Neural tube defects are the most common severe central nervous system anomalies only second to cardiovascular abnormalities resulting in congenital morbidity and mortality. The nervous system is ectodermal in origin. The central nervous system consists of the brain and spinal cord formed by folding of dorsal part neural plates under the influence of underlying notochord and prechordal mesoderm and closure anterior (cranial) and posterior (caudal) neuropores by a process called neurulation that begins as early as 3 and 4 weeks of conception. Failure to complete of neurulation results in neural tube defects (NTDs). Neurulation consists of two phases i.e., primary and secondary neurulation. Primary neurulation is defined by folding of the dorsal part of the neural tube and lengthening of neural plates in the longitudinal axis and narrowing of the cross-section by the phenomenon called convergent extension forming the brain and spinal cord. Primary neurulation is followed by canalization of neural tubes, forming a distal part of the spinal cord called secondary neurulation. Fibroblast growth factor (FGF) signaling concordant with suppression of bone morphogenetic protein 4 (BMP4), a transforming growth factor induces the formation of the neural plate. Also, retinoic acid organizes the cranial-caudal axis by regulating the expression of homeobox genes. Neural tube defects can be present anywhere from the brain to the end of the spinal cord. Open NTDs are due to failure of primary neuralation and associated with hydrocephalus, Chiari II malformation, etc. Neural tissue is exposed to and associated with cerebrospinal fluid (CSF) leakage. Closed NTDs are due to failure of secondary neuralation and are generally confined to the Spinal cord. Neural tissue is not exposed. The closed neural tube defects occur post neurulation and include lipoma with a dorsal defect (lipomyelomeningocele, lipomyelocele), especially when a subcutaneous mass is present. Common variants of NTDs are as follows:
1. Spina bifida occulta: failure of caudal neuropore to close. The spinal cord, meninges, and overlying skin remain intact, with no herniation.
2. Spina bifida cystica: meningocele (herniation of meninges only) and myelomeningocele (herniation of both meninges and neural tissue)
3. Myeloschisis: exposed neural tissue without skin or meninges covering.
4. Anencephaly: failure of rostral neuropore to close thus the brain and cranial vault are grossly malformed with normal hindbrain development.
Genetic and environmental factors have a central role in neural tube defects. However, there are many other contributing factors like obesity, diabetes, immune dysregulation, folic acid antagonists, dihydrofolate reductase inhibitors, socioeconomic status, geography, ethnicity, etc. that play a vital role too. Though the role of geography and ethnicity has unknown, neural tube disorders vary from place to place. Low socioeconomic status is associated with the non-availability of folic acid supplementation during pregnancy. Amniotic bands disrupt the neural tube development, nitrosatable drugs, maternal hyperthermia is the possible additional risk factors. The physical and chemical environment such as radiation, stress, hypervitaminosis A, rubella, toxoplasmosis, Cytomegalovirus, and toxic wastes from landfills within 3 km also contributes to some extent.
The prevalence of neural tube defects has different rates among different ethnicity, geography, gender, and countries. Prevalence is higher among Whites as compared to Blacks and females as compared to males. Southeast Asia has more NTDs rate than western countries; this might be probably due to the low socioeconomic status of eastern countries directly affecting the economic burden and negligence over the folic acid as a part of multivitamin supplementation. NTDs rate has a wide range of variables in place to place even within a country. Such a variable within a country has been found in those countries having a broad extent of lifestyles and economic status. In a systemic review conducted on published data between January 1990 and July 2014, the eastern Mediterranean region exhibited high variability with a swat, Pakistan having 124.1 cases per 10000 births. Even within Pakistan, the estimated rate ranges from 38.6 to 124.1 cases per 10000, signifying variation according to the access of multivitamin supplementation, education, lifestyle, and economic status. Prevalence in the African region ranges from 5.2 to 75.4 per 10000, the European region ranges from 1.3 to 35.9 per 10000 births, and Americas region ranges from 1.4 to 27.9 cases per 10000. After all, these worldwide data show the place to place a variation of prevalence rate assumed to be due to low standard health care facilities though the exact mechanism is still unknown.
Rate of NTDs is more common in twins than singleton, monozygotic twins than dizygotic twins. A study in Los angels showed that the rate of anencephaly and exencephaly is more than spina bifida. But normally, it is supposed that spina bifida is more common than anencephaly. Some studies show chances of stillbirth are more in women though chances of abortion are more in males. The overall incidence rate is 1 to 2 cases per 1000 births.
Genetic and environmental factors have a major impact on the disruption of neurulation. Failure of neural folding or neuropores closure may be due to the genetic changes, environmental factors, or lack of nutritional constituents. These insults cause neural tube defects in different ways, but the ultimate result is abnormal neurulation. Pathophysiology of NTDs based on the different etiologies are summarised:
Folic acid, Antagonists, and its Genetic Correlation
After several experimental pieces of research, it has been concluded that folic acid supplementation in a multivitamin regimen decreases the incidence rate of neural tube defects by 71%.
Folic acid has a major contribution to the pathophysiology of neural tube disorders. Folic acid helps in the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) precursors. Folic acid is converted into tetrahydrofolate by dihydrofolate reductase enzymes. Methylation of folic acid is essential to take the folic acid functional. So, 5-methyl tetrahydrofolate is the active co5factor of enzymes involving one-carbon transfer reactions forming purine and pyrimidine. 5-MTHF is taken up by cell through folate receptors, or carrier protein and glutamates are added to form polyglutamate folates which cannot cross the cell membranes, so that accumulate inside the cell. Hence, folic acid is directly associated with cell proliferation as for in neurulation. The absence of folic acid halts neural tissue proliferation and migration during neurulation leading to neural tube disorders.
But in some cases, even pregnant women who have enough supplementation of folic acid give birth to a child with neural tube disorders. Research has shown that genetic alterations in folate metabolism, folate receptors, and transport proteins make these women in susceptibility. Neural folds express the folate receptors. Genetic defects in these receptors, particularly folate alpha and beta receptors, which take up folate derivatives inside neural cells required for replication, lead to failure of neurulation.
Meta-analysis performed to rule out the relation between MTHFR C677T polymorphism and neural tube defects demonstrated that this mutation decreases the activity of enzymes required for folate metabolism, thus reducing the serum folate concentration.
Folate antagonists such as phenytoin, valproic acid, and carbamazepine have a direct effect on NTDs by inhibiting the activity of folate.
Methotrexate inhibits dihydrofolate reductase. The use of methotrexate increases the apoptosis of neural tissue contributing to NTDs.
Mutation in homeobox genes and fibroblast growth factor (FGF) dysfunction has some roles in the pathogenesis of NTDs.
Vitamin B12, Homocysteine and Folate Receptor Autoantibodies
Vitamin B12 helps in converting homocysteine formed from folate metabolism into methionine s with the help of methionine synthase o reducing the toxicity of homocysteine. The deficiency of vitamin B12 increases the homocysteine level in the serum. One hypothesis suggests that high homocysteine level causes posttranslational modification of folate receptors (homocysteinylation) which forms folate receptors a self-antigen. Antibodies are formed against these auto-antigens, and therefore the activity of folates declines.
Diabetes and Immune Modulation
Gestational diabetes increases the Central nervous system malformations by 2-10 folds. Exposure of elevated glucose is teratogenic to embryos less than seven weeks with the undeveloped pancreas. A study conducted in Xenopus concluded the necessity of chemokines and complement factors in the central nervous system (CNS) development. So absence or reduced level of C3a and C5a has some roles in NTDs.
Women of childbearing age may present with a history of low socioeconomic status, lack of folic acid supplementation during pregnancy, family history, weakness, fatigue, dyspnea due to anemia, diabetes, and drug intake for epilepsy. Diagnosis is usually made both prenatal and postnatal. Prenatal diagnosis is made through ultrasound screening. Sometimes it may be discovered in older children or even adults. Anencephaly is more lethal and so diagnosed easily antenatally. Urinary symptoms, neurological weakness, and cardiovascular complaints are often associated with NTDs.
Physical examination of NTDs varies according to the size and type of defects. Open NTDs are easily visible, whereas it may take through adults to detect closed types. The birth weight of the child may be low. About one-third of the cases are associated with other congenital anomalies present with cleft palate, undescended testis, omphalocele, talipes. Increased circumference of the head complicated by hydrocephalus. Closed spinal defects are associated with lipomyelocele and lipomeningomyelocele. Dorsal enteric fistula, anal imperforation, cardiac and renal abnormalities in abnormal notochord formation, a tuft of hair, and scoliosis in case of diastematomyelia, polydactyly associated with encephalocele are the additional features may be present in rare conditions. Myelomeningocele is often sac-like structure with CSF fluid leak. Late ambulation, cognitive impairment are present. The mother may be pale and anemic.
It is the investigation of choice in prenatal screening. Ultrasound localizes the exact size and site of neural tube defects and vertebrae.
Accurate diagnosis of anomalies with the help of ultrasound depends upon the gestational age of the fetus, careful evaluation of anomalies.
Alpha-fetoprotein is a globulin protein formed by the fetal yolk sac, liver, and gastrointestinal tract. Initially, its concentration is greater in amniotic fluid and fetal plasma as compared to maternal serum. But as gestation advances, due to increased permeability of placenta, alfa-fetoprotein crosses the fetal-placental barrier so that maternal serum alfa-fetoprotein level rises and that of amniotic fluid and fetal plasma decreases. A high level of alfa-fetoprotein indicates neural tube defects. In addition, acetylcholinesterases level is estimated in the case of abnormally high levels of alpha-fetoprotein. Though serum alpha-protein level has an important role in the screening of neural tube defects, it is not a cost-effective approach.
Magnetic Resonance Imaging (MRI)
MRI is performed in cases of uncertain ultrasound description to evaluate the anomalies more accurately. Although MRI has a diagnostic role in cases of neural tube defects, some studies in chick embryos showed that MRI exposure increases the incidence of neural tube disorders.
As it is clear that neural tube disorders have some contribution to genetic abnormalities, genetic testing estimates the association between genetic mutation and neural tube defects.
In many cases, neural tube defects are associated with other anomalies such as cardiovascular, cleft palate, urinary tract infections, coloboma, etc.
Maternal Serum Folic Acid Level
Maternal serum folic acid level before or during conception helps to rule out the causative factors of NTDs.
Folic Acid Supplementation
Many studies suggested that periconceptional folic acid supplementation with the fortification of a diet rich in folic acid has significant results (50% to 70%) in preventing the neural tube disorders. The recommended dose of folic acid to all the women who are who want pregnancy is 0.4 to 0.8 mg per day. But the women who already have had a child with NTD or positive family history should take 4 mg of folic acid daily one month prior to the conception through the first three months of pregnancy to prevent the recurrence. Some studies suggest that it takes around 20 weeks to achieve a normal red-blood-cell level of folic acid to prevent neural tube defects. So women should receive folic acid 5 to 6 months prior to the conception.
Fetal and Postnatal Surgery for Myelomeningocele
Surgical repair of myelomeningocele in fetus seize leakage of spinal fluid and therefore arrest the herniation of cerebellum preventing the formation of hydrocephalus. Postnatal surgical closure of spina bifida should be done within 72 hours. Randomized control trials in the united states proposed that improved ambulation, cognitive behavior is more in prenatal as compared to postnatal surgery. Recently published data indicate that prenatal repair may improve the bladder function and less trabeculation of the bladder as compared to conventional postnatal surgery. 
Hydrocephalus is treated by a ventriculoperitoneal shunt, which drains the CSF from ventricles to the peritoneal cavity.
The use of antipyretics in hyperthermia reduces the chances of NTDs.
Once the prenatal ultrasound and other investigations confirm the diagnosis of NTD, mother and family members should be counseled about the management, possible prognosis, complications, and referral to other specialties for a comprehensive approach of the disease.
Control of Gestational Diabetes
The pregnant mother with diabetes has chances of NTDs. So control of gestational diabetes helps to prevent and reduce the incidence of NTDs.
Postnatal Assessment and Management
In the absence of prenatal screening, NTDs child should be assessed immediately after birth about site of defects, size, leakage of cerebrospinal fluid, any infections and should be managed accordingly. Make sure of aseptic measures during the assessment. The use of non-latex gloves reduces the risk of latex sensitization. Broad antibiotics coverage to prevent infections, sterile and saline-soaked dressing, the neurological assessment helps in a wide range to facilitate postnatal life. The surgical management of closed neural tube defects is challenging and complex. Practitioners must be familiar not only with the underlying embryology associated with the specific defect but also the contemporary surgical management to reduce the risk of CSF fistula formation or neurologic compromise, which leads to high morbidity.
Neural tube disorders are classified on the basis of site and covering and its contents. So they have to be differentiated from each other at first for proper approach and interventions. They may be open or closed, spinal cord originated, or brain originated. Open spinal dysraphisms are myelomeningocele, hemimyelocele and lipomyelomeningocele, meningocele, lipomyelocele are the few closed types. Anencephaly is seen. Few other differentials are briefed as follows:
It is the rare and lethal spondylocostal dysplasia associated with spina bifida, heart defects, cleft palate, and renal abnormalities. The involvement of thoracic vertebra and the absence of ribs along with the presence of kyphosis helps to differentiate this disease from neural tube defects through such clinical presentation that may be minimally present or absent, making it difficult for diagnosis.
Meckel-Gruber syndrome is an autosomal recessive disease comprising of a group of disorders involving the malfunction of cilia. Neural tube defects, mostly occipital encephalocele, are part of this syndrome. Besides encephalocele, this syndrome consists of involvement of other systems which has cilia as main functioning role such as respiratory tract, oviduct or efferent ducts, renal tubules, brain ventricles, etc. Presence of respiratory disease, infertility, polycystic kidney disease hydrocephalus is important to rule out isolated neural tube disorders from Meckel-Gruber syndrome.
Tethered Cord Syndrome
Adhesions cause an abnormal stretching of spinal cords, mostly due to lipoma, dermoid cysts, rumors, etc.
Viral and Neonatal Meningitis
The primary causative organisms of neonatal meningitis are group B streptococcus and enterovirus for viral meningitis. Meningitis cause premature births along with signs and symptoms such as neck rigidity, fever that confuses with meningitis in patients with neural tube defects.
It is an intradural lipoma attached to surrounding soft tissue leading to the tethered spinal cord deteriorating the neurological functions. The formation of hump mainly in the cervicothoracic region confuses neural tube defects.
Myelocystocele is a closed neural tube defect that resembles myelomeningocele, especially when complicated by hydrocele.
It is formed due to an abnormal connection between ectoderm and endoderm. They are common in neural crest cells though found in the brain and spinal cord in rare cases mimicking neural tube defects.
Persistence of Terminal Ventricle
It is a rare case present as a cavity in conus medullaris can be visualized in radiological investigations.
Prenatal screening advancement has brought sound improvement in the management of neural tube defects. Earlier diagnosis and intervention has significantly reduced the postnatal complications of NTDs prolonging life. The most important prognostic factor is the level of disorder and extent of the segmental span. Higher-level lesion and larger segment lesion have poorer prognosis with non-ambulation, dysphasia, more time wheelchair use, etc. Prenatal surgical repair has better outcomes in terms of ambulation, cognition, and other neurological functions than postnatal repair. The presence of other congenital anomalies with NTDs increases the mortality and morbidity of patients.
Stillbirths and Abortion
Stillbirths and preterm labor leading to abortion is the serious complication NTDs.
It is typically associated with anencephaly because there is no mechanism for swallowing reflex so that amniotic fluid remains accumulated in the amniotic sac. This is obvious, patients with neural tube disorders have a learning disability as the development of neural tissue has been arrested. According to the conducted study, it is estimated that around 27% of pregnancies with anencephaly developed polyhydramnios few requiring amniodrainage in the third trimester Polyhydramnios usually develops in second and third trimesters in about 50% of patients.
It is defined as the downward displacement (herniation) of part of the cerebellum into the foramen magnum because of the tethering of the spinal cord in the vertebral column due to its abnormal development (spina bifida).
Brain malformation has a direct impact on the development of hydrocephalus. Encephalocele is associated with the communicating type of hydrocephalus.
Continuous leakage of cerebrospinal fluid paves the easy access to meninges for normal naso-oropharynx such as streptococci, enterococci. The children with NTDs are susceptible to meningitis.
Cognitive disability: Normal CSF pressure, osmolarity, and constituents of CSF are required for the proper development of the brain, mainly the cerebral cortex. Patients with NTDs have less cortical development even with the normal head size due to the free flow of CSF down through spina bifida. Neural cell proliferation and migration are deranged by abnormal CSF physiology.
Spinal fistula: Spinal fistula formation and a continuous discharge of CSF is common in some cases.
Complications due to fetal surgery: Preterm delivery, obstetric complications, pulmonary edema percutaneous fetoscopic vs. open repair: preterm birth and placental rupture are more common in percutaneous fetoscopic surgery whereas the rate of uterine dehiscence is more in open surgery.
NTDs are preventable in most cases. Negligence of community participation in comprehensive health care awareness about dietary management, prenatal screening, and sanitation hits back with neural tube disorders and other congenital anomalies. Proper folic acid supplementation reduces the chances of NTDs in folate preventable cases, and methionine and inositol reduce the NTDs in non-folate preventable cases. Women who are taking antiseizure drugs should be minimized optimally as much as possible, and these patients need a higher dose of folic acid to overcome the antagonism of antiepileptic drugs. A blood test, usually around the fourth month of pregnancy, should be encouraged. Ultrasound screening has been an essential part of every pregnant woman with suspicion, family history, and in the areas of high prevalence rate. Prenatal surgical repair has good outcomes. Genetic counseling of the family should be part of a national campaign. Patients and families have the right to know about the information on the disease process, complications, treatment methods, and outcomes of management. Keeping in view of family counseling, long term follow up is required regardless of initial treatment.
Nutritionists for folic acid supplementation plays a central role in preventing the disease in coordination with lab technicians and radiologists for prenatal screening and diagnosis. The approach of neurosurgery to reduce future complications and restore neurological development should go side by side. Fetal surgery has complications in both mother and child, so gynecologist and obstetrician consultation is a must. Genetic analysts are essential in genetic cases. In the modern era, researches have a huge impact on the evaluation of causes, risk factors, and modulation of treatment methods. Associated syndromes like Meckel-Gruber syndrome, VACTERL syndrome necessitates the call for multiple specialties like cardiologists, nephrologists, neurologists, rheumatologists, etc.
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