neurological disease.145 The isolation procedures for toxoplasmosis require specialized techniques and an experienced, skilled laboratory staff. Detection of T. gondii in amniotic fluid by PCR with a sensitivity of 80% has suggested that this rapid test (result available in 6 hours) could become very important in the diagnosis when the technique is applied to biological fluids of the newborn infant.145,174 However, available data suggest
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that the sensitivity of PCR on placental tissue is only approximately 60%.175 Serological Studies. The identification of most cases of congenital toxoplasmosis is established by serological techniques. The two most commonly used tests are the Sabin-Feldman dye test and the IgM-fluorescent antibody test. The Sabin-Feldman dye test, perhaps the single most reliable test, is performed by mixing live organisms with the test serum (and a human serum component, the accessory factor) and then exposing the mixture to methylene blue. Parasites exposed to the antibody-containing serum are modified and stained. The antibodies for the dye test are passively transferred, and the maternal component does not decrease significantly for several months after birth. Persistence of high titers is necessary for diagnosis and obviously is time consuming. Moreover, the dye test requires hazardous live organisms, and the accessory factor is sometimes difficult to obtain. The Toxoplasma-specific IgM-fluorescent antibody technique is faster and more specific.2,56,57,145,146,176 This test measures fetally produced IgM antibody to the organism. Killed organisms are used to bind specific IgM, which is then detected by exposure to fluorescein-antiserum to human IgM. The reliability of this test is hindered by certain factors that impair both sensitivity and specificity.153,157 The more recently developed IgM-capture ELISA, which isolates and concentrates the infant’s IgM, increases the sensitivity markedly (90% of infected infants are detected), and false-positive reactions are unusual.157 This test has been adapted to filter paper blood specimens.157 More recent data suggest value for analysis of IgA or IgE in neonatal blood.145,175 However, sensitivities for all the latter tests are very low for infants infected in the first 20 weeks of gestation, when severe disease is the most likely result. Neurodiagnostic Studies. Neurodiagnostic studies that particularly suggest congenital toxoplasmosis are evaluations of CSF and brain imaging. Pleocytosis and elevated protein content of CSF indicate meningoencephalitis and may be observed in asymptomatic as well as symptomatic patients. Particularly characteristic of congenital toxoplasmosis is the finding of a very high protein content in the ventricular fluid, usually reflecting the aqueductal obstruction and stagnation of infection within the lateral ventricles. Although skull radiographs are effective in demonstrating the diffuse and periventricular cerebral calcification (Fig. 20-15), CT scan is more effective and, in addition, provides information on the extent and severity of cerebral injury (Fig. 20-16).161 CT data indicate that calcifications of the basal ganglia are more common than previously suspected.161 The calcifications associated with congenital toxoplasmosis, especially of the periventricular type or of the basal ganglia, also can be detected by cranial ultrasound scan (Fig. 20-17).105,108 Moreover, I have observed in congenital toxoplasmosis the echogenic thalamic vasculature described earlier (see ‘‘Cytomegalovirus Infection’’) (Fig. 20-18). MRI scan provides the most detailed assessment of parenchymal necroses.
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Figure 20-17 Congenital toxoplasmosis: cranial ultrasound scan. This coronal scan performed at 3 days of age shows marked hydrocephalus and evidence of calcification in basal ganglia (arrows) and subependymal regions.
Figure 20-15 Congenital toxoplasmosis: diffuse calcification shown on skull radiograph. This is a lateral skull film of an infant with hydrocephalus, chorioretinitis, and multiple, punctate calcifications scattered diffusely in brain. (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
Prognosis Relation to Neonatal Clinical Syndrome. As with CMV, the outcome of untreated congenital toxoplasmosis relates to the severity of the neuropathology, which correlates to a modest extent with the neonatal clinical syndrome (Table 20-11). Infants with congenital toxoplasmosis with prominent neonatal neurological
Figure 20-16 Congenital toxoplasmosis: computed tomography scan. This scan performed at 3 months of age shows cerebral calcifications, both periventricular and diffuse, including involvement of thalamus (large arrow) and basal ganglia (small arrow). A shunt catheter (arrowhead) is in the lateral ventricle.
features do poorly; only 9% are normal on follow-up. Most of the remaining infants exhibit serious disturbances of cerebral function (i.e., mental retardation, seizures, and spastic motor deficits). Essentially all such patients have chorioretinitis and may also have optic atrophy; as a consequence, approximately 70% have severe visual impairment. Somewhat unlike congenital CMV infection, congenital toxoplasmosis with a neonatal syndrome characterized by prominent systemic signs, if untreated, also results in a poor neurological outcome. Approximately 50% of such patients with CMV are normal on followup, whereas only approximately 16% of patients with congenital toxoplasmosis are normal (see Table 20-11). Although the nature of the study populations differs, it seems reasonable to conclude that CNS involvement in congenital toxoplasmosis is more prominent than in congenital CMV infection when non-neurological features dominate the neonatal syndrome. Again, chorioretinitis
Figure 20-18 Congenital toxoplasmosis: cranial ultrasound scan. This parasagittal scan obtained at 3 days of age shows marked hydrocephalus and echogenic vessels (arrows) in thalamus. The latter are consistent with the lenticulostriate vasculopathy seen in congenital cytomegalovirus infection (compare Fig. 20-8).
Chapter 20 TABLE 20-11
Relationship between Neonatal Clinical Signs and Neurological Outcome in Symptomatic Congenital Toxoplasmosis NEONATAL SIGNS*
Neurological Outcome Mental retardation Seizures Spastic motor deficits Severe visual impairment Deafness Normal
Neurological
Systemic
89% 83% 76% 69% 17% 9%
81% 77% 58% 42% 10% 16%
*Values for each neurological outcome are expressed as percentage of infants who exhibited the designated neonatal signs (i.e., neurological [n = 108] or systemic [n = 44]). Data from Remington JS, McLeod R, Thulliez P, Desmonts G: Toxoplasmosis. In Remington JS, Klein JO, Wilson CB, et al, editors: Infectious Diseases of the Fetus and Newborn Infant, 6th ed, Philadelphia: 2006, Elsevier Saunders; and Eichenwald H: A study of congenital toxoplasmosis. In Siim JC, editor: Human Toxoplasmosis, Copenhagen, 1970, Munksgaard.
is found in the majority of such patients with toxoplasmosis, and severe visual impairment occurs in approximately 40%. Antiparasitic treatment, begun in the first 21=2 months of life, has a beneficial effect on outcome in symptomatic congenital toxoplasmosis (see later discussion). Outcome with Asymptomatic Congenital Infection. Infants with subclinical infection (i.e., the majority of cases of congenital toxoplasmosis) comprise an important group. For example, in the United States, approximately 3000 such infants are affected yearly.171 Previous studies emphasized that such infants had a relatively high frequency of chorioretinitis and a modest impairment of intellect.122,145,157,177,178 A prospective study of 13 asymptomatic infants identified by serological screening in the newborn period and evaluated by particularly detailed serial, ocular, neurological, and audiological follow-up studies indicated that few such asymptomatic children escape without deficits TABLE 20-12
Subsequent Deficits with Asymptomatic Congenital Toxoplasmosis
Subsequent Deficit None Chorioretinitis Bilateral Unilateral Neurological sequelae Major Minor Mean intelligence quotient Sensorineural hearing loss
Number Affected* (Total n = 13) 2 11 8 3 5 1 4 89 ± 23 3
*Based on 13 infants identified by serological screening in the newborn period and studied prospectively. Data from Wilson CB, Remington JS, Stagno S, Reynolds DW: Development of adverse sequelae in children born with subclinical congenital toxoplasma infection, Pediatrics 66:767-774, 1980.
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(Table 20-12).65 Thus, 11 infants in this study developed chorioretinitis (3 with unilateral blindness), and 5 had neurological sequelae (1 with severe mental retardation and microcephaly). The neurological sequelae were always associated with chorioretinitis. The mean IQ score for the group was only 89. Sensorineural hearing loss occurred in 3 of 10 infants so tested, although in none was moderate or severe bilateral loss observed. However, diagnosis by neonatal screening and prompt institution of therapy result in a markedly better outcome (see later discussion). Management Prevention. Three major approaches to prevention include (1) avoidance of primary maternal infection, (2) treatment of maternal infection, and (3) abortion in the presence of maternal infection. The first of these approaches is the most important. Pregnant women who have seronegative test results must avoid primary acquisition of Toxoplasma infection; the two measures necessary are avoiding ingestion of infective cysts (e.g., in raw meat) and contact with sporulating oocysts (e.g., in animal intestine and feces).145,146,157,171,179 Ingestion of infective cysts occurs when infected meat is undercooked. It is recommended that consumption of raw or undercooked meat be completely avoided and that handling of raw meat be done with gloves on or followed by careful hand washing. Contact with sporulating oocysts is principally through household cats that carry oocysts in their intestines. It is recommended that pregnant women avoid contact with cat feces and that contact with soil or other materials potentially contaminated with cat feces be avoided or performed while wearing gloves. Cost-to-benefit analyses (relative to other approaches to prevention) demonstrate the particular desirability of a health education campaign to encourage these practices.180 Primary maternal infection has been treated with the antibiotic spiramycin.2,145,146,148,163,171,171a In one large series, a significant reduction in cases of congenital infection was observed in treated (24%) versus untreated (45%) mothers.148 The approximately 50% decrease in incidence of congenital toxoplasmosis was confirmed by subsequent data.163,171,171a Moreover, a more recent multicenter study showed a marked decrease in the incidence of neonatal chorioretinitis and intracranial lesions when prenatal treatment (spiramycin) was instituted within but not after 4 weeks of diagnosis of maternal infection.181 Abortion has been performed in women who have exhibited serological evidence for primary infection during early pregnancy. This approach is less desirable for several reasons, one of which is the finding that only 17% to 25% of women infected in the first and second trimesters transmit the infection to the fetus (see Table 20-8). However, initial work by Desmonts and co-workers,149 and subsequently by others,145,163,182-189 demonstrated the feasibility of prenatal diagnosis of congenital toxoplasmosis. Thus, the evaluation of pregnant women for possible fetal infection with toxoplasmosis is based principally on sampling amniotic fluid by amniocentesis and detection
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TABLE 20-13
INTRACRANIAL INFECTIONS
Neonatal Outcome of Liveborn Infants with Congenital Toxoplasma infection in the Periods before (1972 to 1981) and after (1982 to 1988) Fetal Treatment* TIME OF MATERNAL INFECTION (TRIMESTER) FIRST
SECOND
THIRD
Neonatal Outcome{
1972–1981
1982–1988
1972–1981
1982–1988
1972–1981
1982–1988
Subclinical Benign Severe
10% 50% 40%
67% 22% 11%
37% 45% 18%
77% 23% 0%
68% 29% 3%
100% 0% 0%
*See text for details of prenatal and postnatal treatment. Groups are not entirely comparable, and study was not controlled; data, however, provide an approximation of the effect in the second epoch of prenatal and postnatal treatment with spiramycin (100%) plus pyrimethamine and sulfonamide (85%). { Subclinical, no symptoms. Benign form, infants with chorioretinitis but no visual impairment or with intracerebral calcifications but no neurological impairment. Severe form, infants with hydrocephalus, microcephaly, bilateral chorioretinitis with visual impairment, and abnormal neurological status. Data from Hohlfeld P, Daffos F, Thulliez P, Aufrant C, et al: Fetal toxoplasmosis: Outcome of pregnancy and infant follow-up after in utero treatment, J Pediatr 115:765-769, 1989.
of the organism’s DNA by PCR. Sampling of fetal blood by cordocentesis under ultrasound guidance for serological indicators of infection is less useful. Ultrasonography of the fetal cranium at approximately 19 to 20 weeks of gestation provides information concerning cerebral abnormality. Fetal cranial ultrasonography may show ventriculomegaly, evidence of tissue necrosis, and cerebral calcifications. The diagnosis of fetal infection has also been made by isolation of the organism from fetal blood or from amniotic fluid and by identification in fetal blood of hematological abnormalities (e.g., eosinophilia, thrombocytopenia), elevated gamma-glutamyltransferase activity, and Toxoplasma-specific IgM. The positive identification of fetal infection provides the possibility of treatment of the fetus.2,145,163,171a In the classic study of Hohlfeld and co-workers,163 fetal treatment consisted of administration to the mother of alternating 3-week courses of spiramycin and of pyrimethamine, sulfadiazine, and folinic acid (see later discussion). (The latter three agents are not used before the 18th week of gestation because of the teratogenic potential of pyrimethamine.) The beneficial effect on the severity of fetal infection was dramatic (Table 2013). Although, as in pretreatment years, the incidence TABLE 20-14
Postnatal Evolution of Chorioretinitis in 327 Children with Congenital Toxoplasmosis Treated from Birth*
Time of Assessment 1st mo 2nd–12th mo 2nd yr 3rd–6th yr 7th–9th yr 9th–13th yr Total
Diagnosis of First Lesion 3% 9% 2% 5% 4% 1% 24%
*Infants were treated for approximately the first postnatal year, as described in the text. Eighty-four percent of the mothers had also received therapy in utero.
of severe fetal infection increased the earlier in pregnancy the infection was acquired, only 11% of first trimester infections treated in utero resulted in severe manifestations in the neonatal period. Moreover, of the third trimester fetal infections treated in utero, all resulted in asymptomatic newborns. Continuation of antimicrobial therapy postnatally in 53 infants was accompanied after relatively short-term follow-up by normal neurological development and examination in 52 (98%) and by the development of peripheral chorioretinitis, with no visual impairment, in 5 (9%). These favorable outcomes represent a dramatic improvement when compared with outcomes in the pretreatment era (see Table 20-11). A longer-term study confirmed the favorable effects of combined fetal and postnatal therapy, although delayed onset of chorioretinitis was shown (Table 20-14).168 Thus, by the age of 13 years, 24% of children had developed chorioretinitis, with one half of the lesions appearing after the first year of life and some as late as 13 years. Severe bilateral visual impairment, however, did not occur. Nevertheless, careful long-term follow-up is imperative. Supportive Therapy. Such therapy is carried out as described for congenital CMV infection. Antimicrobial Therapy. Although significant injury has already occurred in many cases of congenital toxoplasmosis by the time of birth, good evidence indicates that some of this injury is reversible and continuing postnatal injury is preventable by therapy directed against the organism.* The drugs of choice are pyrimethamine and sulfadiazine, with the addition of folinic acid to counteract the folic acid antagonistic effect of pyrimethamine on the bone marrow. Pyrimethamine is highly effective in experimental infection with Toxoplasma and, because of its high lipid solubility, appears to be concentrated in brain.145 Sulfadiazine acts synergistically with
*See references 2,145,146,157,158,163,164,166,168,177,184,190-192.
Chapter 20 TABLE 20-15
Effect of Postnatal Treatment on Clinically Symptomatic and Asymptomatic Congenital Toxoplasmosis
Clinically Symptomatic* Motor deficits Intelligence quotient < 70 Retinopathy Asymptomatic{ Motor deficits Severe cognitive deficits Retinopathy
20%–25% 25% 90% (81% present in neonatal period) 2% 2% 29% (19% present in neonatal period)
*Data from Roizen N, Swisher CN, Stein MA, Hopkins J, et al: Neurologic and developmental outcome in treated congenital toxoplasmosis, Pediatrics 95:11-20, 1995 (n = 34); and McLeod R, Boyer K, Karrison T, Kasza K, et al: Outcome of treatment for congenital toxoplasmosis, 1981-2004: The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study, Clin Infect Dis 42:1383-1394, 2006 (n = 120). { Data from Guerina NG, Hsu HW, Meissner HC, Maguire JH, et al: Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection, N Engl J Med 330:1858-1863, 1994 (n = 50).
pyrimethamine, such that their combined activity is eight times that expected if additive effects were operative.193,194 Caution must be exercised with sulfadiazine, particularly in infants with hyperbilirubinemia. The combination of pyrimethamine and sulfadoxine (Fansidar) is more convenient because it can be administered every 2 weeks rather than daily. Thrombocytopenia is a particularly early manifestation of pyrimethamine toxicity, and folinic acid is particularly effective in correcting this phenomenon. These antimicrobials kill actively multiplying parasites but not resistant cyst stages. Therefore, treatment must begin promptly and must continue until the infant’s immune system has matured sufficiently to control the infection. The total recommended duration of therapy in both symptomatic and asymptomatic disease is 1 year.145,163 In infants with evidence of severe inflammation, manifested by markedly elevated CSF protein (1 g/dL) or by severe chorioretinitis, corticosteroids have been recommended. Doses and modes of administration of these various agents are discussed elsewhere.145 The beneficial effects of postnatal onset of therapy in congenital toxoplasmosis, either clinically symptomatic or detected by newborn blood screening (‘‘asymptomatic’’), are illustrated by the data in Table 20-15. Rubella Congenital infection of the infant with rubella occurs in utero by transplacental mechanisms. Before the institution of rubella vaccination, congenital rubella, especially in epidemic years, was a common and devastating disease of the newborn. With the widespread use of rubella vaccination, the frequency of the disorder has diminished markedly. For example, the incidence in the United States is less than 1 per 1 million live births.2,195 There were 47 cases reported in the United States in
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1991, and 22 of these occurred in a cluster in southern California.196 Nevertheless, rubella remains a common illness in many parts of the world, and as a consequence congenital rubella syndrome is not rare (e.g., in Morocco annual rates of congenital rubella syndrome are approximately 1 per 10,000 live births).197 The relationship between intrauterine infection with rubella and congenital defects was first clearly recognized in 1941 by Gregg.198 Pathogenesis Fetal Infection. Clinically significant infection with rubella virus occurs during intrauterine life by transplacental passage of the virus.2,9,195 As with CMV infection and toxoplasmosis, the sequence of events is primary maternal infection, viremia, placental infection, and, finally, fetal infection. Cases of asymptomatic maternal infection are common, outnumbering those of symptomatic infection by nearly 2 to 1.56,57,195 Viremia occurs during the week before the onset of clinical manifestations, which include fever, cervical adenopathy, and a maculopapular rash lasting 3 days. Importance of Time of Maternal Infection. The likelihood and the severity of fetal infection are functions of the time of maternal infection.2,195,199-201 The risk to the fetus begins when the rash in the mother appears at least 12 days after the last menstrual period (i.e., the likely time of conception); in a series of 38 carefully studied pregnancies in the periconceptional period, no cases of fetal infection occurred when the rash appeared at 11 days or less after the last menstrual period.202 In general, both the frequency of occurrence of infection and the severity of clinical disease are greater the earlier in pregnancy the maternal infection occurs (Table 20-16). Thus, it is different from the situation with toxoplasmosis, in which the likelihood of infection is less but the severity of disease greater when acquired early in pregnancy. With congenital rubella, ocular and cardiac defects are particularly common when infection occurs in the first and second months, but they become essentially nonexistent when infection occurs after the first trimester. However, hearing loss, although most common with early infection, is still found in approximately half of infants infected in the fourth month; later maternal infection appears not to be dangerous in this regard. Neurological deficits, especially intellectual retardation and motor deficits, are most common with infection in the first 2 months and are not observed with infection past the fourth month. The most critical gestational periods concerning the major defects have been defined particularly closely.200 In a series of 55 children from carefully dated, affected pregnancies, cataracts were observed with maternal infection between 26 and 57 days of gestational age; heart disease occurred in maternal infection between 25 and 93 days of gestational age; deafness occurred in maternal infection between 16 and 131 days of gestational age; and severe mental retardation occurred in maternal infection between 26 and 45 days of gestational age. The placenta may play the greatest role in
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TABLE 20-16
INTRACRANIAL INFECTIONS
Relationship between the Clinical Manifestations of Congenital Rubella and the Time of Maternal Infection MATERNAL INFECTION: MONTH OF PREGNANCY*
Clinical Manifestation
First
Second
Third
Fourth
> Fourth
Ocular defect Cardiac defect Deafness Neurological deficit
50% 57% 83% 57%
29% 58% 72% 59%
7% 21% 67% 24%
0% 5% 49% 26%
0% 6% 0% 0%
*Values for each clinical manifestation are expressed as the percentage of infants affected after maternal infection during the designated month. Data from Cooper LZ, Ziring PR, Ockerse AB, Fedun BA, et al: Rubella, Am J Dis Child 118:18-29, 1969.
determining the decreasing incidence of fetal infection with progression of gestation. Maturational factors of host tissue may be most important in determining the concomitant changes in organ susceptibility. Neuropathology As with congenital CMV infection and toxoplasmosis, the neuropathology of congenital rubella is characterized by considerable inflammation and tissue necrosis (Table 20-17).2,42,195,203-205 In addition, rubella also appears to interfere with cellular proliferation in the developing brain and, as a consequence, causes microcephaly and, perhaps, impaired myelination. Meningoencephalitis. The meningoencephalitis of rubella infection is similar in certain respects to the other neonatal encephalitides and is characterized by the following: (1) inflammatory cells in the meninges; (2) perivascular infiltrates with inflammatory cells; (3) necrosis of brain parenchyma, with all cellular elements affected; and (4) reactive microglial and astroglial proliferation.
A Vasculopathy. An additional, prominent, and distinctive feature of rubella infection is vasculopathy. Involvement of blood vessels is observed in many organs and prominently in the brain.203 In the wellstudied series of Rorke and Spiro,203 involvement of large leptomeningeal vessels and, particularly, smaller intraparenchymal vessels and capillaries was defined. Destruction of one or more layers of the vessel wall occurs, with replacement by deposits of amorphous granular material (Fig. 20-19). Associated with these vascular lesions are focal areas of ischemic necrosis, especially in the cerebral white matter (centrum semiovale, periventricular regions, and corpus callosum) and in the basal ganglia. The vascular abnormalities may account for the echogenic vessels observable on cranial ultrasonography of the affected newborn (see later discussion).
B TABLE 20-17
Neuropathology of Congenital Rubella Symptomatic in the Neonatal Period
Meningoencephalitis Vasculopathy with focal ischemic necrosis Microcephaly Delayed myelination
Figure 20-19 Congenital rubella infection: vasculopathy. A and B, Cerebral vessels from a 10-week-old infant with a birth weight of 2250 g and involvement of multiple organs. Note the destruction of vessel walls with replacement by deposits of amorphous granular material, which is evident especially in A. Surrounding ischemic changes are also present, especially in B. (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
Chapter 20
Microcephaly and Impaired Myelination. Two additional features of congenital rubella (i.e., microcephaly and impaired myelination) may relate to the effect of the virus on cellular replication. Microcephaly does not appear to be accounted for readily by destructive disease and, indeed, is often not prominent until months after birth. The possibility that the decreased brain mass is related to a decrease in the number of neurons and glia is supported by the observations that rubella disturbs mitotic activity of human fetal cells in culture and also causes a reduced number of cells in a variety of organs in affected infants.2,206,207 In addition to the microcephaly, a cellular deficit may account for the moderately impaired myelination observed by Rorke and Spiro203 and by Kemper and co-workers.208 Indeed, although quantitative data are lacking, an apparent decrease in oligodendrocytes has been observed in association with the retardation of myelination.203 Clinical Aspects Incidence of Clinically Apparent Infection. The devastating rubella pandemic of the mid-1960s afforded the opportunity to define the enormous clinical spectrum of congenital rubella.2,9,32,43,56,57,195,209-221 Because the largest portion of available data was derived from studies of infants identified at birth, the spectrum of manifestations as a function of maternal infection has been more difficult to define than for congenital CMV infection or toxoplasmosis. Nevertheless, it does appear that the likelihood of asymptomatic congenital rubella infection is more nearly comparable to that of congenital toxoplasmosis than to that of congenital CMV infection. Thus, approximately two thirds of patients are asymptomatic in the neonatal period.218 However, most of these infants do develop evidence of disease in the first several years of life, a finding imparting clinical significance to observations that prolonged viral replication is an important feature of this disease.2,210,217 Clinical Features. The clinical features in symptomatic patients are shown in Table 20-18.9,56,57,195,214 Intrauterine growth retardation (followed by postnatal growth failure) is a particularly common feature. Disturbances of the reticuloendothelial system are also prominent and are characterized particularly by hepatosplenomegaly and thrombocytopenia with or without purpura.9 The purpura should be distinguished from the peculiar dermal erythropoiesis that results in the small purple lesions of the ‘‘blueberry muffin’’ syndrome. Cardiovascular defects are characteristic and consist principally of peripheral pulmonic stenoses and patent ductus arteriosus.209,215 Myocardial injury can be demonstrated in a few patients by abnormal electrocardiographic findings, as well as pathologically,211 and it may contribute to the occurrence of congestive heart failure. Other lesions, apparent in 20% to 50% of patients, are linear areas of radiolucency of the metaphyses of long bones (i.e., ‘‘celery stalk lesions’’), prominent especially around the knee, and interstitial pneumonitis.212 The latter abnormalities usually subside in the first few months of life.
Viral, Protozoan, and Related Intracranial Infections TABLE 20-18
871
Clinical Features of Symptomatic Congenital Rubella
Clinical Feature
Approximate Frequency
Pregnancy Intrauterine growth retardation
51%–75%
Central Nervous System Meningoencephalitis Full anterior fontanelle Lethargy Irritability Hypotonia Opisthotonos-retrocollis Seizures
51%–75% 21%–50% 21%–50% 21%–50% 21%–50% 0%–20% 0%–20%
Eye Cataracts Chorioretinitis Microphthalmia
21%–50% 21%–50% 0%–20%
Hearing Suspected or definite hearing loss Cardiovascular System Peripheral pulmonic stenoses Patent ductus arteriosus Myocardial necrosis Reticuloendothelial System Hepatosplenomegaly Hyperbilirubinemia Thrombocytopenia ± purpura Anemia Dermal erythropoiesis (‘‘blueberry muffin’’) Other Bony radiolucencies Pneumonitis
21%–50%
51%–75% 21%–50% 0%–20% 51%–75% 0%–20% 21%–50% 0%–20% 0%–20%
21%–50% 21%–50%
Data from Alford CA Jr: Chronic congenital and perinatal infections. In Avery GB, editor: Neonatology: Pathophysiology and Management of the Newborn, 3rd ed, Philadelphia: 1987, JB Lippincott; and Desmond MM, Wilson GS, Melnick JL, Singer DB, et al: Congenital rubella encephalitides, J Pediatr 71:311-331, 1967.
Neurological phenomena in the newborn period are prominent in approximately 50% to 75% of the cases (see Table 20-18).32,43,56,57,77,214,222 The most common manifestations relate to meningoencephalitis, seen most clearly in most patients by elevated levels of CSF protein and mononuclear cells.214 The anterior fontanelle is full in 25% to 50% of patients. The most common initial neurological features are ‘‘lethargy’’ and hypotonia, accompanied and followed shortly by prominent irritability. The irritability may relate to meningeal irritation, which probably also accounts for the occurrence of retrocollis and opisthotonos. These signs of meningeal irritation may worsen in the first weeks or months of life. Seizures appear in approximately 10% to 15% of infants.214 Definite microcephaly is unusual at birth. Most of the acute clinical features subside over the first several months and evolve to the sequelae outlined subsequently. The ocular lesions consist principally of cataracts, usually white or pearly, especially centrally, and
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chorioretinitis.2,9,223 Chorioretinitis may be more common than was previously appreciated. Indirect ophthalmoscopy is especially helpful to demonstrate the characteristic spotty pigmentation (i.e., ‘‘salt-andpepper’’) appearance, which may be particularly prominent peripherally.213 Microphthalmia is sometimes difficult to appreciate when it is bilateral and is associated particularly with cataract. The auditory lesion may be difficult to demonstrate in the newborn, although the application of brain stem evoked response audiometry has improved detection. In one series, approximately 20% of infants had suspected or definite hearing loss by behavioral testing in the neonatal period.220 The basis for the hearing loss in congenital rubella is a cochlear inflammatory and destructive lesion.219 A significant minority of infants subsequently will exhibit disturbances in response to sound that appear to be on a ‘‘central’’ basis,216 although the locus of this central pathology is unclear. In a detailed study of hearing loss in children with congenital rubella, the hearing deficit was usually uniform over all frequencies, symmetrical, and severe (mean threshold, 93 dB).224 As many as 60% to 80% of infants with congenital rubella are found later to have hearing loss as children.2,195,214,224 This increase in incidence from early infancy to childhood relates to a combination of inadequate testing in infancy with delayed diagnosis and progression of disease in the auditory apparatus; the relative importance of each of these factors remains unclear. Clinical Diagnosis. Clinical features that favor the diagnosis of congenital rubella are intrauterine growth retardation, CSF pleocytosis, salt-and-pepper chorioretinopathy, cataracts, cardiovascular defects, and skeletal lesions. The absences of prominent cerebral calcification, hydrocephalus, overt microcephaly, and vesicular rash are the clinical features that best differentiate congenital rubella from congenital toxoplasmosis, CMV infection, and HSV infection. Laboratory Evaluation Virus Isolation. Determination of rubella virus as the responsible microbe depends particularly on isolation of the virus and serological tests.2,9,195,205 The virus can be isolated best from the nasopharynx and urine, but it can also be isolated from stool and CSF (and various tissues, including lens and brain). Approximately 55% to 85% of patients exhibit positive cultures.2,214 Performance of multiple cultures increases the yield appreciably. The virus has been isolated from approximately 30% to 45% of CSF samples examined.211,214 This relatively high frequency of isolation of virus from CSF is unlike other congenital viral encephalitides. The chronicity of rubella infection is emphasized by the finding of positive CSF cultures in infants as old as 18 months.214 A similar conclusion can be derived from isolation of virus from the cataractous lens of a child aged 2 years, 11 months.221 Moreover, as many as one third of infants with congenital rubella are still excreting virus at 8 months of age.9
Serological Studies. Serological diagnosis may be based on the persistence of hemagglutination inhibition or neutralization antibody titers after 4 to 6 months of age, when passively transferred antibody is usually undetectable. However, the fastest and most useful test is determination of IgM-specific antibody; this is the most definitive serological diagnostic test in the first few weeks of life. Neurodiagnostic Studies. No specific neurodiagnostic tests are available, although a high rate of viral isolation from the CSF and the frequency of CSF signs of inflammation are very helpful in diagnosis. CT scan is useful in the detection of the focal areas of ischemic necrosis secondary to the vasculopathy and the less common calcification in basal ganglia.71,109 CT scans performed between 1 and 3 years of age have demonstrated cerebral white matter hypodensity and multiple calcified nodules in the centrum semiovale,225 presumably reflecting the impaired myelination and focal ischemic lesions described earlier in the section on neuropathology. MRI scan is most useful for detection of the presumed ischemic lesions in cerebral white matter and impairment of myelination.109 Cranial ultrasound scan may show focal areas of calcification,108 subependymal cysts,106,109,226 and echogenic vessels in the basal ganglia and thalamus.106,109,110,227 In a series of 12 infants with echogenic vessels in basal ganglia, 2 patients had congenital rubella.110 Prognosis Relation to Neonatal Clinical Syndrome. Although the outcome is related to the neonatal clinical features, the relationships are not so obvious as with congenital CMV infection and toxoplasmosis. This fact may relate to the particular chronicity of congenital rubella, as well as to the relative infrequency of completely asymptomatic neonatal disease. In a population of 100 infants carefully studied, 90% of whom were overtly symptomatic in the neonatal period and very early infancy, only 9% appeared to be free of deficits at 18 months (Table 20-19).214 Neuromotor deficits (i.e., spastic motor deficits and delayed neurological development) were severe in approximately 50% of the patients. Fully 81% of these infants had microcephaly, and 72% had definite hearing loss or other apparent disturbances related to auditory perception. In a subsequent report of the same population, of patients followed to 16 to 18 years of age, 28% exhibited mental retardation, and an additional 25% exhibited low-average intelligence.228 Of 14 children with ‘‘suspect’’ hearing loss at 18 months, 13 were definitely hearing impaired. In another prospective series of infants with congenital rubella, approximately similar outcomes were observed; approximately 45% of such infants exhibited ‘‘psychomotor retardation,’’ and 50% of these infants were moderately or severely affected.199 Long-Term Hearing Deficits and Other Sequelae. Even those infants who appear to be less severely affected often show evolution of disabling auditory, motor, behavioral, and learning deficits as they grow
Chapter 20 TABLE 20-19
Outcome at Age 18 Months of Survivors of Congenital Rubella Syndrome Percentage Affected
Outcome Neuromotor Deficits None Mild Severe
31% 22% 47%
Microcephaly
81%
Hearing Loss None Definite Poor speech, inconsistent response to sound
28% 45% 27%
Ocular Manifestations Cataract Chorioretinitis
47% 31%
No Hearing, Speech, or Visual Problem
9%
Data from Desmond MM, Wilson GS, Melnick JL, Singer DB, et al: Congenital rubella encephalitides, J Pediatr 71:311-331, 1967.
older (Table 20-20).2,195,220 A multidisciplinary, longitudinal study of 29 ‘‘nonretarded’’ infants with congenital rubella demonstrated definite hearing loss in 1 infant in the first 2 months, in 12 infants by 12 months, in 22 infants by 24 months, in 25 infants by 48 months, and in an additional 2 infants by 11 years, for a total of 27, or 93% of the children. This accretion of patients with definite hearing loss may reflect continuing cochlear injury. The analogy with the delayed onset of hearing loss in congenital CMV infection and of chorioretinopathy in congenital toxoplasmosis is apparent. In the longitudinal study just mentioned, early disturbances of motor development and of tone were followed by impairments of motor coordination and muscle weakness in approximately 50% of the children.220 Behavioral disturbances, which in the early years included impaired attention span and hyperkinesis, evolved to emotional irritability and persisting distractibility in approximately 50%. A propensity for congenital rubella infection to lead to impairment of TABLE 20-20
Identification of Hearing Loss in 29 Nonretarded, Longitudinally Studied Children with Congenital Rubella Syndrome HEARING LOSS
Age Birth–2 mo 3–12 mo 13–24 mo 25–48 mo 4–11 yr
Suspected
Diagnosed
5 10 2 2 —
1 11 10 3 2 27 (93%)
Data from Desmond MM, Fisher ES, Vorderman AL, Schaffer HG, et al: The longitudinal course of congenital rubella encephalitis in nonretarded children, J Pediatr 93:584-591, 1978.
Viral, Protozoan, and Related Intracranial Infections
873
behavioral and emotional development is also apparent in other studies by a 6% incidence of subsequent autism.195 Moreover, although IQ scores remained within the normal range in the study of Desmond and co-workers,220 learning deficits and visualperceptual-motor deficits were prominent in approximately 50%. These abnormalities had major impacts on the adaptation of the children to educational and home environments and underscore the necessity for careful follow-up and appropriate interventions in infants with congenital rubella. An interesting relationship between the rate of linear growth and cognitive outcome was apparent in a 20year follow-up of 105 cases of congenital rubella syndrome.229 Children with normal growth had normal cognitive development, and those whose linear growth was at less than the fifth percentile exhibited moderate to severe mental retardation. Late Progressive Panencephalitis. A rare complication of congenital rubella, the precise frequency and importance of which are not clear, is the occurrence of progressive panencephalitis with onset, usually in the second decade, of intellectual and motor deterioration, elevated CSF protein levels, and elevated antibody titers to rubella virus in serum and CSF.195,230 The virus has been isolated from the brain.231 Whether this disorder represents reactivated infection or bears a relation to the role of measles virus in subacute sclerosing panencephalitis, or both, remains to be determined. Management Prevention. Preventive measures present the realistic hope of eradication of congenital rubella. Of the three major approaches to prevention (avoidance of maternal infection, treatment of maternal infection, and abortion in the presence of maternal infection), the first has been accomplished in large part through vaccination. Active immunization with a live attenuated rubella vaccine has been accomplished by two major approaches.2,9,195,232 In the United States, mass vaccination of all children aged 1 year to puberty has been used to limit the spread of infection to the pregnant woman by curtailing circulation of virus in the community. In the United Kingdom and in many other European countries, selected immunization, especially of girls from ages 11 to 14 years, was used initially to provide protection for the childbearing years.233,234 Mass vaccination of all children in the second year of life was instituted in the United Kingdom in 1988. The policy in the United States has been effective; the incidence of congenital rubella declined by approximately fivefold in the decade following the initiation of this vaccination regimen.9,232 Indeed, as noted earlier, the current incidence of congenital rubella in the United States is less than 1 per 1 million live births.223 However, some questions still remain concerning how long vaccine-induced protection will last or whether inapparent reinfection of the mother with transmission to the fetus may occur.
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Passive immunization with immune globulin may be useful in the special case of a susceptible pregnant woman exposed to rubella. The effectiveness of this approach is controversial, but it is necessary to recognize that passive immunization is useful to prevent viremia and fetal infection and therefore must be given promptly. Abortion in the woman infected with rubella requires understanding of the risks of fetal infection as they relate to the timing of the infection in pregnancy. The demonstration of prenatal diagnosis by fetal blood sampling in the 20th week of gestation may help to prevent abortion of the unaffected fetus.235 Supportive Therapy. Supportive therapy is carried out principally as described for congenital CMV infection. In addition, recognition and prompt control of cardiac failure are critical, particularly in view of cerebral vasculopathy and therefore already compromised cerebral perfusion. Careful auditory assessment, with brain stem evoked response audiometry as well as with behavioral studies, is critical to detect hearing loss and to provide appropriate intervention as early as possible. Similarly, detection of cataract is important because delay of surgery into the second and third years of life prevents useful vision. However, opinions differ about the optimal time of therapy. Nevertheless, the infant with auditory and visual deficits is at great risk for subsequent disturbances of language and other aspects of neurological development, and the earliest interventions regarding vision and audition are critical. Antimicrobial Therapy. No known effective chemotherapeutic agents of value exist in the treatment of congenital (or postnatal) rubella infection.
to 28.2 per 100,000 live births in 1982.244 A twofold increase over the last 4 years of the study suggested that the incidence was continuing to rise rapidly. Later data indicated that the prevalence of HSV type 2 (HSV-2) in the United States was approximately 20% to 30% in adults, with the highest values (40% to 60%) in black women of childbearing age.245,246 However, more recent data suggest that the trajectory of increasing seroprevalence of HSV, especially HSV-2, in the United States has ceased.243 Thus, in a study of more than 11,000 adults, the seroprevalences in 1999 to 2004 versus those in 1988 to 1994 were, for HSV-2, 17.0% versus 21.0%, and for HSV-1, they were 57.7% versus 62.0%.243 Pathogenesis Parturitional and Ascending Infection. Most infants with neonatal HSV infection acquire the infection during passage through an infected birth canal near or at the time of birth. The markedly higher rate of neonatal HSV infection in infants born to mothers shedding virus at delivery when delivery is by the vaginal route than by cesarean section is consistent with this notion (Table 20-21).241 In the classic case, the virus is acquired by direct contact of the infant’s skin, eye, or oral cavity with the virus in the mother’s birth canal. (Overt maternal herpetic lesions are uncommonly present.) Because of the importance of direct contact, it is understandable that the vesicular lesions that result in the infant are usually over the scalp and face in cephalic presentations and over the buttocks in breech presentations.2,237,239,241 Vivid demonstrations of the relation of contact to the site of herpetic lesions are provided by the several reports of vesicular lesions (and serious neonatal disease) at the sites of placement of fetal scalp electrodes for intrapartum
Herpes Simplex Neonatal HSV infection, in most cases, is acquired during passage through an infected birth canal. Less commonly, ascending infection near the time of birth is the means of acquisition of the virus. Still less commonly, transplacental passage of virus causes intrauterine infection, or postnatal acquisition of virus from infected adults or infants causes severe postnatal illness. Neonatal HSV infection is very much less common than the other major neonatal infection caused by a herpes virus, CMV infection. However, unlike CMV infection, essentially all examples of neonatal HSV infection are symptomatic, often with serious neurological concomitants apparent in the newborn period. The premature infant is apparently more susceptible than the full-term infant and accounts for as many as 25% to 35% of cases.2,236-242 The incidence of neonatal HSV infection increased pari passu with the increase in incidence of genital HSV infection in adults in the United States over the several decades before the decline of the past few years.2,239,241,243 In detailed studies from King County, Washington, the incidence of neonatal HSV infection increased progressively from a rate of 2.6 per 100,000 live births during the years 1966 through 1969
TABLE 20-21
Risk Factors for Development of Neonatal Herpes Simplex Virus Infection*
Risk Factor
No. of Infants with Neonatal Herpes Simplex Virus Infection/No. of Deliveries P Value
Type of Delivery Cesarean Vaginal
1/85 (1.2%) 9/117 (7.7%)
0.47
Invasive Monitors Yes 8/79 (10.1%) No 2/123 (1.6%)
.02
Type Isolated HSV-1 HSV-2
5/16 (31.3%) 5/186 (2.7%)
24 hours), and chorioamnionitis (Table 21-4).11,14,21,22,26,28,51,59-67a Maternal urinary tract infection associated with neonatal sepsis and meningitis is usually gram negative, and maternal genital infection associated with these neonatal disorders is usually with group B Streptococcus. Indeed, genital infection secondary to group B Streptococcus (usually asymptomatic) is identifiable at delivery in approximately 15% to 35% of women.59,61,65,68-77 Approximately 40% to 70% of infants delivered to such women become colonized at one or more mucocutaneous sites (e.g., ear, throat, rectum, and umbilicus). Approximately 2% to 4% of such colonized infants exhibit invasive, early-onset group B streptococcal disease. The incidence is particularly high (8%) in those infants heavily colonized (i.e., found to have three to four positive mucocutaneous sites). Factors related to pregnancy and delivery are also particularly important in the pathogenesis of earlyonset neonatal listeriosis.59,78-87 Thus, various obstetrical complications are present in the history of approximately half of such patients, and in most cases maternal isolates of serotypes identical to those infecting the infants have been found. In the majority of cases of early-onset neonatal listeriosis, a maternal history of flulike syndrome, unexplained fever, or urinary tract symptoms in the several days to weeks before delivery can be elicited. In keeping with probable fecal-oral transmission of this organism, epidemics of maternal infection during pregnancy and subsequent neonatal listeriosis have been associated with consumption of contaminated foods.78,84,87 Indeed, unlike the other varieties of neonatal meningitis, listeriosis probably occurs commonly by transplacental passage, as evidenced by the finding of well-developed placentitis with recognizable organisms in carefully studied cases.80,81,87 Factors Related to the Infant Significant host factors operative in the newborn period relate particularly to defense mechanisms versus bacterial infection. Relative defects in so-called nonspecific and specific immunity have been described in detail.
TABLE 21-4
Neonatal Sepsis-Meningitis: Predisposing Factors Related to Pregnancy and Delivery
Complications of labor and delivery Maternal peripartum infection, especially of the genital or urinary tract Prolonged rupture of membranes Chorioamnionitis
Nonspecific immunity refers particularly to functions of granulocytic leukocytes and opsonins. Specific immunity refers particularly to the T-lymphocyte system and the B-lymphocyte–antibody system. Mononuclear phagocytes and natural killer cells bridge nonspecific and specific immunity. The innate immune system is mediated by the monocyte-macrophage series and is discussed later with regard to specific immunity. Nonspecific Immunity. Deficiencies of nonspecific immunity include the following: impaired leukocyte chemotaxis, phagocytosis, and bactericidal activity; defective neutrophilic metabolic responses after phagocytosis (e.g., activation of hexose monophosphate shunt and, especially, oxidative metabolism, with diminished generation of the critical bactericidal hydroxyl radical); impaired chemotaxis of the mononuclear phagocyte system, secondary to a functional deficiency of the critical M3 subset of mononuclear cells; and diminished concentrations of several complement components.16,60,66,69,70,77,87-92 Moreover, lower fibronectin concentrations in the newborn appear to contribute to diminished opsonization and phagocytosis. These defects are accentuated and especially severe in premature infants and in infants subjected to illnesses of diverse types. Specific Immunity. Deficiencies of specific humoral immunity have involved the immunoglobulin M (IgM) and immunoglobulin G (IgG) classes of antibodies.66,92-97 The latter are transferred passively across the placenta, particularly in the third trimester.95 Thus, some premature infants may have decreased levels of IgG antibodies.94 IgM and immunoglobulin A (IgA) are not transferred passively across the placenta and are in very low concentrations in the normal newborn. IgM antibodies include several antibody types important in the defense against gram-negative bacteria, and deficiency of these antibodies in the newborn infant may play a role in the susceptibility to gram-negative bacteria.93 IgA antibodies are abundant at later ages at mucosal surfaces (e.g., the respiratory and gastrointestinal tracts), and their deficiency in the newborn may explain in part the relative ease with which mucosal barriers are colonized and penetrated.96 Newborn infants have diminished production of these antibodies because of both immaturity of the antibodyproducing B cells and plasma cells and diminished Tcell help for antibody production. The deficiency in immune globulins led to clinical trials of the use of intravenous immune globulin in prophylaxis and treatment of bacterial infection in newborns, especially premature newborns.92,98,99 This approach has not proven useful for general practice. Of major importance is the function of the innate immune system and thereby the monocyte-macrophage defense mechanism. The brain microglial cell, which is derived from monocytes (see Chapter 6), is an important part of this defense. Activation of innate immune cells occurs by way of specific cell surface receptors (i.e., Toll-like receptors [TLRs]), which respond to specific molecular motifs shared by the products of large
Chapter 21
classes of microorganisms.100–103 For example, TLR4 is the receptor that recognizes gram-negative bacterial lipopolysaccharide, and TLR2 is the receptor for gram-positive peptidoglycan and lipopeptides. Activation of these receptors triggers an inflammatory response by a mechanism that operates through nuclear factor (NF) kappaB and mitogen-activated protein kinase. A recent study of newborns showed that the basal expression of TLR2 (but not TLR4) is slightly lower in neonatal than in adult phagocytes.103 In infants with sepsis, TLR2 is sharply up-regulated, unlike TLR4. A similar disturbance of TLR4 responsiveness was shown in neonatal monocytes as a function of gestational age.104 Thus, the deficits in TLR2 and TLR4 may be relevant to the importance of such gram-positive organisms as group B Streptococcus and CONS and of such gram-negative organisms as E. coli in neonatal sepsis and meningitis. Immunological Aspects of Group B Streptococcal Infection. Immunological studies of perinatal group B streptococcal infection illustrated the potential roles of both maternal and host defense factors in pathogenesis.59,66,77 Thus, using a sensitive, radioactive antigenbinding assay, Baker and Kasper105,106 showed that the prevalence of antibody to group B Streptococcus (capsular polysaccharide of the type III strain) in mothers with vaginal colonization was 76% for those whose infants did not develop group B streptococcal disease and only 5% for those whose infants did develop group B streptococcal sepsis or meningitis. These data suggest that this IgG antibody is important in protection of the infant and that passive transfer across the placenta did not occur because of maternal failure to synthesize the antibody. In addition, the infants with sepsis or meningitis had low levels of antibody after recovery, a finding suggesting that, in addition, these infants also failed to synthesize this IgG component. Similarly, infants who develop group B streptococcal sepsis have been shown to exhibit defective humoral (opsonic activity) and neutrophilic responses to their infecting strain.107 Factors Related to the Neonatal Environment Certain factors related to the neonatal environment increase the risk of sepsis and meningitis, including the following: use of inhalation therapy equipment; use of aerosols; use of vascular, umbilical, and intraventricular indwelling catheters; and exposure to nursery personnel, parents, or other infants harboring TABLE 21-5
Bacterial and Fungal Intracranial Infections
919
pathogenic organisms.3,14,16,22,51,66,108-110 Operation of some of these factors may be suggested by the organism causing the sepsis or meningitis, as discussed earlier. Horizontal (or nosocomial) transmission of an organism from human contacts has been studied, particularly for group B Streptococcus. Thus, nosocomial infection rates of up to 40% have been reported, particularly in medical centers in which high rates of newborns are already colonized at birth (by vertical transmission from mother) and in which high daily census rates are reported, thereby favoring cross-contamination of infants by nursery personnel.59,111,112 The particular importance of factors related to neonatal intensive care is illustrated by the marked increase in CONS infections with increasing time in neonatal intensive care (see Table 21-2). This issue is particularly important in very premature infants, in whom later-onset sepsis is related primarily to CONS and of whom nearly 80% have a central vascular catheter in place at the time of infection.14 In the subset of very-low-birth-weight infants, CONS are important etiological agents. Indeed, in a series of 134 verylow-birth-weight (< 1500 g) infants with meningitis, 76% of whom weighed less than 1000 g at birth, 29% had positive cerebrospinal fluid (CSF) and blood cultures for CONS.113 Factors Related to the Microorganism Specific Serotypes Related to Meningitis. The propensity for specific strains of group B Streptococcus, E. coli, and L. monocytogenes to be most commonly responsible for neonatal meningitis suggests important pathogenetic roles for the microorganism itself. (Recall the earlier discussion concerning innate immunity and the risk of infection by gram-negative and gram-positive organisms.) Thus, serotype III of group B Streptococcus, K1 strains of E. coli, and serotype IVb of L. monocytogenes are the predominant specific types of these three bacteria that cause neonatal meningitis (Table 21-5).1,51,59,66,67,82,85,114 Approximately 70% to 80% of all cases of neonatal meningitis are caused by these three bacterial types. Importance of Capsular Polysaccharides. The likelihood that capsular polysaccharides reflect, to a considerable degree, an intrinsic virulence of these organisms is suggested by in vivo and in vitro observations.51,59,66,77,87,114-117 Studies with immature rats demonstrated, for K1 strains of E. coli relative to other E. coli strains, a high virulence, particularly regarding
Relationship between Severity of Neonatal Infection and Specific Strain of Group B Streptococcus, Escherichia coli, and Listeria monocytogenes CLINICAL DISEASE
Organism
Asymptomatic
Sepsis
Meningitis
Group B Streptococcus serotype III Escherichia coli K1 strain Listeria monocytogenes serotype IVb
36% 12% ?
32% 39% 42% (early-onset disease)
85% 84% 78% (late-onset disease)
Data for each clinical disorder expressed as a percentage of total cases (caused by the indicated bacterium) resulting from the specific serotype. Data from references 1, 114, and 274.
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TABLE 21-6
INTRACRANIAL INFECTIONS
Outcome of Neonatal Meningitis Caused by K1 and Non-K1 Strains of Escherichia coli OUTCOME
Type of Escherichia coli
Normal
Non-K1 strains K1 strains
8 (89%) 19 (40%)
Neurological Sequelae 1 (11%) 14 (29%)
Dead 0 15 (31%)
n = 57. Data from McCracken GH Jr, Sarff LD, Glode MP, Mize SG, et al: Relation between Escherichia coli K1 capsular polysaccharide antigen and clinical outcome in neonatal meningitis, Lancet 2:246–250, 1974.
bacteremia and meningitis, that was age related.116 The younger the animal, the greater was the likelihood of serious disease. Moreover, investigators showed that group B Streptococcus type III and K1 strains of E. coli have distinctive capsules, which contain polysaccharide with sialic acid in high concentration (25% of total carbohydrate).106,114,115,117 (This distinctive polysaccharide for E. coli is termed K1, hence the name K1 strain.) A relation of the capsular polysaccharide antigen to virulence is suggested by the different outcomes of E. coli meningitis secondary to K1 and non-K1 strains (Table 21-6).118 In addition to a marked preponderance of cases secondary to K1 strains, whereas 60% of reported infants with meningitis secondary to K1 strains died or exhibited neurological sequelae, only 11% of infants with meningitis secondary to non-K1 strains exhibited the poor outcome (see Table 21-6). A protein component of the outer membrane of the K1 strain of E. coli, OmpA, was also shown to be critical for the capacity of this strain to penetrate brain endothelial cells and thus to cause intracranial infection.119 The relation of the capsular polysaccharide antigen to virulence is supported further by the studies reviewed previously, relating the occurrence of group B streptococcal type III neonatal disease to the deficiency in the mother and in the newborn of antibody against the specific capsular polysaccharide of that organism. Neuropathology
TABLE 21-7
Major Neuropathological Features of Neonatal Bacterial Meningitis
Acute Arachnoiditis Ventriculitis: choroid plexitis Vasculitis Cerebral edema Infarction Associated encephalopathy (cortical neuronal necrosis, periventricular leukomalacia) Chronic Hydrocephalus Multicystic encephalomalacia: porencephaly Cerebral cortical and white matter atrophy Cerebral cortical developmental (organizational) defects (?)
The exudate is predominant over the base of the brain in approximately one half of the cases and is distributed more evenly in most of the remainder (Fig. 21-2). The evolution of this inflammatory response was well described by Berman and Banker.88 In the acute state (i.e., approximately the first week), the predominant cells in the arachnoidal (and ventricular) exudate are polymorphonuclear leukocytes. Bacteria are visible, free, and within polymorphonuclear leukocytes and macrophages. The inflammatory exudate is particularly prominent around blood vessels and
Major Features The neuropathology of bacterial meningitis may be considered in terms of acute and chronic changes (Table 217). Moreover, certain additional histological features are particularly characteristic of infection with specific organisms, and these features are discussed separately. Acute Changes The acute changes of bacterial meningitis are dramatic and include arachnoiditis, ventriculitis, vasculitis, cerebral edema, infarction, and associated encephalopathy (see Table 21-7).88,120-124 Because the hallmark of the disease is arachnoiditis, this aspect is discussed first; however, the neuropathological progression of neonatal bacterial meningitis probably begins with choroid plexitis and ventriculitis (Fig. 21-1). I discuss the arachnoiditis first, because it is the dominant feature of bacterial meningitis. Arachnoiditis. The hallmark of bacterial meningitis is infiltration of the arachnoid with inflammatory cells.
Choroid plexitis
Ventriculitis
Arachnoiditis
Vasculitis
Infarction
Edema
“Associated encephalopathy”
Figure 21-1 Neuropathological progression of neonatal bacterial meningitis. The process probably begins with choroid plexitis and ventriculitis. The pathogenesis of associated encephalopathy, especially cerebral cortical neuronal injury and periventricular leukomalacia, is detailed in Figure 21-9.
Chapter 21
A
B
C Figure 21-2 Neonatal bacterial meningitis: arachnoidal exudate. A, From an infant with group B streptococcal meningitis who died at 12 days of age. This right lateral view of the cerebrum shows thick arachnoidal exudate. B, From an infant who died at 13 days of age with Escherichia coli meningitis. This left lateral view of the cerebrum shows thick arachnoidal exudate, especially prominent in the region of the sylvian fissure. C, Closer view of the exudate in the region of the sylvian fissure. (A, From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
extends into the brain parenchyma along the VirchowRobin space. In the second and third weeks of the disease, the proportion of polymorphonuclear leukocytes decreases gradually and constitutes approximately 25% of the cell population. The predominant cells are now mononuclear, mainly histiocytes and
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macrophages. Lymphocytes and plasma cells are present in relatively small numbers, and this paucity is a characteristic feature of neonatal meningitis. Whether this apparent deficiency of cells involved in the immunological response plays a role in the relative tenacity of neonatal bacterial meningitis remains to be determined but seems plausible. A prominent feature of this stage of the disease is infiltration of cranial nerve roots by the exudate; particular involvement occurs in the subarachnoid space of the posterior fossa and especially affects cranial nerves III through VIII. This involvement is clinically relevant (see subsequent discussion). After approximately 3 weeks, the exudate decreases in amount and consists of mononuclear cells. Thick strands of collagen become apparent as arachnoidal fibrosis begins to develop. This process is probably important in the genesis of the obstructions to CSF flow that result in hydrocephalus. The characteristics of the arachnoiditis caused by different bacteria vary little. However, early-onset group B streptococcal meningitis is accompanied by much less arachnoidal inflammation than is late-onset meningitis.59 Indeed, approximately 75% of cases of early-onset meningitis (i.e., positive culture results) are said to exhibit little or no evidence of ‘‘leptomeningeal inflammation’’ at autopsy.59 It is not clear whether the relative lack of arachnoidal inflammatory response relates to rapidity of death after onset of symptoms or to immaturity of host responses to infection within the CNS of premature infants (who represent the largest proportion of fatal cases of early-onset group B streptococcal meningitis). Ventriculitis. Ventriculitis (i.e., inflammatory exudate and bacteria in the ventricular fluid and lining) is a particularly common feature of neonatal meningitis. In the 50 brains studied by Berman and Banker88 and by Gilles and co-workers,122 overt ventriculitis was present in 44 (88%). In a collaborative study of 70 infants with meningitis caused by gram-negative bacteria in whom ventricular tap was performed at the time of diagnosis, 51 (73%) had ventriculitis, as manifested by positive cultures with pleocytosis in the ventricular fluid (comparable data are not available for group B streptococcal meningitis). Although precise, controlled data are not available, ventriculitis appears to be more common in neonatal meningitis than in meningitis at later ages.125 The ventriculitis is initially characterized by exudate most prominent in the choroid plexus stroma and just external to the plexus (Fig. 21-3).69,88,122 Exudative excrescences from the ventricular surface can be visualized in vivo by cranial ultrasonography (see later discussion). In the second and third weeks of the disease course, the ventricular exudate is associated with active ependymitis, characterized by disruption of the ependymal lining and projections of glial tufts into the ventricular lumen. Later, glial bridges may develop and cause obstruction, particularly at the aqueduct of Sylvius (Fig. 21-4). Less commonly, septations in the lateral ventricle may produce a multiloculated state that is similar to abscess formation. The multiple ventricular
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Figure 21-3 Ventriculitis and choroid plexitis from an infant who died of bacterial meningitis in the first month of life. Choroid plexus is in the left lower corner. Plexus stroma is filled with cellular exudate. The lateral ventricle contains mass of protein-rich cellular exudate and necrotic debris organized into layers. The middle layer (arrows) is composed of colonies of bacteria (hematoxylin and eosin, 60). (From Gilles FH, Jammes JL, Berenberg W: Neonatal meningitis: The ventricle as a bacterial reservoir, Arch Neurol 34:560-562, 1977.)
Figure 21-4 Aqueductal obstruction subsequent to ventriculitis from an infant who died of neonatal bacterial meningitis. Stain for glial fibers shows formation of glial bridges that have narrowed and partially occluded the aqueduct. The lower portion of the aqueduct is reduced to a small slit (arrow) (phosphotungstic acid hematoxylin 100). (From Berman PH, Banker BQ: Neonatal meningitis: A clinical and pathological study of 29 cases, Pediatrics 38:6-24, 1966.)
obstructions, in fact, may ‘‘isolate’’ portions of the lateral ventricles or the fourth ventricle, cause disproportionate and severe dilation of the affected ventricle, and present a difficult therapeutic problem.126,127 Ventriculitis with obstructive hydrocephalus may manifest subacutely in newborns (with no history of acute meningitis) after several weeks, especially ventriculitis caused by group B streptococcal meningitis.128 The nearly uniform occurrence of ventriculitis in acute bacterial meningitis in the newborn has pathogenetic and therapeutic implications. Regarding pathogenesis, it appears reasonable to suggest that the initial sequence of events in bacterial invasion of the CNS is for hematogenously borne bacteria to localize first in the choroid plexus and to cause choroid plexitis, with subsequent entrance of bacteria into the ventricular system and later movement to the arachnoid through normal CSF flow (see Fig. 21-1). Gilles and co-workers122 presented considerable data to support this view, including the high glycogen content of the neonatal choroid plexus, which provides an excellent medium for bacteria. Moreover, an age-related effect is suggested by the postnatal decrease in glycogen content of plexus epithelial cells.129 Experimental studies of bacterial meningitis produced in infant rhesus monkeys indicated that infection of the lateral ventricle is a uniform feature.130 Moreover, when discordance between the amount of bacteria in ventricular and subarachnoid CSF samples was observed in these studies of rhesus monkeys, ventricular bacterial densities were greater. These observations further support the notion that the initial events in the genesis of bacterial meningitis are bacteremia and infection of the choroid plexus and lateral ventricles. The therapeutic implications of these data concerning ventriculitis are important and are discussed later in ‘‘Management.’’ Suffice it to say here that the ventricle may be a major reservoir of bacterial infection, inaccessible either to systemic antibiotics, which are unable to penetrate the purulent covering over the ventricular lining, or to intraventricular antibiotics, which are unable to reach the choroid plexus epithelium (and particularly inaccessible to intrathecal antibiotics, which are unable to reach the ventricles because of normal CSF flow). Moreover, if obstruction of the ventricular system is added (e.g., at the aqueduct), a closed infection, approximating an extraparenchymal abscess, will result. Vasculitis. Vasculitis is an almost invariable feature of neonatal bacterial meningitis.88 The involvement of both arteries and veins can be considered an extension of the inflammatory reaction in the arachnoid and within the ventricles. The arteritis is manifested particularly by inflammatory cells in the adventitia, although involvement of the intima is not uncommon.20,131 Although the arterial lumen may be narrowed, only rarely is complete occlusion observed. Involvement of veins is severe and includes arachnoidal, cortical, and subependymal veins.120 In contrast to
Chapter 21
arterial involvement, phlebitis is frequently complicated by thrombosis and complete occlusion. Multiple fibrin thrombi of adjacent veins are often observed in association with areas of hemorrhagic infarction (see ‘‘Infarction,’’ later). The vasculitic changes are apparent in the first days of meningitis and become particularly prominent by the second and third weeks. More similarities than differences exist among various bacteria with regard to the nature and severity of the vascular changes with meningitis. However, vasculitis with thrombosis or even hemorrhage is relatively frequent in early-onset group B streptococcal disease, despite the relatively modest arachnoidal inflammation.59 Cerebral Edema. Cerebral edema is a characteristic of the acute stage of neonatal bacterial meningitis (Fig. 21-5). Indeed, the swelling of brain parenchyma is often so severe that the ventricles are reduced to small slits. The difficulty and hazard of performing ventricular puncture in the acute stage are significant because of this phenomenon. The cause of the edema is related primarily to the vasculitis and increased permeability of blood vessels (i.e., vasogenic edema; see Fig. 21-1). This vasogenic component may be complicated by a cytotoxic component, when parenchymal injury occurs (e.g., through infarction), or when impairment of CSF flow results in development of interstitial edema (see later discussion). Despite the edema, another feature of neonatal bacterial meningitis that is distinctive relative to disease at later ages is the rarity of evidence, clinical or pathological, for herniation of supratentorial structures through the tentorial notch or of cerebellar tonsils into the foramen magnum. This feature may relate to
Figure 21-5 Cerebral edema with neonatal bacterial meningitis. Coronal section of the brain from the same infant shown in Figure 21-2A. Note the diffusely swollen appearance of the cerebral parenchyma, resulting in flattened gyri and small, slitlike ventricles. Purulent material is evident in the ventricles (medial aspect), and a hemorrhagic infarct is apparent in the parasagittal region. (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
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the distensibility of the neonatal cranium, especially because of the separable sutures. This factor also may prevent marked increases in intracranial pressure and therefore impaired cerebral perfusion; studies of intracranial pressure and cerebral blood flow velocity in neonatal bacterial meningitis supported this suggestion (see later discussion).132 Nevertheless, lethal uncal and cerebellar tonsillar herniation has been documented in neonatal bacterial meningitis.133 Moreover, the rare phenomenon of anterior fontanelle herniation has been reported to complicate neonatal meningitis.134 Infarction. Infarction may be a prominent and serious feature of neonatal bacterial meningitis (see Fig. 21-1). Studies of autopsy cases indicate an incidence of 30% to 50% (see Table 21-7).88,120,124 More than one half of the cases in Friede’s120 neuropathological series sustained their lesions in the first week after the diagnosis of meningitis. Thus, although the vascular lesions become particularly prominent in the second and third weeks, infarction often may be an early event. The lesions most frequently are related to venous occlusions and are often hemorrhagic (characteristic of venous infarcts). Occlusion of multiple adjacent veins appears to be necessary to result in infarction, as evidenced by the usual demonstration of several thrombosed vessels contiguous to the infarct. The loci of the infarcts, most often, are cerebral cortex and underlying white matter (Fig. 21-6), although subependymal and deep white matter lesions are not uncommon. Involvement of major cerebral arteries may be more common than previously expected because brain imaging in living infants not uncommonly demonstrates lesions in an arterial distribution (see later discussion; Table 21-8).135 The origin of the infarction is related particularly to the vasculitis, in combination with concomitant thrombotic effects of arachidonic acid metabolites (e.g., thromboxanes, platelet-activating factor), impaired cerebrovascular autoregulation, and decreased cerebral perfusion pressure (caused by systemic hypotension or increased intracranial pressure, or both; see later ‘‘Mechanisms of Brain Injury’’ section). Such a
Figure 21-6 Infarction with neonatal bacterial meningitis. Same specimen as shown in Figure 21-5 but a higher-power view of the hemorrhagic infarct in the parasagittal region. The lesion was secondary to cortical vein thrombosis. (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
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Cerebral Infarction in Neonatal Bacterial Meningitis
30% to 50% of autopsy cases Associated with thrombi in inflamed meningeal, cortical, and/or subependymal veins; venous sinuses; arteries (‘‘arterial distribution’’ often suggested by brain imaging findings) Related to a combination of vasculitis, endothelial injury, thrombotic effects of arachidonic acid metabolites, impaired autoregulation, decreased cerebral perfusion pressure
TABLE 21-9
Impaired Cerebral Blood Flow in Bacterial Meningitis
Vascular Narrowing or Obstruction Vasculitis Vasospasm Thrombosis Increased Intracranial Pressure Vasogenic > cytotoxic > interstitial edema Hydrocephalus Systemic Hypotension Septic shock Impaired Cerebrovascular Autoregulation
combination of factors presumably could lead to infarction in the presence of vascular narrowing and not necessarily complete thrombotic occlusion. Although venous or arterial infarction of cerebral structures predominates, involvement of spinal cord may occur. Indeed, spinal cord necrosis and the clinical picture of a segmental myelopathy may rarely develop.136
conspicuous by its relative lack of prominence, is subdural effusion.88,121 The reason for the notable difference in incidence of significant subdural effusion between meningitis in the newborn and in the infant of 2 to 3 months of age and older is not clear. Subdural empyema is a very rare acute feature of bacterial meningitis. I have seen three cases since the early 1970s.
Associated Encephalopathy. Associated with neonatal bacterial meningitis are parenchymal changes (i.e., ‘‘associated encephalopathy’’ ) the causes of which have been elucidated increasingly in recent years (see later discussion in ‘‘Mechanisms of Brain Injury’’). The major changes are (1) diffuse gliosis of regions subjacent to inflammatory exudate, (2) neuronal loss in cerebral cortex and several other brain regions, and (3) periventricular leukomalacia. The first change, parenchymal gliosis, is observed in cerebral cortex (molecular layer and superficial cortical layers), cerebellar cortex (molecular layer), brain stem and spinal cord (marginal white matter), and subependymal regions. These various regions are immediately subjacent to the inflammatory exudate and presumably are injured by the toxic and metabolic factors associated with the bacterial process (see later discussion). The clinical significance of the gliosis is not entirely clear. The second and third changes, involving cortical neurons and periventricular white matter, are similar in topography, in many ways, to hypoxic-ischemic encephalopathy. The cause of these neuronal and white matter lesions probably relates at least in part to ischemia (see later discussion; Table 21-9). Moreover, it is likely that concentrations of endotoxin and related cytokines in brain and ventricular fluid are high in gram-negative bacterial meningitis and that the endotoxin could injure cerebral white matter through activation of innate immunity in brain (see later and Chapter 6). A similar conclusion applies to the capsular polysaccharides and proteins of group B Streptococcus, which also have been shown to be neurotoxic (see Chapter 6). Further data are needed on these issues, because the clinical significance of the neuronal loss and of the white matter injury is almost certainly considerable.
Long-Term Changes The major neuropathological sequelae of neonatal bacterial meningitis are hydrocephalus, multicystic encephalomalacia, and cerebral cortical and white matter atrophy (see Table 21-7).88,121,123 Experimental observations suggest the possibility of a subsequent impairment in brain development, involving organizational events (see later discussion).
Subdural Effusion and Empyema. One neuropathological feature of neonatal bacterial meningitis,
Hydrocephalus. In studies of postmortem material, hydrocephalus is apparent in approximately 50% of cases.88 Of the 14 autopsy cases of hydrocephalus studied carefully by Berman and Banker,88 the major obstruction to CSF flow appeared to be at the level of the aqueduct in 4, at the outflow of the fourth ventricle in 2, and in the subarachnoid space (i.e., communicating) in 8. Multiple sites of impairment in CSF flow are probable. Ventricular dilation secondary to obstruction to CSF flow should be distinguished from that secondary to loss of cerebral substance. Because both hydrocephalus and cerebral atrophy are usually present concurrently, this distinction may be difficult. Multicystic Encephalomalacia and Porencephaly. Multicystic encephalomalacia and porencephaly are the end of the continuum of multifocal parenchymal injury secondary to neonatal bacterial meningitis. The single or multiple cystic areas of destruction in the cerebral hemispheres appear to reflect primarily residua of infarction (Fig. 21-7). In postmortem material, some of the cavities rarely appear to represent abscesses.120 The implications of multicystic encephalomalacia for neurological outcome are obviously grave. Cerebral Cortical and White Matter Atrophy. Most commonly, the major neuropathological sequela of neonatal bacterial meningitis is cerebral atrophy, manifested particularly by loss of cerebral cortical neurons
Chapter 21
Bacterial and Fungal Intracranial Infections
TABLE 21-10
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Additional Neuropathological Changes Caused by Specific Microorganisms
Citrobacter, Serratia marcescens, Proteus, Pseudomonas, Enterobacter species Tissue necrosis, often hemorrhagic, and/or brain abscess Listeria monocytogenes (Transplacental) Multifocal granulomata with or without microabscesses
Figure 21-7 Multicystic encephalomalacia following neonatal bacterial meningitis: neuropathology. From an infant with neonatal gramnegative bacterial meningitis who died at 5 weeks of age. This coronal section of the cerebrum shows that the cerebral hemispheres have been converted into a necrotic mass with many cystic cavities of various sizes. The corpus callosum is necrotic, and the ventricles cannot be delineated from cystic spaces in the brain. (From Bell WE, McCormick WF: Neurologic Infections in Children, Philadelphia: 1975, Saunders.)
and periventricular white matter. This state appears to be a sequela principally of the associated encephalopathy described previously. Neuronal loss in deep cortical layers and myelin loss in the periventricular region, both areas also infiltrated with glial fibers, are the major histological findings. Possible Cerebral Cortical Developmental (Organizational) Defects. Experimental data suggest that more refined techniques may reveal subsequent aberrations of brain development following neonatal bacterial meningitis. In an infant rat model of bacterial meningitis, disturbances of subsequent dendritic arborization and synaptogenesis were observed.137 Because of the timing of neonatal bacterial meningitis with regard to brain developmental events (see Chapter 2), it is reasonable to postulate that application of Golgi, immunocytochemical, and electron microscopic techniques to the study of cerebral cortex and myelin of infants who survive the acute state of neonatal meningitis would reveal impairment of cerebral organizational events and, perhaps, myelination. Further data in this regard would be of particular importance concerning the effects of neonatal bacterial meningitis on subsequent neurological outcome. Neuropathological Changes Characteristic of Specific Microorganisms Certain neuropathological changes are particularly characteristic of specific microorganisms (Table 21-10). Citrobacter species, Serratia marcescens, Proteus, Pseudomonas, Enterobacter species. These bacteria
have a particular propensity to cause severe cerebral necrosis, usually hemorrhagic (see Table 21-10).41,123,138-146 One consequence of this tissue necrosis, in the presence of bacteremia, is the occurrence of brain abscess. Indeed, the brain abscess may dominate the clinical syndrome, which occasionally may evolve in a less acute fashion than uncomplicated meningitis.144 (The most common organism leading to meningitis complicated by brain abscess is Citrobacter, which is discussed later in the section ‘‘Brain Abscess.’’) An even more dramatic and malignant form of neonatal bacterial meningitis is caused by S. marcescens.123,147 Widespread hemorrhagic necrosis of cerebral cortex and white matter occurs (Fig. 21-8). Striking invasion of brain parenchyma by bacteria, which can be seen streaming from blood vessels (see Fig. 21-8), is a prominent feature. Listeria monocytogenes. Although L. monocytogenes may cause typical bacterial meningitis in the newborn, especially in infants with late-onset disease, transplacental infection of the fetus may occur and may produce a particularly fulminating infection.1,78-82,84-87,121,123,148,149 The latter may be manifest in utero and may result in fetal death or in an early-onset, septicemic type of syndrome. The pathological features of this multifocal variety of listeriosis are miliary granulomatous lesions in many organs, including the CNS (see Table 21-10).121,123 The characteristic lesion is a necrotizing granuloma, which occurs particularly in the meninges, ventricular walls, and choroid plexus. Granulomata may form microabscesses, and organisms can be demonstrated in the necrotic portions of the lesions. As may be expected, this variety of infection is not readily accessible to antibiotics, and death occurs in 25% to 50% of cases, often in utero. Notably, however, treatment of the mother early in her infection can prevent infection and sequelae in the fetus and newborn.87 Mechanisms of Brain Injury The neuropathological features of neonatal bacterial meningitis are caused by the action of a complex series of mechanisms summarized very broadly in Figure 21-1 and in detail in Figures 21-9 and 21-10. The mechanisms shown in Figures 21-9 and 21-10 represent a summary of more detailed physiological and biochemical processes, described briefly next and based on a variety of studies, primarily in animal models and cellular systems but also in human infants.150-182a Thus, the process begins with sepsis, followed by invasion of the CNS; the role of specific
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B
A
Figure 21-8 Neonatal bacterial meningitis secondary to Serratia marcescens. A and B, Note the regions of hemorrhagic necrosis involving both hemispheres. C, Gram-negative bacteria can be seen around a small vein and invading the surrounding parenchyma (cresyl violet). (From Larroche JC: Developmental Pathology of the Neonate, New York: 1977, Excerpta Medica.)
C
capsular polysaccharides in this invasion is crucial, as discussed earlier. The meningitic process begins with the action of specific bacterial components, especially in gram-positive bacteria, the peptidoglycan layers and the teichoic acid of the cell wall, and in gram-negative bacteria, the lipopolysaccharide molecules of the outer cell membrane. Among the early events induced by these products, of particular importance is activation
Figure 21-9 Role of the innate immune response in the pathogenesis of neuronal and oligodendroglial death in bacterial meningitis. Microglia contain the two Toll-like receptors that are activated by specific molecular components of gram-positive (TLR2) and gram-negative organisms (TLR4) (see text and Chapter 6). Microglial activation and release of toxic reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to cell death in both gray (neuronal) and white (oligodendroglial) matter. GBS, group B streptococci.
of the immediate immune response (i.e., the innate immune response; see Fig. 21-9). As noted earlier, these molecular products of gram-positive organisms (e.g., group B Streptococcus) and gram-negative organisms (e.g., E. coli) activate specific receptors on brain microglia (the immune cell of the CNS). For gram-positive organisms, the receptor is TLR2, and for gram-negative organisms, it is TLR4. The resulting microglial activation results in several effects, the most important of which is generation of free radicals, both reactive oxygen and nitrogen species. These reactive compounds ultimately lead to neuronal and oligodendroglial death (see also Chapter 6), the key feature of the associated encephalopathy of neonatal bacterial meningitis. Evidence of neonatal bacterial meningitis leading to generation of free radicals and periventricular leukomalacia has been obtained by direct serial measurements of markers of free radical attack in CSF and correlation of elevations of these markers with the occurrence of magnetic resonance imaging (MRI)–documented cerebral white matter lesions.176 The myriad deleterious biochemical and physiological events initiated by the bacterial products discussed earlier are shown in Figure 21-10. Thus, these components induce an increase in blood-brain barrier permeability and the early phases of the inflammatory response (i.e., the synthesis and secretion of cytokines, especially tumor necrosis factor from CNS macrophages [microglia] and astrocytes and interleukin1beta from astrocytes and endothelial cells). The cytokines lead to the adhesion and interaction of leukocytes with endothelial cells by induction of specific cell surface molecules on both leukocytes and
Chapter 21
Bacterial and Fungal Intracranial Infections
927
Figure 21-10 Major mechanisms leading to brain injury, especially diffuse cerebral cortical neuronal injury and periventricular white matter injury, in neonatal bacterial meningitis. See text for details. CBF, cerebral blood flow; CSF, cerebrospinal fluid; IL-1beta, interleukin-1beta; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NOS, nitric oxide synthase; PL-A2, phospholipase A2; PAF, platelet-activating factor; PGE2, prostaglandin E2; PV space, perivascular space (Virchow-Robin space); ROS/RNS, reactive oxygen species/reactive nitrogen species; TLR, Toll-like receptor; TNF, tumor necrosis factor.
endothelial cells. The result is the ventriculitis, arachnoiditis, and vasculitis described earlier, the generation of free radicals by leukocytes, and the activated microglia just discussed (see Fig. 21-10). A second crucial effect of the cytokines is the activation of phospholipase A2 and thereby arachidonic acid release and subsequent metabolism, the products of which include free radicals, platelet-activating factor, prostaglandins, thromboxanes, and leukotrienes. The interaction of these effects leading to diffuse neuronal injury, periventricular leukomalacia, and thrombotic cerebral infarction is shown in Figure 21-10. The importance of impaired cerebral blood flow is substantial, as discussed earlier. Impairment of cerebrovascular autoregulation is suggested by experimental data (Fig. 21-11), and the importance of systemic hypotension is implied by clinical observations. Ischemia as an important final common denominator is suggested further by the demonstrations of elevations of extracellular glutamate and reactive oxygen and nitrogen species in experimental models of bacterial meningitis. Finally, activation of innate immunity and of many of the mechanisms shown in Figures 21-9 and 21-10 may occur without bacterial invasion of the CNS, as discussed in Chapters 6 and 8 concerning the roles of systemic infection in white matter and neuronal injury, especially in the premature infant. Indeed, in a large study of more than 6000 premature infants (401 to 1000 g at birth), infants with sepsis alone (without meningitis) had 50% to 100% higher rates of cognitive deficits, cerebral palsy, visual impairment, hearing impairment, and neurodevelopmental disability when compared with rates of these outcomes in uninfected infants.183
Clinical Features Two Basic Syndromes The clinical features of neonatal bacterial meningitis occur in the setting of two basic clinical syndromes, separable principally by age of onset: early-onset disease and late-onset disease (see Table 21-1). Both syndromes have been described with the three major
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Figure 21-11 Loss of cerebrovascular autoregulation in experimental bacterial meningitis in rabbits. Change in cerebral blood flow (CBF) as a function of change in mean arterial blood pressure (MABP) in control and meningitic rabbits. Changes in MABP result in corresponding changes in CBF in infected rabbits (indicative of impaired autoregulation) but do not cause similar alterations in control (indicative of intact autoregulation). (From Tureen JH, Dworkin RJ, Kennedy SL, et al: Loss of cerebrovascular autoregulation in experimental meningitis in rabbits, J Clin Invest 85:577-581, 1990.)
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organisms associated with neonatal bacterial meningitis: group B Streptococcus, E. coli, and L. monocytogenes.* Early-Onset Disease Early-onset disease is associated with clinical phenomena usually in the first 72 hours of life. As noted earlier, a history of obstetrical complications and premature birth is common, and, understandably, the mode of transmission is primarily from mother to infant near the time of delivery. Specific serotypes are less likely to be involved, and the course may be fulminating. However, mortality rates in recent years are much lower than previously (see ‘‘Prognosis,’’ later). Dominance of Non-neurological Signs. The clinical presentation is dominated by non-neurological signs (i.e., signs related to sepsis and respiratory disease). The most common signs are hyperthermia, apnea, hypotension, disturbances of feeding, jaundice, hepatomegaly, and respiratory distress; less common signs are hypothermia, skin lesions (e.g., petechiae and sclerema), and overt focal infection (e.g., otitis media, omphalitis, arthritis, and osteomyelitis). Neurological signs are usually limited to stupor (usually termed lethargy) and irritability. Signs suggestive of meningitis (see later discussion) are unusual, in part because overt meningitis occurs in only approximately 30% of the patients with early-onset disease. Indeed, even those infants with culture-proven meningitis often do not exhibit striking CSF pleocytosis. The respiratory manifestations of early-onset sepsismeningitis may be particularly prominent with group B streptococcal infection and, indeed, may simultaneously present serious diagnostic problems and important diagnostic clues. Approximately 40% to 60% of infants with early-onset group B streptococcal disease have manifestations of prominent respiratory disease in the first 6 hours of life.28,59,74,77,186 Only approximately 35% of these infants exhibit radiographic infiltrates suggestive of congenital pneumonia, whereas approximately 50% exhibit radiographic features of respiratory distress syndrome.59 Distinction from nonbacterial respiratory disease is suggested by the history of premature rupture of membranes, low Apgar scores (< 4 at 1 minute in 85%), rapid progression of pulmonary disease, and low or declining absolute neutrophil counts in the first 24 hours of life.59,187 Late-Onset Disease Late-onset bacterial sepsis-meningitis is much more likely to manifest as a neurological syndrome with overt signs of meningitis. Indeed, approximately 80% to 90% of affected infants have CSF findings clearly indicative of meningitis.1,2,51,53,59 As noted earlier, unlike in early-onset disease, obstetrical complications and prematurity are uncommon, and onset is usually after the first week of life. The mode of transmission may be from mother to infant, but often horizontal transmission from human contacts,
*See references 2–4,10,16,21,23,26,28,29,59,74,77,82,87,184,185.
indwelling catheters, or contaminated equipment can be documented. Specific serotypes are usually involved (serotype III for group B Streptococcus, IVb for L. monocytogenes, and K1 strains for E. coli); the course is not so fulminating as in early-onset disease, and the mortality rate is slightly lower. Dominance of Neurological Signs. Although neurological signs associated with meningitis are prominent in late-onset disease, some of the signs prominent in earlyonset disease are also common, especially fever and feeding disturbances. Most impressive, however, are the neurological signs (Table 21-11).16,29,51,60,88,185 In my experience, most patients exhibit impairment of consciousness, manifested usually as varying degrees of stupor, with or without irritability. The disturbances of level of consciousness presumably relate to the cerebral edema and, perhaps, the associated encephalopathy (see ‘‘Neuropathology’’). Seizures develop at some time in the illness in nearly 50% of cases, although these seizures may be predominantly subtle. The convulsive phenomena presumably relate to the cortical effects of the arachnoidal inflammatory infiltration. Focal seizures occur in approximately 50% of infants with seizures and may be prominent. These focal episodes may be related to ischemic vascular lesions. Similar bases are probable for the focal cerebral signs (e.g., hemiparesis and horizontal deviation of eyes), which are movable with the doll’s eyes maneuver. These signs are reported only uncommonly in the literature, but, in my experience, they can be elicited with careful examination in nearly one half of cases. Extensor rigidity occurs in approximately one third of cases and may be so severe that opisthotonos occurs. These phenomena probably relate to the arachnoidal inflammation, especially in the posterior fossa. A similar basis is likely for the nuchal rigidity, which occurs in fewer than 25% of cases. Apparent in most patients, however, is a distinct increase in irritability, elicitable by flexion of the neck and, presumably, the neonatal counterpart of more overt nuchal rigidity. Cranial nerve signs involve usually the seventh, third, and sixth nerves, in that order of frequency, and are more common than often suggested in the literature. These signs relate to involvement of cranial nerve roots by the arachnoidal inflammation (see ‘‘Neuropathology’’). A bulging or full anterior fontanelle is present, often later in the course of the disease, in approximately 35% to 50% of patients. This feature relates to an increase in TABLE 21-11
Neurological Signs of Neonatal Bacterial Meningitis
Neurological Sign Stupor with or without irritability Seizures Bulging or full anterior fontanelle Extensor rigidity, opisthotonos Focal cerebral signs Cranial nerve signs Nuchal rigidity
Approximate Frequency 76%–100% 26%–50% 26%–50% 26%–50% 26%–50% 26%–50% 0%–25%
Chapter 21
intracranial pressure (see following section). Rarely, anterior fontanelle herniation of cerebral tissue occurs and imparts a ‘‘doughy’’ consistency to the bulging fontanelle.134 Moreover, very uncommonly, signs of segmental cord involvement (sensory level, flaccidity below the level of the lesion), secondary to myelopathy, may be present.136 Major Neurological Complications The clinical course of neonatal bacterial meningitis may be complicated by the following four major and often interrelated events: (1) severe increase in intracranial pressure, (2) ventriculitis with localization of infection, (3) acute hydrocephalus, and (4) an intracerebral mass or extraparenchymal collection (e.g., abscess, hemorrhagic infarct, and subdural effusion) (Table 21-12). Increased Intracranial Pressure. Intracranial pressure, although only uncommonly monitored, may be markedly increased in neonatal bacterial meningitis. Major causes include cerebral edema, hydrocephalus, and, uncommonly, formation of an intracranial mass or extracerebral collection (Table 21-13). Cerebral edema (vasogenic and cytotoxic) is a frequent feature in the first several days of the disease and may be aggravated by water retention secondary to inappropriate antidiuretic hormone secretion.188-190 Increased intracranial pressure may persist or worsen in the ensuing days, with the development of acute hydrocephalus or an intracranial space-occupying lesion (see subsequent discussion). The increased intracranial pressure rarely causes signs of transtentorial (e.g., unilateral dilated pupil) or cerebellar (e.g., apnea and bradycardia) herniation, but both these forms of herniation have been reported.133 Although uncommon, the increased intracranial pressure may interfere with cerebral perfusion and may contribute to the associated encephalopathy described in the ‘‘Neuropathology’’ section. Clinical signs suggestive of increased intracranial pressure include a full or bulging anterior fontanelle, separated cranial sutures, and deterioration of the level of consciousness. Ventriculitis with Localization of Infection. Ventriculitis complicated by localization of infection is caused by particularly exuberant inflammation of the ependymal lining, usually in association with obstruction to CSF flow, especially at the aqueduct. Occasionally, formation of glial septa may localize intraventricular infection in a particularly severe manner. No reliable clinical signs exist for these events, and the diagnosis must be suspected on the basis of the failure of clinical and bacterial responses to therapy (see ‘‘Management’’). Ultrasound scanning may show signs suggestive of ventriculitis (see ‘‘Diagnosis’’) and may at least indicate the potential for sequestered infection. Acute Hydrocephalus. Hydrocephalus occurs in an appreciable proportion of infants with neonatal bacterial meningitis who survive into the second and third weeks of life. The causes of hydrocephalus include obstruction to CSF flow, either inside the ventricular system, secondary to ventriculitis, or outside the
Bacterial and Fungal Intracranial Infections
TABLE 21-12
929
Neurological Complications of Neonatal Bacterial Meningitis
Increased intracranial pressure Ventriculitis with localized, inaccessible infection Acute hydrocephalus Intracerebral mass or extracerebral collection
ventricular system, secondary to arachnoiditis. The suggestive clinical signs are those of increased intracranial pressure, as just discussed, and acceleration of head growth. Diagnosis is made best with ultrasound or other brain modality (see ‘‘Diagnosis’’), particularly because ventricular dilation develops before overt clinical signs. Intracerebral Mass or Extracerebral Collection. Formation of an intracerebral mass or extracerebral collection of clinical significance is very uncommon in neonatal bacterial meningitis. Brain abscess can occur, particularly in necrotic brain tissue (e.g., infarction), and it should be suspected if existing clinical signs worsen, despite apparently adequate therapy, and if signs of increased intracranial pressure or focal cerebral disturbance develop (see later section on ‘‘Brain Abscess’’). Sudden onset of a focal deficit with evidence for unilateral mass also may occur with a large hemorrhagic infarct. Abscess and massive infarction, although clinically very important, are very unusual in neonatal bacterial meningitis. Subdural effusion should be suspected in the presence of accelerated head growth and signs of increased intracranial pressure. Increased cranial transillumination can be helpful at the bedside. However, clinically significant subdural effusion is very uncommon in neonatal bacterial meningitis. Similarly, subdural empyema is a rare extracerebral collection that may cause signs of increased intracranial pressure in addition to fever and leukocytosis.
TABLE 21-13
Causes of Increased Intracranial Pressure in Neonatal Bacterial Meningitis
Cerebral Edema Vasogenic: endothelial effects of bacterial components, cytokines, arachidonate metabolites, free radicals, vasculitis Cytotoxic: cellular injury Water intoxication: inappropriate antidiuretic hormone secretion Hydrocephalus, Secondary to Obstruction of Cerebrospinal Fluid Flow Arachnoiditis and extraventricular block Ventriculitis and intraventricular block Intracerebral Mass or Extracerebral Collection Abscess Subdural effusion or empyema Other
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Diagnosis Clinical Evaluation The clinical suspicion of sepsis is based on a wide variety of very common, previously discussed, clinical signs. It is necessary to consider and distinguish not only virtually all nonbacterial infections (see Chapter 20), but also disorders of other organ systems as common as respiratory distress syndrome. Obstetrical and epidemiological factors are very important to evaluate. Indeed, the most significant point is that a high index of clinical suspicion is critical and should provoke the initiation of laboratory studies (reviewed in the next section). Clinical suspicion of meningitis, of course, must always be raised when sepsis is suspected. In addition, certain neurological signs should suggest meningitis (see previous discussion). Unfortunately, too often these signs appear after significant disease is well established. Disturbances of the level of consciousness are the most nearly constant initial neurological signs; indeed, perhaps the most useful early clinical constellation that should lead to the suspicion of neonatal bacterial meningitis is the combination of stupor, even if slight, and irritability. Laboratory Evaluation The essential questions to be answered through laboratory studies in the evaluation of the infant suspected of having bacterial meningitis are principally the following: 1. Is meningitis present? 2. What is the cause? 3. What is the status of the CNS? The answer to the first question is based principally on evaluation of the CSF, the answer to the second is based on the identification of the microorganism, and the answer to the third is based on several important neurodiagnostic studies. Cerebrospinal Fluid Findings. I believe that examination of the CSF is indicated in any infant with
TABLE 21-14
suspected sepsis, even in the absence of overt neurological signs. Indeed, in one series, 37% of cases of primarily early-onset neonatal meningitis would have been missed or the diagnosis delayed if the decision to perform a lumbar puncture had been reserved for infants with ‘‘neurological signs’’ or proven bacteremia.191 Similarly, in a series of 9461 very-low-birthweight infants, one third of those with meningitis had meningitis in the absence of sepsis.113 Because CSF cultures were performed only half as often as blood cultures, the discordance in blood and CSF culture results suggested that ‘‘meningitis may be underdiagnosed among very-low-birth-weight infants.’’113 Interpretation of the CSF findings in the newborn is difficult, especially when that interpretation is critical in making a diagnosis (i.e., bacterial meningitis) that requires urgent intervention. Among the many reasons for the difficulties in interpretation of the CSF findings, the most important relates to the uncertainty of normal values in the specific population of infants at risk for bacterial meningitis (see Chapter 4). Previously published studies dealt with normal or poorly defined populations. Sarff and co-workers192 described the CSF findings in 117 high-risk infants (87 term and 30 preterm, with 95% examined in the first week of life) without meningitis or other clinical evidence of viral or bacterial disease (Table 21-14). Mean values for term and preterm infants, respectively, were as follows: white blood cell (WBC) count, 8 and 9 cells/mm3 (60% polymorphonuclear leukocytes); protein concentration, 90 and 115 mg/dL; glucose concentration, 52 and 50 mg/dL; and ratio of CSF to blood glucose concentration, 81% and 74%. Although the ranges are wide, the values provided a useful framework. A later study by Rodriguez and co-workers193 amplified these findings by focusing on very-low-birth-weight infants, 80% of whom were examined after the first week of life. CSF findings as a function of postconceptional age were defined (Table 21-15). CSF values for protein and glucose contents are highest in the most immature infants and may reflect an increased permeability of the blood-brain barrier in
Cerebrospinal Fluid Findings in High-Risk Newborns without Bacterial Meningitis
CSF Findings
Term
Preterm
8 0–3
9 0–29
90 20–170
115 65–150
52 34–119
50 24–63
81 44–248
74 55–105
3
White Blood Cell Count (cells/mm ) Mean Range Protein Concentration (mg/dL) Mean Range Glucose Concentration (mg/dL) Mean Range CSF/Blood Glucose (%) Mean Range
95% of infants were examined in the first week of life. CSF, cerebrospinal fluid. Data from Sarff LD, Platt LH, McCracken GH Jr: Cerebrospinal fluid evaluation in neonates: Comparison of high-risk infants with and without meningitis, J Pediatr 88:473-477, 1976.
Chapter 21 TABLE 21-15
Bacterial and Fungal Intracranial Infections
931
Cerebrospinal Fluid Findings in Infants Weighing Less than 1500 g as a Function of Postconceptional Age CSF FINDINGS
Postconceptional Age (wk) 26–28 29–31 32–34 35–37 38–40
(n = 17) (n = 23) (n = 18) (n = 8) (n = 5)
3
WBCs/mm (Mean ± SD)
Glucose (mg/dL) (Mean ± SD)
6 ± 10 5±4 4±3 6±7 9±9
85 ± 39 54 ± 18 55 ± 21 56 ± 21 44 ± 10
Protein (mg/dL) (Mean ± SD) 177 ± 60 144 ± 40 142 ± 49 109 ± 53 117 ± 33
80% of infants were examined after the first week of life. CSF, cerebrospinal fluid; WBCs, white blood cells. Data from Rodriguez AF, Kaplan SL, Mason EO Jr: Cerebrospinal fluid values in the very-low-birth-weight infant, J Pediatr 116:971-974, 1990.
these infants (see Table 21-15 and Chapter 4). These additional features are important in assessing the CSF in the large numbers of very premature infants evaluated in modern neonatal intensive care units. The CSF formula for neonatal bacterial meningitis is an elevated WBC count predominantly consisting of polymorphonuclear leukocytes, an elevated protein concentration, and a depressed glucose concentration, particularly in relationship to blood glucose concentration. The abnormalities tend to be more severe for late-onset than early-onset disease and for gram-negative enteric than group B streptococcal meningitis. Of 119 newborn infants with proven bacterial meningitis, more than 1000 WBCs/mm3 were observed in the initial sample of CSF in approximately 75% of patients with gram-negative infection but in only approximately 30% with group B streptococcal infection.192 Values in excess of 10,000 WBCs/mm3 were observed in approximately 20% of gram-negative infections but were rare in group B streptococcal infections. Evaluation of the other end of the continuum is still more informative (Table 21-16). Thus, using the ranges determined in their high-risk newborns (see Table 21-14), Sarff and coworkers192 showed that CSF values for WBC count were within the ‘‘normal’’ range for approximately 30% of infants with culture-proven group B streptococcal meningitis versus only 4% of infants with gram-negative meningitis. Values for CSF protein concentration and CSF to blood glucose ratio were within the ‘‘normal’’ range in nearly 50% of the infants with group B streptococcal meningitis versus
TABLE 21-16
only 15% to 25% of the infants with gram-negative bacterial meningitis (see Table 21-16). The importance of evaluating all the CSF findings, and not just one isolated value, is emphasized by the finding that only 1 of 119 infants had normal values for all three parameters in the initial lumbar puncture sample.192 Thus, the CSF findings should be evaluated in toto and in the context of other clinical, epidemiological, and laboratory data when assessing the possibility of meningitis. In the rare patient with a totally normal CSF examination but a continuing suspicion of meningitis, a second lumbar puncture is indicated. Identification of the Microorganism in Cerebrospinal Fluid. Determination of the bacterial cause of meningitis obviously is made most readily and decisively by culture of the CSF. The yield in the previously untreated patient whose CSF is cultured promptly on the various media necessary to isolate the different microorganisms responsible for neonatal bacterial meningitis (including Listeria) approaches 100%. The result is usually available within 48 hours. Faster techniques available for identifying microorganisms include Gram-stained smears, countercurrent immunoelectrophoresis, limulus lysate assay, and latex particle agglutination. Stained smears demonstrated bacteria on the initial CSF evaluation of 119 newborn infants with meningitis in 83% of patients with group B streptococcal meningitis and in 78% of those with gram-negative bacterial meningitis.192 This universally available, simple procedure should be performed on every CSF sample. Countercurrent immunoelectrophoresis
Cerebrospinal Fluid Findings in Neonatal Bacterial Meningitis BACTERIAL ETIOLOGY OF MENINGITIS
CSF Finding WBC count 12 hours), and markedly elevated CSF protein content. Also of value with specific infections are the quantitative levels in CSF of the type III group B streptococcal or the K1 E. coli antigenic markers; these levels correlate directly with prognosis.53 A careful study of the electroencephalogram during bacterial meningitis in 29 infants indicated value for the degree of background abnormality in prediction of outcome (Table 21-20).238 A more recent study confirmed these initial findings.228 Although not systematically analyzed, I find that the degree of injury on MRI scan performed late in the infant’s course is useful prognostically. However, although these various associations are valuable, outcome in neonatal bacterial meningitis depends on the interplay of so many factors that Figure 21-19 Neonatal bacterial meningitis: computed tomography scan. This scan was obtained 2 weeks after diagnosis and appropriate antibiotic treatment of Escherichia coli meningitis. Note the increased extracerebral fluid, the outer portion of which is of greater attenuation (arrows) than the inner portion. The appearance is consistent with a subdural effusion.
*See references 10,12,16,29,51,53,60,77,113,185,202,228,232,236, 237.
Chapter 21
A
Bacterial and Fungal Intracranial Infections
937
B Figure 21-20 Neonatal bacterial meningitis: magnetic resonance imaging (MRI) scans. The initial MRI scan (A and B), obtained during the acute period, shows, after administration of gadolinium, leptomeningeal enhancement (arrow in A), consistent with leptomeningitis, ependymal enhancement (arrows in B), consistent with ventriculitis (with loculation), and evidence of diffuse cerebral white matter injury and more focal bifrontal lesions, possibly infarcts. Three weeks later (C), note marked dilation of the lateral and third ventricles, indicative of hydrocephalus (with a likely block at the aqueduct) and diffuse cerebral cortical and white matter injury, especially bifrontally. (Courtesy of Dr. Omar Khwaja.)
C
prognostic judgments in every case must be carefully individualized. Indeed, in my experience, in perhaps no other variety of neonatal neurological disease is dramatic recovery from a devastated clinical state more likely to be observed than in an infant with neonatal bacterial meningitis. Management The major issues in the management of neonatal bacterial meningitis relate to prevention, supportive
care, neurological complications, antibiotics, and ventriculitis. Although many aspects of management are surrounded by unresolved problems, the basic fact remains that neonatal bacterial meningitis is a treatable disease. Prevention (Group B Streptococcal Infection) The most critical and challenging problem in the prevention of neonatal bacterial meningitis relates to group B streptococcal disease. Group B Streptococcus is the single most common organism implicated in
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Figure 21-21 Diffusion-weighted magnetic resonance imaging (DWI) scan in Listeria meningitis. Computed tomography and conventional magnetic resonance imaging scans were not definitely abnormal (not shown). By contrast, the DWI scan shows a striking and diffuse decrease in signal intensity in cerebral white matter, indicative of increased diffusion, consistent with vasogenic edema.
many medical centers (see earlier). The enormity of the public health problem associated with neonatal sepsis and meningitis caused by group B Streptococcus has been alluded to earlier (see ‘‘Pathogenesis’’). Two basic approaches to prevention of neonatal disease have been proposed: chemoprophylaxis and immunoprophylaxis. Chemoprophylaxis. Historically, chemoprophylaxis has been an attractive approach because of the susceptibility of group B Streptococcus to penicillin in vitro and the relative ease of administering such a relatively safe and well-known antibiotic. The three major chemoprophylactic approaches used since the late 1980s have included treatment of a colonized woman in the third trimester, or at delivery, and treatment of the newborn at birth.59,72,75,77,239-252 Among these approaches, treatment of the colonized woman at delivery has become the approach of choice.72,75,77,200,239-242,245,247-251,253-255 The findings in several controlled studies showed conclusively that TABLE 21-18
Immunoprophylaxis. Immunoprophylaxis is potentially of greater value than chemoprophylaxis because the approach would be less complex and would be most likely to prevent late-onset as well as earlyonset disease.59,77,242,256,257 Because of the protective value of antibody directed against the capsular polysaccharide of group B Streptococcus, passive immunization of antibody-deficient women or newborns with intravenous gamma globulin is a reasonable consideration.59 Given that transplacental transfer of antibody does not occur until after the 34th week of gestation, this approach requires timing late in pregnancy. The value of intravenous human globulin administration was demonstrated in a newborn animal model of group B streptococcal sepsis.258 Of greatest promise is active immunization with purified group B streptococcal polysaccharide. The type III polysaccharide was shown to be immunogenic in adult volunteers,
Outcome of Meningitis Caused by Group B Streptococcal Infection
Status Dead Normal Mild or moderate sequelae (borderline or mild mental retardation, unilateral sensorineural hearing loss, arrested hydrocephalus, and spastic monoparesis) Severe sequelae (uncontrolled seizures, cortical blindness, spastic quadriparesis, mental retardation [excluding mild cases], severe microcephaly, and hydrocephalus)
intravenous ampicillin or penicillin during labor leads to a marked reduction in colonization of infants born to infected mothers and to a virtual elimination of earlyonset group B streptococcal sepsis-meningitis. The most difficult issue has been whom to treat. The data depicted in Table 21-21 emanated from a classic study and showed the value of intrapartum chemoprophylaxis, especially in certain high-risk groups.247 Indeed, in the years since the advent of widespread intrapartum chemoprophylaxis, the incidence of group B streptococcal disease has declined markedly: for early-onset sepsis-meningitis, it has declined from 1.7 in 1000 births to approximately 0.3 in 1000; and for lateonset disease, it has declined from 0.5/1000 births to 0.3 in 1000 births.77 These and similar observations have led to the current recommendations of the Centers for Disease Control and Prevention: (1) a screening strategy with culture of pregnant women for group B Streptococcus at 35 to 37 weeks of gestation and administration of intrapartum penicillin G (or ampicillin) to all culture-positive women, whether or not they have a risk factor (see next); or (2) a nonscreening approach with administration of intrapartum penicillin G (or ampicillin) to all women with a risk factor (previous delivery of an infant with group B streptococcal disease, history of group B streptococcal bacteremia during pregnancy, preterm labor < 37 weeks of gestation, rupture of membranes 18 hours before delivery, or intrapartum fever).
See text for references.
Percentage of Survivors
Percentage of Total 10%–15%
50% 40% 10%
Chapter 21 TABLE 21-19
939
Outcome of Meningitis Caused by Gram-Negative Enteric Organisms
Status
Percentage of Survivors
Dead Normal Mild or moderate sequelae (see Table 21-18) Severe sequelae (see Table 21-18)
Bacterial and Fungal Intracranial Infections
Percentage of Total 15%
50% 40% 10%
See text for references.
TABLE 21-20
Relationship between Electroencephalographic Background Activity and Outcome OUTCOME
Most Abnormal Background
Normal or Mildly Abnormal
Severely Abnormal
Death
9 5 0
0 3 5
0 1 6
Normal or mildly abnormal Moderately abnormal Markedly abnormal{
Data from Chequer RS, Tharp BR, Dreimane D, Hahn JS, et al: Prognostic value of EEG in neonatal meningitis: Retrospective study of 29 infants, Pediatr Neurol 8:417-422, 1992. From a study of 29 infants, 15 of whom were less than 38 weeks of gestational age. { Markedly abnormal: markedly excessive discontinuity for postconceptional age, burst suppression, markedly excessive interhemispheric asynchrony or asymmetry, diffusely slow background, extremely low voltage ( 200 WBCs/mm3 or organisms on stained smear or culture); the results of treatment of that group are displayed in Table 21-23. No difference between the two groups in the time required to sterilize the CSF was observed. Still more impressive, the mortality rate in the infants treated with parenteral therapy alone was lower than in those treated with parenteral therapy and intraventricular therapy. Thus, routine intraventricular therapy of meningitis produced by gram-negative organisms had no beneficial effect and may have had a deleterious effect. (If the latter is true, the cause of such a deleterious effect is unclear, TABLE 21-23
although injury to myelin and axons in brain stem of an adult human patient and in brain stem and spinal cord of rabbits administered gentamicin by the intrathecal route has been described.292 Deleterious neurological and neuropathological effects of gentamicin also have been demonstrated in rabbits administered gentamicin intraventricularly.293) However, in view of the generally favorable outcome in the control group, it is apparent that ventriculitis only very uncommonly results in a site of infection inaccessible to systemic antibiotics. To determine conclusively whether intraventricular antibiotics are useful in the small subset of patients with such inaccessible intraventricular infection, a much larger study would be required (this requirement may not be possible to fulfill, because the study of McCracken and co-workers272 included 10 institutions). Our approach to this subset of patients is described later in ‘‘Ventriculostomy.’’ Indications for Diagnostic Ventricular Puncture. The failure to improve the prognosis of meningitis caused by gram-negative bacteria with routine intraventricular therapy raises two important questions in the management of neonatal bacterial meningitis: 1. When should the lateral ventricle be tapped? 2. How should the information obtained be used? As discussed earlier in ‘‘Diagnosis,’’ I believe that the indications for evaluating the lateral ventricles in the infant are as follows: (1) bacteriological (i.e., persistence of infection in the lumbar CSF at 4 days) or (2) clinical (i.e., failure of clinical improvement or, still more importantly, the appearance of clinical deterioration, even if lumbar CSF cell count is improving and CSF sterilization occurs). If these indications are present and antibiotic therapy has been appropriate in terms of susceptibilities of the organism, doses of the drugs, and, if available, concentrations of the critical drugs in the CSF, an ultrasound scan or CT or MRI scan should be obtained. If the ventricles are not too small, a ventricular tap should be performed. If the ventricular fluid exhibits marked pleocytosis and organisms demonstrable on smear or culture, it is likely that the systemically administered antibiotics, usually aminoglycosides in meningitis caused by gram-negative bacteria, are not eradicating a reservoir of infection within the ventricular system. Ventriculostomy. Ventriculostomy (with intermittent intraventricular instillation of an antibiotic, usually through a reservoir) is indicated when the ventricular
Effect of Intraventricular Therapy on Neonatal Meningitis and Ventriculitis Caused by GramNegative Enteric Organisms
Mode of Therapy Parenteral{ Parenteral{ and intraventricular{
Days CSF Culture Positive
Mortality Rate
Normal (Percentage of Survivors)
3.6 3.4
13% 44%
54% 60%
CSF, cerebrospinal fluid. Data from McCracken GH Jr, Mize SG, Neonatal Cooperative Study Group: Intraventricular therapy of neonatal meningitis caused by gram-negative enteric bacilli, Pediatr Res 13:464, 1979. Based on 51 cases. { Ampicillin and gentamicin. { Gentamicin.
Chapter 21 TABLE 21-24
Bacterial and Fungal Intracranial Infections
943
Intraventricular Antibiotics for Ventriculitis
Antibiotic
Dose (mg)
Desired Peak Cerebrospinal Fluid Concentration (mg/mL)
Gentamicin Vancomycin Polymyxin
1–5 4–5 1–2
80–120 80–100 Unknown
Histological change in white matter observed with concentrations >150 mg/mL. Data from Smith AL, Haas J: Neonatal bacterial meningitis. In Scheld WM, Whitley RJ, Durack DT, editors: Infections of the Central Nervous System, New York: 1991, Raven Press.
tap demonstrates purulent fluid with persistent infection.198 Antibiotics should be instilled in concentrations that generally exceed those usually sought in serum. Table 21-24 shows the commonly used intraventricular antibiotics and the concentrations sought.198 Serial measurements of the CSF concentrations of the antibiotics are important. The best approach is to administer the agent at a dose calculated to produce a concentration approximately 20-fold greater than the measured minimal bactericidal concentration.198 Ventriculostomy, with external drainage, may be required in neonatal bacterial meningitis when ventriculitis has caused obstruction to CSF flow and acute hydrocephalus, manifested by increased intracranial pressure and dilated lateral ventricles. This condition may develop despite eradication of the ventricular infection by the systemic antibiotics and therefore with a sterile ventricular CSF. In such a circumstance, intraventricular instillation of antibiotic is not needed, and the task is management of the intracranial hypertension by CSF drainage, as described in Chapter 11 in relation to rapidly progressive posthemorrhagic hydrocephalus.
to M. hominis have been recorded.314,318,320 Finally, as noted in the following section, certain fungi, especially Candida, may cause brain abscess, usually multiple and small, especially in very-low-birth-weight infants. Pathogenesis The common conditions for the development of brain abscess are cerebral necrosis and bacteremia. In bacterial meningitis, the parenchymal necrosis that may become infected to form an abscess is usually caused initially by vasculitis with infarction. It is not surprising, then, that the organisms associated with brain abscess are those that produce severe vasculopathy with the meningitis. This point was demonstrated vividly by the study of Foreman and co-workers.324 Severe vasculitis with infarction and with numerous organisms present around inflamed blood vessels and in cerebral parenchyma was shown in two infants who died within 2 days of clinical onset of meningitis caused
TABLE 21-25
BRAIN ABSCESS
Occurrence without Bacterial Meningitis 33% of cases of neonatal brain abscess not accompanied by bacterial meningitis
Brain abscess is an uncommon and devastating, although potentially treatable, disorder in the neonatal period (Table 21-25). Most examples of neonatal brain abscess occur as a complication of bacterial meningitis, especially that resulting from particularly virulent gram-negative organisms.41,146,294-310 However, approximately 25 cases of neonatal brain abscesses have been reported that were apparently not the consequence of meningitis.144,303,311-318
Relation to Bacterial Meningitis 15% of gram-negative bacterial meningitis complicated by abscess Most Common Organisms Citrobacter diversus, Proteus species, Serratia species Neuropathology Abscesses usually large, multiple (60%), frontal (70%), and not well encapsulated
Etiology The most commonly reported organisms associated with brain abscess have been those with the particular capacity to invade nervous tissue and cause necrosis. Gram-negative organisms have been implicated most often, especially Citrobacter, but also Proteus, Pseudomonas, Serratia, and other coliform bacilli (see previous discussion of bacterial meningitis).41,145,146,295-298,301-306,308-310,319 Citrobacter and, to a lesser extent, Proteus and Serratia are the most commonly identified pathogens. Gram-positive organisms are involved much less often, although group B Streptococcus and S. aureus have been identified in isolated cases.109,316,320-322 Spinal epidural abscess secondary to S. aureus also has been reported.323 Still rarer, three cases of neonatal brain abscess secondary
Brain Abscess in the Newborn
Onset of Clinical Features Average age, 9 days Clinical Presentation Seizures > nonspecific signs of sepsis > increasing head circumference Complications Hydrocephalus requiring shunt placement (35%): only in patients with meningitis Treatment Aspiration (ultrasound-guided) and antibiotics generally effective; antibiotics alone may lead to cure Prognosis Mortality rate, 15%; cognitive deficits, 75%; epilepsy, 60%
See text for references.
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by Citrobacter.324 Presumably, the next phase of the illness would have been infection of necrotic tissue and abscess formation, a feature of approximately 50% to 80% of reported cases of Citrobacter meningitis.16,295,296,301-303,308,310 In the rarer cases of brain abscess not associated with primary meningitis, the initial injury to brain is not always clear but often has appeared to be hypoxic-ischemic cerebral injury, periventricular hemorrhagic infarction, or septic embolus. Neuropathology The distinguishing features of brain abscess in the newborn have been threefold: (1) relatively large size of lesions, (2) relatively poor capsule formation, and (3) multiple number. The lesions have been located almost uniformly in the cerebral hemispheres, most often the frontal lobes, and often have encompassed several lobes. Occasionally, the abscess has been tapped inadvertently at the time of ventricular or subdural puncture. Detailed microscopic data are not available, but hemorrhage and necrosis usually have been noted with the purulence. Clinical Features Two major clinical syndromes have been described with neonatal brain abscess: (1) an acute to subacute evolution of signs of cerebral parenchymal involvement, especially seizures (less commonly, hemiparesis), often accompanied by signs of increased intracranial pressure (vomiting, bulging anterior fontanelle, separated sutures, and enlarging head); and (2) an acute onset of fulminating bacterial meningitis. The first syndrome is more common, has its onset from the first few days to weeks of life, and often occurs in association with acute or ongoing bacterial meningitis. The initial diagnosis occasionally has been congenital hydrocephalus. The second syndrome differs little from later-onset neonatal bacterial meningitis (see previous section). Diagnosis Clinical Evaluation The diagnosis of brain abscess should be considered in any infant with the acute or subacute evolution of signs of increased intracranial pressure or possible hydrocephalus. In the absence of meningitis, fever is not a feature; in the six well-studied cases of Hoffman and co-workers,312 four infants were afebrile. In an infant with bacterial meningitis, brain abscess should be suspected when seizures or prominent focal cerebral signs develop, a poor clinical response to antibiotic therapy occurs, or the CSF formula does not appear to be compatible with the clinical syndrome (e.g., several hundred WBCs in the CSF of a gravely ill infant, or, in a child with ‘‘meningitis’’ and a few hundred WBCs in the initial CSF, the sudden appearance of several thousand polymorphonuclear WBCs in a subsequent CSF examination and marked clinical deterioration). (The latter
occurrence develops with rupture of the brain abscess into the lateral ventricle or subarachnoid space.) Laboratory Evaluation Peripheral White Blood Cell Count. The combination of clinical features just described, without fever but with a high peripheral WBC count, is common in brain abscess without meningitis. In the series of Hoffman and co-workers,312 the peripheral WBC count ranged from 18,000 to 34,000. Cerebrospinal Fluid. In the infant without bacterial meningitis, the CSF usually contains pleocytosis consisting predominantly of mononuclear cells and usually numbering less than a few hundred. CSF protein content is elevated, usually to approximately 75 to 150 mg/ 100 mL. Unless bacterial meningitis is also present, the organism will not be apparent on Gram stain or culture. The sudden appearance of clinical deterioration and thousands of polymorphonuclear leukocytes in the CSF is characteristic of rupture of the abscess into the ventricular system. Brain Imaging. The diagnosis of brain abscess is raised most conclusively by CT or, especially, MRI scan and, occasionally, by ultrasound scan. On CT scan, a variably circumscribed region of decreased attenuation is apparent, often much greater in extent than the abscess itself, because of the presence of cerebritis with surrounding edema. The rim of the abscess usually enhances after the injection of contrast material (Fig. 21-22). MRI scanning provides better resolution than does CT scanning (Figs. 21-23 and 21-24). Cranial ultrasound scan has proved somewhat useful in diagnosis of cerebral abscess in the newborn. Thus, in experimental brain abscess, ultrasound scanning was as effective as CT in identification of the early stages. An echogenic rim with a hypoechogenic center was characteristic.325 Such an appearance has been observed in neonatal brain abscess.300,304,322,326,327 Identification of the Organism. The organism occasionally can be isolated from blood, but aspiration of the abscess cavity is usually necessary to obtain a definite bacteriological diagnosis. (In the presence of meningitis, the organism can be isolated from CSF.) Aspiration can be carried out with ultrasonographic guidance (see ‘‘Management’’). Because some of the responsible organisms require special techniques for isolation and identification, the material should be handled in an especially careful manner. Prognosis The prognosis has been poor for those infants in whom correct diagnosis and appropriate treatment were delayed. Overall, approximately 15% of newborns with brain abscess have died of the acute illness, and of the survivors, 75% have experienced mental deficiency (intelligence quotient or development quotient < 80), and 60% have developed epilepsy.16,145,295,296,300-306,308,310,312,316 Perhaps the most
Chapter 21
A
Bacterial and Fungal Intracranial Infections
945
Figure 21-23 Brain abscess: magnetic resonance imaging (MRI) scan. This 2-week-old infant had Citrobacter meningitis. This fluid-attenuated inversion-recovery MRI scan shows a circumscribed lesion in the right frontal white matter (arrow), with surrounding edema, consistent with an abscess. The lesion enhanced after injection of gadolinium (not shown). Resolution of the presumed abscess occurred after antibiotic therapy only.
B Figure 21-22 Brain abscess: computed tomography scans. Scans were obtained from infants with Citrobacter diversus meningitis, after injection of contrast material. Note the areas of decreased attenuation surrounded by a rim of increased attenuation in, A, bilateral frontal areas and, B, right frontal and left parietal areas. (Courtesy of Dr. Mark W. Kline.)
unfavorable outcome has been in infants with abscess and C. diversus meningitis; the mortality rate has been 30%, and only 20% of survivors have been normal on follow-up. Management The most essential issue concerning management is prompt diagnosis. In the infant with meningitis,
Figure 21-24 Brain abscess: magnetic resonance imaging (MRI) scan, after gadolinium contrast. This 5-week-old infant had focal seizures, Proteus sepsis, and a complicated congenital cardiac lesion, including an atrioventricular canal defect. This axial MRI scan shows a striking ring-enhancing cerebral lesion, consistent with brain abscess. Craniotomy with drainage of the abscess was performed. (Courtesy of Dr. Omar Khwaja.)
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particularly that caused by Citrobacter, Proteus, or Serratia, serial brain imaging is indicated to detect abscess as early as possible. In the infant without meningitis, a high index of clinical suspicion is critical, and appropriate imaging procedures are essential. No consensus exists for therapy for brain abscess in the neonatal period. The three principal approaches are (1) medical therapy alone, (2) aspirations through a burr hole or through the percutaneous route, and (3) open surgical drainage and extirpation. The demonstration of cure early in the disease with systemic antibiotics has been observed in newborns as in older children.146,305,306,308,317,318,322,328-332 Whether antibiotics with potent bactericidal activity, broad antibacterial spectrum, and good penetration into the CNS (e.g., third-generation cephalosporins) will prove most useful in this regard remains to be determined. In the case of C. diversus, the addition to the antibiotic regimen of a drug that is concentrated in phagocytes (i.e., trimethoprim-sulfamethoxazole) or to which the organism is especially sensitive (i.e., meropenem or imipenem) may be particularly important.281,301,302,310 Despite the multiple reports of ‘‘medical cure’’ of brain abscess, drainage is necessary in selected cases. Of the two approaches to drainage (i.e., serial aspirations and open surgical drainage), the advent of ultrasound-guided aspirations suggests that this method is of particular value, even for multiple lesions.326,327 CT-guided aspiration also can be used, but this approach is less convenient. Needle aspiration is useful not only for initial diagnosis and drainage, but also for determination of antibiotic levels in the abscess cavity. Open surgical drainage is the most definitive therapeutic approach for brain abscess. However, if the infant’s condition is not deteriorating and the responsible organism has been identified, a trial of intensive antibiotic therapy, followed, if necessary, by serial ultrasound-guided needle aspirations, is reasonable. Careful serial brain imaging should be performed to ensure that the lesion (or lesions) is (are) not worsening. In such a circumstance, prompt open surgical drainage is necessary.
this category of nonbacterial disease in this chapter rather than in Chapter 20 because the clinical features often mimic those of bacterial sepsis and the neuropathological features are similar to those of bacterial meningitis and brain abscess. Although several fungi (e.g., Cryptococcus, Coccidioides, and Aspergillus) have been reported to cause meningitis or abscess, or both, in the newborn, systemic infection by Candida, especially Candida albicans and, more recently, Candida parapsilosis, particularly in the very-low-birth-weight newborn, is by far the most common neonatal disseminated fungal infection.333-358 Earlier studies of somewhat selected cases indicated that at least one third of cases of systemic candidiasis in premature infants exhibited involvement of the CNS.336,340,344 More recent data show that approximately 10% to 25% of cases exhibit CNS involvement.349,352-355 However, the magnitude of the problem is substantial because approximately 10% to 20% of all infants weighing less than 1000 g at birth develop candidiasis, as do approximately 25% of infants of 23 to 24 weeks of gestational age.351,355,357,359 The major features of systemic candidiasis in the newborn are summarized in Table 21-26.
DISSEMINATED FUNGAL INFECTION
Neuropathology
Disseminated fungal infection in the newborn may cause meningitis, often with microabscesses. I discuss
Neuropathological studies of neonatal systemic candidiasis are not abundant.349,357 However, the principal
TABLE 21-26
Pathogenesis The reasons that the newborn, particularly the premature newborn, is vulnerable to disseminated fungal infection are not entirely known but involve a combination of multiple immune deficiencies and insufficient anatomical barriers to infection, in a setting of intensive medical interventions for systemic illness.333,340,356,357,360 The common historical findings of prolonged use of indwelling vascular catheters, endotracheal intubation, necrotizing enterocolitis, and surgery indicate possible portals of entry for the organism.333,335,337,338,340,350,356,357,360 The retrograde medication syringes of total parenteral nutrition systems were important sites for infection in one large study.347 The prior use of multiple courses of broadspectrum antibiotics in most patients is a likely cause of disrupted microbial flora and enhances the potential for fungal infection.340,357,360,361
Major Features of Systemic Candidiasis
Very-low-birth-weight infant (90% mortality rate Choroid Plexus Papilloma Minimal mortality rate and high likelihood of normal outcome Ependymoma Variable prognosis, as stated for astrocytoma, but less commonly curable
microneurosurgical and endovascular techniques, this disorder, when it is severe enough to appear in the newborn, remains a major therapeutic problem. Figure 23-11 Glioma: magnetic resonance imaging scan. This 2-month-old infant had a large, heterogenous mass (undifferentiated glioma) in the diencephalic–upper midbrain region. Disseminated tumor was present in extracerebral spaces, which are markedly widened. (Courtesy of Dr. Omar Khwaja.)
Neuropathology The essential feature of the vein of Galen malformation is aneurysmal dilation of the venous structure generally characterized as the vein of Galen. The most common feeding arterial vessels into this dilated venous structure are, in order of frequency, the posterior choroidal artery, the anterior cerebral (pericallosal) artery, the
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Figure 23-12 Spinal cord and medullary astrocytoma: magnetic resonance imaging (MRI) scan. A, Midsagittal MRI, T1-weighted (TR 600/TE 15), unenhanced. The tumor can be appreciated in the medulla (curved arrow). Additional signal sequences (not shown) had no indication of a fluid
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TABLE 23-7
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Vein of Galen Malformation with Presentation in the Neonatal Period
Neonatal Presentation 60% of all pediatric cases of vein of Galen malformation
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Most Common Arterial Feeding Vessels Choroidal arteries (posterior and anterior), anterior and middle cerebral arteries, and proximal posterior cerebral arteries Clinical Presentation High-output congestive heart failure in virtually all neonatal cases; hydrocephalus present in 15% Diagnosis Made most readily by ultrasonography, Doppler studies of cerebral vessels and peripheral arteries, computed tomographic angiography, and magnetic resonance imaging Outcome In previous years, nearly 100% mortality; more recently, 40% to 65% have favorable outcome Therapy Most commonly embolization, either by selective arterial infusion with liquid adhesive agents or microcoils or by transvenous-transtorcular embolization with metallic coils
middle cerebral artery (especially thalamoperforating branches), the anterior choroidal artery, and the posterior cerebral artery (see Table 23-7).74,76,78,79 Although the vein of Galen is considered in most writings to be the vein that is dilated, careful anatomical study suggests that the so-called median prosencephalic vein of Markowski, a transitory venous structure that normally disappears by the 11th week of gestation, is the vein involved (Figs. 23-13 and 23-14).78 During early development, this vein drains directly into the vein of Galen, and after 11 weeks, it is replaced by the internal cerebral veins. The median prosencephalic vein is involved particularly in venous drainage from the choroid plexus.78,80 The frequent position of the aneurysmally dilated vein anterior to the position of the vein of Galen further supports the notion that the involved vein is the primitive median prosencephalic vein. The frequent association of abnormal venous channels, including the so-called falcine sinus, a normally transient fetal vessel, is additionally consistent with this hypothesis.78 Nevertheless, the term vein of Galen malformation is entrenched in the medical literature, and I continue to use it to characterize this entity. The associated neuropathological findings observed with vein of Galen malformation consist of a variety of ischemic, hemorrhagic, and mass effects of the malformation.74-76,78-92 Thus, in a carefully analyzed series of 13 infants who died in the first 6 weeks of life, ischemic lesions included cerebral infarction (focal vascular and border zone lesions) in 4 infants, basal ganglia or other infarction in 3, periventricular leukomalacia in 7, pontosubicular necrosis in 3, and selective neuronal necrosis of cerebral cortex or brain stem, or both, in 4 infants. Hemorrhagic lesions included
Figure 23-13 Artist’s rendering of the early vascularization of the choroid plexuses. Just before the growth of the neural tube induces the development of the intrinsic vascularization, the meninx primitiva invaginates into the ventricular lumen to produce the choroid plexuses. The arterial afferents are the choroidal arteries, including the terminal branch of the anterior cerebral artery (ACA). The venous blood drains through the median prosencephalic vein of Markowski. This single midline vein forms by collecting blood from the plexuses at the level of the paraphysis and courses backward toward the dorsal (interhemispheric) dural plexus. Simultaneously, the development of the collicular plate is accompanied by development of quadrigeminal (collicular) arteries. Later, when the intrinsic vascularization develops in the basal ganglia and thalamus, the internal cerebral veins develop to drain them. These join with the posterior end of the median prosencephalic vein to form what will become the vein of Galen. Progressively, the internal cerebral veins replace the median prosencephalic vein for choroidal venous drainage; the median prosencephalic vein attenuates and disappears, and the vein of Galen develops. (From Raybaud CA, Strother CM, Hald JK: Aneurysms of the vein of Galen: Embryonic considerations and anatomical features relating to the pathogenesis of the malformation, Neuroradiology 31:109–128, 1989.)
subarachnoid hemorrhage in 3 infants, germinal matrix–intraventricular hemorrhage in 2, and intracerebral hemorrhage in 2. Venous thrombosis was present in 3 infants. Mass effects included hydrocephalus secondary to obstruction, usually at the level of quadrigeminal plate and the aqueduct, in 2 infants, and compression of other structures (e.g., cerebral peduncles) in 1 infant. The mechanisms of these lesions are multifactorial and are summarized in Table 23-8. The ischemic phenomena are related primarily to a combination of intracranial ‘‘steal’’ phenomena, caused by the absence or even the reverse of diastolic cerebral blood flow, and congestive heart failure. The heart failure is caused principally by the remarkably high cardiac output, secondary to both the marked decrease in cerebrovascular resistance and the increased venous return to the heart, and by marked cardiac ischemia. The latter results from decreased coronary blood flow, which normally occurs predominately during diastole, because of the low diastolic pressure associated with the vein of Galen malformation.
Chapter 23 TABLE 23-8
Major Mechanisms of Brain Injury with the Vein of Galen
Intracranial ‘‘steal’’ phenomena because of diastolic ‘‘runoff,’’ resulting in cerebral ischemia Congestive heart failure (secondary to high cardiac output and myocardial ischemia, because of low diastolic pressure and, as a consequence, impaired coronary flow), resulting in cerebral ischemia Thrombosis of the dilated vein of Galen with hemorrhagic infarction or intraventricular hemorrhage, or both Vascular rupture with massive hemorrhage Atrophy secondary to compression of adjacent structures by the dilated vein of Galen Hydrocephalus secondary to aqueductal obstruction (by compression)
Clinical Features The clinical manifestations of the vein of Galen malformation in the neonatal period reflect the large size of the lesions and consist predominately of congestive heart failure (see Table 23-7).73-77,79,87,89-102 Thus, of the approximately 130 cases with adequate clinical data, 80% to 95% of infants presented with congestive
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heart failure. The remaining infants presented with hydrocephalus, subarachnoid hemorrhage, or intraventricular hemorrhage. The features accompanying the congestive failure aid in diagnosis and include a cranial bruit and bounding carotid pulses. The cranial bruit differs from the benign systolic bruit of infancy and early childhood by its continuous nature and by the frequent localization over the posterior cranium rather than the anterior cranium. The marked carotid pulses may be accompanied by prominent peripheral pulses, but in the presence of overt congestive heart failure, the peripheral pulses may be depressed, whereas the carotid pulses remain prominent. A consequence of congestive heart failure, prerenal azotemia, was observed in 11 of 15 infants in a reported series.73 Seizures and other neurological signs are very unusual. The clinical presentation of neonatal cases differs from that in older infants and children with vein of Galen malformation. Thus, older infants present most commonly with hydrocephalus, and children present most commonly with neurological signs (perhaps secondary to intracranial ‘‘steal’’ phenomena), headache, and, occasionally, subarachnoid hemorrhage. The subsequent course in newborns with an untreated vein of Galen malformation who survive the
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Figure 23-14 Artist’s rendering of a vein of Galen malformation. This drawing is based on two anatomical dissections. Two fistula sites are present in the aneurysmal sac (Aneur). The anterior fistula receives blood from the choroidal vessels (anterior cerebral artery [ACA], choroidal branches (Chor A) of the posterior cerebral artery [PCA]) and from posterior perforators of the middle cerebral artery (MCA). The inferior fistula receives blood from an arterioarterial subarachnoid maze formed by anastomoses between the collicular arteries (branches of the superior cerebellar arteries [Sup C A], the PCA, and the posteromedial choroidal arteries). Posterior thalamoperforating arteries also may be involved. The aneurysmal sac is usually drained by dural sinuses, either the normal straight sinus (Str S) or a persistent fetal falcine sinus (Falc S), or both, as shown here. Bas A, basilar artery; Car A, carotid artery; PCom, posterior communicating artery; Torc, torcular. (From Raybaud CA, Strother CM, Hald JK: Aneurysms of the vein of Galen: Embryonic considerations and anatomical features relating to the pathogenesis of the malformation, Neuroradiology 31:109–128, 1989.)
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G
Figure 23-15 Ultrasound scan of an arteriovenous malformation in an infant with cardiac failure. This coronal ultrasound scan shows large, circular, midline, aneurysmal vein of Galen (G); the areas of echolucency in the left hemisphere represent regions of necrosis (arrowheads). (Courtesy of Dr. Gary D. Shackelford.)
neonatal period and whose congestive heart failure is stabilized medically is dominated by the development of neurological disturbances and progressive hydrocephalus. The neurological disturbances include delayed development and development of major neurological deficits, presumably secondary to the intracranial ischemic and hemorrhagic phenomena (see later discussion). Diagnosis The diagnosis of the vein of Galen malformation should be suspected in any newborn with unexplained congestive heart failure, especially high-output heart failure, or with unexplained intracranial hemorrhage or hydrocephalus. The initial diagnostic
A
Figure 23-16 Computed tomography scan of an arteriovenous malformation from an infant with cardiac failure. The scan shows the midline aneurysmal vein of Galen and large areas of necrosis and calcification in both hemispheres, probably secondary to a ‘‘steal’’ phenomenon.
evaluation should be performed using cranial ultrasonography.76,79,85-87,98,103-110 The aneurysmally dilated vein appears as a large, echolucent region in the region of the vein of Galen (Fig. 23-15). The addition of Doppler study of flow velocity in the arterial feeders and in the vein further defines the hemodynamics and the anatomy of the lesion.108,110 CT is useful for assessment of parenchymal ischemic injury or intracranial hemorrhage (Figs. 23-16 and 23-17). In infants with intraventricular hemorrhage, a clue that a vein of Galen malformation is the source of
B
Figure 23-17 Computed tomography scans of intracranial hemorrhage secondary to an arteriovenous malformation, involving the vein of Galen. These scans are from a full-term infant with abrupt onset of seizures and opisthotonic posturing on the fourth day of life. A, Note the large amount of blood distending the posterior third ventricle. B, A relatively small amount of blood has extended into the lateral ventricles and is visible over the head of the caudate nuclei and in the occipital horns. (From Schum TR, Meyer GA, Grausz JP, Glaspey JC: Neonatal intracranial ventricular hemorrhage due to an intracranial arteriovenous malformation: A case report, Pediatrics 64:242–244, 1979.)
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Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Figure 23-18 Vein of Galen malformation: magnetic resonance imaging (MRI) scan. A, Coronal and, B, sagittal MRI scans of a newborn before, and, D, sagittal image 2 months after, embolization show a marked decrease in the size of the aneurysmal dilation (G). In A, feeding arteries are demonstrated in the coronal plane. C, Anteroposterior view of a left vertebral angiogram showing microcoils within feeding arteries from the posterior cerebral arteries (8 days of age). (From Yamashita Y, Abe T, Ohara N, Maruoka T, et al: Successful treatment of neonatal aneurysmal dilation of the vein of Galen: The role of prenatal diagnosis and trans-arterial embolization, Neuroradiology 34:457–459, 1992.)
the hemorrhage is a dilated third ventricle filled with blood in the absence of a large amount of blood in the lateral ventricles.97 The major current value of CT is to identify the vascular details with spiral CT angiography.79 MRI is especially effective not only in the evaluation of the brain parenchyma and the aneurysmally dilated vein but also in the demonstration of major arterial feeding vessels (Fig. 23-18). MR angiography is also an effective noninvasive means of delineating the vascular supply and drainage of the malformation. Angiography is used to define the anatomical details of the vein of Galen malformation. Delineation of the crucial arterial feeders and of the size and location of the aneurysmally dilated vein is crucial for determination of intervention (see later discussion).
Prognosis The natural history of the vein of Galen malformation with clinical presentation in the newborn period is apparent from the review of Hoffman and co-workers74 in 1982 of 16 personal cases and 45 reported by others. Thus, no difference in outcome between those treated and not treated was reported. Overall, of the 61 cases, 51 (84%) died, usually in early infancy, 8 (13%) survived with neurological impairment, and only 2 (3%) were normal on follow-up. Survival with neurological impairment principally reflected the ischemic and hemorrhagic phenomena that complicate the lesion, and some of these pathological features were shown to occur in utero. The development and application of endovascular therapies for this lesion in the late 1980s and 1990s
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Outcome of Neonatal Vein of Galen Malformation after Endovascular Treatment*
Outcome Death Developmental evaluation No permanent disability Permanent disability Neurological examination No/mild abnormality Severe abnormality Epilepsy
Percentage of Total 19% 43%{ 57% 43% 57% 33%
*n = 21. The median length of follow-up was 4.5 years. { Value was 38% for the 16 infants who had congestive heart failure and 60% for the 5 infants without congestive heart failure. Data from Fullerton HJ, Aminoff AR, Ferrierio DM, Gupta N, et al: Neurodevelopmental outcome after endovascular treatment of vein of Galen malformations, Neurology 61:1386–1390, 2003.
brought an increasing improvement in outcome.75,76,99,101 The outcome in the largest neonatal series (n = 21) with the longest duration of follow-up (4.5 years) after neonatal endovascular therapy is shown in Table 23-9. Thus, 80% of the infants survived, and nearly one half had a normal or nearly normal outcome.91 Similarly promising results have been reported by other investigators.79,90,92 Management Management of a vein of Galen malformation large enough to manifest clinically in the neonatal period is a major therapeutic challenge. Medical management requires vigorous therapy of cardiac failure. Aggressive use of beta-adrenergic agents (dobutamine, dopamine) may worsen cardiac output. Best results appear to occur with use of low-dose dopamine in combination with a systemic vasodilator (e.g., a phosphodiesterase inhibitor).92 Concerning the approach to the vein of Galen malformation, in many centers no intervention is chosen if the infant already exhibits evidence of severe cerebral injury.76 Direct neurosurgical attack is made extraordinarily difficult by the large size and complicated nature of the lesions and by the vulnerability of the infant in congestive heart failure and with a compromised myocardium (see earlier discussion). Indeed, the possibility of hypotension in association with surgery greatly increases the risk of fatal myocardial ischemia because of the already low diastolic flow and thereby impaired coronary circulation resulting from the malformation. Currently, the treatment of choice is an endovascular approach (see next). The principal approaches to treatment in the newborn involve attempts to eliminate the high flow through the vascular lesion, either by arterial embolization, usually with a liquid adhesive (glue-forming) agent (e.g., bucrylate or related polymerizing compound) or microcoils, or by venous embolization, usually by retrograde catheterization through femoral or jugular access or by a transtorcular approach with placement of
microcoils.* Technological advances may further improve treatment and outcome. Currently, the most common initial therapeutic intervention is the transarterial femoral approach with delivery of a liquid adhesive agent.79 Multiple procedures are usually necessary. In the large series shown in Table 23-9, three procedures per patient, on average, were required.91 ARACHNOID CYSTS Arachnoid cysts, although fundamentally developmental anomalies, are best discussed briefly in this context because their clinical presentation in the newborn most closely mimics a space-occupying lesion. These congenital or primary arachnoid cysts should be distinguished from arachnoidal cystic collections secondary to hemorrhage or infection. The clinical distinction is usually straightforward. Recognition of arachnoid cysts in the neonatal period has increased markedly in recent years because of the widespread use of fetal cranial ultrasonography and neonatal imaging, especially MRI. Pathology Arachnoid cysts are derived from the developing arachnoid and appear to arise by splitting or duplication of the arachnoid.115 The fine structure of the lining is similar to that of normal arachnoidal cells, which secrete cerebrospinal fluid and cause the expansion often observed in vivo. In some cases, a one-way ball-valve mechanism between the cyst and the subarachnoid space may contribute to the expansion.116 The principal loci of arachnoid cysts include regions particularly rich in arachnoid, often cisterns. The reported distribution of loci differs according to the age of the infant or child, the means of identification, and the clinical features, if any. Approximately 50% of these cysts are located in the region of the sylvian fissure and are often associated with underdevelopment of the anterior superior surface of the temporal lobe.59,115-118 Whether the temporal abnormality is an associated developmental anomaly or occurs secondary to compression is unknown. Other common sites include the following: the suprasellar region, often associated with displacement of the pituitary stalk, hypothalamus, and optic chiasm; the interhemispheric fissure, often with agenesis of the corpus callosum; the supracollicular area, with tectal compression; the cerebellopontine angle, with congenital peripheral nerve paralysis and other signs; and supracerebellar and infracerebellar areas, sometimes confused with Dandy-Walker complex (see Chapter 1).59,115-117,119,120 Clinical Features Arachnoid cysts identified in the fetal and neonatal period most often cause no clinical abnormalities. Clinical features, when present, usually consist of
*See references 73,75-77,79,83,84,87,89-92,99,101,111-114.
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A
AC
B Figure 23-19 Arachnoidal cyst, magnetic resonance imaging (MRI) scans. A, Coronal scan performed in utero at 33 weeks of gestation shows a large arachnoidal cyst in the interhemispheric fissure. B, On this postnatal sagittal MRI, the lesion was shown to be continuous with a multilobulated cyst (AC) in the suprasellar region.
various combinations of macrocrania, hydrocephalus, signs of increased intracranial pressure, or, least commonly, neurological abnormalities related to the locus of the cyst (see earlier). Slight to moderate hemiparesis related to the presence of a cyst in the region of the sylvian fissure or elsewhere in the middle cranial fossa is the most common of these abnormalities.116,117
The diagnosis is often suspected by screening intrauterine or neonatal ultrasonography. The finding of a large, fluid-filled space may mimic an epidermoid lesion or a cystic tumor (e.g., cystic astrocytoma) (Fig. 23-19). The prognosis of arachnoid cysts is largely unknown, because the natural history is obscure. Lesions may
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regress antenatally.116 Many other cysts remain stationary and do not cause neurological symptoms. Nevertheless, some arachnoid cysts clearly increase in size and lead to macrocephaly or hydrocephalus, or both, or to parenchymal signs, progressive hemiparesis, intractable epilepsy, hypothalamic syndromes, or posterior fossa disorders, according to the site of the lesion. Management Management of arachnoid cysts is controversial because of uncertainties about natural history. However, in the neonatal period, the clearest indications for intervention are signs of increased intracranial pressure (vomiting, bulging fontanelle, rapid head growth) and prominent or progressive parenchymal signs. Currently, the two leading neurosurgical interventions are craniotomy, usually with fenestration of the cyst to produce communication with the subarachnoid space, and cyst-peritoneal shunt, especially with a programmable valve.116,117 These approaches have eliminated signs of increased intracranial pressure, have restored normal head growth, and have often reversed or at least halted the progression of parenchymal signs. REFERENCES 1. Wakai S, Arai T, Nagai M: Congenital brain tumors, Surg Neurol 21:597609, 1984. 2. Radkowski MA, Naidich TP, Tomita T, Byrd SE, et al: Neonatal brain tumors: CT and MR findings, J Comput Assist Tomogr 12:10-20, 1988. 3. Fort DW, Rushing EJ: Congenital central nervous system tumors, J Child Neurol 12:157-164, 1997. 4. Rickert CH, Probst-Cousin S, Gullotta F: Primary intracranial neoplasms of infancy and early childhood, Childs Nerv Syst 13:507-513, 1997. 5. Rickert CH: Neuropathology and prognosis of foetal brain tumours, Acta Neuropathol 98:567-576, 1999. 6. Isaacs H: II. Perinatal brain tumors: A review of 250 cases, Pediatr Neurol 27:333-342, 2002. 7. Isaacs H: I. Perinatal brain tumors: A review of 250 cases, Pediatr Neurol 27:249-261, 2002. 8. Erman T, Gocer IA, Erdogan S, Gunes Y, et al: Congenital intracranial immature teratoma of the lateral ventricle: A case report and review of the literature, Neurol Res 27:53-56, 2005. 9. Isaacs H Jr: Perinatal (fetal and neonatal) germ cell tumors, J Pediatr Surg 39:1003-1013, 2004. 10. Bergsagel DJ, Finegold MJ, Butel JS, Kupsky WJ, et al: DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood, N Engl J Med 326:988-993, 1992. 11. Janisch W, Haas JF, Schreiber D, Gerlach H: Primary central nervous system tumors in stillborns and infants, J Neurooncol 2:113-116, 1984. 12. Jellinger K, Sunder-Plassman M: Connatal intracranial tumors, Neuropadiatrie 4:46-63, 1973. 13. Lipman SP, Pretorius DH, Rumack CM, Manco-Johnson ML: Fetal intracranial teratoma: US diagnosis of three cases and a review of the literature, Radiology 157:491-494, 1985. 14. Haddad SF, Menezes AH, Bell WE, Godersky JC, et al: Brain tumors occurring before 1 year of age: A retrospective review of 22 cases in an 11-year period (1977–1987), Neurosurgery 29:8-13, 1991. 15. Kumar R, Tekkok IH, Jones RA: Intracranial tumours in the first 18 months of life, Childs Nerv Syst 6:371-374, 1990. 16. DiRocco C, Iannelli A, Ceddia A: Intracranial tumors of the first year of life, Childs Nerv Syst 7:150-153, 1991. 17. Galassi E, Godano U, Cavallo M, Donati R, et al: Intracranial tumors during the 1st year of life, Childs Nerv Syst 5:288-298, 1989. 18. Arnstein LH, Boldrey E, Naffziger HC: A case report and survey of brain tumors during the neonatal period, J Neurosurg 8:315-319, 1951. 19. Takaku A, Kodama N, Ohara H, Hori S: Brain tumor in newborn babies, Childs Brain 4:365-375, 1978. 20. Raskind R, Beigel F: Brain tumors in early infancy: Probably congenital in origin, J Pediatr 65:727-732, 1964. 21. Sherer DM, Abramowicz JS, Eggers PC, Metlay LA, et al: Prenatal ultrasonographic diagnosis of intracranial teratoma and massive craniomegaly with associated high-output cardiac failure, Am J Obstet Gynecol 168:97-99, 1993.
22. Anderson DR, Falcone S, Bruce JH, Mejidas AA, et al: Radiologic-pathologic correlation. Congenital choroid plexus papillomas, AJNR Am J Neuroradiol 16:2072-2076, 1995. 23. DiRocco C, Iannelli A: Poor outcome of bilateral congenital choroid plexus papillomas with extreme hydrocephalus, Eur Neurol 37:33-37, 1997. 24. Costa JM, Ley L, Claramunt E, Lafuente J: Choroid plexus papillomas of the III ventricle in infants: Report of three cases, Childs Nerv Syst 13:244249, 1997. 25. Narita T, Kurotaki H, Hashimoto T, Ogawa Y: Congenital oligodendroglioma: A case report of a 34th-gestational week fetus with immunohistochemical study and review of the literature, Hum Pathol 28:1213-1217, 1997. 26. Rickert CH, Probst-Cousin S, Louwen F, Feldt B, et al: Congenital immature teratoma of the fetal brain, Childs Nerv Syst 13:556-559, 1997. 27. Chien YH, Tsao PN, Lee WT, Peng SF, et al: Congenital intracranial teratoma, Pediatr Neurol 22:72-74, 2000. 28. Mazouni C, Porcu-Buisson G, Girard N, Sakr R, et al: Intrauterine brain teratoma: A case report of imaging (US, MRI) with neuropathologic correlations, Prenat Diagn 23:104-107, 2003. 29. Chadduck WM, Boop FA, Blankenship JB, Husain M: Meningioma and sagittal craniosynostosis in an infant: Case report, Neurosurgery 30:441442, 1992. 30. Hurst RW, McIlhenny J, Park TS, Thomas WO: Neonatal craniopharyngioma: CT and ultrasonographic features, J Comput Assist Tomogr 12:858-861, 1988. 31. Richmond BK, Schmidt JH: Congenital cystic supratentorial hemangioblastoma: Case report, J Neurosurg 82:113-115, 1995. 32. Hundt C, Auberger K, Munch G, Willemsen UF, et al: Brain hemangiomas of infancy, J Neuroimaging 7:81-85, 1997. 33. Winters JL, Wilson D, Davis DG: Congenital glioblastoma multiforme: A report of three cases and a review of the literature, J Neurol Sci 188:13-19, 2001. 34. Trehan G, Bruge H, Vinchon M, Khalil C, et al: MR imaging in the diagnosis of desmoplastic infantile tumor: Retrospective study of six cases, AJNR Am J Neuroradiol 25:1028-1033, 2004. 35. Oexle K, Dammann O, Bechmann B, Vortmeyer AO, et al: Intracranial chordoma in a neonate, Eur J Pediatr 151:336-338, 1992. 36. Alfonso I, Lopez PF, Cullen RF, Martin-Jimenez R, et al: Spinal cord involvement in encephalocranio-cutaneous lipomatosis, Pediatr Neurol 2:380-384, 1986. 37. Barth PG, Stam FC, Hack W, Delemarre-van de Waal HA: Gliomatosis cerebri in a newborn, Neuropediatrics 19:197-200, 1988. 38. Painter MJ, Pang D, Ahdab-Barmada M, Bergman I: Connatal brain tumors in patients with tuberous sclerosis, Neurosurgery 14:570-573, 1984. 39. Hahn JS, Bejar R, Gladson CL: Neonatal subependymal giant cell astrocytoma associated with tuberous sclerosis: MRI, CT, and ultrasound correlation, Neurology 41:124-128, 1991. 40. Boechat MI, Kangarloo H, Diament MJ, Krauthamer R: Lipoma of the corpus callosum: Sonographic appearance, J Clin Ultrasound 11:447-448, 1983. 41. Wakai S, Nakamura K, Arai T, Nagai M: Extracerebral neural tissue mass in the middle cranial fossa extending into the oropharynx in a neonate, J Neurosurg 59:692-696, 1983. 42. Oikawa S, Sakamoto K, Kobayashi N: A neonatal huge subependymal giant cell astrocytoma: Case report, Neurosurgery 35:748-750, 1994. 43. Saxonhouse MA, Yachnis AT, Burchfield DJ, Quisling R, et al: Neonatal hypothalamic hamartoma: A differentiating nonlethal hamartoblastoma, J Neurosurg 103:277-281, 2005. 44. Thompson WD Jr, Kosnik EJ: Spontaneous regression of a diffuse brainstem lesion in the neonate: Report of two cases and review of the literature, J Neurosurg 102:65-71, 2005. 44a. Brat DJ, Shehata BM, Castellano-Sanchez AA, Hawkins C, et al: Congenital glioblastoma: a clinicopathologic and genetic analysis, Brain Pathol 17:276-281, 2007. 45. Jooma R, Kendall BE, Hayward RD: Intracranial tumors in neonates: A report of seventeen cases, Surg Neurol 21:165-170, 1984. 46. Roosen N, Deckert M, Nicola N, Wechsler W, et al: Congenital anaplastic astrocytoma with favorable prognosis, J Neurosurg 69:604-609, 1988. 47. Rothman SM, Nelson JS, DeVivo DC, Coxe WS: Congenital astrocytoma presenting with intracerebral hematoma, J Neurosurg 51:237-239, 1979. 48. Rutledge SL, Snead OC, Morawetz R, Chandra-Sekar B: Brain tumors presenting as a seizure disorder in infants, J Child Neurol 2:214-219, 1987. 49. Ellams ID, Neuhauser G, Agnoli AL: Congenital intracranial neoplasms, Childs Nerv Syst 2:165-168, 1986. 50. Tomita T, McLone DG, Flannery AM: Choroid plexus papillomas of neonates, infants and children, Pediatr Neurosci 14:23-30, 1988. 51. Lippa C, Abroms JF, Davidson R, DeGiorlami U: Congenital choroid plexus papilloma of the fourth ventricle, J Child Neurol 4:127-130, 1989. 52. Asai A, Hoffman HJ, Hendrick EB, Humphreys RP, et al: Primary intracranial neoplasms in the first year of life, Childs Nerv Syst 5:230-233, 1989. 53. Venes JL: A proposal for management of congenital brain tumors. In Marlin AE, editor: Concepts in Pediatric Neurosurgery, Basel: 1985, Karger. 54. Shafrir Y, Kaufman BA: Quadriplegia after chiropractic manipulation in an infant with congenital torticollis caused by a spinal cord astrocytoma, J Pediatr 120:266-269, 1992. 55. Pascual-Castroviejo I: Congenital tumors or malformations. In PascualCastroviejo I, editor: Spinal Tumors in Children and Adolescents, New York: 1990, Raven Press.
Chapter 23 56. Kaufman BA, Park TS: Congenital spinal cord astrocytomas, Childs Nerv Syst 8:389-393, 1992. 57. Sandbank U: Congenital astrocytoma, J Pathol Bacteriol 84:226-228, 1962. 58. Harmon BH, Yap Ma: One-month-old infant with increasing head size. In Brogdon BG, editor: Cases from the Wards. Philadelphia: 1990, JB Lippincott. 59. Barkovich AJ: Pediatric Neuroimaging, 4th ed. Philadelphia: 2005, Lippincott Williams & Wilkins. 60. Cohen ME, Duffner PK: Brain tumors in children less than 2 years of age. In Familusi J, Fukuyama Y, editors: Brain Tumors in Children, New York: 1984, Raven Press. 61. Johnson DL: Management of choroid plexus tumors in children, Pediatr Neurosci 15:195-206, 1989. 62. Ventureyra EC, Herder S: Neonatal intracranial teratoma, J Neurosurg 59:879-883, 1983. 63. Rivera-Luna R, Medina-Sanson A, Leal-Leal C, Pantoja-Guillen F, et al: Brain tumors in children under 1 year of age: Emphasis on the relationship of prognostic factors, Childs Nerv Syst 19:311-314, 2003. 64. Geyer JR, Sposto R, Jennings M, Boyett JM, et al: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: A report from the Children’s Cancer Group, J Clin Oncol 23:7621-7631, 2005. 65. Kalifa C, Grill J: The therapy of infantile malignant brain tumors: Current status, J Neurooncol 75:279-285, 2005. 66. Ellenberg L, McComb JG, Siegel SE, Stowe S: Factors affecting intellectual outcome in pediatric brain tumor patients, Neurosurgery 21:638-644, 1987. 67. Spunberg JJ, Chang CH, Goldman M, Auricchio E, et al: Quality of longterm survival following irradiation for intracranial tumors in children under the age of two, Int J Radiat Oncol Biol Phys 7:727-736, 1981. 68. Meadows AT, Massari DJ, Fergusson J, Gordon J, et al: Declines in I.Q. scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation, Lancet 2:1015-1018, 1981. 69. Waber DP, Urion DK, Tarbell NJ, Niemeyer C, et al: Late effects of central nervous system treatment of childhood acute lymphoblastic leukemia are sex-dependent, Dev Med Child Neurol 32:238-248, 1990. 70. Waber DP, Gioia G, Paccia J, Sherman B, et al: Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia (ALL), J Pediatr Psychol 15:105-122, 1990. 71. Loeffler JS, Rossitch E, Siddon R, Moore MR, et al: Role of stereotactic radiosurgery with a linear accelerator in treatment of intracranial arteriovenous malformations and tumors in children, Pediatrics 85:774-782, 1990. 72. Pollack IF: Brain tumors in children, N Engl J Med 331:1500-1507, 1994. 73. Wisoff JH, Berenstein A, Choi IS, Friedman D, et al: Management of vein of Galen malformations. In Marlin AE, editor: Concepts in Pediatric Neurosurgery, Basel: 1990, Karger. 74. Hoffman HJ, Chuang S, Hendrick B, Humphreys RP: Aneurysms of the vein of Galen: Experience at the Hospital for Sick Children, J Neurosurg 57:316-322, 1982. 75. Lylyk P, Vinuela F, Dion JE, Duckwiler G, et al: Therapeutic alternatives for vein of Galen vascular malformations, J Neurosurg 78:438-445, 1993. 76. Lasjaunias P: Vascular Diseases in Neonates, Infants, and Children, Berlin: 1997, Springer-Verlag. 77. Johnston IH, Whittle IR, Besser M, Morgan MK: Vein of Galen malformation: Diagnosis and management, Neurosurgery 20:747-758, 1987. 78. Raybaud CA, Strother CM, Hald JK: Aneurysms of the vein of Galen: Embryonic considerations and anatomical features relating to the pathogenesis of the malformation, Neuroradiology 31:109-128, 1989. 79. Gailloud P, O’Riordan DP, Burger I, Levrier O, et al: Diagnosis and management of vein of Galen aneurysmal malformations, J Perinatol 25:542-551, 2005. 80. Lasjaunias P, Garcia-Monaco R, Rodesch G, Terbrugge K: Deep venous drainage in great cerebral vein (vein of Galen) absence and malformations, Neuroradiology 33:234-238, 1991. 81. Takashima S, Becker LE: Neuropathology of cerebral arteriovenous malformations in children, J Neurol Neurosurg Psychiatry 43:380-385, 1980. 82. Norman MG, Becker LE: Cerebral damage in neonates resulting from arteriovenous malformations in the vein of Galen, J Neurol Neurosurg Psychiatry 37:252-258, 1974. 83. Yamashita Y, Abe T, Ohara N, Maruoka T, et al: Successful treatment of neonatal aneurysmal dilation of the vein of Galen: The role of prenatal diagnosis and trans-arterial embolization, Neuroradiology 34:457-459, 1992. 84. Lasjaunias P, Garcia-Monaco R, Rodesch G, Ter Brugge K, et al: Vein of Galen malformation: Endovascular management of 43 cases, Childs Nerv Syst 7:360367, 1991. 85. Yamashita Y, Nakamura Y, Okudera T, Nishiyori A, et al: Neuroradiological and pathological studies on neonatal aneurysmal dilation of the vein of Galen, J Child Neurol 5:45-48, 1990. 86. Baenziger O, Martin E, Willi U, Fanconi S, et al: Prenatal brain atrophy due to a giant vein of Galen malformation, Neuroradiology 35:105-106, 1993. 87. Horowitz BM, Jungreis CA, Quisling RG, Pollack I: Vein of Galen aneurysms: A review and current perspective, AJNR Am J Neuroradiol 15:1486-1496, 1994. 88. de Koning TJ, Meijboom EJ, de Vries LS, Gooskens R, et al: Arteriovenous malformation of the vein of Galen in three neonates: Emphasis on associated early ischaemic brain damage, Eur J Pediatr 156:228-229, 1997. 89. Nakano S, Agid R, Klurfan P, dos Santos Souza MP, et al: Limitations and technical considerations of endovascular treatment in neonates with highflow arteriovenous shunts presenting with congestive heart failure: Report of two cases, Childs Nerv Syst 22:13-17, 2006.
Brain Tumors and Vein of Galen Malformations
1005
90. Wong FY, Mitchell PJ, Tress BM, Dargaville PA, etal: Hemodynamic disturbances associated with endovascular embolization in newborn infants with vein of Galen malformation, J Perinatol 26:13-17, 2006. 91. Fullerton HJ, Aminoff AR, Ferrierio DM, Gupta N, et al: Neurodevelopmental outcome after endovascular treatment of vein of Galen malformations, Neurology 61:1386-1390, 2003. 92. Frawley GP, Dargaville PA, Mitchell PJ, Tress BM, et al: Clinical course and medical management of neonates with severe cardiac failure related to vein of Galen malformation, Arch Dis Child Fetal Neonatal Ed 87:F144F149, 2002. 93. Hirano A, Solomon S: Arteriovenous aneurysm of the vein of Galen, Arch Neurol 3:589-593, 1960. 94. Gomez MR, Shitten CF, Nolke A: Aneurysmal malformation of the great vein of Galen causing heart failure in early infancy: Report of five cases, Pediatrics 31:400-411, 1963. 95. Watson DG, Smith RR, Brann AW: Arteriovenous malformation of the vein of Galen, Am J Dis Child 130:520-525, 1976. 96. Iannucci AM, Buonanno F, Rizzuto N: Arteriovenous aneurysm of the vein of Galen, J Neurol Sci 40:29-37, 1979. 97. Schum TR, Meyer GA, Grausz JP, Glaspey JC: Neonatal intracranial ventricular hemorrhage due to an intracranial arteriovenous malformation: A case report, Pediatrics 64:242-244, 1979. 98. O’Donnabhain D, Duff DF: Aneurysms of the vein of Galen, Arch Dis Child 64:1612-1617, 1989. 99. Rodesch G, Hui F, Alvarez H, Tanaka A, et al: Prognosis of antenatally diagnosed vein of Galen aneurysmal malformations, Childs Nerv Syst 10:79-83, 1994. 100. Lasjaunias PL, Alvarez H, Rodesch G, Garcia-Monaco R, et al: Aneurysmal malformations of the vein of Galen, Interv Neuroradiol 2:15-26, 1996. 101. Friedman DM, Verma R, Madrid M, Wisoff JH, et al: Recent improvement in outcome using transcatheter embolization techniques for neonatal aneurysmal malformations of the vein of Galen, Pediatrics 91:583586, 1993. 102. Meyers PM, Halbach VV, Phatouros CP, Dowd CF, et al: Hemorrhagic complications in vein of Galen malformations, Ann Neurol 47:748-755, 2000. 103. Mullaart RA, Daniels O, Hopman JC: Ultrasound detection of congenital arteriovenous aneurysm of the great cerebral vein of Galen, Eur J Pediatr 139:195, 1982. 104. Schwechheimer K, Kuhl G: Arteriovenous angioma of the vein of Galen causing cardiac failure in the neonate, Neuropediatrics 14:184, 1983. 105. Cubberley DA, Jaffe RB, Nixon GW: Sonographic demonstration of galenic arteriovenous malformations in the neonate, AJNR Am J Neuroradiol 3:435-439, 1982. 106. Langer R, Kaufmann HJ: Arteriovenous malformation of the great cerebral vein of Galen in a newborn, Eur J Pediatr 146:87-89, 1987. 107. Abbitt PL, Hurst RW, Ferguson RDG, McIlhenny J, et al: The role of ultrasound in the management of vein of Galen aneurysms in infancy, Neuroradiology 32:86-89, 1990. 108. Deeg KH, Scharf J: Colour Doppler imaging of arteriovenous malformation of the vein of Galen in a newborn, Neuroradiology 32:60-63, 1990. 109. Vaksmann G, Decoulx E, Mauran P, Jardin M, et al: Evaluation of vein of Galen arteriovenous malformations in newborns by two-dimensional ultrasound, pulsed and colour Doppler method, Eur J Pediatr 148:510512, 1989. 110. Tessler FN, Dion J, Vinuela F, Perrella RR, et al: Cranial arteriovenous malformations in neonates: Color Doppler imaging with angiographic correlation, AJR Am J Roentgenol 153:1027-1030, 1989. 111. McCord FB, Shields MD, McNeil A, Halliday HL, et al: Cerebral arteriovenous malformation in a neonate: Treatment by embolisation, Arch Dis Child 62:1273-1275, 1987. 112. King WA, Wackym PA, Vinuela F, Peacock W: Management of vein of Galen aneurysms: Combined surgical and endovascular approach, Childs Nerv Syst 5:208-211, 1989. 113. Miller VS, Roach ES: Embolization and radiosurgical treatment of cerebral arteriovenous malformations, Int Pediatr 7:173-180, 1992. 114. Swanstrom S, Flodmark O, Lasjaunias P: Conditions for treatment of cerebral arteriovenous malformation associated with ectasia of the vein of Galen in the newborn, Acta Paediatr 83:255-257, 1994. 115. Harding BN, Surtees R: Metabolic and neurodegenerative diseases of childhood. In Graham DI, Lantos PL, editors: Greenfield’s Neuropathology, 7, London: 2002, Arnold Publishers. 116. Gosalakkal JA: Intracranial arachnoid cysts in children: A review of pathogenesis, clinical features, and management, Pediatr Neurol 26:9398, 2002. 117. Germano A, Caruso G, Caffo M, Baldari S, et al: The treatment of large supratentorial arachnoid cysts in infants with cyst-peritoneal shunting and Hakim programmable valve, Childs Nerv Syst 19:166-173, 2003. 118. Arriola G, Castro P, Verdu A: Familial arachnoid cysts, Pediatr Neurol 33:146-148, 2005. 119. Balsubramaniam C, Laurent J, Rouah E, Armstrong D, et al: Congenital arachnoid cysts in children, Pediatr Neurosci 15:223-228, 1989. 120. Erman T, Demirhindi H, Gocer AI, Akgul E, et al: Congenital peripheral facial palsy associated with cerebellopontine angle arachnoid cyst, Pediatr Neurosurg 40:297-300, 2004.
Chapter 24 Teratogenic Effects of Drugs and Passive Addiction Drugs may exert a major impact on the developing central nervous system (CNS) in a variety of direct and indirect ways. The two most important mechanisms are teratogenic effects and the development of passive addiction. In this chapter, I consider, under the term teratogenic effect, any disturbance of CNS development. In many instances, the precise nature of the disturbance remains to be defined. Passive addiction refers to the state of physical dependence that develops in the fetus exposed to a maternal source of drug. The hallmark of this dependence is the occurrence of a withdrawal syndrome after birth and the consequent cessation of the maternal supply of the drug. MAJOR DRUGS IMPLICATED IN TERATOGENIC EFFECTS ON THE CENTRAL NERVOUS SYSTEM AND DEVELOPMENT OF PASSIVE ADDICTION Numerous neuroactive drugs can be implicated in the genesis of neural teratogenic effects, in the development of passive addiction, or in both processes (Table 24-1). Teratogenic effects are observed most clearly after maternal ingestion of several anticonvulsants, alcohol, the vitamin A analogue, isotretinoin, and cocaine. (Although disturbances of brain development or later cognitive function, or both, have been suggested to follow maternal exposure to tobacco, tobacco smoke, and polychlorinated biphenyls, more data are needed to establish the direct neurological teratogenicity of these agents.1-4) Passive addiction is observed particularly prominently as a result of maternal ingestion of certain narcotic-analgesics, especially heroin and methadone, but also of selective serotonin reuptake inhibitors (SSRIs) and certain sedative-hypnotics, especially barbiturates (see Table 24-1). Less commonly recognized causes of passive addiction are other sedative antianxiety agents (e.g., diazepam [Valium], chlordiazepoxide [Librium], hydroxyzine [Atarax], and ethchlorvynol [Placidyl]), tricyclic antidepressants, analgesics (e.g., propoxyphene [Darvon], pentazocine [Talwin], and codeine), and combinations of drugs (e.g., ‘‘T’s and blues,’’ which are pentazocine [T for Talwin] and tripelennamine). The most commonly used drug of all, alcohol, also can result in passive addiction.
DRUGS WITH TERATOGENIC EFFECTS Anticonvulsant Drugs Anticonvulsant drugs administered to the mother may exert three major adverse effects on the fetal and neonatal CNS (Table 24-2): (1) a teratogenic effect, manifested by a constellation of specific defects (dependent, in part, on the specific class of anticonvulsant drug); (2) a coagulation disturbance, manifested by neonatal hemorrhage, including intracranial hemorrhage; and (3) passive addiction, manifested by a neonatal withdrawal syndrome when the supply of drug (i.e., barbiturate) is eliminated by the process of birth. The first of these effects is the subject of this section, and the last is the subject of a later section. However, before reviewing the teratogenic syndromes associated with certain anticonvulsant drugs, I briefly review the second of these three adverse effects (i.e., the coagulation disturbance and its role in the genesis of neonatal hemorrhage). Neonatal Hemorrhage Neonatal hemorrhage is a recognized complication of the maternal administration of anticonvulsant drugs.5-25 The drugs incriminated are hepatic enzyme inducers and have included hydantoins, barbiturates, primidone (which is metabolized to phenobarbital in vivo) and carbamazepine. In a series of 111 infants born to epileptic women who were treated with phenytoin or phenobarbital, 8 infants exhibited ‘‘severe’’ bleeding.19 In this syndrome, the infant develops hemorrhage shortly after birth. This early onset is unlike hemorrhagic disease of the newborn secondary to vitamin K deficiency. Sites of hemorrhage are, in order of decreasing frequency, skin, liver, gastrointestinal tract, intracranial sites, and thorax. Intracranial hemorrhage has been reported in 20% to 25% of patients with hemorrhage. The course may be fulminating, and approximately 40% of reported infants have died. Clotting studies demonstrate diminution of the vitamin K–dependent clotting factors (factors II, VII, IX, and X), with prolongation of either the prothrombin time or partial thromboplastin time, or both. Vitamin K levels in cord blood are depressed, as evidenced by the presence of PIVKA-II (a protein, induced by vitamin K absence), an incompletely carboxylated, functionally defective form of factor II (prothrombin).26,27 Indeed, in a 1009
1010 TABLE 24-1
UNIT X
DRUGS AND THE DEVELOPING NERVOUS SYSTEM
Major Drugs Implicated in Teratogenic Effects on the Central Nervous System and Passive Addiction
Teratogenic Effects Anticonvulsant drugs Hydantoins, barbiturates, primidone, carbamazepine, trimethadione, paramethadione Valproate Alcohol Isotretinoin Cocaine Passive Addiction Heroin-methadone Selective serotonin reuptake inhibitors Barbiturates Alcohol Diazepam Chlordiazepoxide Tricyclic antidepressants Ethchlorvynol Propoxyphene Pentazocine ‘‘T’s and blues’’ Codeine
O CH3
CH2 NH
NH
N O H Phenobarbital
O
CH2 NH
CH3
N H Primidone
CH2
Teratogenic effect, with constellation of specific defects Coagulation disturbance, with neonatal (intracranial) hemorrhage Passive addiction, with neonatal withdrawal syndrome (barbiturates)
CH2
OH
Valproic acid
CH3
O
CH2 CH3 O
N O
Trimethadione
Major Adverse Effects of Anticonvulsant Drugs, Administered during Pregnancy, on the Fetal and Neonatal Central Nervous System
C
H2
CH3 CH3
O
CH2 CH
CH3 O
CH2
O
TABLE 24-2
O
O CH3
CH3
study of 24 infants born to mothers who were receiving anticonvulsant therapy during pregnancy, 13 infants (54%) had detectable levels of PIVKA-II, and when the 4 infants exposed to valproate (none of whom had detectable levels of PIVKA-II) were excluded, the incidence was 65%. Moreover, vitamin K levels also were depressed in these infants.26,27 The findings suggested increased degradation of vitamin K with impaired action of vitamin K on hepatic production of prothrombin. The latter results because of insufficient carboxylation of the glutamic acid residues of prothrombin, a post-translational event that requires vitamin K. The pathogenetic mechanism by which the anticonvulsants lead to vitamin K deficiency may relate primarily to increased degradation of vitamin K by fetal hepatic microsomal mixed-function oxidase enzymes, known to be inducible by phenytoin, phenobarbital, primidone, and carbamazepine.26,27 The similarity in structure of these so-called enzyme-inducible anticonvulsant agents is shown in Figure 24-1. Nevertheless, this disorder appears to have become rare.28-30 Three reports (total numbers of patients, 105, 204, and 662) showed no increased incidence of
N H Phenytoin
O
N O H Ethosuximide
Figure 24-1 Chemical structures of important anticonvulsant drugs. Note the structural similarity of phenobarbital, phenytoin, and primidone; each is composed of a basic five- or six-membered ring and a side chain substitution containing phenol groups. Carbamazepine, not shown in the figure, shares structural similarities. Trimethadione and ethosuximide differ from these drugs by virtue of the aliphatic side chain substitutions. Valproic acid differs markedly from the other anticonvulsant drugs and is essentially a short-chain fatty acid.
hemorrhagic complications among women treated with various combinations of phenobarbital, phenytoin, primidone, and carbamazepine during pregnancy. The women were not treated with vitamin K during pregnancy (although the infants received vitamin K at birth). Whether the decline in incidence in this disorder relates to the diminishing use of polytherapy or the increasing use of alternative drugs or related factors is unclear. Previous management of newborn infants whose mothers had been taking anticonvulsant drugs during pregnancy was recommended as follows: (1) consideration of delivery by cesarean section if a difficult or traumatic delivery was anticipated, (2) administration of oral vitamin K (10 mg/day) to the mother before delivery during the last month of pregnancy (with parenteral vitamin K administered as soon as possible after the onset of labor if oral vitamin K was not given), (3) administration of vitamin K to the infant intravenously immediately after birth, (4) administration of fresh frozen plasma to the infant if clotting studies were distinctly abnormal, and (5) consideration of exchange transfusion if hemorrhage ensued.17,19,20,22,23
Chapter 24
Oral supplementation of vitamin K1 to the mother for 2 to 4 weeks before delivery prevented neonatal coagulation defects in one study,19 and it prevented the occurrence of detectable levels of PIVKA-II and depressed vitamin K levels in another.27 However, in view of the more recent studies that indicated no clearly enhanced risk of hemorrhage in infants whose mothers did not receive vitamin K during pregnancy, the need for prenatal vitamin K has been questioned.29,30 A more selective approach may be preferable (i.e., in pregnancies with a high likelihood of trauma or prematurity or a related risk factor for hemorrhage, prenatal vitamin K could be used). Teratogenic Potential of Anticonvulsant Drugs Current information indicates a teratogenic effect of anticonvulsant drugs on the developing fetus. However, establishing this fact, determining the quantitative aspects thereof, and defining the mechanisms involved have been exceptionally difficult for several reasons. First, the prevalence of epilepsy among pregnant women is relatively low. In a series from the Mayo Clinic of Rochester, Minnesota, that spanned 35 years, only approximately 4 of 1000 live births were to women with active epilepsy.31 Second, the incidence of congenital malformations is relatively low, and the reported incidence for a given malformation varies, depending on the length of the follow-up period and the vigor with which the malformation is sought. Third, the dose of the drug and the timing of its administration during pregnancy are probably critical and are not always known. Fourth, multiple anticonvulsant drugs (i.e., polytherapy) commonly are used in the treatment of the epileptic patient. Delineation of the teratogenic potential of each drug or combinations of drugs can be very difficult. Fifth, maternal seizures and their attendant metabolic consequences may play an alternative or additive deleterious role. Sixth, genetic factors relating to the cerebral disorder underlying the epilepsy may be considerable. Seventh, genetic factors in maternal or fetal disposition of anticonvulsant drugs or in important metabolic effects of the drugs may also be considerable. Other factors could be cited, although the aforementioned are probably the most important. Despite these problems, certain conclusions seem justified. A relationship between the maternal ingestion of anticonvulsant drugs and the occurrence of major congenital malformations was suggested initially by results of careful epidemiological studies in the 1970s and 1980s.16,22-24,32-53 Early work, based largely on retrospective methods but with patient numbers measured in the thousands, suggested a slightly greater than twofold higher incidence of major malformations in the children of epileptic women who were taking anticonvulsant drugs versus those not taking medication or in nonepileptic women. Subsequent studies in the 1990s supported the initial work.22,24,32,47-51 The earlier work also showed no increase in major malformations in the children of epileptic women who were not taking antiepileptic therapy or who were treated later than the first trimester.
1011
Teratogenic Effects of Drugs and Passive Addiction TABLE 24-3
Major Congenital Malformations as a Function of Maternal Ingestion of Anticonvulsant Drugs*
Drug Exposure
MCM Rate
Adjusted Odds Ratio (95% CI)
None Monotherapy Carbamazepine Valproate Lamotrigine Phenytoin
3.5% 3.7% 2.2% 6.2% 3.2% 3.7%
1.0 1.03 1.0 2.97 1.71 1.60
Polytherapy Valproate/ carbamazepine Valproate/ lamotrigine Carbamazepine/ lamotrigine
6.0%
1.76 (0.80–3.86) .16
8.8%
N/A
N/A
9.6%
N/A
N/A
0.0%
N/A
N/A
P Value
— (0.49–2.17) .94 — (1.65–5.35) .001 (0.88–3.32) .114 (0.43–5.95) .484
*Total population was 3607. CI, confidence interval; MCM, major congenital malformation; N/A, not available. Data from Morrow J, Russell A, Guthrie E, Parsons L, et al: Malformation risks of antiepileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register, J Neurol Neurosurg Psychiatry 77:193–198, 2006.
The advent in recent years of large registries of pregnant epileptic women in North America, Europe, the United Kingdom, and elsewhere has begun to clarify the risk of major malformations in the children of epileptic women treated with anticonvulsant drugs.54-64a Although the data are not perfectly consistent, several conclusions appear justified (Table 24-3). Thus, the risk of monotherapy in the genesis of major malformations (‘‘involving an abnormality of essential embryonic structure requiring significant treatment and present at birth or discovered during the first 6 weeks of life’’) is nil or relatively minor, except for valproate (see later). Moreover, polytherapy accentuates the risk of major malformations, but this accentuation has been noted only with regimens that included valproate (see Table 24-3).63,64a The most common major malformations reported in recent large series are neural tube defects, cardiac anomalies, facial clefts, hypospadias and other genitourinary anomalies, gastrointestinal anomalies, and skeletal deficits (Table 24-4).54,63,64,64a This distribution of malformations confirms earlier reports based on generally smaller populations studied.22-24,32,46,50 These epidemiological studies have been of major importance in defining individual major malformations associated with the use of anticonvulsant drugs. However, the nature of such large surveys, which usually and necessarily involve many observers and the determination of abnormal findings by various methodologies, makes difficult the detection of a constellation or cluster of abnormalities, such as the so-called fetal hydantoin syndrome. This syndrome is a sequela to the use of major anticonvulsant drugs during pregnancy and provides insight into the teratogenic mechanisms of these agents.
1012 TABLE 24-4
UNIT X
DRUGS AND THE DEVELOPING NERVOUS SYSTEM
Types of Major Congenital Malformation by Antiepileptic Drugs PERCENTAGE WITH MALFORMATION
Drug Carbamazepine Valproate Lamotrigine Phenytoin
Cases (N)
NTD
Cardiac
Facial Cleft
Hypospadias/Gut
900 715 647 82
0.2% 1.0% 0.2% 0.0%
0.7% 0.7% 0.6% 1.2%
0.4% 1.5% 0.2% 1.2%
0.2% 1.3% 0.9% 0.0%
NTD, neural tube defect. Data from Morrow J, Russell A, Guthrie E, Parsons L, et al: Malformation risks of antiepileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register, J Neurol Neurosurg Psychiatry 77:193–198, 2006.
Fetal Hydantoin Syndrome Although the results of the epidemiological studies just reviewed emphasized the occurrence of specific major malformations (e.g., congenital heart disease and cleft lip or palate), careful observation of individual cases led to the early recognition of a constellation of anomalies that appeared to be characteristic of intrauterine exposure to certain major anticonvulsant drugs.16,65 In subsequent studies, the syndrome was defined in more detail, with emphasis on the occurrence of mild to moderate growth disturbance, delayed neurological development, a characteristic craniofacial appearance, and hypoplastic distal phalanges and nails.22,24,54,66-75 Although most of the patients in the cases initially reported were exposed to phenytoin in combination with barbiturates or, less commonly, primidone, the syndrome (or at least many of the features thereof) has been observed with exposure to phenytoin alone, and hence the term fetal hydantoin syndrome has been used commonly. However, the observation of a similar clinical syndrome in 22 infants exposed to barbiturates but not to phenytoin,76,77 in several infants exposed to primidone alone,78-80 and in infants exposed to carbamazepine81-83 suggests that the so-called fetal hydantoin syndrome can be caused by at least these additional anticonvulsants. Valproic acid, which can interfere with the metabolism of these drugs (see later discussion), may potentiate their teratogenic potential, although more data are needed on this issue. The structural similarities of phenytoin, phenobarbital, primidone, and carbamazepine are noteworthy (see Fig. 24-1), and primidone is metabolized, in part, to phenobarbital in vivo. For the sake of simplicity, I use the term fetal hydantoin syndrome rather than the more inclusive term fetal hydantoin-barbiturate-primidone-carbamazepine syndrome or the less precise terms fetal antiepileptic drug syndrome, fetal anticonvulsant drug syndrome, and anticonvulsant embryopathy. Incidence. The incidence of the fetal hydantoin syndrome is not entirely known, but it is likely to be less than that recorded in earlier reports. In a prospective study of 35 children born to 23 women who were treated with hydantoin anticonvulsant drugs with or without barbiturates, 11% of the children had sufficient features to be classified as having fetal hydantoin syndrome.68 An additional 31% exhibited some features compatible with the prenatal effect of hydantoin.
A matched control evaluation of 104 children, whose mothers had epilepsy and were treated with hydantoins with or without barbiturates, and who were part of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, resulted in detection of 11 children with the fetal hydantoin syndrome (i.e., a similar percentage to that observed with the smaller prospective study).68 In another series, 7% of children exposed to phenytoin were affected.84 Subsequent work has shown that the incidence of the full-blown syndrome is approximately 5% to 10%, although this value remains controversial.22-24,48,54,75,85-93 Clinical Features. The clinical features of the fetal hydantoin syndrome include abnormalities of prenatal and postnatal growth, CNS function, craniofacial appearance, and distal limbs (Table 24-5 and Fig. 24-2).22,39-46,54,65-68,71,73-76,79,85,93-96 Perhaps the most characteristic combination is a relatively small head, ocular hypotelorism, epicanthal folds, midface hypoplasia with broad or depressed nasal bridge, short nose, long upper lip, and flattened maxilla. Ocular hypotelorism and the hypoplastic nails were considered particularly characteristic of phenytoin exposure in prospective studies.93 The magnitude of the cognitive deficits remains to be determined decisively in large populations, but data suggest that a significant disturbance of intellectual function is not rare. In a recent study of 80 infants exposed in utero to anticonvulsant drugs, the strongest correlation of intelligence with the physical features of the exposed children was the presence of microcephaly, which was associated with a deficit of 23.7 points in full-scale intelligence quotient (IQ).75 Marginally significant defects in IQ accompanied midface hypoplasia and digital hypoplasia.75 Neuropathology. The neuropathological findings of the fetal hydantoin syndrome have not been defined. In the one case with detailed neuropathological study, ‘‘generalized gliosis’’ in the cerebrum may have related to the severe congestive heart failure caused by cardiac anomalies; however, migrational disturbances in the cerebellum were also observed and are of interest in view of the tendency for phenytoin to cause cerebellar injury at more advanced ages.70 Microcephaly has been reported in 5% to 30% of affected patients, but the cause of the small brain is unknown.
Chapter 24 TABLE 24-5
Clinical Features of 63 Cases of the Fetal Hydantoin Syndrome
Clinical Features Growth Prenatal growth deficiency Postnatal growth deficiency Central Nervous System Microcephaly Developmental delay or mental deficiency Craniofacial Large anterior and posterior fontanel Metopic ridging Medial epicanthal folds Ocular hypertelorism Broad and/or depressed nasal bridge Cleft lip and/or palate
Percentage Affected* 19% 26% 29% 38%{ 42% 27% 46% 23% 54% 5%
Limb Nail and/or distal phalangeal hypoplasia Fingerlike thumb
32% 14%
Other Short neck with or without low hairline Inguinal hernia Bifid or shawl scrotum Cardiac defect
18% 14% 33% 8%
*Data are expressed as percentage of those patients for whom information is available. { Includes only those patients 4 years of age or older. Data from Hill RM, Verniaud WM, Horning MG, McCulley LB, et al: Infants exposed in utero to antiepileptic drugs, Am J Dis Child 127:645–653, 1974; and Hanson JW, Smith DW: The fetal hydantoin syndrome, J Pediatr 87:285–290, 1975
Pathogenesis. The occurrence of developmental anomalies after intrauterine exposure to major anticonvulsant drugs could relate to maternal seizures, a genetic factor related to epilepsy, or a teratogenic effect related to the action of the anticonvulsant drugs. As indicated previously, the epidemiological data support the notion of a teratogenic effect of anticonvulsant drugs. Hydantoins may be more teratogenic than other agents, but this point is not firmly established. The teratogenic capacity of at least phenytoin and barbiturates is supported by the demonstration that these agents can lead to abnormalities in the rodent that are similar to abnormalities in the human.22,97-105 Dose-dependent effects can be demonstrated. The possibility that a genetic predisposition contributes to the development of the syndrome is suggested by animal studies,98,106-109 and it is suggested in the human by the observation of quite variable degrees of the fetal hydantoin syndrome occurring in trizygotic triplets and in heteropaternal dizygotic twins.72,110 In a careful study of 62 families with fetal hydantoin exposure during two or more pregnancies, in 15 of the families (25%), 1 or more infants were affected, and in the remaining 47 families, none of the infants
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was affected.89 More important, mothers who had a single affected child appeared to be at a much higher risk for having subsequently affected children (9 of 10) than were mothers whose first-born child was unaffected by the hydantoin exposure (1 of 48). The mechanism of the teratogenic effect of phenytoin, phenobarbital, primidone, and carbamazepine may relate to a metabolite of these drugs. Thus, these agents are metabolized to an epoxide by a microsomal monooxygenase that can be induced by the drugs themselves (i.e., autoinduction) (Fig. 24-3).88,106,107 Epoxides are highly reactive oxidative metabolites that can bind to nucleic acids and can impair developmental processes. These highly reactive compounds are detoxified by epoxide hydrolase, the product of which is the harmless dihydrodiol metabolite. The possibility that low fetal levels of epoxide hydrolase could lead to enhanced levels of the dangerous epoxide and teratogenicity was suggested by the work of Buehler and co-workers.88,107,111 In a prospective study of 19 pregnancies in women treated with phenytoin monotherapy and monitored by amniocentesis, the occurrence of the fetal hydantoin syndrome was documented in 4 cases with hydrolase activities less than 30% of the standard value, whereas the 15 fetuses with activities more than 30% of the standard value were unaffected (Fig. 24-4). In a later study, the threshold level of activity was suggested to be 35%.111 The data suggested that infants with lower levels of epoxide hydrolase, perhaps genetically determined, are at markedly increased risk of development of teratogenic levels of the dangerous epoxide derivative. This possibility, as well as the teratogenic potential of the epoxide metabolites, was supported by studies in animals.107,109 The possible potentiating effect of valproate in the teratogenicity of phenytoin, phenobarbital, primidone, and carbamazepine, suggested by clinical data (see earlier discussion), could relate to the demonstration that valproate can lead to inhibition of the epoxide hydrolase. The data raise the possibility that the fetus especially susceptible to the teratogenic effects of the hydantoin group of drugs could be identified in utero by examination of cultured amniocytes. Other potential mechanisms of teratogenesis from phenytoin and related anticonvulsant drugs have included disturbances of folate metabolism.22,24,112 Such a mechanism could underlie the approximately 1% risk of neural tube defects in infants treated with carbamazepine. Folate metabolism may be particularly important in the teratogenic effect of valproate on neural tube formation (see later discussion). Other investigators have suggested a disturbance in certain homeodomain transcription factors.75 Management. The major issue in management of fetal hydantoin syndrome is prevention and, specifically, counseling of young epileptic women about hydantoin, carbamazepine, and barbiturate use during pregnancy. The importance of preventing seizures during pregnancy is recognized, as is continuation of anticonvulsant medication when the risk of recurrent seizures is considerable (see the later discussion ‘‘Guidelines
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A
B
C
D
Figure 24-2 Fetal hydantoin syndrome: clinical appearance. A and B, Two different infants with the syndrome; note the similar facial appearance, especially the broad, depressed nasal bridge, the widely spaced eyes, the epicanthal folds, the low hairline at the forehead, and the short neck. C, Hand of an affected newborn. Note hypoplasia of nails and distal phalanges. D, Hand of an affected child at 1 year of age; some nail growth is evident. (From Hill RM, Verniaud WM, Horning MG, McCulley LB, et al: Infants exposed in utero to antiepileptic drugs, Am J Dis Child 127:645653, 1974.)
Concerning Use Pregnancy’’).
of
Antiepileptic
Drugs
during
Fetal Trimethadione Syndrome Fetal trimethadione syndrome refers to the constellation of developmental defects associated with intrauterine exposure to oxazolidine derivatives, usually trimethadione, but also paramethadione; it consists of intrauterine growth retardation, disturbed CNS development, a characteristic craniofacial appearance, and
cardiac, genitourinary, and, to a lesser extent, other anomalies.16,46,69,113-123 This syndrome now is rare because trimethadione and paramethadione have been supplanted by other anticonvulsant drugs. The teratogenic capacity of oxazolidines, particularly trimethadione, is very pronounced, and it is curious that this capacity was not recognized until approximately 1970.113 This delay may have related to two major factors. First, petit mal seizures are infrequent in adult patients, and thus, in contrast to phenytoin
Chapter 24 Phenytoin (PHT) Phenobarbital (PHB) Primidone (PHB) Carbamazepine (CZ) Auto-induction by PHT, PHB, CZ
TABLE 24-6
TERATOGENICITY
Epoxide hydrolase
Dihydrodiol derivative of PHT, PHB, CZ Figure 24-3 Potential mechanism of teratogenic effect of major anticonvulsant drugs. Generation of epoxide derivative is catalyzed by a mono-oxygenase that is induced by the drugs themselves (i.e., autoinduction). The potentially teratogenic epoxide derivative must be degraded by a hydrolase to the apparently harmless dihydrodiol derivative. Impaired activity of the hydrolase, because of either genetic variability or exogenous factors (e.g., valproic acid), could cause the epoxide derivative to accumulate and exert teratogenic effects.
and phenobarbital, trimethadione is a medication not commonly used by women of childbearing age. Second, other drugs have supplanted oxazolidines in the treatment of petit mal seizures.
Epoxide hydrolase activity (% of standard)
Incidence. The incidence of the syndrome after intrauterine exposure to oxazolidines is very high. Indeed, of the 53 reported pregnancies in which such a drug was used, 13 (24%) resulted in spontaneous abortions; of
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Clinical Features of 40 Children Exposed to Trimethadione or Paramethadione in Utero
Clinical Features Mono-oxygenase
Epoxide derivative of PHT, PHB, CZ
Inhibition by valproic acid
Teratogenic Effects of Drugs and Passive Addiction
Percentage Affected*
Growth Prenatal growth deficiency Postnatal growth deficiency
50% 53%
Central Nervous System Microcephaly Mental retardation Developmental delay Speech disturbance
50% 29% 53% 47%
Facial V-shaped eyebrows Epicanthal folds Broad nasal bridge Malformed ears Palatal anomaly Cleft lip and/or palate
44% 35% 43% 70% 57% 28%
Limbs Single transverse palmar crease Clinodactyly
30% 17%
Cardiac Major anomaly
50%
Genitourinary Major anomaly Renal anomaly Hypospadias
30% 13% 21%
Other Tracheoesophageal defects Inguinal hernia
13% 22%
*See text for references. Includes those cases for which data are available.
the 40 survivors, 33 (83%) had at least one major congenital anomaly characteristic of the fetal trimethadione syndrome.120 Thus, only 17% of the children reported with exposure to trimethadione or paramethadione in utero were born without a major defect. Of the 8 children exposed only to trimethadione, 7 had the features of the syndrome.
100 80 60 40 20 0 Amniocyte samples
Figure 24-4 Epoxide hydrolase activity in amniocyte samples from 19 prospectively monitored fetuses whose mothers were administered phenytoin during the pregnancy. The samples from the 4 fetuses subsequently noted postnatally to exhibit the clinical features of fetal hydantoin syndrome are shown in the front row of bars, and the 15 samples from fetuses subsequently confirmed not to have the characteristic features of the syndrome are shown in the rear row of bars. Note the markedly lower epoxide hydrolase activities in the fetal samples from infants who exhibited the clinical features of fetal hydantoin syndrome. (From Buehler BA, Delimont D, Van Waes M, Finnell RH: Prenatal prediction of risk of the fetal hydantoin syndrome, N Engl J Med 322:1567–1572, 1990.)
Clinical Features. The clinical features of the fetal trimethadione syndrome include aberrations of prenatal and postnatal growth, CNS function, craniofacial appearance, and cardiovascular, genitourinary, and other structures (Table 24-6).16,113-123 The syndrome was clearly described initially by Zackai and co-workers.119 The two most helpful diagnostic features are the V-shaped eyebrows and the malformed ears, which are characterized by low placement, posterior rotation, and anteriorly folded helices (Fig. 24-5). The disturbances of the CNS have not been defined in detail. Nevertheless, approximately 50% of the infants exhibit microcephaly and a definite delay of neurological development, and 29% of the older patients have had overt mental retardation, almost invariably mild. Disturbances of speech, usually not well described, are present in approximately one half of the patients.
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A
B
Figure 24-5 Fetal trimethadione syndrome: clinical appearance. An affected infant at 5 months of age. A, Note the V-shaped eyebrow and broad nasal bridge. B, Note the malformed right ear with small superior aspect of helix and cupped, overlapping helical fold. (From Zackai EH, Mellman WJ, Neiderer B, Hanson JW: The fetal trimethadione syndrome, J Pediatr 87:280–284, 1975.)
The anomalies of the cardiovascular system, genitourinary tract, and tracheoesophageal structures are frequent and very serious. The rate of occurrence of both the cardiac and genitourinary anomalies is approximately 50%, and that of the tracheoesophageal structures is approximately 15%. The anomalies together account for the relatively high neonatal mortality rate (nearly 40% of affected infants) and consist of such disorders as hypoplastic left heart, tetralogy of Fallot, transposition of the great vessels, absent or anomalous kidneys, common laryngotracheoesophagus, and large tracheoesophageal fistulas.121 Neuropathology. The neuropathological findings of the fetal trimethadione syndrome have not been defined. The occurrence of microcephaly in 50% of infants indicates a significant impairment of brain growth. Pathogenesis. The mechanism of the teratogenic effect of oxazolidines is unknown. The drugs do cross the placenta and also were shown to be teratogenic when they were injected directly into the chick embryo.124 Oxazolidines exhibit structural similarities to the major anticonvulsant drugs (e.g., phenytoin and phenobarbital), which also have teratogenic effects, as described earlier (see Fig. 24-1). Management. Prevention is the critical aspect of management. Smith69 recommended that women of childbearing age who are taking trimethadione or paramethadione ‘‘should be informed of their high teratogenicity, should ideally be taking birth control measures as long as they receive these drugs, and should have the option of terminating any pregnancy that occurs while receiving these agents.’’ If the absence seizure disorder requires continuation of therapy, then use of a drug without the basic structure shown in Figure 24-1 could be a rational alternative.
However, valproic acid, a structurally different drug (see Fig. 24-1) with efficacy against absence seizures, also exhibits teratogenic capacity (see the next section). Ethosuximide (Zarontin), currently the most popular drug of first choice for petit mal seizures, is structurally very similar to trimethadione and paramethadione (see Fig. 24-1). This close structural similarity raises the possibility that ethosuximide may have the same teratogenic potential as trimethadione or paramethadione; however, initial epidemiological data do not suggest major teratogenic potential.32 Valproate Valproic acid (see Fig. 24-1) is a widely used anticonvulsant drug. Valproate has teratogenic capability in the human and, concerning the nervous system, has been associated with an increased risk for neural tube defects. The drug also has been associated with the occurrence of systemic major and minor malformations, and the term fetal valproate syndrome has been used. Neural Tube Defects. A relationship between the ingestion of valproate in the first weeks of gestation and the subsequent occurrence of neural tube defects was demonstrated both by a series of individual case reports and by large-scale epidemiological studies.22,24,48,58,60,61,125-139 In a large prospective series of 96 women with epilepsy who were treated with valproate during pregnancy, 6 infants (including a set of monozygotic twins) developed open spina bifida, for an incidence of 6.3% (5.4% when the twins were counted as a single infant).137 Other reports, most retrospective, suggested that the overall risk of neural tube defects after valproate exposure is 1% to 3%.2224,58,60,61,138-140 A role for genetic factors is suggested by the demonstration that the risk for neural tube defect after intrauterine exposure to valproate is considerably greater if a maternal or paternal family history
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Figure 24-6 Fetal valproate syndrome, clinical appearance. Infant (10 months old) whose gestation was complicated by administration of 2000 mg of valproate daily to the mother: note the microbrachycephaly, apparent hypertelorism, broad flat nasal bridge, small mouth with thin lips (A), and thin, tapering fingers (B). (From Schorry EK, Oppenheimer SG, Saal HM: Valproate embryopathy: Clinical and cognitive profile in 5 siblings, Am J Med Genet A 133:202–206, 2005.)
of such a defect is present.136 Moreover, a direct relationship between risk of neural tube defect and maternal dose of valproate is clear.137 Thus, with daily doses of valproate of less than 1000 mg/day, the risk for neural tube defect was 0/54, with doses of 1000 to 1500 mg/day, it was 2/30, and with doses of more than 1500 mg/day, it was 3/8. In a later, larger study (n = 110), the risk increased sharply, with doses exceeding 1400 mg/day.138 A dose-response effect has also been observed for major systemic congenital malformation.64 The pathogenesis of the occurrence of neural tube defects after valproate exposure may relate to an abnormality of folate metabolism.141-144 Thus, the lesion can be produced in a rodent model by exposure to valproate during the time of primary neurulation, a process established to be vulnerable to folate deficiency (see Chapter 1). Moreover, valproate has been shown to mediate inhibition of glutamate formyltransferase, the enzyme responsible for generation of folate metabolites important in the actions of folate.144 Administration of the product of the inhibited enzyme prevents the teratogenic effect of valproate. Other Malformations: Fetal Valproate Syndrome. The possibility of a constellation of major and minor anomalies caused by fetal exposure to valproate (i.e., a fetal valproate syndrome reminiscent of the syndrome described earlier in relation to exposure to phenytoinphenobarbital-primidone or to trimethadione) now seems established. More than 100 cases have been reported.24,59,134,135,140,145-157
The clinical features include craniofacial abnormalities (i.e., a broad nasal bridge, apparent hypertelorism, epicanthal folds, long, flat philtrum, and thin upper lip) (Fig. 24-6).157 Long, thin tapering fingers, and hypoplastic fifth toenails are also common. Cardiac, genital, and musculoskeletal defects occur in approximately 20% of patients. Neurological disturbances are common.59,140,156,158-160 Depressed verbal IQ and autistic disorders occur in a substantial minority of valproate-exposed infants. Overt mental retardation is present in approximately 10%. Guidelines Concerning Use of Antiepileptic Drugs during Pregnancy The multiple issues involved in decisions about how to manage anticonvulsant therapy during the pregnancy of the woman with epilepsy are not all resolved, and thus definition of guidelines for management is very difficult. A revised practice parameter is in preparation by the American Academy of Neurology. Reasonable guidelines should include optimization of antiepileptic therapy before conception, avoidance of valproate if possible, use of monotherapy, monitoring of drug levels, administration of the lowest effective dose, and use of folic acid supplementation. Alcohol Fetal Alcohol Syndrome The term fetal alcohol syndrome refers to a constellation of neural and extraneural anomalies and of impaired prenatal or postnatal brain and body growth that
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occurs in infants born to women with chronic alcoholism. The disorder was described in France in 1968 by Lemoine and co-workers,161 and then it was reported in particular detail in 1973 by Jones and coworkers.162,163 Subsequent work showed that maternal exposure to ethanol may not lead to the full expression of the fetal alcohol syndrome, but rather may result in a variety of less pronounced dysmorphic, cognitive, and behavioral effects, often termed fetal alcohol effects (see later discussion).164 Fetal alcohol spectrum disorders is now used as an umbrella term to include the continuum of alcohol-related disorders, with the fetal alcohol syndrome as the most severe.165-167 At the other end of the continuum, the neurological and behavioral features of fetal alcohol spectrum disorders may occur without apparent dysmorphic disturbance (see later). Incidence. The incidence and prevalence of the fetal alcohol syndrome and the less pronounced fetal alcohol effects are not entirely known but are likely to be high. The overt fetal alcohol syndrome, clearly a more readily defined endpoint than so-called fetal alcohol effects, is one of the most common causes of mental retardation in the world. Prevalence rates in the United States are 0.5 to 2.0 per 1000 live births.166,167 However, rates are as high as 9 per 1000 in certain Native American populations in the United States, and rates of 40 to 50 per 1000 live births have been reported in South Africa. The incidence of the entire group of fetal alcohol spectrum disorders is unknown but has been estimated to be as high as 1% of all live births in the United States.167 The amount, pattern, and timing of alcohol exposure are crucial in determining the likelihood and the severity of alcohol teratogenicity. For example, the incidence varies as a function of the incidence of chronic alcoholism. The rate of occurrence of the fetal alcohol syndrome in women with chronic alcoholism is probably 20% to 40%.162,164,166-169 Moderate drinkers have a lower incidence of newborns with clinical features of fetal alcohol syndrome (i.e., 10%).168 The level of alcohol that is harmless during pregnancy is unknown, and the possibility of a continuum of severity of clinical features is high.166,167,170 The balance of data166,167,169,171 supports the earlier conclusion of Smith69 in 1979 that ‘‘ethanol is the most common chemical teratogen presently causing problems of malformation and mental deficiency in the human.’’ Quantitative relationships between the amount, pattern, and timing of maternal alcohol consumption and adverse fetal outcome have been difficult to delineate precisely. However, available data, although not always entirely congruent, support the following conclusions.164,166-200 First, a distinct relationship exists between the amount of alcohol consumed by the mother, particularly around the time of conception and early in pregnancy, and the subsequent occurrence of full-blown fetal alcohol syndrome. For example, in one series of mothers who consumed 2 or more ounces of absolute alcohol per day before recognition of pregnancy, 19% delivered children with features consistent with the fetal alcohol syndrome. Of those who
consumed between 1 to 2 ounces per day, 11% delivered abnormal children with such features.168 Of those who consumed less than 1 ounce per day, only 2% had infants with features of the fetal alcohol syndrome.168 Second, alcohol consumption in the second and third trimesters of pregnancy is not harmless and is associated with definite cognitive and behavioral deficits. Third, binge drinking, especially around the time of conception, is particularly dangerous, perhaps because of the high concentrations of blood alcohol achieved. Genetic differences in fetal susceptibility to alcohol may be important, as they are in the effects of certain other teratogens (see earlier discussion of anticonvulsant drugs). Thus, the rate of concordance for occurrence of the dysmorphic effects of alcohol exposure and for impairment of intelligence is much greater for monozygotic than dizygotic twins.201 However, even with dizygotic twins, a difference in phenotypic outcome can be pronounced, presumably because of genetic differences in susceptibility.202 A dramatic recent finding delineated an important determinant of genetic susceptibility (i.e., the maternal ADH1B*3 allele at the ADH1B locus, the locus of alcohol dehydrogenase).200,203 The latter enzyme, the first step in alcohol degradation, catalyzes the oxidation of alcohol to acetaldehyde. The ADH1B*3 allele encodes an isoenzyme that rapidly oxidizes alcohol to acetaldehyde and thereby maintains a relatively low blood alcohol concentration. This allele is unique to African Americans, occurs with a population frequency of 22%, and is associated with a reduced susceptibility to fetal alcohol effects.203 The data emphasize that genetic factors may play a key role in determining the risk to the fetus at a given level of alcohol consumption during pregnancy. Clinical Features. The clinical features of the fetal alcohol syndrome are distinctive (Table 24-7).161163,165,167-170,182,186,192,197,204-240a The particularly defining features are growth disturbance, characteristic facial anomalies, and neurological abnormalities. A prominent disturbance of growth is the hallmark of the disorder. At birth, these infants have a distinctive pattern of growth retardation, with length often affected more than weight (the opposite pattern from that expected with intrauterine undernutrition). The growth deficiency persists postnatally, but weight gain becomes more disturbed than linear growth. The abnormalities of growth are not altered appreciably by attempts to change environmental variables, such as nutritional factors and the home setting. The disturbance of the CNS is the most serious feature of the syndrome. Microcephaly is present in nearly all cases, and this reflection of disturbed brain growth is accompanied by delayed neurological development in approximately 90% of patients. The severity of the mental deficiency correlates most closely with the severity of the dysmorphic features. In one series, infants with the most severe dysmorphic manifestations of fetal alcohol syndrome had a mean IQ of 55, those with moderate manifestations had a mean IQ of 68, and those with mild manifestations had a mean IQ of 82. Mean IQ in reported series generally has varied
Chapter 24 TABLE 24-7
Clinical Features of the Fetal Alcohol Syndrome*
Clinical Features
Approximate Frequency
Growth Prenatal growth deficiency Postnatal deficiency
95% 95%
Central Nervous System Microcephaly Developmental delay
95% 90%
Facial Short palpebral fissures Epicanthal folds Midfacial hypoplasia Short, upturned nose Hypoplastic long or smooth philtrum Thin vermilion of upper lip
90% 50% 65% 75% 90% 90%
Limb Abnormal palmar creases Joint abnormalities
55% 50%
Cardiac Cardiac defects
50%
Other Ear anomalies Conductive hearing loss Sensorineural hearing loss Optic nerve hypoplasia External genital anomalies Cutaneous hemangioma
25% 75% 10% 75% 30% 25%
*See text for references. Numbers are rounded off to nearest 5%.
between 65 and 85. The relationship between the severity of dysmorphogenesis and intellectual defect is not invariable; indeed, in some well-documented infants of mothers with chronic alcoholism, neurological disturbance appeared to be the only apparent abnormality, both clinically and neuropathologically.241,242 Moreover, a distinctive abnormality of the electroencephalogram (EEG), termed excessive hypersynchrony, identified by spectral analysis of power on the EEG, was observed in infants in whom dysmorphic features were minor or apparently absent.218,243-245 Similarly, diffusion tensor magnetic resonance imaging (MRI) detected microstructural alterations, especially in corpus callosum, in infants clinically less obviously affected.246 Subsequent school performance in these children is disturbed not only by the defective intellectual function but also by the very frequent accompaniments of hyperactivity, distractibility, and restricted attention span. Particular involvement of speech and language development, verbal more than nonverbal learning and memory, visuospatial abilities, and executive functioning have been emphasized. Subsequent performance on intelligence tests or in school does not change appreciably as a function of the child’s environment. In addition to the serious cognitive deficits, the behavioral disturbances and the impaired communication skills, later maladaptive social function, manifested by lack of reciprocal friendships, impulsive behavior,
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anxiety, and dysphoria, leads to a far-reaching, pervasive state of disability. The facial abnormalities are characteristic (Fig. 24-7). The typical facies includes short palpebral fissures, epicanthal folds, a low nasal bridge with a short or upturned nose, midface hypoplasia, a smooth philtrum, and a long upper lip with a narrow vermilion border. The constellation of short palpebral fissures, smooth philtrum, and thin vermilion border of the upper lip is particularly characteristic. Minor ear anomalies are present in approximately one fourth of these children. Less common anomalies are strabismus, ptosis, micrognathia, and cleft palate. Various limb anomalies occur. Approximately one half of the infants exhibit abnormal palmar creases and minor joint abnormalities. The latter include an inability to extend the elbows completely, camptodactyly, and clinodactyly. Cardiac lesions occur in approximately one half of the infants, but these lesions are usually not severe. Most consist of septal defects (atrial more often than ventricular defects). Numerous additional features occur in a minority of patients, including ear anomalies, ocular anomalies, cutaneous hemangioma, and minor abnormalities of the external genitalia. Although hearing loss, primarily conductive, occurs in 75% of infants, the severity is relatively mild. Optic nerve hypoplasia also occurs in 75% of infants, but disturbances of visual acuity are not marked. Neuropathology. The essential nature of the neural disturbance in the fetal alcohol syndrome is impairment of brain development (Table 24-8). Several aspects of the developmental program appear to be involved, based on neuropathological analysis of approximately 20 affected infants.190,242,247-252 In keeping with the microcephaly, micrencephaly is common. The most striking additional abnormalities reported appear to involve neuronal and glial migration. Thus, in the series of Clarren and co-workers,242 the most frequent abnormality was leptomeningeal neuroglial heterotopia that took the form of a sheet of aberrant neuronal and glial cells covering portions of the cerebral, cerebellar, and brain stem surfaces (Fig. 24-8). Aberrations of brain stem and cerebellar development, in large part related to faulty migration, also have been particularly frequent.242,247 Schizencephaly and polymicrogyria are other migrational disturbances observed.247 In addition, disordered midline prosencephalic formation (e.g., agenesis of the corpus callosum, septo-optic dysplasia, and incomplete holoprosencephaly) has been documented.249,251,252 Other developmental defects have included anencephaly, lumbar meningomyelocele, lumbosacral and sacral meningomyelocele, absent olfactory bulbs or ‘‘arrhinencephaly,’’ and disturbances of dendritic development.247,250,253,254 Thus, it appears that multiple aspects of CNS development can be affected, including (in chronological order) neurulation, canalization and retrogressive differentiation, prosencephalic development, neuronal proliferation, neuronal migration, and organizational
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A
B
C Figure 24-7 Fetal alcohol syndrome: clinical appearance. Two children: one, A, in the newborn period and, B, at the age of 6 months and, C, the other at the age of 16 months. Note the short palpebral fissures, especially prominent in the newborn (A), and the low nasal bridge with short, upturned nose, epicanthal folds, long, hypoplastic philtrum, and convex upper lip with narrow vermilion border. (A and B, From Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy, Lancet 2:999–1001, 1973; C, from Hanson JW, Jones KL, Smith DW: Fetal alcohol syndrome: Experience with 41 patients, JAMA 235:1458–1460, 1976.)
events (see Chapter 2). The time periods of the most frequently reported occurrences (i.e., disorders of neuronal proliferation and migration and of midline prosencephalic development) range from the second to the fifth month of gestation, and hence the teratogens
could be acting either during these time periods or, of course, earlier. These data are entirely compatible with those from studies relating time of maternal alcohol intake during pregnancy to subsequent fetal outcome (see subsequent discussion). However, few data are
Chapter 24 TABLE 24-8
Major Neuropathological Features of Fetal Alcohol Syndrome*
In Order of Decreasing Frequency: Micrencephaly Migrational abnormalities: neuronal > glial Midline prosencephalic abnormalities: agenesis of the corpus callosum, septo-optic dysplasia, incomplete holoprosencephaly Dendritic abnormalities Disorders of neural tube formation *See text for references.
Teratogenic Effects of Drugs and Passive Addiction TABLE 24-9
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Major Central Nervous System Alterations Defined by Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorders*
Decreased brain size Disproportionately reduced volume of parietal, temporal (perisylvian) and inferior frontal lobes Disproportionate reduction of white matter in areas of reduced volume Decreased volume of basal ganglia Decreased volume of cerebellum Abnormal corpus callosum: agenesis or hypoplasia, especially most anterior and posterior regions *See text for references.
A
B Figure 24-8 Fetal alcohol syndrome: neuropathology. Brain from a 6-week-old infant who was born after a 32-week gestation. A, Right superolateral view of the cerebrum. Note that nearly all of the left hemisphere is covered by a massive sheet of tissue that crosses the midline and extends onto the superior and medial aspect of the right frontal lobe. B, Section through the cerebral cortex covered by the aberrant tissue. Extending through a break in the pial surface (upper left of cortex) is the heterotopic sheet of tissue composed of neuronal, glial, and pial elements that have covered the true cortex. (A much smaller break in the pial surface is evident in the lower left of the figure.) (From Jones KL, Smith DW: The fetal alcohol syndrome, Teratology 12:1–10, 1975.)
available concerning the status of neuronal differentiation and other aspects of organizational events in infants of mothers with alcoholism. Disturbance of dendritic development has been documented,250 and epidemiological data indicate impaired cognition in infants exposed to alcohol late in pregnancy (see later discussion) when organizational events are active. Moreover, experimental studies have demonstrated distinct disturbances of neuronal development (see ‘‘Pathogenesis’’). Advanced MRI techniques (e.g., volumetric MRI) have been used to define further the neuropathology of fetal alcohol spectrum disorders (Table 24-9).167,227,246,255257 Some of the findings confirm those defined post mortem (see earlier), but regional disturbances of cerebral underdevelopment, disproportionate involvement of white matter, particular involvement of basal ganglia and cerebellum, and regional details of the corpus callosal abnormalities have been identified. These findings have correlates in the neurocognitive deficits described earlier. Thus, the verbal memory defect may relate to the temporal disturbances, the impulsiveness and defective inhibition may relate to frontal involvement, the visuospatial deficits may relate to parietal abnormality, the intermodal learning deficits may relate to callosal abnormality, and the motor and perhaps some of the learning deficits may relate to cerebellar abnormality. Pathogenesis. The pathogenesis of the disturbances of CNS development has been studied in a variety of experimental models. The basis for the deleterious effect of ethanol on neuronal cell number may relate to a disturbance both of neuronal proliferation, particularly in the ventricular zone, and of programmed cell death (i.e., apoptosis).190,196,258-266 The impairment of neuronal migration may be associated with both impairment of cell-cell adhesion and a loss of radial glial guides, the apparent result of either the premature differentiation of radial glial cells to astrocytes or a direct deleterious effect on astrocytic function.196,262,267-269 Disturbances of organizational events in experimental models have included impaired synaptogenesis and development of neurotransmitter systems, including receptors, uptake mechanisms, synthetic and catabolic enzymes, and transduction mechanisms.270-273
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The affected neurotransmitters have included glutamate, serotonin, dopamine, norepinephrine, acetylcholine, and histamine. Additionally, disturbances of both astrocytic and oligodendroglial development have been defined in cell culture models.274,275 A particular vulnerability of cerebral white matter was shown in a fetal sheep model.276 The disturbances of organizational events, particularly neuronal development, may be crucial, and search for potential human correlates of these disturbances is a fertile area for future research. The fundamental mechanisms whereby ethanol administration leads to the disturbances of CNS development have not been delineated definitively. Current evidence favors the concept that ethanol or a metabolic product thereof is responsible for the teratogenic effects expressed in the fetal alcohol syndrome.190,196,258,262-264,267,268,277-298 Alcohol rapidly crosses the placenta and the blood-brain barrier of the fetus. Indeed, a dose-dependent relationship between maternal alcohol intake in the first weeks of human pregnancy and the appearance of certain features of the fetal alcohol syndrome has been demonstrated (see earlier discussion). Whether ethanol acts directly on target organs or indirectly is unknown. Suggested pathogenetic mechanisms have included direct molecular effects of alcohol or its metabolites (e.g., acetaldehyde), maternal undernutrition or malnutrition (e.g., vitamin or trace metal deficiencies), fetal hypoglycemia, and fetal hypoxia-ischemia.196,264,265,268,273,288,294,295,297-304 The last of these mechanisms is based on the demonstrations that (1) maternal ethanol exposure caused a striking impairment of uterine blood flow with resulting fetal hypoxia and acidosis in the third trimester fetal monkey, (2) ethanol induced vasoconstriction of uterine vessels in vitro, and (3) maternal ethanol exposure near term in sheep caused fetal hypoglycemia, a decrease in fetal cerebral metabolic rates for oxygen and glucose, and suppressed fetal breathing movements and electrocorticographic activity.302,305-307 However, the deleterious effects of maternal ethanol exposure on fetal cerebral blood flow and metabolism did not occur in immature sheep,308 a stage of development when the teratogenic effects of alcohol presumably are operative. Several direct molecular effects of alcohol may be involved in the deleterious effects on the developing nervous system. The first of these may involve fetal zinc deficiency caused by decreased maternal supply, in turn related to the induction by alcohol of the zinc binding protein metallothionein in maternal liver, with subsequent sequestration of zinc by metallothionein and redistribution in the liver.304 Zinc is necessary for many CNS developmental events including neurogenesis, neuronal migration, and synaptogenesis. Notably, in a mouse model of fetal alcohol effects, prenatal zinc treatment limited the functional neural deficits produced by maternal ethanol exposure.304 A second molecular mechanism may involve the generation of free radicals with subsequent disturbances of neural development.303,309-311 Prevention of these effects by antioxidant interventions is under investigation.
A third mechanism could involve disturbance of glutamate receptor function. For example, blockade of the Nmethyl-D-aspartate (NMDA) type of glutamate receptor during a period in the rat corresponding to the third trimester of human gestation resulted in widespread apoptotic neurodegeneration.264 Ethanol is a potent NMDA antagonist, and thus exposure to ethanol may lead to diminished cell number by deprivation of glutamate activation, crucial for neuronal survival.264 Other deleterious effects of ethanol involve alteration of NMDA receptor subunit expression and potential enhancement of excitotoxicity.312,313 A fourth mechanism involves inhibition by ethanol of the synthesis of retinoic acid.297,298 Retinoic acid, a vitamin A metabolite, plays an essential role in many aspects of development through an effect on transcription of multiple genes.314,315 Ethanol is a competitive inhibitor of the alcohol dehydrogenase that catalyzes the conversion of retinol (vitamin A) to retinal, which, in turn, is converted to retinoic acid by an aldehyde dehydrogenase. The alcohol dehydrogenase is the rate-limiting step in the synthesis of retinoic acid. The developmental role of retinoic acid is focused particularly on epithelial cell– derived tissues, and thus CNS, limbs, and face (sites characteristically affected in fetal alcohol syndrome) are especially involved. Because of the far-reaching effects of retinoic acid in development, the defect in retinoic acid synthesis could be a final common pathway for many of the teratogenic effects of alcohol on both neural and extraneural systems. A fifth mechanism may be particularly important in the impairment of neuronal migration, a central feature of the fetal alcohol syndrome (see ‘‘Neuropathology’’ earlier). Thus, ethanol has been shown to inhibit neural cell-cell adhesion at levels readily attained by ‘‘social drinking.’’268 Such a disturbance could be crucial by disrupting the critical cell-cell interactions that are obligatory for neuronal and glial migration. A sixth mechanism could involve an effect on apoptosis. Ethanol in immature mice triggered activation of caspase-3 and widespread apoptotic neuronal death in forebrain.265 This effect could be relevant to the occurrence of micrencephaly. Notably, nicotinamide, which inhibits caspase-3, protects against this ethanolinduced apoptotic neurodegeneration. Similarly, erythropoietin, which has antiapoptotic properties, was neuroprotective in another model of ethanol-induced apoptosis in immature brain.311 Management. Management clearly consists primarily of prevention. It is critical that women be advised concerning the risks to the fetus as early in pregnancy as possible because the risk of malformations is greatest when the fetus is exposed during the first weeks and months of gestation. Indeed, advice ideally should be rendered before pregnancy, because most women do not begin prenatal care until after the important first weeks of pregnancy have passed. In a recent report from the Centers for Disease Control, more than half of the women of childbearing age in the United States consumed alcohol in the month before the survey, 15% of these were moderate or heavy drinkers, and
Chapter 24
approximately 15% continued to use alcohol during their pregnancy.166,167 Reduction or cessation of alcohol consumption during pregnancy has been shown to have major beneficial preventive effects.* When this restriction is initiated very early in pregnancy, growth retardation and malformations are prevented. When it is carried out in midpregnancy, although, as would be expected, malformations are not prevented, growth retardation is clearly diminished. Thus, benefit is gained, even if cessation of drinking is delayed. The degree of reduction in alcohol consumption necessary to prevent adverse effects is unknown. Moreover, because clinical and experimental data suggest a dose-dependent relationship (see earlier discussion), total abstinence continues to be recommended in the United States and in at least seven other countries.164,166,321-323 Future interventions may follow from the experimental studies described earlier (see ‘‘Pathogenesis’’). Thus, such compounds as antioxidants, zinc, nicotinamide, and erythropoietin could ultimately play a role. The potential role of genotyping for alleles involved in determining susceptibility (e.g., ADH1*3 allele, discussed earlier) remains to be clarified. Isotretinoin The vitamin A analogue isotretinoin (Accutane) was identified as the teratogenic agent in reports of more than 100 infants exposed in the first weeks of pregnancy.324-334 The magnitude of the problem is potentially great because isotretinoin is used widely for treatment of severe acne, and more than one third of all isotretinoin prescribed is consumed by female patients 13 to 19 years old.329 The clinical features are characterized by a distinctive craniofacial appearance, cleft palate, CNS defects, and congenital heart lesions. The most distinctive and frequent craniofacial feature is anomalous ear development, consisting usually of small, malformed, or absent ears and atretic ear canals (Fig. 24-9). The congenital heart lesions have included, particularly, anomalies of the great vessels (conotruncal and aortic arch abnormalities) and septal defects. The CNS abnormalities have included, most notably, hydrocephalus (with aqueductal stenosis or obstruction of the outflow of the fourth ventricle), focal cerebral cortical migrational defects (pachygyria, agyria, and neuronal and glial heterotopias), micrencephaly, absent cerebellar vermis, and migrational abnormalities in cerebellum and brain stem. The CNS malformations are the most consistent of the anomalies reported and occur in at least 85% of affected infants. Pathogenesis involves the teratogenic effect of isotretinoin, a vitamin A analogue (13-cis-retinoic acid). The syndrome has been identified after exposure to similar retinoid analogues of vitamin A (e.g., acitretin).335 Anomalies similar to the human syndrome were
*See references 164,166,169,171,184,187,188,192,194,195,316-320.
Teratogenic Effects of Drugs and Passive Addiction
1023
Figure 24-9 Fetal isotretinoin syndrome: clinical appearance. This patient at 8 months had a high forehead, hypoplastic nasal bridge, and, particularly, abnormal ears, including microtia. (From Lott IT, Bocian M, Pribram HW, Leitner M: Fetal hydrocephalus and ear anomalies associated with maternal use of isotretinoin, J Pediatr 105:597– 600, 1984.)
produced in various experimental animals, including subhuman primates, exposed to excessive retinoic acid or vitamin A itself during early development.336-338 Indeed, the pattern of defects observed in infants born to women who had consumed high levels of vitamin A (>10,000 units daily) before the seventh week of gestation bears important similarities to the pattern of defects observed in the isotretinoin-exposed infant.339,340 The molecular mechanism appears to relate to an impairment of the normal role of retinoic acid in development of epithelial cells, including particularly the cephalic neural crest cells. The latter are of particular importance in promotion of differentiation of craniofacial structures. The site of the molecular disturbance bears close similarities to that proposed for alcohol (see previous section), except in the case of isotretinoin exposure, excessive levels of retinoic acid may be present, as opposed to the postulated depressed levels in alcohol exposure. The teratogenicity of retinoic acids may relate in particular to an effect on the expression of the homeobox gene Hoxb-1 that regulates axial patterning in the embryo.341,342 Management consists primarily of prevention. The gravity of exposure to isotretinoin during pregnancy is emphasized by the high incidence of either spontaneous abortion or malformed infants in women who have taken the drug. Indeed, in a prospective series of 36 isotretinoin-exposed pregnancies (first trimester), only 64% of infants were born without major malformations.326 The remaining 36% of pregnancies resulted in spontaneous abortion (22%), stillbirth of a malformed infant (3%), or birth of an infant with major malformations (11%), as described earlier. In a
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retrospective series of pregnancies exposed to isotretinoin in the first trimester, 80% to 90% ended in spontaneous abortion, stillbirth, or live birth with malformations. Because the first trimester, and probably early in this trimester, is the vulnerable period, it is important that women of childbearing age take measures to avoid becoming pregnant while taking the drug. Moreover, with inadvertent exposure to the agent while pregnant, the desirability of continuing the pregnancy should be addressed. Topical retinoic acid (tretinoin, also used in the treatment of acne) administered in the first trimester of pregnancy has been associated with the occurrence of ear and cerebral anomalies,343 although the frequency of this relationship is unknown.344 A more recent review of 106 pregnant women with first trimester exposure to topical tretinoin identified no examples of ear or cerebral anomalies.345 Thus, the risk of using topical tretinoin is unclear. The possibility should be considered that some women and fetuses are genetically susceptible or uniquely capable of absorbing relatively high doses of tretinoin after topical application.345 Finally, because of the similarity in phenotypic expression of the teratogenicity of high maternal vitamin A intake, it is recommended that women who are or who may become pregnant not consume daily supplements of more than 8000 IU of vitamin A.340 Cocaine The effect on the fetus, and thereby the newborn, of cocaine use by the pregnant woman is a topic of major public health importance, in considerable part because of the relatively high incidence of cocaine abuse worldwide (see later discussion). Cocaine has profound effects on the central and peripheral neural systems of the adult and may have the potential to cause, directly and indirectly, adverse alterations in neurological, cognitive, and behavioral functions and brain structure in the fetus. Delineation of the effects of intrauterine exposure to cocaine on the fetus and the newborn is difficult for several reasons, and these methodological difficulties must be considered in any analysis of the available information on this topic. First, accurate determination of which infants have been exposed to cocaine in utero awaits development of a simple, sensitive, and specific test. Currently, infant exposure to cocaine in utero often is ascertained initially by maternal urine analysis for cocaine and its metabolites, by maternal interview, or both. The importance of both these approaches is well illustrated by the data of Zuckerman and co-workers (Table 24-10).346-348 In a prospective study of 1226 mothers, cocaine use was determined by maternal interview and urine analysis. Based on a maternal interview alone, 24% of exposed infants would have been missed; urine analysis alone would have missed 47% of exposed infants. Moreover, because neonatal urine analysis provides evidence only of recent cocaine exposure (within 1 week), the duration of intrauterine exposure cannot be determined. The importance of this issue was emphasized by the observation that
TABLE 24-10
Estimation of Frequency of Cocaine Use during Pregnancy, According to Method of Ascertainment MATERNAL INTERVIEW
Neonatal Urine Assay
Positive
Negative
Positive Negative
20% 47%
24% —
Data from Zuckerman B, Frank DA, Hingson R, Amaro H, et al: Effects of maternal marijuana and cocaine use on fetal growth, N Engl J Med 320:762–768, 1989.
deleterious effects on the fetus could not be documented in women who used light or moderate amounts of cocaine and who decreased drug use during their pregnancies.349 Indeed, a dose-dependent effect of cocaine on the fetus was quantitated in a careful study.350 The determination of cocaine metabolites in meconium351,352 is an excellent addition or alternative to urine analysis.352-358 Analyses of meconium provide information on the degree of cocaine exposure over many weeks during pregnancy following onset of meconium production (i.e., 14 to 16 weeks). Investigators have suggested that serial analyses of meconium may provide information about timing, with the initial sample of meconium relevant to early pregnancy and later samples relevant to later in pregnancy. The demonstration of a cocaine metabolite in hair from adult cocaine users, the correlation of hair levels with reported quantity of cocaine used, and the ability to detect changes in content along the hair shaft as a function of the time of cocaine use suggested that analysis of hair may be particularly valuable.359 Cocaine metabolite has been detected in hair of newborn infants of women who used cocaine during pregnancy,359,360 and available data suggest that detection of fetal exposure during the last trimester of pregnancy is possible.354 Relevant neonatal hair samples may be obtained for approximately 3 postnatal months.360 A more readily applied approach in the newborn period may be analysis of maternal hair samples shortly after delivery.350 The second difficulty in determining the effects of intrauterine exposure to cocaine is the frequent presence of many potentially deleterious, confounding variables in the prenatal and postnatal periods of the infants.348,358,361-364 Thus, pregnant women who abuse cocaine commonly also abuse other illicit drugs, smoke cigarettes or marijuana, or both, drink alcohol, have poor nutrition, fail to seek prenatal care, transmit to the fetus such infections as syphilis or human immunodeficiency virus, and provide the newborn with a poor postnatal nutritional and social environment.169,358,361-363,365-379 Indeed, in a study of 619 mothers who reported abusing cocaine, only 2% reported no use of other drugs, and 77% used cocaine and at least two other drugs.358 A third difficulty relates to the choice of outcome measures for infants exposed to cocaine in utero. The neural systems most likely to be affected by cocaine are involved in neurological and behavioral functions that are not readily quantitated, particularly by standard measures of infant
Chapter 24 TABLE 24-11
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hydroxybenzoylecgonine, when detected in meconium, is a highly sensitive indicator of fetal exposure.358
Incidence of Cocaine Use in a Suburban U.S. Hospital
Cocaine use (meconium) Cocaine use (maternal report)
Teratogenic Effects of Drugs and Passive Addiction
Private (n = 366)
Clinic (n = 134)
6.3% 0%
26.9% 4.0%
Data from Schutzman DL, Frankenfield CM, Clatterbaugh HE, Singer J: Incidence of intrauterine cocaine exposure in a suburban setting, Pediatrics 88:825–827, 1991.
development and cognition. Such functions relate to attention, arousal, motivation, and social interaction, among others (see later discussions). A fourth difficulty relates to selection bias for the reporting of positive rather than negative results in studies of the effects of intrauterine exposure to cocaine.380 Among abstracts submitted to the Society for Pediatric Research from 1980 to 1989, only 11% of those describing no effect of cocaine were accepted for presentation versus 57% of those describing a positive effect. Indeed, I suspect that I have been guilty of this bias in attempting to prepare a succinct section in this book, although I have tried to minimize this bias. Incidence Of women cared for at urban teaching hospitals, 5% to 45% use cocaine during their pregnancies.346, 350-352,356,358,365,379,381-390 The problem of fetal cocaine exposure is not confined to urban hospital populations; in one study, 6% of infants born to women at a private suburban hospital had a cocaine metabolite in meconium (Table 24-11).391 In a study of more than 29,000 women delivering in California, the percentage of positive urine assays for cocaine and its metabolites, and therefore an indication of exposure only in approximately the last week of pregnancy, was 1.1%.169 Pharmacology Cocaine Preparations and Metabolism. Cocaine is benzoylmethylecgonine, an alkaloid derived from the leaves of the Erythroxylon plant species.392,393 It is available in two forms: cocaine hydrochloride and highly purified cocaine alkaloid (free base).392-401 The latter is derived from the former principally by alkali extraction. Cocaine hydrochloride is heat labile but water soluble and therefore is generally administered by nasal insufflation, orally, or intravenously. Cocaine alkaloid is heat stable but highly water insoluble and therefore is generally administered by inhalation (smoking). The cocaine alkaloid preparation is also called ‘‘crack’’ because of the popping sound made by the heated crystals. The activities of the cocaine-metabolizing cholinesterases and therefore elimination of cocaine are relatively low in the pregnant female, fetus, and newborn rodent.400 However, systematic data in humans are lacking. Infants born to mothers who used cocaine 1 or 2 days before delivery excrete cocaine for 12 to 24 hours after delivery and benzoylecgonine for as long as 5 to 7 days.397,402 Another metabolite,
Mechanisms of Action. Cocaine has pronounced effects on both the peripheral and central neural systems. First, it impairs the reuptake of norepinephrine and epinephrine by presynaptic nerve endings, and consequently, these neurotransmitters accumulate at synapses.169,392-394,403-406 The result is a striking activation of adrenergic systems, and it is indeed the pronounced stimulation of the sympathetic nervous system that causes the most dramatic acute effects of the drug in the adult (e.g., hypertension, tachycardia, vasoconstriction). Second, cocaine impairs the reuptake of dopamine by binding to the dopamine transporter, the reuptake carrier.407 Dopamine therefore accumulates in synaptic clefts and activates dopaminergic systems. This activation is crucial for the sense of euphoria that follows acute cocaine ingestion and involves mesolimbic or mesocortical pathways, or both.403 Activation of mesolimbocortical dopaminergic pathways also accounts for the strong reinforcing qualities of the drug.407,408 However, with longer-term use, dopamine becomes progressively depleted from nerve endings, and this depletion may lead to the dysphoria so prominent during withdrawal and to the subsequent craving for the drug. Third, cocaine impairs the homeostasis of serotonin by blocking the uptake of both tryptophan, its precursor, and serotonin itself.392,409411 The result may account for the striking acute alteration in sleep-wake cycling (i.e., the decreased need for sleep) and may enhance the central excitatory effects of dopamine. Fourth, cocaine acts on peripheral nerves to prevent the increase in permeability of sodium ions required for initiation and propagation of nerve impulses.394 This effect underlies the local anesthetic action of cocaine. Clinical Features Maternal-Fetal Effects. Cocaine use during pregnancy may have deleterious effects on both the mother and the fetus.169,350,379,412-420 The specific features and the magnitude of these effects are relatively consistent among reported studies. For example, in one large, multisite, prospective randomized study, compared with nonexposed infants, cocaine-exposed infants had lower birth weights, lower gestational age, higher rate of prematurity, shorter length, smaller head circumference, and increased likelihood to be small for gestational age (Table 24-12).379 The mechanisms of the adverse effects just mentioned are undoubtedly multiple and interrelated (Fig. 24-10). However, the occurrence of premature labor and delivery relates, at least in part, to the increased uterine contractility associated with the increase in catecholamines stimulated by cocaine.421-423 A direct effect of cocaine on human myometrial contractile activity also is likely.424 The increased uterine contractility also may underlie the higher risk of abruptio placentae reported in some studies.412 An important factor in the pathogenesis of the impairment of fetal growth is a disturbance in nutrient transfer to the fetus, probably
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TABLE 24-12
DRUGS AND THE DEVELOPING NERVOUS SYSTEM
Selected Perinatal Outcomes for Cocaine Exposed versus Nonexposed during Pregnancy Cocaine Exposed (n = 717)
Birth weight (mean ± SD, g) 2,531±695 Gestational age (mean ± SD, cm) 37.1±3.4 Small for gestational age (%)* 29.4% Length at birth (mean ± SD, cm) 46.3±4.4 Head circumference at birth (mean ± SD, cm) 31.9±2.8
Nonexposed (n = 7442) P Value 3,067±776