Neurulation Overview

• Notochord (mesodermal structure) induces overlying ectoderm to form the neural plate (day 17–18)
• Neural plate folds → neural groove → neural folds → fusion into neural tube (weeks 3–6)
• Neural crest cells migrate from the dorsal edges of the neural folds before and during closure
• Neural tube lumen → ventricular system and central canal of spinal cord

Primary Neurulation

• Fusion begins day 22 at the region of the 4th–6th somite (future cervical region)
• Closure proceeds bidirectionally — cranially and caudally (zipper-like fashion)
• Anterior neuropore closes day 25 → failure causes anencephaly
• Posterior neuropore closes day 27 → failure causes spina bifida / myelomeningocele
• Primary neurulation forms the brain and spinal cord down to the upper sacral level

Secondary Neurulation

• Forms the caudal neural tube (sacral and coccygeal segments), days 28–32
• Occurs by canalization of a solid cord of cells (not folding of a neural plate)
• Defects in secondary neurulation → occult spinal dysraphisms (lipomyelomeningocele, tethered cord, dermal sinus tract)

Alpha-Fetoprotein (AFP)

• Elevated maternal serum AFP → open neural tube defects (anencephaly, myelomeningocele), also elevated in omphalocele, gastroschisis, twin pregnancy
• Decreased maternal serum AFP → Down syndrome (trisomy 21), Edwards syndrome (trisomy 18)
• Elevated amniotic fluid AFP + acetylcholinesterase → confirms open neural tube defect

Primary → Secondary Vesicles → Adult Structures

Overview

• Neural crest cells originate from the dorsal neural tube/neural fold junction and undergo extensive migration
• Give rise to most of the peripheral nervous system and a diverse array of non-neural structures
• Neurocristopathies = disorders of neural crest development (e.g., Hirschsprung disease, Waardenburg syndrome, neurofibromatosis)

Embryonic Organization of the Neural Tube

• Sulcus limitans — longitudinal groove on the inner surface of the developing neural tube; divides it into dorsal and ventral halves
• Alar plate (dorsal) → sensory structures: sensory nuclei, dorsal horn of spinal cord
• Basal plate (ventral) → motor structures: motor nuclei, ventral horn of spinal cord
• Roof plate (dorsal midline) and floor plate (ventral midline) → commissural pathways; floor plate guided by Sonic Hedgehog (SHH) from notochord
• In the brainstem, the alar-basal organization is preserved: motor nuclei are medial (near midline), sensory nuclei are lateral (near surface)

Proliferation

• Neurons are generated in the ventricular zone (VZ) and subventricular zone (SVZ) lining the ventricles
• Peak neuronal proliferation: weeks 8–16 of gestation
• Disorders of proliferation → microcephaly (decreased) or megalencephaly (increased)

Radial Migration

• Radial glia serve as scaffolding for neuronal migration from ventricular zone to cortical plate
• Radial glia also serve as neural progenitors and later transform into astrocytes
• Inside-out pattern: earlier-born neurons populate deeper cortical layers (V, VI); later-born neurons migrate past them to populate superficial layers (II, III)
• Peak migration: weeks 12–24 of gestation
• Cortical layers fully present by 27 weeks gestation

Tangential Migration

• GABAergic interneurons migrate tangentially from the ganglionic eminences (medial and lateral) in the ventral forebrain
• This is a separate pathway from radial migration of pyramidal neurons
• Defects in tangential migration may contribute to epilepsy and autism spectrum disorders

Myelination

• Begins 4th month of gestation, continues into the 3rd decade of life
• PNS myelinates before CNS
• PNS: motor roots myelinate before sensory roots
• CNS: sensory tracts myelinate before motor tracts (opposite of PNS)
• Myelination proceeds caudal → rostral and posterior → anterior in general
• Frontal lobe white matter is among the last to fully myelinate (explains late maturation of executive function)

Spectrum of Neural Tube Defects

Risk Factors & Prevention

• Folic acid deficiency — most important modifiable risk factor
• Antiepileptic drugs: valproate (>1% risk), carbamazepine (∼0.5–1%)
• Maternal diabetes mellitus
• Maternal obesity, hyperthermia
• Prevention: folic acid 0.4 mg/day for all women of childbearing age; 4 mg/day if prior affected pregnancy

Classification

Holoprosencephaly

• Definition: failure of prosencephalon (forebrain) to cleave into two hemispheres
• Genetics: SHH (Sonic Hedgehog) gene mutations; also trisomy 13 (Patau syndrome), trisomy 18
• Spectrum (severe → mild):
  • Alobar — single ventricle, fused thalami, no interhemispheric fissure; cyclopia or proboscis
  • Semilobar — partial separation posteriorly; partially fused frontal lobes
  • Lobar — near-complete separation; mild frontal fusion; may have normal appearance
• Facial anomalies: "the face predicts the brain" — cyclopia, single nostril, median cleft lip, hypotelorism

Agenesis of the Corpus Callosum (ACC)

• Corpus callosum develops from anterior to posterior (genu → body → splenium; rostrum last)
• Complete or partial agenesis — partial ACC preferentially affects the posterior body and splenium
• May be isolated (asymptomatic) or syndromic
• MRI findings: widely spaced lateral ventricles ("racing car" sign on axial), colpocephaly (dilated occipital horns), radial sulci on medial surface ("starburst" pattern)
• Aicardi syndrome: ACC + infantile spasms + chorioretinal lacunae; X-linked dominant (lethal in males; occurs almost exclusively in females)

Septo-Optic Dysplasia (de Morsier Syndrome)

• Triad: absent septum pellucidum + optic nerve hypoplasia + hypothalamic-pituitary dysfunction
• Diagnosis requires at least 2 of 3 features
• Associated with HESX1 gene mutations
• Pituitary dysfunction → growth hormone deficiency, diabetes insipidus, panhypopituitarism
• May present with neonatal hypoglycemia, visual impairment, or short stature

Classification

Key Disorders