Spina Bifida (Neural Tube Defects)

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Page Links on Spina Bifida Topics: Definition, Prevalence, Classification, Risk Factors, Etiology, Genetics, Prevention, Outcome, Differential Diagnosis, References

Definition of Spina Bifida

The following definitions are from National Library of Medicine – Medical Subject Headings, 2008 MeSH.

Meningocele: A congenital or acquired protrusion of the meninges, unaccompanied by neural tissue, through a bony defect in the skull or vertebral column.

Meningomyelocele: Congenital, or rarely acquired, herniation of meningeal and spinal cord tissue through a bony defect in the vertebral column.

Spinal dysraphism: Congenital defects of closure of one or more vertebral arches, which may be associated with malformations of the spinal cord, nerve roots, congenital fibrous bands, lipomas, and congenital cysts. These malformations range from mild (spina bifida occulta) to severe, including rachischisis where there is complete failure of neural tube and spinal cord fusion, resulting in exposure of the spinal cord at the surface. Spinal dysraphism includes all forms of spina bifida. The open form is called spina bifida cystica and the closed form is spina bifida occulta.

Fetal Prevalence of Spina Bifida

Above. United States data show the prevalence of neural tube defects has declined due to: preconceptual supplementation with folic acid and, prenatal diagnoses with resultant selective termination of pregnancies.

Above. There is significant geographic variations in the rates of spina bifida and anencephaly. The rates (per 10,000 population) for neural tube defects are twice in certain areas of Russia compared to Norway, for example. [1],[2],[3],[4],[5],[6],[7]

*Sweden, 6.1 = 2.4/10,000 newborns plus 3.7/10,000 termination of pregnancy.

In summary, the incidence of neural tube defect is affected by racial, geographic and seasonal variations as well as the risk factors listed above. Most NTDs which are not related to a syndrome are multifactorial in origin.

There is also an increased frequency in: maternal hyperthermia valproate ingestion.

No Mendelian inheritance pattern is noted.

Genetic contribution evidence is present due to the following: single gene defects, recurrence among siblings, and higher likelihood in twins.

Classification

Neural tube defects can be classified as either abnormalities of the skull or brain. Those of the skull and brain include Arnold Chiari malformation, which represents secondary changes within the fetal brain associated with spinal defects. [8]

A separate classification includes abnormalities of the vertebral arches (dysraphism) and includes open defects such as meningocele and spina bifida cystica. [8] Spina bifida occulta represents a closed spinal defect. [9]

Above. A separate classification for Spinal Dysraphism (spinal defects which affect the vertebra arches) has been proposed. [10] This classification divides the spinal lesions into open and closed defects and suggests certain associations with each.

Risk Factors

Above. Neural tube defects can broadly be described as syndromic and non-syndromic. [11] In the non-syndromic multifactorial group, a number of specific risk factors have been reported.

Above are risk factors reported for spina bifida. [11]

Exposure to agricultural pesticides and to fumonisin, a mycotoxin that often contaminates corn, appear as causative links for the occurrence of neural tube defects. [12],[13]

Retinoid acid (RA) plays a role in the development of the spinal cord while genetic polymorphism of the human retinoic acid-metabolizing enzyme is being explored for its role in the development of spina bifida.

[14],[15]

Etiology

Above. The etiology of neural tube defects is related to environmental and genetic factors and may be considered heterogeneous and multifactorial. The genetic component is discussed separately.

Congenital spinal defects are associated with intracranial changes and the Arnold Chiari malformation. The Chiari malformation, associated with hindbrain herniation, is related to low spinal pressure relative to cranial pressure and results in hindbrain-related symptoms caused by cerebellar and brainstem compression. [16] Increased CNS volume, with any space-occupying lesion, compresses veins and raises venous pressure which in turn raises the volume of cerebrospinal fluid (CSF). When blood enters the CNS during fetal movement, the compressed posterior fossa prevents the spine-to-head flow of CSF. These movement-induced pressure events may result in spinal cord injury.

Above. Williams [17] proposes a venous hypothesis for spinal lesions and hydrocephalus related to the overall pressure in the CNS, which is dependent upon all of the volume within the closed CNS space. Arterial supply is maintained normally because of venous outflow from the CNS. Increased CNS volume with any space-occupying lesion compresses veins and raises venous pressure, which in turn raises the volume of cerebrospinal fluid (CSF). These changes affect hydrocephalus and the associated spinal lesions, while the Chiari malformation leads to reductions in CSF flow that can occur intermittently.

Genetics

Above. Neural tube defects are due to multiple environmental and genetic factors. [18]

Above. These gene-gene factors and gene-environmental factors are operable through a variety of maternal conditions. [23]

Above. With respect to genetic risk factors, multiple genes are responsible.

Above. Among fetuses with open neural tube defects, a rate of chromosomal abnormalities of 7% has been reported. [19] Among 10 fetuses: 3/21 (14%) were encephalocele defects, 6/66 (9%) were spina bifida abnormalities and 1/57 (2%) were lethal defects. [24]

Above. Specific chromosomal abnormalities have been reported with neural tube defects and are variable [20], while the risk factors for a chromosomal abnormality vary with:

maternal age,
gestational age at diagnosis,
the presence of other malformations family history of chromosomal abnormalities.

In 587 women, when central nervous system malformations were isolated, specific associations were noted with Trisomy 21, Trisomy 13, and Trisomy 18. [21]

Above. Both chromosomal structural deletions and duplications have been associated with NTDs. [22]

Above. Over a 6-year period, 144 fetuses with open NTD underwent prenatal chromosome analysis between 12 and 37 weeks of gestation as part of a prospective, multicenter prenatal diagnosis and counseling program. The prevalence of chromosomal abnormality varied with the defect, with a 14% (3/21) prevalence among those with cephalocele, a 9% prevalence (6/66) among those with spina bifida, and a 2% (1/57) prevalence among those with lethal defects such as acrania, anencephaly or iniencephaly. [24]

Above. Genetically detectable human chromosome abnormalities were studied to identify patients with 14 brain malformations including 542 with deletions, and 290 carrying duplications. [23] Among CNS malformations many chromosomal deletions and duplications were identified among associated bands in various regions.

Many folate metabolism-related genes have been reported. [24] The gene VANGL-1 and its mutations have been implicated as risk factors for the development of neural tube defects. [25] Other specific VANGL-1 mutations have been reported. [26] The endothelial nitric oxide synthase gene has been implicated as a risk factor in women with impaired homocysteine metabolism. [27] Some deletion allele may be a protective NTD genetic factor [28] but these effects remain under investigation. [29] Specific maternal genotypes such as MTRR 66GG genotype are a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low. [30]

Prevention of Spina Bifida

Page Links: Imaging Considerations, References

Imaging Considerations

Ultrasound versus Alpha-Fetoprotein

Most studies suggest routine ultrasound is superior to AFP as a screening test alone for neural tube defects and is likely to replace routine AFP surveillance. [48],[49],[50],[51]

AFP sensitivity for the diagnosis of NTDs can be improved by using ultrasound to confirm dates to reduce gestational age error in the calculation of the AFP result. [3]

Multi-planar views of CNS anatomy offer excellent visualization and improved diagnostic accuracy. [52]

Above. In 189 patients with neural tube defects, 102 underwent MSAFP screening. The results of MSAFP testing were negative in 25 (25%). Without other testing, these 25 NTD patients would have been missed. These included 15 with spina bifida, 6 with encephalocele and 4 with anencephaly. [53]

Overall, competent ultrasound screening replaces amniotic fluid AFP and cholinesterase measurements for the diagnosis of NTDs. [54]

Ultrasound Diagnosis

The diagnosis of open spinal defects has been reported as early as the first trimester using trans-vaginal ultrasound. Findings include a step or angulations of the posterior aspect of the embryo. Abnormal contours of the head and spine as well as empty or enlarged intracranial contents may be seen.

The findings related to an open spinal defect are commonly associated with alterations of the brain anatomy. One of the most common of these is the Arnold Chiari, or Chiari II malformation. The cerebellum is displaced inferiorly due to the open spinal defect which results in ultrasound changes which can be noted before birth.

Above. The ultrasound detection of neural tube defects is accompanied by intracranial signs. The skull itself is commonly “lemon” shaped. Due to the Arnold Chiari II malformation, the cerebellum is effaced creating the “banana” sign and the posterior fossa is frequently obliterated. The dilatation of the lateral ventricles completes the major intracranial signs of open spinal defects. [55],[56]

Above. The axial view of the head to obtain the biparietal diameter will demonstrate dilatation of the lateral ventricles and the “lemon” shaped configuration of the fetal head suggesting a neural tube defect. The cerebellar view will demonstrate effacement of the cerebellum and obliteration of the posterior fossa.

Above. The “lemon” shaped configuration of the fetal head is associated with certain open neural tube defects.

Above. “Banana” shaped cerebellum (yellow arrow) and obliteration of posterior fossa (green arrow) is also associated with certain open neural tube defects.

Above. In most large ultrasound series, open spinal lesions were associated with classical findings of the banana sign or lemon sign while the closed lesions did not present with intracranial changes. [57]

Above. Ultrasound signs were studied for the diagnosis of spina bifida during mid-trimester scans performed between 18 and 28 weeks; the lemon sign was noted in over 50% of cases while small cerebellum, effaced cisterna magna, small posterior fossa and visualization of spinal defect were present in over 90% of cases. [58] Ventriculomegaly was noted in 81% and the spinal defect was observed in 98%. [11]

Above. Enlargement of the ventricles or ventriculomegaly is seen with open spinal lesions and the associated Chiari II malformation. The other major causes of ventriculomegaly include aqueductal stenosis, Dandy-Walker complex and absence of the corpus callosum. [59],[60],[61]

Above. Supratentorial abnormalities in the Chiari II malformation are reported in a series of papers. [62],[63],[64] The shape of the occipital horn of the lateral ventricle is described as pointed rather than rounded; the tectum is described as elongated or beaking while an interhemispheric cyst is sometimes present. Others suggest that occipital pointing was present in up to 77.3% of fetuses with spina bifida. [65]

Above. Views of the posterior horn of the lateral ventricle can suggest a triangle sign, which is associated with a low vertebral open spinal lesion, while a square appearance of the posterior horn of the lateral ventricle on coronal views suggests an upper spinal lesion. [66]

Associated Malformations

Above. In this study, associated malformations are described in infants with neural tube defects. 360 infants were born with neural tube defects among 334,262 consecutive births. Associated malformations were more frequent in infants with encephalocele (37.5 %) than in infants with anencephaly (11.8 %) or infants with spina bifida (23.7 %). [67]

Above. In 51 cases of central nervous system defects, 24 cases were spina bifida and 27 cases were anencephaly, exencephaly and encephaloceles. Among these 51 cases, other associated anomalies included: isolated CNS, other neural defects, midline or lateralization anomalies and musculoskeletal, urogenital, vascular anomalies as well as known syndromes. [68]

In the above series, 78 of 178 patients presented with associated anomalies. 50% of the anomalies came from fetuses with sacral or lumbosacral lesions. In those 100 with spina bifida only, 88% had sacral or lumbosacral lesions. [69] Tomographic ultrasonographic techniques may further increase diagnostic accuracy.[70]

Accuracy

Above. In the European Multi-Center Study, of the 252 cases of isolated spina bifida, 171 (68%) were correctly identified prenatally; 66% of these before 24 weeks’ gestation. The diagnosis was missed on scan in 24% cases and 8% were not scanned. [71]

Above. Antenatal definition of the level of the spinal lesion may be difficult with standard ultrasound application. The accuracy of defining the upper level of the spina bifida defect suggested that community physicians were less likely to define the accurate level of the lesion compared to academic staff physicians. Neither group agreed exactly with the the level of the lesion compared to the actual level determined after birth although academic physicians agreed within 1 level of the lesion 78% of the time. [72] However, ultrasound detection rates are variable and reported as low as 24% in some populations. [73]

Above. A postmortem evaluation was made of 220 prenatally diagnosed fetuses with neural tube defects. Additional malformations not detected by prenatal ultrasound were noted on postmortem examination in 21.6% of the cases. [74]

MRI and Ultrasound in Diagnosis of Neural Tube Defects

Ultrasound plays an important role in the detection of neural tube defects while MRI may be especially useful in the evaluation of specific abnormalities. [75] Advances in MRI technology include rapid pulse sequences, parallel imaging and improved coil design. Recent applications include in vivo brain development and early diagnosis of congenital malformations and as adjunct to lesions not well visualized with ultrasound. [76],[77] MRI confirms sonographically demonstrated CNS malformations while additional findings may be discovered. In addition, MRI findings may influence parental counseling decisions. [78]

However, some studies demonstrate no significant advantage of antenatal MRI compared to ultrasound in detecting the level of spinal lesions and the presence of ventriculomegaly. [79]

Ultrasound may not define all spinal cord lesions. Diagnostic accuracy is poor in defining some cord abnormalities such as diastematomyelia and segmental spinal dysgenesis but this factor may not make a difference in outcome. [80]

The role of MRI is often considered an accessory imaging modality to confirm questionable lesions or anatomy, to define and to characterize lesions and associated anomalies. [81]

While prenatal MRI readily defines CNS lesions and candidates for neonatal neurosurgery [82], most CNS lesions are appropriately assessed by antenatal ultrasound with the exception of neuronal migration disorders, and ventriculomegaly in the early second trimester of pregnancy. [83], and certain spinal cord anomalies.[33]

In the MRI evaluation of the posterior fossa, the presence of the cerebrospinal fluid signal on on both sagittal and axial images is indicative of a normal posterior fossa while its absence is suggestive of a Chiari 11 malformation. [84]