Neural tube defects (NTDs) are among the most common congenital malformations and occur in more than 1 per 1,000 live births. For this reason, they are also among the best studied. The fetal nervous system begins development on the eighteenth day of gestation. The primordial neural tube is derived from the ectodermal layer, and the ectoderm on the dorsal portion of the embryo, along with the underlying notochord and chordal mesoderm, induces the formation of the neural plate. Closure of the neuroectoderm begins on the twenty-second day of gestation and is accomplished by invagination of the lateral margins of the neural plate. Experimental animal data and empirical human data suggest that closure of the neural tube begins independently in several different sites along the tube; bidirectional “zippering” between closure sites then follows. The anterior neuropore closes by day 25 or 26 and the posterior neuropore closes 2 to 3 days later to form a closed, continuous cavity that constitutes the primitive ventricular system and central canal of the cord.

Disruption of the neural tube closure process at any of the primary closure sites produces variable-sized defects in different anatomic locations, resulting in the recognized conditions of anencephaly, spina bifida, encephalocele, and spinal dysraphism. In the majority of cases, the NTD is the only malformation present in the affected child; however, a significant fraction of patients have additional congenital malformations, an underlying genetic condition, or both.

Anencephaly, the presence of an exposed rostral mass of neural tissue, is produced by the early failure of anterior neural tube closure and has an incidence of approximately .3 to .35 in 1,000 births. Approximately 15% of these infants are stillborn, and the rest die shortly after birth.

Encephalocele, an insult thought to occur on approximately the twenty-sixth gestational day, can be a less severe malformation involving defective closure of a portion of the neural tube in association with a bony skull defect. Although 75% to 80% of these lesions occur in the occipital region, similar abnormalities have been noted in the frontal and parietal regions. Frontal and nasal encephaloceles are more common in infants of Asian ancestry and frequently present in the newborn period. In this condition, a soft sac of varying size protrudes through a bony defect and may contain only cranial meninges or meninges and neural tissue. Communication usually is present between the ventricular cavity and the encephalocele, and hydrocephalus may be noted. Encephaloceles are the least frequent of the NTDs and occur in 1 in 5,000 to 1 in 10,000 live births. Compared with anencephaly and spina bifida, however, encephaloceles are more commonly associated with other birth defects or occur as part of genetic syndromes.

The most common form of spina bifida, myelomeningocele, is a restricted failure of posterior caudal neural tube closure believed to occur before 26 days’ gestation. The majority of these lesions occur in the lumbar and lumbosacral regions, and the incidence is said to be between .4 and .5 per 1,000, with one of the highest incidences found in the northern regions of the British Isles. Pathologically, the majority of lesions result in a dorsal displacement of neural tissue such that a sac or an open placode remains on the infant’s back. Skeletal anomalies, including absence of the vertebral arches, lateral displacement of the pedicles, and a widened spinal canal, are present uniformly, and an incomplete, although variable, dermal covering is present. Clinical features relate to the level of the spinal cord that is involved and to the extent of the lesion. Generally, disturbances in lower extremity motor function, sphincter function, and bladder function are noted. Secondary orthopedic problems of the lower extremities (dislocated hips, clubfeet, and congenital contractures known as arthrogryposis) can occur in utero because of lack of fetal movement. Hydrocephalus is seen in almost 75% of cases and is associated nearly always with a type II Chiari malformation or kinking and elongation of brainstem structures. The morbidity and mortality seen in this disorder are dictated by the level of the lesion. High lesions (above T11) are associated with higher morbidity, lower intelligence, and greater disability, whereas the outcome for individuals with lower lesions (below L3) is considerably better. Other factors influencing outcome include complications of meningitis (from the open sac), hydrocephalus, and renal involvement. In addition, delivery by cesarean section has been advocated to preserve lower extremity function to the fullest extent.

Other dysraphic states include meningocele and diastematomyelia. Meningocele is herniation of the meninges unaccompanied by neural tissue and covered by skin or a thin-walled membrane. Similar to myelomeningocele, these lesions are most common in the lumbosacral region, and defects in the vertebral arches may be present. Some patients have abnormalities of gait, particularly during periods of rapid growth, or loss of previously acquired bladder control. Meningoceles generally are not associated with hydrocephalus.

Spina bifida occulta usually refers to a vertebral defect without herniation of the contents of the spinal canal. This condition is found most commonly in the lumbosacral region and has been noted radiographically in as many as 15% of the general population. Occasionally, spina bifida occulta may be suspected by the presence of hairy tufts or birthmarks at the base of the spine. Rarely, a sinus tract may lead into an intraspinal cyst or epidermoid structure. All infants with recurrent gram-negative bacterial meningitis should be examined carefully for sinus tracts, because these may act as a source of infection.

In diastematomyelia, the spinal cord is divided by a bony or cartilaginous spur extending from the dorsal surface of the vertebral body. This is associated with an NTD in more than 50% of cases and may cause neurologic deficits by producing traction on the cord. Lipomas are hamartomatous lesions associated with dysraphic states and are located most commonly in the region of the filum terminale.

Although the occult dysraphic states may go undetected in early childhood, 80% are associated with dermal lesions and vertebral defects. Later in childhood, as the spinal cord ascends to its position in adult life, patients may have gait disturbances, foot deformities, sphincter dysfunction, and scoliosis. The failure of the spinal cord to ascend, as a result of either primary malformation or secondary tumor, is known as tethering of the cord.

The cause, or causes, of NTDs are currently under investigation. Candidate genes involved in NTDs include many genes in the folate metabolism pathway as well as those responsible for folate transport. Genes in this pathway have been the focus of intense research effort since convincing proof that periconceptual vitamin supplementation with folic acid reduces NTD occurrence by approximately 70%. Although variations in several genes, such as 5,10-methylenetetrahydrofolate reductase, appear to confer risk of NTDs in selected populations, no single gene has been identified as causal of NTDs in humans. Research in model organisms, such as the recent discovery that mutations in the gene Scrb1 cause NTDs in mice, suggest that gene identification in humans will be shortly forthcoming.

The majority of NTDs occur as isolated birth defects but as many as 20% occur in association with other birth defects, chromosome abnormalities, or specific genetic syndromes; recognition of the latter subgroups is important, as the recurrence risk could be high. Another group at high risk for NTDs is the children of women receiving anticonvulsants such as valproic acid or carbamazepine; the incidence of spina bifida is as high as 1% to 2% in exposed fetuses. However, most cases of NTDs are isolated and are attributed to “multifactorial inheritance,” meaning a combination of unidentified genes and environmental factors that interact to interfere with normal neural tube closure. Once a couple has given birth to a child with a multifactorially caused NTD, the chance of a second child being affected is approximately 3% to 4%. If a couple has two children with NTDs, the recurrence risk rises to 10% to 15% for subsequent children. Prenatal diagnosis of NTDs is widely available and is strongly recommended for mothers at higher than baseline population risk. Maternal serum alpha-fetoprotein tests performed during the fifteenth to eighteenth weeks of pregnancy detect 88% to 100% of cases of anencephaly and 80% of cases of open spina bifida. False-positive test results are related to twin gestation, underestimation of gestational age, other open body defects, or threatened or missed abortion. When the serum alpha-fetoprotein level is elevated, ultrasonographic examination to evaluate for gestational age, multiple pregnancy, or congenital malformations is indicated. If sonographic examination fails to identify the cause of the elevated serum alpha-fetoprotein, an amniocentesis and amniotic fluid alpha-fetoprotein determination should be performed.

Data from numerous studies have demonstrated that periconceptual vitamin supplementation with folic acid significantly reduces the occurrence of NTDs in all couples, whether or not a family history of this problem exists. The biologic basis for this effect is as yet unknown but presumably is attributable to correction of an underlying genetic defect with high-dose folate supplementation.

The concept of ventral induction refers to the developmental events that occur under the primary influence of the prechordal mesoderm. The major inductive relationship between the prechordal mesoderm and the developing cerebrum occurs ventrally at the rostral end of the fetus and influences the development of the forebrain and facial structures.