Demyelinating and Degenerative Disorders of the CNS


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Demyelinating and Degenerative Disorders of the CNS

  1. 1. Demyelinating and Degenerative Disorders of the CNS<br />By Noel C. Santos, M.D.<br />
  2. 2. DEMYELINATING DISEASES<br />Acquired conditions<br />Preferential damage to myelin<br />Relative preservation of axons<br />Clinical neurologic deficits<br />Effect of myelin loss on the transmission of electrical impulses along axons<br />Natural History<br />Limited capacity of CNS to regenerate normal myelin<br />Degree of secondary damage to axons<br />
  3. 3. Demyelinating Diseases<br />Other disease processes can involve the myelin<br /><ul><li>Acquired:
  4. 4. Infection: oligodendrocytes, ex. JC virus
  5. 5. Autoimmune: MULTIPLE SCLEROSIS
  6. 6. Inherited disorders:
  7. 7. affect myelin synthesis and turnover
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  10. 10. Metachromatic Leukodystrophy<br />most common, autosomal recessive<br />accumulation of a cerebroside (galactosyl sulfatide) in the white matter<br />predominates in infancy, but rare juvenile or adult cases have been described<br />lethal within several year<br />deficiency in the activity of arylsulfatase A, a lysosomal enzyme involved in the degradation of myelin sulfatides.<br />progressive accumulation of sulfatides within the lysosomes of myelin-forming cells<br />
  11. 11. A coronal section of the brain reveals conspicuous loss of myelin in the superior half of the white matter of the parietal lobe. <br />
  12. 12. Krabbe Disease<br />rapidly progressive, invariably fatal, autosomal recessive neurologic disorder<br />deficiency of galactocerebroside-galactosidase<br />infants and progresses to death within 1 to 2 years<br />perivascular aggregates of mononuclear and multinucleated “globoid cells” in the white matter – “globoid cell leukodystrophy”: macrophages that contain undigested galactocerebroside (galactosylceramide)<br />Severe motor, sensory, and cognitive impairment<br />almost complete loss of oligodendroglia and myelin<br />the enzyme deficiency results in toxic, alternative metabolites that destroy oligodendroglia<br />
  13. 13. Krabbe Disease<br />Small brain, diffuse loss of myelin, but the cerebral cortex is normal<br />Marbled areas of partial and total demyelination, astrogliosis is typically severe<br />As demyelination proceeds, clusters of globoid cells are found around blood vessels<br />measure up to 50 µm in diameter and contain as many as 20 peripherally located nuclei<br />In end-stage disease, the number of globoid cells decreases, and in areas of severe myelin loss, only scattered globoid cells remain<br />By electron microscopy, the globoid cells contain crystalloid-like inclusions with straight or tubular profiles.<br />
  14. 14. Adrenoleukodystrophy<br />X-linked (Xq28), inherited disorder<br />dysfunction of the adrenal cortex & demyelination associated with high levels of saturated very-long-chain fatty acids (VLCFAs) in tissue and body fluids<br />children between the ages of 3 and 10 years<br />neurologic symptoms precede the signs of adrenal insufficiency<br />progresses rapidly, quickly reduced to a vegetative state, which may persist for several years before death<br />
  15. 15. Adrenoleukodystrophy<br />enzyme mutation that impairs the capacity to degrade VLCFAs<br />defect in the peroxisomal membrane prevents the normal activation of free VLCFAs by the addition of coenzyme A (CoA)<br />unable to degrade VLCFAs, the fatty acids accumulate in gangliosides and myelin<br />accumulation of abnormal cholesterol esters and the toxic effects of VLCFAs.<br />
  16. 16. A coronal section of the brain discloses extensive degenerative changes throughout the white matter. <br />
  17. 17. MULTIPLE SCLEROSIS<br />Autoimmune demyelinating disorder<br />Distinct episodes of neurologic deficits separated in time due to white matter lesions separated in space<br />Most common, F>M, any age<br />Clinical course evolves as relapsing and remitting episodes of neurologic deficit during variable intervals of time followed by gradual and partial recovery of neurologic functions<br />Frequency of relapses decreases over course of time<br />Steady neurologic deterioration<br />
  18. 18. Multiple Sclerosis<br />Pathogenesis:<br />Cellular immune response directed against components of myelin sheaths – AUTOIMMUNE PROCESS<br />Genetic (susceptibility) and Environmental (initiator) Factors<br />
  19. 19. Multiple Sclerosis<br />Morphology:<br />White matter disease:<br />multiple, well-circumscribed, depressed, glassy, gray-tan, irregularly shaped plaques, firm (sclerotic)<br />commonly beside ventricles, follow the course of paraventricular veins; optic nerves and chiasm, brain stem, fiber tracts, cerebellum and spinal cord<br />
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  22. 22. Multiple Sclerosis<br />MICROSCOPIC:<br />ACTIVE PLAQUE<br />Ongoing myelin breakdown: lipid-rich macrophages, PAS(+) debris, perivascular cuffs of inflammatory cells (lymphocytes, monocytes)<br />Relative preservation of axons<br />Depletion of oligodendrocytes<br />In time, reactive astrocytes<br />
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  25. 25. Multiple Sclerosis<br />INACTIVE PLAQUE<br />Become quiescent – diminution of inflammatory cells<br />At the center – no myelin, reduced nuclei of oligodendrocytes; astrocytic proliferation and gliosis<br />Depleted myelin in axons<br />
  26. 26. Multiple Sclerosis<br />SHADOW PLAQUE<br />Border between normal and affected white matter – not sharply circumscribed<br />Abnormally thinned-out myelin sheaths (partial or incomplete loss of myelin OR remyelinization of surviving oligodendrocytes)<br />
  27. 27. Multiple Sclerosis<br />Clinical Features<br /><ul><li>Anywhere in the CNS – wide range of clinical manifestation
  28. 28. Unilateral visual impairment – optic neuritis or retrobulbar neuritis
  29. 29. Brain stem – cranial nerve signs, ataxia, nystagmus, ophthalmoplegia
  30. 30. Spinal cord – motor/sensory impairment, spasticity, difficulties in voluntary control of bladder function
  31. 31. CSF: mildly elevated protein, moderate pleocytosis, increased gamma globulin – oligoclonal bands</li></li></ul><li>Multiple Sclerosis Variants<br />Neuromyelitis Optica or Devic Disease<br /><ul><li>Bilateral optic neuritis, spinal cord involvement
  32. 32. Rapidly and relentlessly progressive or as single episode
  33. 33. More destructive lesions</li></ul>Acute MS (Marburg form)<br /><ul><li>Young with fulminant clinical course
  34. 34. Plaques are large and numerous</li></li></ul><li>DEGENERATIVE DISEASES<br />Gray matter disease with progressive loss of neurons<br />Secondary changes in white matter tracts<br />Characteristics:<br />SELECTIVE PATTERN OF NEURONAL LOSS<br />ARISES WITHOUT CLEAR INCITING EVENT IN PATIENT WITHOUT PREVIOUS NEUROLOGIC DEFICITS<br />Findings:<br /><ul><li>Intracellular abnormalities
  35. 35. Only loss of affected neurons</li></li></ul><li>DEGENERATIVE DISEASES<br />Grouped according to anatomic regions affected<br />CEREBRAL CORTEX – Alzheimer disease<br />SUBCORTICAL AREAS – movement disorders (tremors and dyskinesias): Parkinsonism, Huntington’s chorea, etc.<br />Development of protein aggregates<br />Resistant to degradation<br />Recognized as inclusion<br />Generally cytotoxic<br />
  36. 36. ALZHEIMER DISEASE<br />DEMENTIA – progressive loss of cognitive function independent of the state of attention<br />Insidious impairment of higher intellectual function, mood and behavioral alterations<br />Progressive disorientation, memory loss, aphasia<br />5 to 10 yrs – disabled, mute, immobile<br />Mostly sporadic, elderly – major medical, social and economic problems<br />
  37. 37. ALZHEIMER DISEASE<br />Grossly:<br />Cortical atrophy: wide sulci (frontal, temporal, parietal lobes), narrowed gyri, compensatory ventricular enlargement (hydrocephalus ex vacuo)<br />
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  39. 39. ALZHEIMER DISEASE<br />Microscopic:<br />Neuritic (senile) plaques: dystrophic neurites, amyloid core of Aβ from APP (amyloid precursor protein)<br />Neurofibrillary tangles: cytoplasmic filaments (protein tau)<br />Amyloid angiopathy, granulovacuolar degeneration, Hirano bodies<br />Pattern:<br />Earliest in the entorhinal cortex<br />Spread to hippocampal formation and isocortex<br />Extend to the neocortex<br />
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  46. 46. ALZHEIMER DISEASE<br />Clinical Features:<br />Progression is slow (> 10 yrs) but relentless<br />Initial symptoms – forgetfulness<br />Language deficits, loss of mathematical skills, loss of learned motor skills<br />Final stage: incontinent, mute, unable to walk with intercurrent disease, ex. Pneumonia<br />
  47. 47. DEGENERATIVE DISEASES OF BASAL GANGLIA AND BRAINSTEM<br />Movement disorders: rigidity, abnormal posturing, chorea<br />Reduction of voluntary movement or abundance of involuntary movement<br />Parkinson disease<br />Multiple System Atrophy (cerebellar ataxia, autonomic dysfunction)<br />Huntington disease<br />Progressive Supranuclear Palsy (PSP)<br />Corticobasal Degeneration (CBD) with cognitive impairment<br />
  48. 48. PARKINSONISM<br />CLINICAL SYNDROME of MOTOR DISTURBANCE<br />Diminished facial expression<br />Rigidity with stooped posture<br />Slowness of voluntary movement<br />Festinating gait: progressively shortened, accelerated steps<br />“pill-rolling” tremor<br />Damage to nigrostriatal dopaminergic system <br />
  49. 49. PARKINSON DISEASE<br />Parkinsonism in the absence of toxic or other known underlying etiology<br />Changes in mental function – dementia<br />Morphology<br />Pallor of the substantia nigra and locus ceruleus<br />Loss of pigmented, catecholaminergic neurons with gliosis<br />Lewy bodies: cytoplasmic inclusions with dense core and pale halo – fine filaments composed of α-synuclein<br />
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  53. 53. PARKINSON DISEASE<br />Pathogenesis:<br />Degeneration of dopaminergic neurons with reduction of striatal dopamine content<br />Severity of motor syndrome is proportional to the dopamine deficiency correctable by L-DOPA<br />Clinical Features:<br />Motor disturbance, dementia<br />Fluctuating course, hallucinations, prominent frontal signs<br />Symptomatic response to L-DOPA which become less effective in time<br />
  54. 54. HUNTINGTON DISEASE<br />Inherited autosomal dominant<br />Progressive movement disorders and dementia<br />CHOREA: jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body<br />Later develop parkinsonism with bradykinesia and rigidity<br />Relentlessly progressive<br />Degeneration of striatal neurons<br />
  55. 55. HUNTINGTON DISEASE<br />Morphology:<br />Small brain, atrophy of caudate nucleus and putamen<br />Secondarily atrophic globus pallidus and dilated ventricles<br />Frontal and less often parietal<br />Severe loss of striatal neurons with fibrillary gliosis<br />
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  57. 57. HUNTINGTON DISEASE<br />Clinical Features:<br />4th to 5th decades<br />Direct relationship between the degree of degeneration in the striatum and severity of clinical symptoms<br />Motor symptoms precede cognitive impairment<br />Increased risk of suicide, intercurrent infection<br />