OVERVIEW OF PATHOGENESIS

Neuronal migration is a complex process occurring primarily between 8 to 16 weeks of gestation. It involves the movement of post-mitotic neurons from the ventricular and subventricular zones to their final destination in the six-layered cerebral cortex.

• Radial Migration: Neurons move along radial glial fibers to form the projection neurons of the neocortex (Inside-out pattern). Defects lead to Lissencephaly and Subcortical Band Heterotopia.
• Tangential Migration: Neurons move perpendicular to radial glia, contributing to inhibitory interneurons.

CLASSIFICATION BY TIMING OF INSULT

1. Proliferation/Apoptosis Defects: Microcephaly or Megalencephaly.
2. Migration Defects:
   • Under-migration: Lissencephaly, Periventricular Nodular Heterotopia.
   • Over-migration: Cobblestone Malformations (Lissencephaly Type 2).
3. Organization/Post-migrational Defects: Polymicrogyria and Schizencephaly.

DIAGNOSTIC APPROACH

• Neuroimaging (Gold Standard): MRI Brain with 3D-T1 weighted sequences and Thin-slice (1mm) Volumetric acquisition. MRI is superior to CT for identifying gray-white matter differentiation.
• Genetic Panel: Evaluation for LIS1, DCX, FLNA, and ARX mutations.
• Metabolic Screening: Indicated if there is a history of regression or multi-system involvement (e.g., Peroxisomal disorders).

GENERAL MANAGEMENT PRINCIPLES

• Seizure Control: Often requires a combination of Sodium channel blockers and GABAergic drugs. Vagal Nerve Stimulation (VNS) or Ketogenic diet may be considered for refractory cases.
• Neuro-rehabilitation: Early intervention with PT/OT/ST to manage hypertonicity and communication delays.
• Genetic Counseling: Essential for recurrence risk assessment (X-linked vs. Autosomal recessive).

SPECIFIC NEURONAL MIGRATION DISORDERS

1. SCHIZENCEPHALY

Definition: A migration disorder characterized by full-thickness clefts in the cerebral hemispheres, extending from the pial surface to the ventricular ependyma.

Pathophysiology: Failure of the germinal matrix to form or early destruction of radial glial fibers (Type I: Closed lip; Type II: Open lip).

Clinical Features:

• Motor Deficits: Hemiparesis (unilateral clefts) or quadriparesis (bilateral clefts).
• Seizures: Highly epileptogenic; often refractory to multiple ASMs.
• Developmental Delay: Significant cognitive impairment, especially in open-lip varieties.
• Microcephaly: Common in bilateral, extensive clefting.

2. LISSENCEPHALY (Smooth Brain)

Definition: A malformation characterized by a smooth cerebral surface with absent (agyria) or reduced (pachygyria) convolutions.

Pathophysiology: Arrest of neuronal migration between 12-16 weeks of gestation. Often associated with LIS1 or DCX gene mutations.

Clinical Features:

• Dysmorphism: High forehead, bitemporal narrowing, and anteverted nostrils (Miller-Dieker Syndrome).
• Severe Neurodevelopmental Delay: Profound intellectual disability; failure to achieve milestones.
• Infantile Spasms: Frequently presents as West Syndrome (hypsarrhythmia on EEG).
• Feeding Difficulties: Severe bulbar dysfunction and recurrent aspiration pneumonias.

3. HETEROTOPIA (Periventricular/Subcortical)

Definition: Presence of normal neurons in abnormal locations due to premature arrest of migration.

Pathophysiology: X-linked dominant (FLNA gene) or autosomal recessive inheritance. Neurons fail to leave the ventricular zone.

Clinical Features:

• Seizures: Most common presenting feature, typically starting in the second decade of life.
• Cognition: Can be near-normal in isolated periventricular nodular heterotopia (PVNH) or severely impaired in subcortical band heterotopia ("Double Cortex").
• Associated Malformations: Cardiovascular issues (aortic aneurysm) in FLNA-related cases.
• Focal Neurological Deficits: Dependent on the location and volume of the heterotopic band.

4. POLYMICROGYRIA (PMG)

Definition: A malformation characterized by an excessive number of small, prominent convolutions with shallow sulci.

Pathophysiology: Late migration/organizational defect often linked to intrauterine insults (CMV infection) or genetic syndromes.

Clinical Features:

• Pseudobulbar Palsy: Bilateral perisylvian PMG presents with drooling, dysarthria, and dysphagia (Worster-Drought Syndrome).
• Epilepsy: Occurs in ~80% of patients; focal or generalized.
• Diplegia/Hemiplegia: Depending on the distribution of the cortical involvement.
• Oro-motor dysfunction: Difficulty with tongue protrusion and chewing.

SUMMARY OF NEUROIMAGING FINDINGS