eMedicine Specialties > Neurology > Pediatric Neurology

Neural Tube Defects

Author: George I Jallo, MD, Associate Professor of Neurosurgery, Pediatrics and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine
Coauthor(s): Tibor Becske, MD, Assistant Professor, Department of Neurology, New York University Medical Center
Contributor Information and Disclosures

Updated: Dec 15, 2008

Introduction

Background

Neural tube defects (NTD) occur because of a defect in the neurulation process. Since the anterior and posterior neuropores close last, they are the most vulnerable to defects. Consequently, a majority of NTDs arise in these areas.

NTDs can be classified, based on embryological considerations and the presence or absence of exposed neural tissue, as open or closed types.

• Open NTDs frequently involve the entire CNS (eg, associated hydrocephalus, Chiari II malformation) and are due to failure of primary neurulation. Neural tissue is exposed with associated cerebrospinal fluid (CSF) leakage.
• Closed NTDs are localized and confined to the spine (brain rarely affected) and result from a defect in secondary neurulation. Neural tissue is not exposed and the defect is fully epithelialized, although the skin covering the defect may be dysplastic.

Cranial presentations include the following:

• Anencephaly
• Encephalocele (meningocele or meningomyelocele)
• Craniorachischisis totalis
• Congenital dermal sinus

Spinal presentations include the following:

• Spina bifida aperta (cystica)
• Myelomeningocele
• Meningocele
• Myeloschisis
• Congenital dermal sinus
• Lipomatous malformations (lipomyelomeningoceles)
• Split-cord malformations
• Diastematomyelia
• Diplomyelia
• Caudal agenesis

For more information on the classification of neural tube defects, see eMedicine article Spinal Dysraphism/Myelomeningocele.

Pathophysiology

Two distinct processes appear to be involved in the formation of the neural tube: primary neurulation and secondary neurulation (ie, canalization). The neural plate and the notochord are formed during early embryonic development. The neural groove develops by the third gestational week. Subsequently, the neural folds form bilaterally.

Primary neurulation

• The neural folds elevate, approximate each other, and start closing, thus forming the neural tube.
• The point of initial closure occurs at the caudal rhombencephalon or cranial spinal cord.
• The cutaneous ectoderm fuses first, followed by the neuroectoderm.
• The cranial neuropore closes during the fourth gestational week. The last area to close is the commissural plate.
• The caudal neuropore closes between T11 and S2.
• Parallel to this process, the cutaneous ectoderm separates from the neuroectoderm to form the overlying skin, while the lateral mesoderm migrates between the 2 ectodermal layers to form the posterior vertebral arches.

Secondary neurulation (canalization)

• This comprises further neural development occurring caudal to the caudal neuropore after the termination of primary neurulation.
• This process includes formation of the filum terminale and conus medullaris from a poorly differentiated cell mass of the medial eminence.
• Because of differential growth between the vertebral column and the spinal cord, the conus becomes more rostral during later development.

Open NTDs have been suggested to result from defective primary neurulation while defective secondary neurulation gives rise to closed NTDs. However, this issue is not settled. Another possible explanation is that open NTDs (spina bifida in particular) result from defects in either primary or secondary neurulation, depending on their site being cranial or caudal to the posterior neuropore (ie, upper and lower spina bifida, respectively).

Frequency

United States

• The incidence of NTDs declined 50% between 1970 and 1989 (0.6-1.3 cases per 1000 live births) in the United States.
• During this period, the proportion of spina bifida cases increased relative to anencephaly.
• The race ratio of whites to other races for isolated NTDs decreased and the risk of isolated NTDs in female infants also decreased.
• The highest incidence is in Appalachia (1 case per 1000 live births).
• Incidence is higher in the eastern United States than on the West Coast.

International

• NTDs are among the most common birth defects.
• They exhibit a marked geographical variation, with the incidence higher in Great Britain and lower in Japan.
• In white populations, the lowest birth incidence was noted in mainland Europe and the highest in Great Britain (especially Ireland).
• Currently, the highest reported incidence is in Northern China (3.7 cases per 1000 live births).
• Indian and Eastern Mediterranean populations (with the exception of Israeli Jews) also have relatively high incidences of NTDs. However, unlike the Western white populations, anencephaly is more common than spina bifida.

Mortality/Morbidity

• Anencephaly is incompatible with life.
  • No differentiated supratentorial neural tissue is present, and the brain stem consists of nests of poorly differentiated neural elements.
  • The brain stem is believed by some to be not sufficiently developed to be responsible for the temporary brainstem reflexes that are observed. Some have implicated the upper cervical cord as the seat of these functions.
  • The survival of these newborns is limited to a few hours (rarely >2 d).
  • In an earlier policy statement, the American Medical Association recommended that organs could be harvested from anencephalic infants even before the traditional criteria of death are met. However, the statement has since been revoked.
• Other NTDs may give rise to progressive neurological deterioration, which may present early after birth or later in life.
  • The neurological deficits may be due to accompanying hydrocephalus, a Chiari II malformation, tethering of the cord, cystic mass, or fibrous band compressing the neural elements.
  • Another possible complication is meningitis (infectious or chemical), especially in open NTDs.
  • The average recurrence risk of NTDs for parents with one affected child has been estimated to be about 5%, and that for monozygotic twins about 20%. Recurrence risks are higher in populations with a higher birth incidence.
• The most common NTD compatible with life is myelomeningocele (see Media files 1-2).
  • Its incidence is 1 case in 1,200-1,400 live births. It is a disease affecting 6,000-11,000 newborns in the United States each year.
  • Paralysis, bladder and bowel incontinence, and hydrocephalus are the most common clinical complications. Severe mental retardation is present in 10-15% of these patients.
  • Despite aggressive medical care, 10-15% of these children die prior to reaching the first grade. However, most children with isolated myelomeningocele (without major anomalies of other organs) survive to adulthood, and life expectancy is nearly normal.
  • Sixty percent have normal intelligence, although of these, 60% have some learning disability (math and problem solving being particularly difficult).
    • Attention deficit disorder without hyperactivity also has been described in these children.
    • Hydrocephalus is present in 85% but bears little relationship to intelligence.
    • About 80% are socially continent (although many require clean intermittent catheterization).

Race

• In studies done before the availability of prenatal screening and prophylactic vitamin supplementation, birth incidence of both spina bifida and anencephaly was reported to be higher in the European white population than in the black population.
• In North America, the risk of NTDs was found to be highest in the Hispanic population (more than 3-fold higher than that for non-Hispanic whites).
• Migration studies in the white migrant population showed a prevalence of NTDs that corresponded more closely to the risk of the place to which they had migrated, as opposed to the place of their origin.
  • In contrast, similar studies in descendants of the black and Asian migrant populations in Europe and North America showed prevalences not substantially higher than those of their parent countries.
  • These variations are consistent with the theory that NTDs are a phenotypically heterogeneous group of malformations with multifactorial inheritance in some cases and single gene defects in others.

Sex

• Anencephaly has a female preponderance, especially among premature births, with a female-to-male ratio of 3:1.
• Other NTDs above the thoracolumbar junction show a mild female preponderance.
• No such gender difference has been noted in more distal forms of spina bifida.

Age

• Open NTDs are readily visible at birth, with the majority being discovered during pregnancy.
• Closed NTDs may remain undetected for years, even decades, especially in the absence of cutaneous markers.

Clinical

History

• Most open NTDs are readily apparent at the time of birth.
• Closed NTDs have a variable presentation.
  • The most common presentation of a closed NTD is an obvious abnormality along the spine such as a fluid-filled cystic mass, area of hypopigmentation or hyperpigmentation, cutis aplasia, congenital dermal sinus, capillary telangiectasia/hemangioma, hairy patch (hypertrichosis), skin appendages, or asymmetrical gluteal cleft.
    • Common to all these patients is a fully epithelialized lesion and no visible neural tissue.
    • A closed NTD can present without a cutaneous marker.
  • The second most common reason for seeking medical attention is asymmetry of the legs and/or feet. One calf can be thinner, with a smaller foot on the same side, higher arch, and hammering or clawing of the toes.
  • Other children exhibit progressive spinal deformities such as scoliosis.
  • Some children present with a picture of progressive neurological deficits that may include weakness in one distal lower extremity, sensory loss in the same distribution, and bladder or bowel dysfunction.
  • Low back pain also can occur, sometimes without neurological deficit. Pain is more common in older children or adolescents.
  • Adults can present with the sudden onset of pain, motor and sensory loss, and bladder dysfunction after an acute trauma (eg, fall, motor vehicle accident, placement in lithotomy position). The reason for such presentation may be related to tethering of the cord (the distal end of the spinal cord is fixed in position). Mechanical forces associated with motion may produce compression and/or vascular insufficiency.
  • A patient with a closed NTD such as a congenital dermal sinus with an intraspinal dermoid cyst or a neurenteric cyst can present with symptoms of spinal cord compression due to enlargement of the mass.
  • A patient with a dermal sinus also can present with bacterial meningitis or spinal abscess.
  • Neurenteric or dermoid cysts also can present with repeated bouts of aseptic meningitis due to leaking of the contents into the spinal subarachnoid space.

Physical

A complete neurological assessment of the newborn with an open NTD should be performed to document the many possible structural and neurological problems. This provides a baseline for future comparison.

• Particularly important aspects of the evaluation are measurement of head circumference, assessment of general vigor (especially cry and sucking), upper extremity motor function, anal sphincter, and urinary stream, as well as thorough motor and sensory examination of the lower extremities and trunk.
• Usually the level of sensory dysfunction is slightly greater than the dysfunction detected on the motor examination.
• Motor examination involves observation of muscle bulk, spontaneous active movements, movements in response to stimulation, as well as assessment of muscle tone by palpation.
• Further information regarding the level of neurological dysfunction can be obtained from evaluation of hip and foot deformities. If the disparity in segmental level between the 2 sides is more than 1 level, an occult neurological problem must be suspected (eg, hemimyelia).
• The spine should be examined carefully, with determination of the size and site of the lesion.
  • The shape of the defect, size of the placode, and health and laxity of the surrounding skin and soft tissue should be noted carefully.
  • The presence of early spinal deformity (eg, kyphosis) also should be assessed.

Causes

• Several genetic and environmental factors have been implicated in the pathogenesis of NTDs.
  • A slight female predominance, and the higher incidence in certain ethnic groups and in the offspring of consanguineous marriages, have suggested a genetic basis for NTDs.
  • Chromosomal abnormalities (trisomy 13, 18, 21) also have been associated with NTDs.
  • Concordance between monozygotic twins is low. Thus, genetic abnormalities are more likely to predispose to environmental factors.
• Possible environmental factors include geographic location, season of conception, socioeconomic class, maternal diabetes, maternal age, zinc and folate deficiencies, maternal alcohol abuse, maternal use of valproate, and intrauterine hyperthermia.
• Marked seasonal trends in the birth incidence of NTDs have been reported. Anencephaly and spina bifida tend to occur more frequently in spring conceptions (anencephaly peaking in early spring and spina bifida in late spring). This is especially true in areas where the risk is high; however, most US studies failed to demonstrate such variations.
• Since encephaloceles do not exhibit geographic, gender, or ethnic variations, some have proposed that they occur after the completion of neurulation.

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