| Day / Week | Event |
|---|---|
| Week 3 (day 18–22) | Notochord induces overlying ectoderm → neural plate |
| Day 22–24 | Neural folds form and elevate; fusion begins at the 3rd–5th somite level (future cervical region) and proceeds bidirectionally (cranial and caudal) |
| Day 25 | Anterior (rostral) neuropore closes — failure causes anencephaly |
| Day 27–28 | Posterior (caudal) neuropore closes — failure causes spina bifida (occulta to myelomeningocele depending on severity) |
| Week 4–5 | Three primary vesicles (prosencephalon / mesencephalon / rhombencephalon) |
| Week 5 | Five secondary vesicles (telencephalon / diencephalon / mesencephalon / metencephalon / myelencephalon) |
| Week 6–8 | Pontine flexure forms 4th ventricle; cerebellar primordia develop |
| Week 8–16 | Neural progenitor proliferation in the ventricular zone |
| Week 12–24 | Radial neuronal migration (“inside-out” cortex — layer VI first, layer II last); myelination begins late 2nd trimester |
Maternal folate (0.4 mg/d preconception, 4 mg/d if prior NTD pregnancy or on valproate/carbamazepine/methotrexate) reduces NTD risk ~70% (MRC Vitamin Study). Maternal serum AFP is elevated in open NTDs (open spina bifida, anencephaly); closed NTDs (occulta, meningocele covered by skin) typically have normal AFP. Folate antagonists (valproate, carbamazepine, methotrexate, trimethoprim, sulfasalazine) increase NTD risk.
| Primary Vesicle | Secondary Vesicle | Adult Derivatives | Ventricular Cavity |
|---|---|---|---|
| Prosencephalon (forebrain) | Telencephalon | Cerebral hemispheres, cortex, white matter, basal ganglia (caudate, putamen, NA), amygdala, hippocampus, olfactory bulb (CN I) | Lateral ventricles |
| Diencephalon | Thalamus, hypothalamus, epithalamus (pineal, habenula), subthalamus, neurohypophysis (posterior pituitary), retina + optic nerve (CN II), globus pallidus* | 3rd ventricle | |
| Mesencephalon (midbrain) | Mesencephalon | Midbrain (tectum — superior + inferior colliculi; tegmentum — red nucleus, substantia nigra, CN III/IV nuclei); cerebral peduncles | Cerebral aqueduct (of Sylvius) |
| Rhombencephalon (hindbrain) | Metencephalon | Pons + cerebellum | Upper 4th ventricle |
| Myelencephalon | Medulla | Lower 4th ventricle + central canal |
*Globus pallidus: classically taught as diencephalic; modern developmental data show it derives from the medial ganglionic eminence (telencephalic) but migrates ventrally. The board answer remains diencephalon.
Neural crest cells delaminate from the dorsal neural folds and migrate widely. Major derivatives:
| Defect | Description | Maternal AFP | Key Features |
|---|---|---|---|
| Spina bifida occulta | Failure of posterior vertebral arches to close; meninges & cord remain intra-canal and skin-covered | Normal | Often asymptomatic; tuft of hair, dimple, lipoma, hyperpigmented patch over the lumbosacral area; may have tethered cord (urinary symptoms, weakness, scoliosis) |
| Meningocele | Herniation of meninges (CSF-filled sac) through bony defect; spinal cord remains in canal | Normal or mildly elevated | Skin-covered or partially covered; cord typically intact; better prognosis than myelomeningocele |
| Myelomeningocele | Herniation of meninges + neural tissue (spinal cord / cauda equina) through defect; open lesion | Elevated | ~80% lumbosacral; virtually always associated with Chiari II; 90% develop hydrocephalus; lower limb paralysis, bladder/bowel dysfunction. MOMS trial: prenatal repair improves motor outcomes |
| Anencephaly | Failure of anterior neuropore closure (day 25) → absence of forebrain and calvarium | Markedly elevated | Incompatible with life; classic association with maternal folate deficiency and uncontrolled diabetes |
| Craniorachischisis | Complete failure of neural tube closure → anencephaly + extensive open spina bifida along the entire length of the cord | Very high | Most severe end of the NTD spectrum; incompatible with life |
| Congenital dermal sinus | Midline lumbosacral epithelium-lined tract extending from skin to dura (sometimes to cord); ~50% with associated dermoid/epidermoid | Normal | Skin dimple/sinus opening; recurrent meningitis (esp. Staphylococcus); abscess; tethered cord. Full surgical excision required — do NOT probe in clinic. |
| Diastematomyelia / Diplomyelia | Longitudinal splitting of the spinal cord (Type I = bony spur dividing two dural sacs; Type II = single dural sac); associated with tethering, scoliosis, hair tuft | Normal | MRI for diagnosis; surgical untethering and spur removal if symptomatic |
| Encephalocele | Herniation of brain and meninges through skull defect (most often occipital) | Elevated | Often syndromic (Meckel-Gruber); imaging shows herniated brain tissue through midline cranial defect |
Closed dysraphisms (occulta, lipomyelomeningocele, dermal sinus) can present years later as tethered cord syndrome: progressive lower-extremity weakness, back/leg pain, urinary incontinence, scoliosis. MRI shows the conus medullaris below L1–L2. Surgical detethering can prevent further neurologic decline.
| Malformation | Anatomy | Clinical Features |
|---|---|---|
| Chiari I | Cerebellar tonsils ≥5 mm below foramen magnum; NO supratentorial malformation | Often presents in adolescents/adults; suboccipital headache (worse with Valsalva), neck pain, downbeat nystagmus; syringomyelia in ~50% (cape distribution suspended sensory loss) |
| Chiari II (Arnold-Chiari) | Vermis + brainstem + 4th ventricle herniation through foramen magnum (± tonsils); virtually always with myelomeningocele; small posterior fossa; tectal beaking | Hydrocephalus (90%, often requires shunt); stridor, apnea, dysphagia, weak cry from lower brainstem dysfunction; cord-level deficits from myelomeningocele |
| Chiari III | Chiari II features plus low occipital / high cervical encephalocele containing cerebellum and brainstem | Rare; severe; high mortality |
| Dandy-Walker malformation | Vermian hypoplasia/agenesis + cystic dilation of the 4th ventricle + enlarged posterior fossa with elevated tentorium / torcula | Macrocephaly, hydrocephalus, developmental delay; ~50% have other CNS anomalies (corpus callosum agenesis); seizures common |
| Joubert syndrome | “Molar tooth sign” on axial MRI (thickened elongated superior cerebellar peduncles + deep interpeduncular fossa + vermis hypoplasia) | Ataxia, oculomotor apraxia, abnormal breathing pattern (hyperpnea-apnea), intellectual disability, retinal dystrophy — a ciliopathy |
Holoprosencephaly (HPE) = failure of the prosencephalon to cleave into two cerebral hemispheres. Severity spectrum:
Causes: sporadic; SHH (sonic hedgehog) pathway mutations (SHH, ZIC2, SIX3, TGIF); trisomy 13 (Patau); maternal diabetes; maternal alcohol use; cholesterol synthesis disorders (Smith-Lemli-Opitz). “Single midline maxillary central incisor” is a subtle marker.
| Disorder | Mechanism | Imaging / Pathology | Clinical |
|---|---|---|---|
| Lissencephaly Type I (classic) | Failure of neuronal migration; LIS1 (PAFAH1B1) on 17p13.3 or DCX (X-linked, females = subcortical band heterotopia) | Smooth cortex with little/no gyration; thickened 4-layer cortex (vs normal 6-layer) | Severe developmental delay, refractory epilepsy (including infantile spasms), feeding difficulty. Miller-Dieker syndrome = 17p13.3 contiguous deletion (LIS1 + YWHAE) with facial dysmorphism |
| Lissencephaly Type II (cobblestone) | Overmigration through breached pial limiting membrane; dystroglycanopathies (Walker-Warburg, muscle-eye-brain, Fukuyama CMD); RELN/reelin mutations → lissencephaly with cerebellar hypoplasia | Cobblestone cortical surface; eye abnormalities; muscular dystrophy | Severe developmental delay, eye malformations, congenital muscular dystrophy |
| Periventricular nodular heterotopia | Failure of neurons to leave the ventricular zone; FLNA (filamin A), X-linked dominant (lethal in males), affects females | Subependymal gray-matter nodules lining lateral ventricles | Often normal cognition; epilepsy in adolescence/adulthood; vascular abnormalities possible |
| Subcortical band heterotopia (“double cortex”) | Partial arrest of migration; DCX (X-linked, females have band; males = lissencephaly) | Smooth band of gray matter beneath cortex on MRI | Epilepsy, intellectual disability of variable severity |
| Polymicrogyria | Late migration/post-migrational disorder; many small abnormal gyri | Excessive small gyri, irregular cortical surface; perisylvian most common pattern | Bilateral perisylvian PMG: pseudobulbar palsy, epilepsy, intellectual disability |
| Schizencephaly | Full-thickness cleft from ependyma to pia, lined by gray matter | Open lip (CSF cleft) vs closed lip (apposed walls); often with absent septum pellucidum | Hemiparesis, seizures, intellectual disability (severity depends on bilateral vs unilateral and open vs closed) |
| Hemimegalencephaly | Unilateral hemispheric overgrowth with cortical dysplasia; somatic mosaic mTOR pathway (MTOR, AKT3, PIK3CA) | Asymmetric hemispheric enlargement; cortical thickening; abnormal gyration | Severe early-onset epilepsy, hemiparesis; surgical hemispherectomy is often curative for seizures |
| Focal cortical dysplasia (FCD) | Blümcke/ILAE classification: Type I (lamination), Type IIa (dysmorphic neurons), Type IIb (balloon cells = mTORopathy), Type III (associated with adjacent lesion) | MRI may show cortical thickening, blurred gray-white junction, “transmantle sign”; often MRI-negative | Most common cause of medically refractory focal epilepsy in children leading to surgery; FCD IIb shares pathology with TSC cortical tubers |
