Chapter 38. Developmental Diseases of the Nervous System

This broad heading subsumes a large number of both genetically driven developmental malformations and diseases acquired during intrauterine or early neonatal periods of life. They number in the hundreds according to the tabulation of Dyken and Krawiecki although many, if not most, are rare. Taxonomically, they make up two broad categories. The first includes specific gene defects, either mutations, deletions, or duplications of parts of genes (copy number variation), or single nucleotide polymorphisms that give rise to developmental aberrations or delays. The second category comprises a variety of environmental and infectious agents acting at different times on the immature nervous system during embryonal, fetal, and perinatal periods of life.

Several points should be noted regarding the frequency of malformations. Jones, in the Smith monograph, has pointed out that a single minor malformation, usually of no clinical significance, occurs in 14 percent of newborns. Two malformations appear in 0.8 percent of newborns, and in this group, a major defect is five times more frequent than in the normal population. Three or more malformations are found in 0.5 percent of newborns, and in this latter group, more than 90 percent have one or more major abnormalities that seriously interfere with viability or physical well-being. The figures for major congenital malformations compiled by Kalter and Warkany are comparable but somewhat higher. What is most important for the neurologist is the fact that the nervous system is involved in most of infants with major malformations. Indeed, approximately 40 percent of deaths during the first postnatal year are in some manner related to prenatal malformations of the central nervous system.

Certain principles are applicable to the entire group of malformations. First, the abnormality of the nervous system is frequently accompanied by an abnormality of some other structure or organ (eye, nose, cranium, spine, ear, and heart), which relates them chronologically to a certain period of embryogenesis. Conversely, the presence of these malformations of nonnervous tissues suggests that an associated abnormality of the nervous system is developmental in nature. For example, the conjunction of cardiac, limb, gut, and bladder abnormalities with a neurologic disorder indicates the time at which the insult takes place: cardiac abnormalities occur between the fifth and sixth week; extroversion of the bladder at less than 30 days; duodenal atresia, before 30 days; syndactyly, before 6 weeks; meningomyelocele, before 28 days; anencephaly, before 28 days; cleft lip, before 36 days; syndactyly, cyclopia, and holoprosencephaly, before 23 days. Each is discussed in this chapter. This principle is not inviolable; in certain maldevelopments of the brain that must have originated in the embryonal period, all other organs are normal. One can only assume that the brain was more vulnerable than any other organ to prenatal as well as natal influences. Perhaps this occurs because the nervous system, of all organ systems, requires the longest time for its development and maturation, during which it is susceptible to disease. Low birth weight and gestational age, indicative of premature birth, increase the risk of cognitive or sensory developmental delay, seizures, and cerebral palsy.

A maldevelopment of whatever cause should be present at birth and remain stable thereafter, that is, be nonprogressive, in contrast to the majority of metabolic diseases of infancy discussed in the preceding chapter. However, this principle requires qualification: The abnormality may have affected parts of the brain that have not matured at birth, so that an interval of time must elapse postnatally before the defect can express itself.

Many of the teratologic conditions that cause birth defects pass unrecognized because they end in spontaneous abortions. For example, defects caused by chromosomal abnormalities occur in approximately 0.6 percent of live births, but such defects are found in more than 5 percent of spontaneous abortuses at 5 to 12 weeks gestational age.

Regarding the genetic causes of malformations and developmental delay, much has been learned in the past decade but a picture of the genetic influences on these conditions is still incomplete. For half a century, whole chromosome karyotyping allowed the recognition of conditions such as Down syndrome and its association with triplication of the entire chromosome 21. As more refined techniques became available, such as high-resolution banding, subtle changes such as small deletions in chromosomal architecture became apparent, as occur in Angleman and Prader-Willi syndrome and fragile-X syndrome. What followed, by the use of linkage analysis and other genetic techniques, was the elucidation of single gene mutations that were obligatorily associated with malformations or developmental delays; most of the inherited metabolic disorders of infancy and childhood discussed in Chap. 37 are of this type but also certain gross malformations of the brain such as lissencephaly, discussed further on.

These were the forerunners of a completely different category of technical innovations, anchored by the original method of sequencing short lengths of part of a gene by the Sanger method and its derivatives. With the development of the polymerase chain reaction and automated methods, longer and longer sequences of genes could be studied. This has allowed large population studies, merged with statistical techniques that expose genes in affected individuals that may be responsible for disease and are not present in high frequency in the general populations. From there, the rapid evolution of technology that is able to analyze thousands of portions of DNA in parallel and compare numerous sequences to a reference library of DNA has revealed variants at the resolution of single base pairs, single nucleotide polymorphisms (SNPs). Most exploration of human disease has been, until recently, based on the "common disease–common variant" model, in which a disease is attributable to limited number variants that exist in more than 1 to 5 percent of a population. For example, five polymorphisms are each responsible for doubling or tripling the risk of macular degeneration. However, most of these variants are probably not themselves responsible for the disease.

These types of genetic changes do not appear to explain the majority of the various developmental diseases. A newer concept of duplication or deletion of portions of genes, "copy number variation" is emerging as possibly explanatory of some proportion of diseases such as autism as discussed further on. What is interesting about copy number variation is that they give rise to several phenotypes of similar disorder, quite unlike conventional mendelian mutations. This indicates that copy number variants, like SNPs, probably are not directly causative of a condition but instead modulate other functions that express proteins. This is the situation for many of the forms of developmental abnormalities such as generic cognitive developmental delay, autism, and certain psychiatric diseases.

A textbook on the principles of neurology cannot catalog all the hereditary and congenital developmental abnormalities that affect the nervous system. For such details, the interested reader should refer to several excellent monographs. Three that the authors consult are Brett's Pediatric Neurology, Berg's Principles of Child Neurology, and Lyon and Evrard's Neuropediatrie. These are supplemented by special atlases of congenital malformations mentioned further on. In this chapter, we sketch only the major groups and discuss in detail a few of the more common entities. The classification in Table 38-1 adheres to a grouping in accordance with the main presenting abnormality. Represented here are the common problems that lead families to seek consultation with the pediatric neurologist: (1) structural defects of the cranium, spine, and limbs, and of eyes, nose, ears, jaws, and skin; (2) disturbed motor function, taking the form of retarded development or abnormal movements; (3) epilepsy; and (4) developmental delay—mental retardation. The following discussion focuses on each of these clinical states.

A majority of the disorders in this group is the result of a genetic error, including those with a specific chromosomal abnormality. One has only to walk through an institution for the developmentally delayed to appreciate the remarkable number and diversity of dysmorphisms that attend abnormalities of the nervous system. Smith, in the third edition of his monograph on the patterns of human malformations, listed 345 distinctive syndromes; in the fourth edition (edited by K.L. Jones [1988]), many new ones were added. Indeed, a normal-appearing and severely cognitvely impaired individual stands out in such a crowd and will frequently be found to have an inherited metabolic defect or birth injury.

The intimate relationship between the growth and development of the cranium and that of the brain is likely responsible for many of the associations in maldevelopment. In embryonic life the most rapidly growing parts of the neural tube induce unique changes in, and at the same time are influenced by, the overlying mesoderm (a process termed induction); hence abnormalities in the formation of skull, orbits, nose, and spine are regularly associated with anomalies of the brain and spinal cord. During early fetal life the cranial bones and vertebral arches enclose and protect the developing brain and spinal cord. Throughout the period of rapid brain growth, as pressure is exerted on the inner table of the skull, the latter accommodates to the increasing size of the brain. This adaptation is facilitated by the membranous fontanels, which remain open until maximal brain growth has been attained; only then do they ossify (close). In addition, stature is apparently controlled by the nervous system, as shown by the fact that a majority of mentally retarded individuals are also stunted physically to a varying degree. Thus disorders of craniovertebral development assume importance not merely because of the physical disfigurement but also because they often reflect an abnormality of the underlying brain and spinal cord, whereby they become the main diagnostic signs of the maldevelopment.

Cranial Malformations at Birth and in Early Infancy

Certain alterations in size and shape of the head in the infant, child, or even the adult, always signify a pathologic process that affected the brain before birth or in early infancy. Because the size of the cranium reflects the size of the brain, the tape measure is one of the most useful tools in pediatric neurology—no examination in a neurologically affected child is complete without a measurement of the circumference of the head. Graphs of head circumference in males and females from birth to 18 years of age were compiled by Nellhaus and are commonly used by pediatricians. A newborn whose head circumference is below the third percentile for age and sex and whose fontanels are closed may be judged to have a developmental abnormality of the brain. A head that is normal in size at term but fails to keep pace with body length (microcephaly) reflects a later failure of growth and maturation of the cerebral hemispheres (microencephaly).

Enlargement of the Head (Macrocephaly)

This can be caused by factors extrinsic to the brain tissue, such as hydrocephalus and hydrancephaly (as defined below), or excessive brain growth (megalo- or macroencephaly; Table 38-2). The hydrocephalic head is distinguished by several features: frontal protuberance, or bossing; a tendency for the eyes to turn down so that the sclerae are visible between the upper eyelids and iris (sunset sign); thinning of the scalp and prominence of scalp veins; separation of the cranial sutures; and a "cracked pot" sound on percussion of the skull. Infantile hydrocephalus usually comes to medical attention because of an expanding cranium that exceeds normal dimensions for age. The usual causes are type II Chiari malformation, hereditary aqueductal stenosis, and prenatal infections, for example, toxoplasmosis. These disorders are discussed further on.

Hydranencephaly, defined as hydrocephalus and destruction or failure of development of parts of the cerebrum, is often associated with enlargement of the skull. When the cranium is transilluminated with a strong flashlight in a darkened room, the fluid-filled region of the cranium glows like a jack-o'-lantern. It can be caused by cerebral infarction from intrauterine vascular occlusion or by diseases such as toxoplasmosis and cytomegalovirus (CMV) disease, which destroy parts of each cerebral hemisphere. The lack of brain tissue reduces resistance to intraventricular pressure, permitting great enlargement of both lateral ventricles; it is especially marked if there is an added hydrocephalic state because of interference with cerebrospinal fluid circulation. This type of destruction of the cerebral mantle in the embryonal period may lead to the formation of huge brain defects with apposition of ventricular and pial surfaces (porencephaly) and subsequent failure of development of that part of the brain. Yakovlev and Wadsworth referred to the localized failure of evagination as schizencephaly and postulated that it was the result of a focal developmental defect in the wall of the cerebral mantle. They based their interpretation on the finding of malformed cortex in the margins of the defect but this might indicate only that the lesion preceded neuronal migration. Levine and coworkers attributed it to a destructive, possibly ischemic, lesion occurring in the first few weeks of gestation, at a time when neuronal migration was incomplete. However, at least some forms have been traced to genetic defects as detailed further on.

The macrocephalic head (a large head with normal or only slightly enlarged ventricles) may be indicative of an advancing metabolic disease that enlarges the brain, as in Alexander disease, Canavan spongy degeneration of infancy, and later phases of Tay-Sachs disease, all of which are described in Chap. 37. Agenesis of the corpus callosum, a common congenital defect, may be associated with macrocephaly and varying degrees of mental impairment, optic defects, and seizures. In a series of 56 patients with agenesis of the corpus callosum, Taylor and David reported the presence of epilepsy in 32 and varying degrees of developmental delay in 28; only 9 had no recognizable neurologic defects. Also noted was a high incidence of psychiatric disturbances in these patients. In such cases, CT and MRI reveal the characteristic "bat-wing" deformity of the ventricles. There is also asynchrony of electrical activity of the two cerebral hemispheres on the electroencephalogram (EEG). In a few of these patients, an autosomal dominant inheritance was found (Lynn et al). Agenesis of the corpus callosum is also part of the Aicardi syndrome (see further on) and the Andermann syndrome, and it has been noted, without explanation, in some cases of nonketotic hyperglycinemia.

Subdural hematomas also enlarge the child's head and cause bulging of the fontanels and separation of the sutures. The infant is usually irritable and listless, taking nourishment poorly. Infants and children with neurofibromatosis, osteogenesis imperfecta, and achondroplasia also have enlarged heads; in the last of these, some degree of hydrocephalus appears to be responsible. Ultrasonography, which can be performed in the prenatal and neonatal periods, is usually diagnostic in all these cranial enlargements. Also MRI and CT scanning will disclose the size of the ventricles and the presence of subdural blood or fluid (hygroma).

Apart from patients with these pathologic states, there are individuals whose heads and brains are enlarged but who are normal in all other respects. Many of them come from families with large heads. Schreier and colleagues, who traced this condition through three generations of several families, declared it to be an autosomal dominant trait. This group represented 20 percent of 557 children referred to a clinic because of cranial enlargement, according to Lorber and Priestley.

Hemimegalencephaly

This term refers to a marked enlargement of one cerebral hemisphere as a result of a developmental abnormality. The cortical gray matter and sometimes the basal ganglia are greatly increased in volume and weight. The cerebellum, brainstem, and spinal cord retain their normal dimensions. The cranium may be misshapen or enlarged but is normal in size in some cases. Rarely, the face and body are enlarged on the side of the enlarged hemisphere. The cortex of the giant hemisphere is thick and disorganized. Neurons are in disarray and some are enlarged; in some places the natural lamination of the cortex is effaced. Nothing is known about causation, but clearly embryogenesis has been deranged at the stage of neuroblast formation.

Clinically, these individuals are cognitively delayed and some have epilepsy. A degree of hemiparesis may be present but severe hemispheral neurologic deficits are generally not reported. However, hemimegalencephaly has been discovered at autopsy in a few individuals who had no mental or neurologic deficits.

Craniostenoses

Some of the most startling cranial deformities are caused by premature closure of the cranial sutures (membranous junctions between bones of the skull). Such conditions are estimated to occur in 1 of every 1,000 births, with predominance in males (Lyon and Evrard). The growth of the cranium is inhibited in a direction perpendicular to the involved suture(s), creating a compensatory enlargement in other dimensions as allowed by the patent sutures. For example, when the lambdoid and coronal sutures are both affected, the thrust of the growing brain enlarges the head in a vertical direction (tower skull, or oxycephaly, also referred to as turricephaly and acrocephaly). The orbits are shallow, the eyes bulge, and skull films show islands of bone thinning (lückenschädel). When only the sagittal suture is involved, the head is long and narrow (scaphocephalic) and the closed suture projects, keel-like, in the midline. With premature closure of the coronal suture, the head is excessively wide and short (brachycephalic). The nervous system is usually normal in these restricted craniostenoses. If this condition is recognized before 3 months of age, the surgeon can make artificial sutures that may permit the shape of the head to become more normal (Shillito and Matson). Once brain growth has been completed, little can be done aside from complex reconstructive surgery. When several sutures (usually coronal and sagittal) are closed, so as to diminish the cranial capacity, intracranial pressure may increase, causing headache, vomiting, and papilledema. An operation is then needed to increase the capacity of the skull.

In acrocephalosyndactyly, or Apert syndrome, craniostenoses are combined with syndactyly (fused, or webbed, fingers or toes). There are often added complications: mental retardation, deafness, convulsions, and loss of sight secondary to papilledema. The so-called clover-shaped skull is the most severe and lethal of the craniostenoses because of the associated developmental anomalies of the brain (see further on).

Approximately one-quarter of affected children with craniostenoses will be found to have a single gene or chromosomal abnormality, most commonly in the FGFR3 gene.

When, for any reason, an infant lies with the head turned constantly to one side (because of a shortened sternomastoid muscle or hemianopia, for example), the occiput on that side, over time, becomes flattened, as does the opposite frontal bone. The other occipital and frontal bones bulge, so that the maximum length of the skull is not in the sagittal but in the diagonal plane. This condition is called plagiocephaly, or wry head. Craniostenosis of one-half of a coronal suture may also distort the skull in this way.

Disturbances of Neuronal Migration and Cortical Development

Neuroembryologic studies have identified several milestones of neuroblast formation, migration, cortical organization, neuron differentiation, and connectivity. Certain developmental anomalies can be traced to one of these stages of cytogenesis and histogenesis in the first trimester of gestation and to the growth and differentiation that take place in the second and third trimesters. During the first trimester, postmitotic neurons that will ultimately reside in the cortex arise in the ventricular zone adjacent to the ventricles. They migrate along the scaffold of radial glia to form the multilayered cortex. It is interesting that neurons moving up the scaffold must pass through neurons that are already in position in the cortex, leading to an "inside-out" lamination in which the most recently born and arrived neurons reside on the outermost surface of the forming cortex.

Originally there is an excess of neurons, many of which degenerate during development—a process properly called apoptosis. There are recorded instances in which the full complement of neuroblasts and neurons fails to be generated. In the extreme, the emergence of two separate cerebral hemispheres may not occur (holoprosencephaly), or the bihemispheric brain may remain small (microcephaly). In other described instances, a diminished number of neurons are less obvious than their failure to migrate to the cortical surface; they remain scattered through the mantle zone in sheets and heterotopic aggregates. One type of focal band-shaped subcortical heterotopia is termed "double cortex." Polymicrogyria refers to an excessive number of abnormally small gyri. It is expressed by a syndrome of mental retardation, seizures, delayed speech, and motor abnormalities. The cortex may fail to become sulcated—that is, it is lissencephalic or may be defectively convoluted, forming microgyric and pachygyric (broad gyral) patterns. In yet other brains, neuronal migration is normal for the most part, but small groups of neurons in particular regions may lag or present in regional heterotopias (focal dysgeneses; Fig. 38-1). These migrational disorders, particularly heterotopias, are now being recognized more often by MRI and are found to have a functional significance in epilepsy but also possibly in such states as nonspecific developmental delay, and dyslexia. Finally, the cortex may be normally formed and structured but there is a failure of differentiation of intra- and intercortical and interhemispheral connections, the most obvious one being agenesis of the corpus callosum.

The timing of embryogenesis of the main visceral organs and of the coincident stages of neural tube closure were given in the introduction. With these elementary facts of neuroembryology in mind, the bases of the following clinical states are readily conceptualized: anencephaly, lissencephaly, holoprosencephaly, polymicrogyria and pachygyria, microcephaly, and special combinations of cranial and somatic abnormalities. Each is described below.

In regard to disorders of brain development, there are also special types of tumors that are the consequence of abnormal neuronal or glial development. These are variously termed gangliomas, or gangliocytomas, dysembryoplastic neuroepitheliomas (DNETs), and low-grade astrocytomas. Sometimes they become manifest in the first year of life or even before birth. Their relatively slow growth and benign character suggest that some of them represent hamartomas rather than true neoplasms (see Chap. 31). Among the ones we have encountered in adults is the Lhermitte-Duclos type of cerebellar gangliocytoma that is characterized by a "tigroid" appearance on MRI (see Fig. 31-15).

Genetics of Cerebral Disorders of Neuronal Migration (Table 38-3)

Because each phase of cerebral development is under genetic control, it comes as no surprise that aberrant development might have a genetic basis. A singular advance in this field has been the identification in recent years of large numbers of genetic defects that underlie disorders of neuronal migration. These mutations, and what are known of their effects on the developing nervous system, were reviewed extensively by Mochida and Walsh, by Kato and Dobyn, and by Barkovich and colleagues; a summary is given in Table 38-3. The reader will notice that several quite different mutations may give rise to the same type of maldevelopment and that any given gene can cause malformations of varying severity but in most cases, the affected gene is active at a stage in brain development that makes the nature of the malformation understandable.

It should at the same time be noted that metabolic disturbances may also give rise to malformations of cerebral development. For example, in their review of the inborn errors of metabolism those are linked to cerebral dysgeneses. Nissenkorn and colleagues point out that disorders such as Zellweger syndrome and disorders of fatty oxidation, phenylketonuria (PKU), hyperglycinemia, and pyruvate dehydrogenase deficiency cause aberrant neuronal migration and dysgenesis of the corpus callosum.

Anencephaly

This is one of the most frequent and also most appalling congenital malformations of the brain. Its incidence is 0.1 to 0.7 per all 1,000 births and females predominate in ratios ranging between 3:1 and 7:1 in different series. The concordance rate is low, both in identical and fraternal twins, but the incidence of the malformation is, nonetheless, several times the expected rate if one child in the sibship has been affected. Anencephaly has also been more frequent in certain geographic areas, for example, Ireland, for which various explanations of population genetics or environmental exposure have been postulated.

Missing in cases of anencephaly are large portions of scalp, cranial bones, and brain, including both cerebral cortex and white matter. All that remains is a hemorrhagic nubbin of nerve, glial, and connective tissue. Brainstem, cerebellum, and spinal cord are present but often, they too are malformed, as are the heart and other organs (15 to 40 percent of cases). In anencephalics who survive for a few days (65 percent die in utero and almost 100 percent before the end of the first postnatal week), startle reactions may be observed, as well as movements of limbs, spontaneous respirations, pupillary light reactions, ocular movements, and corneal reflexes. In a few, avoidance reactions, crying, and feeding reflexes can be elicited, indicating that only the rudimentary brain structures are required for these functions.

This condition, or a related one, can be anticipated if the mother's serum levels of alpha-fetoprotein and acetylcholinesterase are elevated—even more reliably anticipated if they are elevated in the amniotic fluid. Positive tests should lead to ultrasonograph imaging of the fetus. Hydramnios is common.

The causes of anencephaly are multiple and include chromosomal abnormalities, maternal hyperthermia, and, apparently, deficiencies of folate, zinc, and copper (see Medical Task Force on Anencephaly). Of these, there is fairly secure evidence that supplemental intake of folic acid during the first trimester of pregnancy (i.e., from the time of conception) reduces the incidence of anencephaly and of myelomeningocele. Additional comments on anencephaly are given further on in this chapter in the section on "Dysraphism, or Rachischisis" (lack of fusion of the neural tube).

Lissencephaly (Agyria), Holoprosencephaly, and Gyral Malformations

Included under this heading are several forms of defects of cerebral sulcation. In the lissencephalies, cortical convolutions may be absent altogether and there is morphologic evidence of several types of neuroblast deficiency. Such cases are of particular interest to neonatologists because of their associated physical abnormalities. The degree of impairment of neurologic function seldom allows longevity, so that relatively few affected individuals are found in institutions for the developmentally delayed. Seizures, poor temperature regulation, failure to accept nourishment, and apneic attacks combine to shorten life.

The failures of sulcation vary in severity. Neurons may fail to form or to migrate along glial projections to reach the more superficial layers of the cortex (a condition called in the past, Bielschowsky type); or the cortex, meninges, and eyes may fail to differentiate normally except for the dentate gyrus and hippocampus (Walker-Warburg type); or there may be other more minor focal derangements of cortical migrations and laminations with heterotopias of neurons in the white matter.

In the complete lissencephalies, the lateral and third ventricles enlarge because of a lack of the normal quantities of surrounding cerebral tissue (i.e., the aforementioned hydranencephaly). The cerebellar cortex is also abnormal. In some lissencephalic brains, there is slight sulcation presenting as abnormally broad or narrow convolutions, with thick, poorly laminated cortex; these are called pachygyrias or microgyrias, respectively, but the fundamental migratory abnormality is basically the same. The cerebellum is also abnormal, usually showing hypoplasia or aplasia involving the vermis or neocerebellum.

In the severe defects, the cranium is small at birth. In one type, which is inherited as an autosomal recessive trait, there are subtle craniofacial features (short nose, small mandible, ear abnormalities) as well as congenital heart disease. In another group, there is an associated familial congenital muscular dystrophy, placing the case between the Fukuyama and Walker-Warburg syndromes (see "Congenital Muscular Dystrophy" in Chap. 48).

Alobar and lobar holoprosencephalies are other examples of sulcation defects with craniofacial abnormalities in which development has gone awry in the fifth and sixth weeks of gestation (see Volpe, 1995). In these subtypes, the two cerebral hemispheres, either totally or only in part, form as a single telencephalic mass. In nearly all cases the cerebral defect is reflected by a single eye (cyclopia) and the absence of the nose, imparting an astonishing and diagnostic appearance.

Most of the severe disorders are sporadic, and the infants seldom survive for long. In a few of the malformations, a congenital infection with CMV or rubella has been implicated (Hayward et al).

The Dandy-Walker syndrome represents a more restricted form of migration and neural tube defect. There is cerebellar vermian hypoplasia with or without hydrocephalus and, in some cases, an added agenesis of the corpus callosum with cerebral cortical dysgeneses (Landrieu). This defect, which is identified by the cystic enlargement of the fourth ventricle, is discussed further on, with the dysraphic neural tube defects.

That some instances of lissencephaly have a genetic basis has already been mentioned (see Table 38-3). Two genes that modify microtubular function have been identified: LIS1 and "doublecortin" or DCX. Large chromosomal deletions that span LIS1 cause Miller-Dieker syndrome, in which lissencephaly is associated with distinctive facial abnormalities; small defects in the same gene cause only lissencephaly. Lissencephaly with cerebellar hypoplasia is caused by mutations in the human "reelin" gene (RELN), the analogue of the defective gene in reelin mice (which have a reeling gait and abnormal cortical neuronal lamination). Defects in the transcription factor ARX are associated with X-linked lissencephaly, agenesis of the corpus callosum, and hypogonadism. Periventricular nodular heterotopia is caused by another gene defect, filamin A gene on the X chromosome. Some cases of holoprosencephaly have been traced to mutations in the sonic hedgehog gene.

Microcephaly

In most of the above-described cerebral dysplasias, the cranium and brain are small, but there is also a primary form of hereditary microcephaly, called microcephaly vera, in which the head is astonishingly reduced in size (circumference less than 45 cm in adult life—i.e., 5 standard deviations below the mean). In contrast, the face is of normal size, the forehead is narrow and recedes sharply, and the occiput is flat. The brain often weighs less than 300 g (normal adult range: 1,100 to 1,500 g) and shows only a few primary and secondary sulci. The cerebral cortex is thick and unlaminated and grossly deficient in neurons. A few cases have an associated cerebellar hypoplasia or an infantile muscular atrophy. Stature is usually moderately reduced. Such individuals can be recognized at birth by their anthropoid appearance and later by their lumbering gait, extremely low intelligence, and lack of communicative speech. Vision, hearing, and cutaneous sensation are spared. In one of the cases studied by our colleagues, laborious effort using operant conditioning made it possible to teach the patient the shapes of simple figures. (His sister's brain, examined by R.D. Adams, was malformed and weighed only 280 g.) Skull films show that the cranial sutures are present, as are convolutional markings on the inner table.

Lesser degrees of microencephaly have been associated with progressive motor neuron disease and degeneration of the substantia nigra (Halperin et al). Evrard and associates have described another rare type of microcephaly, which they call "radial microbrain." The sulcal pattern is normal, and neuronal arrangements in the cerebral cortex are normal as well. The defect appears to be in the small number of neurons that are generated, not in their migration.

Disorders of the Pial Surface

This category of maldevelopment is characterized by inappropriate migration of neurons to the pial surface, leading to a nodularity of the surface described as a cobblestone appearance. In the three disorders with this pathologic finding, the clinical picture is one of developmental delay conjoined with congenital muscular dystrophy. Three identified gene defects are thought to alter the glycosylation of critical proteins in the brain and in skeletal muscle. These genes include the gene fukutin in Fukuyama muscular dystrophy (see "Congenital Muscular Dystrophy" in Chap. 48), the POMGNT1 gene in muscle-eye-brain disease, and the POMT1 gene in Walker-Warburg syndrome, as summarized in Table 38-3.

Combined Cerebral, Cranial, and Somatic Abnormalities

There are so many cerebrosomatic anomalies that one can hardly retain visual images of them, much less recall all the physicians' names by which they are known. There is great advantage in grouping these anomalies according to whether the extremities, face, eyes, ears, and skin are associated with a cerebral defect. The sheer number and variety of these anomalies permit only an enumeration of the more common ones and their most obvious physical characteristics. Unfortunately, apart from certain genetic linkages, no useful leads as to their origin have been forthcoming. Of necessity, one turns to atlases, one of the most thorough of which was compiled by Holmes and colleagues and is based on clinical material drawn in large part from the Fernald School and Eunice K. Shriver Center in Massachusetts. The reader may also turn to the texts by Gorlin and colleagues and by Jones for specific information. The older Ford's Diseases of the Nervous System in Infancy, Childhood, and Adolescence is still a valuable reference, as is Jablonski's Dictionary of Syndromes and Eponymic Diseases.

The Syndactylic–Craniocerebral Anomalies (Acrocephalosyndactyly)

Fusion of two fingers or two toes or the presence of a tab of skin representing an extra digit may be seen at birth in an otherwise normal individual. However, when syndactylism is more severe and is accompanied by premature closure of cranial sutures, the nervous system usually proves to be abnormal as well. The general term acrocephalosyndactyly is used to describe the several combinations of craniostenotic and facial deformities and fusion of digits. Several of these disorders are a consequence of mutations in genes encoding one of two fibroblast growth factors or proteins related to them. The following descriptions include only the major features; most have, in addition, distinctive malformations of the orbits, ears, and palate.

1. Acrocephalosyndactyly types I and II (typical and atypical Apert syndrome). Turribrachycephalic skull, syndactyly of hands and feet ("mitten hands," "sock feet"), moderate to severe mental retardation.

2. Acrocephalosyndactyly III (Saethre-Chotzen syndrome). Various types of craniostenoses, proximally fused and shortened digits, moderate degree of mental retardation. Transmission as an autosomal dominant trait.

3. Acrocephalosyndactyly IV (Pfeiffer syndrome). Turribrachycephaly; broad, enlarged thumbs and great toes; partially flexed elbows (radiohumeral or radioulnar synostoses); mild and variable mental retardation; autosomal dominant inheritance.

4. Acrocephalopolysyndactyly V (Carpenter syndrome). Premature fusion of all cranial sutures with acrocephaly, flat bridge of nose, medial canthi displaced laterally, excess digits and syndactyly, subnormal intelligence.

5. Acrocephalosyndactyly with absent digits. High, bitemporally flattened head; absent toes and syndactylic fingers; moderate mental retardation.

6. Acrocephaly with cleft lip and palate, radial aplasia, and absent digits. Microbrachycephaly because of craniostenosis, cleft lip and palate, absent radial bones, severe mental retardation.

7. Dyschondroplasia, facial anomalies, and polysyndactyly. Keel-shaped skull and ridge through center of forehead (metopic suture), short arms and legs, postaxial polydactyly and short digits, moderate mental retardation.

In all the foregoing types of syndactylism and cranial abnormalities, which may be regarded as variants of a common syndrome, the diagnosis can be made at a glance because of the deformed head, protuberant eyes, and abnormal hands and feet. The degree of cognitive delay proves to be variable, usually moderate to severe, but occasionally intelligence is normal or nearly so. The brain has been examined in only a few instances and not in a fashion to display fully the type and extent of this developmental abnormality.

Other Craniocephalic–Skeletal Anomalies

Members of this group have distinctive anomalies of the cranium, face, and other parts, but craniostenosis is not a consistent feature.

1. Craniofacial dysostosis (Crouzon syndrome). Variable degrees of craniosynostosis; broad forehead with prominence in the region of the anterior fontanel region; shallow orbits with proptosis; midline facial hypoplasia and short upper lip; malformed auditory canals and ears; high, narrow palate; moderate mental retardation. As noted above, a genetic defect in one of the fibroblast growth factor receptors is responsible for about one-third of cases that are not associated with other deformities (Moloney et al). Autosomal dominant inheritance is seen in most cases.

2. Median cleft facial syndrome (frontonasal dysplasia; hypertelorism of Greig). Widely spaced eyes, broad nasal root, cleft nose and premaxilla, V-shaped frontal hairline, heterotypic anterior frontal fontanel (midline cranial defect); mild to severe mental retardation.

3. Chondrodystrophia calcificans congenita (chondrodysplasia punctata, Conradi-Hünermann syndrome). Prominent forehead; flat nose; widely separated eyes; short neck and trunk with kyphoscoliosis; dry, scaly, atrophic skin; cicatricial alopecia; irregularly deformed vertebral bodies; mental retardation infrequent. Severe shortening of limbs is seen in some cases.

4. Orofaciodigital syndrome. All the patients are female; they have pseudoclefts involving the mandible, tongue, maxilla, and palate; hypertrophied buccal frenula; hamartomas of tongue; sparse scalp hair; subnormal intelligence in one-half of cases.

5. Pyknodysostosis. Large head and frontal-occipital bossing, underdeveloped facial bones, micrognathia, unerupted and deformed teeth, dense and defective long bones with shortened limbs, short and broad terminal digits of fingers and toes, mental retardation in one-quarter of the cases.

6. Craniotubular bone dysplasias and hyperostoses. Included under this title are several different genetic disorders of bone, characterized by modeling errors of tubular and cranial bones. Frontal and occipital hyperostosis, overgrowth of facial bones, and widening of long bones occur in various combinations. Hypertelorism, broad nasal root, nasal obstruction, seizures, visual failure, deafness, prognathism, and retardation of growth are the major features.

Oculoencephalic (Cranio-Ocular) Defects

In this category of anomalies, there is simultaneous failure or imperfect development of eye and brain. One member of this group, the oculocerebrorenal syndrome of Lowe, has already been mentioned and, of course, many of the mucopolysaccharidoses are characterized by corneal opacities, skeletal changes, and psychomotor regression as considered separately in Chap. 37. Also, congenital syphilis, rubella, toxoplasmosis, and CMV inclusion disease may affect retina and brain; hypoxia at birth requiring treatment with oxygen may injure the brain and lead to retrolental fibrodysplasia. The true developmental defects in this group are as follows:

1. Anophthalmia with mental retardation. Sex-linked recessive. Absent eyes; orbits and maxillae remain underdeveloped, but adnexal tissues of eyes (lids) are intact; subnormal intelligence. Some cases of anophthalmia have been ascribed to genes encoding transcription factors that play a role in the development of the neuraxis (SOX2, RAX, RAX6).

2. Norrie disease. Also sex-linked recessive; some sight may be present at birth; later, eyes become shrunken and recessed (phthisis bulbi); some have short digits, outbursts of anger, hallucinations, and possibly regression of psychomotor function. A novel gene, norrin, on the X chromosome has been implicated.

3. Oculocerebral syndrome with hypopigmentation. Autosomal recessive with absence of pigment of hair and skin; small, cloudy, vascularized corneas and small globes (microphthalmia); marked mental retardation; athetotic movements of limbs.

4. Microphthalmia with corneal opacities, eccentric pupils, spasticity, and severe mental retardation.

5. Aicardi syndrome with ocular abnormality. Chorioretinopathy, retinal lacunae, staphyloma, coloboma of optic nerve, microphthalmos, mental retardation, infantile spasms and other forms of epilepsy, agenesis of corpus callosum, and cortical heterotopias. The "batwing" deformity of the third and lateral ventricles on MR images and asynchronous burst-suppression discharges and sleep spindles are diagnostic. The condition is found only in females.

6. Lissencephaly of the Walker-Warburg type. This anomaly has already been mentioned, as has its association with congenital muscular dystrophy. Inheritance is autosomal recessive. Ocular lesions are a regular feature but of variable type (retinal dysplasia, microphthalmia, coloboma, cataracts, corneal opacities). There may be hydrocephalus, and CT scans and MRI disclose the lack of cerebral sulci (lissencephaly). The abnormal eyes and orbits and absence of cerebellar vermis are diagnostic (see Table 38-3).

7. Congenital tapetoretinal degeneration (Leber amaurosis). Visual loss from birth, moderate to severe mental retardation, and microcephaly. Early onset of blindness and absent electrical potentials on the electroretinogram (ERG) distinguish it from later-onset Leber optic atrophy, which is a mitochondrial disorder (see Chaps. 13 and 37).

8. Septooptic dysplasia (de Morsier syndrome). Diminished visual acuity, small optic discs, absence of septum pellucidum, and precocious puberty. Varying degrees of pituitary insufficiency may be present, requiring endocrine replacement.

Oculoauriculocephalic Anomalies

These are less important from the neurologic standpoint, and mental retardation is present only in some cases.

1. Mandibulofacial dysostosis (Treacher-Collins syndrome, Franceschetti-Zwahlen-Klein syndrome)

2. Oculoauriculovertebral dysplasia (Goldenhar syndrome)

3. Oculomandibulodyscephaly with hypotrichosis (Hallermann-Streiff syndrome)

Dwarfism

Midgets are abnormally small but perfectly formed people of normal intelligence; they differ from dwarfs, who are not only very small but whose bodily proportions are markedly abnormal and who may or may not be cognitively normal. It should be commented that a majority of severely cognitively delayed patients fall below average for height and weight, but there is a small group whose fully attained height is well below 135 cm (4.5 ft) and who stand apart by this quality alone (see Jones for Smith's classification of dwarfs). The main types of dwarfism are as follows:

1. Nanocephalic dwarfism (Seckel bird-headed dwarfism). The uncomplimentary term bird head has been applied to individuals with a small head, large-appearing eyeballs, beaked nose, and underdeveloped chin. Such a physiognomy is not unique to any disease, but when combined with dwarfism it includes a few more or less specific syndromes. Up to 1976, approximately 25 cases had been reported, some with other skeletal and urogenital abnormalities, such as medial curvature of middle digits; occasional syndactyly of toes; dislocations of elbow, hip, and knee; premature closure of cranial sutures; and clubfoot deformity. These individuals are short at birth and remain so, living until adolescence or adulthood. Retardation is severe. The cause is a homozygous or compound heterozygous mutation in RAD3-realted protein, which is also implicated in ataxia-telangectasia. At autopsy the brain is found to have a simplified convolutional pattern; one of our patients had a type of myelin degeneration similar to that of Pelizaeus-Merzbacher disease.

2. Russell-Silver syndrome. Possibly an autosomal dominant pattern of inheritance, with short stature of prenatal onset, craniofacial dysostosis, short arms, congenital hemihypertrophy (arm and leg on one side larger and longer), pseudohydrocephalic head (normal-sized cranium with small facial bones), abnormalities of genital development in one-third of cases, delay in closure of fontanels and in epiphyseal maturation, elevation of urinary gonadotropins. Some cases appear to be caused by a nonmutational modification of genes, which are nonetheless inherited (imprinting).

3. Smith-Lemli-Opitz syndrome. Autosomal recessive inheritance with microcephaly, broad nasal tip and anteverted nares, wide-set eyes, epicanthal folds, ptosis, small chin, low-set ears, enlarged alveolar maxillary ridge, cutaneous syndactyly, hypospadias in boys, short stature, subnormal neonatal activity, and normal amino acids and serum immunoglobulins. Older survivors are bereft of language and are paraparetic, with increased reflexes and Babinski signs. The hips are usually dislocated. The responsible mutation is in DHCR7. The brain is small but has not been fully examined. Two of our patients are sibling girls.

4. Rubinstein-Taybi syndrome. Microcephaly but no craniostenosis, downward palpebral slant, heavy eyebrows, beaked nose with nasal septum extending below alae nasi, mild retrognathia, "grimacing smile," strabismus, cataracts, obstruction of nasolacrimal canals, broad thumbs and toes, clinodactyly, overlapping digits, excessive hair growth, hypotonia, lax ligaments, stiff gait, seizures, hyperactive tendon reflexes, absence of corpus callosum, mental retardation, and short stature. This dominantly inherited disease is a result of disruption of so-called CREB-binding protein, a nuclear protein necessary for gene expression that is modulated by cyclic adenosine monophosphate (cAMP).

5. Pierre Robin syndrome. Possible autosomal recessive pattern of inheritance with microcephaly but no craniostenosis, small and symmetrically receded chin, glossoptosis (tongue falls back into pharynx), cleft palate, flat bridge of nose, low-set ears, mental deficiency, and congenital heart disease in half the cases. Camptomelia (bent bones) and diastrophic dwarfism (short limbs) are common.

6. DeLange syndrome (Cornelia DeLange syndrome). This phenotype shows some degree of variability but the essential diagnostic features are intrauterine growth retardation and stature falling below the third percentile at all ages, microbrachycephaly, generalized hirsutism and synophrys (eyebrows that meet across the midline), anteverted nostrils, long upper lip, and skeletal abnormalities (flexion of elbows, webbing of second and third toes, clinodactyly of fifth fingers, transverse palmar crease). All are moderately or, more often, severely retarded mentally, which, with the above craniofacial abnormalities, is diagnostic. It has been said, and it has been our experience, that many of these patients are prone to have a bad disposition, manifested by biting and spitting. Over half of cases are due to mutations in the NAPBL gene; the others involve SMC1A or SMC3.

7. Smith-Magenis syndrome. This is caused by deletions on chromosome 17, in which there is learning disability, severe behavioral problems (violence and self-injury), hyperactivity, deafness, and ocular abnormalities.

Neurocutaneous Anomalies with Mental Retardation

It is not surprising that skin and nervous system should share in pathologic states that impair development, as both have a common ectodermal derivation. Nevertheless, it is difficult to find a common theme in the diseases that affect both organs. In some instances, it is clear that ectoderm has been malformed from early intrauterine life; in others, a number of nondevelopmental acquired diseases of skin may have been superimposed. For reasons to be discussed later in this chapter, neurofibromatosis, tuberous sclerosis, and Sturge-Weber encephalofacial angiomatosis must be set apart in a special category of disease termed phakomatoses.

Hemangiomas of the skin are without doubt the most frequent cutaneous abnormalities present at birth, and usually they are entirely innocent. Many recede in the first months of life. However, an extensive vascular nevus located in the territory of the trigeminal nerve—and sometimes in other parts of the body as well—causes permanent disfigurement and usually portends an associated and topographically underlying cerebral lesion (Sturge-Weber syndrome).

Other neurocutaneous diseases are summarized below. A more complete review of these diseases will be found in the article by Short and Adams in Fitzpatrick's Dermatology and the 1987 monograph by Gomez. The importance of recognizing the cutaneous abnormalities relates to the fact that the nervous system is usually abnormal, and often the skin lesion appears before the neurologic symptoms are detectable. Thus the skin lesion becomes a predictor of potential neurologic involvement.

Basal-cell nevus syndrome. This condition is transmitted as an autosomal dominant trait and is characterized by superficial pits in the palms and soles; multiple solid or cystic tumors over the head, face, and neck appearing in infancy or early childhood; mental retardation in some cases; frontoparietal bossing; hypertelorism; and kyphoscoliosis.

Congenital ichthyosis, hypogonadism, and mental retardation. This disorder is inherited as a sex-linked recessive trait. Aside from the characteristic triad of anomalies, there are no special features.

Xeroderma pigmentosum. The genetic pattern of inheritance is autosomal recessive. Skin lesions appear in infancy, taking the form of erythema, blistering, scaling, scarring, and pigmentation on exposure to sunlight; old lesions are telangiectatic and parchment-like, covered with fine scales; skin cancer may develop later; loss of eyelashes, dry bulbar conjunctivae; microcephaly, hypogonadism, and mental retardation (50 percent of cases). Kanda and associates classify this disease with what in the past had been called DeSanctis-Cacchione syndrome of "xerodermic idiocy" and believe the basic mechanism to be a faulty repair of DNA. They described two young adults with low intelligence, evidence of spinal cord degeneration, and peripheral neuropathy. The peripheral nerve lesions resembled those of amyloidosis, Riley-Day syndrome, and Fabry disease in that there was a predominant loss of small fibers. Other variants are described.

Sjögren-Larsson syndrome. Autosomal recessive with congenital ichthyosiform erythroderma, normal or thin scalp hair, sometimes defective dental enamel, pigmentary degeneration of retinae, spastic legs, and mental retardation.

Poikiloderma congenitale (Rothmund-Thompson syndrome). Autosomal recessive heredity; appearance of skin changes from the third to sixth months of life; diffuse pink coloration of cheeks spreading to ears and buttocks, later replaced by macular and reticular pattern of skin atrophy mixed with striae, telangiectasia, and pigmentation; sparse hair in half of the cases; cataracts; small genitalia; abnormal hands and feet; short stature; and mental retardation.

Linear sebaceous nevus syndrome. Here there is a linear nevus of one side of face and trunk, lipodermoids on bulbar conjunctivae, vascularization of corneas, mental retardation, focal seizures, and spike and slow waves in the EEG. Genetics remain uncertain.

Incontinentia pigmenti (Bloch-Sulzberger syndrome). Only females are affected; appearance of dermal lesions in first weeks of life; vesicles and bullae followed by hyperkeratoses and streaks of pigmentation, scarring of scalp, and alopecia; abnormalities of dentition; hemiparesis; quadriparesis; seizures; mental retardation; and up to 50 percent eosinophils in blood. The status of this disease is uncertain.

Focal dermal hypoplasia. Also a disease limited to females. Areas of dermal hypoplasia with protrusions of subcutaneous fat, hypo- and hyperpigmentation, scoliosis, syndactyly in a few, short stature, thin body habitus. Intelligence is occasionally subnormal.

Other rare entities are neurocutaneous melanosis, neuroectodermal melanolysosomal disease with mental retardation, progeria, Cockayne syndrome, and ataxia-telangiectasia (see Chap. 37; also Gomez, 1987).

Dysraphism, or Rachischisis: Meningocele, Encephaloceles, and Spina Bifida

Included under this heading is the large number of disorders of fusion of dorsal midline structures of the primitive neural tube, a process that takes place during the first 3 weeks of postconceptual life. Exogenous factors are presumed to be operative in most cases but there are genetic forms. The most extreme form is anencephaly, as described earlier; it is characterized by the absence of the entire cranium at birth, and the undeveloped brain lies in the base of the skull, a small vascular mass without recognizable nervous structures.

An eventration of brain tissue and its coverings through an unfused midline defect in the skull is called an encephalocele. Frontal encephaloceles may deform the forehead or remain occult. Associated defects of the frontal cortex, anterior corpus callosum, and optic-hypothalamic structures, as well as cerebrospinal fluid (CSF) leakage into frontal or ethmoid sinuses, pose a risk of meningitis. Some of these children are relatively normal mentally. Far more severe are the posterior encephaloceles, some of which are enormous and are attended by grave neurologic deficits such as blindness, ataxia, and mental retardation. However, lesser degrees of the defect are well known and may be small or hidden, such as a meningoencephalocele connected with the rest of the brain through a small opening in the skull. Small nasal encephaloceles may cause no neurologic signs, but if they are mistaken for nasal polyps and snipped off, CSF fistulae result.

A failure of development of the midline portion of the cerebellum referred to earlier, forms the basis of the Dandy-Walker syndrome (Fig. 38-2). A cyst-like structure, representing the greatly dilated fourth ventricle, expands in the midline, causing the occipital bone to bulge posteriorly and displace the tentorium and torcula upward. In addition, the cerebellar vermis is aplastic, the corpus callosum may be deficient or absent, and there is dilatation of the aqueduct as well as the third and lateral ventricles.

Even more frequent are abnormalities of closure of the vertebral arches. These take the form of a spina bifida occulta, meningocele, and meningomyelocele of the lumbosacral or other regions. In spina bifida occulta, the cord remains inside the canal and there is no external sac, although a subcutaneous lipoma or a dimple or wisp of hair on the overlying skin may mark the site of the lesion. In meningocele, there is a protrusion of only the dura and arachnoid through the defect in the vertebral laminae, forming a cystic swelling usually in the lumbosacral region; the cord remains in the canal, however. In meningomyelocele, which is 10 times as frequent as meningocele, the cord (more often the cauda equina) is extruded also and is closely applied to the fundus of the cystic swelling.

The incidence of spinal dysraphism (myeloschisis), like that of anencephaly, varies widely from one locale to another, and the disorder is more likely to occur in a second child if one child has already been affected (the incidence then rises from 1 per 1,000 to 40 to 50 per 1,000).

Etiology

Exogenous factors (e.g., potato blight in Ireland) were many times implicated in an increased rate of both myeloschisis and anencephaly, but the effects of starvation and vitamin deficiency could never be separated from the potential effect of a toxic factor. It has now been established by numerous case-control and randomized treatment trials that inadequate intake of folate in early pregnancy is associated with an increased risk of these malformations. Folic acid, given before the 28th day of pregnancy is protective; vitamin A may also have slight protective benefit. Similar associations have been found with less certainty with exposure during pregnancy to certain antiepileptic drugs, particularly valproic acid and carbamazepine. Maternal diabetes and possibly obesity have been risk factors in some epidemiologic studies, as summarized by Mitchell and colleagues. The greatest risk, however, almost 30-fold higher, attaches to a previous pregnancy affected with spina bifida in particular.

Diagnosis

As with anencephaly, the diagnosis can often be inferred from the presence of alpha-fetoprotein in the amniotic fluid (sampled at 15 to 16 weeks of pregnancy) and the deformity confirmed by ultrasonography in utero. Blood contamination is a source of error in the fetoprotein test (Milunsky). Acetylcholinesterase immunoassay, done on amniotic fluid, is another reliable means of confirming the presence of neural tube defects.

In the case of meningomyelocele, the child is born with a large externalized lumbosacral sac covered by delicate, weeping skin. The defect may have ruptured in utero or during birth, but more often the covering is intact. There is severe dysfunction of the cauda equina roots or conus medullaris contained in the sac. Stroking of the sac may elicit involuntary movements of the legs. As a rule the legs are motionless, urine dribbles, keeping the patient constantly wet, there is no response to pinprick over the lumbosacral dermatomal zones, and the tendon reflexes are absent. In contrast, craniocervical structures are normal unless a Chiari malformation is associated, as it often is (see further on). Differences are noted in the neurologic picture depending on the level of the lesion. If the lesion is entirely sacral, bladder and bowel sphincters are affected but legs escape; if lower lumbar and sacral, the buttocks, legs, and feet are more impaired than hip flexors and quadriceps; if upper lumbar, the feet and legs are sometimes spared and ankle reflexes retained, and there may be Babinski signs. The two common complications of these severe spinal defects are meningitis and progressive hydrocephalus from a Chiari malformation (see below). The subject of spina bifida and neural tube defects was reviewed by Botto and colleagues and by Mitchell and coworkers.

Treatment

Prevention by the administration of folate during pregnancy is obviously paramount. Opinions as to proper management of the established lesion vary considerably. Excision and closure of the coverings of the meningomyelocele in the first few days of life are advised if the objective is to prevent fatal meningitis. After a few weeks or months, as hydrocephalus reveals its presence by a rapid increase in head size and enlargement of the ventricles, a ventriculoperitoneal shunt is required. Less than 30 percent of such patients survive beyond 1 year and the long-term results of treating these patients have not been encouraging. Lorber and colleagues report that 80 to 90 percent of their surviving patients are developmentally delayed to some degree and are paraplegic. The decision to undertake rather formidable surgical procedures is being questioned more frequently. Exceptionally, patients with meningomyelocele, and most of those with lumbar meningocele, are mentally normal.

Other Developmental Spinal Defects Including Tethered Cord

The problems of meningomyelocele and its complications are so largely pediatric and surgical that the neurologist seldom becomes involved—except perhaps in the initial evaluation of the patient—in the treatment of meningeal infection, or in the case of shunt failure with decompensation of hydrocephalus. Of greater interest to the neurologist are a series of closely related abnormalities that produce symptoms for the first time in late childhood, adolescence, or even adult life. These include sinus tracts with recurrent meningeal infections, lumbosacral lipomas with low tethering of the spinal cord ("tethered cord") causing an early childhood or delayed radicular or spinal cord syndrome; diastematomyelia, cysts, or tumors with spina bifida and a progressive myeloradiculopathy; and the Chiari malformation and syringomyelia that first present in adolescence or adult life. These abnormalities are described below.

Another class of disorders involves an occult lumbosacral dysraphism that is not inherited but is a result of faulty development of the cell mass that lies caudal to the posterior neuropore (normally this undergoes closure by the 28th day of embryonic life). Occult spinal dysraphism of this type is also associated with meningoceles, lipomas, and sacrococcygeal teratomas. Another well-recognized anomaly is agenesis of the sacrum and sometimes the lower lumbar vertebrae (caudal regression syndrome). Interestingly, in 15 percent of such cases, the mother is diabetic (Lyon and Evrard). Here there is flaccid paralysis of legs, often with arthrogrypotic contractures and urinary incontinence. Sensory loss is less prominent, mental function develops normally, and there is no hydrocephalus.

Another class of disorders involves an occult lumbosacral dysraphism that is not inherited but is a result of faulty development of the cell mass that lies caudal to the posterior neuropore (normally this undergoes closure by the 28th day of embryonic life). Occult spinal dysraphism of this type is also associated with meningoceles, lipomas, and sacrococcygeal teratomas. Another well-recognized anomaly is agenesis of the sacrum and sometimes the lower lumbar vertebrae (caudal regression syndrome). Interestingly, in 15 percent of such cases, the mother is diabetic (Lyon and Evrard). Here there is flaccid paralysis of legs, often with arthrogrypotic contractures and urinary incontinence. Sensory loss is less prominent, mental function develops normally, and there is no hydrocephalus.

Sinus tracts in the lumbosacral or occipital regions are of importance, for they may be a source of bacterial meningitis at any age. They are often betrayed by a small dimple in the skin or by a tuft of hair along the posterior surface of the body in the midline. (The pilonidal sinus should not be included in this group.) The sinus tract may lead to a terminal myelocystocele and be associated with dermoid cysts or fibrolipomas in the central part of the tract. Cloacal defects (no abdominal wall and no partition between bladder and rectum) may be combined with anterior meningoceles. Evidence of sinus tracts should be sought in instances of unexplained meningitis, especially when there has been recurrent infection or the cultured organism is of nosocomial dermal origin.

Of great interest are congenital cysts and tumors, particularly lipoma and dermoid, that arise in the filum terminale and attach (tether) the cord to the sacrum. Progressive symptoms and signs are produced as the spine elongates during development, thereby stretching the caudally fixed cord (Fig. 38-3). Some of these children have bladder and leg weakness soon after birth. Others deteriorate neurologically at a later age (generally between 2 and 16 years, sometimes later—see below). Complex disturbances of bladder function that produce urgency and incontinence beginning in the second or third decade may be the only manifestation, or the bladder symptoms may be combined with impotence (in the male) and numbness of the feet and legs or foot-drop (Pang and Wilberger). Several of our adult patients have had unusual visceral reflex reactions, such as involuntary defecation or priapism with stimulation of the abdomen or perineum. According to most surgeons, it is not the myelolipoma but the tethering of the cord that gives rise to symptoms; removal of the tumor is of little benefit unless the cord is detached from the sacrum at the same time. This may be difficult, for the lipoma may be fused with the dorsal surface of the spinal cord.

Diastematomyelia is another unusual abnormality of the spinal cord often associated with spina bifida. Here a bony spicule or fibrous band protrudes into the spinal canal from the body of one of the thoracic or upper lumbar vertebrae and divides the spinal cord into halves for a variable vertical extent. In extreme examples, the division of the cord may be complete, each half with its own dural sac and complete set of nerve roots. This longitudinal fissuring and doubling of the cord are spoken of as diplomyelia. With body growth, the restriction created by the bone spicule leads to a traction myelopathy, presenting with pain and progressive sensory, motor, and bladder symptoms, sometimes as late as adult life. Removal of the fibrous-bony spicule and untethering of the spinal cord have been beneficial in some cases.

Syringomyelia (see also Chap. 44) is a developmental cavity within the cervical cord, extending a variable distance caudally or rostrally, and usually associated with an Arnold-Chiari malformation that is described below. There are a variety of other neurodevelopmental spinal abnormalities in the high cervical region, such as fusion of atlas and occiput or of cervical vertebrae (Klippel-Feil syndrome), congenital dislocation of the odontoid process and atlas, platybasia, and basilar impression. These abnormalities are discussed in Chap. 44, with other diseases of the spinal cord.

Chiari Malformation

Encompassed by this term are a constellation of related congenital anomalies at the base of the brain, the most consistent of which are (1) extension of a tongue of cerebellar tissue posterior to the medulla and cord that extends into the cervical spinal canal; (2) caudal displacement of the medulla and the inferior part of the fourth ventricle into the cervical canal; and (3) a frequent but not invariable association with syringomyelia or a spinal developmental abnormality. These and associated anomalies were first clearly described by Chiari (1891). Several translations of his original material have been made, but they have been criticized as inaccurate. Arnold's name is attached to the syndrome, but his contribution to our understanding of these malformations was relatively insignificant. Use of the double eponym Arnold-Chiari malformation is so entrenched that a dispute over its propriety serves little purpose. Chiari recognized four types of abnormalities. In recent years, the term has come to be restricted to Chiari's types I and II—that is, to cerebellomedullary descent without and with a meningomyelocele, respectively. Type III Chiari malformation is no more than a high cervical or occipitocervical meningomyelocele with cerebellar herniation, and type IV consists only of cerebellar hypoplasia.

The incidence among adults, acquired from autopsy series and more recently, from incidentally discovered descent of the cerebellar tonsils on imaging procedures, is about 0.6 percent of the population. It should be emphasized that a proportion of normal individuals have a small tongue of the posterior cerebellum protruding by a few millimeters below the lower lip of the foramen magnum; this is usually of no significance and does not justify inclusion as a Chiari malformation. A historical account of the clinical, pathologic, and imaging aspects of this malformation and the evolution of ideas concerning it has been given by Bejjani.

Several other morphologic features are characteristic of the true Chiari anomaly. The medulla and pons are elongated and the aqueduct is narrowed. The displaced tissue (medulla and cerebellum) occludes the foramen magnum; the remainder of the cerebellum, which is small, is also displaced so as to obliterate the cisterna magna. The foramina of Luschka and Magendie often open into the cervical canal, and the arachnoidal tissue around the herniated brainstem and cerebellum is fibrotic. All these factors are probably operative in the production of hydrocephalus, which is always associated. Just below the herniated tail of cerebellar tissue there is a kink or spur in the spinal cord, which is pushed posteriorly by the lower end of the fourth ventricle. In this fully expressed form of the malformation, a meningomyelocele is nearly always found. It should again be emphasized that hydromyelia or syringomyelia of the cervical cord are commonly associated findings and the main theories of causation of the latter are based on the change in CSF dynamics produced by the Chiari malformation.

Developmental abnormalities of the cerebrum, particularly polymicrogyria may infrequently coexist, and the lower end of the spinal cord may extend as low as the sacrum (i.e., a tethered cord). There are usually cranial bony abnormalities as well. The posterior fossa is small; the foramen magnum is enlarged and grooved posteriorly. Nishikawa and colleagues suggested that smallness of the posterior fossa with overcrowding is the primary abnormality leading to the brain malformation. Often the base of the skull is flattened or infolded by the cervical spine (basilar impression).

Clinical Manifestations

In type II Chiari malformation (with meningomyelocele), the problem becomes one of progressive hydrocephalus. Cerebellar signs cannot be discerned in the first few months of life. However, lower cranial-nerve abnormalities—laryngeal stridor, fasciculations of the tongue, sternomastoid paralysis (causing head lag when the child is pulled from lying to sitting), facial weakness, deafness, bilateral abducens palsies—may be present in varying combinations. If the patient survives to later childhood or adolescence, one of the syndromes that are more typical of the type I malformation may become manifest.

In the more common type I Chiari malformation (without meningocele or other signs of spinal dysraphism), neurologic symptoms may not develop until adolescence or adult life. The symptoms are those of (1) increased intracranial pressure, mainly headache, (2) progressive cerebellar ataxia, (3) progressive spastic quadriparesis, (4) downbeating nystagmus, or (5) the syndrome of cervical syringomyelia (segmental amyotrophy and sensory loss in the hands and arms, with or without pain). Or the patient may show a combination of disorders of the lower cranial nerves, cerebellum, medulla, and spinal cord (sensory and motor tract disorders), usually in conjunction with headache that is mainly occipital. This combination of symptoms is easily mistaken for multiple sclerosis or a tumor at the foramen magnum. The symptoms are usually chronic but may have an acute onset after sustained or forceful extension of the neck, as, for example, after a long session of dental work, hairdressing in women, or chiropractic manipulation. The physical habitus of such patients may be normal, but approximately 25 percent have signs of an arrested hydrocephalus, or a short "bull neck." When basilar impression (a congenital abnormality of the occipital bone that invaginates the posterior atlas into the cranial cavity) and a Chiari malformation coexist, it may be impossible to decide which of the two is responsible for the clinical findings.

The nature and severity of headache that are reasonably attributable to a Chiari malformation is somewhat unclear. Occipitonuchal pain with coughing, position change, or the Valsalva maneuver is the most dependable association, but even then, decompression may not relieve the symptoms. Exertional headache alone is a questionable association. Only large and genuine malformations, not minor descent of the tonsils should be considered causative. More generalized headaches may or may not be explained by the finding of a Chiari malformation and the advisability of a surgical treatment then depends on the degree of disability created by other aspects of the malformation. Further discussion of this subject is found in Chap. 10.

The tongue of cerebellar tissue and the kinked cervical cord obstruct the upward flow of CSF and give a highly characteristic imaging profile, particularly on sagittal MRI (Fig. 38-4). Inspection of the axial sections of scans at the level of the foramen magnum demonstrates crowding of the upper cervical canal by inferiorly displaced cerebellar tissue, but one must be aware of the variations in the normal position of the cerebellar tonsils at this level. A slight descent of the cerebellar tonsils that is reversible is also seen with low cerebrospinal fluid pressure and not indicative of a Chiari malformation. Recent inceptions in phase contrast MRI technology allow the imaging of CSF flow in the region of the foramen magnum but the relevance to choosing patients for surgical decompression has not been clarified (see summary by Menick). The CSF in Chiari malformation is usually normal but may show an elevated pressure and protein level in some cases for unexplained reasons.

Treatment

The treatment of Chiari malformation and any associated basilar impression is far from satisfactory. If clinical progression is slight or uncertain, it is probably best to do nothing. If disability by way of spasticity, ataxia, pain in the shoulders or arms, or lower cranial-nerve disease is increasing, upper cervical laminectomy and enlargement of the foramen magnum are indicated. The proper course for patients that have headaches alone is uncertain but many such patients are operated upon if their cranial pain has been progressive, or if it is consistently and markedly worsened by cough or similar Valsalva actions, or if there is fainting or another associated symptom that can be reasonably related to the Chiari abnormality. The outcome of surgery, in our experience, has been less satisfactory when decompression was performed mainly for intractable headache, but there have been exceptions, especially when exertion or Valsalva maneuver elicits the symptoms.

The basic operation is suboccipital and C-1 decompression; various forms of shunting may be added if there is syringomyelia (the shunt is to the adjacent subarachnoid space) or hydrocephalus. The surgical procedure must be done cautiously. Opening of the dura and extensive manipulation of the malformation or excision of herniated cerebellum may aggravate the symptoms but is performed by some neurosurgeons to decompress the lower brainstem. Often, surgery halts the progress of the neurologic illness, arrests the hydrocephalus, or results in some other clinical improvement. The surgical series reported by Alzate and colleagues is representative. Emphasis was placed on proper patient selection, but the analysis of 66 cases, as in most other reports, was retrospective. (This reference is part of a very informative monograph). Most series report that a CSF leak follows surgery in about 5 percent of patients. The fate of an associated syringomyelia has been uncertain but most series report optimistic results.

As alluded to earlier, the role of phase-contrast MRI of CSF flow around the foramen magnum in selecting patients for decompression is unknown. The treatment of an associated syringomyelia and other developmental abnormalities in this region is discussed further in Chap. 44 under "Intramedullary Syringomyelic Syndrome." We are unable to comment on the use by a limited number of neurosurgeons of posterior fossa decompression for the treatment of chronic fatigue syndrome and all manner of other symptoms except to say that it is entirely illogical, even when a Chiari malformation is detected.

As mentioned in the introduction, mid-twentieth-century discovery of outstanding significance was the recognition of a group of developmental anomalies of the brain and other organs associated with a demonstrable abnormality of the karyotype of autosomal and sex chromosomes. Jacobs and Lejeune in 1959 almost simultaneously were the first to note a triplication of the 21st chromosome in Down syndrome, and there followed the discovery of a number of other trisomies as well as deletions or translocations of other autosomal chromosomes and a lack or excess of one of the sex chromosomes. Such an event must take place sometime after the formation of the oocyte, during the long period when it lies fallow in the ovary or during the process of conception or germination and first cell divisions. Thus, all the cells in the embryo may carry the changed chromosome, or only some of them may carry it, the latter condition being called mosaicism.

The precise manner in which triplication or some other imperfection of a chromosome is able to derail the pathways of ontogenesis is a mystery. In some instances, a chromosomal imperfection may result from the lack of a gene or a distortion or fragmentation of an unstable gene, as in the fragile X syndrome. These germ line alterations are to be distinguished from acquired partial duplications and deletions of parts of genes that occur as acquired somatic mutations in many tremors and from variations in copy number of segments of genes that are emerging as possible explanations for a number of diseases such as autism.

Certain chromosomal abnormalities are incompatible with life, and it has been found that the cells of many abortuses and stillborns show abnormal karyotypes. Conversely, the organism may survive and exhibit any one of many syndromes, of which the following are the most frequent: (1) Down syndrome (mongolism, trisomy 21); (2) one type of arrhinencephaly (trisomy 13, Patau syndrome); (3) trisomy 18 (Edwards syndrome); (4) cri-du-chat syndrome (deletion of short arm of chromosome 5); (5) monosomy 21 (so-called antimongolism); (6) ring chromosomes; (7) Klinefelter syndrome (XXY); (8) Turner syndrome (XO); (9) others (XXXX, XXX, XYY, YY, XXYY); (10) fragile X syndrome, the most common form of inherited mental retardation; (11) Williams syndrome; and (12) Prader-Willi and Angelman syndromes. There are numerous less-frequent types, some of which are also discussed below because they have special neurologic interest. The overall frequency of chromosomal abnormalities in live births is 0.6 percent (see the review by Kalter and Warkany). For a comprehensive account of the chromosome-linked disorders the reader is referred to the article by Lemieux and for speculations on the nature of genetic retardations, can be found in the article by Nokelainen and Flint.

Down Syndrome (Trisomy 21)

Described first in 1866 by Langdon Down, this is easily the best known of the chromosomal dysgeneses. Its frequency is 1 in 600 to 700 births, and it accounts for approximately 10 percent of all cases in every large series of cases of severe mental retardation. One cannot distinguish the Down syndrome with the common triplication of chromosome 21 from that caused by a translocation, and therefore duplication, of one arm, specifically the distal portion of the long arm that seems to contain the region responsible for the syndrome. Two genes have been of greatest interest in that region: DYRK1A and DSCR1.

Familiarity with the condition permits its recognition at birth, but the somatic appearance becomes more obvious with advancing age. The round head, open mouth, stubby hands, slanting palpebral fissures, and short stature impart an unmistakable appearance. The ears are low-set and oval, with small lobules. The palpebral fissures slant slightly upward and outward owing to the presence of medial epicanthal folds that partly cover the inner canthi (hence the old term mongolism). The bridge of the nose is poorly developed and the face is flattened (hypoplasia of the maxillae). The tongue is usually enlarged, heavily fissured, and protruded. Gray-white specks of depigmentation are seen in the irides (Brushfield spots). The little fingers are often short (hypoplastic middle phalanx) and incurved (clinodactyly). The fontanels are patent and slow to close. The hands are broad, with a single transverse (simian) palmar crease and other characteristic dermal markings. Lenticular opacities and congenital heart lesions (septal and other defects), as well as gastrointestinal abnormalities (stenosis of duodenum), are frequent. The patient with Down syndrome is slightly below average size at birth and is characteristically of short stature at later periods of life. The height attained in adult life seldom exceeds that of a 10-year-old child.

Hypotonia of the limbs is a prominent finding. At first, the Moro response is reduced or absent, and feeding is difficult. Most affected children do not walk until 3 to 4 years of age; their acquisition of speech is delayed, but over 90 percent talk by 5 years. The IQ is variable, and that of a large group follows a Gaussian curve with the median IQ being 40 to 50 and the range, 20 to 70. A placid, docile, and affectionate personality characterizes most Down patients. A high incidence of atlantoaxial instability puts these individuals at risk of traumatic spinal cord compression in athletic ventures.

An increased incidence of myelocytic and lymphocytic leukemia takes its toll. A number of patients have had embolic strokes and brain abscesses secondary to cardiac abnormalities and there is disproportionate occurrence of the rare cerebrovascular disorder known as moyamoya (see Chap. 34). Life expectancy is later shortened by the almost universal development of Alzheimer disease by the 40th year of life. This is explained by the presence on the duplicate copy of chromosome 21 of the gene for the precursor of the protein amyloid, a central factor in the development of Alzheimer disease. As Alzheimer disease develops, the usual clinical picture is marked by inattentiveness, reduced speech, impairment of visuospatial orientation, loss of memory and judgment, and seizures.

The triplication is found mostly in the offspring of older mothers, whereas the less-frequent translocation is found equally in the offspring of young and older women. In other subtypes of the Down syndrome, referred to as mosaics, some cells share in the chromosomal abnormality and others are normal. Affected individuals have atypical forms of the syndrome, and some such individuals are of normal intelligence.

The genetic changes that lead to cerebral maldevelopment and dysmorphic physical features are just beginning to be understood. A connection to genes that code for enzymes of folate has been suggested (among other mechanisms). The genetic aspects, as well as features pertaining to the medical care of these patients, are well summarized by Roizen and Patterson. They emphasize the high frequency of enteric sprue (celiac disease) and hypothyroidism and the need for screening for these conditions.

Laboratory and Pathologic Findings

Brain weight is approximately 10 percent less than average. The convolutional pattern is rather simple. The frontal lobes are smaller than normal, and the superior temporal gyri are thin. There are claims of delayed myelination of cerebral white matter and also of immature and poorly differentiated cortical neurons. Alzheimer neurofibrillary changes and neuritic plaques are practically always found in Down patients who are older than 40 years of age, as mentioned.

It is possible to make the diagnosis of Down syndrome by demonstrating the chromosomal abnormalities in cells of the amniotic fluid. About one-third of pregnant mothers also have an abnormal elevation of serum alpha-fetoprotein in the second trimester of pregnancy. Other independent predictors of fetal Down syndrome are elevated serum chorionic gonadotropin and decreased estriol (Haddow et al). One can uncover a considerable proportion of the Down population by prenatal screening for these serum markers and by performing amniocentesis on women with positive tests to search for the chromosomal abnormality. Early detection is aided by the absence on imaging of a nasal bone between 11 and 14 weeks, at which time it is normally detected (Cicero et al).

Other Chromosomal Dysgeneses

These are listed here with brief descriptions of their main features.

1. Trisomy 13 (Patau syndrome). Frequency 1 in 2,000 live births, more female than male, average maternal age 31 years, microcephaly and sloping forehead, microphthalmos, coloboma of iris, corneal opacities, anosmia, low-set ears, cleft lip and palate, capillary hemangiomata, polydactyly, flexed fingers, posterior prominence of heels, dextrocardia, umbilical hernia, impaired hearing, hypertonia, severe mental retardation, death in early childhood.

2. Trisomy 18. Frequency 1 in 4,000 live births, more in females, average maternal age 34 years, slow growth, occasional seizures, severe mental retardation, hypertonia, ptosis and lid abnormalities, low-set ears, small mouth, mottled skin, clenched fists with index fingers overlapping the third finger, syndactyly, rocker-bottom feet, shortened big toe, ventricular septal defect, umbilical and inguinal hernias, short sternum, small pelvis, small mandible, death in early infancy.

3. Cri-du-chat syndrome (deletion in short arm of chromosome 5). Abnormal cry, like a kitten, severe mental retardation, hypertelorism, epicanthal folds, brachycephaly, moon face, antimongoloid slant of palpebral fissures, micrognathia, hypotonia, strabismus.

4. Ring chromosomes. Mental retardation with variable physical abnormalities.

5. Klinefelter syndrome (XXY). Only males affected. Eunuchoid appearance, wide arm span, sparse facial and body hair, high-pitched voice, gynecomastia, small testicles, usually developmentally delayed but not severely so; high incidence of psychosis, asthma, and diabetes.

6. Turner syndrome (XO). Only females affected. Triangular face, small chin, occasionally hypertelorism and epicanthal folds, widely spaced nipples, clinodactyly, cubitus valgus, hypoplastic nails, short stature, webbed neck, delayed sexual development, mild developmental delay. The manner of inheritance of the X chromosome may have bearing on the patient's personality and level of functioning, as noted in Chap. 21.

7. Colpocephaly. A rare type of malformation of the brain consisting of marked dilatation of the occipital horns of the lateral ventricles, thickening of the overlying rim of cortical gray matter, and thinning of the white matter. The associated clinical picture comprises developmental delay, spasticity, seizures, and visual abnormalities (because of optic nerve hypoplasia). This disorder is probably of diverse causation, but it is listed here with the chromosomal abnormalities because some cases have been associated with the mosaicism for trisomy 8 (Herskowitz et al). The term colpocephaly is often used incorrectly to apply to all forms of ventricular enlargement (including hydrocephalus) associated with abnormal development of the brain.

8. Fragile X syndrome (see further on for additional clinical details in the section on developmental delay). This abnormality is among the most common inherited forms of developmental delay, estimated to occur in 1 of every 1,500 male live births and accounting for 10 percent of severe developmental delay in males. Females, with two X chromosomes, are affected about half as frequently, and then only to a slight degree. With the advent of new markers for the detailed structure of chromosomes, Lubs observed an unusual site of frequent breakage ("fragility") on the X chromosome and related it to a syndrome that included developmental delay, flaring ears, elongated facies, slightly reduced cranial perimeter, normal stature, and enlarged testes. More recently, rare progressive ataxia has been reported in adults who harbor the chromosomal abnormality and had displayed little or no cognitive deficiency.

9. The chromosomal fragility appears to be due to a heritable, unstable CGG repeating sequence in the X chromosome. Affected individuals have over 230 repeats and carriers have 60 to 230 repeats. The prolonged sequence inactivates a gene (FMR1) that codes for an RNA-binding protein of as yet an unknown connection to brain function. The genetics of this and other retardations was reviewed by Nokelainen and Flint. Rousseau and colleagues described a simple and sensitive test using DNA analysis for the diagnosis of the syndrome both prenatally and after birth. Because of mosaicism, the length of the triplet repeat does not directly relate to the degree of expression of retardation, and the fragile X alteration occasionally turns up in mentally normal males; in some instances, the male children of their daughters have the disease. In some of the cases we have observed, the intellectual deficit has been mild in degree and the main abnormalities have taken the form of troublesome behavior, logorrhea, an autistic type of gaze aversion, and asociality. These and other neurobehavioral features of the syndrome and its unique pattern of inheritance (it is neither recessive nor dominant) have been discussed by Shapiro.

10. Williams syndrome. Described by J.C.P. Williams and colleagues of Australia from the perspective of a supravalvular aortic stenosis and a year later by Beuren and colleagues, this unique combination of cerebral maldevelopment and cardiovascular abnormalities has been traced in most patients to a microdeletion on chromosome 7 in the region of the gene that codes for the protein elastin. Its frequency is 1 in 20,000 newborns. Further discussion of clinical features of this syndrome is found later in the chapter.

11. Prader-Willi and Angelman syndromes. The Prader-Willi syndrome was already mentioned in relation to the hyperphagia of hypothalamic disorders (adiposogenital dystrophy, Froehlich syndrome). It is not uncommon (1 in 20,000 births) and affects both sexes equally. Hypotonia (floppy infant), areflexia, small stature, dysmorphic facies, and hypoplastic genitalia are evident, and arthrogryposis may be present at birth. After the first year, developmental delay becomes obvious and obesity, due to hyperphagia, becomes prominent. Patients are identified by the "H3O" mnemonic, referring to hypomentia, hypotonia, hypogonadism, and obesity. The disorder is associated with a deletion at 15q11-q13 (a so-called microdeletion, as in Williams syndrome), which can be identified by a combination of cytogenetic and DNA analyses. In 70 percent of cases the disease is caused by a noninherited deletion from the paternal X chromosome.

12. The Angelman syndrome, another cause of severe developmental delay, is associated with the identical chromosomal abnormality to that found in the Prader-Willi syndrome, but there is usually a maternally inherited single-gene defect. The difference in phenotype derives from a complex genetic phenomenon termed spatially restricted imprinting. The phenotype comprises severe developmental delay, microcephaly, refractory seizures, absence of speech, ataxia, inappropriate laughter, prominent jaw, thin upper lip, and prolonged tongue. Outstanding are an unusual marionette-like stance coupled with a persistent tendency to laugh and smile (hence the old name "happy puppet syndrome"; see also Chap. 37).

13. Rett syndrome, discussed more fully further on, is mentioned here because it is to the result of a dominant defect on the X chromosome. It affects 1 of every 10,000 to 15,000 girls. After 6 to 18 months of normal development, motor skills and mental abilities seem slowly to regress. Certain handwringing and other stereotyped hand movements appear as the disease progresses and are characteristic.

Several generalizations can be made about these chromosomal dysgeneses. First, the autosomal ones are often lethal (Rett syndrome is an exception), and they almost always have a devastating effect on cerebral growth and development, whether the infant survives or not. Anomalies of nonneural and a degree of externally visible dysmorphism structures are regularly present—an association so constant that one may safely predict that an otherwise normally formed infant will not have a detectable chromosomal defect. However, only in the Down syndrome and trisomy 13 (and possibly trisomy 18) are the physiognomy and bodily configuration highly characteristic. Surprisingly, some of the most grotesque disfigurements, such as anencephaly and multiple severe congenital anomalies, are not related to a morphologic abnormality of chromosomes. By contrast, an insufficiency of sex chromosomes induces only subtle effects on the brain, affecting intellect and personality; to some extent this is true of supernumerary sex chromosomes (XYY, for example).

The basic abnormality of the brain underlying the developmental delay in many of these chromosomal dysgeneses has not been ascertained. The cerebrum is slightly small, but only minor changes are seen in the convolutional pattern and cortical architecture in conventional microscopic preparations. Neurocellular methodologies to date are not sufficiently advanced to reveal the fundamental cerebral abnormality.

Teratologic Deformations of the Nervous System

A number of observations have repudiated the former belief that the human embryo is naturally shielded against exogenous causes of maldevelopment. Irradiation during the first trimester, rubella and CMV infections, severe hypothyroidism of the mother during this same period, and the action of alcohol, vitamin A, and thalidomide have all been observed, among a multitude of other agents, to give rise to serious disorders of development. Quite relevant to the neurologist, the offspring of mothers receiving anticonvulsant drugs during the early months of pregnancy have a slightly increased risk of developing birth defects (approximately 5 percent, compared to 3 percent for the general population—see "Teratogenic Effects of Antiepileptic Medications" in Chap. 16). Cleft lip and palate are the most common anomalies attributable to anticonvulsant drugs; other craniofacial defects, spina bifida, minor cardiac defects, and dysraphisms have also been reported at a slightly increased rate. Claims and counterclaims have been made concerning the pathogenicity of numerous other substances. Mainly, the data are from animals given amounts far in excess of any possible therapeutic doses in humans. The data from humans are so meager from a multitude of such substances that they are not discussed here. The reader may refer to the article by Kalter and Warkany for further information.

As stated earlier, there are two broad categories of neurocutaneous diseases. In one, the infant is born with a special type of skin disease or develops it in the first weeks of life; in the other forms, the cutaneous abnormality, although often present in minor degree at birth, later evolves as quasineoplastic disorders. The quasineoplastic disorders to which van der Hoeve in 1920 applied the term phakomatoses (from the Greek phakos, meaning "mother spot," "mole," or "freckle") are tuberous sclerosis, neurofibromatosis, and cutaneous angiomatosis with central nervous system (CNS) abnormalities, which have many features in common: hereditary transmission, involvement of organs of ectodermal origin (nervous system, eyeball, retina, and skin), slow evolution of lesions in childhood and adolescence, a tendency to form hamartomas (benign tumor-like formations because of maldevelopment), and a disposition to fatal malignant transformation. These disorders are discussed below and listed in Table 38-4.

Tuberous Sclerosis (Bourneville Disease)

Tuberous sclerosis is a congenital disease of hereditary type in which a variety of lesions, because of a limited hyperplasia of ectodermal and mesodermal cells, appear in the skin, nervous system, heart, kidney, and other organs. It is characterized by the triad of adenoma sebaceum, epilepsy, and developmental delay. Hypomelanotic skin macules ("ash-leaf" lesions) and the subepidermal fibrotic "shagreen patch" are diagnostic features.

It is stated that Virchow recognized scleromas of the cerebrum in the 1860s and that von Recklinghausen reported a similar lesion combined with multiple myomata of the heart in 1862, but Bourneville's articles, appearing between 1880 and 1900, presented the first systematic accounts of the disease and it was he who related the cerebral lesions to those of the skin of the face. Vogt (1890) fully appreciated the significance of the neurocutaneous relationship and formally delineated the triad of facial adenoma sebaceum, epilepsy, and developmental delay. "Epiloia," a term for the disease introduced by Sherlock in 1911, never gained general acceptance. These and other historical aspects are reviewed in Gomez's monograph.

Epidemiology

The disease has been described in all parts of the world and is equally frequent in all races and in both sexes. Heredity is self-evident in only a minority of cases— 50 percent in some series and as little as 14 percent in the series of Bundag and Evans (cited by Brett). The disease is determined by two autosomal dominant genes (see below), but it has been estimated as 1 in 20,000 to 300,000. The disease is inherited in an autosomal dominant fashion but with variable penetrance. The abnormal gene may be in one of two sites—the long arm of chromosome 9, designated as TSC 1 (hamartin), or in the short arm of chromosome 16, TSC 2 (tuberin), which is common. A wide variety of mutations have been described and both alleles must be affected for expression of the disease ("loss of heterozygosity"). Approximately 15 percent of sporadic cases show no identifiable mutation and tend to have milder manifestations, perhaps on the basis of mosaicism. Hamartin and tuberin function as tumor suppressor proteins and interact to suppress cell growth. This may, in part, explain the proclivity to develop various growths and hamartomas. The cerebral lesions and two of the three associated skin lesions of tuberous sclerosis are of this type. Several hypotheses relating to neuronal migration or to excessive secretion of growth factors have been proposed to link the inactivation of these genes with the pathogenesis of the characteristic lesions. Much of the work in understanding the function of these two proteins and their role in tumor formation has been performed in Drosophila and are summarized in the extensive review by Crino and colleagues.

The disease involves many organs in addition to the skin and brain and it may assume a diversity of forms, the least severe of which (i.e., the forme fruste) is difficult to diagnose; hence, one cannot be precise about its incidence. Tuberous sclerosis accounts for about 0.66 percent of the developmentally delayed in institutions and 0.32 percent of epileptics. The medical literature contains a number of reports of patients whose mentality is preserved and who have never had convulsions.

Etiology and Pathogenesis

The cellular elements within the nodular cerebral lesions (called tubers; see below) are abnormal in number, size, and orientation. The tumor-like growths in different organs may include cells of more than one type (e.g., fibroblasts, cardiac myoblasts, angioblasts, glioblasts, and neuroblasts), and their number is locally excessive. Something appears to have gone awry with the proliferative process during embryologic development, yet it is kept under control, in the sense that only rarely do the growths undergo malignant transformation. Highly specialized cells within the lesions may attain giant size; neurons 3 to 4 times normal size may be observed in the cerebral scleroses. These facts emphasize the potentially blastomatous character of the process.

Surgically resected tubers show activation of a cell-size control pathway (mammalian target of rapamycin [mTOR]); this is in keeping with the effects of TSC mutations on this cascade and probably explains the giant neurons as mentioned further below.

Clinical Manifestations (Table 38-5)

The disease may be evident at the time of birth (the diagnosis has been made by CT scan in neonates), but more often the infant is judged at first to be normal. In approximately 75 percent of cases, attention is drawn to the disease initially by the occurrence of focal or generalized seizures or by slowed psychomotor development. As with any condition that leads to developmental delay, the first suspicion is raised by delay in reaching normal maturational milestones. Whatever the initial symptom, the convulsive disorder and developmental delay become more prominent within 2 to 3 years. The facial cutaneous abnormality, adenoma sebaceum, appears later in childhood, usually between the fourth and tenth years, and is progressive thereafter.

As the years pass, the seizures change pattern. In the first year or two they take the form of massive flexion spasms with hypsarrhythmia (irregular dysrhythmic bursts of high-voltage spikes and slow waves in the EEG). As many as 25 percent of patients with these types of seizures have been found to have tuberous sclerosis. Later, the seizures change to more typical generalized motor and psychomotor attacks or atypical petit mal. Any one of the seizure types may be brief, especially if the patient is receiving anti-epileptic medication. Focal neurologic abnormalities, which one might expect to occur from the size and location of some of the lesions, are distinctly uncommon.

Mental function continues to deteriorate slowly. Exceptionally there is a spastic weakness or mild choreoathetosis of the limbs and in a few cases an obstructive hydrocephalus develops. As in any state of severe developmental delay, a variety of nonspecific motor peculiarities—such as constant crying, muttering, stereotypical rocking and swaying movements, and digital mannerisms—may be observed. In nearly half of the cases, affective and behavioral derangements, often of hyperkinetic and aggressive type, are added to the intellectual deficiency.

The lack of parallelism in the severity of the epilepsy, the mental deficit, and cutaneous abnormalities has been noted by all clinicians who have wide experience with this disease. Some patients are subject to recurrent seizures while retaining relatively normal mental function; in others, trivial skin lesions or a retinal phakoma (see below) may suggest the diagnosis in a mentally normal person with few seizures. In such cases, recognition may elude competent neurologists and dermatologists. As a general rule, early onset of seizures is predictive of developmental delay. Gomez and colleagues suggested that the seizures damage the brain, a point with which we tend to agree in part. However, it seems likely that both the epilepsy and developmental delay are the product of severe involvement of the brain by the lesions of tuberous sclerosis.

Limitation of space allows no more than a catalogue of the other visceral abnormalities in tuberous sclerosis. In about half the cases, gray or yellow plaques (in reality gliomatous tumors) may be found in the retina in or near the optic disc or at a distance from it. It is from this lesion, called a phakoma, that van der Hoeve derived the term that is applied to all neurocutaneous diseases of this class. About half of all benign rhabdomyomas of the heart are associated with tuberous sclerosis; if located in the wall of the atrium, they may cause conduction defects. Other benign tumors of mixed cell type (angiomyolipomas) have been found in the kidneys, liver, lungs, thyroid, testes, and gastrointestinal tract. Cysts of the pleura or lungs, bone cysts in digits, and zones of marbling or densification in bones are some of the less common abnormalities.

In approximately 90 percent of patients with tuberous sclerosis, congenital hypomelanotic macules—"ash-leaf" lesions—formerly mistaken for partial albinism or vitiligo, appear before any of the other skin lesions (Fitzpatrick et al). Gold and Freeman, as well as Fitzpatrick and colleagues, emphasized the frequency of these leukodermic lesions and their value in the diagnosis of tuberous sclerosis during infancy, before the appearance of the other characteristic cutaneous lesions. The hypomelanotic areas are arranged in linear fashion over the trunk or limbs and range in size from a few millimeters to several centimeters; their configuration is oval, with one end round and the other pointed, in the shape of an ash leaf. A Wood lamp, which transmits only ultraviolet rays, facilitates the demonstration of the ash-leaf lesions because of the absence of melanoblasts, which normally absorb light in the ultraviolet range (360-nm wavelength). These lesions become pink when rubbed and contain sweat glands; they are not usually present on the face or head. There is occasionally a white tuft of hair (poliosis). Electron microscopic examination of the hypomelanotic lesions shows a normal or reduced number of melanocytes, but their dopa reaction is reduced and melanosomes are small.

The well-developed facial lesions (adenomas of Pringle), pathognomonic of tuberous sclerosis, are present in 90 percent of patients older than 4 years of age. Although called "adenoma sebaceum," these nodules are actually angiofibromas; the sebaceous glands are only passively involved (Fig. 38-5). Typically they are red to pink nodules with a smooth, glistening surface, and they tend to be limited to the nasolabial folds, cheeks, and chin; sometimes they also involve the forehead and scalp. The earliest manifestation of facial angiofibromatosis may be a mild erythema over the cheeks and forehead that is intensified by crying. The occurrence of large plaques of connective tissue on the forehead is usually expressive of a severe form of the disease.

On the trunk, the diagnostic lesion is the "shagreen patch" (in reality a plaque of subepidermal fibrosis) found most often in the lumbosacral region. It appears as a flat, slightly elevated, flesh-colored area of skin 1 to 10 cm in diameter, with a "pigskin," "elephant hide," or "orange peel" appearance (Fig. 38-6). Another common site of fibromatous involvement is the nail bed; subungual fibromas usually appear at puberty and continue to develop with age. Other common skin changes, not in themselves diagnostic, include fibroepithelial tags (soft fibromas), café-au-lait spots, and port-wine hemangiomas.

Pathology

The brain exhibits a number of diagnostic anomalies. Broadening, unnatural whiteness, and firmness of parts of some of the cerebral convolutions are simulated by no other disease. These are the tubers after which the disease is named. On the surface of the brain, they range in width from 5 mm to 2 or 3 cm. Their cut surface reveals a lack of demarcation from cortex and white matter and the presence of white flecks of calcium; these, which are readily seen on CT and MRI, are called brain stones (see below and Fig. 38-7). The walls of the lateral ventricles may be encrusted with white or pink-white masses resembling candle gutterings. When calcified, they appear in radiographs as curvilinear opacities that follow the outline of the ventricle. Rarely, nodules of abnormal tissue are observed in the basal ganglia, thalamus, cerebellum, brainstem, and spinal cord.

Under the microscope the tubers are seen to be composed of interlacing rows of plump, fibrous astrocytes (much like an astrocytoma, though lacking in glial fibrillar protein). In the cerebral cortex and ganglionic structures, derangements of architecture result from the presence of abnormal-appearing cells: greatly enlarged "monstrous," or "balloon" neurons and glia cells—often difficult to distinguish from one another. Also, displaced normal-sized neurons contribute to the chaotic histologic appearance. Gliomatous deposits may obstruct the foramina of Monro or the aqueduct or floor of the fourth ventricle, causing hydrocephalus. Neoplastic transformation of abnormal glia cells, a not infrequent occurrence, usually takes the form of a large-cell astrocytoma, less often of a glioblastoma or meningioma. Recently, certain relationships have been drawn between the balloon cells of this disease and similar cells in focal cortical dysplasias (see Crino and colleagues for details).

The phakomas of the retina are also composed mainly of neuronal and glial components, but occasionally there is an admixture of fibrous tissue.

Diagnosis

When the full combination of seizures and mental and dermal abnormalities is conjoined, the diagnosis is self-evident. It is the early stage of the disease and the formes frustes that give trouble, and here the experienced dermatologist can be of great help. Epilepsy—that is, flexion spasms in infancy—and delay in psychomotor development are by no means diagnostic of tuberous sclerosis, as they occur in many diseases. It is in these cases, and also in every sizable population of the epileptic or developmentally delayed, especially when the family history is unrevealing, that a search for the dermal equivalents of the disease—the hypomelanotic ash-leaf spots, adenoma sebaceum, collagenous skin patch, phakoma of the retina, or subungual or gingival fibromas—is so rewarding. The finding of any one of these lesions provides confirmation of the partial and atypical case. Adenoma sebaceum may occasionally occur alone and is easily confused with acne vulgaris in the adolescent. The history of epilepsy or demonstration of developmental delay is helpful but neither is a requisite for the diagnosis of tuberous sclerosis (see the monograph by Gomez).

The most useful laboratory measures for corroborating the disease are the CT scan and MRI (see Fig. 38-7). The calcific tuber lesions tend to be periventricular and are particularly well shown on the CT scan, whereas MRI is more sensitive in detecting the hamartomatous giant cell subependymal and subcortical lesions. There is an absence of edema in the surrounding tissue. Roach and colleagues have indicated that an increasing number of cortical lesions demonstrated with MRI appear to correlate with an increased impairment of neurologic function. Clinics that treat large numbers of these patients recommend imaging of the kidneys and lungs and, in children, echocardiography. Serial examinations to detect enlargement of the subependymal tumors is advised annually for those younger than age 21 years and every 2 to 3 years thereafter, but the best course of action if a glioma emerges has not been clearly established.

Treatment

Nothing can be offered in the way of prevention other than genetic counseling. Antiepileptic therapy of the standard type suppresses the convulsive tendency more or less effectively and should be applied assiduously. Adrenocorticotropic hormone (ACTH) suppresses the flexor spasms in infancy and tends to normalize the EEG for a time.

It is usually pointless to attempt the excision of tumors, especially in severely affected individuals (with the exception of renal hamartomas that impair kidney function). However, sirolimus, which suppresses the mTOR signaling pathway, causes slight regression of the bodily angiolipomas (Bissler et al) and, of greater interest to the neurologist and neurosurgeon, the similar drug rapamycin has tentatively been shown in a report by Franz and colleagues to shrink subependymal giant cell astrocytomas in some patients. Everolimus, another mTOR inhibitor has been found to be useful in suppressing the status epilepticus associated with some cases of tuberous sclerosis (Krueger et al).

Some patients undergo dermabrasion of the facial lesions for cosmetic reasons, with the knowledge that these slowly regrow. To an increasing degree, neurosurgeons are excising single epileptogenic cortical tubers in otherwise relatively normal children. There are about 15 specialized centers in the United States, and several abroad, that are expert at caring for these patients and establishing a regimen of radiologic surveillance. (See http://www.tsalliance.org for further information including guidelines for testing and surveillance.)

Course and Prognosis

In general, the disease advances so slowly that years must elapse before one can be sure of progression. Of the severe cases, approximately 30 percent die before the fifth year, and 50 to 75 percent before attaining adult age. Worsening is mainly in the mental sphere. Status epilepticus accounted for many deaths in the past, but improved medication therapy has reduced this hazard. Neoplasias take their toll; the authors have had several such patients who died of malignant gliomas arising in striatothalamic regions.

Neurofibromatosis of Von Recklinghausen (NF1 and NF2)

Neurofibromatosis (NF) is a comparatively common hereditary disease in which the skin, nervous system, bones, endocrine glands, and sometimes other organs are the sites of a variety of congenital abnormalities, often taking the form of benign tumors. The typical clinical picture, usually identifiable at a glance, consists of multiple circumscribed areas of increased skin pigmentation accompanied by dermal and neural tumors of various types.

The condition known as multiple idiopathic neuromas was the subject of a monograph by R.W. Smith in 1849; even at that time, he referred to examples recorded by other writers. It was von Recklinghausen, however, who, in 1882, gave the definitive account of its clinical and pathologic features. The subsequent studies of the disease by Yakovlev and Guthrie; Lichtenstein; Riccardi; and Martuza and Eldridge; and more recently by Créange and colleagues; and the comprehensive monographs of Crowe and colleagues and of Riccardi and Mulvihill are informative references that provide a complete analysis of the clinical, pathologic, and genetic data pertaining to the disease.

Epidemiology

Crowe and associates calculated the prevalence of the disease to be 30 to 40 per 100,000, with the expectancy of 1 case in every 2,500 to 3,300 births over 50 years ago and these rates pertain in the all series from the current era. Approximately half of their cases had affected relatives, and in all instances the distribution of cases within a family was consistent with an autosomal dominant mode of inheritance. The disease has been observed in all races in different parts of the world, and males and females are about equally affected.

Cause and Pathogenesis

The hereditary nature of NF has been appreciated for a century. More recently, it has been established that NF comprises two distinct disorders, the genes for which are located on different chromosomes. Both are inherited in an autosomal dominant pattern with a high degree of penetrance, but half the cases are a result of spontaneous mutations. The classic form of the disease with multiple neurofibromas, described below, is caused by a mutation located near the centromere on chromosome 17 in a gene called neurofibromin (Barker et al). The second type, in which the main feature is bilateral acoustic nerve neuromas, described further on, is caused by a mutation in the merlin gene (also called schwannomin). These two forms of NF have been loosely referred to as peripheral and central, respectively, but the terms neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are less confusing (Martuza and Eldridge) and are used in the following discussion.

The large size of the NF1 gene (60 exons) and the widely scattered mutations has made genetic testing complex but such testing is available. Virtually all families manifest different mutations and there have been no clear associations between specific mutations and phenotypic characteristics except that the rare complete deletion leads to early onset multiple neurofibromas, developmental delay, and facial dysmorphism.

The pathogenesis is less obscure now that the genes implicated in both diseases have been identified. Both involve tumor suppression. As with tuberous sclerosis, there is a suggestion of a disorder that allows low-grade ectodermal cell proliferation without tumor transformation. Cellular elements derived from the neural crest (i.e., Schwann cells, melanocytes, and endoneurial fibroblasts, the natural components of skin and nerves) proliferate excessively in multiple foci, and the melanocytes function abnormally. The hormones and growth factors involved in this proliferative process and the mechanism by which it occurs are as obscure as they are in tuberous sclerosis. It is known, however, that most of the numerous mutations in the NF1 gene lead to premature termination of protein synthesis and a consequent "loss of function." This is in keeping with the tumor suppressor characteristics of the gene and the emergence of neoplasms in the presence of homozygous mutations.

Neurofibromatosis Type 1 (Classic, or Peripheral, NF) (Table 38-6)

In the majority of patients, spots of hyperpigmentation (café-au-lait lesions) and cutaneous and subcutaneous neurofibromatous tumors are the basis of clinical diagnosis. Pigmentary changes in the skin are nearly always present at birth, but neurofibromas are infrequent at that age. Both lesions increase in number and size during late childhood and adolescence. There may be a spurt of new lesions at puberty or during pregnancy. Exceptionally, a neurofibroma of a cranial nerve or a spinal root (sometimes with compression of the cord), disclosed during imaging of the spine or a neurosurgical intervention, may be the initial manifestation of the disease. In a large series of patients with neurofibromatosis (Crowe et al), approximately one-third were found to have only the cutaneous manifestations that were noted while being examined for symptoms of some other disease; that is to say, the NF was asymptomatic. Usually these are the patients with the slightest degree of cutaneous abnormality. Of the remaining two-thirds, most consulted a physician because of the disfigurement produced by the skin tumors or because some of the neurofibromas were producing neurologic symptoms.

The patches of cutaneous pigmentation, appearing shortly after birth and occurring anywhere on the body, constitute the most obvious clinical expression of the disease. They are approximately oval in shape and vary in size from a 1 to 2 mm to many centimeters, and in color from a light to dark brown (the term café-au-lait is applied) and are rarely associated with any other pathologic state (Fig. 38-8).

They do not appear to change in number as the patient ages, but they do enlarge during puberty and become more pigmented. In a survey of pigmented spots in the skin, Crowe and associates found that 10 percent of the normal population had one or more spots of this type; however, anyone with more than 6 such spots, some exceeding 1.5 cm in diameter in postpubertal individuals (bigger than 0.5 mm in prepubertal ones), nearly always proved to have neurofibromatosis. Of their 223 patients with NF, 95 percent had at least 1 spot and 78 percent had more than 6 large spots. Freckle-like or diffuse pigmentation of the axillae and other intertriginous areas (groin, under breast) and small, round, whitish spots are characteristic; when coupled with café-au-lait patches, they are together virtually pathognomonic of the disease.

The appearance of multiple cutaneous and subcutaneous tumors in late childhood or early adolescence is the other principal feature of the disease. The cutaneous tumors are situated in the dermis and form discrete soft or firm papules varying in size from a few millimeters to a centimeter or more (molluscum fibrosum; Fig. 38-9). They assume many shapes—flattened, sessile, pedunculated, conical, lobulated, and so on. They are flesh-colored or violaceous and often topped with a comedo. When pressed, the soft tumors tend to invaginate through a small opening in the skin, giving the feeling of a seedless raisin or a scrotum without a testicle. This phenomenon, spoken of as "buttonholing," is useful in distinguishing the lesions of this disease from other skin tumors, for example, multiple lipomas. A patient may have anywhere from a few of these dermal tumors to hundreds.

The subcutaneous neural tumors, which are also multiple, take two forms: (1) firm, discrete nodules attached to a nerve or (2) an overgrowth of subcutaneous tissue, sometimes reaching enormous size. The latter, which are called plexiform neuromas (also pachydermatocele, elephantiasis neuromatosis, la tumeur royale), occur most often in the face, scalp, neck, and chest, and may cause hideous disfigurement. When palpated, they feel like a bag of worms or strings; the bone underlying the tumor may thicken. Neurofibromas are easily distinguished from lipomas, which are soft, unattached to the skin or nerve, and not accompanied by any neurologic disorder. An exception to this last statement is the rare disease of multiple symmetrical lipomatosis with axonal polyneuropathy (Launois-Bensaude disease). As a rule, congenital neurofibromas tend to be highly vascular and invasive and are especially prominent in the orbital, periorbital, and cervical regions. They may be accompanied by hypertrophy of a segment of the body (a sign also seen in the arteriovenous malformation of Klippel-Trenaunay-Weber syndrome). When the hyperpigmentation lesion overlies a plexiform neurofibroma and extends to the midline, one should suspect an intraspinal neurofibroma tumor at that level.

Another unique finding is the Lisch nodule. This is a small whitish spot (actually a hamartoma) in the iris that was present in 94 percent of Riccardi's type 1 cases, but was not found in patients with NF2 or in normal individuals (Fig. 38-10 and below).

Headache, hydrocephalus, and tumors involving the optic pathways, meningiomas, gliomas, and malignant peripheral nerve tumors are common, even among adults, according to the survey of 158 patients by Créange and colleagues; also, pain was a common symptom in adults and often related to a malignant peripheral nerve sheath tumor.

Other abnormalities associated less consistently with type 1 (peripheral) NF include bone cysts, pathologic fractures (pseudoarthrosis), cranial bone defects with pulsating exophthalmos (sphenoid bone dysgenesis), bone hypertrophy, precocious puberty, pheochromocytoma, scoliosis, syringomyelia, nodules of abnormal glia cells in brain and spinal cord, and macrocephaly, rarely with obstructive hydrocephalus as a result of overgrowth of glial tissue around the sylvian aqueduct and fourth ventricle. Some degree of intellectual impairment is common; it was found in 40 percent of Riccardi's series of 133 patients. But in our experience, the figure is much lower and the impairment is usually not profound. Learning difficulty, developmental disorder, and hyperactivity have been more frequent abnormalities, occurring in almost 40 percent of patients. Rosman and Pearce have ascribed developmental delay in NF to congenital malformation of the cerebral cortex (cortical dysgenesis). The incidence of seizures is about 20 times higher than that in the general population, but these tend not to be a very frequent or intractable problem.

Exceptionally, NF is associated with peroneal muscular atrophy, congenital deafness, and partial albinism (Bradley et al).

In childhood, progressive blindness is a particularly dire complication from a tumor mass composed mainly of astrocytes (optic glioma). The tumor may involve one or both optic nerves. The diagnosis comes to mind at once in a child with any of the cutaneous manifestations of NF and this tumor. Uncertainty as to its nature arises from the fact that the neuropathologist may be unable to decide between a benign hamartoma and a grade 1 astrocytoma. Progressive enlargement in a succession of MRI scans may be needed to affirm its nature.

It needs to be stated that neurofibromas of the spinal roots occur regularly in patients without NF (see Chap. 44). Whether multiple such lesions implicate NF is not clear.

Neurofibromatosis Type 2 (Acoustic, or Central, NF)

This condition is considerably less frequent than NF1. Here there is an absence or paucity of cutaneous lesions. Progressive deafness and the demonstration by enhanced CT or MRI of bilateral acoustic neuromas afford accurate diagnosis (see Fig. 31-18). Also, an acoustic neuroma developing before age 30 years is suspect as being caused by NF2. Other cranial or spinal neurofibromas, meningioma (sometimes multiple), and glioma may be added to the syndrome of deafness or may occur prior to its emergence. Juvenile cataracts of the subcortical or capsular variety are seen in some affected patients.

Analysis for the NF2 gene has become available from several laboratories. The genetics and affected protein (merlin or schwannomin) are discussed in "Cause and Pathogenesis" above.

Familial Schwannomatosis

As commented in Chap. 31 in the discussion of acoustic neuroma, it is now apparent that the propensity to develop multiple schwannomas can also be inherited as a dominant trait, without the vestibular tumors characteristic of NF2. This trait maps to a genetic locus on chromosome 22 that is distinct from the one for NF2. It has been estimated that 2 to 5 percent of schwannomas requiring resection are from this disease. The diagnostic criteria are based on the presence of two of more schwannomas without vestibular nerve tumors in an individual older than age 18 years, as summarized in a thorough review by MacCollin and colleagues, and more recently by Plotkin and colleagues. Pain is the dominant problem.

Pathology of NF1 and NF2

The cutaneous tumors are characterized by a rather thin epidermis whose basal layer may or may not be pigmented. The collagen and elastin of the dermis is replaced by a loose arrangement of elongated connective tissue cells. The lack of compactness of the normal dermal collagen allows the palpable opening in the skin. The pigmented (café-au-lait) lesions contain only the normal numbers of melanocytes; the dark color of the skin is instead the result of an excess of melanosomes in the melanocytes. Some of the abnormally large melanosomes measure up to several microns in diameter.

The nerve tumors are composed of a mixture of fibroblasts and Schwann cells (except the optic nerve tumors, which contain a combination of astrocytes and fibroblasts). Predominance of one or the other of these cells in the nerve is the basis of the diagnosis of neurofibroma or schwannoma. Palisading of nuclei and sometimes encircling arrangements of cells (Verocay bodies) are features of both (see Chap. 31). Occasionally, along spinal roots or sympathetic chains, one may find a tumor made up of partially or completely differentiated nerve cells, a typical ganglioneuroma. Clusters of abnormal glia cells may be found in the brain and spinal cord, and, according to Bielschowsky, they imply a link with tuberous sclerosis that has never been proved. Clinically and genetically, the two diseases are quite independent.

Malignant degeneration of the tumors is found in 2 to 5 percent of cases; peripherally they become sarcomas and centrally, astrocytomas or glioblastomas (Fig. 38-11).

Diagnosis

If skin tumors and café-au-lait spots are numerous and Lisch nodules are present in the iris, the identification of the disease as type 1 neurofibromatosis offers no difficulty. A history of the illness in antecedent and collateral family members makes diagnosis even more certain. Doubt arises most frequently in patients with bilateral acoustic neuromas or other cranial or spinal neurofibromas or schwannomas with no skin lesions or only a few random ones. The tendency for these forms of NF to have few skin lesions is well known, but differentiation of type 1 from type 2 may be uncertain unless genetic studies are undertaken. Plexiform neuromas with muscle weakness because of nerve involvement and abnormalities of underlying bone may be confused with other tumors, especially in young children, who tend to have few café-au-lait spots and few cutaneous tumors. Hypertrophy of a limb requires differentiation from other developmental anomalies including Klippel-Trenaunay-Weber syndrome.

As already mentioned, Crowe and coworkers expressed the view that 80 percent of patients with von Recklinghausen disease can be diagnosed by the presence of more than 6 café-au-lait spots. Of the remaining 20 percent, those older than 21 years of age will be found to have multiple cutaneous tumors, axillary freckling, and a few pigmented spots; in those younger than 21 years of age with no dermal tumors and only a few café-au-lait patches, a positive family history and radiographic demonstration of bone cysts will be helpful in some instances. Café-au-lait spots and cutaneous tumors should always be sought, for they may help the neurologist diagnose an otherwise obscure progressive spinal syndrome, a cerebellopontine angle syndrome, bilateral deafness, progressive blindness, and an occasional case of precocious puberty, hydrocephalus, or developmental delay.

Because of the many potentially dangerous conditions that accompany classic NF, the initial clinical evaluation should be supplemented by a number of ancillary examinations that may include measurement of IQ, EEG, slit-lamp examination of irides, visual and auditory evoked responses, and CT scans or MRI of cranium and, sometimes, of the spine and mediastinum. In the series reported by Duffner and colleagues, 74 percent of cases had abnormal signals in T2-weighted images of the basal ganglia, thalamus, hypothalamus, brainstem, and cerebellum. The EEG was abnormal in 25 percent. If there is suspicion of a pheochromocytoma, 24-h urine should be tested for metabolites of epinephrine. Each of these tests not only is an aid to diagnosis but also is essential to the effective management of the illness.

Treatment

The skin tumors should not be excised unless they are cosmetically objectionable or show an increase in size, suggesting malignant change. The effects of radiotherapy on these lesions are so insignificant that they do not justify the risk of exposure. Plexiform neuromas about the face pose especially difficult problems. Here one must resort to plastic surgery, but the results are not always satisfactory because the growths may encompass distal branches of cranial nerves (with risk of greater paralysis after surgical excision) or alter the underlying bone, the latter being either eroded from pressure or hypertrophied from increased blood supply. Cranial and spinal neurofibromas are amenable to excision, and the gliomas and meningiomas usually demand surgical measures as well. Here the differentiation of hamartomas from gliomas of structures such as the optic nerves, hypothalamus, or pons may be difficult. Bilateral optic nerve gliomas are usually treated with radiation; unilateral ones are excised. Peripheral nerve tumors that have undergone malignant (sarcomatous) degeneration pose special surgical problems.

Affected individuals should be advised not to have children, a precaution that may not be necessary because fertility, especially in males, seems to be reduced by the disease. Prognosis varies with the grade of severity, being most favorable in those with only a few lesions. But the disease is always progressive, and the patient should remain under surveillance.

Other Cutaneous Angiomatoses with Abnormalities of the Central Nervous System

There are at least 7 additional diseases in which a cutaneous or ocular vascular anomaly is associated with an abnormality of the nervous system: (1) meningo- or encephalofacial (encephalotrigeminal) angiomatosis with cerebral calcification (Sturge-Weber syndrome); (2) dermatomal hemangiomas and spinal vascular malformations (sometimes with limb hypertrophy, as also occurs in Klippel-Trenaunay-Weber syndrome and in neurofibromatosis); (3) the epidermal nevus (linear sebaceous nevus) syndrome; (4) familial telangiectasia (Osler-Rendu-Weber disease); (5) hemangioblastoma of cerebellum and retina (von Hippel-Lindau disease); (6) ataxia-telangiectasia (Louis-Bar disease); and (7) angiokeratosis corporis diffusum (Fabry disease). The last three disorders are considered elsewhere: ataxia-telangiectasia and Fabry disease with the inherited metabolic disorders in Chap. 37, and von Hippel-Lindau disease below and with hemangioblastoma in Chap. 31.

Sturge-Weber Syndrome (Meningo- or Encephalofacial Angiomatosis with Cerebral Calcification)

This condition has been referred to as the Sturge-Weber syndrome, as it was W. Allen Sturge who, in 1879, described a child with sensorimotor seizures contralateral to a facial "port-wine mark," and Parkes Weber (1922, 1929), who gave the first radiographic demonstration of the atrophy and calcification of the cerebral hemisphere ipsilateral to the skin lesion. This eponym overlooks the important intervening contributions of Kalischer (1897, 1901), who first described the meningeal angioma in conjunction with the facial one; of Volland (1913), who demonstrated the intracortical calcific deposits; and of Dimitri (1923), who described the characteristic double-contoured radiographic shadows. Krabbe (1932, 1934) showed conclusively that the calcification lay not in the blood vessels (as Dimitri and many others had concluded), but in the second and third layers of the cortex (see Wohlwill and Yakovlev for historical review and bibliography).

A vascular nevus is observed at birth to cover a large part of the face and cranium on one side (in the territory of the ophthalmic division of the trigeminal nerve). In one-quarter of the cases the nevus is bilateral. The lesions vary in extent, the most limited being an involvement of only the upper eyelid and forehead, and the most extensive being the entire head and even other parts of the body. The skin lesion is deep red (port-wine nevus) and its margins may be flat or raised; soft or firm papules, evidently composed of vessels, cause surface elevations and irregularities. Orbital tissue, especially the upper eyelid, is almost invariably involved; congenital buphthalmos may enlarge the eye before birth and glaucoma may develop later in that eye, causing blindness. The choroid is implicated in some cases. The increased cutaneous vascularity may result in an overgrowth of connective tissue and underlying bone, giving rise to a deformity like that of the Klippel-Trenaunay-Weber syndrome. Indications of cerebral disease appear as early as the first year of life or later in childhood; the most frequent clinical manifestations are unilateral seizures followed by increasing degrees of spastic hemiparesis with smallness of the arm and leg, hemisensory defect, and homonymous hemianopia, all on the side contralateral to the trigeminal nevus. Skull films (usually normal just after birth) taken after the second year reveal a characteristic "tramline" calcification, which outlines the involved convolutions of the parietooccipital cortex. CT scanning and MRI show the abnormalities of the involved cortex at an earlier age (Fig. 38-12).

It is not the case that all cranial hemangiomas affect the cerebrum; the common facial nevi, especially the flat midline ones and the elevated strawberry nevi, are of no neurologic significance. And a cerebral–meningeal angiomatosis may be present without skin lesions. The involvement of the upper eyelid is of greatest importance since nearly all such cases are associated with cerebral lesions (Barlow). There seems to be a close correlation between the persistence or maldevelopment of the embryonic vascular plexus of the eyelid and forehead and that of the occipitoparietal parts of the brain. When the nevus lies entirely below the upper eyelid or high on the scalp, a cerebral lesion is usually absent, although in a few instances such an angioma has been associated with a vascular malformation of the meninges overlying the brainstem and cerebellum. In angiograms, the abnormal meningeal vessels, which are largely veins, are not well seen; thus they can be distinguished from true arteriovenous malformations. These purely meningeal venous nevi are rarely the source of subarachnoid or cerebral hemorrhage and they do not enlarge to form a mass. The cortical lesion is, however, destructive of cortical tissue, which is replaced by glial tissue that calcifies. One explanation holds that diversion of blood to the meninges during seizures causes progressive ischemia of the cerebral cortex. Barlow has stated that the seizures themselves are responsible for the progressive neurologic deficits and that a special effort should be made to prevent them by carefully regulated medical therapy. Occasionally surgical excision of intractable discharging foci may be necessary, but often this may not be feasible in view of the magnitude of the cerebral lesion. Radiotherapy is unsuccessful in reducing the skin blemish; sensitive individuals usually try to hide it with cosmetics. There is little literature on treating the brain vascular malformation with endovascular techniques.

Although a heredofamilial trait has long been known, it was only recently that Shirley and colleagues found a polymorphism in the responsible gene, GNAQ, in almost 90 percent of individuals with the trait and in a similar number of patients with non-syndromic port-wine stains on the cranium. The variant may be of a mosaic type, being present only in affected tissues. This substitution in the gene activates extracellular signal-regulated kinase. Similar SNPs have been known to participate in other conditions that feature abnormal skin pigmentation.

Dermatomal Hemangiomas with Spinal Vascular Malformations

A hemangioma of the spinal cord may rarely be accompanied by a vascular nevus in the corresponding dermatome, as was first pointed out by Cobb. Such nevi are most frequent on the arm and trunk. When the cutaneous lesion involves an arm or leg, there may be enlargement of the entire limb or fingers in combination with underdevelopment of certain other parts (Klippel-Trenaunay-Weber syndrome). Some of these angiomatous syndromes combine a spinal or retinal-diencephalic arteriovenous malformation (AVM) with a nevus of the trunk or face, respectively. Such cases provide a link to the common AVMs described in Chap. 34.

Epidermal Nevus Syndrome

This is a closely related congenital neurocutaneous disorder in which a specific skin lesion (epidermal nevus or linear sebaceous nevus) is associated with a variety of hemicranial and neurologic abnormalities. The skull and brain abnormalities are ipsilateral to the nevus. One-sided thickening of the bones of the skull is characteristic. Developmental delay, seizures, and hemiparesis are the usual neurologic manifestations and have their basis in a wide variety of cerebral lesions—unilateral cerebral atrophy, porencephalic cyst, leptomeningeal hemangioma, arteriovenous malformation, and atresia of cerebral arteries and veins. The somatic and neurologic abnormalities of this syndrome have been comprehensively reviewed by Solomon and Esterley and by Baker and associates.

Hereditary Hemorrhagic Telangiectasia (Osler-Rendu-Weber Disease)

This vascular anomaly is transmitted as an autosomal dominant trait. To date, two mutant genes have been identified as causes of this disease: endoglin and novel kinase. The small arteriovenous malformations affect the skin, mucous membranes, gastrointestinal and genitourinary tracts, lungs, and occasionally the nervous system. The basic lesion is probably a defect in the vessel wall, and the main complication, bleeding, is thought to be a result of the mechanical fragility of the vessel. Located sparsely in the skin of any part of the body, these vascular lesions first appear during childhood, enlarge during adolescence, and may assume spidery forms, resembling the cutaneous telangiectases of cirrhosis in late adult life. The lesions range from the size of a pinhead to 3 mm or more, are bright red or violaceous, and blanch under pressure.

The significance of the lesions lies in their hemorrhagic tendency. During adult years they may give rise to severe and repeated epistaxis or gastric, intestinal, or urinary tract bleeding and result in an iron-deficiency anemia. Pulmonary fistulas constitute another important feature of the generalized vascular dysplasia; patients with such lesions are particularly subject to brain abscesses and less so to bland embolic strokes.

The angiomas of this disease may infrequently form in either the spinal cord or brain, where they can produce acute hemorrhage, or as in one of our patients, there may be an intermittently progressive focal thalamic syndrome resulting from enlargement of the vascular lesions or possibly from a succession of small hemorrhages. Repeated unexplained gastrointestinal, genitourinary, intracranial, or intraspinal hemorrhages warrant a search for small cutaneous lesions, which are easily overlooked. Satellite lesions tend to form after obliteration of an angioma.

Von Hippel-Lindau Disease

This is a genetic disease of multiple neoplasms, specifically by the presence of a hemangioblastoma, sometimes multiple (these are discussed with other cerebral tumors in Chap. 31). The tumor is situated in the cerebellum in most cases, but may also arise in the brainstem or spinal cord. In addition to the characteristic cerebellar tumor with its nodule within a cyst, half of these patients have retinal hemangioblastomas and somewhat fewer develop renal cell cancer; an even smaller number have a pheochromocytoma, pancreatic tumors or cysts, or cystadenomas. Polycythemia vera is an interesting feature in a few cases. We have encountered rare cases that presented as subarachnoid hemorrhage.

The cerebellar hemangioblastoma typically develops in the fourth decade and causes symptoms of ataxia and headache. On imaging studies, the lesions have a striking appearance of a cyst with a nodule contained in its wall, and angiography demonstrates the highly vascular nature of the nodule, which represents the actual neoplasm (see Fig. 31-13). The other identifying features of the disease, retinal hemangiomas, are smaller but indistinguishable histologically from the craniospinal ones. They are multiple and bilateral, usually appearing earlier than the cerebellar lesions but remaining asymptomatic until they become extensive (retinal detachment is one feature). Their diagnosis is made by funduscopy, by which a large feeding vessel leading to an irregularly shaped ovoid tumor in the retina can usually be appreciated. Imaging studies of the cranium that use dye enhancement will reveal them as well.

Inheritance is autosomal dominant with variable but high penetrance by older age. The causative mutation is in the VHL gene located on chromosome 3. This is a tumor suppressor gene that is inactivated by the mutation and may induce oncogenesis by increasing the expression of vascular mitogenic factors such as vascular endothelial growth factor (VEGF) but the precise mechanisms are not known. Renal cell cancer is a serious component of the disease, occurring in up to 60 percent of cases, but the tumors, although multiple, tend initially to be small and of low grade. Nonetheless, renal cancer accounts for one-third of deaths from the disease, the remainder being largely the result of complications of the cerebellar neoplasm. An extensive review of the subject was written by Losner and colleagues.

Mentioned here is the cerebellar gangliocytoma of Lhermitte-Duclos disease. There are no cutaneous malformations but small vascular anomalies in the brain and elsewhere may accompany the cerebellar tumor as discussed in Chap. 31 (see Fig. 31-15).

Ataxia-Telangiectasia

This disease, also referred to as the Louis-Bar syndrome, was first described by Sylaba and Henner in 1926, long before Louis-Bar's report in 1941. It combines a progressive ataxia with humoral immune deficiency and telangiectasias. Like xeroderma pigmentosum and the Cockayne syndrome, ataxia-telangiectasia has been attributed to defective repair of DNA. The inheritance pattern is autosomal recessive and the clinical presentation is somewhat heterogeneous, with certain features predominating in a particular child and his siblings, as summarized by Boder and Sedgwick. An adult form may show few of the characteristic telangiectasias.

The disorder first presents as an ataxic-dyskinetic syndrome in children who appear to have been normal in the first few years of life. The onset of the disease coincides more or less with the acquisition of walking, which is awkward and unsteady. Later, by the age of 4 to 5 years, the limbs become ataxic, and choreoathetosis, grimacing, and dysarthric speech are added. The eye movements become jerky, with slow and long-latency saccades, and there is also apraxia for voluntary gaze (the patient turns the head but not the eyes on attempting to look to the side). This movement of the head and eyes in tandem is the most specific feature of the process. Optokinetic nystagmus is lost and reading becomes all but impossible. Severe cognitive developmental delay is infrequent, affecting perhaps 10 percent of children but in those affected, it is apparent by the age of 9 to 10 years; slight intellectual limitation is more common. Signs of mild polyneuropathy are evident at this age as well, appearing similarly the Charcot-Marie-Tooth phenotype. Seizures are not part of the syndrome.

Muscle power is reduced little if at all until late in the illness, but tendon reflexes may disappear. The characteristic telangiectatic lesions, which are mainly transversely oriented subpapillary venous plexuses, appear at 3 to 5 years of age or later (they are not apparent in some patients until approximately age 7) and are most apparent in the outer parts of the bulbar conjunctivae (Fig. 38-13), over the ears, on exposed parts of the neck, on the bridge of the nose and cheeks in a butterfly pattern, and in the flexor creases of the forearms. Vitiligo, café-au lait spots, loss of subcutaneous fat, and premature graying of hair are observed in some older patients. Many of the patients have endocrine alterations (absence of secondary sexual development, glucose intolerance). The disease is progressive, and death may occur in the second decade from intercurrent bronchopulmonary infection or neoplasia—usually lymphoma, less often glioma, that develop in fewer one-third of patients.

As mentioned, the adult form of ataxia-telangiectasia, in which some of the deficient enzyme activity is retained (see below), manifests few telangiectasias but may be identified by an extrapyramidal syndrome in childhood and only later, with mild ataxia as summarized by Verhagen and colleagues; there may be a family history of cancers.

The significant abnormalities in the CNS are severe degeneration in the cerebellar cortex (visible on MRI scans); loss of myelinated fibers in the posterior columns, spinocerebellar tracts, and peripheral nerves; degenerative changes in the posterior roots and cells of the sympathetic ganglia; and loss of anterior horn cells at all levels of the spinal cord. In a few cases, vascular abnormalities, like the mucocutaneous ones, have been found scattered diffusely in the white matter of the brain and spinal cord, but they are of questionable significance. Also, there may be a loss of pigmented cells in the substantia nigra and locus ceruleus (a feature shared with PKU), and cytoplasmic inclusions (Lewy bodies) in the cells that remain (Agamanolis and Greenstein). During early development there are abnormalities of Purkinje cell migration and variations in nuclear size. Intranuclear inclusions and bizarre nuclear formations have also been found in the satellite cells (amphicytes) of dorsal root ganglion neurons (Strich).

There is an absence or decrease in several immunoglobulins—IgA, IgE and isotypes, IgG2, IgG4—in practically every patient. These deficiencies, shown by McFarlin and associates to be a result of decreased synthesis, are associated with hypoplasia of the thymus, loss of follicles in lymph nodes, failure of delayed hypersensitivity reactions, and lymphopenia. This immunodeficient state accounts for the striking susceptibility of these patients to recurrent pulmonary infections and bronchiectasis. Transplantation of normal thymus tissue into the patient and administration of thymus extracts have been of no therapeutic value.

The defective gene (designated ATM) is a kinase that is a transducer in the pathway for DNA repair that halts the cell cycle after DNA damage. For this reason, there is faulty repair of DNA after radiation and a greatly increased risk of lymphomas, leukemias, and other tumors as well as certain specific susceptibilities to the effects of cancer treatment. The protein is normally expressed ubiquitously and 90 percent of patients have no ATM protein, usually because of a stop codon in the mutated gene.

The only therapy centers on the control of infections. Free radical scavengers such as vitamin E have been recommended without proof of their effectiveness. Because of radiation sensitivity, even conventional diagnostic tests (dental, chest radiography) should be avoided unless there is a compelling reason for them.

In the course of clinical practice, one encounters a remarkable number of restricted disorders of the nervous system, many of which are transmitted from generation to generation as a mendelian, usually dominant, trait. Of the more severe ones, only a few of the more striking examples are described here. Milder and more restricted conditions, such as stuttering and dyslexia, that are pervasive in the population are described in Chap. 28. The reader may turn to books on genetics or teratology for an account of such oddities as hereditary unilateral ptosis, hereditary Horner syndrome, pupillary inequalities, jaw winking, and absence of a particular skeletal muscle.

Bifacial and Abducens Palsies (Möbius Syndrome)

The syndrome of congenital facial diplegia with convergent strabismus is referred to as Möbius syndrome, although Von Graefe had described it earlier. Its presence at birth is disclosed by the lack of facial movements and of full eye closure. A review of the subject in the English literature was written by Henderson, and a more recent analysis of 37 affected individuals was written by Harriëtte and colleagues. In Henderson's study of 61 cases of the congenital facial diplegia syndrome, there were 45 instances of associated abducens palsy, 15 of complete external ophthalmoplegia, 18 of lingual palsy, 17 of clubfeet, 13 of a brachial disorder, 6 of mental defect, and 8 of an absent pectoral muscle. Thus the overlap with other neuromuscular and CNS abnormalities is evident. Moreover, at least two configurations of brainstem dysfunction have been proposed, one because of a lack of the facial nerve nucleus and the other in the nerve, perhaps acquired in type, based on electrophysiologic studies, but we have no basis to judge the validity of this. Harriëtte and coworkers emphasize the frequency of hypoplastic or dysplastic tongue, palatal involvement, and general motor clumsiness. They suggest that the disorder represents a widespread form of brainstem maldevelopment.

Early in life the mouth hangs open, the lower lip is everted, and there is difficulty in sucking. Usually this syndrome can be distinguished from the facial palsy of forceps or birth injury by its bilaterality and the other associated weaknesses. Occasionally, more than one family member is affected (usually in a pattern suggesting autosomal dominant inheritance). The cause of this peculiar condition is not known. The few adequate pathologic studies have shown a paucity of nerve cells in the motor nuclei of the brainstem, changes that also characterize the Fazio-Londe type of muscular dystrophy discussed in Chap. 50. Rarely, there may be an aplasia of facial muscles. The Möbius syndrome is also referred to in Chap. 47 in relation to restricted palsies of myopathic and nuclear origin.

Partial paralysis of facial muscles that dates from birth and cannot be attributed to obstetric trauma is not infrequent. In a common type, the lower lip on one side remains immobile when the child smiles or cries; the lip on the unaffected side is drawn downward and outward, resulting in a prominent asymmetry of the lower face. Often it is not appreciated that the side that droops during crying is the normal side (Hoefnagel and Penry).

Congenital Lack of Lateral Gaze (Cogan Oculomotor Apraxia)

Children with this congenital defect are unable to turn their eyes to either side volitionally or on command. Attempting to look to the right, the child turns the head to the right (there is no associated apraxia of head turning), but the eyes lag and turn to the left. As a result, the patient has to overshoot the mark with the head in order to attain ocular fixation. Once the eyes fixate, the head returns to the primary position. To compensate for the deficiency of eye movements, the patient develops jerky thrusting movements of the head, which characterize all attempts at voluntary gaze. Caloric stimulation of the labyrinth causes tonic movement of the eyes but not nystagmus, as in the normal person. Also, optokinetic nystagmus cannot be induced. Vertical eye movements are normal. A similar ocular condition may occur in conjunction with ataxia-telangiectasia and in Gaucher disease. Children with oculomotor apraxia are slow to walk; Ford observed one such child whose sibling had an absence of the vermis of the cerebellum. Aside from this observation, the anatomic basis of the condition has not been studied.

In this group of congenital disorders, a major disturbance of motor function, usually nonprogressive, has been present since infancy or early childhood. The popular terms for these conditions have been infantile cerebral paralysis (Freud) and cerebral palsy. The latter name is neither appropriate nor useful from the physician's viewpoint, collocating as it does diseases of widely differing etiologic and anatomic types, wherein the hereditary and acquired and the intrauterine, natal, and postnatal diseases lose their identity. But the name has been adopted as a slogan by fund-raising societies and for rehabilitation clinics throughout the United States, hence it will not soon disappear from medical terminology. The term, often abbreviated CP, is still being used indiscriminately to designate every conceivable cognitive and motor disorder of corticospinal, extrapyramidal, cerebellar, and even neuromuscular type in infants and children.

Etiology of the Congenital Cerebral Motor Disorders

Motor abnormalities that have had their onset early in life are numerous and diverse in their clinical manifestations. Marked prematurity is an associated factor in a large proportion of cases. Each year, approximately 50,000 infants weighing less than 1,500 g are born in the United States; approximately 85 percent survive. Of these, 5 to 15 percent have a motor disorder of cerebral origin and 25 to 30 percent are found to be mentally impaired at school age (Volpe, 1995; also Hack et al). It is helpful to categorize a given case according to the extent and nature of the motor abnormality. A careful history of prenatal, perinatal, or postnatal insults to the developing nervous system must be sought; certain correlations of these factors with the resulting pattern of neurologic deficit are outlined below. Most patients with these motor abnormalities reach adult years. Many but not all have epilepsy in addition to the motor abnormalities and there is an unavoidable overlap in considering the causes and mechanisms of these three clinical states.

The following discussion is given from the perspective of the three major etiologic syndromes: matrix hemorrhages in the immature infant, hypoxic-ischemic encephalopathy, and certain other developmental motor abnormalities including those due to intrauterine stroke.

Germinal Matrix (Subependymal) Hemorrhage in Premature Infants

In low-weight and premature immature infants (20 to 35 weeks' gestational age), there sometimes occurs, within a few days after birth, a catastrophic decline in cerebral function, usually preceded by respiratory distress (hyaline membrane disease) with spells of cyanosis and apnea. Also evident are deficiencies of brainstem automatisms (sucking and swallowing), bulging of the fontanels, and sanguineous CSF. If the infant becomes completely unresponsive, death usually ensues within a few days. Autopsy discloses a small lake of blood in each cerebral hemisphere (often asymmetrically distributed), occupying the highly cellular (subependymal) germinal matrix zone, near the caudate nucleus at the level of the foramen of Monro. This region is supplied by the lenticulostriate, choroidal, and Heubner recurrent arteries and is drained by deep veins, which enter the vein of Galen. In approximately 25 percent of cases, the blood remains loculated in the matrix zone, while in the majority it ruptures into the lateral ventricle or adjacent brain tissue. In a series of 914 consecutive autopsies in newborns, subependymal hemorrhage was found in 284 (31 percent); practically all of these neonates were of low birth weight, according to Banker and Bruce-Gregorios.

Lesser degrees of this cerebral hemorrhage are now being identified by ultrasonography (Fig. 38-14) and CT scans, and it is apparent that many infants with smaller hemorrhages survive. Some rapidly develop an obstructive hydrocephalus and require a ventricular shunt. In others, the hydrocephalus stabilizes and there is clinical improvement. Several series of surviving cases have now been followed for many years. Those in whom the hemorrhage was more extensive are often left with motor and intellectual handicaps.

Viewed from the perspective of cerebral palsy, just over half of the patients in the Swedish series of Hagberg and Hagberg with spastic diplegia had matrix hemorrhages, leukomalacia (see further on), or both. Congenital hemiplegia or quadriplegia was observed at a lower frequency. In another series of 20 cases of posthemorrhagic hydro-cephalus (Chaplin et al), 40 percent had significant motor deficits and more than 60 percent had IQ scores of less than 85. In an experience with 12 less severely affected surviving cases (mean birth weight 1.8 kg and gestational age of 32.3 weeks), R.D. Adams noted that only 1 had a residual spastic diplegia and 9 had IQs in the low-normal or normal range (personal communication).

The cause of matrix hemorrhage is not entirely clear. In all probability it is related to greatly increased pressure in the thin-walled veins of the germinal matrix coupled with a lack of adequate supporting tissue in these zones. During periods of unstable arterial or venous blood pressure that occur with the pulmonary disorders of immature infants, these thin-walled vessels rupture. These infants are also prone to the development of another characteristic lesion of the cerebral white matter (periventricular leukomalacia; see below), and the neurologic deficits resulting from these two lesions may be additive.

Treatment

Control of the respiratory distress of prematurity may reduce the incidence of matrix hemorrhages and periventricular leukomalacia. Claims have been made that the administration of indomethacin ethamsylate, a drug that reduces capillary bleeding, and the intramuscular injection of vitamin E for the first 3 days after birth and possibly the use of betamethasone or other corticosteroids appears to be of value in reducing the incidence of periventricular hemorrhage (Benson et al; Sinha et al; see also Volpe [1989] for discussion of control of cerebral hemodynamics and effects of medications in the neonatal period). Acetazolamide and furosemide, which reduce the formation of spinal fluid, have been widely used in the treatment of posthemorrhagic hydrocephalus. However, in a large-scale controlled study, the effects were negligible and shunt placement was required to control worsening hydrocephalus (see International PHVD Drug Trial Group in the references).

Periventricular Leukomalacia

These are zones of necrosis of white matter in the deep territories of cortical and central arteries. They lie lateral and posterolateral to the lateral ventricles, in a position to involve the occipital radiations and the sensorimotor fibers in the corona radiata (first described by Banker and Larroche; see also Shuman and Selednik). The white matter lesions occur in about one-third of cases of subependymal hemorrhage as mentioned, but they may develop independently in both premature and full-term infants who have suffered hypotension and apnea. In a study of 753 preterm infants, those born at 28 weeks' gestation or less were at highest risk of this complication; the combination of intrauterine infection and premature rupture of membranes carried a 22 percent risk (Zupan et al). Survivors often manifest cerebral hemiplegia or diplegia and variable degrees of mental impairment. The motor disorder is usually more severe than the cognitive and language impairment. Increasingly, small lesions of this nature are being identified in term infants by cerebral imaging including ultrasound.

The mechanism of this type of periventricular infarction has been debated, and the terminology and clinical features, insofar as they overlap with germinal matrix hemorrhage, have been confusing. In recent years, most theories and experimental evidence converge on the notion that these represent regions of venous ischemia and infarction.

Hypoxic-Ischemic Damage and Neonatal Encephalopathy

It has been estimated that in the range of 1 to 6 of every 1,000 live births manifests a neonatal encephalopathy (as quoted in the review by Ferriero). The seriousness of the condition is further emphasized by the associated mortality rate of 20 percent in the newborn period and the 25 percent rate of neurodevelopmental disability in survivors. Little's conception of the hypoxic-ischemic form of "birth injury," enunciated in 1862, has been reconsidered over the years. Although it is evident that many newborns suffer some degree of perinatal asphyxia, relatively few seem to manifest brain damage. Moreover, many, if not most, infants with a variety of cerebral motor syndromes appear to have passed the parturitional (perinatal) period without mishap, indicating the greater importance of other prenatal and postnatal causative factors. Nonetheless, severe neonatal asphyxia of term or preterm babies can be an important cause of spastic, dystonic and ataxic syndromes, often accompanied by seizures and mental delay in development.

This field has been sullied by an unprecedented rise in malpractice litigation, spawned in part by the belief that early detection of asphyxia and rapid delivery would have prevented the motor, epileptic, and cognitive problems of birth injury. The fallacy of this assumption is highlighted both by the below comments and by the observation that the incidence of cerebral palsy has not changed in term infants over the past 30 years, despite the institution of fetal monitoring and more frequent cesarean sections.

One has the impression that the brain tolerates hypoxia and reduced blood flow in the immediate postnatal period better than at any other time in life. Indeed, animal experimentation supports this view. Not until the arterial oxygen tension is reduced dramatically to 10 to 15 percent of normal does brain damage occur, and even then the impaired function of other organs contributes to the damage. It is probably correct to think of the encephalopathy in terms of both hypoxia and ischemia, both of which usually occur in utero and are expressed postnatally by recognizable clinical syndromes.

Fenichel (1990), following the original work of Sarnat and Sarnat and of Levene and colleagues, has found it helpful to divide the encephalopathies that follow a complicated birth into three purely descriptive groups according to their severity, each having a prognostic value beyond that of the Apgar score: (1) In newborns with mild hypoxic-ischemic encephalopathy, the symptoms are maximal in the first 24 h and take the form of hyperalertness and tremulousness of the limbs and jaw (the "jittery baby") and a low threshold of the Moro reaction. The tone of the limbs is normal except for a mild increase in head lag during traction. The reflexes are brisk and there may be ankle clonus. The anterior fontanel is soft. The EEG is normal. Recovery is usually complete and the risk of handicap is low. (2) Newborns with moderate hypoxic-ischemic encephalopathy are lethargic, obtunded, and hypotonic, with normal movements. After 48 to 72 h, the neonate may improve (having passed through a jittery hyperactive phase) or worsen, becoming less responsive in association with convulsions, cerebral edema, hyponatremia, and hyperammonemia from liver damage. The EEG is abnormal. Fenichel associates epileptiform activity and voltage suppression with an unfavorable outcome. Abnormal visual and auditory evoked potentials are other poor prognostic signs. (3) In neonates with severe hypoxic-ischemic encephalopathy, stupor or coma is present from birth; respirations are irregular, requiring mechanical ventilation. There are usually convulsions within the first 12 h. The limbs are hypotonic and motionless even during attempts to elicit the Moro response. Sucking and swallowing are depressed or absent, but pupillary reactions and eye movements may at first be retained, only to be lost as the coma deepens.

It is in the second and third categories, that is, the states of moderate to severe encephalopathy, where correction of the respiratory insufficiency and the metabolic abnormalities permits survival, that a number of motor abnormalities (corticospinal, extrapyramidal, and cerebellar) and developmental delay eventually emerge. Included in the category of severe hypoxic-ischemic encephalopathy are also newborns with a variety of developmental anomalies of the brain and other organs. However, clouding the issue of causality is the absence of perinatal complications in a large number of children with cerebral palsy and the large number of normal babies who are born after complicated deliveries. Notably, only a few cases result from often blamed intrapartum factors such as forceps delivery, breech presentation, cord prolapse, abruptio placentae, and maternal fever.

In addition, such infants may have been exposed to certain prenatal risk factors (toxemia of pregnancy, antepartum uterine hemorrhage, maternal hypotension, and certain epidemiologic associations such as hypothyroidism or fertility treatment), or their growth may have been abnormal (small-for-date babies). Some of these babies are born at term; others are premature, and the birth process may or may not have been abnormal. One must then consider the possibility, originally pointed out by Sigmund Freud, that the abnormality of the birth process, instead of being causal, was actually the consequence of prenatal pathology. The latter might include preterm intrauterine hypoxia-ischemia.

Other evidence of multifactorial etiology in the "causation" of cerebral palsy has been provided by Nelson and Ellenberg, who found that maternal developmental delay, birth weight below 2,000 g, and fetal malformation were among the leading predictors. Breech presentation was another factor, and one-third of these cases also had some noncerebral malformation. Twenty-one percent of the 189 children in their series had also suffered some degree of asphyxia. Additional determinants were maternal seizures, a motor deficit in an older sibling, two or more prior fetal deaths, hyperthyroidism in the mother, preeclampsia, and eclampsia. In children with cerebral diplegia born at term, likely contributory factors that were operative in nearly half included toxemia of pregnancy, low birth weight for age, placental infarction, and intrauterine asphyxia.

The factors enumerated above are involved to different degrees in the outcome of pregnancies but are informative because they bring to light the significant proportion of cases of cerebral birth injury in which hypoxia-ischemia, matrix hemorrhages, and leukomalacia were not operative. In this group, can be included the symmetrical porencephalies and hydranencephalies.

Thus the complexity of assigning a cause for cerebral palsy is evident. In respect to the motor disorders discussed below, hypoxic-ischemic perinatal injury is still the most commonly specified cause of neonatal encephalopathy but is often unrelated to a permanent defect of cerebral palsy. This statement has been amply confirmed by a large and often cited study from Western Australia that detected neonatal encephalopathy in 3.8 of 1,000 live term births but was able to identify causative intrapartum factors alone in only 5 percent (Badawi et al). Furthermore, only 10 percent of all the infants with neonatal encephalopathy developed spastic quadriplegia, according to Evans and colleagues.

Imaging studies of cerebral palsy have increasingly appeared and it has even been suggested, perhaps with excessive enthusiasm, that all such children undergo scanning. Cowan and colleagues (2003) used MRI to determine the proportion of infants with a neonatal encephalopathy who had antenatal brain injury. Excluding those with major congenital malformations or obvious chromosomal abnormalities, 80 percent of cases had no established lesion or brain atrophy. In contrast, those with only seizures and no neonatal encephalopathy in 69 percent of cases had evidence of antenatal damage on MRI; infarctions because of thrombophilic disorders were most common. An MRI–clinical correlative study of children with cerebral palsy by Bax and colleagues in The European Cerebral Palsy Study came to similar conclusions but found that periventricular leukomalacia of prematurity was the most common MRI change, present in 42 percent of infants, followed in frequency by basal ganglionic damage (13 percent), cortical-subcortical lesions (9 percent), malformations (9 percent), and focal infarcts (7 percent). These authors found a correspondence between the clinical and MRI findings. These studies demonstrate the utility of MRI in identifying neonatal forms of encephalopathy and indicate that few are the result of obstetric accidents. Added difficulty is caused by the fact that the clinical signs of perinatal injury may emerge only when the maturational process of the nervous system exposes them at a later period of life. Woodward and coworkers suggested that the MRI pattern is predictive of developmental outcome in preterm infants, but this requires corroboration.

Treatment

Much of the resources of neonatal intensive care is devoted to sustaining oxygenation and blood pressure, and reducing hyperbilirubinemia in premature and full-term but ill infants. Techniques such as the predelivery administration of corticosteroids in premature births to promote lung maturity, attempting to bring early births to 34 to 36 weeks' gestation, and the treatment of maternal infection have all contributed to improved outcomes in children.

The avoidance of the ostensible causes of cerebral palsy has been discussed in previous sections and endlessly in the medical literature. None of the usually assigned causes of birth injury, particularly perinatal hypoxia-ischemia, explains most cases. In addition, several trials have investigated the effects of induced hypothermia for severe neonatal encephalopathy from hypoxia but have given mixed results. Attempts to ameliorate brain injury by the use of hypothermia, a technique that has met with success in adult cardiac arrest, have given conflicting results. A randomized trial by Shankaran and colleagues using systemic hypothermia administered to infants with neonatal encephalopathy or a need for resuscitation showed a reduction in death or moderate to severe disability from 62 to 44 percent and a small benefit in IQ at age 7 that was not statistically significant. Hypothermia was applied soon after birth, at a mean of about 4 hours. The effects were seen mostly among infants with only moderate and not severe encephalopathy and none of the measures of mental and psychomotor disability was improved by cooling. Previous trials, such as the one reported by Azzopardi and colleagues, had shown no difference in outcomes but used different techniques, mainly selective cerebral cooling. Cooling appears promising but requires further study, and at the time of this writing, has not been widely adopted. It is also unclear if the short-term followup will be reflected at school age and beyond.

Clinical Syndromes of Congenital Spastic Motor Disorders

The most frequent motor disorder evolving from the four major categories of neonatal cerebral disease—matrix hemorrhage, periventricular leukomalacia, hypoxic-ischemic encephalopathy, kernicterus (discussed further on)—is spastic diplegia; that is, a motor disturbance that is severe in the lower limbs and mild in the upper, as discussed below. In addition, hypoxic-ischemic injury occurring in the term or preterm infant may take the form of a hemiplegia, double hemiplegia (quadriplegia), or a mixed pyramidal–extrapyramidal or spastic–ataxic syndrome.

A second form of motor disorder is characterized by the development of severe spastic quadriplegia and developmental delay. The major insult is usually intrapartum asphyxia and attendant fetal distress. Usually such infants will have required resuscitation and will have had low 5-min Apgar scores and seizures, which have important predictive value in this circumstance. The pathologic lesions of the brain in this second group consist of hypoxic-ischemic infarction in distal fields of arterial flow, primarily in the cortex and white matter of parietal and posterior frontal lobes, leaving a ulegyric sclerotic cortex.

A third group, discussed below, is characterized mainly by extrapyramidal abnormalities, combining athetosis, dystonia, and ataxia in various proportions. After reviewing the results of several large series of congenital and neonatal motor disorders, we have concluded that spastic diplegia occurs in 10 to 33 percent of cases, spastic quadriplegia in 19 to 43 percent, extrapyramidal forms in 10 to 22 percent, and mixed forms in 9 to 20 percent.

Spastic Diplegia ("Little Disease")

The pattern of paralysis is more variable than the term spastic diplegia implies; actually, several subtypes may be distinguished: paraplegic, diplegic, quadriplegic, pseudobulbar, and generalized. Pure paraplegic and pseudobulbar types are relatively rare. The eponymic "Little disease" has been applied mainly to the spastic diplegic type, but it also has been attached to all forms of motor cerebral palsy in some older writings.

Usually all four extremities are affected, but the legs much more than the arms, which is the real meaning of diplegia. Hypotonia—with retained tendon reflexes and hypoactivity—is usually present initially. Only after the first few months will evident weakness and spasticity appear, first in the adductors of the legs. The plantar reflexes, which often take on ambiguous direction in the normal infant, here are clearly extensor, a finding that is pathologic at any later age. Also, stiff, awkward movements of the legs, which are maintained in an extended, adducted posture when the infant is lifted by the axillae, often do not attract attention until several weeks or months have passed. Seizures occur in approximately one-third of the cases, and it is not uncommon to observe a delay in all developmental sequences, especially those that depend on the motor system.

Once walking is attempted, usually at a much later date than usual, the characteristic stance and gait become manifest. The slightly flexed legs are advanced stiffly in short steps, each describing part of an arc of a circle; adduction of the thighs is often so strong that the legs may actually cross (scissors gait); the feet are flexed and turned in with the heels not touching the floor. In the adolescent and adult, the legs tend to be short and small, but the muscles are not markedly atrophic, as they are in spinal muscular atrophy. Passive manipulation of the limbs reveals spasticity in the extensors and adductors and slight shortening of the calf muscles. The arms may be affected only slightly or not at all, but there may be awkwardness and stiffness of the fingers and, in a few, pronounced weakness and spasticity. In reaching for an object, the hand may overpronate and a grasp may be difficult to release. Speech may be well articulated or noticeably slurred, and in some instances the face is set in a spastic smile. Scoliosis is frequent and may secondarily give rise to root compression and impaired respiratory function. As a rule, there is no disturbance of sphincteric function, although delay in acquiring voluntary bowel and bladder control is usual. Athetotic postures and movements of the face, tongue, and hands are present in some patients and may actually conceal the spastic weakness.

One subtype of spastic diplegia is associated with a relatively slight diminution in head size and of intelligence. As indicated above, there is no unifying neuropathology; the condition occurs independently of matrix hemorrhages and periventricular leukomalacia as well as with them. The frequency of cerebral spastic diplegia, which is closely related to the degree of prematurity, has declined significantly since the introduction of neonatal intensive care facilities, and there is reason to believe that genetic factors are of more importance.

Infantile Hemiplegia and Quadriplegia

Hemiplegia is a common condition of infancy and early childhood. The functional difference between the two sides may be noticed soon after birth, but more often it is not perceived by the mother until after the first 4 to 6 months of life. In a second group, the child is in excellent health for a year or longer before the abrupt onset of hemiplegia (see below). In hemiplegia that dates from earliest infancy—that is, congenital hemiplegia—the parents first notice that movements of prehension and exploration are carried out with only one arm. A manifest hand preference at an early age should always raise the suspicion of a unilateral motor defect. The affection of the leg is usually recognized later, that is, during the first attempts to stand and walk. Sitting and walking are usually delayed by a few months. In the older child, there is evident hyperactivity of tendon reflexes and usually a Babinski sign. The arm is held flexed, adducted, and pronated, and the foot assumes an equinovarus posture. Sensory and visual field defects can be detected in some patients. A mental slowness may be associated with infantile hemiplegia but is less common and lesser in degree than with cerebral diplegia. There may also be speech delay, regardless of the side of the lesion; when this is present, there is usually developmental delay and bilaterality of motor abnormality. Convulsions occur in 35 to 50 percent of children with congenital hemiplegia, and these may persist throughout life. They may be generalized but are frequently unilateral and limited to the hemiplegic side (or the contralateral side if the hemiplegia is severe). After a series of seizures, the weakness on the affected side will be increased for several hours or longer (Todd paralysis). Gastaut and associates have described a hemiconvulsive–hemiplegic syndrome in which progressive paralysis and cerebral atrophy are attributed to the convulsions. As months and years pass, the osseous and muscular growth of the hemiplegic limbs is impeded, leading to an obvious hemiatrophy of the body.

With respect to the causation of congenital hemiplegia, it is generally agreed that perinatal asphyxia is only one of the possibilities. In the series of 681 children with "cerebral palsy" collected by Hagberg and Hagberg, there were 244 with hemiplegia of whom 189 were full-term babies and 55 were preterm. Prenatal risk factors were identified in only 45 percent, and mostly in the infants born prematurely. In nearly half of the cases, there was no clue as to the time in the intrauterine period when the cerebral lesion occurred.

In another group—acquired infantile hemiplegia—a normal infant or young child, usually between the ages of 3 and 18 months, develops a massive hemiplegia, with or without aphasia, within hours. The disorder often begins with seizures, and the hemiplegia may not be recognized until the seizures have subsided. In Banker's series of autopsy cases, there was arterial or venous thrombosis in some cases, but instances without vascular occlusions were found. Some of the latter cases, in which arteriography had been normal, may have been embolic, possibly of cardiac origin. In the recent era, imaging has shown a large area of cerebral infarction, consistent with a stroke in the territory of the middle cerebral artery (Fig. 38-15). If the stroke occurs at an early age, the recovery of speech may be complete, though reduced scholastic capacity remains. The degree of recovery of motor function varies. Often, as the deficit recedes, the arm becomes involved by athetotic, tremulous, or ataxic movements; there may be an interval of months or years between the hemiplegia and the athetosis.

Destructive lesions underlie most of the cases of infantile hemiplegia and some cases of bilateral hemiplegia (as well as many cases of seizures in the first few days of life). The pathologic change is essentially that of ischemic necrosis. In many cases, the lesions must have been acquired in utero. Precipitant delivery, fetal distress, and prepartum uterine hemorrhage may have been indications, more so than causes, of the process. What is most notable is that the ischemia tends to affect the tissues lying in arterial cortical border zones; there may also be venous stasis with congestion and hemorrhage occurring particularly in the deep central structures such as the basal ganglia and periventricular matrix zones. If they are purely hypoxic, the lesions should be bilateral. Myers has reproduced such lesions in the neonatal monkey by reducing the maternal circulation for several hours. As the lesions heal, the monkeys develop the same gliotic changes in the cortex and white matter of the cerebrum (lobar sclerosis) and the "marbling" (état marbré) that characterizes the brains of patients with spastic diplegia and double athetosis (see below).

The quadriplegic state differs from bilateral hemiplegias in that the bulbar musculature is often involved in the latter and developmental delay is more severe. The condition is relatively rare and is usually a result of a bilateral cerebral lesion. However, one should also be alert to the possibility of a high cervical cord lesion. In the infant, this is usually the result of a fracture dislocation of the cervical spine incurred during a difficult breech delivery. Similarly, in paraplegia, with weakness or paralysis limited to the legs, the lesion may be either a cerebral or a spinal one. Sphincteric disturbances and a loss of somatic sensation below a certain level on the trunk always point to a spinal localization. Congenital cysts, tumors, and diastematomyelia are more frequently causes of paraplegia than of quadriplegia. Another recognized cause of infantile paraplegia is spinal cord infarction from thrombotic complications of umbilical artery catheterization.

Extrapyramidal Syndromes

The spastic cerebral diplegias discussed above shade almost imperceptibly into the congenital extrapyramidal syndromes. These children are found in every cerebral palsy clinic, and, ultimately, they reach adult neurology clinics. Corticospinal tract signs may be absent and the student, familiar only with the syndrome of pure spastic diplegia, is always puzzled as to their classification. Some cases of extrapyramidal type are undoubtedly attributable to severe perinatal hypoxia and others to diseases such as erythroblastosis fetalis with kernicterus. To state the probable pathologic basis and future course of these illnesses, it is useful to separate the extrapyramidal syndromes of prenatal-natal origin (which usually become manifest during the first year of life) from the acquired or hereditary postnatal syndromes, such as familial athetosis, Wilson disease, dystonia musculorum deformans, and the hereditary cerebellar ataxias, which become manifest later.

Double Athetosis

This is probably the most frequent of the congenital extrapyramidal disorders. Two types stand out—one that is caused by hyperbilirubinemia or Rh incompatibility (kernicterus; see below) and hypoxic-ischemic encephalopathy. With control of neonatal hyperbilirubinemia (by use of anti-Rh immune globulin, exchange transfusions, and phototherapy), kernicterus has almost disappeared, whereas the severe hypoxic-ischemic form regularly continues to be seen. Rarely, a congenital, nonhemolytic icterus or a glucose-6-phosphate dehydrogenase deficiency produces the same syndrome.

Like the spastic states, double athetosis may not be recognized at birth but only after several months or a year has elapsed. In some cases, the appearance of choreoathetosis is for unexplained reasons delayed for several years; it may seem to progress during adolescence and even early adult life. It must then be differentiated from some of the inherited metabolic and degenerative extrapyramidal diseases. Chorea and athetosis dominate the clinical picture, but bewildering combinations of involuntary movements—including dystonia, ataxic tremor, myoclonus, and even hemiballismus—may be found in a single case. At times, we have been unable to classify the movement disorder because of its complexity. It should be noted that practically all instances of double athetosis are also associated with a defect in voluntary movement.

Choreoathetosis in infants and children varies greatly in severity. In some, the abnormal movements are so mild as to be misinterpreted as restlessness or "the fidgets"; in others, every attempted voluntary act provokes violent involuntary spasms, leaving the patient nearly helpless. The clinical features of choreoathetosis and other involuntary movements are discussed in Chap. 4.

Early hypotonia, followed by delayed motor development, is the rule in these cases. Erect posture and walking may not occur until the age of 3 to 5 years and may never be attained in some patients. Tonic neck reflexes or fragments thereof tend to persist well beyond their usual time of disappearance. The plantar reflexes are usually flexor, although they may be difficult to interpret because of the continuous flexion and extension of the toes. Sensory abnormalities are not found. Because of the motor and speech impairment, patients are often erroneously thought to be mentally slow. In some, this conclusion is doubtless correct, but intellectual function is adequate in many others.

A variety of rehabilitative measures have been tried: physiotherapy, surgery, sensory integrative therapy, progressive patterned movement, and various undocumented forms of neuromuscular facilitation. We agree with Hur, who has critically reviewed this subject, that properly controlled studies provide no proof of the success of any of them. Surely, with growth and development, new postures and motor capacities are acquired. The less-severely affected patients make successful occupational adjustments. The more-severely affected children rarely achieve a degree of motor control that permits them to live independently. One sees some of these unfortunate persons bobbing and twisting laboriously as they make their way in public places.

Imaging studies are seldom of diagnostic value. Mild cerebral atrophy and loss of volume of the basal ganglia are seen in some cases, and cavitary lesions are present in some of the severe anoxic encephalopathies. The EEG is rarely helpful unless there are seizures.

The most frequent pathologic finding in the brain has been a whitish, marble-like appearance of the putamen, thalamus, and border zones of the cerebral cortex. These whitish strands represent foci of nerve cell loss and gliosis with condensation of bands of transversing myelinated fibers—so-called status marmoratus (état marbré). This lesion does not develop if the insult occurs after infancy, that is, after myelination has completed its early developmental cycle.

Kernicterus

This is now a rare cause of extrapyramidal motor disorder in children and adults. Such cases are the neurologic sequelae of erythroblastosis fetalis secondary to Rh and ABO blood incompatibilities or to a deficiency of the hepatic enzyme glucuronosyltransferase. The symptoms of kernicterus appear in the jaundiced neonate on the second or third postnatal day. The infant becomes listless, sucks poorly, develops respiratory difficulties as well as opisthotonos (head retraction), and becomes stuporous as jaundice intensifies. The serum bilirubin is usually greater than 25 mg/dL. In acidotic and hypoxic infants (e.g., those with low birth weight and hyaline membrane disease), the kernicteric lesions develop with much lower levels of serum bilirubin.

A proportion of infants with this disease die within the first week or two of life. Many of those who survive are developmentally delayed, deaf, hypotonic, and totally unable to sit, stand, or walk. There are exceptional patients, however, who are mentally normal or at most only slightly limited. They develop a variety of persistent neurologic sequelae—choreoathetosis, dystonia, and rigidity of the limbs—a picture not too different from that of cerebral spastic diplegia with involuntary movements. Kernicterus should always be suspected if an extrapyramidal syndrome is accompanied by bilateral deafness and paralysis of upward gaze. Later, in childhood there may be a greenish pigmentation of the dental enamel.

Neonates who die in the acute postnatal stage of kernicterus show a unique yellow staining (icterus) of nuclear masses at one time was called the "Kern nuclei" and gave the disease its name in the basal ganglia, brainstem, and cerebellum. In those surviving this postnatal insult, the pathologic changes consist of a symmetrically distributed nerve cell loss and gliosis in the subthalamic nucleus, the globus pallidus, the thalamus, and the oculomotor and cochlear nuclei; these lesions are the result of the hyperbilirubinemia. In more than 30 cases examined by R.D. Adams, the immature cerebral cortex including the hippocampus was spared. In the newborn, unconjugated bilirubin can pass through the poorly developed blood–brain barrier into these nuclei, where it is assumed to be directly toxic. Acidosis and hypoxia exacerbate the effect. Also in the newborn, the development of hyperbilirubinemia is enhanced by a transient deficiency of the enzyme glucuronosyltransferase, essential for the conjugation of bilirubin. Hereditary hyperbilirubinemia, caused by lack of this enzyme (Crigler-Najjar syndrome), may exhibit the same effects on the nervous system at a later period of infancy or childhood as hyperbilirubinemia because of Rh incompatibility.

Immunization, phototherapy, and exchange transfusions designed to prevent high levels of unconjugated serum bilirubin have been shown to protect the nervous system from the toxic effects of erythroblastosis fetalis. If the blood bilirubin level can be held to less than 20 mg/dL (10 mg/dL in premature infants), the nervous system may escape perinatal damage. The effective use of these measures has practically eradicated this disease.

Both kernicterus and ischemic état marbré must be differentiated clinically from hereditary choreoathetosis, the Lesch-Nyhan syndrome, and—later in life, from ataxia-telangiectasia and Friedreich ataxia.

Congenital and Neonatal Ataxias

In these patients, difficulty in standing and walking cannot be attributed to spasticity or paralysis. Hypotonia and poverty of movement are the initial motor abnormalities—as they are in athetoid cerebral palsy. The cerebellar deficit becomes manifest only later when the patient begins to sit, stand, and walk. There may or may not be a delay in reaching the normal motor milestones. Attempts to attain sitting balance early on reveal an unsteadiness that is not soon overcome, even with practice. Reaching for a proffered toy is accomplished by jerky, incoordinated movements. The first steps are unsteady, as would be expected, with many tumbles, but the gait remains clumsy. Instability of the trunk may be accompanied by similar, more or less rhythmic bobbing movements of the head—titubation. Despite the severity of the ataxia, the muscles are of normal size, and voluntary movements, although weak in some patients, are possible in all the limbs. The tendon reflexes are present, and the plantar reflexes are either flexor or extensor. In some cases, the ataxia is later associated with spasticity rather than hypotonia (spastic-ataxic diplegia). Relative improvement may occur in later years. In the older child, a cerebellar gait, ataxia of limb movements, nystagmus, and uneven articulation of words are readily distinguished from myoclonus, chorea, athetosis, dystonia, and tremor.

In only a few cases have the pathologic changes been studied. Aplasia or hypoplasia of the cerebellum has been observed, but sclerotic lesions of the cerebellum are more common. The CT scan or MRI verifies the cerebellar atrophy. However, in a few cases of a cerebellar-like tremor in adults under our care that had been attributed to neonatal injury the MRI did not show cerebellar atrophy. A cerebral and cerebellar lesion may coexist in patients with congenital ataxia, which is the reason for the term cerebrocerebellar diplegia.

Several risk factors have been identified in the congenital ataxias. Most importantly, cerebellar ataxia may be the most prominent or sole effect of neonatal ischemia-hypoxia. A genetic factor is operative in some cases (Hagberg and Hagberg). Mercury poisoning in utero is another cause of congenital ataxia. The many cases that are not the result of a degenerative condition, some of which are described just below, remain unexplained in our experience.

Pontocerebellar Hypoplasias and Joubert Syndrome

Aside from the congenital ataxia described above, there are several rare familial forms in which a failure of cerebellar development is associated with developmental delay. What has now come to be called Joubert syndrome was reported in a family in which the central feature is dysgenesis of the vermis; developmental delay; episodic hyperpnea; irregular, jerky eye movements; and unsteady gait in 4 of 6 siblings. In other reports, choroidal-retinal colobomas, polydactyly, cryptorchidism, and prognathism have been mentioned. Detailed examination of the cerebra of such individuals has been lacking but the MRI has a characteristic configuration of a "molar tooth sign" that reflects a deep invagination caused by vermian hypoplasia with a narrow cleft separating the cerebellar hemispheres and thickening of the superior cerebellar peduncles. Several genetic loci have been implicated, most acting as recessive traits.

In the Gillespie syndrome, a combination of aniridia, cerebellar ataxia, and developmental delay is the denominating feature. In the Paine syndrome, a familial disorder with developmental delay and developmental delay, there is microcephaly, spasticity, optic hypoplasia, and myoclonic ataxia, the last presumably related to the cerebellar hypoplasia. These dysgeneses and the disequilibrium syndrome reported from Sweden are unified by the cerebellar ataxia; in the past, they were categorized as ataxic cerebral palsies. Imaging studies demonstrate the cerebellocerebral abnormality. Genetic factors are operative in some, but matters pertaining to etiology remain obscure (see the older monograph by Harding for details). One form of a pure nonprogressive congenital cerebellar hypoplasia has been mapped to a gene locus on chromosome Xq; it does not appear to be related to the fragile X syndrome, which may cause ataxia and tremor in adults as noted further on.

Differential Diagnosis of the Congenital Ataxias

The congenital ataxias must be distinguished from the progressive hereditary ataxias. The latter are likely to begin at a later age than the congenital ones. Some hereditary ataxias are intermittent or episodic, one of which is responsive to acetazolamide and is the result of an abnormality of the calcium channel as discussed in Chaps. 5 and 37.

Also to be distinguished from the ataxias of congenital and neonatal origin is an acute cerebellar ataxia of childhood, which can usually be traced to a viral infection or postinfectious encephalitis, particularly after chickenpox. The opsoclonus-myoclonus ("dancing eyes") syndrome of Kinsbourne is another postinfectious disease peculiar to childhood (see Chaps. 14 and 39). The cerebellar ataxia in this disease may be overshadowed by polymyoclonus, which mars every attempted movement. With improvement, under the influence of corticosteroids, a cerebellar disorder of speech and movement becomes evident. A majority of the patients in which the disease became chronic (16 of the 26 cases followed by Marshall et al) were found later to be mentally slowed. The cause of the disease has never been established. An occult neuroblastoma or other tumor is uncovered occasionally. In the differential diagnosis of these acute forms of cerebellar ataxia, one must not overlook intoxication with phenytoin, barbiturates, or similar drugs.

The Flaccid Paralyses and the "Floppy Infant" (Table 38-7; See also Chaps. 39 and 48)

The rare cerebral form of generalized flaccidity, first described by Foerster and called cerebral atonic diplegia, has already been alluded to in the discussion of cerebral palsy. It can usually be distinguished from the paralysis of spinal and peripheral nerve origin and congenital muscular dystrophy by the retention of postural reflexes (flexion of the legs at the knees and hips when the infant is lifted by the axillae), preservation of tendon reflexes, and coincident failure of mental development. The Prader-Willi syndrome, discussed earlier in the chapter, also presents at first as a generalized hypotonia.

The syndrome of infantile spinal muscular atrophy (Werdnig-Hoffmann disease) is the leading example of flaccid paralysis of lower motor neuron type. Perceptive mothers may be aware of a paucity of fetal movements in utero; in most cases the motor defect becomes evident soon after birth or the infant is born with arthrogrypotic deformities. Several other types of familial progressive muscular atrophies have been described in which the onset is in early or late childhood, adolescence, or early adult life. Weakness, atrophy, and reflex loss without sensory change are the main features and are discussed in detail in Chap. 39. A few patients suspected of having infantile or childhood muscular atrophy prove, with the passage of time, to be merely inactive "slack" children, whose motor development has proceeded at a slower rate than normal. Others may remain weak throughout life, with thin musculature. These and several other congenital myopathies—central core, rod-body, nemaline, mitochondrial, myotubular, and fiber-type disproportion and predominance—are described in Chap. 52. Unlike Werdnig-Hoffmann disease, the effects of many of them tend to diminish as the natural growth of muscle proceeds. Rarely, polymyositis and acute idiopathic polyneuritis manifest themselves as a syndrome of congenital hypotonia.

Infantile muscular dystrophy and lipid and glycogen storage diseases may also produce a clinical picture of progressive atrophy and weakness of muscles. The diagnosis of glycogen storage disease (usually the Pompe form) should be suspected when progressive muscular atrophy is associated with enlargement of the tongue, heart, liver, or spleen. The motor disturbance in this condition may be related in some way to the abnormal deposits of glycogen in skeletal muscles, although it is more likely the result of degeneration of anterior horn cells that are also distended with glycogen and other substances. Certain forms of muscular dystrophy (myotonic dystrophy and several types of congenital dystrophy) may also be evident at birth or soon thereafter. The latter may have led to arthrogryposis and clubfoot (see Chap. 52 for an extensive discussion of the congenital neuromuscular disorders).

Brachial plexus palsies, well-known complications of dystocia, usually result from forcible extraction of the fetus by traction on the shoulder in a breech presentation or from traction and tipping of the head in a shoulder presentation. The effects of such injuries are sometimes lifelong. Their neonatal onset is betrayed later by the small size and inadequate osseous development of the affected limb. Either the upper brachial plexus (fifth and sixth cervical roots) or the lower brachial plexus (seventh and eighth cervical and first thoracic roots) suffer the brunt of the injury. Upper plexus injuries (Erb palsy) are about 20 times more frequent than lower ones (Klumpke palsy). Sometimes the entire plexus is involved. Further details are found in Chap. 46.

Facial paralysis, because of forceps injury to the facial nerve immediately distal to its exit from the stylomastoid foramen, is another common (usually unilateral) peripheral nerve affection in the newborn. Failure of one eye to close and difficulty in sucking make this condition easy to recognize. It must be distinguished from the congenital facial diplegia that is often associated with abducens palsy, that is, the Möbius syndrome discussed earlier in the chapter. In most cases of facial paralysis caused by physical injury, function is recovered after a few weeks; in some, the paralysis is permanent and may account for lifelong facial asymmetry.

Treatment

Once the motor features of cerebral palsy have been established, assistive devices, stretching therapy, and conventional orthopedic measures for joint stabilization and relief of spasticity are all useful. Injection of botulinum toxin for the relief of spasticity has gained wide favor and is now used early in the child's life to preempt deformities. Most published trials have been too small, however, to allow firm conclusions to be drawn about the durability of this treatment. Finally, hyperbaric oxygen treatment of children with cerebral palsy was ineffective in a randomized trial conducted by Collet and colleagues, despite periodic claims to the contrary.

In summary, it can be said that all these forms of disabling motor abnormalities rank high as important issues in neuropediatrics. In attempts at prevention, steps have been taken in most hospitals to identify and eliminate risk factors. Indeed, better prenatal care, reduction in premature births, and control of respiratory problems in critical care wards have reduced their incidence and prevalence. Physical and mental therapeutic measures appear to be helpful, but many of the methods have been difficult to evaluate in a nervous system undergoing maturation and development. The neurologist can contribute most by segregating groups of cases of identical pattern and etiology and in differentiating the congenital groups of delayed expressivity from the treatable acquired diseases of this age period. Woefully lacking are critical neuropathologic studies.

Throughout the intrauterine period the embryo and fetus are subject to particular infections. Because the infective agent must reach the fetus through the placenta, it is evident that the permeability of the latter at different stages of gestation and the immune status of the maternal organism are determinative. We include a discussion of these intrauterine infections here because some of them may lead to malformations or destructive lesions of the brain and, later in life, must be distinguished from developmental abnormalities.

Until the third to fourth month of gestation, the large microbial organisms—such as bacteria, spirochetes, protozoa, and fungi—cannot invade the embryo, even if the mother harbors the infection. Viruses, however, may do so, specifically rubella, CMV, HIV, and possibly others. The rubella virus enters embryonal tissues during the first trimester, Treponema pallidum in the fourth to fifth postconceptional months, and Toxoplasma after that period. Bacterial meningitis (except for that caused by Listeria monocytogenes, described below) is essentially a perinatal infection contracted during or immediately after parturition. Neonatal herpes simplex encephalitis, as a result of the type 2 (genital) virus, is also usually acquired by passage through an infected birth canal. Some cases of HIV infection may be acquired during delivery, but most are a result of transplacental transmission.

The main neonatal infections—toxoplasmosis, rubella, CMV, and herpes—have been commonly designated by the acronym TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex). With the persistence of Listeria, the rise of AIDS infections, and a marked reduction in rubella infections, the mnemonic LATCH, which includes Listeria and AIDS, might be more appropriate. Infants with any of these infections share certain common features, such as low birth weight, prematurity, congenital heart disease, purpura, jaundice, anemia, microcephaly or hydrocephaly, cerebral calcifications, chorioretinitis, cataracts, microphthalmia, and pneumonitis; as a corollary, if any combination of these features is manifest, one should suspect one of these infectious agents and take measures to identify it. However, all these clinical manifestations are unlikely to be present in any one infant, and in the cases of rubella and CMV, only a small percentage of infected infants will show major systemic signs or symptoms. Nevertheless, on clinical grounds alone, certain infections can be identified and others excluded. For example, cerebral calcifications are present mainly in toxoplasmosis and CMV encephalopathy, being rare in rubella and absent in herpes simplex virus (HSV) encephalitis; the calcifications are widely disseminated in toxoplasmosis (Fig. 38-16) and have a periventricular distribution in CMV infection. Cardiac lesions are present only with rubella, and deafness occurs only with CMV and rubella. Thus, there are clinical signposts to guide the clinician in selecting the appropriate diagnostic tests. And importantly, in considering neonatal infections, one must also search for other, less-common infectious types (see Chaps. 32 and 33).

Added difficulty in the diagnosis of embryonal and fetal infections arises when the mother has been entirely asymptomatic. Isolation of the organism from fetal and neonatal tissues is possible, but usually they are inaccessible, and it may be impossible to demonstrate antibodies or other immune responses because of the early stage of the infection or limitations of the infant's immune response.

Congenital Rubella

Gregg, in 1941, first reported the association of maternal rubella and congenital cataracts in the neonate. His observations were quickly verified, and soon it became widely known that cataracts, deafness, congenital heart disease, and developmental delay constituted a kind of tetrad diagnostic of this disease. That a virus could affect so many tissues, causing in essence a noninflammatory developmental disorder of multiple organs, was a novel concept, and it raised the interesting prospect that other viruses might have similar effects. Surprisingly, however, only CMV and possibly HSV have been incriminated in embryonal-developmental neuropathology. A large number of other viruses (e.g., influenza, Epstein-Barr, hepatitis) have been implicated in human teratogenesis, but in none is the relationship beyond doubt.

It is now well established that most instances of congenital rubella infection occur in the first 10 weeks of gestation and that the earlier the infection occurs, the greater the risk to the fetus. However, there may be some risk beyond the first trimester, up to the twenty-fourth week, according to Hardy.

Following the experience of the massive rubella epidemics of 1964 and 1965, the congenital rubella syndrome has been expanded to include low birth weight; sensorineural deafness, sometimes unilateral (the most common complication); microphthalmia; pigmentary degeneration of the retina (salt-and-pepper chorioretinitis); glaucoma, cloudy corneas, and cataracts of special type (the latter two abnormalities usually cause visual impairment); hepatosplenomegaly, jaundice, and thrombocytopenic purpura; and patent ductus arteriosus or interventricular septal defect. There may be one, a few, or many of these abnormalities, in various combinations. The developmental delay is severe and may be accompanied by seizures and motor defects such as hemiplegia or spastic diplegia and rarely by seizures. Psychiatric symptoms, some resembling autism, are said to occur.

Infection of the fetus after the first trimester results in a less impressive neonatal syndrome. The infant may seem lethargic and fail to thrive. The cranium is abnormally small. Only a cardiac abnormality, deafness, or chorioretinitis may provide clues to the diagnosis. The CSF later may show an increase of mononuclear cells and an elevated protein. The infection may persist for a year or longer. Foci of calcification are rare, and CT scanning and MRI are of little help in diagnosis. The maternal infection may be so mild that it is passed off as minor; but even when it is evident, the fetus is spared in approximately 50 percent of cases. Diagnosis can be verified in the neonate by demonstrating immunoglobulin (Ig) M antibodies to the virus or by the isolation of the virus from the throat, urine, stool, or CSF. Also, the virus has been obtained from cells in the amniotic fluid. In subsequent pregnancies, the fetus has been normal in our experience.

The neuropathology is of considerable interest. In the nervous system of fetuses exposed to maternal rubella in the first trimester, R.D. Adams found no visible lesions by light microscopy, even though the virus had been isolated from the brain by Enders (personal communications). At this period of development there is no inflammatory reaction because of the absence of polymorphonuclear leukocytes, lymphocytes, and other mononuclear cells in the fetus. At birth the brain is usually of normal size, and there may be no discernible lesions. There may be a mild meningeal infiltration of lymphocytes, and a few zones of necrosis and vasculitis with later calcification of vessels are seen, as are small hemorrhages, presumably related to the thrombocytopenia. Smallness of the brain and delay in myelination have been observed in children who died at 1 to 2 years of age. None of the brains in Adam's series was malformed. Rubella virus continues to be recoverable from the CSF for at least 18 months after birth. A form of delayed progressive rubella encephalitis in childhood is also known and is described in Chap. 33 under "Progressive Rubella Panencephalitis." Because there is no treatment for the active infection, the obvious approach to the problem of congenital rubella infection is to make sure that every woman of childbearing age has been vaccinated against rubella or has antibodies as a result of infection prior to pregnancy. The widespread use of rubella vaccine has reduced the chance of major outbreaks, but sporadic infections continue to be seen, and outbreaks of epidemic proportions continue to occur in developing countries.

Congenital Cytomegalovirus Infection

For many years it was known that there were swollen cells containing intranuclear and cytoplasmic inclusions in the tissues of some infants who died in the first weeks and months of life. This cytologic change seemed related to the fatalities. In 1956 and 1957, three different laboratories isolated what has come to be called the human cytomegalovirus (see Weller). This has proved to be the most frequent intrauterine viral infection, rivaled in the current era only by HIV.

CMV disease is widespread in the general population. Although cervicitis is common, the virus is probably transmitted to the fetus transplacentally. Infection of the fetus usually occurs in the first trimester of pregnancy, sometimes later, by way of an inapparent maternal viremia and infection of the placenta. The newborn can also be infected in the course of delivery or afterward by the mother's milk or by transfusions. However, only a small proportion of women known to harbor the virus give birth to infants with active infection. The likelihood of the fetus being infected is much greater if the seronegative mother becomes infected for the first time during pregnancy. In one study, 18 percent of infants born to such mothers were symptomatic at birth, and 25 percent became blind, deaf, or cognitively impaired within a few years (Fowler et al). In mothers with recurrent CMV infection, the infants were asymptomatic at birth, and only a few developed serious sequelae. Evidently, the presence of maternal antibodies before conception protects against congenital CMV infection.

Early infection of the fetus may result in a malformation of the brain; later, there is only inflammatory necrosis from encephalitis in parts of the normally formed brain. Disseminated inflammatory foci have been observed in the cerebrum, brainstem, and retinae. Here there were aggregates of lymphocytes, mononuclear cells, and plasma cells. The mononuclear histiocytes (microglia cells) contain inclusion bodies; some astrocytes are similarly affected. Granulomas form and later calcify, particularly in the periventricular regions. Often there is hydrocephalus. In the low-birth-weight or full-term infant, the clinical picture is one of jaundice, petechiae, hematemesis, melena, direct hyperbilirubinemia, thrombocytopenia, hepatosplenomegaly, microcephaly, mental defect, and convulsions. Cells in the urine may show cytomegalic changes. There is a pleocytosis and an increased protein in the CSF.

Congenital CMV infections pose a much greater problem than does rubella. There is no way of identifying the infected fetus prior to birth or to prevent inapparent infections in the pregnant woman. As indicated above, if the pregnant woman has measurable titers of antibodies to CMV at the time of conception, her infant is relatively protected. Moreover, some infected infants (with viruria) may appear normal at birth but develop neural deafness and developmental delay several years later. Viral replication in infected organs continues after the first year and health workers are at risk. A second child may be infected.

There is no known treatment. The difficulties in prenatal diagnosis of maternal infection preclude planned abortion. Routine serologic testing should be done on every young woman of childbearing age. Until an effective vaccine becomes available, pregnancy should be avoided if a sexual partner is infected.

Congenital HIV Infection and AIDS

In the United States, approximately 10 percent of cases of AIDS have occurred in women, almost all of them of childbearing age, and the rate of new cases is increasing at a faster rate among them than among men. The numbers are higher in many developing countries and particularly in parts of Africa. In children, practically all instances of AIDS come from an HIV-infected mother ("vertical transmission"). The infection may be acquired in utero, during delivery, or from breast-feeding. The relative importance of each of these modes of transmission has not been settled.

It is estimated that HIV infection and AIDS occur in 15 to 30 percent of infants born to HIV-seropositive mothers (see Prober and Gerson). Infected infants present special difficulties in diagnosis, and the infection runs a more accelerated course in them than in adults. In the perinatal period, infected and noninfected infants can only rarely be distinguished clinically, and laboratory diagnosis is hampered by the presence of maternally derived antibody to HIV. The initial clinical signs usually appear within a few months after birth; practically all infected infants become ill before their first birthday, and very few are asymptomatic beyond 3 years of age. Early signs consist of lymphadenopathy, splenomegaly, hepatomegaly, failure to thrive, oral candidiasis, and parotitis. In the European Collaborative Study, comprising 600 children born to HIV-infected mothers, 83 percent of infected children showed laboratory or clinical features of HIV infection by 6 months of age. By 12 months, 26 percent had clinical symptoms of AIDS and 17 percent had died of HIV-related diseases. Once AIDS is established in children, it does not differ materially from the syndrome in adults as described in Chap. 33.

There is often a delay in the attainment of psychomotor milestones. Or after a period of normal development, a psychomotor decline begins, with corticospinal or peripheral nerve signs, often with pleocytosis in the CSF. The typical giant cell AIDS encephalitis, neuritis, and myelitis are easily distinguished from CMV encephalitis and toxoplasmosis.

Infected children are also subject to a variety of opportunistic infections, including bacterial meningitis, toxoplasmosis, CMV encephalitis, fungal infections (cryptococcosis, aspergillosis, candidiasis), herpes simplex, syphilis, zoster, and mycobacterial meningitis. There may also be vascular lesions, with infarction or hemorrhage and lymphoid neoplasia. These are discussed in Chaps. 32 and 33. To date, there is little that one can do for these children, but this may be changing with the current use of 3-drug antiretroviral therapy.

Congenital Toxoplasmosis

This tiny protozoan Toxoplasma gondii, occurring freely or in pseudocyst form, is a frequent cause of meningoencephalitis in utero or in the perinatal period of life. The disease exists in all parts of the world but is more frequent in Western European countries, particularly in those with hot, humid climates, than it is in the United States. The mother is most often infected by exposure to cat feces, handling uncooked infected mutton or other meat, or eating partially cooked meat, but she is nearly always asymptomatic or has only a mild fever and cervical lymphadenopathy.

The precise times of placental and fetal invasion are unknown, but presumably they occur late in the gestational period. The clinical syndrome usually becomes manifest in the first days and weeks of postnatal life, when seizures, impaired alertness, hypotonia, weakness of the extremities, progressive hydrocephalus, and chorioretinitis appear. The retinal lesions consist of large pale areas of destroyed retina surrounded by deposits of pigment. If the infection is severe, the maculae are destroyed; optic atrophy and microphthalmos follow. We have several times observed hemiplegias in older infants, first on one side and then on the other, followed by tension hydrocephalus. The latter is present in about one-third of the cases.

The CSF contains a moderate number of white blood cells, mostly lymphocytes and mononuclear cells, and the protein content is in the range of 100 to 400 mg/dL (i.e., a higher protein content than all other neonatal infections except bacterial meningitis). The glucose values are normal. Fewer than 10 percent of infected children recover; the others are developmentally delayed to varying degrees, with seizures and paralysis. In those without symptoms of infection at birth, the outcome is better.

Granulomatous masses and zones of inflammatory necrosis abut the ependyma and meninges. The organisms, 6 to 7 mm in length and 2 to 4 mm in width, are visible in and near the lesions. Microcysts may also be found, lying free in the tissues without surrounding inflammatory reaction. The necrotic lesions calcify rapidly and, after several weeks or months, are readily visible in plain films of the skull. These appear in periventricular and other regions of the brain as multiple nodular densities (see Fig. 38-16).

In adults, often in association with AIDS, the disease takes the form of a rapidly evolving meningitis and multifocal encephalitis in conjunction with myocarditis, hepatitis, and polymyositis.

This syndrome is described in Chap. 32, as are the diagnostic tests and current treatment. In the infant, infections such as rubella, syphilis, CMV disease, and herpes simplex must be considered in the differential diagnosis. The most reliable means of diagnosis is the IgM indirect fluorescent antibody test, performed on umbilical cord blood. Passive transfer of IgG antibody from mother to fetus takes place, but its presence in the fetus is not proof of active infection.

In women who develop antibodies in the first 2 or 3 months of pregnancy, treatment with spiramycin (Rovamycine) prevents fetal infection. Once the fetus is infected, pyrimethamine and sulfadiazine must be used. A later second pregnancy is not affected.

Congenital Neurosyphilis

The clinical syndromes and pathologic reactions of congenital neurosyphilis of the newborn are similar to those of the adult, as described in Chap. 32. Such differences that exist are determined principally by the immaturity of the nervous system at the time of spirochetal invasion. The syphilitic infection may be transmitted to the fetus at any time from the fourth to the seventh months. The fetus may die, with resulting miscarriage or stillbirth, or may survive only to be born with florid manifestations of secondary syphilis. The dissemination of the spirochetes throughout the body, the time of appearance of the secondary manifestations, and the time of formation of antisyphilitic antibodies (reagin) in the blood are all governed by the same biologic principles that apply to adult syphilis.

At birth, the spirochetemia may not have had time to cause syphilitic antibodies to appear; hence a negative Venereal Disease Research Laboratory (VDRL) reaction in umbilical cord blood does not exclude congenital syphilis. In unselected groups of syphilitic mothers, 25 to 80 percent of fetuses have been infected, and in 20 to 40 percent of those infected, the CNS is invaded as judged by the finding of abnormal CSF. The types of congenital neurosyphilis (asymptomatic and symptomatic meningitis, meningovascular disease, hydrocephalus, general paresis, and tabes dorsalis) are the same as those in the adult except for the great rarity of tabes dorsalis. The classic Hutchinson triad (dental deformities, interstitial keratitis, and bilateral deafness) is infrequently observed in complete form.

The sequence of neurologic syndromes is also the same as in the adult, all stemming basically from chronic spirochetal meningitis. The infection may become symptomatic in the first weeks and months of postnatal life, meningovascular lesions and hydrocephalus reaching maximal frequency during the period from 9 months to 6 years. An early form of syphilitic meningoencephalitis may occur at 1 to 2 years and result in severe developmental delay. More often, a congenital paresis and tabes usually appear between the ninth and fifteenth years. The pathologic basis of the neurosyphilitic syndromes is discussed in Chap. 32.

Fewer cases of congenital neurosyphilis are being observed as the years pass, but there may be a recrudescence of the disease in HIV-infected patients. If the syphilitic mother is treated before the fourth month of pregnancy, the fetus will not be infected. The affected infant may be normal at birth or exhibit only mucocutaneous lesions, hepatosplenomegaly, lymphadenopathy, and anemia. In the neonatal period, there are no signs of meningeal invasion, or there may be only asymptomatic meningitis. If the latter is actively treated until the CSF is normal, vascular lesions of brain and spinal cord, hydrocephalus, general paresis, and tabes dorsalis will not develop.

Congenital syphilis must be considered a potential, albeit rare, cause of epilepsy and developmental delay. Once the syphilitic infection has been treated in early life and rendered inactive (acellular CSF, normal protein), the occurrence of a congenital infection can only be substantiated by an accurate history; the finding of the syphilitic stigmata in the eyes, teeth, and ears; or a positive serologic reaction in the CSF.

Treatment of syphilis in the child follows along the same lines as treatment of the syphilitic adult (see Chap. 32), with appropriate adjustment of dosage in accordance with the child's weight.

Other Viral and Bacterial Infections

Several other infections of late fetal life or the neonatal period are only mentioned here, for to describe them all would be excessive and would elucidate no new neurologic principles. Meningitis as a result of the small gram-positive rod L. monocytogenes may be acquired in the usual way, at the time of passage through an infected birth canal or in utero, as a complication of maternal and fetal septicemia because of this organism. In the latter case, it causes abortion or premature delivery. Neonatal bacterial meningitis with this organism is a particularly devastating and often fatal type of bacterial infection, not easily diagnosed unless the pediatrician is alert to the possibility of a silent meningitis in every case of neonatal infection. Coxsackievirus B, polioviruses, other enteroviruses, and arboviruses (western equine) seem to be able to cross the placental barrier late in pregnancy and cause encephalitis or encephalomyelitis in the near-term fetus, which is indistinguishable from the disease in the very young infant. Herpes zoster may occur in utero, leaving cutaneous scars and retarding development. Or zoster may appear soon after birth, the infection having been contracted from the mother. Only later in childhood can varicella induce an autoimmune perivenous demyelination and possibly a direct infection, affecting predominantly the cerebellum (see Chap. 33), or it may precede the now rare Reye syndrome.

Epstein-Barr virus is another frequent cause of meningoencephalitis. In some instances, it may present as aseptic meningitis or a Guillain-Barré type of acute polyneuritis. This infection tends to affect the nervous system of children rather than that of adults, but there are exceptions to this comment. It is estimated that approximately 2 percent of children and adolescents with this infection have some type of neurologic dysfunction; rarely will this be the only manifestation of the disease. Stupor, chorea, and aseptic meningitis were the main neurologic findings in the case reported by Friedland and Yahr, and acute cerebellar ataxia and deafness were observed in the case of Erzurum and associates (see also Chaps. 32 and 33).

The major types of seizure disorder have already been discussed in some detail in Chap. 16. In bringing them up here, attention is drawn to the fact that epilepsy is mainly a disease of infancy and childhood. Approximately 75 percent of epileptics fall into these age periods, and some of the most interesting and unique types of seizures are peculiar to these epochs of life. Epilepsies that are observed exclusively in infants and children are benign neonatal convulsions; benign myoclonic epilepsy of infancy; febrile seizures (both genetic and acquired); infantile spasms of West; absence seizures; the Lennox-Gastaut syndrome; rolandic and occipital paroxysms and other benign focal epilepsies; and the juvenile myoclonic epilepsies.

One principle that emerges is that the form taken by seizures in early life is in part age-linked. Neonatal seizures are predominantly partial or focal; infantile seizures take the form of myoclonic flexor (sometimes extensor) spasms; and the various forms of petit mal are essentially diseases of childhood (4 to 13 years). The motor phenomena of epilepsy in young children are often termed myoclonic, but this should not be confused with other, later-occurring epilepsies that are endowed with the same name. Furthermore, certain epileptic states tend to occur only during certain epochs of life—one type of febrile seizure from 6 months to 6 years, generalized or temporal spike-wave activity with benign motor and complex partial seizures from 6 to 16 years, and juvenile myoclonic epilepsy in the mid- and late-adolescent years. In general, idiopathic epilepsy, so called because the cause cannot be determined, is predominantly a pediatric neurologic problem. This is not to say that seizures of unknown cause do not occur for the first time in adult life but rather that the onset of such seizures is far more frequent in childhood and tends to diminish once adulthood is reached.

The clinical characteristics of infantile and childhood seizures, including those of genetic origin, are fully described in Chap. 16.

Developmental Delay Without Physical Morphologic Changes (Nondysmorphic Developmental Delay)

Clinical Features

Two clinical types can be recognized based on the adequacy of motor skills that are acquired in parallel with cognitive skills. In the first, the essential characteristic is that, almost from birth, the infant is delayed in all aspects of development. There is a tendency to sleep more, to be less demanding of nourishment, to move less than normal, and to suck poorly and regurgitate. Parents comment on how good their baby is, how little he troubles them by crying. As the months pass, every expected achievement is late. The baby is usually more hypotonic and turns over, sits unsupported, and walks later than the normal infant. Yet despite these obvious motor delays, there is later no sign of paralysis, ataxia, chorea, or athetosis. These babies do not smile at the usual time and take little notice of the mother or other persons or objects in their environment. They are less attentive to visual, and often to auditory, stimuli, to the point where questions may be raised about blindness or deafness. Certain phases of normal development, such as hand regard, may persist beyond the sixth month, when they are normally replaced by other activities. Mouthing (putting everything in the mouth) and slobbering, which should end by 1 year of age, also persist. There are only fleeting signs of interest in toys, and the impersistence of attention becomes increasingly prominent. Vocalizations are scant, often guttural, piercing, or high-pitched and feeble. Babbling is not replaced by attempts at word formation at the usual time.

In the second type, early motor milestones (supporting the head, rolling over, sitting, standing, and walking) are attained approximately at their normal times, yet the infant is inattentive and slow in learning the usual nursery tricks. It seems as though motor development had somehow escaped the retardation process. There may, however, be aimless overactivity and persistence of rhythmic movements, grinding of the teeth (bruxism), and hypotonia.

Because the developmental sequence of motor function and speech may be normal, even to the point where the baby acquires a few words by the end of the first year, the examiner may be misled into thinking that the delayed infant was at first normal and had then deteriorated. In such infants it can even be shown that various test procedures yield lower scores with progressing age (from 3 years onward); this is not the result of a decline in ability but of the fact that the tests are not comparable at different times. In the early years, the tests are weighted toward sensorimotor functions and after that toward perception, memory, and concept formation. Interestingly, the development of language depends upon both groups of functions, needing a certain maturation of the auditory and motor apparatus at the start and highly specialized cognitive skills for continued development. These and other aspects of development of speech and language were considered earlier in this chapter and are commented on further in Chaps. 23 and 38.

Members of both groups of these mildly delayed individuals exhibit a number of noteworthy features that have medical and social implications. Although not overtly dysmorphic and having a normal or low-normal head circumference, they have a high incidence of minor congenital anomalies of the eyes, face, mouth, ears, and hands; they tend to be sickly, and the more severely affected among them have poor physiques and are often under-sized. Difficult behavior occurs frequently, most often taking the form of poor self-control and aggressiveness, especially pronounced in children with temporal lobe epilepsy. Other behavioral disturbances are restlessness, repetitive activity, explosive rage reactions and tantrums, stereotyped play, and the seeking of sensory experiences in unusual ways (Chess and Hassibi). Pica (the compulsive ingestion of nonnutritive substances) is a problem between ages 2 and 4 years of age, but is also seen in normal, neglected children.

An endless debate is centered on matters of causation—whether this category of mild delay is the product of genetic influence or of societal discrimination and lack of training and education coupled with the effects of malnutrition, infections, or other exogenous factors. Surely both factors are at work, with the genetic being dominant for the reasons discussed above, although the relative importance of each has proved difficult to determine (Moser et al).

A pathologic basis for most cases of mild developmental delay has not been established and new methodologies, perhaps relating to neuronal connectivity, will be needed if the brains of these individuals are to be differentiated from normal children. Differences might be expected in terms of the number of neurons in thalamic nuclei and cortex, in dendritic–axonal connectivity, or in synaptic surfaces, elements that are not being assayed by the conventional techniques of tissue neuropathology. The observations of Huttenlocher, who found a sparsity of dendritic arborization in Golgi-Cox preparations, and of Purpura, who found an absence of short, thick spines on dendrites of cortical neurons and other abnormalities of dendritic spines, are first steps in this direction but require confirmation.

Genetic Aspects of Nonsyndromic Developmental Delay

Sex linkage is a notable feature of some types of mild developmental delay. The fragile X syndrome, discussed later, is the most important of this group, predominating in males and accounting for approximately 10 percent of all cases of male developmental delay. These individuals may be physically normal except for large testicles. Renpenning and colleagues reported a series of 21 developmentally delayed males in three generations of a Canadian family, all free of any congenital malformations and with normal head size, and Turner and coworkers have described a similar Australian series. Other X-linked forms of developmental delay that have few or no dysmorphic features include the Partington, Lowe, Lesch-Nyhan, and Menkes syndromes and adrenoleukodystrophy, each with special characteristics in addition to developmental delay, as discussed in Chap. 37. Numerous other X-linked retardation syndromes with profound accompanying neurologic anomalies have been delineated; for example, the one caused by a mutation in the oligophrenin gene, in which there is epilepsy, and another involving cerebellar hypoplasia. The relationship of intelligence in general to the X chromosome is discussed in Chap. 21.

However, there is emerging information relating autosomal mutations, rather than X-linked ones, in genes that control synaptic function such as SYNGAP1, and non-dysmorphic developmental delay as detailed in the publication by Hamdan and coworkers. There are approximately 30 X-linked and 6 autosomal recessive genes associated with nonsyndromic developmental delay and more are sure to be found. Investigated from another perspective, de Ligt and colleagues sequenced the coding regions of over 21,000 genes in a series of 100 individuals with IQ below 50 and round that there were numerous de novo mutations that involved cerebral development of function. Together, all of the aforementioned genetic alterations, mutations, lesser polymorphisms and copy number variants, account for approximately 15 to 20 percent of cases of mild, moderate, and severe developmental delay and autism. Most are de novo mutations, making their discovery difficult. The challenge will be to elucidate the manner in which they disrupt cerebral development on a synaptic or subcellular level.

Diagnosis

Infants should be considered at risk for developmental delay when there is a family history of mental slowness, low birth weight in relation to the length of gestation (small-for-date babies), marked prematurity, maternal infection early in pregnancy (especially rubella), and toxemia of pregnancy. In the first few months of life, certain of the behavioral characteristics described above are of value in predicting developmental delay. Prechtl and associates have found that a low Apgar score (especially at 5 min after delivery, Table 28-3), flaccidity, underactivity, and asymmetrical neurologic signs are the earliest indices of subnormality in the infant. Slow habituation of orienting reactions to novel auditory and visual stimuli and the presence of "fine motor deficits" (as previously discussed under "Delays in Motor Development") are other early warnings of developmental delay.

In the first year or two of life, suspicion of developmental delay is based largely on clinical impression, but it should always be validated by psychometric procedures. Most pediatric neurologists use some of the criteria laid down by Gesell and Amatruda or the Denver Developmental Screening Scale, from which a DQ is calculated.

For testing of preschool children, the Wechsler Preschool and Primary Scale of Intelligence is used, and for school-age children, the Wechsler Intelligence Scale for Children is preferred. IQ tests for preschoolers must be interpreted with caution, as they have had less predictive validity for school success than the tests that are used after 6 years of age. In general, however, normal scores for age on any of these tests essentially eliminate developmental delay as a cause of poor school achievement and learning disabilities; special cognitive defects may, however, be revealed by low scores on particular subtests. Developmentally delayed children not only have low scores but exhibit more scatter of subtest scores. Also, like demented adults, they generally achieve greater success with performance than with verbal items. It is essential that the physician know the conditions of testing, for poor scores may be due to fright, inadequate motivation, lapses in attention, dyslexia, or a subtle auditory or visual defect rather than a developmental lag.

The EEG, in addition to exposing asymptomatic seizure activity, shows a high incidence of other abnormalities in the developmentally delayed child. Presumably this is because of a greater degree of immaturity of the cerebrum at any given age. However, a normal EEG is not infrequent and of relatively little help. Moreover, CT scanning and MRI have been singularly unhelpful in revealing abnormalities in this group of children.

In the diagnosis of milder grades of retardation, the possible effects of severe malnutrition, neglect and deprivation, chronic systemic disease, iodine deficiency, impaired hearing and vision, and possibly childhood psychosis should be considered. Of particular importance is the differentiation of a group of patients who are normal for a variable period after birth and then manifest a progressive decline from disease of the nervous system. This type of disorder is representative of the group of hereditary metabolic and degenerative diseases discussed in Chap. 37. Seizure disorders (and antiepileptic medications) can impair cerebral function, and several special childhood seizure disorders are associated with a progressive decline in mental function in this group of patients (see Chap. 16).

Management of Mild Developmental Delay

Because there is little or no possibility of restoring function to a nervous system that is developmentally or structurally damaged, the medical objective is to assist in planning for the patient's training, education, and social and occupational adjustments. As Voltaire remarked long ago, guidance is needed more than education. The parents must be guided in forming realistic attitudes and expectations. Psychiatric and social counseling may help the family to maintain gentle but firm support of the patient so that he can acquire, to the fullest extent possible, self-help skills, self-control, good work habits, and a congenial personality.

Most individuals with an IQ above 60 and no other handicaps can be trained to live an independent life. Special schooling enables such patients to realize their full potential. Social factors that contribute to underachievement must be eliminated if possible. Later, there is need for advice about possible occupational attainments. Great care must be exercised in deciding about institutionalization. Whereas severe degrees of retardation are all too apparent by the first or second year, less-severe degrees are difficult to recognize early. As stated above, psychologic tests alone are not trustworthy. The method of assessment suggested many years ago by Fernald still has a ring of soundness. It includes (1) physical examination, (2) family background, (3) developmental history, (4) school progress (grade achieved), (5) performance in schoolwork (tests of reading, arithmetic, etc.), (6) practical knowledge, (7) social behavior, (8) industrial efficiency, (9) moral reactions, and (10) intelligence as measured by psychologic tests. All these data except (5) and (10) can be obtained by a skillful physician during the initial medical and neurologic examination and are used to guide the family in its difficult decisions.

The subject of developmental delay was introduced in Chap. 28, where it was pointed out that two major categories of this disorder have been delineated. In one, and by far the more common group, the mental limitation is relatively mild, allowing the individual to succeed with training and education; it is often familial and is featured by a lack of definite neurologic abnormalities (except possibly a slightly higher incidence of seizures) and the absence of neuropathologic changes. A large part of this group, falling between 2 and 3 standard deviations below the normal mean IQ, probably are the lower end of the Gaussian curve of intelligence, the converse of which is genius. This group is, however, contaminated with a small number of defined diseases of the nervous system occurring in a less-severe form. In a second group, the degree of developmental delay is usually more severe (IQ of 50 to 70), and yet more so in the third group (IQ less than 50 or not measurable because of limitations of cooperation or physical impediments). Most of the cases in the second and third groups are nonfamilial, and a wide variety of neuropathologic changes are in evidence. The subdivisions are not absolute, for there are a few metabolic and developmental diseases in which developmental delay is profound yet with no somatic or neurologic abnormalities and, most importantly, well-defined neuropathologic changes are lacking. Here we refer to conditions such as Rett syndrome, autism, and the X-linked developmental delay syndromes (Renpenning and fragile X types). In this chapter, these major types of severe developmental delay are described.

The overall frequency of severe developmental delay cannot be stated precisely. Rough estimates place the figure at 0.2 to 0.4 percent of the general population and at approximately 10 percent of the general developmentally delayed segment of society. It is important to emphasize that in a large proportion of individuals with severe developmental delay, a particular congenital abnormality or anomaly of development cannot at present be traced to any of the disorders reviewed in the preceding pages. More precisely stated, when groups of such severely impaired patients are studied clinically, a reasonably accurate etiologic determination of the underlying brain disease can be made in only slightly more than half. According to Penrose, chromosomal abnormalities account for 15 percent, single-gene disorders for 7 percent, and environmental agents for 20 percent. More recent studies of the subtelomeric parts of chromosomes reportedly find abnormalities in another 7 percent of severely retarded children (Knight et al). No cause is found for the remaining cases. Males outnumber females 3 to 1.

However, from the neuropathologic standpoint, the examination of the brains of the severely developmentally delayed by conventional histopathologic methods discloses lesions in approximately 90 percent, and in fully three-quarters of the entire group, an etiologic diagnosis can be determined or tentatively assigned. Many of the remaining 10 percent lack definite pathologic changes, but their brains are lighter in weight by 10 to 15 percent than age-matched normal brains. Interestingly, the proportion of vascular, hypoxic-ischemic, metabolic, and genetic lesions in this group of severely impaired individuals is much the same as is found in a group selected on the basis of "cerebral palsy."

Here it is important to repeat a point made earlier and in Chap. 28: A few of the severely disabled and a large majority of the mildly affected do not have a recognizable cerebral pathology or exhibit any of the familiar and conventional signs of cerebral disease. Although the milder forms of developmental delay tend to be familial, this does not by itself separate them from the severe forms of developmental delay. There are several types of hereditary developmental delay, in which the retardation may be severe and in some of which there may be maldevelopment of the cerebral cortex. These are discussed further on.

Clinical Characteristics of the Severely Developmentally Delayed

These cases can be broadly divided into four groups. In one large group, designated dysmorphic retardation, a variety of physical deformities, including microcephaly, is commonly present. In a second group, with multiple-system retardation, the developmental delay is linked to nonskeletal abnormalities (e.g., hepatosplenomegaly, hematologic and skin disorders), which provide reliable clues to the underlying somatic disease. In a third group, neurologic retardation, somatic abnormalities are lacking but a configuration of neurologic signs leads to the diagnosis. In the fourth group, and the most difficult one to clarify, that comprising uncomplicated retardation, there are no or minimal somatic, visceral, or neurologic abnormalities. One is then forced to turn to special features of the developmental delay itself for identification of the underlying disease. Table 38-8 elaborates a reasonable classification of the types of developmental delay.

The profoundly developmentally delayed infant with a virtually untestable IQ is identified early in life because he does not sit, stand, or walk. If any one of these motor activities is acquired, it appears late and is imperfectly performed. Language never develops; at most a few spoken words or phrases are understood and fewer are uttered, or the patient only vocalizes in a meaningless way. Such a person may not even indicate bodily needs for food, drink, excretion, and so on. Usually the patient is continuously idle and interacts little with people and objects. Only the most primitive emotional reactions are exhibited, often without connection to an appropriate stimulus. Physical growth is usually retarded, nutrition may be poor, and susceptibility to infections is increased. Sphincteric control may never be attained and, if attained, is precarious.

When the mental defect is less severe than described above, falling into the IQ ranges of 20 to 45, or 45 to 70, there may be somatic neurologic abnormalities. If specific motor defects do not coexist, then sitting, standing, and walking are achieved but not at the expected times. The existence of a mental defect is most clearly evidenced by a delay in psychomotor development and a failure to speak by the second or third postnatal year. The patient does not acquire the usual household and play activities as well as other children. However, delay in speech development must not, by itself, be taken as a mark of developmental delay, for in some children a unique delay in speech can be an isolated abnormality as described in Chap. 28, with subsequent normal development of speech and mental ability. Toilet training may be difficult to accomplish in the developmentally delayed child, but, again, bedwetting may be a problem in an otherwise normal child. Also, the deaf child may have to be considered separately; here the problem becomes apparent by an indifference to noise and reduced vocalization (stereotypy of babbling).

More thorough analyses of cognitive functions in the moderately cognitively impaired child have been undertaken by O'Connor and Hermelin, Pulsifer, and others. These authors measured the efficiency of visual and auditory perception, adequacy of communication, relations between language development and thought, crossmodal sensory encoding, alertness, attention, and memory. It was concluded that none of these functions was specifically impaired. Instead, the child could not properly encode new information because the memory systems and the stock of past assimilated knowledge were insufficient to provide a framework of items and categories with which new information could be integrated. Some patients also seemed unable, perhaps on the basis of this encoding problem, to extract from perceived material selective features that could be interpreted. Furthermore, they were unable to deal with an array of sensory experiences like normal children. The complexity of these mental operations, which we would reduce to a global failure of the normal processes of apperception and integration, was called by Piaget a "failure of assimilation and accommodation." However, within the spectrum of developmental delay, apart from cognitive impairments, there are curious differences in behavior and personality, even in those with more or less the same IQ. Some individuals with moderately severe retardation are pleasant and amiable and achieve a satisfactory social adjustment. This is particularly notable in patients with Down and Williams syndromes. At the opposite end of the behavioral scale are the syndromes of autism and that of Smith-Magenis and of DeLange, in which the individual fails to manifest normal interpersonal social contact, including communicative language. The phenylketonuric child is usually irritable, unaffectionate, and implacable, and the same is said of certain other forms of retardation, discussed earlier in the section on retardation with dwarfism.

Regarding differences in motor activity levels, many developmentally delayed individuals are slow, clumsy, and relatively akinetic. Others, as many as half, display an incessant hyperactivity characterized by a restless, seemingly inquisitive searching of the environment. When thwarted, they may exhibit a low frustration tolerance. They may be destructive and recklessly fearless and impervious to the risk of injury. Some exhibit a peculiar anhedonia that renders them indifferent to both punishment and reward. Other aberrant types of behaviors, such as violent aggressiveness and self-mutilation, are common.

Rhythmic rocking, head-banging, incessant arm movements—so-called rhythmias or movement stereotypies—are observed in the majority of those who are severely and moderately severely impaired. These movements are maintained hour after hour without fatigue and may be accompanied by breathing sounds, squeals, and other exclamations. A number of them tend to be particularly common in certain forms of retardation: hand-flapping in autism, handwringing in Rett syndrome, and hand-waving in Down syndrome and other disorders. Self-stimulation, even hurtful—such as striking the forehead or ears or biting the fingers and forearms—seems to be compulsive or perhaps to provide some sort of satisfaction. It is not that these rhythmias are by themselves abnormal, for some of them occur for brief periods in normal babies, but that they persist. Nevertheless, many moderately delayed persons, when assigned to a simple task such as putting envelopes in a box, can continue this activity under supervision for several hours.

In the least-severe types of retardation, all the mental activities are intact but subnormal. The point to be made is that all aspects of intellectual life, personality, and deportment are affected in slightly differing degrees and that these effects have a neurologic basis. There is more than a hint that in particular diseases, because of their anatomy, the cognitive experience, affective life, and behavior are affected in special ways.

The group of moderately delayed, like the severely affected ones, is divisible into groups with somatic systemic and neurologic abnormalities, although the proportions are not the same. There are fewer of the dysmorphic type and more of the nondysmorphic, nonneurologic group.

Etiology of Severe Developmental Delay

From Table 38-1 it is obvious that many diseases can blight the development and maturation of the brain. Some of these are acquired and some are congenital and hereditary. Some affect all parts of the organism, giving rise to associated dermal, skeletal, and visceral abnormalities, while others affect only the nervous system in particular patterns. With respect especially to the milder degrees of developmental delay, in all populations thus far studied, infants of extremely low birth weight are more likely to have disabilities, brain abnormalities, and poorer language development and scholastic achievement (see Chap. 28). Mild developmental delay also tends to correlate with lower social status, which must relate in some manner to biological factors, as pointed out in the Scottish Low-Birth-Weight Study. Viral and spirochetal infections and parturitional accidents are other common causes. They act acutely and are theoretically preventable.

The factor of malnutrition during the fetal or infantile period of life as a cause of severe developmental delay has received considerable attention because it is a worldwide problem. Animal experiments by Winick and others demonstrated that severe undernutrition in early life leads to behavioral abnormalities and biochemical and morphologic changes in the brain, which may be permanent (see Chap. 41). Galler studied a group of infants in Barbados who were severely malnourished during the first year of life and then given an adequate diet. These children were followed to adulthood and compared with normally nourished siblings. No effect was observed on physical growth, but there were persistent attention deficits in 60 percent of the undernourished group and in only 15 percent of controls. The IQ scores of the former were also lower. Unfortunately, genetic factors could not be completely controlled for. In general, it may be said that the data showing developmental delay to be caused by malnutrition, while suggestive, are far from convincing.

Severe protein-calorie malnutrition in the first 8 months of life, which induces kwashiorkor, has been reported to retard mental development. However, such patients are said to regain mental function when fed. The authors have been impressed with the ability of the nervous system to withstand the effects of nutritional deficiency, perhaps better than any other organ.

The action of exogenous toxins during pregnancy is another factor to be considered. Severe maternal alcoholism has been linked to a dysmorphic syndrome and developmental delay, but the findings of several studies have not been consistent (see Chap. 42); a similar problem attaches maternal exposure to anticonvulsant medications (see Chap. 16). Surprisingly, maternal addiction to opiates, while causing an opiate withdrawal in infants for weeks or even months (Wilson et al), seems not to result in permanent injury to the nervous system. The importance of exposure to extremely small amounts of environmental lead is also controversial.

The effect of psychologic deprivation on cognitive development has been of interest. Following the observations that complete isolation of young female monkeys had a devastating effect on their later sexual and nurturing behavior, the idea became popular that such deprivation might cause faulty mental development in humans. Orphaned and neglected babies were found to be inactive, apathetic, and backward in comparison with those who were constantly stimulated by caring mothers. But surprisingly, when nurtured properly at a later time, these babies soon caught up with their peers. This general idea of psychologic deprivation has been the basis of many interesting educational programs for poor and neglected children. To this day, however, it has not been proven that sensory, emotional, and psychologic deprivations of a degree observed in humans are the causes of severe developmental delay or repeated scholastic failure. The controversies regarding the effects of prematurity, maternal hypertension, and eclampsia, which are often associated with neonatal cerebral pathology and slowed psychomotor development, have been mentioned earlier in this chapter. The problem is complex and the argument's pro and con have been elaborated by Haywood and Wachs.

A Clinical Approach to Developmental Delay

As a particular guide to the pediatrician and neurologist who must assume responsibility for the diagnosis and management of backward children harboring a wide array of diseases and maldevelopments of the nervous system, the following clinical approach is suggested. First, as already described, there is an advantage in setting aside as one large group those who are only mildly developmentally delayed from those who have been severely delayed in psychomotor development since early life. With regard to the former group, having no obvious neurologic signs or physical stigmata, one should nevertheless initiate a search for the common metabolic, chromosomal, and infective diseases. In this large group, one must be sure that their deficit is a general one and not one of hearing, poor sight, or the special isolated language and attention deficits.

For patients with moderately severe and very severe cognitive deficits, one begins with a careful physical examination, searching specifically for somatic stigmata and neurologic signs. Abnormalities of eyes, nose, lips, ears, fingers, and toes are particularly important, as are head circumference and a variety of neurologic abnormalities, as outlined in Table 38-8. Data so obtained allow classification into one of three categories, as follows:

In those with somatic abnormalities (with or without obvious neurologic signs), one assumes the presence of a maldevelopment of the brain, possibly caused by a chromosomal abnormality. The psychomotor retardation is usually severe and often nongenetic and, as a rule, has a well-defined neuropathology. Diagnosis is determined by the gestalt of physical signs. The possible maldevelopments are numerous and diverse and are summarized in Tables 38-1 and 38-8; some of the main ones are described earlier in the chapter. Inevitably, one turns to the several atlases to denominate the syndromes (Holmes et al; Jones).

In the group in which the abnormalities are confined to the nervous system, attention is focused on a larger number of diseases, many caused by exogenous factors such as perinatal hypoxia-ischemia, pre- or postnatal infections, trauma, and so on. There are usually conspicuous neurologic signs. The degree of developmental delay is variable, depending on the location and extent of a demonstrable neuropathology. Usually the family history is negative, but careful questioning of parents regarding the pregnancy, delivery, and early postnatal period and examination of hospital records from birth may disclose the nature of the neurologic insult.

The third category is one in which neither somatic anomalies nor focal neurologic signs are present, or if present, they are minimal. The more severely delayed in cognitive development of this special group are represented by the following disease states: autism (Asperger-Kanner syndrome), the Rett and Williams syndromes, and the fragile X and Renpenning syndromes. All of these but autism are now known to have a genetic basis as noted earlier in the chapter and are described together below.

The practical importance of this clinical approach is that it directs the intelligent use of laboratory procedures for confirmation of the diagnosis. CT scanning and MRI are useful in clarifying maldevelopment and neurologic diseases but are seldom helpful in the third group of cases. EEG confirms seizure discharges when there is uncertainty as to the nature of episodic neural dysfunction. Karyotyping and genetic studies are useful in group 1 and rarely in group 2.

A major pitfall in this clinical approach is in mistaking a hereditary metabolic disease for a developmental one. Here one is helped by the fact that manifestations of the metabolic diseases are not usually present in the first days of life; they appear later and are progressive and often associated with specific visceral abnormalities. However, some metabolic diseases are of such slow progression that they appear almost stable, especially the late-onset ones, such as one type of metachromatic leukodystrophy, late-onset Krabbe leukodystrophy, adult adrenoleukodystrophy, and adult hexosaminidase deficiency (see Chap. 37).

Hereditary Developmental Delays

Fragile X Syndrome

(See earlier discussion under "Other Chromosomal Dysgeneses.")

There has been great interest in this syndrome, which some geneticists hold accountable at least in part for the preponderance of developmentally delayed males in whom an etiology could not be previously established. A large kindred in whom developmental delay was inherited in an X-linked pattern was first reported by Martin and Bell in 1943. It was in such a family, with X-linked developmental delay, that Lubs, in 1969, discovered a fragile site at the distal end of the long arm of the X chromosome; subsequently, it was established that there is an unstable inherited CGG repeating sequence at this site, which leads to breakage, as discussed previously. At first, it was assumed that the fragile X syndrome was only an example of the Renpenning syndrome (an X-linked hereditary developmental delay in males; see below) until it was pointed out that in this latter condition, stature was reduced, as was the cranial circumference, and further that the X chromosomes of the Renpenning patients were normal. The nature of chromosomal breakage that can be attributed to an expanded trinucleotide repeat sequence of the FMR1 gene and a resultant loss of protein function were discussed earlier in "Other Chromosomal Dysgeneses."

In some series, fully 10 percent of developmentally delayed males have this fragile X chromosomal abnormality, although 2 to 4 percent is more accurate according to other series. Females are sometimes affected, but their mental function is only slightly reduced. Affected males have only mild dysmorphic features (large ears, broad forehead, elongated face, and enlarged testes) that may not become obvious until puberty. Others are somatically normal. Behavioral problems of one sort or another are almost universal. Pulsifer, whose review of the neuropsychologic aspects of developmental delay is recommended, lists self-injurious, hyperactive, and impulsive behaviors as the most common. The hand-flapping that is more characteristic of autism may be seen.

Fragile X Premutation Syndrome of Adults

As discussed in Chap. 5, a curious form of progressive adult onset ataxia and tremor, previously thought to be of a degenerative type, has been discovered to be caused by a "premutation" of the fragile X gene (50 to 200 trinucleotide repeats). Some of these patients have characteristic symmetrical signal MRI changes in the middle cerebellar peduncles in the T2 sequence. Other unusual late presentations have been described, including a spastic paraparesis without ataxia or tremor (Cellini et al). A report by Grigsby and coworkers suggests that cognitive function may be diminished in these men, but only when adjusted for their level of education and not compared to normative data; the observation requires confirmation and any suggestions that a fragile X premutation is responsible for dementia in adults should be accepted cautiously. The permutation expansion may be manifest in women as premature ovarian failure. In contrast to the mutation that causes developmental delay, this disorder is thought to be related in some way to an excess of messenger RNA. Several papers suggest that the premutation may also be the cause of some cases of mild retardation and autistic-like behavior.

Rett Syndrome

This is yet another hereditary form of developmental delay, but one that affects girls. None of the cases in the extensive studies of Hagberg and coworkers (1983) was male. The responsible spontaneous mutation was shown to relate to a defect at chromosomal site Xq28, making it one of the X-linked developmental delays. A fatal outcome in boys because of a severe neonatal encephalopathy explains the expression of the disease only in girls, who are mosaics for the mutation. The involved gene, MECP2, is responsible for suppressing various other genes at critical stages of development (see Dunn and MacLeod). It has this effect by binding to methylated DNA. Defective function of the gene leads to an alteration in synaptogenesis and neural connectivity (Neul and Zoghbi). Severe inactivation of gene expression causes classic Rett syndrome, but it has become apparent that incomplete expression and mosaicism lead to a number of partial syndromes, including nonspecific developmental delay, tremor, psychiatric disturbances, and autism-like presentations.

Prevalence studies from Sweden indicate an occurrence of 1 per 10,000 girls; thus Rett syndrome is more common than phenylketonuria. Although most cases appear to be sporadic, there is a high familial incidence and some degree of concordance in twins (this is still uncertain).

The syndrome is usually marked by withdrawn behavior that simulates autism, dementia, ataxia, loss of purposeful hand movements, and respiratory irregularities. Highly characteristic is a period of 6 to 18 months of normal development followed by the rapid appearance and progression of all these signs, and then by relative stability for decades. Spasticity, muscle wasting, scoliosis, and lower limb deformities may become evident in the late stages of the illness. Handwringing and similar stereotypes are very typical features (and are different in subtle ways from the hand-flapping of autistic children).

Armstrong and Naidu, who have reviewed the neuropathology of Rett syndrome, have drawn attention to a number of subtle cortical abnormalities, most of which are consistent with disruption of the postnatal integrative phase of cerebral development; however, not all cases showed these abnormalities. There is generally a decrease in brain size, most marked frontally. Dendritic branching is reduced in several areas. The MRI scan is normal, but some patients show frontal or cerebellar atrophy in their teenage years.

Partington Syndrome

This is yet another X-linked type of developmental delay, which in its fully expressed form is associated with prominent dystonia of the hands and sometimes of the feet, or ataxia. Like Rett syndrome, discussed above, variations in gene expression appear to cause other syndromes including myoclonic epilepsy, West syndrome, autism, and nonspecific retardation, as well as lissencephaly. The mutated gene, termed Aristaless-related homeobox (ARX), is involved with regulation of protein-DNA interactions. The subject is reviewed by Sherr.

Renpenning Syndrome

A similar type of hereditary, male-sex-linked developmental delay was described by Renpenning and associates (and subsequently associated with Renpenning's name). The originally described family comprised 21 males in 2 generations of Mennonites in western Canada whose IQs ranged from 30 to 40. It has now been described in 15 families. As with the fragile X syndrome, female siblings may show slight degrees of retardation. Affected members were small in stature and slightly microcephalic but otherwise free of somatic and neurologic abnormalities. The mutated gene responsible is PQBP1, the polyglutamine binding protein of which produces the syndrome through unknown means.

Williams (Williams-Beuren) Syndrome

This inherited form of developmental delay is manifest in both males and females and was mentioned earlier. It is characterized by mild and variable developmental delay but with sometimes striking retention and even precocity or superiority of musical aptitude and social amiability. In some instances, a retained facility for writing permits the production of long, written descriptions; yet at the same time, these subjects are barely able to draw simple objects. The child is physically slow and has minor but distinctive somatic changes (wide mouth, almond-shaped eyes, short upturned nose, flat nasal bridge, long philtrum, delicate chin, and small pointed ears), together imparting an "elfin appearance" that is nonetheless variable and not as apparent in adulthood as the facial features coarsen. There is often an unusual sensitivity to auditory stimuli. The delay in acquisition of communicative speech and defects in visual, spatial, and motor skills make these children seem more deficient than they actually are. Striking sociability and empathy set them apart; they represent virtually the converse of autism in this respect. Memory for musical scores—such as memorizing parts of a complete symphony after one hearing—may be prodigious.

By the use of high-resolution cytogenetics, the disease was traced in over 90 percent of cases to a deletion on chromosome 7 in the ELN gene that controls the production of elastin (Nickerson et al). This is of interest because one index feature of these cases is supravalvular aortic stenosis and variations (but not necessarily deletions) in the same gene account for cases of familial supravalvular stenosis without developmental delay. This cardiovascular disease is the main cause of death in these individuals.

It is not known whether there is a characteristic brain pathology, but one 35-year-old patient examined by Golden and associates showed no cerebral abnormalities except for Alzheimer changes, mainly plaque formation in the entorhinal cortex and amygdala. The laboratory diagnosis can be established by the use of ELN-specific probes or other techniques that show only one allele of the gene. A most interesting related finding by Somerville and colleagues is that duplication at the same site on chromosome 7 implicated in Williams syndrome can cause a delay in the acquisition of expressive speech. The reader is referred to an extremely thorough clinical and genetic review of the syndrome by Pober.

Doublecortin Mutations

Among the disorders of cerebral sulcation, lissencephaly and the related disorder of subcortical band heterotopia are usually associated with severe defects in mental development. However, in female carriers, other mutations in the doublecortin gene (DCX) on the X chromosome have given rise to mild nondysmorphic developmental delay and cryptogenic epilepsy (see Guerrini and colleagues). Thus this disorder joins the group of X-linked developmental delays with minimal dysmorphic features and has implications for the understanding of X-chromosome inactivation in female carriers.

Autism (Kanner-Asperger Syndrome; Autistic Spectrum Disorders)

This condition was described almost simultaneously by Kanner in Baltimore (in 1943) and Asperger in Vienna (in 1944). Among a large group of developmentally delayed children, Kanner observed exceptional ones who appeared to be asocial, lacking in communicative skills both verbal and nonverbal, and committed to repetitive ritualistic behaviors. At the same time certain intellectual capacities—such as focused attention, retentive memory, skilled sensory and motor aptitudes, and capacity for visuospatial perception—were often retained or overly developed. In other words, the disorder pervaded only certain aspects of mental development.

It is the gestalt of negative and positive aptitudes that sets this syndrome apart from other types of delay. Kanner incorrectly ascribed the condition to psychosocial factors—such as a cold, aloof parent—and regarded it as a psychopathy. The implication that these children are literally "autistic"—that is, that they have a rich inner psychic life or dream world out of relation to reality—is an assumption wholly without foundation. Asperger, whose observations included somewhat older children who were less completely disabled, later ascribed the retardation (also incorrectly) to a metabolic disease, possibly related to hyperammonemia. Opinion varied as to the relationship between the severe Kanner syndrome and the less-severe Asperger syndrome. The authors have taken the more modern view that these forms of autism represent a single syndrome of varying severity, with similar pathologic underpinnings but possibly of multiple etiologies, including genetic. Some 1 percent of autistic children are of normal or superior intelligence.

In our opinion, the overarching issues in classification have become (1) the existence or embedding of autistic traits in a vast number of syndromes that are characterized by developmental delay; examples of this confluence include processes as divergent as fragile X syndrome, phenylketonuria, and tuberous sclerosis; and (2) the extent and margins of the diagnosis of "autistic spectrum disorder." If most socially awkward children are included, the disease begins to encroach on the spectrum personality structure and presents serious problems in diagnosis and the allocation of resources. With regard to the first issue of autistic elements that are part of another well-defined disease, it has become all too easy to ascribe genetic findings to that feature of the syndrome, confusing the problem of sorting out the true etiologies of a clearly identifiable clinical syndrome of autism alone. Baker takes another perspective in an article on the history of the definitions of the disorder that also comments on the DSM classification.

Despite many claims to the contrary, there is no evidence of a psychogenesis. However, as Rapin points out, behavioral modification and special education are beneficial for less-severely affected children.

The overall prevalence of the autistic state has been calculated at 4.5 to 20 per 10,000. Although there was said in the past to be no familial tendency, this is almost certainly incorrect; we have seen the disease in both identical twins and in brothers, and small familial subgroups are known to exist. Autistic traits, without the full syndrome, are being found with increasing frequency in sibs and other family members, suggesting a polygenic inheritance. DeMyer found that 4 of 11 monozygotic twins were concordant for autism and that siblings have a 50 times greater risk of developing the disorder than normal children. Bailey and associates and also LeCouteur and associates have reported a concordance rate in monozygotic twins of 71 percent for the autistic spectrum disorder (as defined below) and 92 percent for an even broader phenotype of disordered social communication and stereotypic or obsessive behaviors. DeLong has found an increased incidence of bipolar disease in the families of one group of autistic children and superior mathematical aptitudes in other family members.

The recent elucidation of microdeletions and microduplications within chromosome 16p by Weiss and the Autism Consortium is the first hint of a genetic locus for susceptibility to autism. Despite a high degree of penetrance in individuals with these changes, the importance of these findings is as a biologic direction for research as it explains no more than 1 percent of cases. Furthermore, certain polymorphisms, particularly in the SHANK3 may explain a small number of cases and this gene has variants that appear disproportionately often in schizophrenia, leading to speculation on common biologic processes. The reader is also referred to the discussion of genetic changes in mental retardation in the earlier sections of the chapter.

Clinical Features

The autistic child is ostensibly normal at birth and may continue to be normal in achieving early behavioral sequences until 18 to 24 months of age. Then an alarming regression occurs, sometimes fairly abruptly. In some instances, the abnormality appears even before the first birthday and the child is identified as different in some way by the mother; or, if there had been a previously autistic child, she recognizes the early behavioral characteristics of the disorder. The level of activity is reduced or increased. There may be less crying and an apparent indifference to surroundings. Toys are ignored or held tenaciously. Spinning toys or running water may hold a strange fascination for the child. Cuddling may be resisted. Motor developments, on the other hand, proceed normally and may even be precocious. Later there may be an unusual sensitivity to all modes of sensory stimulation. Occasionally the onset appears to have a relationship to an injury or an upsetting experience.

Regardless of the time and rapidity of onset, the autistic child exhibits a disregard for other persons; this is typically quite striking but can be subtle in milder cases. Little or no eye contact is made, and the child is no more interested in another person than in an article of furniture. Proffered toys may be manipulated cleverly, placed in lines, or rejected. Insistence on constancy of environment may reach a point where the patient becomes distraught if even a single one of his possessions has been moved from its original place and remains distressed until it is replaced. If speech develops at all, it is automatic (echolalic) and not used effectively to communicate. A repertoire of elaborate stereotyped movements—such as whirling of the body, manipulating an object, toe-walking, and particularly hand-flapping—are characteristic. It is important to point out, that in any sizable group of autistic children there is a wide range of deficits in sociability, drive, affect, and communicative (verbal and gestural behavior) ability, ranging from an averbal, completely isolated state to considerable language skill and some capacity for attachment to certain people as well as for scholastic achievement. However, the IQ of the majority is below 70 and in 20 percent it is below 35; 1 percent, however, have normal or superior intelligence. In this higher-functioning group, taken to typify the Asperger syndrome, the child may be unusually adept or even supernormal in reading, calculating, drawing, or memorizing ("idiot savant") while still having difficulty in adjusting socially and emotionally to others and in interpreting the actions of others. Many are clumsy and inept in athletic activities. The least degree of deficit allows success in a professional field but with handicap in the social sphere.

We take the current emphasis on the term autistic spectrum disorders to reflect a concept that each of the core elements of autism (in social, language, cognitive, and behavioral domains) may occur in widely varying degrees of severity. This view expands the diagnosis to many children who are highly functional except for a tendency to gaze aversion and other "soft signs," together called "pervasive developmental disorder" (Filipek). There is also crossover with a number of namable developmental delays as noted below.

Rapin, drawing on a large clinical experience, has carefully documented the linguistic, cognitive, and behavioral features of the syndrome. She uses the term semantic-pragmatic disorder to designate the characteristic problem with language and behavior and to distinguish it from other forms of developmental disorders and developmental delay. There is a striking ability to understand isolated facts but not to comprehend concepts or conceptual groupings; consequently, these children and adults seem to have difficulty generalizing from an idea. Temple Grandin, a patient with a high-functioning Asperger type of autism who has written of her experiences and has been described by Sacks, indicates that she thinks in pictures rather than in semantic language. She reports a curious comfort from being tightly swaddled and has a highly developed emotional sensibility to the experiences of cattle, which has allowed her success in reforming and designing abattoirs. According to Eisenberg, who reviewed many of Kanner's original cases and followed many other cases into adult life, one-third never spoke and remained social isolates, one-third acquired a rudimentary language devoid of communicative value, and the remainder were functional to various degrees, possessing an affected, stilted, colorless speech. It is in the latter group, representing the mildest degrees of autism, that one finds eccentrics, the mirthless, flat personalities, unable to adapt socially and habitually avoiding eye contact but sometimes possessing certain unusual aptitudes in memory, mathematics, factual knowledge, history, and science. Rutter, who has written extensively on the subject, says that the degree of language impairment and lowered intelligence predicts outcome; those who do not speak by 5 years of age will never learn to speak well.

As mentioned, elements of autism, but not the whole syndrome with its positive and negative attributes, may appear in other diseases that interfere with brain development, specifically fragile X and Rett syndromes, and fragmentary similarities are found in a few children with phenylketonuria, tuberous sclerosis, Angelman syndrome, and, rarely, Down syndrome—but these patients are easily distinguished from those with the far more common type of autism. Bolton and Griffiths have made the intriguing observation that autistic traits in patients with tuberous sclerosis correspond to the finding of tubers in the temporal lobe, and DeLong and Heinz point out that patients with seizures from bilateral (but not unilateral) hippocampal sclerosis may fail to develop (or may lose) language ability as well as failing to acquire social skills after a period of normal development, in a manner similar to autism.

Etiology and Pathology of Autism

The basis of childhood autism is as much a mystery today as it was when Kanner and Asperger described it. Most of these children are physically normal except for a slightly larger head size, on average, but with no other somatic anomalies. Despite instances in which the onset of mental and behavioral regression seems to be quite sudden, no environmental factors, including the often-mentioned measles-mumps-rubella (MMR) vaccination, mercury exposure, and food allergies, have been credibly connected to autism. The genetic microdeletions and microduplications described earlier have given few hints as to the biologic cause.

The EEG is normal, as is CT or MRI. The significance of cerebellar vermal changes, reported originally by Courchesne and colleagues, remains uncertain (Filipek). In the few brains examined postmortem, no lesions of any of the conventional types have been found. In 5 brains studied in serial sections by Bauman and Kemper, smallness of neurons and increased packing density were observed in the medial temporal areas (hippocampus, subiculum, entorhinal cortex), amygdala and septal nuclei, and mammillary bodies. In a subsequent review of the neuropathology, Kemper and Bauman concluded that three changes stood out: a curtailment of the normal development of neurons in the limbic system; a decrease in the number of Purkinje cells that appears to be congenital; and age-related changes in the size and number of the neurons in the diagonal band of Broca (located in the basal frontal and septal region), as well as in the cerebellar nuclei and inferior olive. The latter changes were inferred from studying the brains of autistic children who died at different ages, and they gave the appearance of a progressive or ongoing pathology that continues into adult life. These findings are in keeping with the concept of autism as a neurodevelopmental disorder, but they allow only speculation regarding the derivation of the clinical features of the disease. An increased concentration of platelet serotonin and low serum serotonin is detected in many but not all patients; also, serum oxytocin is reduced. The biologic significance of these findings is unclear.

Course, Treatment, and Prognosis

The disease is essentially nonprogressive although some patients, as they grow older, begin to manifest additional visuoperceptive or auditory defects. In the typical case, the outcome is bleak, although many less affected children show improvement in social relationships and schoolwork when given a serotonin reuptake inhibitor, sometimes in very small doses (DeLong; Filipek, personal communication). Administration of the peptide secretin had produced a number of anecdotal successes, but this could not be reproduced in controlled studies. Selective serotonin reuptake inhibitors (e.g., fluoxetine, citalopram) have also shown some benefit in managing repetitive behaviors and mood swings such that medications in this class are being widely prescribed to autistic children. In addition, serious behavioral changes such as self-injurious activities, aggression, and severe tantrums have been treated with drugs such as risperidone. These represent a therapeutic advance but, as pointed out by Hollander and colleagues in their review of the drug treatment of autism, the patients studied were selected for the severity and type of their symptoms for which reason these medications cannot be expected to be of help to all autistic individuals.

Management of Developmental Delay

Because there is little or no possibility of treating most of the diseases underlying developmental delay and there is no way of restoring function to a nervous system that is developmentally subnormal, the objective is to assist in planning for the patient's care, training, education, and social adjustment. The parents must be guided in forming realistic attitudes and expectations. Psychiatric and social counseling may help the family to maintain gentle but firm support of the patient so that he can acquire, to the fullest extent possible, good work habits and a congenial personality.

Most individuals with an IQ above 60 and no other handicaps can be trained to live an independent life; special schooling may enable them to learn skills useful in a vocation. Social factors that contribute to underachievement must be sought and eliminated if possible.

If the IQ is below 20, institutionalization is almost inevitable, for few families can provide the long-term custodial care that is needed. Well-run institutions are usually better than community homes because they offer many more facilities (medical, educational, recreational). Often institutional care is necessary for individuals with IQs of 20 to 50. Patients in this group, if stable in temperament and relatively well adjusted to society, can work under supervision, but they rarely become vocationally independent. For the more severely cognitively impaired, special training in hygiene and self-care is the most that can be expected.

Great care must be exercised in recommending institutionalization. Whereas the need will be all too apparent in the gravely impaired by the first or second year of life, the less-severely affected are difficult to evaluate at an early age. As stated earlier, psychologic tests alone are not altogether trustworthy. It is best to observe the patient over a period of time. As noted in Chap. 28, the method of evaluation suggested long ago by Fernald has a ring of soundness, albeit in quite dated terms. It should include observations of (1) the physical, medical, and neurologic findings; (2) family background; (3) developmental history; (4) school progress or lack thereof; (5) performance tests; (6) social behavior; (7) industrial efficiency; (8) behavioral disinhibition, which was called in Fernald's time "moral behavior"; and (9) intelligence as measured by psychologic tests.