Pathophysiology
Summary
During the 4th week of fetal development, the neural tube forms from the fusion of neural crests, eventually developing into the brain and spinal cord. A subset of congenital malformations called neural tube defects (NTDs) arise from the failure of closure of the anterior or posterior neuropore, and are the most common malformations of the brain and spinal cord.
Folate deficiency during early pregnancy can cause NTDs, as can drugs that impede folate metabolism, such as valproic acid, methotrexate, and trimethoprim-sulfamethoxazole. Elevated alpha fetoprotein (AFP) levels in maternal blood suggest an NTD in the fetus, due to the leakage of CSF and proteins from an open neuropore into the amniotic sac. Acetylcholinesterase is also released into the in amniotic fluid, and can help confirm the presence of an NTD.
Anterior neural tube defects can result in anencephaly, a lethal NTD that causes polyhydramnios during pregnancy, resulting in the the absence of brain tissue and an open skull, as well as encephalocele, a sac-like protrusion in the occipital region containing herniated brain tissue or meninges, which can also be lethal.
Posterior neural tube defects include spina bifida occulta, where non-fusion of the posterior vertebral arch presents in with a tuft of hair or skin dimple but no herniation of neural tissue. Meningocele occurs when the meninges herniate through the body defect, but no neural tissues, and myelomeningocele results when the meninges and neural tissues of the lower spinal cord herniates through the defect. Myelomeningocele presents with neurological deficits at birth like motor, sensory, and bowel/bladder incontinence. It is also associated with Chiari type II malformations.
Holoprosencephaly occurs when the left and right hemispheres fail to separate during development and can result from mutations in the sonic hedgehog gene. It is associated with trisomy 13 & fetal alcohol syndrome. Symptoms can range from a cleft lip or palate in moderate cases to severe manifestations such as cyclopia.
Chiari malformations are congenital anomalies of the posterior fossa, leading to cerebellum displacement into the spinal canal. Chiari type I malformations involves the herniation of only the cerebellar tonsils, while Chiari type II malformations involve the herniation of the medulla, cerebellar tonsils, and vermis. Type I is associated with syringomyelia, which presents with loss of bilateral pain and temperature sensation in the upper extremities due to the dilation of the central canal compressing the anterior white commissure. Type II malformation can cause non-communicating hydrocephalus due to obstruction of CSF flow through foramen magnum. Both types can present with headaches, dizziness, nystagmus, ataxia, and UMN dysfunction.
Lastly, Dandy-Walker syndrome is a congenital brain malformation characterized by agenesis of the cerebellar vermis, cystic dilatation of the 4th ventricle, and enlarged posterior fossa, presenting with non-communicating hydrocephalus.
Lesson Outline
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FAQs
Neural tube defects (NTDs) are congenital malformations of the brain and spinal cord that arise due to the failure of the neural tube to close properly during the 4th week of fetal development. A significant cause of NTDs is folate deficiency during the early stages of pregnancy, before the formation of the neural tube. Additionally, drugs that impede folate metabolism, such as valproic acid, methotrexate, and trimethoprim-sulfamethoxazole, can also lead to NTDs. Elevated alpha fetoprotein (AFP) levels in maternal blood and increased acetylcholinesterase in the amniotic fluid suggest the presence of an NTD in the fetus.
Holoprosencephaly is a developmental anomaly where the left and right brain hemispheres fail to separate. Potential causes include mutations in the Sonic Hedgehog gene, association with Trisomy 13 (Patau syndrome), or fetal alcohol syndrome. Manifestations can range from cleft lip or palate to more severe presentations like cyclopia, where the individual has a single eye.
Chiari malformations are congenital defects of the posterior fossa, leading to the downward displacement of the cerebellum into the spinal canal. Symptoms can vary but often include headaches from meningeal irritation, dizziness, nystagmus, and ataxia due to cerebellar dysfunction. Additionally, there may be upper motor neuron dysfunction, characterized by hyperreflexia and clasp knife rigidity, resulting from the compression of corticospinal motor tracts in the brainstem.
Syringomyelia refers to a cystic dilation within the central canal of the spinal cord. It's frequently associated with Type I Chiari malformations. The dilation, predominantly found in the lower cervical cord, compresses the anterior white commissure. This compression leads to a distinctive symptom: the loss of bilateral pain and temperature sensation in the upper extremities, often described as a ‘cape-like’ distribution.
Elevated alpha fetoprotein (AFP) levels in maternal blood suggest an NTD in the fetus, due to the leakage of CSF and proteins from an open neuropore into the amniotic sac. Acetylcholinesterase is also released into the in amniotic fluid, and can help confirm the presence of an NTD.
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