• definition- destruction of normally constitutied myelin
• primary- immunologic destruction of myelin with relative axonal preservation (ex: MS)
• secondary- myelin loss resultin from another CNS pathology
  • neuronal/axonal destruction
  • CNS edema
  • viral infection
  • toxic metabolic insult

• epidemiology
  • Nordic Caucasian females age 20-40
  • northern residence before age 15 (above 40 degree)
• etiology unknown
  • hereditary: HLA type DR2, A3, B7, DR4, DR6
  • retroviral demyelination
  • abnormal response to measles
  • IgG molecules of narrow specificities in CSF

• gross
  • lesions (plaques) at multiple CNS sites
    • white matter
      • around lateral ventricles
      • optic N's, chiasms, tracts
      • corpus callosum
      • cerebellar peduncles
      • cerebellum
      • spinal cord
    • gray matter
      • cortex
      • basal ganglia, thalamus, hypothalamus, brainstem

• loss of myelin (see on luxol fast blue stain) with relative preservation of axons (Bielschowsky silver stain)
• plaques often centered around or extend alon bv's (venules) with perivascular lymphocytes and plasma cells
• lipid laden macrophages filled with myelin fragments and breakdown products
• reactive astrocytes

• signs and symptoms disseminated in time and space
• multiple episodes of relapse/remiossion
  • visual
  • motor
  • sensory
  • cerebellar
  • brainstem
• multiple affected CNS sites
• stress (infection, trauma) precipitate exacerbations
• dx- MRI most sensitive technique
  • demyelinating foci hypertense (bright) on T2 weighted image

• long course of alternating relapses and remissions with increasing functional limitations
• eventual death from intercurrent infection, respiratory compromise, pulmonary embolism
• acute form (acute MS/Marburg variant) with involvement of vital brainstem centers fatal at first presentation

• pathogenesis
  1. immune challenge presented
     • vaccination (rabies, smallpox)
     • infection (measles, mumps, rubella, influenza, pertussis, streptococcal)
  2. precipitating infection cleared and organism no longer present at onset of ADEM
  3. immune function altered so that myelin antigens appear to be "foreign" and not "self"
  4. days/wks later, acute fulminating immunologic destruction of myelin
• pathology- resemble acute MS
  • demyelinating lesions centered around venules with perivascular chronic inflammation and macrophages

• pathogenesis
  1. defective enzyme in metabolic pathway related to neurolipids, carbohydrates, AA's, nucleic acids, pigments, or metals
  2. non catabolized metabolite accumulate and destroy neurons and/or glia
• clinical presentation
  • rare diseases of infancy, childhood
  • motor disturbances, seizures, deafness, blindness, retardation
  • insidious onset, relentlessly progressive

• CNS metabolism perturbed by extra-CNS disease
  • metabolic substrate deprivation (oxygen, glucose)
  • metabolic cofactor deficiency (vitamin, hormone)
  • major organ failure
  • chemical imbalance (fluid, electrolytes, acid base, calcium, osmolality)
  • intox (drugs, poisons, hormons
  • miscellaneous (sepsis, temp extreme, trauma)
• clinical presentation
  • common at ANY STAGE OF LIFE
  • acute/subacute onset
  • amenable to tx

• epidemiology
  • malnourished, esp. alcoholics
• effects
  • potentially, CNS, PNS, and heart
  • Wernicke's encephalopathy/Korsakoff's syndrome
    • necrosis in mammillary bodies
    • necrosis in periventricular gray matter
  • peripheral neuropathy
  • heart failure

• pathogenesis
  1. elevated ammonia levels
  2. toxic to CNS metabolism
     • neuronal membrane depolarization and neuron hyperexcitability
     • perterubed NT metabolism and imbalance among NT's
• histopathology- Alzheimer's type 2 astrocyte
  • gray matter astrocyte with swollen clear nuclie and no visible cytoplasm

• cerebral cortical necrosis
• neuronal necrosis in hippocampus (CA1 region), Purkinje cells of cerebellum
• necrosis in watershed zones of major vascular territories

• etiology- patient with abnormal serum sodium corrected too rapidly
• epidemiology
  • alcoholics
  • other debilitated chronically ill patients
• pathological lesion- diamond shaped area of myelin destruction in central pons

• etiology unknown or incompletely understood
• insidious onset and relentless progression
• neurons/axons primary disease target
• pathologic alterations- neuronal death with reactive gliosis
• often involves groups of functionally related neurons (systems)

• reflects targeted neurons/axons
• dementia
• movement disorder
  • pyramidal
  • extrapyramidal
• dementia plus movement disorder

1. AD inheritance at chronmsome 4 hunington gene
2. leads to more than 36 CAG repeats on the gene (normal is less than 34)
3. loss of neurons in caudate nucleus, putamen, thalamus, cerebral cortex
4. eventually, extrapyramidal movement disorder w/ or w/o dementia

1. AR inheritance at chromsome 9
2. leads to trinucletide repeat (GAA) in frataxin gene
3. loss of axons/neurons in spinal cord, cerebellum causing spinocerebellar degeneration
4. gait ataxia followed by other cerebellar, post. column, and pyramidal tract signs and symptoms

1. AD inheritance at chromosome 17 leading to segmental repeat in PMP22 gene for myelin structural protein
2. leads to myelin damage and axonal loss in PNS
3. causes distal leg weakness and muscle atrophy with or without sensory loss

1. XR inheritance of deletion of dystrophin gene coding for structural protein in muscle
2. leads to slow progressive wasting of skeletal and cardiac muscle
3. progressive loss of muscle function, then immobility,  and finally respiratory paralysis

• decrease in higher cognitive function
  • memory
  • reasoning
  • judgement
  • language
  • spatial construction
  • learned motor skills
• intact consciousness

• widespread neuronal loss and gliosis
  • location- cerebral cortex, brainstem, basal ganglia
  • decrease in brain weight and volume
  • increase in ventricular volume (hydrocephalus)
• overlap in brain microscopic changes between the disease and normal aging

• senile plaques
  • extracellular
  • amyloid core
  • neurites with abnormal cytoskeletal filaments (paired helical filaments composed of tau proteins)
• neurofibrillary tangles
• granulovacuolar degeneration
• hirano bodies
• amyloid angiopathy (deposit alpha beta amyoid in bv's of leptomeninges, cerebral cortex)

• NT's decrease due to neuronal loss
  • decrease ACh in cerebral cotrex and nucleus basalis of Meynert
  • decrease NE, dopamine, serotonin, somatostatin, substance P
• etiology
  • genetic predisposition (several different chromsomes implicated: 21, 14, 1, 19)
    • Down's syndrome people develop senile plaques and neurofibrillary tangles at early age (gene for precursor amyloid protein is on chromosome 21)
  • init event: amyloid deposition or faulty neuronal cytoskeleton?

• clinical presentation- dementing illness similar to Alzheimer's
• gross changes
  • marked atrophy of frontal lobe and anterior 1/3 of superior temporal gyrus
• histo changes- round silver positive neuronal inclusions called Pick bodies (intracellular aggregated tau protein)

1. multiple small strokes lead to a cumulative consequence of multiinfact dementia
2. causes diffuse damage to CNS white matter due to arteriolar disease

Usually due to HTN aka Binswanger encephalopathy

• pathogenesis
  1. intermittent increase in CSF pressure
  2. leads to enlarged ventricles
• characteristic clinical triad
  • dementia
  • gait ataxia
  • urinary incontinence

• pathogenesis
  1. unknown etiology
  2. loss of pigmented neurons in substantia nigra
  3. extrapyramidal movement disorder
• clinical presentation (think TRAP)
  • tremor (resting, pill rolling)
  • rigidity (cogwheel)
  • akinesia/bradykinesia
  • postural instability
• pathology
  • gross- pallor of substantia nigra and locus coeruleus
  • microscopic
    • Lewy bodies (round pink target like inclusions of surviving neurons of substantia nigra and locus coeruleus)
      • may also be seen in cerebral cortex associated with dementia

• pathogenesis
  1. unknown etiology
  2. degeneration of LMN in spinal cord and cranial N. nuclei with degeneration of axons of UMN (corticospinal tract)
• clinical presentation- UMN and LMN signs
• pathology
  • neuronal loss and gliosis
  • ventral horns of spinal cord and lower CN motor nuclei (esp. CN XII)
  • neurogenic atrophy of denervated skeletal muscle

1. AR disease carried on chromosome 5
2. fetal infantile degeneration of LMN's (spinal cord, CN nuclei) without corticospinal tract signs
   • SMA type I(Werdnig Hoffman disease) important and fatal cause of neonatal hypotnonia