Neural tube defects (NTD) are significant birth deformities of the central nervous system that occur due to a defect in the neurulation process of embryogenesis. They are among the most common type of birth defects and are thought to have multifactorial etiology, including multigenetic and environmental influences. Because the neural tube is ultimately formed from the migration and fusion of the neural plate, the type and severity of malformation varies based on the location of the defect. This includes both cranial and spinal cord malformations. Since rostral and caudal neuropore closure is the last phase of neurulation, they are particularly vulnerable to defects. Consequently, a majority of NTDs arise in these areas.[1, 2]
NTDs can be classified as “open” or “closed” types, based on embryological considerations and the presence or absence of exposed neural tissue (i.e., failure of incomplete fusion of the neural plate).
Open NTDs frequently involve multiple aspects of the CNS (e.g., associated hydrocephalus, Chiari II malformation) and are due to failure of primary neurulation, thus the neural tube fails to appropriately close along the dorsal midline. Neural tissue is completely exposed, or covered by a membrane, with associated cerebrospinal fluid (CSF) leakage.[3] Open NTD’s represent roughly 80% of all NTD’s, with the most common being meningocele (spina bifida), myelomeningocele, encephalocele, and anencephaly.
Closed NTDs are localized and confined to the spine (the brain is rarely affected) and result from a defect in secondary neurulation. Neural tissue is not exposed and the defect is fully covered by epithelium, although the skin covering the defect may be dysplastic (i.e., tuft of hair, dimple, birthmark, or other superficial abnormality).[4]
Cranial manifestations include the following:[5]
Anencephaly
Encephalocele (meningocele or meningomyelocele)
Craniorachischisis totalis
Congenital dermal sinus
Spinal presentations include the following:[5]
Spina bifida occulta
Spina bifida in relation to a dermoid cyst
Spina bifida aperta (meningocele, myelomeningocele (see images below), meningomyelocele, myeloschisis)
Split-cord malformations
Diastematomyelia
Diplomyelia
Caudal agenesis
Lipomatous malformations (lipomyelomeningocele)
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Myelomeningocele in a newborn.
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Myelomeningocele in a newborn - Lateral view.
For more information on the classification of neural tube defects, see Medscape Reference article Imaging in Spinal Dysraphism and Myelomeningocele.
Two distinct and critical processes are involved in the formation of the neural tube: primary neurulation and secondary neurulation (i.e., canalization).[6] The neural plate and the notochord are formed during early embryonic development. The neural groove develops by the third gestational week and the neural folds subsequently form bilaterally.
Primary neurulation (weeks three and four during embryogenesis, forming the early brain and spinal cord):[7]
The neural folds elevate, approximate each other, and start fusing along the dorsal midline, thus forming the neural tube. This begins during the third week after conception.
The cranial neuropore closes during the fourth gestational week. The last area to close is the commissural plate.
The point of initial closure occurs at the caudal rhombencephalon, or cranial neuropore, on day 25 of embryogenesis.
The cutaneous ectoderm fuses first, followed by the neuroectoderm.
The caudal neuropore closes between T11 and S2, two days after closure of the cranial neuropore (roughly day 27)
Occurring in 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: weeks five and six, forming the early sacral and coccygeal cord)
This characterizes further neural development caudal to the caudal neuropore after the termination of primary neurulation, and the caudal neuropore closes
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.
By 8 weeks after conception, spinal cord tissue runs the entire length of the spinal cord.[8]
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).
Epidemiological studies have demonstrated multifactorial influences underlying NTDs. Variations in incidence have been seen across geographical variation, ethnic groups, socioeconomic status, and genetic predisposition.
Frequency
United States
The incidence of NTDs declined 50% between 1970 and 1989 (0.6–1.3 cases per 1000 pregnancies) in the United States, thought to be due to improved prenatal care and nutrient fortification (i.e., folate) of common food products.[9] 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 1,000 live births).
Incidence is higher in the Eastern United States than on the West Coast.
International
NTDs are among the most common birth defects globally.[9] 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 prevalence 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.[10]
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[11] 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.[12]
Mortality/Morbidity
Anencephaly is incompatible with life.[13] 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 days).
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 and a positive prognosis is myelomeningocele (see the images below).
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Myelomeningocele in a newborn.
The incidence of myelomeningocele is 1 case in 1200–1400 live births. It is a disease affecting 6000–11000 newborns in the United States annually.
Paralysis, bladder and bowel incontinence, and hydrocephalus are the most common clinical complications. Severe intellectual disability is present in 10–15% of these patients.
Neurologic deficits are overall difficult to predict based on the level of the lesion, as some segments of the spinal cord may retain central connections and maintain partial function, allowing voluntary control or sensation in affected limbs. Most commonly, distal cord may retain function, but afferent pathways are interrupted. This may preserve reflexes and pain withdrawal, but voluntary movement and pain sensation are affected.
Prospects for independent ambulation are correlated with the level of the spinal lesion. Independent mobility is preserved for nearly all cases with low lumbar and sacral lesions; with lesions above L2, loss of quadriceps and iliopsoas muscle function often occurs, and independent mobility is unlikely.[14]
Bowel and bladder function are affected in roughly 90–95% of patients with myelomeningocele, manifesting as neurogenic bladder and/or fecal incontinence.[15]
Presence or severity of urinary dysfunction cannot be predicted by location of the spinal lesion or by neurologic exam. The level of spinal cord responsible for mediating bladder function is below the level that controls lower extremity function.[16]
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.[17] 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 as higher in the European white population than in the black population.[9]
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 a prevalence 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 environmental factors, 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; it has been estimated that roughly 70% of asymptomatic patients with a closed NTD present with one or more cutaneous lesion.[18, 19]
NTDs are commonly discovered during prenatal screening and are often associated with poor prenatal care.
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.[20]
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 (e.g., 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).[21]
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 neuro-enteric 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.
Neuro-enteric or dermoid cysts also can present with repeated bouts of aseptic meningitis due to leaking of the contents into the spinal subarachnoid space.
Functional complications most often occur during early years of life, but can manifest at any age. The prevalence of medical comorbidities depends on the level and severity of the lesion. However, urologic abnormalities (i.e., UTI and nephrolithiasis) are the most common issues among adults with NTDs. Scoliosis, pain, epilepsy, and pressure ulcers are also often reported in adult patients with myelomeningocele.[22]
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.
Other common findings include oral clefts and renal, cardiovascular, and musculoskeletal malformations.
Multifactorial genetic and environmental factors have been implicated in the pathogenesis of neural tube defects (NTDs).[2]
The most common historical cause of NTDs globally is folate deficiency in the maternal diet. 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) are also associated with NTDs. Interestingly, concordance between monozygotic twins is higher than dizygotic twins.[23]
Possible environmental factors include geographic location, season of conception, socioeconomic class, maternal diabetes, maternal age, zinc and folate deficiencies,[24, 25] maternal alcohol abuse, maternal use of valproate, and intrauterine hyperthermia.
Seasonal trends in the birth incidence of NTDs have historically 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.[26, 27, 28]
Since encephaloceles do not exhibit geographic, gender, or ethnic variations, some have proposed that they occur after the completion of neurulation.
A cohort study by Jentink et al suggests that carbamazepine monotherapy in the first trimester produces fetal malformations specific to spina bifida; however, the risk is lower than for valproic acid.[29]
Ultrasonography is used antenatally for neural tube defect (NTD) screening. All pregnant women should be offered screening for NTDs via ultrasound. Postnatally, its role has been limited because of advances in other imaging modalities. It is also helpful for quickly screening for hydrocephalus.
MRI is the study of choice for imaging neural tissue and for identifying contents of the defect in the newborn. This is not routinely performed in the neonate unless unusual deficits not associated with the open defect are present. This allows for visualization of associated anomalies, both intraspinal and intracranial.
CT scan allows direct visualization of the bony defect and anatomy. This study is also used to determine the presence or absence of hydrocephalus or other intracranial anomalies, although exposure of young children to radiation from CT studies should be considered. Hence, the use of CT scan is usually reserved for adults or older kids with spina bifida occulta.
Maternal serum alpha-fetoprotein can be measured in maternal serum (MSAFP), amniotic fluid, and fetal plasma. It is typically measured around 16–18 weeks' gestation. MSAFP is a fetal-specific protein synthesized by the fetal yolk sac, GI tract, and liver. Interpretation of results varies by institution, but typically levels 2–2.5-fold above average (for a particular gestational age) is considered abnormal. However, many factors, both fetal and maternal, can affect interpretation of results. Abnormal MSAFP tests are typically followed by an ultrasound exam to assess for possible NTD, confirm gestational age, fetal viability, number of fetuses, and so on.
Genetic counseling and further testing with amniocentesis may be indicated for equivocal MSAFP and ultrasound findings.
The newborn with an open neural tube defect (NTD) should be kept warm and the defect covered with a sterile wet saline dressing. The patient should be positioned in the prone position to prevent pressure on the defect.[30]
Neurosurgical intervention is the mainstay of treatment for open neural tube defects (NTDs); closed NTDs typically do not warrant urgent surgery.
The newborn with an open NTD should be kept warm and the defect covered with a sterile wet saline dressing, with consideration for prophylactic antibiotics. The patient should be positioned in the prone position to prevent pressure on the defect. Prompt closure of the defect is indicated, ideally within the first 72 hours after birth for myelomeningocele. The closure involves classic neurosurgical techniques, involving the approximation of the lateral edges of the open neural plate to form a neural tube; this covers the open caudal end of the spinal cord with a layer of pia mater.[30] For closed defects associated with cord tethering, surgery involves removal of structures that are anchoring the cord.
In children born with severe hydrocephalus, a ventriculoperitoneal shunt placement should be considered at the time of myelomeningocele closure. However, this view is debated given potential differences in complications such as rate of infection and CSF leak, as well as considerations such as length of hospital stay and wound morbidity.[31] 41 Although simultaneous repair is often not feasible in developing countries, which have higher rates of hydrocephalus and are more likely to present at more delayed and/or advanced stages, patients with co-occurring hydrocephalus should undergo shunt placement 5–10 days following myelomeningocele closure (provided they have sterile CSF).[32] Patients with mild to moderate ventriculomegaly are observed closely for increased intracranial pressure, including bradycardia, bulging fontanelles, poor feeding, vomiting, irritability, lethargy, sundowning of the eyes, and/or apnea. A subgaleal shunt can be placed temporarily in pre-term infants. Third ventriculostomy is a procedure more common in developing countries, but still rarely performed, where access to follow-up or tertiary care is limited.[33]
Patients presenting with symptomatic Chiari II malformations (see image below), are closely correlated with myelomeningoceles. The classic treatment of suboccipital craniectomy with duraplasty and decompression of the posterior fossa and cerebellar tonsils is rarely done in patients with Chiari II malformation.
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Child with Chiari malformation, in whom the tonsils have descended to the level of C2.
Children with syrinx (see following images) and previous open lumbar defect usually mandate revision for tethered cord. In some cases posterior fossa decompression is needed as for Chiari I malformation. In rare cases a syringosubarachnoid stent to divert the CSF from the central canal is needed.
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MRI of a cervical syrinx in the sagittal plane.
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MRI of a cervical syrinx in the axial plane.
Spinal cord tethering (sometimes associated with myelomeningoceles or lipomeningocele) may cause progressive neurologic deterioration. Untethering procedures are required for those with significant and progressive impairment, characterized by growth and/or flexion of the vertebral column and stretching the tetherd cord.
Improvements and increased frequency in maternal screening (i.e., serum and ultrasound) have enabled early intervention. Fetal surgery before 26 weeks' gestation has been performed with the aim of reducing development of Arnold-Chiari malformations and eventually hydrocephalus; fetal surgery for myelomeningocele can prevent excess CSF loss from the back and therefore prevent Chiari II malformation, hydrocephalus, and syringomyelia. Investigators for the Management of Myelomeningocele Study (MOMS) demonstrated the success of in utero surgical repair for open NTDs.[34] This prospective randomized controlled trial compared fetuses with prenatally diagnosed myelomeningocele treated via standard postnatal repair vs in utero. Outcomes demonstrated a significant reduction in hydrocephalus, and thus need for ventriculoperitoneal shunt, and decreased incidence of Chiari malformation. There was also improvement in spinal-neurologic functional outcomes as motor skills were superior in the fetal surgery group, and twice as many children were ambulating independently at 2.5 years of age relative to the post-natal surgery group. However, maternal complications were also observed, such as pre-term birth, placental abruption, need for future caesarean delivery, among others within the surgical cohort. Overall the trial demonstrated more favorable outcomes from pre-natal treatment beyond the maternal risks from surgery.
Since publication of the MOMS trial results, fetal myelomeningocele repair has become a standard of care option for prenatally diagnosed patients.[35] As such, increased demand for this procedure was observed. However, a growing concern in the “post-MOMS” era for women carrying a subsequent pregnancy is uterine dehiscence and rupture, as well as a requirement for caesarean delivery for subsequent pregnancies. Imaging techniques such as magnetic resonance imaging or sonographic evaluation of uterine wall thickness have been used to evaluate post-operative hysterotomy scarring and integrity. Due to these concerns for open prenatal surgery on maternal morbidity, minimally invasive techniques using fetoscopy have been developed, and are becoming increasingly popular worldwide.[36] Compared to traditional open repair (requiring hysterotomy), fetoscopic repair is via laparoscopy. While there is a clear benefit in avoiding hysterotomy, notable risks include preterm premature membrane rupture, premature delivery, and inadequate coverage of the NTD (leading to CSF leak, possible Chiari malformation, and infection).[37] Comparative studies between open repair and fetoscopic techniques have thus far been equivocal, however, further development of the fetoscopic approach and techniques may ultimately lead to improved outcomes.[38, 39]
The addition of nutrients (notably folic acid, vitamin C, and riboflavin) to common foods, such as cereals and grain products, has significantly decreased the incidence of neural tube defects (NTDs) globally. Notably, adequate levels of folate intake are important during the first month of pregnancy, particularly given the early phases of neurulation. The metabolic pathways and role of folate in neurulation remains unclear, however, studies have demonstrated that folate has a direct role in neural tube closure.[40]
Conversely, lack of folate and/or defects in the enzymes involved in folate metabolism are correlated with higher rates of NTDs.[41]
This is why all pregnant women, women who are planning pregnancy, and women who may become pregnant, are recommended to consume 400 mcg of folate daily in most countries, particularly developing countries. Otherwise, there is a chance that by the time they inadvertently find out they are pregnant (i.e., anticipated start of the next menstrual cycle), there is already a critical period of missed nutrition.
Many groups exist with interests concerning the particular child.
For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Spina Bifida.
Nir Shimony, MD, Neurosurgeon, Pediatric, Epilepsy, NeuroOncology, Neuroscience Researcher, Institute of Brain Protection Sciences, Johns Hopkins All Children's Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Christopher E Louie, MB, MPH, Geisel School of Medicine at Dartmouth
Disclosure: Nothing to disclose.
George I Jallo, MD, Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Amy Kao, MD, Attending Neurologist, Children's National Medical Center
Disclosure: Have stock (managed by a financial services company) in healthcare companies including Allergan, Cellectar Biosciences, CVS Health, Danaher Corp, Johnson & Johnson.
Additional Contributors
Robert Stanley Rust, Jr, MD, MA, Former Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthor Tibor Becske, MD, to the writing and development of this article.
Dirks PB, Rutka JT. The neurogenetic basis of pediatric neurosurgical conditions. In: Albright L, Pollack I, Adelson D, eds. Principles and Practice of Neurosurgery. New York: Thieme Medical Publishers; 1999:. 23-4.
Harris LW, Oakes WJ. Open neural tube defects. In: Tindall GT,Cooper PR, Barrow DL, eds. The Practice of Neurosurgery. Baltimore: Williams & Wilkins; 1996:. 2779-89.
McComb JG, Chen TC. Closed spinal neural tube defects. In: Tindall GT,Cooper PR, Barrow DL, eds. The Practice of Neurosurgery. Baltimore: Williams & Wilkins; 1996:. 2754-77.
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