Delve into CNS cellular pathology, examining how neurons and astrocytes react to injury. Cover acute neuronal injury ("red neurons"), chronic degeneration, glio
NEUROPATHOLOGY — Complete Study Notes Unit: CNS Cellular Pathology, Malformations & Cerebral Edema --- PART 1: CELLULAR PATHOLOGY OF THE CNS --- The Neuron — The Functional Unit The neuron is the principal functional unit of the CNS. Key characteristics: - Postmitotic — cannot divide or replace themselves once destroyed - Highly metabolically active — require continuous oxygen and glucose - Selectively vulnerable — different neuron populations are vulnerable to different insults based on shared properties (neurotransmitters, metabolic needs, connectivity) - Long-lived — their lengthy lifespan makes them unusually prone to accumulation of misfolded proteins , triggering the unfolded protein response , central to many neurodegenerative diseases 💡 Key Concept: Because neurons cannot regenerate, even small focal losses can produce permanent neurological deficits. Clinical signs depend on both the pathological process AND the anatomical region affected. --- Reactions of Neurons to Injury 1. Acute Neuronal Injury — "Red Neurons" Seen after acute hypoxia/ischemia, hypoglycemia, or trauma - Earliest morphological marker of neuronal cell death - Changes visible by 6–12 hours after irreversible injury Morphological Features: Feature Change --- --- Cell body Shrinkage Nucleus Pyknosis (dark, shrunken) Nucleolus Disappears Nissl substance Lost Cytoplasm Intensely eosinophilic (hence "red") --- 2. Subacute/Chronic Neuronal Injury — "Degeneration" Occurs over months to years in progressive diseases e.g. ALS, Alzheimer disease Sequence of events: 1. Loss of synapses — aberrant synaptic pruning 2. Neuronal cell death — selective for functionally related groups 3. Reactive gliosis - At early stages, glial changes are the best indicator of neuronal injury - Predominant cell death mechanism: Apoptosis --- 3. Axonal Reaction — Chromatolysis Occurs during axonal regeneration after axon cutting or damage. Best seen in anterior horn cells of the spinal cord Morphological Features: - Cell body enlarges and rounds up - Nucleus displaced to periphery - Nucleolus enlarges - Nissl substance disperses to periphery → central chromatolysis 💡 Reflects increased protein synthesis for axonal repair --- 4. Neuronal Inclusions Inclusion Disease/Context --- --- Lipofuscin Normal aging Neurofibrillary tangles Alzheimer disease Lewy bodies Parkinson disease Cowdry A/B bodies Herpes virus infection Negri bodies Rabies CMV inclusions Cytomegalovirus infection Vacuolization Creutzfeldt-Jakob disease (prion) 💡 Wallerian Degeneration = degeneration of axon distal to the site of nerve fiber disruption --- Reactions of Astrocytes to Injury Structure and Function - Star-shaped cells with multipolar branching processes - Express GFAP (Glial Fibrillary Acidic Protein) — specific astrocyte marker - Functions: - Metabolic buffering and detoxification - Blood-brain barrier maintenance via foot processes around capillaries - Extend to subpial and subependymal zones --- Gliosis Most important histopathologic marker of CNS injury, regardless of cause - Characterized by hypertrophy and hyperplasia of astrocytes - Reactive astrocytes = gemistocytic astrocytes - Bright pink cytoplasm (↑ GFAP) - Large vesicular nuclei - Stout ramifying processes Two subtypes exist (morphologically identical but functionally distinct): - Type A → promotes CNS injury - Type B → contributes to CNS repair --- Special Astrocytic Pathological Forms Alzheimer Type II Astrocyte (not related to Alzheimer disease) - Large nucleus (2–3× normal), pale chromatin, intranuclear glycogen droplet, prominent nucleolus - Seen in hyperammonemia : chronic liver disease, Wilson disease, urea cycle disorders --- Rosenthal Fibers - Thick, elongated, eosinophilic structures in astrocytic processes - Contain: αB-crystallin, hsp27, ubiquitin - Found in: long-standing gliosis, pilocytic astrocytoma - Abundant in Alexander disease (GFAP gene mutation — leukodystrophy) - Located periventricularly, perivascularly, subpially --- Corpora Amylacea (Polyglucosan Bodies) - Round, faintly basophilic, PAS-positive , concentrically lamellated (5–50 μm) - Located at astrocytic end processes — subpial and perivascular zones - Contain: glycosaminoglycan polymers, heat-shock proteins, ubiquitin - Increase with advancing age — represent degenerative astrocyte change - Similar structure to Lafora bodies (neurons, hepatocytes, myocytes in myoclonic epilepsy) --- Reactions of Microglia to Injury Normal Function - Phagocytic cells — resident macrophages of the CNS - Derived from yolk sac or fetal liver early in embryonic development - Share surface markers with bone marrow–derived monocytes/macrophages - At rest: tiled arrangement (non-overlapping territories) - During development: prune unused synaptic connections via complement system ⚠️ Aberrant reactivation of microglial synaptic pruning implicated in schizophrenia, Alzheimer disease, frontotemporal dementia, and encephalitis Responses to Injury Microglia respond by: 1. Proliferating 2. Developing elongated nuclei 3. Forming microglial nodules around small necrotic foci 4. Neuronophagia — congregating around dying neurons --- Reactions of Other Glial Cells Oligodendrocytes - Form myelin by wrapping processes around axons - One oligodendrocyte myelinates multiple axons (vs. Schwann cells in PNS — only one axon each) - Injury → feature of demyelinating disorders and leukodystrophies - PML → viral inclusions in oligodendroglial nuclei - Multiple System Atrophy (MSA) → α-synuclein glial cytoplasmic inclusions in oligodendrocytes Ependymal Cells - Ciliated columnar cells lining the ventricles - No specific reaction pattern - Ependymal granulations — disruption of lining by inflammation/dilation → subependymal astrocyte proliferation - CMV → extensive ependymal injury with viral inclusions --- PART 2: MALFORMATIONS AND DEVELOPMENTAL DISORDERS --- Etiology - Both genetic and environmental factors involved - Many toxic compounds and infectious agents are teratogenic ⚠️ Golden Rule: The earlier in development a malformation occurs → the more severe the morphological and functional phenotype --- Neural Tube Defects (NTDs) Most common CNS malformations. Two pathogenic mechanisms: Mechanism Examples --- --- Failure of neural tube closure → secondary skeletal defects Anencephaly, Myelomeningocele Primary bony defects → secondary CNS abnormality Encephalocele, Meningocele, Spina bifida --- Specific NTDs Anencephaly - Malformation of anterior neural tube - Forebrain development disrupted at ~ 28 days gestation - Absence of most brain and calvarium - Remnant = area cerebrovasculosa (disorganized brain tissue with ependyma, choroid plexus, meningothelial cells) --- Myelomeningocele (Meningomyelocele) - Extension of CNS tissue through vertebral column defect - Most common in lumbosacral region - Meningocele = only meningeal extrusion (no neural tissue) - Clinical features: Lower limb motor/sensory deficits, bowel and bladder dysfunction - Complication: Superimposed infection due to thin overlying skin --- Encephalocele - Extrusion of malformed brain tissue through midline cranial defect - Most common in the occiput - Nasofrontal variants sometimes misleadingly called "nasal glioma" --- Spina Bifida - Most common NTD - Ranges from spina bifida occulta (asymptomatic bony defect) to severe malformation with meningeal outpouching --- Risk Factors and Prevention - Folate deficiency during early gestation — well-established risk factor - Neural tube closure complete by day 28 — before most pregnancies are recognized - Folate supplementation must be given throughout reproductive years - Mechanism: effects on DNA methylation (epigenetic gene regulation) suspected - Recurrence rate in subsequent pregnancies: 4–5% --- Forebrain Anomalies Neuronal Migration Neurons migrate from the germinal matrix (adjacent to ventricular system) via: - Radial migration → excitatory neurons - Tangential migration → inhibitory interneurons Disruption → abnorm