Etiology

The cause of myelomeningocele is unknown, but as with all neural tube closure defects including anencephaly, a genetic predisposition exists; the risk of recurrence after one affected child is 3-4% and increases to 10% with 2 prior affected children. Both epidemiologic evidence and the presence of substantial familial aggregation of anencephaly, myelomeningocele, and craniorachischisis indicate heredity, on a polygenic basis, as a significant contributor to the etiology of NTDs. Nutritional and environmental factors have a role in the etiology of myelomeningocele as well.

Folate is intricately involved in the prevention and etiology of NTDs. Folate functions in single-carbon transfer reactions and exists in many chemical forms. Folic acid (pteroylmonoglutamic acid), which is the most oxidized and stable form of folate, occurs rarely in food but is the form used in vitamin supplements and in fortified food products, particularly flour. Most naturally occurring folates (food folate) are pteroylpolyglutamates, which contain 1-6 additional glutamate molecules joined in a peptide linkage to the γ-carboxyl of glutamate. Folate coenzymes are involved in DNA synthesis, purine synthesis, generation of formate into the formate pool, and amino acid interconversion; the conversion of homocysteine to methionine provides methionine for the synthesis of S-adenosyl-methionine (SAM-e, an agent important for in vivo methylation). Mutations in the genes encoding the enzymes involved in homocysteine metabolism include 5,10 methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase, and methionine synthase. An association between a thermolabile variant of MTHFR and mothers of children with NTDs might account for up to 15% of preventable NTDs. Maternal periconceptional use of folic acid supplementation reduces the incidence of NTDs in pregnancies at risk by at least 50%. To be effective, folic acid supplementation should be initiated before conception and continued until at least the 12th wk of gestation, when neurulation is complete. The mechanisms by which folic acid prevents NTDs remain poorly understood.

Prevention

The U.S. Public Health Service has recommended that all women of childbearing age and who are capable of becoming pregnant take 0.4 mg of folic acid daily. If, however, a pregnancy is planned in high-risk women (previously affected child), supplementation should be started with 4 mg of folic acid daily, beginning 1 mo before the time of the planned conception. The modern diet provides about half the daily requirement of folic acid. To increase folic acid intake, fortification of flour, pasta, rice, and cornmeal with 0.15 mg folic acid per 100 g was mandated in the United States and Canada in 1998. The added folic acid will be insufficient to maximize the prevention of preventable NTDs. Therefore, informative educational programs and folic acid vitamin supplementation remain essential for women planning a pregnancy and possibly for all women of childbearing age. In addition, women should also strive to consume food folate from a varied diet. Certain drugs, including drugs that antagonize folic acid, such as trimethoprim and the anticonvulsants carbamazepine, phenytoin, phenobarbital, and primidone, increase the risk of myelomeningocele. The anticonvulsant valproic acid causes NTDs in approximately 1-2% of pregnancies when administered during pregnancy. Some epilepsy clinicians recommend that all female patients of childbearing potential who take anticonvulsant medications also receive folic acid supplements.

Clinical Manifestations

Myelomeningocele produces dysfunction of many organs and structures, including the skeleton, skin, and gastrointestinal and genitourinary tracts, in addition to the peripheral nervous system and the CNS. A myelomeningocele may be located anywhere along the neuraxis, but the lumbosacral region accounts for at least 75% of the cases. The extent and degree of the neurologic deficit depend on the location of the myelomeningocele and the associated lesions. A lesion in the low sacral region causes bowel and bladder incontinence associated with anesthesia in the perineal area but with no impairment of motor function. Newborns with a defect in the midlumbar or high lumbothoracic region typically have either a saclike cystic structure covered by a thin layer of partially epithelialized tissue (Fig. 585-4) or an exposed flat neural placode without overlying tissues. When a cyst or membrane is present, remnants of neural tissue are visible beneath the membrane, which occasionally ruptures and leaks CSF, whereas the placode is composed of neural tissue.

Figure 585-4 A lumbar myelomeningocele is covered by a thin layer of skin.

Examination of the infant shows a flaccid paralysis of the lower extremities, an absence of deep tendon reflexes, a lack of response to touch and pain, and a high incidence of lower extremity deformities (clubfeet, ankle and/or knee contractures, and subluxation of the hips). Some children have constant urinary dribbling and a relaxed anal sphincter. Other children do not leak urine and in fact have a high-pressure bladder and sphincter dyssynergy. Thus, a myelomeningocele above the midlumbar region tends to produce lower motor neuron signs due to abnormalities and disruption of the conus medullaris and above spinal cord structures.

Infants with myelomeningocele typically have an increasing neurologic deficit as the myelomeningocele extends higher into the thoracic region. These infants sometimes have an associated kyphotic gibbus that requires neonatal orthopedic correction. Patients with a myelomeningocele in the upper thoracic or cervical region usually have a very minimal neurologic deficit and, in most cases, do not have hydrocephalus. They can have neurogenic bladder and bowel.

Hydrocephalus in association with a type II Chiari malformation develops in at least 80% of patients with myelomeningocele. Generally, the lower the deformity is in the neuraxis (sacrum), the less likely is the risk of hydrocephalus. The possibility of hydrocephalus developing should always be considered, no matter what the spinal level. Ventricular enlargement may be indolent and slow growing or may be rapid causing a bulging anterior fontanel, dilated scalp veins, setting-sun appearance of the eyes, irritability, and vomiting associated with an increased head circumference. About 15% of infants with hydrocephalus and Chiari II malformation develop symptoms of hindbrain dysfunction, including difficulty feeding, choking, stridor, apnea, vocal cord paralysis, pooling of secretions, and spasticity of the upper extremities, which, if untreated, can lead to death. This Chiari crisis is due to downward herniation of the medulla and cerebellar tonsils through the foramen magnum as well is endogenous malformations in the cerebellum and brainstem.

Treatment

Management and supervision of a child and family with a myelomeningocele require a multidisciplinary team approach, including surgeons, physicians, and therapists, with one individual (often a pediatrician) acting as the advocate and coordinator of the treatment program. The news that a newborn child has a devastating condition such as myelomeningocele causes parents to feel considerable grief and anger. They need time to learn about the handicap and the associated complications and to reflect on the various procedures and treatment plans. A knowledgeable individual in an unhurried and nonthreatening setting must give the parents the facts, along with general prognostic information and management strategies and timelines. If possible, discussions with other parents of children with NTDs are helpful in resolving important questions and issues.

Surgery is often done within a day or so of birth but can be delayed for several days (except when there is a CSF leak) to allow the parents time to begin to adjust to the shock and to prepare for the multiple procedures and inevitable problems that lie ahead. Evaluation of other congenital anomalies and renal function can also be initiated before surgery. Most pediatric centers aggressively treat the majority of infants with myelomeningocele. After repair of a myelomeningocele, most infants require a shunting procedure for hydrocephalus. If symptoms or signs of hindbrain dysfunction appear, early surgical decompression of the posterior fossa is indicated. Clubfeet can require taping or casting, and dislocated hips can require operative procedures.

Careful evaluation and reassessment of the genitourinary system are some of the most important components of the management. Teaching the parents, and ultimately the patient, to regularly catheterize a neurogenic bladder is a crucial step in maintaining a low residual volume and bladder pressure that prevents urinary tract infections and reflux leading to pyelonephritis, hydronephrosis, and bladder damage. Latex-free catheters and gloves must be used to prevent development of latex allergy. Periodic urine cultures and assessment of renal function, including serum electrolytes and creatinine as well as renal scans, vesiculourethrograms (VCUGs), renal ultrasonography, and cystometrograms (CMGs), are obtained according to the risk status and progress of the patient and the results of the physical examination. This approach to urinary tract management has greatly reduced the need for urologic diversionary procedures and significantly decreased the morbidity and mortality associated with progressive renal disease in these patients. Some children can become continent with surgical implantation of an artificial urinary sphincter (these are used less often) or bladder augmentation at a later age.

Although incontinence of fecal matter is common and is socially unacceptable during the school years, it does not pose the same organ-damaging risks as urinary dysfunction, but occasionally fecal impaction and/or megacolon develop. Many children can be bowel-trained with a regimen of timed enemas or suppositories that allows evacuation at a predetermined time once or twice a day. Special attention to low anorectal tone and enema administration and retention is often required. Appendicostomy for antegrade enemas may also be helpful (Chapter 21.4).

Functional ambulation is the wish of each child and parent and may be possible, depending on the level of the lesion and on intact function of the iliopsoas muscles. Almost every child with a sacral or lumbosacral lesion obtains functional ambulation; approximately half the children with higher defects ambulate with the use of braces, other orthotic devices, and canes. Ambulation is often more difficult as adolescence approaches and body mass increases. Deterioration of ambulatory function, particularly during earlier years, should prompt referral for evaluation of tethered spinal cord and other neurosurgical issues.

In utero surgical closure of a spinal lesion has been successful in a few centers. Preliminary reports suggest a lower incidence of hindbrain abnormalities and hydrocephalus (fewer shunts) as well as improved motor outcomes. This suggests that the defects may be progressive in utero and that prenatal closure might prevent the development of further loss of function. In utero diagnosis is facilitated by maternal serum α-fetoprotein screening and by fetal ultrasonography (Chapter 90).

Prognosis

For a child who is born with a myelomeningocele and who is treated aggressively, the mortality rate is 10-15%, and most deaths occur before age 4 yr, although life-threatening complications occur at all ages. At least 70% of survivors have normal intelligence, but learning problems and seizure disorders are more common than in the general population. Previous episodes of meningitis or ventriculitis adversely affect intellectual and cognitive function. Because myelomeningocele is a chronic disabling condition, periodic multidisciplinary follow-up is required for life. Renal dysfunction is one of the most important determinants of mortality.

Lissencephaly

Lissencephaly, or agyria, is a rare disorder that is characterized by the absence of cerebral convolutions and a poorly formed sylvian fissure, giving the appearance of a 3-4 mo fetal brain. The condition is probably a result of faulty neuroblast migration during early embryonic life and is usually associated with enlarged lateral ventricles and heterotopias in the white matter. In some forms, there is a four-layered cortex, rather than the usual six-layered one, with a thin rim of periventricular white matter and numerous gray heterotopias visible by microscopic examination.

These infants present with failure to thrive, microcephaly, marked developmental delay, and a severe seizure disorder. Ocular abnormalities are common, including hypoplasia of the optic nerve and microphthalmia. Lissencephaly can occur as an isolated finding, but it is associated with Miller-Dieker syndrome (MDS) in about 15% of cases. These children have characteristic facies, including a prominent forehead, bitemporal hollowing, anteverted nostrils, a prominent upper lip, and micrognathia. About 90% of children with MDS have visible or submicroscopic chromosomal deletions of 17p13.3.

The gene LIS-1 (lissencephaly 1) that maps to chromosome region 17p13.3 is deleted in patients with MDS. CT and MRI scans typically show a smooth brain with an absence of sulci (Fig. 585-6). Doublecortin is an X chromosome gene that causes lissencephaly when mutated in males and subcortical band heterotopia when mutated in females. Other important forms of lissencephaly include the Walker-Warburg variant and other cobblestone cortical malformations.

Figure 585-6 MRI of an infant with lissencephaly. Note the absence of cerebral sulci and the maldeveloped sylvian fissures associated with enlarged ventricles.

Schizencephaly

Schizencephaly is the presence of unilateral or bilateral clefts within the cerebral hemispheres owing to an abnormality of morphogenesis (Fig. 585-7). The cleft may be fused or unfused and, if unilateral and large, may be confused with a porencephalic cyst. Not infrequently, the borders of the cleft are surrounded by abnormal brain, particularly microgyria. MRI is the study of choice for elucidating schizencephaly and associated malformations.

Figure 585-7 Unilateral schizencephaly shown on axial MR images of the brain. Example of an open-lip schizencephaly with a cleft communicating between the ventricle and the extra-axial cranial space (arrow on left panel). Many of these clefts are lined with abnormal gray matter (arrow on right panel).

Many patients are severely mentally retarded, with seizures that are difficult to control, and microcephalic, with spastic quadriparesis when the clefts are bilateral. Some cases of bilateral schizencephaly are associated with septo-optic dysplasia and endocrinologic disorders. Unilateral schizencephaly is a common cause of congenital hemiparesis. It remains controversial whether genetic causes of schizencephaly exist.

Neuronal Heterotopias

Subtypes of neuronal heterotopias include periventricular nodular heterotopias, subcortical heterotopia (including band-type), and marginal glioneuronal heterotopias. Intractable seizures are a common feature. Several genes have been identified that are a cause of these conditions.

Polymicrogyrias

Polymicrogyria is characterized by an augmentation of small convolutions separated by shallow enlarged sulci. Epilepsy, including drug-resistant forms, is a common feature. Several genes have been identified that cause several of the forms of this condition.

Focal Cortical Dysplasias

Focal cortical dysplasias consist of abnormal cortical lamination in a discrete area of cortex. High-resolution, thin-section MRI can reveal these areas sometimes in the setting of drug-resistant epilepsy.

Porencephaly

Porencephaly is the presence of cysts or cavities within the brain that result from developmental defects or acquired lesions, including infarction of tissue. True porencephalic cysts are most commonly located in the region of the sylvian fissure and typically communicate with the subarachnoid space, the ventricular system, or both. They represent developmental abnormalities of cell migration and are often associated with other malformations of the brain, including microcephaly, abnormal patterns of adjacent gyri, and encephalocele. Affected infants tend to have many problems, including mental retardation, spastic hemiparesis or quadriparesis, optic atrophy, and seizures.

Several risk factors for porencephalic cyst formation have been identified including: hemorrhagic venous infarctions, various thrombophilias such as protein C deficiency and factor V Leiden mutations, perinatal alloimmune thrombocytopenia, von Willebrand’s disease, maternal warfarin use, maternal cocaine use, congenital infections, trauma such as amniocentesis, and maternal abdominal trauma. Mutations in the COL4A1 gene have been described in cases of familial porencephaly.

Pseudoporencephalic cysts characteristically develop during the perinatal or postnatal period and result from abnormalities (infarction, hemorrhage) of arterial or venous circulation. These cysts tend to be unilateral, do not communicate with a fluid-filled cavity, and are not associated with abnormalities of cell migration or CNS malformations. Infants with pseudoporencephalic cysts present with hemiparesis and focal seizures in the 1st year of life and sometimes present with neonatal encephalopathy or as a floppy newborn or infant.

Holoprosencephaly

Holoprosencephaly is a developmental disorder of the brain that results from defective formation of the prosencephalon and inadequate induction of forebrain structures. The abnormality, which represents a spectrum of severity, is classified into 3 groups: alobar, semilobar, and lobar, depending on the degree of the cleavage abnormality (Fig. 585-9). A fourth type, the middle interhemispheric fusion (MIHF) variant or syntelencephaly, involves a segmental area of noncleavage, actually a nonseparation, of the posterior frontal and parietal lobes. Facial abnormalities including cyclopia, synophthalmia, cebocephaly, single nostril, solitary central incisor tooth, and premaxillary agenesis are common in severe cases, because the prechordal mesoderm that induces the ventral prosencephalon is also responsible for induction of the median facial structures. Alobar holoprosencephaly is characterized by a single ventricle, an absent falx, and nonseparated deep cerebral nuclei. Care must be taken not to overdiagnose holoprosencephaly based on ventricular abnormalities alone. Evidence of nonseparated midline deep brain structures such as caudate, putamen, globus pallidus, and hypothalamus is the critical element for diagnosis.

Figure 585-9 Lobar holoprosencephaly. T1-weighted MRI scan demonstrates failure of separation of the hemispheres and a persistent fused ventricle.

Affected children with the alobar type have high mortality rates, but some live for years. Mortality and morbidity with milder types are more variable, and morbidity is less severe. Care must be taken not to prognosticate severe outcomes in all cases. The incidence of holoprosencephaly ranges from 1/5,000 to 1/16,000. A prenatal diagnosis can be confirmed by ultrasonography after the 10th wk of gestation for more severe types, but fetal MRI at later gestational ages gives far greater anatomic precision.

The cause of holoprosencephaly is often not identified. There appears to be an association with maternal diabetes. Chromosomal abnormalities, including deletions of chromosomes 7q and 3p, 21q, 2p, 18p, and 13q, as well as trisomy 13 and 18, account for upwards of 50% of all cases. Mutations in the sonic hedgehog gene at 7q have been shown to cause holoprosencephaly. OMIM lists 10 loci and 6 single-gene causes. Clinically, it is important to look for associated anomalies, because many syndromes are associated with holoprosencephaly.

Congenital Cranial Dysinnervation Disorders

Absence of the cranial nerves or the corresponding central nuclei has been described in several conditions and includes the optic nerve, congenital ptosis, Marcus Gunn phenomenon (sucking jaw movements causing simultaneous eyelid blinking; this congenital synkinesis results from abnormal innervation of the trigeminal and oculomotor nerves), the trigeminal and auditory nerves, and cranial nerves IX, X, XI, and XII. Increased understanding of these disorders and their genetic causes has led to the term congenital cranial dysinnervation disorders (CCDD).

Optic nerve hypoplasia can occur in isolation or as part of the septo-optic dysplasia complex (De Morsier syndrome). Septo-optic dysplasia can be caused by a mutation in the HESX1 gene.

Möbius syndrome is characterized by bilateral facial weakness, which is often associated with paralysis of the abducens nerve. Hypoplasia or agenesis of brainstem nuclei as well as absent or decreased numbers of muscle fibers has been reported. Affected infants present in the newborn period with facial weakness, causing feeding difficulties owing to a poor suck. The immobile, dull facies might give the incorrect impression of mental retardation; the prognosis for normal development is excellent in most cases. The facial appearance of Möbius syndrome has been improved by facial surgery.

Duane retraction syndrome is characterized by congenital limitation of horizontal globe movement and some globe retraction on attempted adduction and is believed to be the result of abnormal innervations by the oculomotor nerve of the lateral rectus muscle. Abnormalities of cranial nerve development have been demonstrated in this condition.

Less common than Duane retraction syndrome and Möbius syndrome are the group of disorders known as congenital fibrosis of the extraocular muscles (CFEOM). CFEOM is characterized by severe restriction of eye movements and ptosis from abnormal oculomotor and trochlear nerve development and/or from abnormalities of extraocular muscle innervations.

Brainstem and Cerebellar Disorders

Disorders of the posterior fossa structures include abnormalities of not only the brainstem and cerebellum but also the cerebrospinal fluid spaces. Commonly encountered malformations include Chiari malformation, Dandy-Walker malformation, arachnoid cysts, mega cistern magna, persisting Blake pouch, Joubert syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, and pontocerebellar hypoplasias.

Chiari malformation is the most common malformation of the posterior fossa and hindbrain. It consists of herniation of the cerebellar tonsils though the foramen magnum. There is also an associated developmental abnormality of the bones of the skull base leading to a small posterior fossa. Cases are either asymptomatic or symptomatic. When symptoms develop, they often do not do so until late childhood. Symptoms include headaches that are worse with straining and other maneuvers that increase intracranial pressure. Symptoms of brainstem compression such as diplopia, oropharyngeal dysfunction, tinnitus, and vertigo can occur. Obstructive hydrocephalus and/or syringomyelia can also occur.

Dandy-Walker malformation is part of a continuum of posterior fossa anomalies that include cystic dilatation of the fourth ventricle, hypoplasia of the cerebellar vermis, hydrocephalus, and an enlarged posterior fossa with elevation of the lateral venous sinuses and the tentorium. Extracranial anomalies are also seen. Variable degrees of neurologic impairment are usually present. The etiology of Dandy-Walker malformation includes chromosomal abnormalities, single gene disorders, and exposure to teratogens.

Arachnoid cysts of the posterior fossa can be associated with hydrocephalus. Mega cistern magna is characterized by an enlarged CSF space inferior and dorsal to the cerebellar vermis and when present in isolation may be considered a normal variant. Persisting Blake pouch is a cyst that obstructs the subarachnoid space and is associated with hydrocephalus.

Joubert syndrome is an autosomal recessive disorder with significant genetic heterogeneity that is associated with cerebellar vermis hypoplasia and the pontomesencephalic molar tooth sign (a deepening of the interpeduncular fossa with thick and straight superior cerebellar peduncles). It is associated with hypotonia, ataxia, characteristic breathing abnormalities including episodic apnea and hyperpnea, global developmental delay, nystagmus, strabismus, and oculomotor apraxia. There can be many associated systemic features including progressive retinal dysplasia, coloboma, congenital heart disease, microcystic kidney disease, liver fibrosis, polydactyly, tongue protrusion, and soft tissue tumors of the tongue.

Rhombencephalosynapsis is an absent or small vermis associated with a nonseparation or fusion of the deep midline cerebellar structures. Ventriculomegaly or hydrocephalus is often seen. There is variable clinical presentation from normal to cognitive and language impairments, epilepsy, and spasticity. Lhermitte-Duclos disease is a dysplastic gangliocytoma of the cerebellum leading to focal enlargement of the cerebellum and macrocephaly, cerebellar signs, and seizures.

Pontocerebellar hypoplasias are a group of disorders characterized by impairment of cerebellar and pontine development together with histopathologic features of neuronal death and glial replacement. Clinical features tend to be nonspecific and include hypotonia, feeding difficulties, developmental delay, and breathing difficulties. Causes include type I (with features of anterior horn cell involvement), type II (with extrapyramidal features, seizures, and acquired microcephaly), Walker-Warburg syndrome, muscle-eye-brain disease, congenital disorders of glycosylation type 1A, mitochondrial cytopathies, teratogen exposure, congenital cytomegalovirus (CMV) infection, 3-methylglutaconic aciduria, PEHO syndrome (progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy), autosomal recessive cerebellar hypoplasia in the Hutterite population, lissencephaly with cerebellar hypoplasia, and other subtypes of pontocerebellar hypoplasia.

Etiology

Primary microcephaly refers to a group of conditions that usually have no associated malformations and follow a mendelian pattern of inheritance or are associated with a specific genetic syndrome. Affected infants are usually identified at birth because of a small head circumference. The more common types include familial and autosomal dominant microcephaly and a series of chromosomal syndromes that are summarized in Table 585-2. Primary microcephaly is also associated with at least 7 loci, and 4 single etiologic genes have been identified. It is known as autosomal recessive primary microcephaly (MCPH) and has autosomal inheritance. Many X-linked causes of microcephaly are caused by gene mutations that lead to severe structural brain malformations such as lissencephaly, and these should be sought on MRI. Secondary microcephaly results from a large number of noxious agents that can affect a fetus in utero or an infant during periods of rapid brain growth, particularly the 1st 2 yr of life.

Table 585-2 CAUSES OF MICROCEPHALY

Acquired microcephaly can be seen in conditions such as Rett syndrome and in genetic conditions known also to cause primary microcephaly.

Clinical Manifestations and Diagnosis

A thorough family history should be taken, seeking additional cases of microcephaly or disorders affecting the nervous system. It is important to measure a patient’s head circumference at birth to diagnose microcephaly as early as possible. A very small head circumference implies a process that began early in embryonic or fetal development. An insult to the brain that occurs later in life, particularly beyond the age of 2 yr, is less likely to produce severe microcephaly. Serial head circumference measurements are more meaningful than a single determination, particularly when the abnormality is minimal. The head circumference of each parent and sibling should be recorded.

Laboratory investigation of a microcephalic child is determined by the history and physical examination. If the cause of the microcephaly is unknown, the mother’s serum phenylalanine level should be determined. High phenylalanine serum levels in an asymptomatic mother can produce marked brain damage in an otherwise normal nonphenylketonuric infant. A karyotype and/or array-comparative genomic hybridization (array-CGH) study is obtained if a chromosomal syndrome is suspected or if the child has abnormal facies, short stature, and additional congenital anomalies. MRI is useful in identifying structural abnormalities of the brain such as lissencephaly, pachygyria, and polymicrogyria, and CT scanning is useful to detect intracerebral calcification. Additional studies include a fasting plasma and urine amino acid analysis; serum ammonia determination; toxoplasmosis, rubella, cytomegalovirus, and herpes simplex (TORCH) titers as well as HIV testing of the mother and child; and a urine sample for the culture of cytomegalovirus. Single gene mutations as a cause of both primary microcephaly and syndromic microcephaly are being increasingly identified.

Treatment

Once the cause of microcephaly has been established, the physician must provide accurate and supportive genetic and family counseling. Because many children with microcephaly are also mentally retarded, the physician must assist with placement in an appropriate program that will provide for maximal development of the child (Chapter 33).

Physiology

The CSF is formed primarily in the ventricular system by the choroid plexus, which is situated in the lateral, 3rd, and 4th ventricles. Although most CSF is produced in the lateral ventricles, approximately 25% originates from extrachoroidal sources, including the capillary endothelium within the brain parenchyma. There is active neurogenic control of CSF formation because adrenergic and cholinergic nerves innervate the choroid plexus. Stimulation of the adrenergic system diminishes CSF production, whereas excitation of the cholinergic nerves can double the normal CSF production rate. In a normal child, about 20 mL/hr of CSF is produced. The total volume of CSF approximates 50 mL in an infant and 150 mL in an adult. Most of the CSF is extraventricular. The choroid plexus forms CSF in several stages; through a series of intricate steps, a plasma ultrafiltrate is ultimately processed into a secretion, the CSF.

CSF flow results from the pressure gradient that exists between the ventricular system and venous channels. Intraventricular pressure may be as high as 180 mm H₂O in the normal state, whereas the pressure in the superior sagittal sinus is in the range of 90 mm H₂O. Normally, CSF flows from the lateral ventricles through the foramina of Monro into the 3rd ventricle. It then traverses the narrow aqueduct of Sylvius, which is about 3 mm long and 2 mm in diameter in a child, to enter the 4th ventricle. The CSF exits the 4th ventricle through the paired lateral foramina of Luschka and the midline foramen of Magendie into the cisterns at the base of the brain. Hydrocephalus resulting from obstruction within the ventricular system is called obstructive or noncommunicating hydrocephalus. The CSF then circulates from the basal cisterns posteriorly through the cistern system and over the convexities of the cerebral hemispheres. CSF is absorbed primarily by the arachnoid villi through tight junctions of their endothelium by the pressure forces that were noted earlier. CSF is absorbed to a much lesser extent by the lymphatic channels directed to the paranasal sinuses, along nerve root sleeves, and by the choroid plexus itself. Hydrocephalus resulting from obliteration of the subarachnoid cisterns or malfunction of the arachnoid villi is called nonobstructive or communicating hydrocephalus.

Pathophysiology and Etiology

Obstructive or noncommunicating hydrocephalus develops most commonly in children because of an abnormality of the aqueduct or a lesion in the 4th ventricle. Aqueductal stenosis results from an abnormally narrow aqueduct of Sylvius that is often associated with branching or forking. In a small percentage of cases, aqueductal stenosis is inherited as a sex-linked recessive trait. These patients occasionally have minor neural tube closure defects, including spina bifida occulta. Rarely, aqueductal stenosis is associated with neurofibromatosis. Aqueductal gliosis can also give rise to hydrocephalus. As a result of neonatal meningitis or a subarachnoid hemorrhage in a premature infant, the ependymal lining of the aqueduct is interrupted and a brisk glial response results in complete obstruction. Intrauterine viral infections can also produce aqueductal stenosis followed by hydrocephalus, and mumps meningoencephalitis has been reported as a cause in a child. A vein of Galen malformation can expand to become large and, because of its midline position, obstruct the flow of CSF. Lesions or malformations of the posterior fossa are prominent causes of hydrocephalus, including posterior fossa brain tumors, Chiari malformation, and the Dandy-Walker syndrome.

Nonobstructive or communicating hydrocephalus most commonly follows a subarachnoid hemorrhage, which is usually a result of intraventricular hemorrhage in a premature infant. Blood in the subarachnoid spaces can cause obliteration of the cisterns or arachnoid villi and obstruction of CSF flow. Pneumococcal and tuberculous meningitis have a propensity to produce a thick, tenacious exudate that obstructs the basal cisterns, and intrauterine infections can also destroy the CSF pathways. Leukemic infiltrates can seed the subarachnoid space and produce communicating hydrocephalus.

Clinical Manifestations

The clinical presentation of hydrocephalus is variable and depends on many factors, including the age at onset, the nature of the lesion causing obstruction, and the duration and rate of increase of the intracranial pressure (ICP). In an infant, an accelerated rate of enlargement of the head is the most prominent sign. In addition, the anterior fontanel is wide open and bulging, and the scalp veins are dilated. The forehead is broad, and the eyes might deviate downward because of impingement of the dilated suprapineal recess on the tectum, producing the setting-sun eye sign. Long-tract signs including brisk tendon reflexes, spasticity, clonus (particularly in the lower extremities), and Babinski sign are common owing to stretching and disruption of the corticospinal fibers originating from the leg region of the motor cortex. In an older child, the cranial sutures are partially closed so that the signs of hydrocephalus may be subtler. Irritability, lethargy, poor appetite, and vomiting are common to both age groups, and headache is a prominent symptom in older patients. A gradual change in personality and deterioration in academic productivity suggest a slowly progressive form of hydrocephalus. With regard to other clinical signs, serial measurements of the head circumference often indicate an increased velocity of growth. Percussion of the skull might produce a cracked pot sound or MacEwen’s sign, indicating separation of the sutures. A foreshortened occiput suggests Chiari malformation, and a prominent occiput suggests the Dandy-Walker malformation. Papilledema, abducens nerve palsies, and pyramidal tract signs, which are most evident in the lower extremities, are apparent in many cases.

Chiari malformation consists of two major subgroups. Type I typically produces symptoms during adolescence or adult life and is usually not associated with hydrocephalus. Patients complain of recurrent headache, neck pain, urinary frequency, and progressive lower extremity spasticity. The deformity consists of displacement of the cerebellar tonsils into the cervical canal (Fig. 585-10). Although the pathogenesis is unknown, a prevailing theory suggests that obstruction of the caudal portion of the 4th ventricle during fetal development is responsible. Other theories include tethering of the cord or additional anomalies (syrinx).

Figure 585-10 Sagittal MR scan of a patient with Chiari malformation type I. Cerebellar tonsils are displaced through the foramen magnum (white bar) to the lower aspect of C2 with clear crowding at the foramen. A syrinx (white asterisk) is visible extending from C3 to T2.

(From Yassari R, Frim D: Evaluation and management of the Chiari malformation type 1 for the primary care pediatrician, Pediatr Clin North Am 51:477–490, 2004.)

The type II Chiari malformation is characterized by progressive hydrocephalus with a myelomeningocele. This lesion represents an anomaly of the hindbrain, probably owing to a failure of pontine flexure during embryogenesis, and results in elongation of the 4th ventricle and kinking of the brainstem, with displacement of the inferior vermis, pons, and medulla into the cervical canal (Fig. 585-11). Approximately 10% of type II malformations produce symptoms during infancy, consisting of stridor, weak cry, and apnea, which may be relieved by shunting or by decompression of the posterior fossa. A more indolent form consists of abnormalities of gait, spasticity, and increasing incoordination during childhood.

Figure 585-11 A midsagittal T1-weighted MRI of a patient with type II Chiari malformation. The cerebellar tonsils (white arrow) have descended below the foramen magnum (black arrow). Note the small, slitlike 4th ventricle, which has been pulled into a vertical position.

Plain skull radiographs show a small posterior fossa and a widened cervical canal. CT scanning with contrast and MRI display the cerebellar tonsils protruding downward into the cervical canal and the hindbrain abnormalities. The anomaly is treated by surgical decompression, but asymptomatic or mildly symptomatic patients may be managed conservatively.

The Dandy-Walker malformation consists of a cystic expansion of the 4th ventricle in the posterior fossa and midline cerebellar hypoplasia, which results from a developmental failure of the roof of the 4th ventricle during embryogenesis (Fig. 585-12). Approximately 90% of patients have hydrocephalus, and a significant number of children have associated anomalies, including agenesis of the posterior cerebellar vermis and corpus callosum. Infants present with a rapid increase in head size and a prominent occiput. Transillumination of the skull may be positive. Most children have evidence of long-tract signs, cerebellar ataxia, and delayed motor and cognitive milestones, probably due to the associated structural anomalies. The Dandy-Walker malformation is managed by shunting the cystic cavity (and on occasion the ventricles as well) in the presence of hydrocephalus.

Figure 585-12 Dandy-Walker cyst. A, Axial CT scan (preoperative) showing large posterior fossa cyst (Dandy-Walker cyst; large arrows) and dilated lateral ventricles (small arrows), a complication secondary to cerebrospinal fluid (CSF) pathway obstruction at the 4th ventricular outlet. B, Same patient, with a lower axial CT scan showing splaying of the cerebellar hemispheres by the dilated 4th ventricle (Dandy-Walker cyst). The dilated ventricles proximal to the 4th ventricle again show CSF obstruction caused by the Dandy-Walker cyst. C, MRI of the same patient showing decreased size of the Dandy-Walker cyst and temporal horns (arrows) after shunting. The incomplete vermis (small arrow) now becomes recognizable.

Diagnosis and Differential Diagnosis

Investigation of a child with hydrocephalus begins with the history. Familial cases suggest X-linked or autosomal hydrocephalus secondary to aqueductal stenosis. A past history of prematurity with intracranial hemorrhage, meningitis, or mumps encephalitis is important to ascertain. Multiple café-au-lait spots and other clinical features of neurofibromatosis point to aqueductal stenosis as the cause of hydrocephalus.

Examination includes careful inspection, palpation, and auscultation of the skull and spine. The occipitofrontal head circumference is recorded and compared with previous measurements. The size and configuration of the anterior fontanel are noted, and the back is inspected for abnormal midline skin lesions, including tufts of hair, lipoma, or angioma that might suggest spinal dysraphism. The presence of a prominent forehead or abnormalities in the shape of the occiput can suggest the pathogenesis of the hydrocephalus. A cranial bruit is audible in association with many cases of vein of Galen arteriovenous malformation. Transillumination of the skull is positive with massive dilatation of the ventricular system or in the Dandy-Walker syndrome. Inspection of the eyegrounds is mandatory because the finding of chorioretinitis suggests an intrauterine infection, such as toxoplasmosis, as a cause of the hydrocephalus. Papilledema is observed in older children but is rarely present in infants because the cranial sutures separate as a result of the increased pressure.

Plain skull films typically show separation of the sutures, erosion of the posterior clinoids in an older child, and an increase in convolutional markings (beaten-silver appearance) with long-standing increased ICP. The CT scan and/or MRI along with ultrasonography in an infant are the most important studies to identify the specific cause and severity of hydrocephalus.

The head might appear enlarged and can be confused with hydrocephalus secondary to a thickened cranium resulting from chronic anemia, rickets, osteogenesis imperfecta, and epiphyseal dysplasia. Chronic subdural collections can produce bilateral parietal bone prominence. Various metabolic and degenerative disorders of the CNS produce megalencephaly due to abnormal storage of substances within the brain parenchyma. These disorders include lysosomal diseases (Tay-Sachs, gangliosidosis, and the mucopolysaccharidoses), the aminoacidurias (maple syrup urine disease), and the leukodystrophies (metachromatic leukodystrophy, Alexander disease, Canavan disease). In addition, cerebral gigantism and neurofibromatosis are characterized by increased brain mass. Familial megalencephaly is inherited as an autosomal dominant trait and is characterized by delayed motor milestones and hypotonia but normal or near-normal intelligence. Measurement of parents’ head circumferences is necessary to establish the diagnosis.

Megalencephaly

Megalencephaly is an anatomic disorder of brain growth defined as a brain weight:volume ratio >98th percentile for age (or ≥2 standard deviations [SD] above the mean) that is usually accompanied by macrocephaly (an occipitofrontal circumference [OFC] >98th percentile). Various storage and degenerative diseases are associated with megalencephaly, but anatomic and genetic causes exist as well. The most common cause of anatomic megalencephaly is benign familial megalencephaly. This condition is easily diagnosed by careful family history and measurement of the parents’ head circumferences (OFCs). On the other hand, in >100 syndromes macrocephaly a known feature.

Anatomic megalencephaly is usually apparent at birth, and head growth continues to run parallel to the upper percentiles. Sometimes, in some syndromes, increased OFC is the presenting sign. Neuroimaging is critical in identifying the various structural and gyral abnormalities seen in syndromic macrocephaly and determining whether anatomic megalencephaly exists.

Common megalencephaly-associated macrocephaly syndromes include syndromes with prenatal and/or postnatal somatic overgrowth such as Sotos, Simpson-Golabi-Behmel, fragile X, Weaver, M-CMTC, and Bannayan-Ruvalcaba-Riley syndromes and syndromes without somatic overgrowth such as FG, Greig cephalopolysyndactyly, acrocallosal, and Gorlin syndromes.

Sotos syndrome (cerebral gigantism) is the most common megalencephalic syndrome, with 50% of patients having prenatal macrocephaly and 100% of patients having macrocephaly by age 1 yr. Early postnatal overgrowth normalizes by adulthood. Facial features include high forehead with frontal bossing, sparse hair in the frontoparietal region, downslanting palpebral fissures, apparent hypertelorism, long narrow face, prominent mandible, and malar flushing. Hypotonia, poor coordination, and speech delay are common. Most children show mental retardation, ranging from mild to severe.

Hydranencephaly

Hydranencephaly may be confused with hydrocephalus. The cerebral hemispheres are absent or represented by membranous sacs with remnants of frontal, temporal, or occipital cortex dispersed over the membrane. The midbrain and brainstem are relatively intact (Fig. 585-13). The cause of hydranencephaly is unknown, but bilateral occlusion of the internal carotid arteries during early fetal development would explain most of the pathologic abnormalities. Affected infants can have a normal or enlarged head circumference at birth that grows at an excessive rate postnatally. Transillumination shows an absence of the cerebral hemispheres. The child is irritable, feeds poorly, develops seizures and spastic quadriparesis, and has little or no cognitive development. A ventriculoperitoneal shunt prevents massive enlargement of the cranium.

Figure 585-13 Hydranencephaly. MRI scan showing the brainstem and spinal cord with remnants of the cerebellum and the cerebral cortex. The remainder of the cranium is filled with cerebrospinal fluid.

Treatment

Therapy for hydrocephalus depends on the cause. Medical management, including the use of acetazolamide and furosemide, can provide temporary relief by reducing the rate of CSF production, but long-term results have been disappointing. Most cases of hydrocephalus require extracranial shunts, particularly a ventriculoperitoneal shunt. Endoscopic third ventriculostomy (ETV) has evolved as a viable approach and criteria have been developed for its use, but the procedure might need to be repeated to be effective. Ventricular shunting may be avoided with this approach. The major complications of shunting are occlusion (characterized by headache, papilledema, emesis, mental status changes) and bacterial infection (fever, headache, meningismus), usually due to Staphylococcus epidermidis. With meticulous preparation, the shunt infection rate can be reduced to <5%. The results of intrauterine surgical management of fetal hydrocephalus have been poor, possibly because of the high rate of associated cerebral malformations in addition to the hydrocephalus, except for some promise in cases of hydrocephalus associated with fetal meningomyelocele.

Prognosis

Prognosis depends on the cause of the dilated ventricles and not on the size of the cortical mantle at the time of operative intervention, except in cases in which the cortical mantle has been severely compressed and stretched. Hydrocephalic children are at increased risk for various developmental disabilities. The mean intelligence quotient is reduced compared with the general population, particularly for performance tasks as compared with verbal abilities. Many children have abnormalities in memory function. Vision problems are common, including strabismus, visuospatial abnormalities, visual field defects, and optic atrophy with decreased acuity secondary to increased ICP. The visual-evoked potential latencies are delayed and take some time to recover after correction of the hydrocephalus. Although most hydrocephalic children are pleasant and mild mannered, some children show aggressive and delinquent behavior. Accelerated pubertal development in patients with shunted hydrocephalus or myelomeningocele is relatively common, possibly because of increased gonadotropin secretion in response to increased ICP. It is imperative that hydrocephalic children receive long-term follow-up in a multidisciplinary setting.

Development and Etiology

The bones of the cranium are well developed by the 5th mo of gestation (frontal, parietal, temporal, and occipital) and are separated by sutures and fontanels. The brain grows rapidly in the 1st several years of life and is normally not impeded because of equivalent growth along the suture lines. The cause of craniosynostosis is unknown, but the prevailing hypothesis suggests that abnormal development of the base of the skull creates exaggerated forces on the dura that act to disrupt normal cranial suture development. Genetic factors have been identified for some isolated and for many syndromic causes of craniosynostosis (Table 585-4).

Table 585-4 COMMONLY USED CLINICAL GENETIC CLASSIFICATIONS OF CRANIOSYNOSTOSES

From Ridgway EB, Weiner HL: Skull deformaties, Pediatr Clin North Am 51:359–387, 2004.

Clinical Manifestations and Treatment

Most cases of craniosynostosis are evident at birth and are characterized by a skull deformity that is a direct result of premature suture fusion. Palpation of the suture reveals a prominent bony ridge, and fusion of the suture may be confirmed by plain skull roentgenograms, CT scan or bone scan in ambiguous cases (Table 585-5).

Premature closure of the sagittal suture produces a long and narrow skull, or scaphocephaly, the most common form of craniosynostosis. Scaphocephaly is associated with a prominent occiput, a broad forehead, and a small or absent anterior fontanel. The condition is sporadic, is more common in males, and often causes difficulties during labor because of cephalopelvic disproportion. Scaphocephaly does not produce increased ICP or hydrocephalus, and results of neurologic examination of affected patients are normal.

Frontal plagiocephaly is the next most common form of craniosynostosis and is characterized by unilateral flattening of the forehead, elevation of the ipsilateral orbit and eyebrow, and a prominent ear on the corresponding side. The condition is more common in females and is the result of premature fusion of a coronal and sphenofrontal suture. Surgical intervention produces a cosmetically pleasing result. When imaging does not reveal a closed suture, positional factors are of primary importance.

Occipital plagiocephaly is most often a result of positioning during infancy and is more common in an immobile child or a child with a disability, but fusion or sclerosis of the lambdoid suture can cause unilateral occipital flattening and bulging of the ipsilateral frontal bone. Trigonocephaly is a rare form of craniosynostosis caused by premature fusion of the metopic suture. These children have a keel-shaped forehead and hypotelorism and are at risk for associated developmental abnormalities of the forebrain. Milder forms of metopic ridging are more common. Turricephaly refers to a cone-shaped head due to premature fusion of the coronal and often sphenofrontal and frontoethmoidal sutures. The kleeblattschädel deformity is a peculiarly shaped skull that resembles a cloverleaf. Affected children have very prominent temporal bones, and the remainder of the cranium is constricted. Hydrocephalus is a common complication.

Premature fusion of only one suture rarely causes a neurologic deficit. In this situation, the sole indication for surgery is to enhance the child’s cosmetic appearance, and the prognosis depends on the suture involved and on the degree of disfigurement. Neurologic complications, including hydrocephalus and increased ICP, are more likely to occur when two or more sutures are prematurely fused, in which case operative intervention is essential. The role of early repositioning efforts and therapy for torticollis and the use of cranial molding devices are beyond the scope of this review.

The most prevalent genetic disorders associated with craniosynostosis include Crouzon, Apert, Carpenter, Chotzen, and Pfeiffer syndromes. Crouzon syndrome is characterized by premature craniosynostosis and is inherited as an autosomal dominant trait. The shape of the head depends on the timing and order of suture fusion but most often is a compressed back-to-front diameter or brachycephaly due to bilateral closure of the coronal sutures. The orbits are underdeveloped, and ocular proptosis is prominent. Hypoplasia of the maxilla and orbital hypertelorism are typical facial features.

Apert syndrome has many features in common with Crouzon syndrome. Apert syndrome is usually a sporadic condition, although autosomal dominant inheritance can occur. It is associated with premature fusion of multiple sutures, including the coronal, sagittal, squamosal, and lambdoid sutures. The facies tend to be asymmetric, and the eyes are less proptotic than in Crouzon syndrome. Apert syndrome is characterized by syndactyly of the 2nd, 3rd, and 4th fingers, which may be joined to the thumb and the 5th finger. Similar abnormalities often occur in the feet. All patients have progressive calcification and fusion of the bones of the hands, feet, and cervical spine.

Carpenter syndrome is inherited as an autosomal recessive condition, and the many fusions of sutures tend to produce the kleeblattschädel skull deformity. Soft tissue syndactyly of the hands and feet is always present, and mental retardation is common. Additional but less common abnormalities include congenital heart disease, corneal opacities, coxa valga, and genu valgum.

Chotzen syndrome is characterized by asymmetric craniosynostosis and plagiocephaly. The condition is the most prevalent of the genetic syndromes and is inherited as an autosomal dominant trait. It is associated with facial asymmetry, ptosis of the eyelids, shortened fingers, and soft tissue syndactyly of the 2nd and 3rd fingers.

Pfeiffer syndrome is most often associated with turricephaly. The eyes are prominent and widely spaced, and the thumbs and great toes are short and broad. Partial soft tissue syndactyly may be evident. Most cases appear to be sporadic, but autosomal dominant inheritance has been reported.

Mutations of the fibroblast growth factor receptor (FGFR) gene family have been shown to be associated with phenotypically specific types of craniosynostosis. Mutations of the FGFR1 gene located on chromosome 8 result in Pfeiffer syndrome; a similar mutation of the FGFR2 gene causes Apert syndrome. Identical mutations of the FGFR2 gene can result in both Pfeiffer and Crouzon phenotypes.

Each of the genetic syndromes poses a risk of additional anomalies, including hydrocephalus, increased ICP, papilledema, optic atrophy resulting from abnormalities of the optic foramina, respiratory problems secondary to a deviated nasal septum or choanal atresia, and disorders of speech and deafness. Craniectomy is mandatory for management of increased ICP, and a multidisciplinary craniofacial team is essential for the long-term follow-up of affected children. Craniosynostosis may be surgically corrected with good outcomes and relatively low morbidity and mortality, especially for nonsyndromic infants.