Part 2. Abnormal Development of the Nervous System

The central nervous system (CNS) is the most complex organ in the human body comprising a highly organized anatomic scaffold of billions of cells and a network of trillions of connections. Structural brain development proceeds through an integrated series of often rapid developmental events from early embryogenesis through fetal life and into early adulthood. It is therefore not surprising that many common childhood neurologic and developmental disorders have their origins in genetic or environmental perturbations of embryonic or fetal brain development.

Advances in genetics and diagnostic imaging, including prenatal imaging, have led to earlier and more complete diagnosis and enhanced prognostication for CNS malformations and the ability to counsel effectively regarding recurrence. The diagnosis of malformations has been revolutionized by magnetic resonance imaging (MRI), and the challenge for the pediatrician is often to translate the imaging diagnosis to effectively counsel the family and plan further care and management for the child. Modern neonatal neurologic and neurosurgical intensive care together with progress in early intervention and pediatric rehabilitation means children with malformations of the brain or spinal cord may now survive longer and with improved quality of life.

Malformations of the CNS are among the most common problems in child neurology. Brain development is abnormal in an estimated 25% of conceptions and is responsible for a high percentage of miscarriage and stillbirth. Brain malformations are, together with congenital heart disease, the leading cause of neonatal and postneonatal mortality in the developed world. Brain malformations are after cerebral palsy, the leading cause of childhood morbidity and mortality related primarily to consequent neurologic disability and epilepsy. Brain malformations frequently coexist with other malformations of organ systems, in particular the eye, heart, kidneys, gut, and skeleton.

The neuraxis develops following the fate decision of several early embryonic cells to become neural progenitors and by the second week of embryogenesis the three primary layers of ectoderm, mesoderm, and endoderm are formed. It subsequently proceeds through the dorsal and ventral induction to form the neural tube, lower spinal cord and eventually the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). This is followed by massive cellular proliferation of both neuronal and glial precursors and later differentiation into specific neuronal and glial types. Cortical development occurs with migration of neuronal and glial precursors away from the ventricular and subventricular zone towards the pial surface to form the neocortex and major commissures such as the corpus callosum. This is followed by cortical organization that includes alignment, orientation, and layering of cortical neurons together with synaptogenesis. From the end of the second trimester into early childhood late glial differentiation and myelination, together with programmed and experience-dependent synaptic formation and pruning predominate.

The range of known malformations is almost as complex as the series of developmental events that lead to the formation of the brain. They are perhaps best understood as the effects of insults—regardless of type—at key points in the development of the brain. Although much emphasis has been placed on genetic etiologies—cytogenetic abnormalities, single gene disorders, and polygenic syndromes—environmental insults at key points in the developmental program may result in similar malformations with common clinical findings in the infant or child. As the developing brain, particularly during the first two trimesters, is not capable of generating the common glial response to injury, the etiological cause is frequently difficult to discern. For example early vascular or infectious events may cause abnormalities of cortical migration such as polymicrogyria indistinguishable from a primary genetic causation. An overview of the key developmental events in brain and spinal cord formation, together with examples of corresponding disorders related to developmental changes at these steps is given in Table 548-1.

The clinical sequelae of these malformations are broad and often location specific, but some general themes emerge. Disorders of embryonic CNS development (neurulation, prosencephalic development, and neuronal proliferation) are frequently associated with morphological findings. These include abnormal head size and shape; facial dysmorphology (in particular midline abnormalities); facial clefting; and anomalies of optic globe size, shape, and position. Intra-axial anomalies frequently lead to major variations in ventricular size and structure and consequently these lesions are diagnosed on routine obstetric fetal anomaly scans. Spinal closure abnormalities may be associated with external stigmata such as fistulae, dimples, nevi or ectopic hair, or fat. In addition fetal lower limb positioning may be abnormal with talipes and fixed flexion of the hips of extension of knees detectable prenatally. In addition to fetal miscarriage and death, other fetal manifestations of early CNS malformations include polyhydramnios, decreased fetal movement, and preterm labor. Malformations related to abnormalities in later fetal stages of CNS formation may present postnatally, often in late infancy or childhood, frequently without evident dysmorphic features or neonatal manifestation. Early symptoms may include hypotonia and motor delay, as well as feeding difficulties. Later symptoms usually encompass speech and language delay and variable degrees of cognitive impairment including mental retardation. Epilepsy is particularly associated with disorders of migration and cortical organization but may not present until late childhood or adolescence. This chapter covers developmental disorders up to and including disorders of migration. Conditions associated with aberrant organization, synaptogenesis, pruning, and myelination are covered elsewhere in detail.

Anomalies of Prosencephalic Development

The developing forebrain and face is contingent on the ventral induction by the prechordal mesoderm at the rostral end of the neural tube. The sonic hedgehog signaling pathway is critical to the development of the prosencephalon, with sonic hedgehog protein (Shh) secreted from the prechordal mesoderm to activate the Patch receptor and downstream genes.

The major events are formation of the prosencephalon at the end of the first month; cleavage in three planes to give the basic structure of paired cerebral hemispheres, basal ganglia, and ventricles; separation from the midbrain; and development of paired optic and olfactory structures. These events are followed by midline prosencephalic development with thickening of the commissural, chiasmatic, and hypothalamic plates necessary for formation of the corpus callosum, septum pellucidum, optic nerve chiasm, and the hypothalamus. The corpus callosum forms as developing cortical axons cross the midline under the influence of chemoattractants and repellents.

Holoprosencephaly

This group of disorders is the result of different degrees of failure of prosencephalic cleavage and distinguished by the severity of failed cleavage of the cerebral hemispheres and deep nuclear structures. The most severe form is alobar holoprosencephaly where there is a single sphere cerebral structure and monoventricle with fusion of the thalami and deep nuclei together with absence of the corpus callosum and olfactory bulbs. Neuronal migration and cortical organization is severely disordered. In semilobar holoprosencephaly there is failure of separation of the anterior cerebral cortex and absence of the anterior corpus callosum. The least severe forms are lobar holoprosencephaly, in which the cerebral hemispheres are fully separated and the deep nuclei partially separated, and the middle interhemispheric variant, in which only the posterior frontal and parietal regions fail to separate. Hydrocephalus is present in most infants with alobar holoprosencephaly due to fusion of the thalami and impaired drainage of cerebrospinal fluid (CSF) through the aqueduct. Infants with semilobar and lobar forms are usually microcephalic. Facial anomalies are usual and range from severe cyclopia with proboscis through to ocular hypotelorism with a flat single nostril nose (cebocephaly) to mild hypotelorism with or without cleft palate. Malformations of other organ systems are present in 75% of patients.

Alobar holoprosencephaly occurs in 1/10,000 live births but is 100 times more common in conceptuses examined after miscarriage or abortion. Causes include both genetic and cytogenetic etiologies as well as teratogens. Over two thirds are related to full or partial chromosomal aneuploidies, in particular trisomy 13. A list of known etiologic factors is given in Table 548-2.

The clinical features relate to the severity of failure of cleavage of the cerebral hemispheres, basal ganglia, and abnormal hypothalamic function. Most patients with alobar holoprosencephaly do not survive infancy. Children with less severe forms do have prolonged survival. Seizures are common as is profound visuomotor and cognitive impairment. The failure of basal ganglia and thalamic cleavage leads to dystonia and motor impairment, as well as early apnea. Hypothalamic dysfunction leads to often life-threatening endocrinopathies such as diabetes insipidus, as well as poikilothermia. Management is primarily supportive. Although shunting is performed, the development of hydrocephalus is often a sign of unrecognized severe failure of cleavage.

Agenesis of the Corpus Callosum and Absent Septum Pellucidum

This group of disorders is characterized by varying degrees of failure of midline prosencephalic development. Agenesis of the corpus callosum (ACC) may be complete or partial and is associated with deformation of the lateral ventricles to give a parallel ventricular arrangement known as colpocephaly. This is usually accompanied by longitudinal fibers coursing along the medial aspect of the hemispheres known as Probst bundles. Partial ACC usually comprises absence of the posterior callosum. Agenesis of the corpus callosum (ACC) may be isolated or in up to 40% to 50% of cases associated with other cerebral abnormalities, specifically cerebellar malformation and cortical migration anomalies. Agenesis of the corpus callosum is one of the most common anomalies occurring in up to 7 in 1000 live births and 3% of children with developmental delay. It is increasingly diagnosed in fetal life. Agenesis of the corpus callosum may be completely asymptomatic or have symptoms only detected on very refined testing of interhemispheric transfer. In association with other anomalies however there is a strong risk of cognitive and neuromotor impairment. Agenesis of the corpus callosum is associated with well over 65 known genetic syndromes and the presence of extra-axial abnormalities or cytogenetic abnormalities is a risk factor for impaired neurologic development (Table 548-3). A notable condition is Aicardi syndrome, an X-linked dominant condition affecting females associated with neuronal heterotopias, chorioretinal lacunes, early onset infantile spasms and subsequent refractory epilepsy and profound developmental delay.

Absence of the septum pellucidum is another common anomaly and frequently associated with more diffuse cerebral malformations such as schizencephaly, septo-optic dysplasia, ACC, holoprosencephaly, and hydrocephalus. Failure of fusion of the septal leaflets is known as cavum septum pellucidum. This is a normal finding in fetal life and in premature infants, but, after the neonatal period, has a weak association with later cognitive deficits. As with ACC, the outcome of absent septum pellucidum is related to associated brain malformations. The most common and important of these is septo-optic dysplasia (SOD, de Morsier syndrome) where absent septal leaflets are associated with optic nerve hypoplasia and disturbances of the hypothalamic-pituitary axis. Children with SOD may have profound panhypopituitarism. Identification of absent septal leaflets on prenatal imaging should be accompanied by postnatal magnetic resonance imaging (MRI), ophthalmic examination, and complete endocrinology evaluation.

Cerebellar Malformations

Cerebellar development varies considerably and coincides with prosencephalic development. As the cerebellum is intimately related to development of the aqueduct of Sylvius and foramina outflow of the fourth ventricle, hydrocephalus and posterior fossa fluid collections are frequent accompaniments. Common malformations are listed in Table 548-4.

Of these the Dandy-Walker malformation (DWM) is the most frequently encountered and together with stenosis or atresia of the aqueduct of Sylvius accounts for over 40% of cases of congenital hydrocephalus. DWM comprises agenesis of the cerebellar vermis, enlargement of the posterior fossa with rostral displacement of the torcula, and cystic dilatation of the fourth ventricle. Hydrocephalus and supratentorial migrational abnormalities are common accompaniments (70–90%). It is associated with a range of genetic syndromes including Smith-Lemli-Opitz, Meckel-Gruber, and Rubinstein-Taybi syndrome. The hydrocephalus may be striking at birth and the majority of children require shunting. Outcome is related to the onset of hydrocephalus (early fetal onset being associated with a high mortality and severely impaired neurologic outcomes) and the associated cerebral malformations.

Joubert syndrome is another important pediatric cerebellar malformation. Characterized by vermian dysplasia, neuronal heterotopias, absent decussation of the cerebellar peduncles, and multiple brainstem abnormalities. This group of disorders is identifiable by the “molar tooth” conformation of the superior cerebellar peduncles on magnetic resonance imaging (MRI). At least 5 gene loci have been identified. The disorder is characterized by hypotonia, craniofacial dysmorphisms, nystagmus, and respiratory dysrhythmia. Associated anomalies include retinal colobomata, renal malformations, and hepatic fibrosis. Cognitive impairment may be mild and not apparent until later in schooling.

Abnormalities of Neuronal Proliferation and Migration

Following establishment of the basic pattern of the developing neuraxis, brain growth proceeds by rapid proliferation of progenitor neurons and glia and migration from the ventricular surface to the developing fetal cortex. Neuronal and glial progenitors are formed by symmetric and asymmetric division of pluripotent stem cells in the ventricular and subventricular zones. These cells exit the cell cycle and migrate into the intermediate zone and thence to the cortical plate at the pial surface.

Abnormalities of proliferation give rise to disorders of brain size (primary micrencephaly and megalencephaly) that are covered in more detail in Chapter 550. These include the autosomal recessive disorders of micrencephaly vera (primary micrencephaly or microcephaly with simplified gyri) and radial microbrain (where, despite the extremely small brain size, gyration, and cortical lamination are normal). Children with micrencephaly vera often do not have major neurologic findings and cognitive impairment may be mild. There is often associate migrational abnormality, in particular simplification of the gyri, which is usually associated with more profound mental retardation. By contrast, infants with radial microbrain usually die in the neonatal period.

Macrencephaly/megalencephaly is a highly heterogeneous group of disorders that includes macrocosmic syndromes such as Soto, fragile X, and Beckwith-Tiedemann syndromes. It is a common finding in neurocutaneous syndromes such as neurofibromatosis and Sturge-Weber syndrome. Of interest is autosomal dominant and recessive isolated familial macrencephaly where the head size is large at birth and continues to grow rapidly postnatally. Neurologic and cognitive development is usually normal.

Migrational disorders are a large and complex group of conditions characterized by relative impairments in the radial migration of neurons into the cerebral cortex and tangential migration of interneurons into the cortex (Fig. 548-1). This process requires the presence of radial glial guides, a series of fetal transient zones, and a complex panoply of molecular determinants including guidance molecules, signaling pathways, surface ligands, cytoskeletal elements, ion channels, and neurotransmitters, in particular glutamate. Clinically these disorders are manifested by neonatal hypotonia, early onset of often refractory seizures, and developmental delay. MRI is the most useful initial investigational tool when a migrational disorder is suspected, with the hallmark finding of gyral abnormalities and occasionally abnormalities of the corpus callosum.

Lissencephaly-pachygyria represents a spectrum of disorders marked by underdevelopment or absence of normal gyrification. In type 1 lissencephaly there are absent gyri and an immature cerebral mantle with disorganized and heterotopic neuronal layering. Type II lissencephaly is characterized by clustered, whorled arrays of neurons separated by glia and large heterotopic formations of neurons, often migrating into the pia giving a characteristic “cobblestone” appearance. Pachygyria is demonstrated by thickened simple gyri that are underdeveloped and is a continuum of lissencephaly. Radiologic features are shown in Chapter 550, Figure 550-1. The known causes of these types of lissencephalies are listed in Table 548-5 together with salient clinical features and diagnostic indicators.;

Clinically type I lissencephaly are characterized by postnatal deceleration of head growth, profound neonatal hypotonia evolving to a spastic quadriparesis, severe dysphagia, poor movement, early seizures often evolving to infantile spasms, and eventually Lennox-Gastaut syndrome. Mental retardation is prominent. Type II lissencephalies in addition to those clinical features seen in type I lissencephaly, differ by the presence of microcephaly, retinal and anterior chamber malformations, congenital muscular dystrophy, and cerebellar malformations. Epilepsy and hypotonia predominant and death in infancy are common.

Polymicrogyria is characterized by numerous small folds of gyri that may have a basic four-layered anatomy, or unlayered with a poorly laminated heterotopic collection of neurons below the cerebral mantle. Polymicrogyria is associated with a number of primary genetic conditions, as well as metabolic conditions, in particular disorders of peroxisomal biogenesis, such as Zellweger syndrome. It frequently accompanies other dysgenetic brain malformations as well as in utero encephaloclastic events such as vascular insults or congenital infection (congenital infection in particular). The neurologic sequelae are very variable and range from severe mental retardation and refractory epilepsy to milder disorders of neuromotor function or mild learning disability. A special note is made of perisylvian polymicrogyria syndromes, particularly the bilateral form, which is associated with specific deficits in orolingual impairment and pseudobulbar palsy, with expressive language delay and feeding problems prominent.

Neuronal heterotopias and focal cortical dysplasias represent arrest of migration of neurons. These may be located close to the ventricular surface in the subependyma following arrest in early radial migration. These are usually nodular and multiple. Other heterotopias are seen in the subcortical white matter and may be small nests of cells or more commonly bands. A list of conditions associated with heterotopias is given in Table 548-6. The clinical manifestation is usually epilepsy, often presenting in early adolescence or adulthood. Although heterotopias may be clinically occult, they elevate the lifetime seizure risk to 40% to 50%. Focal cortical dysplasias represent abnormalities of the later stages of migration and are a cause of intractable epilepsy, which may respond to epilepsy surgery. They may comprise collections of abnormally laminated normal neurons or large dysplastic multipotent cells known as balloon cells.

Schizencephaly is a severe restricted disorder of cortical formation characterized by failure of development of a portion of the cerebral wall leaving a cleft extending from the ependymal surface to the pial surface. The cleft is usually lined by dysplastic heterotopic gray matter in particular polymicrogyria. The lesion may be unilateral or bilateral, usually frontal or perirolandic. The edges of the pial surface may be opposed (“closed-lip”) or more commonly, widely separated (“open-lipped”). Like polymicrogyria the disorder may have a primarily genetic etiology (eg, mutation in the EMX2 gene) but vascular disruption and congenital infection such as congenital infection (CMV) is also associated with this abnormality.

Clinically the condition is associated with cognitive deficits (particular in bilateral clefts), late-onset seizures and motor deficits (particular in frontal open-lipped lesions). Agenesis of the corpus callosum or absent septum pellucidum may be frequent accompaniments. Hydrocephalus of unclear mechanism, complicates up to half of cases.1-8

Disorders of neural tube formation and closure relate to disturbances in the inductive events involved in primary neurulation, aberrant closure of the anterior or posterior neuropore, or failure of the caudal regression and differentiation events that lead to formation of the lower spinal cord. Correct development of the neural tube is necessary for formation of the dura and other meninges, cranium and vertebrae, and the dermal coverings. Dysraphism refers to persistent continuity between the posterior neurectoderm and cutaneous ectoderm. External manifestations of abnormal cutaneous ectoderm may be the only initial clinical signs of occult dysraphism.

The incidence of neural tube defects varies widely by geography and by type of dysraphism. For example, rates of myelomeningocele as high as 3% have been reported in the United Kingdom, but extremely low in Japan. There are also significant secular trends with a steady decline in incidence for myelomeningocele and anencephaly in Great Britain, northern Europe, and the United States since the late 1980s. Further details of incidence and etiology are discussed below.

Cranioraschisis and Anencephaly

Cranioraschisis and anencephaly represent the most severe failures of primary neurulation. Cranioraschisis is a rare and lethal condition of essentially total failure of neurulation with a neural plate-like structure present, but with no skeletal or dermal elements overlying it. The incidence is unknown. The equally rare disorder of failure of posterior neuropore closure known as myeloschisis represents the inverse of cranioraschisis, where a neural platelike structure without overlying vertebrae or dermis replaces large portions of the spinal cord. This sometimes involves the base of the skull, the condition of iniencephaly. Infants with this condition are frequently stillborn with severe arthrogryphosis multiplex.

Anencephaly is a defect of anterior neural tube closure and comprises failure of formation of elements from the rostral portion of the neural tube anywhere from the foramen magnum caudally. The forebrain and upper brain stem are usually involved; normal neural tissue is replaced by a formless mass of degenerated, hemorrhagic neuronal and glial tissue; and there is an absence of the frontal, parietal, and squamous occipital bones. The disorder varies considerably with geographic location, race, sex and ethnic group, maternal age, and socioeconomic status. The incidence is higher in whites, especially those of Irish ethnicity, in very young and very old mothers, and in those of lower socioeconomic status as well as in those with a history of previously affected siblings. The incidence in the United States declined from 0.5 per 1000 live births in 1970 to 0.2 per 1000 births in 1989. Polyhydramnios is a frequent prenatal finding and the malformation is now commonly diagnosed in the second trimester during obstetric screening, allowing for elective termination of pregnancy. Babies born alive with anencephaly rarely survive beyond 7 days (< 2%) without intensive care, and even with intensive care, rarely beyond 8 weeks. Neurologic findings in live born babies are usually restricted to residual brain stem activity, including primarily reflexive motor movements and limited basic cranial nerve function, consistent with preservation of a rudimentary brainstem.

Encephalocele

This group of disorders represents herniation of the brain or meninges through the skull. The underlying pathogenesis is not known but relates in part to failure of normal closure of the anterior neuropore. It is relatively uncommon with an estimated incidence of 1 to 3 in 10,000 live births; antenatal detection by ultrasound examination has been increasing. More than 70% of encephaloceles herniate through the occipital part of the skull, although nasofrontal encephaloceles are relatively more common in Southeast Asia. Basilar, temporal, and parietal encephaloceles are unusual. The herniated mass may comprise one or more of meninges, cerebrospinal fluid (CSF), and neural tissue, which may be surprisingly well organized. Hydrocephalus occurs in 50% of occipital encephaloceles; other malformations are common including agenesis of the corpus callosum, Chiari III malformation, and subependymal nodular heterotopia. The degree of neural tissue herniated and the associated brain malformations determine outcome; encephaloceles containing CSF and/or meninges only or patients with an isolated skull defect (cranium bifidum occultum) usually having normal outcomes.

Encephaloceles are found in a number of multiple congenital anomaly syndromes, including Meckel syndrome, and Walker-Warburg syndrome, and are associated with first trimester maternal hyperthermia. Prenatal detection and assessment allows for potential termination of the pregnancy in those cases in which the lesions are massive, with a large amount of herniated neural tissue or in which there is marked microcephaly. Prenatal detection also facilitates postnatal management. This usually comprises neurosurgical intervention to close the defect and to treat associated hydrocephalus. Patients with anterior defects generally have better operative outcomes, with lower mortality and better developmental outcome. More than 50% may be expected to have normal intelligence. Motor deficits are common in survivors. Basal or frontonasal encephalocele may be occult and present with later meningitis or CSF leaks.

Myelomeningocele

Failure of posterior neural tube closure results in a malformation of the spinal cord, myelomeningocele. This is the most commonly encountered neural tube defect in pediatric practice as most infants born with this anomaly survive. The lesion consists of neural plate or rudimentary neural tube tissue herniating through a defect in the vertebra (spina bifida) in the form of a sac containing meninges, cerebrospinal fluid, nerve roots, and spinal cord. The dorsal cord is most commonly affected and some dermal covering may also be present. The vast majority of myelomeningoceles occur in the lumbar region; 10% may contain no neural tissue and are known as meningoceles. Hydrocephalus and Chiari II malformation are frequent associations.

The incidence of myelomeningocele varies widely by ethnic population and geographic location but ranges from 0.2 to 4 in 1000 live births. Girls are more frequently affected than boys. Recurrence risk is 5%, increasing to 15% if 2 siblings are affected. The etiology is unknown but syndromic associations are recognized (eg, Meckel syndrome), as well as a wide range of aneuploidies. Specific teratogens are associated, particularly thalidomide, carbamazepine, and valproic acid. Other maternal susceptibility factors include hyperthermia, low vitamin B12 levels, diabetes mellitus, and obesity. Periconceptual folate supplementation has been shown to significant reduce the incidence of neural tube defects (up to 83% reduction with 400 μg daily supplemental folate). Factors related to folate metabolism have been identified; defective levels of methylene tetrahydrofolate reductase have been demonstrated in up to 20% of pregnancies affected with neural tube defects. Prenatal diagnosis may be made from the second trimester by screening for increased alpha fetoprotein levels in maternal blood resulting from transudation through an open neural tube defect, as well as by fetal ultrasonography and increasingly by fetal magnetic resonance imaging (MRI).

Clinical features relate to the extent and severity of the myelomeningocele, hydrocephalus and Chiari II malformation. In addition other CNS anomalies may be present with migrational abnormalities such as polymicrogyria and cortical dysplasia being present in 40% to 90% of patients. The neurologic features relate primarily to the segmental level of the lesion; the muscles of the trunk and legs and bladder and rectal sphincters are primarily involved. The cord distal to the site of the lesion will be nonfunctional. In general, patients with lesions affecting L2 or above will be nonambulatory and incontinent, often developing later severe scoliosis, while patients with lesions at S1 and below will be ambulatory and partially continent. Intermediate lesions will have variable degrees of ambulation. Good strength-of-hip flexors and knee extensors are good predictors of ambulation.

Hydrocephalus develops in up to 80% of patients and may be insidiously progressive. The clinical signs of full fontanel, separated cranial sutures, and rapidly increasing head size, or signs of raised intracranial pressure usually become evident by 4 to 6 weeks after birth. Chiari II malformation, present in nearly all lumbar myelomeningoceles, is the primary cause of hydrocephalus. In addition, in a minority of cases it causes severe brainstem dysfunction. The malformation consists of inferior displacement of the fourth ventricle, medulla, and lower cerebellum through the foramen magnum into the upper cervical canal; elongation and deformation of the upper medulla and lower pons, together with bony defects in the foramen magnum or upper cervical vertebrae. The hindbrain malformation may block cerebrospinal fluid (CSF) outflow from the 4th ventricle, and aqueductal stenosis or atresia is present in up to 75% of patients, leading to hydrocephalus. The brainstem dysfunction, related to intrinsic abnormalities of the cranial nuclei and outflow tracts, as well as mechanical traction, includes stridor, apnea, dysphagia, facial weakness, and vocal cord paresis. These clinical features are associated with a high mortality. Associated CNS anomalies are responsible for some of the intellectual deficits seen in a minority of patients, as well as the 25% incidence of epilepsy in patients with myelomeningocele.

Initial therapy is directed towards early closure (within 3 days of birth) of the defect to prevent infection. Broad-spectrum antibiotic coverage from birth until closure is also indicated; cesarean section is strongly recommended if a postoperative surgical repair is planned. Early treatment of hydrocephalus with ventriculoperitoneal shunting has been shown to have a positive effect on intellectual development. Brain stem dysfunction related to Chiari II malformation is difficult to treat, but early decompressive cervical laminectomy and shunting have been shown to be effective.

Later management is most effective through multidisciplinary team management directed at management of orthopedic and urologic sequelae. These teams usually comprise neurologists, neurosurgeons, urologists, orthopedic surgeons, general and developmental pediatricians, specialty nurses, rehabilitation therapists, social workers, and psychologists. Orthopedic management and physical therapy are directed towards the promotion of ambulation, prevention and treatment of bony deformity, and maintenance of posture. Urodynamic evaluation from the neonatal period onwards is important. Strategies such as anticholinergic or pro- or antiadrenergic medication and clean intermittent catheterization promote bladder continence in the patient with myelodysplasia.

The combination of selective aggressive therapy that combines careful patient selection for neurosurgical intervention, together with early closure and shunting, has lead to significant improvements in survival (> 85% at age 3 years) and ambulation (> 75% ambulatory) with preserved IQ (> 73% with IQ > 80). Multidisciplinary management and careful attention to the psychosocial and educational needs of children with myelodysplasia, in particular continence and rehabilitation, has improved health-related quality of life. A recent development has been the advent of fetal management. In utero closure of the defect to prevent further deterioration of exposed spinal tissue to amniotic fluid is promising with studies showing reversal of the Chiari II malformation and reduced need for postnatal shunting.

Occult Spinal Dysraphism

This group of conditions relates to disturbances in the processes of posterior neural tube canalization and dedifferentiation towards the end of neurulation. These result in caudal defects and in the vertebrae and dermal structures with subtle or absent neural abnormalities. As the lesions are covered by skin, they are often occult and comprise bony and soft tissue abnormalities of the conus medullaris or filum terminale. The primary anomaly is failure of separation of the neural tube from the overlying ectoderm and abnormal insertion of the mesoderm between these layers. This results in a spectrum of anomalies including ectodermal and mesodermal malformations such as excessive hair, pigmented maculae, hemangiomata, lipomata, dermal tracts or sinuses, division of the spinal cord by a bony or fibrous septum (diastematomyelia), and vertebral anomalies. The failure of caudal canalization causes “tethering” of the conus or filum by fibrous bands or lipomata.

Dermal manifestations are the most common early findings; when present, additional investigation should be pursued, usually spinal ultrasound up to 6 months of age, and thereafter magnetic resonance imaging (MRI) of the spinal cord. Later findings include back pain, delay in walking, delay in development of continence, gait disturbance, and foot or leg deformity or asymmetry. These symptoms relate in part to abnormal neural tissue or to traction restricting normal mobility and growth of the lower spinal cord. Investigation is optimal by MRI of the entire cord supplemented by urodynamics. Neurosurgical management of asymptomatic patients remains controversial. However, untethering techniques designed to prevent traction injury and sudden neurological decompensation, are considered safe in experienced hands. Symptomatic patients are managed with neurosurgical untethering to prevent further progression (some patients may have postoperative improvement in symptoms) combined with orthopedic management of bony deformity.1-8

Normal head growth is affected by the growth and alteration of structures within the cranium (brain, blood, cerebrospinal fluid, and bone) and the timing of these changes in relation to closure of the fontanels. Standards have been determined for head growth in healthy children up to 18 years of age, and the Centers for Disease Control and Prevention has constructed revised standard head circumference for age, based on national survey data from the general US population.1 In addition, special adjusted growth curves have been developed for children with specific underlying medical conditions, such as neurofibromatosis type 1.2

Deviations from normal head growth may be the first indication of an underlying congenital, genetic, or acquired problem. Because of the rapid pace of neuronal and glial cell proliferation and the relative restriction in time during development, it is understandable that an appropriately timed insult could result in profound effects on the number of neurons that result.3 For example, insults that are sustained before embryonic day 40, when the number of neurons is increasing exponentially, would be expected to have a larger impact than those that occur after day 40, when postmitotic neurons have already been formed. A number of disorders exist that presumably represent excessive or deficient production of neurons and glia.

Macrocephaly typically refers to a head circumference that is greater than two standard deviations above the mean and can be caused by an increase in size of any of the intracranial contents (brain, cerebrospinal fluid, blood or bone). Megalencephaly refers to an abnormally large and heavy brain. Macrocephaly can be classified as anatomic or metabolic, distinguishing increases in head size resulting from an increase in the size or number of brain cells from increases in head size that result from the deposition and subsequent accumulation of metabolic products, without a concomitant increase in the number of cells. A large brain that results from cerebral edema or neoplasia is not classified as megalencephaly.

Familial macrocephaly is the most common type of anatomic macrocephaly, and refers to an autosomal dominantly inherited increased head size associated with normal somatic size, development, and neurologic examination.4,5 The next most common etiology for anatomic macrocephaly is increased intracranial pressure with hydrocephalus (see Chapter 553). Macrocephaly may also be associated with a variety of cutaneous or systemic anomalies, such as neurofibromatosis, tuberous sclerosis, linear sebaceous nevus syndrome, and hypomelanosis of Ito.6,7 Lastly, macrocephaly may also be associated with abnormalities of somatic size, such as cerebral gigantism (Sotos syndrome)8,9 and Beckwith-Wiedemann syndrome.10

Although most metabolic disorders result in decreased head size, several metabolic disorders are characterized by progressive macrocephaly.11 Examples include aminoaciduria and leukodystrophies, such as Alexander disease,12 Canavan disease,13 and lysosomal storage disorders (Tay-Sachs, mucopolysaccharidosis and gangliosidosis).14

Microcephaly, by contrast, refers to a head circumference that is greater than two standard deviations below the mean for age and gender-based norms.15 Except in cases of craniosynostosis, microcephaly always implies microencephaly, or an abnormally small brain. The microcephalic brain may be small but otherwise well formed architecturally; in other cases, malformations or destructive lesions may be present with symmetrically or asymmetrically dilated ventricles.16 Microcephaly is classified as “primary” when resulting from a developmental aberration or insult early in neurogenesis and/or neuronal migration, resulting in an overall decrease in the number or size of proliferative units. Figure 550-1 illustrates lissencephaly in a young child who had microcephaly and seizures. “Secondary” microcephaly results from injury or insult to a previously normal brain. The presence of microcephaly alone does not provide a specific clue as to the underlying etiology.

Autosomal recessive, X-linked recessive, and autosomal dominant patterns of inheritance have been described in primary microcephaly, including several familial patterns associated with ocular disorders; however, there is often no identifiable pattern of inheritance.17 The autosomal dominant type of microcephaly is thought to be less severe, with relatively normal intelligence or mild mental retardation. By contrast, children with autosomal recessive forms may have moderate to severe mental retardation. Primary microcephaly is also a feature of some chromosomal disorders (trisomies, deletions, and translocations), neurocutaneous disorders (incontinentia pigmenti), neural tube defects, and disorders of cerebral cleavage and migration.

Secondary microcephaly typically results from an insult that occurs during the last part of the third trimester or during the perinatal or early postnatal period. Several environmental factors have been implicated, including irradiation, congenital/intrauterine infections,18 in utero toxin exposures (alcohol, substance use,19 anticonvulsant medications,20 organic substances), hypoxic-ischemic insults, placental insufficiency, intraventricular hemorrhage or stroke,21 untreated maternal phenylketonuria,22 or systemic disease. The degree of mental retardation is thought to correlate directly with the severity of microcephaly.23

Evaluation and Workup of Abnormal Head Size

The evaluation for abnormal head size should be prompted by one head circumference measurement that is two standard deviations above or below the norm for age and gender, or when serial measurements reveal progressive changes on standard charts. A detailed medical history is important, including birth, prenatal, and developmental history, as this may elicit predisposing factors, such as maternal infection, substance use, maternal medical history and medication use, and perinatal complications. This may also help determine the time of onset. In addition, family history may reveal the occurrence of underlying neurocutaneous disorders or metabolic abnormalities. Physical examination includes measurement of head circumference and comparison to prior measurements, evaluation of the anterior fontanel, evaluation for hypo- or hyperpigmented lesions (aided by the use of a Wood’s lamp), evaluation for dysmorphic features, organomegaly (indicative of storage disease), and cataracts or retinal abnormalities. Neurologic evaluation is important to evaluate for accompanying developmental, neuromuscular, or accompanying reflex abnormalities. The head circumference should be plotted on a standard curve and compared to prior measurements to help distinguish acute onset from a more insidious development (Fig. 550-2). CDC head circumference growth charts for boys and girls are available at: http://www.cdc.gov/growthcharts/charts.htm (accessed Sept. 19, 2010). WHO head circumference growth tables are available at: http://www.cdc.gov/growthcharts/who_charts.htm. The standard scores for the child and parents should be plotted to determine any genetic contribution to the macrocephaly, such as benign familial macrocephaly. It is important to recognize this syndrome in order to avoid potential costly and unnecessary evaluations.

Diagnostic testing should be considered if abnormal development is noted or with plateau or loss of developmental milestones. Imaging studies may include ultrasound or magnetic resonance imaging of the brain to delineate structural or migrational abnormalities.24,25 Additional vascular studies or plain radiographs may be indicated to evaluate possible skeletal disturbance or growth abnormalities. Laboratory and metabolic investigations should be guided by the history and physical examination. For example, children with loss of developmental milestones may require metabolic evaluation, chromosomal studies, or an electroencephalogram. Evaluation of urine or blood samples for amino- and organic acidurias and/or evaluation for congenital infection may be indicated. Subsequent therapy for macrocephaly or microcephaly depends on the underlying etiology.