Congenital deformities involving the coverings of the nervous system are called neural tube defects (NTDs). Neural tube defects vary in severity. The mildest form is spina bifida aperta, in which osseous fusion of one or more vertebral arches is lacking, without involvement of the underlying meninges or neural tissue. A slightly more severe form of spina bifida, which is discussed in detail in this article, is spina bifida cystica, or myelomeningocele, in which a saclike casing is filled with cerebrospinal fluid (CSF), spinal cord, and nerve roots that have herniated through a defect in the vertebral arches and dura, as shown below.
Anencephaly and rachischisis are extremely severe forms of neural tube defects, in which an extensive opening in the cranial and vertebral bone is present with an absence of variable amounts of the brain, spinal cord, nerve roots, and meninges. Anencephaly has been studied since antiquity, and an almost dizzying array of synonyms and classifications is noted.  For a more complete description of anencephaly, see the seminal work by Lemire, Beckwith, and Warkany in 1978. 
Malformations of the brain and spinal cord may result from genetic mutation or may be acquired deformities. Most malformations, especially those such as neural tube defects, occur early in embryogenesis and are likely the result of aberrant expression of a yet undefined developmental gene or family of genes. The nervous system develops in a precise temporal embryologic sequence; therefore, an interruption of one part of the developmental sequence often affects remaining development.
The neural tube defect discussed in this article is classified as an embryologic induction disorder. It results in failure to properly form both the mesoderm and neuroectoderm. The primary embryologic defect in all neural tube defects is failure of the neural tube to close, affecting neural and cutaneous ectodermal structures. The inciting event can be traced to days 17-30 of gestation.
The precise etiology and the specific genes that may be involved during this abnormal neural ontogenesis have not yet been elucidated. These deformities are not only disorders of embryologic induction but also disorders of cellular migration and include the secondary mechanical complications that occur with an unprotected nervous system. Specifically, the amniotic fluid can have a caustic and destructive effect on the open neural structures.
As described, the primary defect is a failure of the neural folds to fuse in the midline and form the neural tube, which is neuroectoderm. However, the subsequent defect is the maldevelopment of the mesoderm, which, in turn, forms the skeletal and muscular structures that cover the underlying neural structures. These neural tube defects can be open (neural structures that communicate with the atmosphere) or closed (skin covered). They can be ventral or dorsal midline defects.
Several interesting characteristics in the epidemiology of neural tube defects (NTDs) are as follows:
In the United States, myelomeningoceles occur in about 1 of 1500 births. 
Significant ethnic differences in prevalence are recognized; people of Celtic origin have the highest rate of spina bifida.
A female predominance is observed, with females accounting for 60-70% of affected children.
Significant differences in geographic distribution are noted, with countries in the British Isles having a higher rate than Asian countries. However, in 2005, the Shanxi province in Northern China was reported to have one of the highest incidence rates of neural tube defects in the world. Many risks were associated with this increased rate, and factors that seemed to be protective included meat consumption, legume consumption, or both.
In a 2014 retrospective review (1996-2009) of 103 Saudi Arabian newborns admitted to the neonatal intensive care unit (NICU) with a diagnosis of neural tube defects, 20 (19.4%) had an underlying genetic syndromic, chromosomal, and/or other anomalies.  The investigators attributed the high rate of such anomalies to a high rate of consanguinity among the studied population.
In a 2013 retrospective study (2002-2010), Nigerian investigators at a tertiary teaching hospital found 460 of 7401 neonates had surgical conditions, of which 408 (88.7%) were congenital anomalies, including 101 (24.8%) neural tube defects. 
In another 2013 retrospective study (2003-2011), Turkish investigators found 100 of 8408 infants (1.2%) admitted to the NICU in a tertiary care hospital were diagnosed with neural tube defects; 74% of the mothers were graduates of primary school or illiterate, and none had used preconception folic acid. 
A worldwide decline in neural tube defect births has been recognized over the past 3 decades. For example, in the United States, New England has seen the incidence of spina bifida drop from 2.31 per 1000 births during the 1930s to 0.77 per 1000 births during the 1960s.
Reasons for the dramatic drop are not completely clear; however, certain factors probably play a part. The decline in neonates with neural tube defects paralleled the development of commonly used prenatal screening tests such as alpha-fetoprotein (AFP) and ultrasonography. Termination of pregnancy increased 50-fold in the British Isles after the introduction of prenatal screening. Termination of pregnancy probably accounted for a significant amount of the decline of neural tube defects in the United States, as well. In Atlanta in the early 1990s, more than 30% of affected pregnancies were terminated based on prenatal test results. When epidemiologic analysis is complete, use of periconception folate in the United States is most likely to impact the incidence of neural tube defects in the late part of the 20th century.
In September of 1992, the US Public Health Service made the following strong recommendation: All women of childbearing age in the United States who are capable of becoming pregnant should consume 0.4 mg folic acid per day for the purpose of reducing the risk of having a pregnancy affected with spina bifida and other neural tube defects. Because the effects of high intakes are not well known, but include complicating the diagnosis of vitamin B-12 deficiency, care should be taken to keep total consumption less than 1 mg per day, except under the supervision of a physician.
That statement and the abundance of scientific data available to the public have reinforced the observation that risk of delivering a child with a neural tube defect significantly decreases with the ingestion of periconception folate.
The evidence of reduction in neural tube defects after folic acid fortification has continued to mount. In 1998, folic acid fortification in specific foods such as cereal became mandatory in Canada, a country in which the prevalence of neural tube defects was higher in the eastern provinces compared with the western provinces. In 2007, scientists in Canada published a population-based study in the New England Journal of Medicine, in which they analyzed the effect of this fortification.  The observed reduction in incidence rates of neural tube defects due to food fortification with folate included a 53% decrease of spina bifida cases, a 38% reduction in anencephaly cases, and a 31% reduction in encephalocele cases. [7, 8]
Incidence of neural tube defects such as anencephalus and spina bifida seems to be higher in people of Celtic descent, such as the Welsh, Irish, and Scotch. Their prevalence rate is significantly higher than incidence rate seen in persons of Anglo-Saxon or Norman origin. In the United States, the highest rates of neural tube defects are found in Boston in people of Irish descent. In contradistinction, Africans, blacks, and Asians seem to have very low incidence of neural tube defects. Recurrence risk of giving birth to a second child with a neural tube defect varies with incidence. Investigators found the risk of having an additional affected birth after an anencephalic or spina bifida birth to be approximately 10.4% in Belfast but only about 4.12% in London. The risk in the United States is 1-3%.
The sex difference seems to be consistent in most studies. About 55-70% of neural tube defects occur in females. This female predominance is seen in both still and live births. 
The human embryo passes through 23 stages of development after conception, each occupying approximately 2-3 days. Two different processes form the CNS. The first is primary neurulation, which refers to the formation of the neural structures into a tube, thereby forming the brain and spinal cord. Secondary neurulation refers to the formation of the lower spinal cord, which gives rise to the lumbar and sacral elements. The neural plate is formed at stage 8 (days 17-19), the neural fold occurs at stage 9 (days 19-21), and the fusion of the neural folds occurs at stage 10 (days 22-23). Any disruption during stages 8-10 (ie, when the neural plate begins its first fold and fuses to form the neural tube) can cause craniorachischisis, the most severe form of neural tube defect (NTD).
Stage 11 (days 23-26) is when the closure of the rostral neuropore occurs. Failure at this point results in anencephaly, shown below.
Myelomeningocele is a result of disruption of stage 12 (days 26-30), closure of the caudal neuropore. Beyond day 26, a disruption is unlikely to be able to cause an NTD such as myelomeningocele, shown below. 
Studies on mice embryos have provided some unifying theories for explaining the associated anomalies seen with neural tube defects. Associated defects include hydrocephalus and hindbrain malformations such as Chiari II malformation. In 1992, McLone and Naidich proposed a unifying theory of neural tube defects that explains both the hindbrain anomalies and the spinal cord anomalies.  According to these investigators, the initial event is a failure of the neural folds to close completely, leaving a dorsal defect or myeloschisis. This permits the cerebral spinal fluid (CSF) to leak from the ventricles through the central canal and into the amniotic fluid and causes collapse of the primitive ventricular system.
Failure of the primitive ventricular system to increase in size and volume leads to both downward and upward herniation of the small cerebellum. In addition, the posterior fossa does not develop to its full size, and the neuroblasts do not migrate outward at a normal rate from the ventricles into the cortex. Therefore, the panoply of defects occurs from an initial inciting event.
The precise genes (overexpressed or underexpressed) involved in this event have not been identified. The sonic hedgehog (Shh) gene has been identified in defects that cause hydrocephalus secondary to holoprosencephaly. This gene is believed to induce growth of the neural plate and helps close the neural tube by exerting a strong influence on the ventral and medial structure of the prosencephalon. The precise relationship of the Shh gene with neural tube defects is yet to be defined. Many mutant and gene-targeted mouse models can develop cranial and spinal neural tube defects. Some studies appear to indicate that a single molecular signaling cascade, called the planar polarity pathway, is the cause of the neural tube defect in the mutant murine model. Below is a table with the suspected embryologic event and result.
Table 1. Human CNS Malformations (Open Table in a new window)
|Days of Gestation||Event||Resultant Malformation|
|0-18||Formation of 3 germ layer and neural plate||Death or unclear effect|
|18||Formation of neural plate and groove form||Anterior midline defects|
|22-23||Appearance of optic vessels||Hydrocephalus (18-60 d)|
|24-26||Close anterior neuropore||Anencephaly|
|26-28||Close posterior neuropore||Cranium bifidum, spina bifida cystica, spina bifida occulta|
|32||Vascular circulation||Microcephaly (30-130 d), migration anomalies|
|33-35||Splitting of prosencephalon to make paired telencephalon||Holoprosencephaly|
|70-100||Formation of corpus callosum||Agenesis of the corpus callosum|
Over the last century, teratogens implicated in the etiology of neural tube defects (NTDs) in experimental animals and in humans include potato blight, hyperthermia, low economic status, antihistamine and sulfonamide use, nutritional deficiencies, vitamin deficiencies, and anticonvulsant use. Of all the suspected teratogens, carbamazepine, valproic acid, and folate deficiency have been most strongly tied to the development of neural tube defects. In humans, carbamazepine and valproic acid have been definitively identified as teratogens. Valproic acid is a known folate antagonist and its association with neural tube defects may be through that action. A woman taking valproic acid during pregnancy has an estimated risk of 1-2% of having a child with a neural tube defect. Therefore, women taking antiepileptic drugs during pregnancy are advised to undergo routine prenatal screening with AFP.
In the 1970s, Smithells first advanced the concept that nutrition may be related to the development of neural tube defects. [11, 12, 13] He noted that women with low erythrocyte folate and leukocyte ascorbic acid levels during the first trimester of pregnancy carried fetuses more commonly affected by neural tube defects than in controls. His early work led to 2 important randomized controlled studies on the use of periconception folate by British and Hungarian research groups.
The Medical Research Council in Britain performed a prospective, randomized, double-blind, multicenter trial to determine if women who previously delivered children with neural tube defects could lower the recurrence rate with multivitamins or folate (4 mg/d).  Thus, 1817 women who had a previous child with an neural tube defects were compared with 1195 women who had children without neural tube defects were randomized into 4 groups. One group received multivitamins, one group received folate, the third group received both, and the fourth group received neither. The study was terminated early when a significant protective effect was observed in the groups that received folic acid compared with the groups that did not. Multivitamins alone had no significant protective effect. Folic acid ingestion in the preconception period prevented an estimated 72% of predicted recurrent neural tube defects. The article with this conclusion was published in Lancet in 1991.
Hungarian investigators performed a randomized, double-blind, multicenter trial of folic acid to determine if it exerted a protective effect for a first occurrence of neural tube defects. One group of 2104 women received 0.8 mg of folic acid with their multivitamins, whereas the second group of 2052 women received no folic acid with their multivitamins. The folic acid group had no cases of NTD, while the non–folic acid group had 6 cases. This finding, published in the New England Journal of Medicine in 1992, indicated that ingestion of preconception folic acid significantly decreased the first occurrence of neural tube defects.  For this reason, the US Public Health Service issued their strongly worded recommendation to women of childbearing age to take folic acid supplements.
The precise mechanism by which folic acid is protective is unclear. Bjorkland hypothesized that folic acid provides the methyl group used for posttranslational methylation of arginine and histidine in the regulatory domains of the cytoskeleton, which is required for neural tissue differentiation. 
Despite compelling experimental evidence, as well as clear public health recommendations, Botto et al reported that, by 2005, the effectiveness of the educational campaign promoting the use of periconceptual folate had less than desired results.  New cases of neural tube defects, potentially preventable by ingestion of folate, continue to surface in 13 birth registries in Europe. He suggested the integration or fortification of folate into food could help prevent some of these cases. However, food fortification is neither the only, nor the simplest answer. The results of folic acid food fortification, reported by Canfield et al in 2005, reveal a modest but not overwhelming benefit in reducing the incidence of neural tube birth defects. 
Thus, several important issues have been raised. Because only 50% or fewer of the pregnancies in the United States are planned, compliance with the request to ingest preconception folic acid is not always easy to achieve. The neural tube defects occurs before day 26 postfertilization, often before many women have discovered their pregnancies. Thus, folic acid is not protective unless ingested in the periconception period. The precise minimal dose of folate required to be protective against a neural tube defect has not been determined, which complicates the issue of routine food fortification. Furthermore, folic acid supplementation can mask a vitamin B-12 deficiency that can cause neurologic damage in the deficient individual. For these reasons, ingesting daily folic acid as a component of a multivitamin tablet has become the preferred recommendation for women who are of reproductive age.
The reported effects of maternal periconceptional smoking and alcohol consumption on the risk of neural tube defects is of interest. In 2008, results of a population-based, case-control study in California conducted from 1998-2003 were published.  Maternal alcohol use increased the risk of neural tube defects, whereas smoking was associated with a lower risk of neural tube defects. The proposed mechanism of these observations is elusive.
Spina bifida cystica
The 2 major types of defects seen with spina bifida cystica are myelomeningoceles and meningoceles. Cervical and thoracic regions are the least common sites, and lumbar and lumbosacral regions are the most common sites for these lesions.
Myelomeningocele is a condition in which the spinal cord and nerve roots herniate into a sac comprising the meninges. This sac protrudes through the bone and musculocutaneous defect. The spinal cord often ends in this sac, in which it is splayed open, exposing the central canal. The splayed-open neural structure is called the neural placode. This type of neural tube defect is the subject of most of this article and is shown below.
Certain neurologic anomalies, such as hydrocephalus and Chiari II malformation (discussed below), accompany myelomeningocele. In addition, myelomeningoceles have a higher incidence of associated intestinal, cardiac, and esophageal malformations, as well as renal and urogenital anomalies. Most neonates with myelomeningocele have orthopedic anomalies of their lower extremities and urogenital anomalies due to involvement of the sacral nerve roots.
A meningocele is simply herniation of the meninges through the bony defect (spina bifida). The spinal cord and nerve roots do not herniate into this dorsal dural sac. These lesions are important to differentiate from myelomeningocele because their treatment and prognosis are so different from myelomeningocele. Neonates with a meningocele usually have normal findings upon physical examination and a covered (closed) dural sac. Neonates with meningocele do not have associated neurologic malformations such as hydrocephalus or Chiari II.
A subtype of spina bifida is called lipomeningocele, or lipomyelomeningocele, which is a common form of neural tube defect treated by pediatric neurosurgeons. These lesions have a lipomatous mass that herniates through the bony defect and attaches to the spinal cord, tethering the cord and often the associated nerve roots. The lipomyelomeningocele can envelop both dorsal and ventral nerve roots, only the dorsal nerve roots, or simply the filum terminale and conus medullaris. These lesions do not have associated hydrocephalus but have a more guarded prognosis than simple meningoceles. The surgical correction of these lesions is more complex, and the retethering rate, in which an additional surgery is required, is as high as 20% in some series.
In a third, rare type of spina bifida cystica called myelocystocele, the spinal cord has a large terminal cystic dilatation resulting from hydromyelia. The posterior wall of the spinal cord is often attached to the skin (ectoderm) and is undifferentiated, thus giving rise to a large terminal skin-covered sac. The vast majority of the lesions are dorsal, although a small minority (approximately 0.5%) are ventral in location. The most common ventral variant is an anterior sacral meningocele, which is most often discovered in females as a pelvic mass.
Spina bifida occulta
In this group of neural tube defects, the meninges do not herniate through the bony defect. This lesion is covered by skin (ie, closed), therefore rendering the underlying neurologic involvement occult or hidden. These patients do not have associated hydrocephalus or Chiari II malformations. Often, a skin lesion such as a hairy patch, dermal sinus tract, dimple, hemangioma, or lipoma points to the underlying spina bifida and neurologic abnormality present in the thoracic, lumbar, or sacral region. Presence of these cutaneous stigmata above the gluteal fold signifies the presence of an occult spinal lesion. Dimples below the gluteal fold signify a benign, nonneurologic finding such as a pilonidal sinus. This is an important point for differentiating the lesions that have neurologic involvement from those that do not.
An experienced pediatrician or surgeon should examine any neonate with cutaneous stigmata on the back around the gluteus. A good rule of thumb is that a lesion (eg, pit, tract) below the gluteal crease is often a pilonidal sinus and needs no further evaluation. Those tracts, pits, or lesions above the gluteal fold should be evaluated further.
Lesions that are questionable can be scanned with ultrasonography in a neonate or with MRI in an older child. Ultrasonography or MRI delineates the presence or absence of a tethered cord or other spinal anomaly. Plain radiology can reveal a panoply of anomalies, such as fused vertebrae, midline defects, bony spurs, or abnormal laminae. An MRI is often useful in evaluating for a split cord malformation (ie, diastematomyelia), in which a bony spur splits the spinal cord, or a duplication of the spinal cord and nerve roots (diplomyelia). More commonly, the neurosurgeon is searching for tethering of the spinal cord by a sinus tract or thickened filum that can cause traction on the spinal cord with subsequent neurologic deficits as the child grows.
A growing body of evidence indicates that the surgical repair of these lesions is more effective when performed prophylactically. Once the patient experiences a significant neurologic deficit, such as a neurogenic bladder or leg weakness, from these occult spinal lesions, the surgical remedy may not return the patient to the baseline neurologic status.
Signs and symptoms of occult spinal disorders in children include the following:
- Lamina defects
- Widening of interpedicular distance
- Butterfly vertebrae
- Capillary hemangioma
- Caudal appendage
- Dermal sinus
- Extremity asymmetry
- Foot deformities
- Weakness of leg or legs
- Leg atrophy or asymmetry
- Loss of sensation, painless sores
- Unusual back pain
- Abnormal gait
- Neurogenic bladder
Several types of midline skull defects are classified under this term, ranging from simple (with minimal clinical significance) to serious life-threatening conditions. The most benign type of cranium bifidum occultum is the persistent parietal foramina or persistent wide fontanelle. The parietal foramina can be transmitted as an autosomal dominant trait via a gene located on the short arm of chromosome 11. The condition is sometimes called "Caitlin marks," after the family for which it was described. Both parietal foramina and a persistent anterior fontanelle are generally asymptomatic and a pediatric neurosurgeon may be asked to evaluate the child for skull fracture, craniosynostosis, or some other reason related to these findings. The best management is longitudinal observation, as these skull defects often close over time.
Cranium bifidum, such as an encephalocele, is much more serious. Encephaloceles are theorized to occur when the anterior neuropore fails to close during days 26-28 of gestation. Incidence of this anomaly is 10% of the incidence of spina bifida cystica. In the United States, approximately 80% of lesions are found on the dorsal surface of the skull, as shown below, with most near the occipital bone.
In contradistinction, most encephaloceles in Asia are ventral and involve the frontal bone. In the Philippines and other Pacific Rim countries, incidence of anterior encephaloceles that present as hypertelorism, obstructed nares, anterior skull masses, and cleft palate, among other presentations, is high. In most lesions, the sac that has herniated through a midline skull defect is covered with epithelium.
A small number of encephaloceles are associated with syndromes such as Meckel-Gruber syndrome. This syndrome is characterized by an occipital encephalocele that is associated with holoprosencephaly, orofacial clefts, microphthalmia, polycystic kidneys, and cardiac anomalies. This condition is autosomal recessive and has been mapped to chromosome bands 17q21-q24. In the United States, only about 30% of occipital encephaloceles contain cerebral cortex. The rest contain cerebellar tissue, dysplastic tissue with little normal function, glial tissue, or are simple meningeal sacs filled with CSF (as in cranial meningocele).
An MRI is invaluable in planning a surgical approach. The surgeon needs to know the contents of the sac, which can be quite large. In addition, the surgeon needs to know the relationship of the major cerebral venous sinuses to the sac in order to plan a safe operative approach. Finally, the surgeon needs to know if the patient has hydrocephalus. Approximately 60% of these patients require placement of a ventricular peritoneal (VP) shunt after the removal of their encephaloceles. Children whose encephaloceles contain large quantities of cerebral cortex often become microcephalic and display significant subsequent developmental and learning disabilities.
Anencephaly is the most severe form of neural tube defect. Rachischisis and craniorachischisis, often used as synonyms, refer to a severe deformity in which an extensive defect in the craniovertebral bone causes the brain to be exposed to amniotic fluid. Neonates with anencephaly rarely survive more than a few hours or days. Historically, these children have been the subject of myths, folklore, and superstitions, and have been referred to as monsters based on their unusual and frightening appearance. See the images below. Scientists have studied this malformation because it serves as a paradigm of the other dysraphic states.
The fetus has a partially destroyed brain, deformed forehead, and large ears and eyes with often relatively normal lower facial structures. Both genetic and environmental insults appear to be responsible for this outcome. The defect normally occurs after neural fold development at day 16 of gestation but before closure of the anterior neuropore at 24-26 days' gestation.
A variety of teratogens have been implicated, including radiation, folic acid deficiency, drugs, and infections. Regardless, 3 basic defects occur in the developing fetus. The first is the defect in notochord development, which results in failure of the cephalic folds to fuse in the midline and make a normal neural tube. The next defect is failure of the mesoderm to develop; mutual induction of all 3 germ layers in a temporally related sequence fails to occur. Therefore, the calvaria and vertebrae (mesoderm) fail to form correctly, exposing the brain to further insult. Finally, this skull and dural defect permits the brain to be exposed to amniotic fluid, thus destroying the developing forebrain neural cells.
Anencephaly is the most common major CNS malformation in the Western world, and no neonates survive. It is seen 37 times more frequently in females than in males. The recurrence rate in families can be as high as 35%. The incidence is highest in Ireland, Scotland, Wales, Egypt, and New Zealand and lowest in Japan.
If the mother decides not to terminate a pregnancy in which the fetus is affected with a neural tube defect, extensive counseling should ensue. Education is provided on optimal prenatal care and expectations once a child is born. If diagnosed early enough, a discussion of fetal surgery is warranted. Currently, this option is available at only 2 major centers: Vanderbilt Medical Center and University of Pennsylvania. Although this approach has not been proven scientifically advantageous, preliminary evidence suggests that this experimental approach has promise in decreasing resultant neurologic problems in the neonate. Long-term outcome data are currently lacking.
If conventional delivery is chosen, the study by Shurtleff and his colleagues is important to note.  Infants with neural tube defect who were exposed to labor and vaginal delivery were more than twice as likely to have severe paralysis or motor deterioration than those who undergo Cesarean delivery without labor. Although this remains a controversial point, most centers, such as that of the author, recommend a Cesarean delivery prior to labor in mothers carrying a fetus with a myelomeningocele.