CNS MALFORMATIONS & DEVELOPMENTAL DISORDERS Neuropathology Dr. Lilian Bosire --- GENERAL PRINCIPLES Both genetic and environmental influences contribute to CNS
CNS MALFORMATIONS & DEVELOPMENTAL DISORDERS Neuropathology Dr. Lilian Bosire --- GENERAL PRINCIPLES Both genetic and environmental influences contribute to CNS malformations, though the pathogenesis of many remains unknown. Genomic sequencing continues to uncover associated genetic variants. Toxic compounds and infectious agents also exert teratogenic effects . Key principle: The earlier in development a malformation occurs, the more severe the morphologic and functional phenotype. --- 1. NEURAL TUBE DEFECTS (NTDs) The most common CNS malformations — midline defects involving some combination of neural tissue, meninges, and overlying bone or soft tissue. Two Pathogenic Mechanisms Mechanism Result Examples --- --- --- Failure of neural tube closure → secondary mesenchymal defects from aberrant skeletal modeling Anterior/posterior tube open Anencephaly, Myelomeningocele Primary bony defects from abnormal axial mesoderm → secondary CNS abnormalities Bone defect with CNS herniation Encephalocele, Meningocele, Spina bifida --- 1a. ANENCEPHALY Malformation of the anterior end of the neural tube → absence of most of the brain and calvarium. - Forebrain development disrupted at ~28 days gestation - Remnant = area cerebrovasculosa — a flattened, disorganized tissue mass with ependyma, choroid plexus, and meningothelial cells - Posterior fossa structures may be spared depending on extent of skull deficit - Incompatible with sustained life --- 1b. MYELOMENINGOCELE (Meningomyelocele) Extension of CNS tissue (cord + meninges) through a vertebral column defect. Meningocele = meninges only herniate (no cord tissue) - Most common in the lumbosacral region - Clinical features: - Motor and sensory deficits in lower extremities - Bowel and bladder dysfunction - Risk of cord infection — defective barrier from thin overlying skin --- 1c. ENCEPHALOCELE Extrusion of malformed brain tissue through a midline cranial defect. - Most often in the occiput - Nasofrontal variants: orbit, ethmoid, cribriform plate - Sometimes called a "nasal glioma" (misleading term) --- 1d. SPINA BIFIDA The most common neural tube defect. Spectrum of severity: Form Description --- --- Spina bifida occulta Asymptomatic bony defect only; no herniation Meningocele Meningeal outpouching only Myelomeningocele Flattened, disorganized cord + meningeal sac --- CLINICAL FEATURES OF NTDs - Recurrence risk in subsequent pregnancies: 4–5% - Folate deficiency in the first weeks of gestation is a well-established risk factor - Polymorphisms in folic acid metabolism enzymes contribute to population differences in NTD rates - Neural tube closure is complete by day 28 — before most pregnancies are recognized - Therefore, folate supplementation must be given throughout reproductive years to be effective - Mechanism of folate deficiency risk: possibly effects on DNA methylation (epigenetic gene regulation) --- 2. FOREBRAIN ANOMALIES Abnormal neuronal generation and migration result in focal or widespread forebrain malformations. Normal Cortical Development (Background) - Proliferating precursor cells lie in the germinal matrix adjacent to the ventricular system - Migration follows two paths: - Radial migration → excitatory neurons - Tangential migration → inhibitory interneurons - Total neuron number = fraction of proliferating cells transitioning to migrating cells per cycle --- 2a. ABNORMAL BRAIN SIZE Condition Description Associations --- --- --- Megalencephaly Abnormally large brain volume Rare Microencephaly Abnormally small brain + small head circumference Chromosome abnormalities, fetal alcohol syndrome, in utero HIV-1, Zika virus Microencephaly is thought to result from reduced neurons reaching the neocortex → simplified gyral folding. --- 2b. LISSENCEPHALY Reduction in the number of gyri; extreme form = agyria (no gyral pattern). Type Surface Mechanism Genetic Basis --- --- --- --- Type 1 Smooth Disrupted cell migration — cytoskeletal motor protein mutations LIS1, DCX mutations Type 2 Rough / cobblestone Disrupted "stop signal" for migration — defective glycoprotein signalling Glycosyltransferase enzyme mutations --- 2c. POLYMICROGYRIA Numerous small, irregularly formed cerebral convolutions with shallow sulci. - Cortex has 4 or fewer layers (normal = 6 layers) - Molecular layers between gyri are fused - Caused by: localized tissue injury at end of neuronal migration OR genetic mutations (typically bilateral and symmetric) --- 2d. NEURONAL HETEROTOPIAS Collections of neurons in inappropriate locations along the migration pathway — neurons that failed to complete migration. Type Location Gene/Mechanism --- --- --- Periventricular nodular heterotopia Along ventricular surface (never migrated) Filamin A mutation (X-linked; male lethal) Subcortical band heterotopia Band of gray matter beneath cortex ("double cortex") Doublecortin (DCX) mutation (X-linked; lissencephaly in males, band heterotopia in females) Nodular subcortical heterotopias Within white matter Various --- 2e. HOLOPROSENCEPHALY Spectrum of malformations from incomplete separation of cerebral hemispheres across the midline. - Severe forms: midline facial abnormalities including cyclopia - Less severe (arrhinencephaly): absence of olfactory nerves and related structures - Intrauterine diagnosis by ultrasound now possible - Associations: Trisomy 13 , other genetic syndromes, mutations in sonic hedgehog signalling pathway components --- 2f. AGENESIS OF THE CORPUS CALLOSUM Absence of white matter bundles carrying cortical projections between hemispheres. Relatively common malformation. - Imaging: " bat-wing " deformity of lateral ventricles - Histology (coronal sections): " Probst bundles " — anteroposteriorly oriented white matter that failed to cross - May be associated with intellectual disability OR found in normal individuals - Can be sporadic or familial; isolated or associated with other malformations --- 3. POSTERIOR FOSSA ANOMALIES Primarily affect the brainstem and cerebellum , often with dramatic changes in size and shape. May be accompanied by changes elsewhere in the brain. --- 3a. CHIARI MALFORMATIONS Feature Chiari Type I Chiari Type II (Arnold-Chiari) --- --- --- Severity Less severe More severe Key finding Low-lying cerebellar tonsils extend into vertebral canal Small posterior fossa + misshapen midline cerebellum + downward vermis herniation through foramen magnum Hydrocephalus Not always Almost invariably present Myelomeningocele Absent Lumbar myelomeningocele almost invariably associated Other changes Usually silent Caudal medulla displacement, tectal malformation, aqueductal stenosis, cerebral heterotopias, hydromyelia Symptoms May be silent; if symptomatic: impaired CSF flow, medullary compression Symptomatic Treatment Neurosurgical intervention if symptomatic Complex management --- 3b. DANDY-WALKER MALFORMATION - Enlarged posterior fossa - Cerebellar vermis is absent or rudimentary (anterior portion only) - In its place: large midline cyst — lined by ependyma, contiguous with leptomeninges on outer surface - This cyst = expanded, roofless 4th ventricle in the absence of a normally formed vermis - Brainstem nuclei dysplasias commonly associated --- 3c. JOUBERT SYNDROME & RELATED DISORDERS - Shared features: hypoplasia of cerebellar vermis + elongated superior cerebellar peduncles + altered brainstem shape - Imaging: "molar tooth sign" - Genetic basis: mutations in genes encoding primary (non-motile) cilium components - Represents a group of ciliopathies --- 4. SYRINGOMYELIA & HYDROMYELIA Both involve abnormal fluid-filled spaces in the spinal cord. Condition Description --- --- Hydromyelia Expansion of the ependyma-lined central canal of the cord Syringomyelia (syrinx) Fluid-filled cleft-like cavity in the inner cord, separate from the central canal Syringobulbia Syrinx extending into the brainstem Associations: - Chiari malformation - Intraspinal tumors - Post-traumatic injury Histology: Destruction of adjacent gray and white