Neural Tube Defects

Updated: Dec 14, 2015
  • Author: George I Jallo, MD; Chief Editor: Amy Kao, MD  more...
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Overview

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. [1, 2]

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. [3]
  • 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. [4]

Cranial presentations include the following [5] :

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

Spinal presentations include the following [5] :

  • Spina bifida aperta (cystica)
  • Myelomeningocele (see following images)
    Myelomeningocele in a newborn. Myelomeningocele in a newborn.
    Myelomeningocele in a newborn - Lateral view. Myelomeningocele in a newborn - Lateral view.
  • 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 Medscape Reference article Imaging in Spinal Dysraphism and Myelomeningocele.

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Pathophysiology

Two distinct processes appear to be involved in the formation of the neural tube: primary neurulation and secondary neurulation (ie, canalization). [6] 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).

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Epidemiology

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. [7]
  • 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. [7]
  • 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).
  • A study of long-term trends in prevalance of NTDs in Europe found that, overall, the pooled total prevalence of NTD during the study period was 9.1 per 10 000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. [8]
  • 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. [9] However, unlike the Western white populations, anencephaly is more common than spina bifida.
  • Brazil has experienced a decrease in infant and perinatal mortality, but no change in its under-five mortality due to congenital disorders, which are the second leading cause of infant death. Recommended changes include a revision of the policy of flour folic acid fortification. [10]

Mortality/Morbidity

Anencephaly is incompatible with life. [11]

  • 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 the images below).

Myelomeningocele in a newborn. Myelomeningocele in a newborn.

 

See the list below:

  • 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. [12]
  • 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. [7]

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.

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