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.
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 naso-frontal 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.
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 ultra-sonography 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 non-ambulatory 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 hind-brain 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. Neuro-surgical 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