Neural tube defects

Neural tube defects (NTDs) are the most common congenital malformations of the central nervous system (CNS). They develop between the 3^rd and 4^th week of pregnancy and are often caused by folate deficiency. Most commonly, a deficiency in folate results in improper closure of the neural tube in the embryo, mainly at the caudal or cranial ends. The formation of defects at the caudal end is more common and is known as spina bifida. Spina bifida may occur without any apparent clinical features (spina bifida occulta) or manifest with protrusion of the meninges and, potentially, the spinal cord (myelomeningocele) through a gap in the vertebrae. Myelomeningoceles predominantly cause symptoms of sensory and motor function loss, such as bladder dysfunction and paraplegia. NTDs at the cranial end can cause cranial fissure malformations; the most severe manifestation of this, anencephaly, is incompatible with life. The diagnosis of NTDs is often established during pregnancy via ultrasound and detection of elevated alpha-fetoprotein levels in the maternal serum or amniotic fluid. Treatment involves prophylactic administration of antibiotics and rapid surgical closure of the defect to avoid CNS infections. Supplementation with folate is an important preventative measure and should ideally be initiated 4 weeks prior to conception.

• Neural tube defects (NTDs) are congenital malformations of the central nervous system (CNS), spine, and cranium.
• NTDs are caused by incomplete closure of the neural tube during neurulation, which takes place during the 3^rd and 4^th week after conception.
  • Cranial defects: incomplete closure of anterior neuropores → cranial cleft formation (mostly open defects) with involvement of the skull and brain
  • Spinal defects: incomplete closure of posterior neuropores → bone defects of the vertebral arches (mostly lower lumbar or sacral region ) → possible herniation of spinal neural tissue and meninges
• NTDs can be classified according to affected structure and degree to which the defect is covered by tissue.
  • Open NTDs: Meninges and/or neural tissue are uncovered and, therefore, freely exposed to the surrounding (e.g., amniotic fluid). ^[1]
  • Closed NTDs: Defect is covered by skin and/or connective tissue.

• NTDs are among the most common severe congenital malformations. ^[2]
• Spina bifida and anencephaly are the most frequent NTDs with a combined prevalence of approx. 6.5:10,000 live births per year in the US. ^[3]

Epidemiological data refers to the US, unless otherwise specified.

Most NTDs are isolated malformations with multifactorial etiology.

• Maternal risk factors
  • Folate deficiency during pregnancy ; due to:
    • Insufficient folate supplementation (see “Prevention” below)
    • Drugs that interfere with folate metabolism
      • Methotrexate
      • Anticonvulsants: valproate, carbamazepine
      • Sulfonamides, trimethoprim
  • Pregestational diabetes mellitus
  • Obesity
  • Fever/hyperthermia during the first trimester
• Fetal causes
  • Chromosomal aberrations (e.g., trisomy 13, trisomy 18) and other genetic factors
  • Amniotic band syndrome
  • Chiari II malformation

The most common NTDs are spina bifida and anencephaly.

Prenatal period ^[1]

• Screening test (16–18 weeks' gestation): ↑ AFP in maternal serum (MSAFP)
  • MSAFP is only elevated in open NTDs.
  • MSAFP is not elevated in spina bifida occulta.
  • Usually part of the quad screen test
• Ultrasonography (18–20 week's gestation)
  • Characteristic findings depend on the specific defect
    • Findings in anencephaly
      • Cranial vault and brain tissue are absent.
      • Residual, disorganized cerebellar and/or brainstem tissue may be present.
      • Bulging eyes and underdeveloped forehead
      • Associated with polyhydramnios
  • Screen for malformations of other structures (e.g., abdominal wall defects)
  • Rule out other causes of elevated MSAFP (e.g., miscalculated gestational age, multiple gestations, fetal death)
• Amniocentesis: ↑ AFP and ↑ AChE in amniotic fluid (increase in open NTDs only)
  • Used as confirmation test when MSAFP is elevated but ultrasound findings are inconclusive
  • When both AFP and AChE are elevated, an open NTD is very likely.
  • Amniocentesis may also be used to test for chromosomal abnormalities associated with NTDs (e.g., trisomy 13, trisomy 18)

AFP is only elevated in open NTDs.

Postnatal period ^[1]

• Complete physical examination
  • Lumbar skin dimple or tuft of hair (often seen in spina bifida occulta)
  • Associated malformations (e.g., abdominal wall defects)
  • Extent of neurological deficits (e.g., muscle weakness, spasticity, abnormal reflexes)
  • Signs of elevated intracranial pressure (e.g., bulging fontanel)
• Imaging
  • Cranial ultrasonography: to monitor hydrocephalus
  • CT scans and/or MRI
    • Monitor hydrocephalus
    • Evaluate bone defects and/or neural tissue lesion (imaging is especially important to plan surgery)

Tethered cord syndrome ^[5][6]

• Definition: a functional neurologic disorder caused by abnormal stretching of the spinal cord as a result of adhesions or obstructions attaching the caudal spinal cord to the spinal canal
• Etiology
  • Myelomeningocele/lipomyelomeningocele (most common cause)
  • Lipoma, dermoid cysts
  • Meningeal adhesions (e.g., after surgery for myelomeningocele or spinal trauma)
  • Adhesion or thickening of the filum terminale
  • Tumors
• Clinical features
  • Lower back pain (aggravated by flexion of lower spine)
  • Sensory and motor deficits of the lower limbs (e.g., muscle weakness, spasticity, abnormal reflexes)
  • Bladder/bowel dysfunction
  • Skeletal malformations (e.g., foot deformities, scoliosis)
  • Visible tumors or skin lesions on lower back (e.g., discoloration, hairy patch, dimple, lipoma)
• Diagnostics: MRI may show abnormally low position of the conus medullaris, thickening of the filum terminale, meningeal adhesions, lipomas, dermoid, cysts, or tumors.
• Treatment: removal of structure tethering the spinal cord (e.g., adhesiolysis, resection of lipoma)

Congenital dermal sinus

• Definition: : mostly lumbar or lumbosacral fistulae that extend from the surface of the skin to the spinal canal and frequently end in a dermoid or epidermoid cyst
• Etiology: incomplete or lack of separation of the neural ectoderm from the dermal ectoderm
• Clinical features
  • Visible ostium, dimple, possibly hyperpigmentation of the skin, and hypertrichosis
  • May manifest with clinical features of tethered cord syndrome (see above)
  • Complications: intradural infections (recurring meningitis, abscesses)
• Treatment: neurosurgical exploration and potential resection of the dermoid or epidermoid cysts

The differential diagnoses listed here are not exhaustive.

• Prenatal
  • After counseling, patients should be referred to specialized clinics for continuation or termination of the pregnancy
  • Myelomeningocele: fetal surgery may be indicated, depending on fetal and maternal risk factors.
• Delivery
  • Should take place in a specialized center (providing neonatal ICU and pediatric neurosurgery)
  • Birth mode: usually cesarean delivery (prelabor) ^[7][8]
• Postnatal
  • General management
    • Cover defect with sterile, wet compresses (avoid pressure on defect)
    • Prophylactic administration of broad-spectrum antibiotics
  • Surgical treatment
    • Open NTDs: Surgery should be performed within 72 hours after delivery (to reduce the risk of CNS infection).
    • Closed NTDs: monitoring and possibly elective surgery
    • Hydrocephalus: consider placement of a ventriculoperitoneal shunt
  • Long-term care
    • Complex treatment
    • May involve physical therapy, rehabilitation programs, and specific treatment of neurological disorders (e.g., neurogenic bladder dysfunction).

• Folate supplementation in pregnancy: according to the US Preventive Services Task Force ^[3]
  • 400–800 μg/day for all women planning or capable of pregnancy (at least 4 weeks prior to conception)
  • Women with a history of a previous pregnancy resulting in an NTD
    • 400–800 μg/day when no pregnancy is planned
    • 4 mg/day when pregnancy is planned (at least 4 weeks prior to conception) ^[9]
  • Intake should be continued through the first trimester.

Supplementation of 400–800 μg of folate per day is recommended for all women who are planning for pregnancy.