Nervous system

Neural tube defects (NTDs)

Severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely.

Severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely.

  • M/C birth defect of central nervous system (CNS)
  • M/complex birth defect compatible with survival


In higher vertebrates, the neural tube is generated by the processes that shape, bend, and fuse the neural plate, and fusion in the dorsal midline progressively seals the neural tube as it forms. If closure is not completed, the neuroepithelium remains exposed to the environment and consequently subject to degeneration and neuronal deficit.

Neurulation and the origin of open and closed spinal bifida
Neurulation and the origin of open and closed spinal bifida: (a) Schematic transverse sections showing the process of primary neurulation, which involves bending of the neural plate, convergence of the neural folds and closure of the neural tube. (b) A histological section through the open spinal neural folds of an unaffected human embryo (Carnegie stage 12, 26 days post-fertilization), showing the closing neural tube during primary neurulation. (c) Failure of the neural groove to close in the low spinal region in the fourth week after fertilization leads to myelomeningocele (also termed open spina bifida). (d) Schematic sagittal sections showing the process of secondary neurulation, which involves condensation of the caudal eminence, followed by the formation of the lumen (canalization), completion of secondary neurulation and regression of the tail. This process finalizes in the sixth week after fertilization. (e) A histological section through an unaffected human embryo (Carnegie stage 13, 30 days post-fertilization), showing formation of the secondary neural tube (nt) through canalization. (f) Failure of the secondary neural tube to separate from non-neural tissues (tethering) leads to closed spinal dysraphism, in this case with massive lipoma. no, notochord; np, neural plate; so, somite. | Spina bifida. (2015). Nature Reviews Disease Primers, 1, 15051. Retrieved from

Primary (closure) neuralation:

Neural tube formation via bending of the neuroepithelium at the midline to generate neural folds that elevate, meet, and fuse in the dorsal midline to form most of the spinal cord

Secondary (canalisation) neuralation:

Follows on seamlessly from primary neurulation, and is the process by which the neural tube forms in the lower sacral and coccygeal regions. Malformations resulting from disturbance of secondary neurulation are closed (skin covered) and often involve tethering of the spinal cord, with associated ectopic lipomatous material
Developmental origin of neural tube defects
Diagrammatic representation of the developmental origin of malformations broadly classified as neural tube defects in humans. (a,b) Disorders of primary neurulation include craniorachischisis (a) in which the neural tube fails to initiate closure, leaving most of the brain and the entire spine open. If closure initiates successfully, then the cranial and/or spinal neural folds may fail to close (b) generating exencephaly/anencephaly and open spina bifida (myelomeningocele), respectively. (c) Disorders of secondary neurulation comprise failure of the neural tube to separate completely from adjacent tissues, resulting in tethering and diminished mobility. The spinal cord is covered by skin and often associated with fatty tissue accumulation (lipoma) through as-yet-unknown mechanisms. (d) Postneurulation defects can arise when the bony structure of the skeleton fails to develop fully. Herniation of the meninges, with or without brain tissue, through a skull defect (shown here as occipital but sometimes parietal or fronto-ethmodial) generates encephalocele, while an analogous defect in the spinal region produces meningocele. | Greene, N. D., & Copp, A. J. (2014). Neural tube defects. Annual review of neuroscience, 37, 221–242.


Cranial dysraphism:

Failure of cranial neural tube closure
  1. Anencephaly: Failure of cephalic folds to fuse into a neural tube
  2. Cranium bifida (midline skull defects):
    • Cranium bifidum occultum (mild form): Persistent wide fontanelle, or persistent parietal foramina, which often close over time
    • Encephalocele (severe form): Failure of the anterior neuropore to close during days 26-28 of gestation; associated with various syndromic malformations

Spinal dysraphism:

Failure of caudal neuropore closure
  • Spina bifida cystica (open spinal dysraphism): Originate from defective closure of the primary neural tube, with persistence of a segment of incompletely fused plaque of neural tissue, referred to as the neural placode
    1. Myelocele (herniation of meninges only): Flat appearance
    2. Myelomeningocele (herniation of meninges and neural tissue): Bulging appearance
  • Closed spinal dysraphisms (associated with subcutaneous mass):and meningocele)
    1. Lipomas with dural defect: Characterized by a subcutaneous fatty mass located above the gluteal crease. The lipomatous mass herniates through the bony defect and attaches to the spinal cord, tethering the cord, and often the associated nerve roots
      • Lipomyelomeningocele
      • Lipomyelocele
    2. Meningocele: Herniation of the meninges through the bony defect (spina bifida) without an associated herniation of the spinal cord or nerve roots into the dural sac
    3. Terminal myelocystocele: Large terminal cystic dilatation of the spinal cord resulting from hydromyelia
Classification of spinal dysraphisms
Classification of spinal dysraphisms. | Salih, M. A., Murshid, W. R., & Seidahmed, M. Z. (2014). Classification, clinical features, and genetics of neural tube defects. Saudi medical journal, 35 Suppl 1(Suppl 1), S5–S14.

Common variants:

  • Spina bifida occulta: Failure of caudal neuropore to close. The spinal cord, meninges, and overlying skin remain intact, with no herniation.
  • Myeloschisis: Exposed neural tissue without skin/meninges covering.
  • Anencephaly: Failure of rostral neuropore to close thus the brain and cranial vault are grossly malformed with normal hindbrain development.
Overview of neural tube defects
Overview of neural tube defects: Schematic representation of several neural tube defects (NTDs). Spina bifida occulta is found in up to 10% of people and usually occurs in the low spinal region. Closed spinal dysraphism has many variants, including lipomyelomeningocele, low-lying conus and thickened filum terminale. CSF, cerebrospinal fluid. | Spina bifida. (2015). Nature Reviews Disease Primers, 1, 15051. Retrieved from
Sagittal views of spina bifida malformations
Sagittal views of spina bifida malformations. Magnetic resonance image (A) and corresponding views showing spina bifida occulta (A, B) and spina bifida cystica (C, meningocele; D, meningomyelocele). CSF, cerebrospinal fluid | Development of the Nervous System [Internet]. Clinical Gate. 2017 [cited 22 March 2017]. Available from:


Non-genetic risk factors:

  • Reduced folate intake
  • Maternal anticonvulsant therapy (interferance with folate metabolism)
  • Diabetes mellitus
  • Obesity


Spina bifida oblongata:

  • Asymptomatic
  • May develop neurogenic degradation later in life


  • Asymptomatic
  • May develop hydrocele

Myelomeningocele (M/C, M/severe):

Spinal cord open dorsally, forming a placode on the back of the fetus or newborn baby that frequently rests on a meningeal sac (then named spina bifida cystica). The vertebrae at the level of the lesion lack neural arches, and so are incomplete dorsally.
  • Loss of sensation
  • Paralysis
  • Bowel & bladder problems
  • Learning problems
  • Seizures
  • Leg & Feet deformities (Clubfeet)
  • Associated withArnold Chiari II Malformation (cerebellar and medulla oblongata slide down into Foramen Magnum)
    • FindingsHydrocephalus


Screening test:

  • Maternal serum α-fetoprotein (AFP) (M/C): 15-20 weeks
  • Acetylcholine esterase (M/sensitive)

Level-2 USG scan:

  • Small bi-parietal diameter (BPD)
  • Ventriculomegaly
  • Lemon sign: Frontal bone scalloping
  • Banana sign: Elongation and downward displacement of cerebellum
  • Frog-eye/Mickey mouse sign (anencephaly)
Myelomeningocele and associated cranial signs on ultrasonography
Myelomeningocele and associated cranial signs on ultrasonography: Diagnostic ultrasonography images of normally developing fetuses and fetuses with myelomeningocele. Compared with the regular, parallel vertebrae covered with skin in a normal fetus (part a), the spine is protruding from the vertebral column in myelomeningocele (arrow, part b). The low spinal view of a normal fetus (part c) shows the cauda equina within the vertebral canal, whereas in spina bifida, a protruding meningeal cyst is visible (arrow, part d). In a typically developing fetus, the skull has a regular, smooth frontal appearance (part e). By contrast, cranial signs that accompany myelomeningocele include the lemon sign, which is due to scalloping of the frontal bones (arrows, part f). Of note, the size of the anterior horn is also marked in part f. Compared with the dumb-bell shape of the unaffected fetal cerebellum (part g), the banana sign seen in myelomenigocele is characterized by a convex-shaped cerebellum (arrows, part h). | Spina bifida. (2015). Nature Reviews Disease Primers, 1, 15051. Retrieved from


MRI appearance of brain dysmorphology in myelomeningocele
MRI appearance of brain dysmorphology in myelomeningocele: Mid-sagittal MRI images of a typically developing child (parts a, d and g), a child with myelomeningocele and a hypoplastic corpus callosum (parts b, e and h) and a child with myelomeningocele and a hypogenetic corpus callosum (parts c, f and i). T1-weighted MRI images (parts a–c) that reveal a downward shift of the cerebellum (cb) in the children with spina bifida, representing the Chiari II malformation. Also note the tectal beaking (t) and the structural abnormalities in the corpus callosum (cc). Diffusion imaging tractography (parts d–i) showing connectivity emanating from the corpus callosum. This connectivity is divided into anterior (frontal; blue) and posterior (yellow) segments (parts g–i). Note the relative preservation of frontal connectivity in the individuals with spina bifida. There is a greater and more aberrant pattern of connectivity in the child with the hypogenetic corpus callosum. | K. Bradley (University of Houston, Texas, USA) and J. Juranek (University of Texas Health Science Center at Houston, USA).


Folic acid supplementation: 0.4 mg (400 mcgr) folic acid daily.

Prevention up to 70% of NTDs can be achieved by supplementation with 4 mg/day of folic acid
Fetal surgery for spina bifida
Fetal surgery for spina bifida: When a human fetus with spina bifida reaches 22 weeks of gestation, the mother and fetus can undergo surgery to repair the fetal spinal lesion. First, a hysterotomy is made in the mother by a uterine stapler, exposing the myelomeningocele lesion and neural placode (part a). This is followed by closure of the myelomeningocele lesion using a dural and myofascial flap (part b). | Spina bifida. (2015). Nature Reviews Disease Primers, 1, 15051. Retrieved from


Spina bifida is a congenital disorder characterized by failed closure (primary neurulation) or formation (secondary neurulation) of the neural tube, resulting in abnormalities of the vertebral column and/or spinal cord
Spina bifida is a congenital disorder characterized by failed closure (primary neurulation) or formation (secondary neurulation) of the neural tube, resulting in abnormalities of the vertebral column and/or spinal cord. This PrimeView discusses the risk factors for spina bifida, including myelomeningocele — the most common and disabling form. | Spina bifida. Nat Rev Dis Prim [Internet]. 2015 Apr 30;1:15051. Available from:

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