Clinics in Developmental Medicine No. 193

THE DEVELOPING HUMAN BRAIN: GROWTH AND ADVERSITIES

Clinics in Developmental Medicine No. 193

The Developing Human Brain: Growth and Adversities

FLOYD H. GILLES, MD

Children’s Brain Center, Department of Pathology and Laboratory Medicine, Neuropathology Section, Burton E. Green Professor of Pediatric Neuropathology, Children’s Hospital Los Angeles, and Professor, Departments of Pathology (Neuropathology), Neurology, and Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

MARVIN D. NELSON, JR., MD, MBA, FACR

Pediatric Neuroradiology, Chairman, Department of Radiology, and John L. Gwinn Professor of Radiology, Children’s Hospital Los Angeles, and Professor of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

2012

Mac Keith Press

© 2012 Mac Keith Press

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Editor: Hilary Hart

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The views and opinions expressed herein are those of the authors and do not necessarily represent those of the publisher

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First published in this edition 2012

British Library Cataloguing-in-Publication data

A catalogue record for this book is available from the British Library

The cover shows a magnetic resonance image of a living fetus in the uterus. The image illustrates the dependence of normal fetal brain development on a healthy placenta and umbilical cord.

ISBN: 978-1-908316-41-7

Typeset by Prepress Projects Ltd, Perth, UK

Printed by Latimer Trend and Company Ltd, Estover Road, Plymouth, Devon

Mac Keith Press is supported by Scope

CONTENTS

PREFACE

ACKNOWLEDGMENTS

1.     INTRODUCTION

SECTION 1

2.     BRAIN GROWTH

3.     FETAL VENTRICULAR SIZE, SURFACES, AND APPENDAGES

4.     GERMINAL TISSUE (SUBVENTRICULAR ZONE)

5.     SURFACE CONFIGURATION—GYRAL PATTERN DEVELOPMENT

6.     MYELINATED TRACTS: GROWTH PATTERNS

7.     DEVELOPING BRAIN IMAGING AND MAGNETIC RESONANCE SPECTROSCOPY

8.     ANGIOGENESIS

SECTION 2

9.     DEVELOPMENTAL HUMAN FETAL REACTIONS: AVOID, SQUINT, SCOWL, SNEER, AND PUCKER

10.  BLAKE’S POUCH AND RETROCEREBELLAR CYSTS: POSTERIOR FOSSA CYSTS

11.  DEVELOPMENTAL CENTRAL NERVOUS SYSTEM ABERRATION

12.  CEREBRAL WHITE MATTER ABNORMALITIES

13.  LATE FETAL AND PERINATAL BRAIN VASCULAR ABNORMALITIES AND NECROSES

14.  FETAL AND NEONATAL INTRACRANIAL HEMORRHAGE

15.  VENTRICULOMEGALY, LARGE HEAD, MEGALENCEPHALY, AND HYDROCEPHALUS

16.  DEVELOPING BRAIN REACTIONS DURING CHRONIC CHILDHOOD DISEASE

17.  CONCLUDING REMARKS

INDEX

COLOR PLATE SECTION

PREFACE

Acquired damage to the developing human brain occurs mainly during the second half of gestation—a critical developmental period. Most neuronal migration has already happened, but many other events will progressively unfold, resulting in complex interactions between naturally evolving and unexpected deleterious forces. This book comprehensively describes many normal developmental events in the human brain such as brain weight accretion, myelination, germinal subventricular tissue evolution and involution, angiogenesis, and gyrus formation, as well as some common adverse influences that may distort the course of these events.

Simultaneously in early development internal connections become functional without myelin and contribute to embryonic and fetal reflexes. Both normal and pathologic conditions, utilizing anatomic and radiologic comparisons, are illustrated. Because of widespread confusion about fetal and neonatal pathologic conditions, we have emphasized the specific history of each entity in order to more effectively delineate the evolution of current terms and concepts.

ACKNOWLEDGMENTS

FHG Over the years I have been fortunate to have had many esteemed mentors and colleagues. Among them I would like to acknowledge several whose teachings were of enduring personal significance. DN Buchanan and DB Clark introduced me to the world of pediatric neurology, and GF Vawter to that of pediatric pathology. R Lindenberg clarified the concept of the borderzone lesion and led me into neuropathology. R O’Rahily and PI Yakovlev illuminated the anatomic wonders of the developing human brain. Importantly, LW Swanson, more than any other neuroanatomist, unveiled for me a panoramic concept uniting the differing vertebrate neuroanatomies.

Finally, I would like to recognize my indebtedness to A Leviton for introducing me to the power of populations, to the role of biologic variability in human development, to statistical and epidemiologic tools, and to critical thinking applied to human disease.

MDN I would like to thank Floyd Gilles for inviting me to be a part of this project and for 24 years of learning and friendship. I have enjoyed every minute.

I would also like to thank my long-time associates and collaborators S Bluml and A Panigrahy for their contributions to Chapter 7 in this volume.

Lastly, thanks to PhDc Mary, the love of my life, and my fine sons Kevin and Andrew. I hope that they are as fortunate as I have been in finding professions and people that keep them interested, challenged, and learning for the rest of their lives.

Also to be recognized for their work in contributing to some chapters in this volume: BA Brody, JG Chi, EC Dooling, I Gonzalez-Gomez, HC Kinney, KCK Kuban, JE McLennan, SF Murphy, and CJ Tavaré.

We would also like to acknowledge our emendator and neuropathologist BW Zaias. Still, this volume would not have been possible without DA Prosak’s oversight, assistance, and attention to detail.

1

INTRODUCTION

Book subject matter

The developing human brain has an innate beauty and inherent intricacy, and is extraordinary in its assemblage, sequence, and the complexity of its integrated parts and circuits. However, adverse fetal, maternal, or environmental events may hamper the remarkable process of development.

This book concentrates on human brain development in the last half of gestation and in neonates and infants—periods that are regarded as largely responsible for the acquisition of childhood functional neurologic deficits, generally known as ‘cerebral palsy,’ ‘developmental delay,’ and ‘mental retardation.’^a Section 1 covers selected topics in typical development, including growth in brain weight, ventricular surfaces, gyral development, myelinated tract development, magnetic resonance spectroscopy, and angiogenesis. Section 2 addresses the common aforementioned acquired brain abnormalities. Between the two sections, Chapter 9 details embryonic and fetal physiologic reactions to external stimuli. We have intentionally excluded discussion of infectious diseases, bilirubin encephalopathy, and malformations because they are well reviewed in recent texts of pediatric neuropathology.¹

This book is based, in part, on the same database as the previous review, which discussed the epidemiology of fetal brain lesions [National Collaborative Perinatal Project (NCPP)].² We rely on some data from the NCPP but here have emphasized brain growth, pathology, and neuroimaging. The NCPP database remains the only large autopsy survey of late fetal brain lesions in infants for each of whom a large number of data (1200+ variables) such as maternal lifestyle, gestation, delivery, and neonatal potential antecedents had been collected in a priori fashion before death.

Brain growth and development

We emphasize the incredible manner and speed with which the embryonic and fetal brain generates, relocates, and unites substantial numbers of central nervous system neurons. If one assumes a large figure for this ultimate number (for instance, estimated at 10¹¹—L. Swanson, personal communication, 2009), then, during the first half of gestation, neuronal precursor cells develop in the ventricular zone, move to a new location, mature in very large numbers (for example, many hundreds of thousands every second), and make innumerable correct connections. Neuronal production and movement is not random; on the contrary, it seems tightly genetically controlled. Even so, there is considerable variance in developmental rates, for both early and late events, such as increase in weight, gyrus formation, and myelination. Growth acceleration alters abruptly toward the end of the second trimester and the growth rate becomes maximal at the end of gestation.

Traditional accounts of embryonic, early, and late fetal development tend not to appreciate the significance of the end of the second trimester: by this time most (but not all) neuronal proliferation and migration has ceased, fundamental brain anatomy has been established, and multiple, relatively simple, physiologic responses are occurring.

At second-trimester completion, brain weight accretion is accelerating maximally. Primary gyri begin maturation and subdivision, forming distinctive individual patterns, which are not mirror images of those in the opposite hemisphere, whereas total surface area remains similar in both hemispheres throughout gestation. Gyral outward growth, in configurations unique to each hemisphere and probably to each individual, introduces considerable functional imaging difficulties. The variability in human gyral patterns has been known for more than a century. Concomitantly, myelination flow accelerates, maximizing almost a year later, in the second half of the first postnatal year. Early myelination occurs in groups and is related to vestibular connections to the upper cervical cord via the medial longitudinal fasciculus and cerebellum; auditory connections with the brainstem, inferior colliculus, and medial geniculate; and peripheral sensory systems ascending from body peripheral nerves and the spinal cord to the brainstem, cerebellum, diencephalon, and eventually to the isocortex. Surprisingly, the tractus and nucleus solitarius, vital brainstem sites of central pattern generators for respiratory, cardiac, and visceral function, myelinate very late. Also late to myelinate are the fornix, hippocampus, and cingulum, considering that they lie at the medial hemispheral edge, which is first to form during embryonic life. Again, there is great variability in timing for any individual tract.

Identifying significant associations between neonatal neurologic damage and its antecedents is problematic for several reasons: the complex interaction between two individuals (fetus and mother) and their environments may obscure antecedents, and the living neonate, with its immature nervous system, sometimes stubbornly refuses to yield adequately valuable diagnostic and prognostic information until long after the neonatal period.

Investigative studies

DECREASING AUTOPSY RATES

Widespread decreasing autopsy rates and an inability to retain autopsy tissue for future study, coupled with a serious decline in neuroanatomic training for physician trainees, have resulted in few population studies, leading to much uncertainty regarding the precise location of brain lesions as well as misunderstanding of pathologic processes. For instance, a commonly used term, ‘periventricular,’ denoting an anatomic location, is of little value and is nonspecific, as all brain and spinal cord is periventricular at some time during development, and also because the term includes gray as well as white matter. Another frequently mentioned concept is the theorized vascular borderzone in deep fetal cerebral white matter to explain focal white matter lesions. Traditional borderzone lesions, lying between arterial beds, are well known to extend over some distance; they are not focal lesions in any sense and usually involve both gray and white matter. Moreover, not all necrosis is infarct, even though all infarction is necrosis. Further varied designations such as ‘stroke,’ ‘brain attack,’ ‘frontoparietal,’ or ‘prefrontal’ have no anatomic or pathologic specificity; they are of little worth in epidemiologic, statistical, or functional imaging studies. Neuroimaging terms are frequently conflated, which obscures meaning. For example, the term ‘periventricular leukomalacia’ (multiple focal white matter necroses, as originally defined)³ is used to describe diffuse white matter astrocytosis, or diffuse neuroimaging changes, or focal white matter lesions. Finally, there is widespread lack of autopsy evaluation and correlation of neuroimaging descriptions and interpretations, a potential source of manifold ambiguities.

INTERPRETATION

Labels used as antecedents or ‘causes’ need to be precise. For instance, some 34 different pathologic abnormalities, ranging from hemorrhage to necrosis, have been attributed to anoxia, hypoxia, hypoxia–ischemia, and asphyxia. The absence of adequate definitions of these clinical states in most reports suggests the possibility of other potentially modifiable risk factors having been missed by an obstetrician or neonatologist.⁴

For these reasons, we emphasize selected historic features of each entity and consider the original author’s interpretation. Many older studies were based on large autopsy populations, contributing much to our understanding; nevertheless, they recognized normal biologic variation often overlooked today. Even though anatomic, embryologic, and pathologic nomenclature may be cumbersome, the many noteworthy normal and abnormal events occurring during human nervous system development can be narrated in a perceptive style and enhance our understanding.

History of cerebral palsy

Over a century of intense neuroanatomic and neuropathologic work elapsed before Wallenberg introduced the term ‘cerebral palsy’ in 1886 to summarize the underlying clinical and anatomic aspects of brain damage in a child with a motor disability.⁵ Within a few years, the term was in general use (Table 1.1),^6–8 and, more recently, ELGAN study investigators⁹ developed an algorithm based on a reliable, standardized neurologic examination to subclassify these individuals.^10,11

NEUROANATOMIC KNOWLEDGE UNDERLYING BRAIN FUNCTION

Neuroanatomic knowledge was slow in developing. Leeuwenhoek (1717) and Fontana (1779)¹² recognized the nerve fiber and axon; in 1761, Morgagni realized that a lesion in one hemisphere caused contralateral paralysis.¹³ A century later, Rolando maintained that the cerebrum controls motor function, Gall identified the pyramid, and Ehrenberg, Valentin, and Koelliker described the nerve cell and its origin of nerve fibers.¹²

TABLE 1.1

Overview: history, anatomy, and multiple pathologies of ‘cerebral palsy’ (CP)

Year	Investigator
Cerebral palsy
1886	Wallenberg	Summarized the clinical and anatomic aspects of ‘infantile cerebral palsy’ and first used the term
1888	Lovett	Used the term ‘cerebral palsy’
1888	Osler	Used the term ‘cerebral palsy’
1893	Freud	‘Infantile cerebral diplegia’
1897	Freud	History of CP; emphasized preterm birth in association with diplegia; spent much of his book discussing lesions acquired during development, failure of development, and developmental retardation, but apparently did not recognize malformations of brain as understood today. Explained CP spasticity from brainstem and cord pyramidal tract secondary atrophy
Anatomic knowledge
Seventeenth century	Malpighi	Introduced the microscope to medicine
1717	Leeuwenhoek	Nerve fiber and axon
1761	Morgagni	Lesions of one hemisphere result in contralateral paralysis
1781	Fontana	Nerve fiber and axon
1799	Bichat	Brought histology to pathology
1809	Rolando	Cerebrum controls motor function
1810–19	Gall	Pyramid. Functional localization in brain
1820s	–	Achromatic compound microscope introduced
1833	Ehrenberg	Microscopic structure of nerve cell and fiber
1836	Valentin	Nerve cell, its nucleus, and nucleolus
1837	Purkynje	Cerebellar nerve cells
1839	Schwann	Cell theory and serious use of microscope in neurologic disease
1849	Koelliker	Nerve fibers originate from nerve cells
1849	Waller	Secondary degeneration
1851	Türck	Secondary anterograde atrophy in spinal cord after cerebral lesions
1856	Turner	Secondary anterograde atrophy in crus, pons, and pyramids. Crossed cerebellar atrophy. Understood trophic dependence of thalamus upon its ipsilateral cerebral cortex
1875	Erb	Described quadriceps reflex; arrest of pyramid development
1876	Raymond (Charcot trainee)	Special localization of motor function in internal capsule
1877	Flechsig	Delineated pyramidal tract in posterior limb of internal capsule
1883	Golgi	Neuronal syncitial net
1887	His	Each neuron is a distinct unit
1888	Cajal	Each neuron is independent of other neurons
1891	Waldeyer	Neuron
1896	Babinski	Babinski’s sign; prior descriptions in the 1850s by Vulpian and in 1893 by Remak. All three linked it to brain or pyramidal tract damage
Acquired defects: Central nervous system cerebral gray and white matter
1818	Abercrombie	Parturitional spinal cord injuries
1822	Pinel (the son)	Lobar sclerosis
1826	Denis	Mechanical birth injuries cause hemorrhages in newborn brain
1827	Cazauvielh	Multiple small cysts; two cases with larger cysts; small pallium
1829–37	Cruveilhier	Small brain. Hemiatrophy of brain
1830	Delpech	Small brain
1842	Henoch	Infantile cerebral atrophy
1853–70	Little	Abnormalities of birth and neonatal asphyxia. Recognized that the majority of stillborn infants, when resuscitated, recover unharmed
1855	Friedleben	65% of newborn autopsies revealed cerebral lesions; brain sclerosis and atrophy
1859–68	Heschl	Porencephaly; vascular affection in fetus
1862	Parrot	Intracerebral hemorrhages; cervical spinal cord injury
1868	Cotard	Partial atrophy of brain; diffuse lobar sclerosis; lesions in specific arterial beds
1870	Parrot	Upper spinal cord lesions
1882	Ross	Lobar sclerosis results from arterial emboli
1884	Strümpell	Acute infantile hemiplegia ‘polioencephalitis’
1885	McNutt	Convolutional sclerosis; bilateral paracentral atrophy
1887	Abercrombie	Found embolus in artery leading to cerebral defect
1888	Lovett	60 cases of CP: Embolism and parenchymal hematomas important
1888	Osler	50 cases of CP: Partial or lobar sclerosis; paracentral in all; arterial occlusion
1888	Gowers	Birth palsies: Arterial thrombosis and embolism
1890	Sachs	Cerebral palsies of early life
1891	Freud	Choreatic form of CP
1893	Anton	Status marmoratus
1896	Schultze	Parturitional cysts and scars in medulla and spinal cord
1899	Bresler	Ulegyria
1958	Crome	Multicystic encephalopathy
Acquired defects: Cerebral white matter only
1850	Bednar	Focal cerebral necroses newborn brain are mostly deep white matter
1862	Parrot	Focal necroses in white matter-metabolic disorder
1865–7	Virchow	Focal necroses in white matter-infection
1904	Schmorl	Described 280 cases of focal necroses in white matter; summarized previous studies from 1862 (Parrot) to 1903 (Moebius, Vivius, Herschfeld, and Hlava)
1940–5	McClelland, Benda, Crome	White matter hypoplasia; (separately) delayed myelination

Compiled from data in Freud,⁸ Yakovlev,¹⁵ Gilles et al,¹⁶ and Laird et al.¹⁷

Embryonic and fetal age

One traditional independent variable, estimated gestational age, has an error of several weeks. Furthermore, gestational age estimates, adjusted for ‘correctness’ of body length or weight, may be ‘improved’ but suffer seriously from the bias of selective loss of data (for instance, how do you deal with the excluded case?) and of dependent factors that may often contaminate the estimate. The major advantage of gestational age as an independent variable is that it is regularly sequenced throughout gestation and, once determined, is free of events occurring within the mother or infant. Various terms are commonly used: menstrual age (time from the last menstrual period) is approximately 2 weeks longer than the postovulatory age; gestational age (the mother’s best estimate of when she was fertilized); and implantation age (the time of uterine wall blastocyst implantation)—about 7.5 days. The best assessment of embryonic or fetal age is the conceptional, postconceptional, or postovulatory age, which is approximately 2 weeks less than the menstrual age. Of course, the actual age in days cannot be known. For this book, we use postovulatory age when we know it or can estimate it. For the neuroimaging sections, specific gestational age was often ambiguous and the author’s estimates were used, implying possible appreciable variation in gestational age of a particular function.

For embryonic material, we use postovulatory dates unless otherwise stated; for developmental stages, we use Carnegie staging.¹⁴ In the remainder of the book, we use the original author’s statements as to embryonic or fetal age unless there are obvious errors. Embryonic stages are based on the apparent developmental morphologic state and hence are not directly dependent on either chronologic age or size. Embryo length as a single criterion is not in itself sufficient to establish a stage, as length may vary concomitantly with development of the brain abnormality.

National Collaborative Perinatal Project

The National Institute of Neurological and Communicative Disorders and Stroke prospectively collected data throughout pregnancy and childhood for a large number of children in an attempt to ascertain modifiable maternal, fetal, or perinatal events that could account for aspects of childhood cerebral dysfunction. Thus, all clinical data were similarly prospectively collected in both groups of infants: those who subsequently died and those who survived.

THE NATIONAL COLLABORATIVE PERINATAL PROJECT PATHOLOGIC MATERIAL

The NCPP pathologic material includes several distinct populations. Cases with recorded gestational and survival ages and fresh brain weights numbered 1537: correlation of pathologic and epidemiologic data used 1100 brains, Yakovlev selected 425 individuals for whole-brain serial sectioning after celloidin embedding,¹⁵ while the remainder were processed through paraffin. See our previous volume² for details of other subpopulations. Each serially sectioned brain was photographed in six planes, yielding some 2400 black-and-white prints. More than 100 000 slides were generated and are currently maintained at the US Armed Forces Institute of Pathology. Paraffin-processed brains were cut in a standardized fashion at approximately 3-mm intervals; each slab was photographed and multiple blocks were prepared. In excess of 30 000 color transparencies of whole brains and slabs, as well as multiple stains on sections from each block, were obtained.

OBSERVER VARIABILITY

To minimize observer variability in data ascertainment, two observers simultaneously reviewed each selected photograph and slide either grossly or with a double-headed microscope.¹⁶ The data were recorded on standard check-off sheets abstracted from a matrix of approximately 700 possible combinations of brain site and disease process.

STUDY ASSUMPTIONS

Any study is based on assumptions and biases, some identified and many unrecognized. We acknowledged and tried to deal operationally with the following assumptions.

We assumed that all brains were abnormal, as most were derived from fetuses or infants in some way sufficiently abnormal to have aborted spontaneously or to have died shortly after birth. Thus, statements about acquisition of a brain structure compare ‘early’ and ‘late’ in a population of abnormal infants. On one hand, this assumption may exaggerate a risk factor contribution in some circumstances, but, on the other hand, it may diminish such a contribution to a morphologic condition if the existent risk factor is otherwise common to all dead children. While assuming that all brains were abnormal, still it cannot be denied that some brains approached what is considered to be ‘normal.’ Then again, in making judgments about the developing human brain, this is the best we can do.

The second assumption was that, in evaluating the development of an organ, growth could be measured in many ways. Growth is generally a continuous process; however, one cannot repeatedly sample a single growing fetus. This limits the best growth estimates to fetuses that died at different times in development. As each way of measuring growth has its own strengths in contributing to our understanding, each is valued. Although we use the traditional strategy of measuring growth against the independent variable of estimated gestational age, we also use, in some instances, other parameters as the independent variable.

Body weight and crown–rump length are two variables frequently used as abscissae and ordinates. Although they are easily ascertained at birth or autopsy, they have serious limitations. First, changes in body length and brain or body weight are unequal throughout gestation and tend to decrease near term, when greatest discrimination is desired (in comparison with degree of myelination, for instance). Thus, one would recognize only coarse discrepancies, probably even with the use of ratios such as body/brain weight. Second, factors potentially inhibiting or failing to support some brain growth component could also affect body weight or length; consequently, if weight or length is the independent variable, such factors could conceivably be overlooked. Third, the allometric relationship between brain and body part growth precludes meaningful analysis of growth itself.¹⁷

The following assumptions are associated. We assumed that recognizable structural abnormalities underlie some functional cerebral deficits, such as mental retardation or cerebral palsy, and that they appear during gestation, originating in events that altered the fetal and/or neonatal environment. These alterations constitute ‘natural experiments,’ usable when investigating disease etiology. This last point is important because appropriate experiments on an infant are inconceivable and direct extrapolation from experiments on subhuman primates is fraught with conceptual and ethical problems. It is hoped that maternal and perinatal factors, which contribute to perinatal cerebral morbidity, can be directly modifiable (even if exact etiologic mechanisms are not understood). A related assumption was that these structural abnormalities are separable from nervous system morphologic abnormalities allied with ‘dying.’ Extrapolation of conclusions from information about dead to living children must be done with care. We may strongly suspect comparable processes in live children, but, without additional evidence, one must restrain this conjecture.

Despite the societal definition, the process of death is rarely instantaneous. Even when cardiac action ceases, some cellular metabolic activities continue. Before final cardiostasis, there is considerable internal milieu discord from cardiovascular, respiratory, and metabolic instability. Thus, a wide variety of nervous system changes (for instance, neuropil vacuolization, cellular shrinkage, neuronal hyperchromia) potentially merely reflect those terminal events. Although acute terminal brain morphologic changes may be similar to those sustained during a survived insult, their equivalence has never been adequately demonstrated in the human. Further, one must assume that there are, most likely, quantitative and qualitative differences between insults damaging development in a surviving brain and those accompanying death. Termination of life may indeed be associated in some brains with abnormalities traditionally called ‘ischemic’ or ‘hypoxic’ neuronal change; this supports, but does not prove, a causal relationship. Consequently, the observation that both some hypoxia and brain damage occur with a difficult delivery does not identify an initiator and, even more importantly, prevents an adequate search for other potentially treatable antecedents coincident with difficult delivery. For our purposes, we found karyorrhexis, coagulative necrosis, macrophages, glial scars, intramural vascular deposits, and neuronal depletion to be of greater interest than acute neuronal changes.

Another assumption was that morphologic abnormalities commonly found in dead newborn brains are similar in nature, site, and rate to those found in brains of people afflicted with mental retardation and cerebral palsy. This supposition is difficult to resolve owing to a lack of adequate data. For the purposes of these studies, we postulated comparability, at least at some level, with two accompanying corollaries. There were almost no NCPP cases of storage disease, tumors, or progressive degenerative diseases, and it became clear that the majority of individuals with mental retardation or cerebral palsy do not have these conditions. Thus, the NCPP brain population was quite appropriate in this respect. The second obvious corollary is that brain abnormalities in institutionalized individuals likely differ qualitatively or quantitatively from the NCPP population.

RANGE OF ABNORMALITIES

The range of NCPP cerebral abnormalities reflected those encountered on any usual neonatal neuropathology service. There were few congenital malformations similar to those found in the brains of institutionalized individuals. Thus, this volume records observations in a general sense; it focuses mainly on topics such as myelination delay, intracranial hemorrhage, and telencephalic leukoencephalopathies rather than malformations or genetic or metabolic conditions.

The pathologist, when examining neonatal brains of differing gestational ages, should be aware that some adult criteria of abnormality are potentially misleading. For instance, macrophages in moderately cellular leptomeninges, perivascular cuffs of small mononuclear cells adjacent to ventricle, or large numbers of microglia-like cells in telencephalic structures are abnormal in the adult brain but are typical in the infant brain.

Lesions in neonatal brain range in complexity from simple loss of neural tissue (for instance, necrosis) to complex malformations arising from diverse mixtures of developmental arrests, migration abnormalities, and abortive repair attempts. Delay in acquiring an evolving brain component (such as myelin) characterizes another broad group of ‘lesions.’ This latter ‘lesion,’ and evaluation of its antecedents, likely has greater long-term social significance than the more dramatic lesions referred to above, as more children are at risk for more prevalent antecedents (such as malnutrition). Moreover, assessment of delayed nervous system development (in terms of weight, neuronal mass, complexity of dendritic tree and spine arborization, or myelination degree, for instance) presupposes that adequate standards, controlled for site and systemic disease, are available. Unfortunately, such standards that exist are largely unsatisfactory, most being based on small samples, anecdotal evidence, or populations limited by arbitrary case exclusion. A similar predicament applies to the phenomenon of fetal brain myelination: available tables are constructed from small case numbers or fail to estimate normal biologic variation within each tract as it myelinates (for example, time of onset or rate of myelination). Thus, one of our tasks is to identify histologic and pathologic clues in unmyelinated and/or myelinating brain tissue, the tactile and visual characteristics of which are distinct from tissue in adult brain and whose normal constituents and ‘reacting’ cells are still immature, not having reached their full capabilities.

At term, the brain is at its maximal growth rate; by the second year it will almost have tripled its birthweight. Deposition of a large amount of myelin in the last gestational weeks and during the first few neonatal months probably accounts for most of this weight gain. Importantly, then, this transient and unique tissue (myelinating white matter) is potentially vulnerable to multiple and heterogeneous insults, and thus estimation of its degree of maturation is crucial. Similarly, another transient tissue, germinal tissue lining the ventricular system, may be subject to distinctive damage.

REFERENCES

1.      Golden JA, Harding BN, editors (2004) Developmental Neuropathology. Basel: International Society of Neuropathology.

2.      Gilles FH, Leviton A, Dooling EC (1983) Developing Human Brain: Growth and Epidemiologic Neuropathology. Boston: John Wright-PSG Publishing Co.

3.      Banker BQ, Larroche JC (1962) Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch Neurol 7: 386–410.

4.      Gilles FH (1977) Lesions attributed to perinatal asphyxia in the human. In: Gluck L, editor. Intrauterine Asphyxia and the Developing Fetal Brain. Chicago: Year Book Medical Publishers, Inc, pp. 99–107.

5.      Wallenberg A (1886) Ein Beitrag zur Lehre von den cerebralen Kinderlähmungen. Jahrbuch für Kinderheilkunde 24: 384–439.

6.      Lovett R (1888) A clinical consideration of sixty cases of cerebral paralysis in children. Boston Med Surg J 26: 641–646.

7.      Osler W (1888) The cerebral palsies of children. Med News (Phila) 2–5.

8.      Freud S (1897) Die Infantile Cerebrallähmung, Vol. IX. In: Nothnagel, series editor. Specielle Pathologie und Therapie. Vienna: Holder.

9.      O’Shea TM, Allred EN, Dammann O, et al; ELGAN study investigators (2009) The ELGAN study of the brain and related disorders in extremely low gestational age newborns. Early Hum Dev 85: 719–725.

10.    Kuban KC, Allred EN, O’Shea M, Paneth N, Pagano M, Leviton A (2008) An algorithm for identifying and classifying cerebral palsy in young children. J Pediatr 153: 466–472.

11.    Accardo PJ, Hoon AH Jr. (2008) The challenge of cerebral palsy classification: the ELGAN study. J Pediatr 153: 451–452.

12.    Clarke E, O’Malley C (1996) The Human Brain and Spinal Cord; A Historical Study Illustrated by Writings from Antiquity to the Twentieth Century. San Francisco: Norman Publishing.

13.    Morgagni G (1761) The Seats and Causes of Diseases. Translated by Alexander B. London: Johnson and Payne.

14.    O’Rahilly R, Müller F (1994) The Embryonic Human Brain: An Atlas of Developmental Stages. New York: Wiley-Liss.

15.    Yakovlev PI (1970) Whole brain histological sections. In: Tedeschi C, editor. Neuropathology; Methods and Diagnosis. Boston: Little, Brown, pp. 371–378.

16.    Gilles FH, Winston K, Fulchiero A, Leviton A (1977) Histologic features and observational variation in cerebellar gliomas in children. J Natl Cancer Inst 58: 175–181.

17.    Laird A, Barton A, Tyler S (1968) Growth and time: an interpretation of allometry. Growth 32: 347–354.

Footnote

^aUK usage: learning disability.

Section 1