114: Neural Tube Defects

Neural tube defects (NTDs) are malformations of the developing brain and spinal cord. In normal development, the closure of the neural tube occurs over a 4- to 6-day period with completion around the 29th day postconception, often before a woman has realized that she is pregnant. Most current hypotheses consider NTDs to be defects from failure of a neural tube closure rather than the reopening of a previously closed tube. Most likely, the closure starts at several distinct sites rather than being one continuous process. The nomenclature for NTDs is not standardized and is thus often confusing. Frequently used terms are as follows:

1. Anencephaly. The defective closure of the upper or rostral end of the anterior neural tube. Hemorrhagic and degenerated neural tissue is exposed through an uncovered cranial opening extending from the lamina terminalis to the foramen magnum. Infants with anencephaly have a typical appearance with prominent eyes when viewed face on. Craniorachischisis totalis (a neural platelike structure without skeletal or dermal covering resulting from complete failure of neural tube closure) and myeloschisis or rachischisis (in which the spinal cord is exposed posteriorly without skeletal or dermal covering because of failure of posterior neural tube closure) are other, less frequent open lesions.

2. Encephalocele. Herniation of brain tissue outside the cranial cavity resulting from a mesodermal defect occurring at or shortly after anterior neural tube closure; usually a closed lesion. Approximately 80% of encephaloceles occur in the occipital region.

3. Myelomeningocele. Often also referred to as spina bifida (protrusion of the spinal cord into a sac on the back through a deficient axial skeleton with variable dermal covering). Considering that, strictly speaking, “spina bifida” only describes the bony defect, the term spinal dysraphism is considered more accurate by some. More than 80% of defects in this category occur in the lumbar region, and ∼80% are not covered by skin. In contrast to myelomeningoceles, meningoceles (closed lesions involving the meninges only) usually do not result in neurologic deficits.

4. Spina bifida occulta and occult spinal dysraphism. Disorders of the caudal neural tube that are covered by skin (skin dimples or only very small skin lesions are present). These dysraphic disturbances range from cystic dilation of the central canal (myelocystocele), over bifida spinal cords with or without a separating bony, cartilaginous, or fibrous septum (diastematomyelia or diplomyelia), to a tethered cord with a dermal sinus or other visible changes such as hair tufts, lipomas, or hemangiomas. The term spina bifida occulta is used incorrectly when it is applied to an incomplete ossification of the posterior vertebral arch, a frequent and insignificant finding that is neither clinically nor genetically related to NTDs.

Ninety-five percent of children with NTDs are born to couples with no family history of such defects.

1. Statistics related to NTDs are to be interpreted with caution and in the context of population, location, and time because occurrence of NTDs is affected by many epidemiologic and medical factors (see later sections).

2. The overall worldwide incidence has been quoted as ∼1 in 1000 live births. More recently, frequency has been given as ∼0.2 per 1000 live births.

3. Spina bifida occulta, myelomeningocele, and anencephaly are the more frequently encountered NTDs.

4. At early embryonic stages, the incidence of NTDs is as high as 2.5%; many abort spontaneously.

5. The Centers for Disease Control and Prevention (CDC) reports that ∼1500 infants with spina bifida are born in the United States per year. The prevalence of neural tube defects (spina bifida and anencephaly) is decreasing (data include more than half of the U.S. states): prevalence was 7.92 per 10,000 for 1996 (year of birth) and decreased during the years after introduction of mandatory fortification to a prevalence of 4.61 per 10,000 in 2006 (year of birth).

6. Medical costs are significant. For 2009, the medical costs for an infant with spina bifida in the United States are estimated at more than $50,000; even later in life, the costs of health care are estimated to be 3–6 times higher for a person with a neural tube defect as compared with a person without such defect.

7. Countries that have implemented mandatory fortification programs have reported a 30–50% reduction in incidence. For the United States, a 19% reduction in the birth prevalence of NTDs was reported after the introduction of folic acid fortification of the U.S. food supply.

8. Geographic variation, sex, race, and social class

   1. The incidence is higher in females versus males.

   2. The risk is approximately doubled for infants born to Hispanic women compared with white women. The risk seems lower in Ashkenazi Jews than in whites of European descent.

   3. Some populations with frequent consanguineous matings have an increased risk.

   4. The risk for African Americans and Asians is lowest. But the incidence in northern China is higher: 5–6 in 1000 births.

   5. The risk is increased in infants of particularly young or particularly older mothers of lower socioeconomic class. This increase may be related to nutritional factors and/or lower compliance with the recommendations for vitamin and folate supplementation.

The causes of NTDs seem to be multifactorial in most cases of anencephaly, encephalocele, myelomeningocele, and meningocele. Interactions between genetic and environmental factors result in disturbance of normal development. Recognized causes or contributing factors include the following:

1. Nutritional and vitamin deficiencies. Main concern: folic acid deficiency; other deficiencies linked to NTDs: vitamin B₁₂ and zinc.

2. Chromosome abnormalities. Include trisomies 13 and 18, triploidy, unbalanced translocations, and ring chromosomes.

3. Genetic syndromes. NTDs have been observed as part of a variety of syndromes, some with Mendelian inheritance patterns. A typical example is Meckel-Gruber syndrome (autosomal recessive), which presents with encephalocele, microcephaly, polydactyly, cystic dysplastic kidneys, and other anomalies of the urogenital system. Genetic references and databases list >50 syndromes associated with NTDs in the differential diagnosis. Recent advances into the understanding of neurodevelopment emphasize the importance of intact primary cilia and signaling pathways for normal development.

4. Teratogens. Nitrates (cured meat, blighted potatoes, salicylates, and hard water), antifolates (aminopterin, methotrexate, phenytoin, phenobarbital, primidone, carbamazepine, and valproic acid), thalidomide, and abnormal glucose homeostasis in diabetic mothers have all been implicated as causes of neural tube defects. The role of other potential causes of NTD remains controversial; a potential interference with normal neurodevelopment has been discussed for a variety of exposures, including (but not limited to) lead, glycol, clomiphene, hazardous waste, and maternal hyperthermia.

5. Other causes. An overall increase in birth defects has been reported in infants of teenage mothers (<20 years old) compared with those mothers in the 25- to 29-year age range. The relative risk of nervous system defects in infants of teen mothers is 3.4 times that for children of 25- to 29-year-old mothers. Although a low body mass index does not increase the risk for NTDs, obesity does. The parents' ages are not related to the occurrence of NTDs per se; the risk for twins seems higher (a 2- to 5-fold increase).

1. The occurrence of NTDs appears higher in the following:

   1. Women with insulin-dependent diabetes mellitus (the risk appears to be influenced by the level of control).

   2. Women with seizure disorders who are being treated with valproic acid or carbamazepine.

   3. Women with a family history of NTDs.

2. The recurrence risk is as follows:

   1. Two to three percent with 1 affected sibling. Some types of NTDs may be folic acid resistant, and even with folic acid treatment, a residual risk of ∼1% remains.

   2. Approximately 4–6% with 2 affected siblings. Higher if other associated findings suggest a syndrome/condition with possible Mendelian inheritance.

Clinical presentations of the most severe NTDs are the obvious cranial defect in anencephaly and open spinal defects of the thoracic and/or lumbar spine with open spinal NTDs, both with exposure of neural tissue. NTDs with an intact skin cover may show an obvious mass (eg, an occipital encephalocele) or be more subtle. Subtle findings include bulging of the skin cover over the occipital or spinal defect, small openings sometimes missed on initial examination, dimples, or hair patches. See Section I for definitions and description of the different NTDs.

1. Prenatal screen using maternal serum α-fetoprotein (AFP) at 14–16 weeks' gestation. Elevated levels (>2.5 multiples of the mean, which are adjusted to gestational age) are indicative of open NTDs at a sensitivity of 90–100%, a specificity of 96%, and a negative predictive value of 99–100% but a low positive predictive value.

2. Prenatal diagnosis. Documentation of an elevated maternal serum AFP is followed by:

   1. Genetic counseling. The patient should receive counseling on the risk of NTDs and other conditions with elevated AFP (gastroschisis or other conditions leading to fetal skin defects) in her fetus. Causes of possible false-positive results (imprecise dates or twin pregnancies) need to be investigated. Options regarding further evaluation (see later) are to be discussed, and nondirective counseling regarding treatment options should be provided.

   2. Detailed fetal ultrasonography with anomaly screening. In skilled hands, a detailed ultrasonogram (now often enhanced by 3-dimensional images) can be extremely sensitive and specific for detection of NTDs. Sonographic determination of the level of the lesion is useful in predicting the ambulatory potential of fetuses with NTDs. Ultrasonography is also done to rule out other major congenital defects and is now often aided by fetal magnetic resonance imaging (MRI).

   3. Measurement of the amniotic fluid AFP and acetylcholinesterase. Amniocentesis is usually done between 16 and 18 weeks' gestation, although it can technically be done as early as 14 weeks' gestation. If indicated, a karyotype can also be obtained. The detection rate for anencephaly and open spina bifida is 100% when results of amniotic fluid acetylcholinesterase and AFP are combined, with a false-positive rate of only 0.04%.

1. Prevention of NTDs

   1. The British Medical Research Council (MRC) demonstrated in 1991 that high-dose folate (4 mg/d) reduced the recurrence risk of NTDs by 72%.

   2. Based on results from the MRC, the U.S. National Institute of Child Health and Human Development (NICHD), CDC, U.S. Preventative Services Task Force, and American Academy of Pediatrics (AAP) published recommendations regarding folic acid intake for women of childbearing age. The American Academy of Pediatrics Committee on Genetics gives the following recommendations in their policy statement from 1999 (reaffirmed in 2007):

      1. All women of childbearing age who are capable of becoming pregnant should consume 0.4 mg of folic acid daily. The committee encourages food fortification. In the absence of optimal fortification, supplementation is encouraged. Use of a multivitamin with 0.4 mg of folic acid is quoted as the most convenient, inexpensive, and direct way to meet the recommended dosage.

      2. Women with a previous pregnancy resulting in a fetus affected by an NTD should consume 4 mg of folic acid. High levels of folic acid intake should not be achieved by use of over-the-counter multivitamin preparations. The higher-level folic acid intake is also recommended for certain other high-risk persons.

      3. Folic acid should ideally be taken before conception and at least through the first few months of gestation. See the AAP Policy Statement for further details of the recommendations.

   3. Sources of folic acid

      1. Dietary. The average U.S. diet used to contain about 0.2 mg of folate, which is less bioavailable than folic acid. Folate intake of 0.4 mg/d can be achieved through careful selection of folate-rich foods (spinach and other leafy green vegetables, dried beans, peas, liver, and citrus fruits). Since January 1998, enriched grains (including flour, bread, rolls, cornmeal, pasta, and rice) in the United States are fortified with folic acid by order of the U.S. Food and Drug Administration. Some countries have opted against food fortification due to concerns about adverse effects (masking of vitamin B₁₂ deficiency, potential promotion of tumor growth) and issues relating to freedom of choice.

      2. Supplementation. Folic acid is available over the counter and by prescription. Prenatal vitamins typically contain 0.8 or 1 mg of folic acid. A survey by the March of Dimes revealed that only 27% of nonpregnant women 18–45 years of age took a vitamin preparation containing folic acid in 2001. Awareness of the U.S. Public Health Service recommendation regarding folic acid did more than double from 1995–2002 (from 15 to 32%) for the same group. Multiple sources are available to provide educational material: March of Dimes (www.marchofdimes.com), CDC (www.cdc.gov), AAP (www.aap.org), and American College of Obstetrics and Gynecology (www.acog.org).

   4. Current epidemiologic and biochemical evidence suggests that NTDs are not primarily due to folate insufficiency but rather arise from changes in the metabolism of folate and possibly vitamin B₁₂ in predisposed women. The mechanisms may also involve homocysteine metabolism. Polymorphisms of methylene tetrahydrofolate reductase and other genes encoding proteins involved in folate metabolism may be associated with an increased frequency of NTDs. Due to the homocysteine-lowering effect of folic acid, supplementation may also reduce the risk for cardiovascular disease. Some studies suggest that folate and vitamin supplementation may also reduce the risk for other birth defects (including congenital heart defects, orofacial clefts, urinary tract and limb defects, or even occurrence of trisomy 21). Other reports suggest an inverse association between folate intake and breast cancer, childhood neuroblastoma, and acute lymphoblastic leukemia. Promotion of tumor growth and the obscuring of vitamin B₁₂ deficiency have been discussed as potential adverse effects of folate supplementation.

2. Specific management

   1. Anencephaly

      1. Approximately 75% of anencephalic infants are stillborn. Most live-born infants with anencephaly die within the first 2 weeks of birth.

      2. Considering the lethality of anencephaly, usually only supportive care is given. This includes warmth, comfort, and enteral nutrition. Support services for the family, including social work and genetic and general counseling, are essential. There are some ethically controversial issues regarding the extent of care and other issues (eg, organ donation), and it may be advisable to involve other support systems (eg, ethics committees, support groups, or religious guidance—if desired by the family). For family support or other resources, see Section VII.B.3h.

   2. Encephalocele

      1. Physical examination and initial management. In addition to the general principles of neonatal resuscitation, an especially careful physical examination is indicated. Look for associated malformations. As mentioned in Section III.C, some genetic reference texts and databases list >50 syndromes associated with NTDs. We recommend that the child be given nothing by mouth until the consultations by subspecialties such as neurosurgery are obtained and a treatment plan has been formulated. Imaging studies (ultrasonography, computed tomography, and MRI) should be arranged. Genetic evaluation and testing should be initiated early, considering the turnaround time of many tests that may be ordered (eg, karyotype and others).

      2. Neurosurgical intervention. May be indicated to prevent ulceration and infection, except in those cases with massive lesions and marked microcephaly. The encephalocele and its contents are often excised because the brain tissue within is frequently infarcted and distorted. Surgery may be deferred, depending on the size, skin coverage, and location. Ventriculoperitoneal (VP) shunt placement may be required because as many as 50% of cases have secondary hydrocephalus.

      3. Counseling and long-term outcome. A multidisciplinary approach is necessary to counsel the family regarding recurrence risk, long-term outcome, and follow-up. For family support and other resources, see Section VII.B.3h. The degree of deficits is determined mainly by the extent of herniation and location; one or both cerebral hemispheres, the cerebellum, and even the brainstem can be involved. Visual deficits are common with occipital encephaloceles. Motor and intellectual deficits are found in ∼50% of patients.

   3. Myelomeningocele. Traditionally, postnatal surgery and management by a multidisciplinary team is the treatment for myelomeningocele. After the publication of the Management of Myelomeningocele Study (MOMS) in 2011, a review of this approach might need to be considered. The study found that prenatal surgery for myelomeningocele reduced the need for placement of a cerebrospinal fluid shunt and improved motor outcomes at 30 months but was associated with maternal and fetal risks. After birth, a multidisciplinary team approach, including the primary care physician, geneticist, genetic counselor, neonatologist, urologist, neurosurgeon, orthopedic surgeon, and social worker, is necessary.

      1. Physical examination. A physical examination should include careful evaluation for other malformations (see Section III.C). In addition, special efforts should be made to correlate motor, sensory, and sphincter function and reflexes to the functional level of lesion (Table 114–1). Voluntary muscle movements are difficult to elicit in newborns with myelomeningocele and therefore are not helpful during initial evaluation. Furthermore, motor examination may be distorted initially by reversible spinal cord dysfunction above the level of the actual defect induced by exposure of the open cord.

         1. Extent of neurologic dysfunction tends to correlate with the level of the spinal cord lesion.

         2. Paraplegia typically below the level of the defect.

         3. The presence of the anal wink and anal sphincter tone suggests functioning sacral spinal segments and is prognostically important. In one study, 90% of patients with a positive anocutaneous reflex were determined to be “dry” on a regimen of intermittent catheterization as opposed to 50% of those with a negative reflex.

      2. Initial management. In addition to following the general principles of neonatal resuscitation and newborn care, appropriate management of the spinal lesion is essential.

         1. There are institutional differences in the specifics of how to cover the lesion, and provision of a sterile cover can be achieved by several means. Some surgeons request that the infant be placed in a sterile plastic bag; others prefer application of plastic wrap to cover the lesion. Many recommend avoiding contact with gauze or other material that could adhere to the tissue and result in mechanical damage when removed. It is advisable to try to keep the defective area moist while avoiding bacterial contamination. If tolerated, the patient should be positioned on the side. Fecal contamination should be avoided, which sometimes is easier with methods covering the site only rather than placement of the infant's complete lower body in a plastic bag.

         2. Be aware that a high rate of latex allergies are reported in patients with NTDs. All patients with myelodysplasia should be considered at risk for anaphylaxis and other allergic complications. Latex avoidance is practiced as a preventive protocol. One study showed that after 6 years of a latex-free environment, the prevalence of latex sensitization fell from 26.7% to 4.5% of children with spina bifida. A resource regarding issues relating to latex allergy is the website of the American Latex Allergy Association (www.latexallergyresources.org).

         3. In most centers, patients are started on antibiotics and given nothing by mouth.

         4. Arrange for imaging studies to evaluate for hydrocephalus or other malformations detected or suspected on physical examination.

      3. Surgical management. Usually closure of the back lesion is done within 48 hours to prevent infection and further loss of function.

      4. Hydrocephalus. Common and often noncommunicative secondary to associated Arnold-Chiari malformation of the foramen magnum and upper cervical canal (usually type II) with resultant downward displacement of the medulla, pons, and cerebellum and obstruction of cerebrospinal fluid flow.

         1. The risk of hydrocephalus is 95% for infants with thoracolumbar, lumbar, and lumbosacral lesions and 63% for those with occipital, cervical, thoracic, or sacral lesions.

         2. In some cases, hydrocephalus may not be evident until after closure of the myelomeningocele, and placement of a VP shunt may be required at a later date.

         3. Aggressive treatment with early VP shunt placement may improve cognitive function.

         4. Serial ultrasound scans are necessary to monitor the degree of hydrocephalus because ventricular dilation may occur without rapid head growth or signs of increased intracranial pressure. The hydrocephalus often becomes clinically overt 2–3 weeks after birth.

         5. Despite treatment of the myelomeningocele and hydrocephalus, some infants may still succumb to death from complications or associated anomalies.

      5. Urinary tract dysfunction. One of the major causes of morbidity and mortality after the first year of life.

         1. More than 85% of myelomeningoceles located above S2 are associated with neurogenic bladder dysfunction, urinary incontinence, and ureteral reflux. Poor bladder emptying immediately after NTD closure may be temporary (“spinal shock”) and improvement of bladder function may be observed up to 6 weeks after repair.

         2. Without proper management, hydronephrosis may develop, with progressive scarring and destruction of the kidneys.

         3. Renal ultrasonography and a voiding cystourethrogram may identify patients who may benefit from anticholinergic medication, clean and intermittent catheterization, prophylactic antibiotics, or early surgical intervention.

         4. Other associated renal anomalies may be present in patients with NTDs, including renal agenesis, horseshoe kidneys, and ureteral duplications.

      6. Orthopedic issues

         1. With impairment of lower extremity innervation, the risk of atrophy is high.

         2. Deformities of the foot, knee, hip, and spine are common as a result of muscle imbalance, abnormal in utero positioning, or teratologic factors.

         3. Hip dislocation or subluxation may occur and is usually evident within the first year of life; common in patients with midlumbar myelomeningocele.

         4. Treatment of orthopedic abnormalities should be instituted as soon as there is sufficient healing of the back wound.

         5. Physical therapists assist with proper positioning of the extremities to minimize contractures and to maximize function.

      7. Outcome of aggressive therapy

         1. The overall mortality rate is now <15% by 3–7 years of age; 1-year survival of infants with spina bifida has been reported as high as 87.2%. In multivariable analysis, factors associated with increased mortality were low birthweight and high lesions.

         2. Infants with sacral lesions have essentially no mortality.

         3. The outcome in regard to the highest potential for ambulation depends largely on the level of the original lesion (see Table 114–1) and is modified by the orthopedic treatment and potential complications (see Section VII.B.3f).

         4. A significant percentage of children with lumbar myelomeningocele score within the normal range on intelligence and achievement tests. Deficits, possibly progressive, for performance IQ, arithmetic achievement, and visuomotor integration have been reported; reading and spelling may be less affected.

         5. An IQ >80 is found in essentially all patients with lesions below S1; ∼50% of survivors with thoracolumbar lesions have IQ >80.

         6. Cognitive function is improved in the presence of favorable socioeconomic and environmental factors.

      8. Family support groups, educational material and other resources. Educational material and information regarding existing support groups may be found at the following sites: March of Dimes (www.marchofdimes.com); Spina Bifida Association of America (www.spinabifidaassociation.org); International Federation for Spina Bifida and Hydrocephalus (based in Europe; www.ifglobal.org); National Institute of Neurological Disorders and Stroke (www.ninds.nih.gov). For information about latex allergy and its prevention, see American Latex Allergy Association (www.latexallergyresources.org).

   4. Spina bifida occulta

      1. Neonatal features. The presence of spina bifida occulta is suggested by overlying abnormal collections of hair, hemangiomas, pigmented macules, aplasia cutis congenita, skin tags, subcutaneous masses, cutaneous dimples, or tracts, usually in the lumbosacral area.

      2. If undetected in the neonatal period, clinical presentation later in infancy may include delay in development of sphincter control, delay in walking, development of a foot deformity, and/or recurrent meningitis. Sudden symptoms may represent vascular insufficiency produced by tension on a tethered cord, angulation of the cord around fibrous or related structures, or cord compression from a tumor or cyst.

      3. Diagnosis

         1. Ultrasonography is useful for screening. Note that the acoustic window used to diagnose a tethered cord closes at 3–6 months.

         2. Magnetic resonance imaging provides superior anatomic details. An advantage of an MRI is the lack of exposure to radiation; contrast is usually not needed.

      4. Early surgical correction may be necessary to avoid the onset of symptoms. A timely surgical release of a tethered cord or decompression of the spinal cord in patients developing symptoms may completely or partially reverse recently acquired deficits.

See individual topics in management section.