Neural Tube Defects

Basics

Description

Neural tube defects (NTDs): CNS malformations due to abnormalities of neural tube closure during early embryonic development that can be either open or closed defects. Spina bifida (SB) is a term referring to a subset of NTDs involving the spinal cord and means “spine split in two.”

  • Anencephaly: due to failed closure of rostral neural tube with total or partial absence of cranial vault and cerebral hemispheres
  • Encephalocele: partial failure of rostral neural tube closure
    • Abnormal brain tissue protrudes through a skull defect usually covered by skin.
    • 70–80% are occipital; 20% are frontal.
    • 10–20% of occipital defects are meningoceles and contain no brain tissue.
  • Open SB: Exposed neural tissue and membranes protrude through a bony defect.
    • Due to failure of primary neural tube closure during the 3rd and 4th weeks after fertilization
    • Includes myelomeningocele (MMC) and myeloschisis
    • MMC: open NTD of the spine, most common type of SB, and characterized by herniation of dysplastic spinal cord and meninges through a posterior vertebral column defect
  • Closed SB: Often referred to as occult spinal dysraphism (OSD). Theorized to be due to defects of secondary neurulation; less common than open NTDs
    • Often not diagnosed at birth
    • Skin-covered lesions
    • Wide spectrum of defects including lipomyelomeningocele, dermal sinus tracts, diastematomyelia (split cord malformations), myelocystocele, other tumors and cysts of the cord, and congenital spinal cord tethering

Epidemiology

  • NTDs affect ~1 in 1,000 established pregnancies worldwide, with significant geographic variation.
  • In the United States, birth prevalence has been decreasing due to periconceptional supplementation with folic acid, food fortification, as well as prenatal diagnosis and termination of pregnancy.
  • Centers for Disease Control and Prevention (CDC) data from 2004 to 2006 showed 0.64 NTDs per 1,000 births (~2,660 cases per year), with 54% classified as SB, 32% anencephaly, and 13% encephalocele.

Risk Factors

Most NTDs are due to the interaction of genetic, environmental, and dietary risk factors.

  • Variants of multiple genes probably confer some increased genetic susceptibility.
  • Maternal nutrition and dietary factors, including inadequate maternal folic acid intake
  • Maternal diabetes mellitus
  • Maternal obesity
  • Maternal use of valproic acid (10 times risk), carbamazepine, or alcohol during pregnancy
  • Maternal exposure to hyperthermia during early pregnancy (e.g., sauna, hot tub, fever)
  • Prior pregnancy with NTD

Genetics

  • A specific genetic cause is not found for most NTDs.
  • Positive family history in ~5% NTD cases
  • After one child with an NTD, the recurrence rate is 2–5% for subsequent pregnancies.
  • A chromosomal or cytogenetic abnormality found only in ~10% of isolated NTDs; higher percentage in those with multiple congenital anomalies
  • NTDs are common in trisomy 13 and 18 and can be seen with duplications and deletions.
  • Found in single gene disorders or syndromes (e.g., Meckel, Waardenburg, 22q11 deletion syndromes)
  • A number of candidate risk factor genes have been studied; the most implicated are those in the folate one-carbon metabolic pathway.
    • A homozygous 677C > T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene in mother or child is associated with ~1.8 times increased risk.

General Prevention

  • Periconceptual folic acid supplementation has the potential to reduce NTDs by 50–70%.
  • Because many pregnancies are not identified until after neural tube closure occurs and because >50% of pregnancies are unplanned, the CDC recommends that all women of childbearing age receive a minimum of 0.4 mg (400 mcg) of folic acid daily.
  • Women at high risk (prior pregnancy with NTD, on valproic acid, etc.) should take high-dose folic acid (4 mg daily), starting 1 month before and through the first 3 months of pregnancy.
  • If taking valproic acid, consider switching to alternative medication during pregnancy.

Commonly Associated Conditions

  • MMC is virtually always associated with some malformation of the brain.
  • Most children with MMC have a Chiari II (Arnold-Chiari) malformation, small posterior fossa with elongation of the cerebellum, and herniation through the foramen magnum.
    • Chiari II malformation often causes obstructive hydrocephalus.
    • Historically, about 80% of children with MMC required a CSF shunt.
  • Callosal dysgenesis, cortical dysplasia, and subependymal heterotopias are also common.
  • MMC is commonly associated with nonverbal learning disabilities and executive dysfunction.
  • Open and closed SB impairments from spinal cord dysfunction:
    • Paraparesis and sensory loss usually correlating with the level of the lesion
    • Neurogenic bladder dysfunction
    • Neurogenic bowel dysfunction
  • Congenital foot deformities (club foot) and hip dysplasia are common with NTDs.

Diagnosis

History

  • Anencephaly, occipital encephaloceles, and open forms of SB are usually diagnosed prenatally and are obvious at birth.
  • Occult frontal encephaloceles may come to attention because of developmental delays, seizures, or focal neurologic signs.
  • OSDs can present with progressive neurogenic bowel and bladder dysfunction, lower extremity (LE) weakness and/or sensory loss, gait abnormalities, foot deformities, and (rarely) recurrent meningitis.

Physical Exam

  • Serial head circumferences (HC) are used to monitor infants for progressive hydrocephalus.
    • Macrocephaly strongly suggests increased intracranial pressure (ICP).
    • Normal HC but, with increasing percentiles over time, may indicate hydrocephalus
  • Dysmorphic features may indicate a syndrome.
  • Cranial nerve palsies (strabismus, vocal cord paresis, facial asymmetry), upper extremity (UE) weakness, and abnormal muscle tone can be seen with Chiari II malformation.
  • OSD often signaled by a dimple, sinus tract, lipoma, hemangioma, or tuft of hair in the lumbosacral area.
  • Functional motor level correlates with ambulatory potential in patients with SB.
  • Flaccid paralysis is usually seen below the SB lesion; however, spasticity can be seen.
  • Sensory level may not correspond to motor level.
  • Signs/symptoms of tethered cord syndrome include worsening LE weakness, spasticity, and/or positional back pain.
  • Limb growth may be asymmetric with shorter limb on more affected side (especially in OSD).
  • Orthopedic exam should focus on hips, feet/ankles, and spine.
  • Skin exam is important for identifying pressure ulcers in areas of impaired sensation.

Diagnostic Tests and Interpretation

Initial Tests

  • Maternal:
    • Maternal serum α-fetoprotein (MSAFP) testing, routinely done at 16 to 18 weeks’ gestation, is usually elevated with open NTDs.
    • Elevated MSAFP should prompt referral for high-resolution ultrasound.
    • Genetic testing including chromosomal microarray is often done to look for cause.
  • Child:
    • Annual evaluations of renal function with serum creatinine (cystatin C also being used, as it is not dependent on muscle mass)
    • Annual vitamin D 25-OH levels given risk of deficiency and fractures
  • Prenatal ultrasound
    • Identifies >99% of cases of anencephaly and 90% of cases of MMC
  • Postnatal neuroimaging
    • CT: often used to evaluate hydrocephalus: for initial newborn scan and older children when acute shunt malfunction suspected
    • Ultrasound: useful before anterior fontanel closes, especially to monitor hydrocephalus
    • MRI: gold standard for evaluating congenital anomalies of the spine and brain
      • For most patients with MMC, MRI is not necessary in the newborn period.
      • MRIs are better for defining the Chiari II malformation and other brain anomalies.
      • Spine MRI is used to evaluate tethered cord or syringomyelia.
  • Evaluation for suspected OSD
    • Spine ultrasound may be useful for ruling out OSD or tethered cord in newborn or young infant.
    • MRI is used to diagnose and define OSD in infants >6 months of age.
      • Lumbosacral MRI will identify most lesions.
      • However, consider MRI of brain and entire spine to evaluate for higher associated CNS anomalies (e.g., syringomyelia, diastematomyelia, Chiari malformation).
    • OSD is common incidental finding on imaging.
    • Isolated OSD can be found in ~10% of the general population at autopsy.
    • OSD is usually asymptomatic but should be vigilant for signs/symptoms of neurologic involvement.
    • Further imaging is usually not necessary.
  • Renal imaging is commonly done in children with MMC or other types of SB.
    • Ultrasound of kidneys and bladder is used to evaluate urinary tract in newborns and on regular basis in older children to monitor for hydronephrosis, hydroureter, and stones.
    • Voiding cystourethrogram (VCUG) is used to evaluate bladder emptying and vesicoureteral reflux in newborns and later as needed.
    • Nuclear medicine studies can be useful for evaluating kidney function and scarring from previous pyelonephritis.

Diagnostic Procedures/Other

  • Urodynamic studies (cystometrograms) are used to evaluate bladder function and identify those at high risk for hydronephrosis as well as for objective data that can be used in conjunction with history and physical examination to evaluate for neuropathic changes as a result of tethered cord.
  • EEG for suspected seizures

Treatment

General Measures

  • Route of delivery
    • For most NTDs with vertex presentation, no clear benefit of cesarean section (CS)
    • Infants who undergo fetal surgery delivered by CS
  • Clean intermittent catheterization (CIC):
    • Commonly used for neurogenic bladder dysfunction
    • CIC started in newborns with hydronephrosis, high-grade reflux, or high postvoid residuals
    • In addition to above, CIC used in older children just to achieve continence
  • Latex precautions: avoidance of natural rubber latex to prevent development of latex allergy

Medication (Drugs)

  • Anticholinergic medications (e.g., oxybutynin, tolterodine) are used to relax the spastic bladder and increase capacity.
  • Prophylactic antibiotics used for significant vesicoureteral reflux or recurrent urinary tract infections (UTIs)

Additional Therapies

  • Infants with SB are generally referred to their state’s early intervention program.
  • Older children typically receive therapy in school but may benefit from additional therapy through the health care system.

Diagnostic Procedures/Other

  • Open encephalocele and SB: neurosurgical closure usually done within first few days of life to prevent infection and protect brain/spinal cord from injury. A moist, sterile dressing is applied to the defect until it is closed.
  • Hydrocephalus often develops after an open NTD is closed (stopping leakage of CSF).
  • CSF shunts (usually ventriculoperitoneal [VP]) are placed to treat progressive hydrocephalus.
  • Open fetal closure of MMC has been associated with reduced risk of hydrocephalus and improved developmental and motor outcomes in one prospective randomized trial.
  • Fetal surgery for MMC should be considered in select patients prior to 26 weeks’ gestation and is considered a new standard of care option at select fetal surgery centers; long-term follow-up studies still needed
  • OSD: Neurosurgical exploration and untethering of the spinal cord is usually done after diagnosis.
  • Multiple urologic and orthopedic procedures are used to treat the complications of SB. Extensive discussion is beyond the scope of this chapter.

Ongoing Care

Children with symptomatic SB ideally should be followed in a multidisciplinary SB clinic that includes neurosurgery, urology, and orthopedics as well as a medical generalist (pediatrics, physiatry, or neurology) with experience evaluating and treating children with SB.

  • Other important specialties include:
    • Physical therapy (mobility, LE function, bracing)
    • Occupational therapy (ADLs, UE function, including self-catheterization)
    • General psychology, neuropsychology, and/or behavioral psychology (cognitive and executive function, addressing increasing independence)
    • Social work (coping, adjustment to chronic illness, linkage to resources)
    • Ophthalmology (can identify increased ICP when imaging is equivocal)

Prognosis

  • Anencephaly: 75% are stillborn; the remainder do not survive beyond the neonatal period.
  • Encephalocele: Prognosis depends on the size of the defect, the amount of brain tissue involved, development of hydrocephalus, and the extent of associated brain malformation.
  • MMC
    • Most survive into adulthood.
    • Most have IQ in normal range, and almost all of remainder have mild intellectual disability. However, nonverbal learning disabilities and executive dysfunction are very common.
    • Risk of epilepsy ~15%; corresponds to degree of intellectual disability
  • SB (open and closed types)
    • Prognosis for ambulation depends on the functional level of the lesion:
      • Sacral level: Most are community ambulators without assistive devices.
      • Low lumbar (L4–L5): Most will walk, but many require bracing and some require crutches or other assistive devices.
      • Midlumbar (L3): often require bracing of the knee (and sometimes hip) to walk with crutches or a walker
      • High lumbar (L1–L2) and thoracic: usually walk in therapy only and use wheelchair as primary means of mobility

Complications

  • Encephalocele: Hydrocephalus, intellectual disability, motor deficits, and epilepsy are common.
  • MMC
    • VP shunt infection or malfunction
    • Symptomatic Chiari II malformation
      • Infants: feeding difficulties/aspiration, hoarse cry or stridor (due to vocal cord paralysis), and central apnea
      • Older children: cranial nerve palsies, occipital headaches, UE weakness, sleep-disordered breathing, increasing tone over time
    • Syringomyelia
    • Strabismus
  • SB (open and closed types)
    • Neurogenic bladder: UTI, hydronephrosis, stones, incontinence, risk of CKD
    • Neurogenic bowel: constipation, impaction, incontinence
    • Orthopedic deformities: scoliosis, hip dysplasia, ankle/foot deformities
    • Tethered spinal cord syndrome
    • Latex allergy
    • Pressure ulcers
    • Osteoporosis and pathologic fractures
    • Deep venous thrombosis
    • Obesity (especially nonambulatory patients)
    • Sexual dysfunction

Additional Reading

  1. Adzick NS, Thom EA, Spong CY, et al; for MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993–1004.  [PMID:21306277]
  2. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol. 2013;12(8):799–810.  [PMID:23790957]
  3. Dennis M, Barnes MA. The cognitive phenotype of spina bifida meningomyelocele. Dev Disabil Res Rev. 2010;16(1):31–39.  [PMID:20419769]
  4. Liptak GS, Dosa NP. Myelomeningocele. Pediatr Rev. 2010;31(11):443–450.  [PMID:21041422]
  5. Sandler AD. Children with spina bifida: key clinical issues. Pediatr Clin North Am. 2010;57(4):879–892.  [PMID:20883878]

Codes

ICD-9

  • 740.0 Anencephalus
  • 742.0 Encephalocele
  • 756.17 Spina bifida occulta
  • 741.93 Spina bifida without mention of hydrocephalus, lumbar region
  • 741.00 Spina bifida with hydrocephalus, unspecified region
  • 741.03 Spina bifida with hydrocephalus, lumbar region
  • 741.90 Spina bifida without mention of hydrocephalus, unspecified region

ICD-10

  • Q00.0 Anencephaly
  • Q01.9 Encephalocele, unspecified
  • Q76.0 Spina bifida occulta
  • Q05.7 Lumbar spina bifida without hydrocephalus
  • Q05.2 Lumbar spina bifida with hydrocephalus
  • Q07.9 Congenital malformation of nervous system, unspecified
  • Q07.8 Other specified congenital malformations of nervous system
  • Q07.03 Arnold-Chiari syndrome with spina bifida and hydrocephalus
  • Q06.8 Other specified congenital malformations of spinal cord
  • Q05.9 Spina bifida, unspecified

SNOMED

  • 89369001 anencephalus (disorder)
  • 55999004 encephalocele (disorder)
  • 76916001 spina bifida occulta (disorder)
  • 204012009 Lumbar spina bifida without hydrocephalus - closed (disorder)
  • 203950009 Lumbar spina bifida with hydrocephalus - closed (disorder)
  • 253117002 closed spina bifida with Arnold-Chiari malformation (disorder)

FAQ

  • Q: Are neural defects genetic?
  • A: Genetic factors are definitely involved, but in most cases, a single genetic cause is not found.
  • Q: What is the chance of having another child with an NTD?
  • A: Recurrence risk with each subsequent pregnancy is about 2–5%.
  • Q: How can someone reduce their risk of having a child with an NTD?
  • A: Take 400 mcg of folic acid daily (or 4 mg if prior pregnancy with NTD), preferably starting 1 month prior to conception, and avoid alcohol and drugs that can increase risk (especially valproic acid).
  • Q: What are examples of reasons to initiate CIC for management of a neurogenic bladder?
  • A: To avoid kidney damage as a result of high transmitted pressures from the bladder; to reduce risk of UTIs; to achieve continence

Authors

Eric B. Levey, MD

Sarah A. Korth, MD


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