Pathology of Demyelinating Disease
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Pathology of Demyelinating Disease

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Pathology of Demyelinating Disease Presentation Transcript

  • 1. “ Demyelinating” diseases Mark L Cohen, M.D. Department of Pathology University Hospitals Case Medical Center January 6 th , 2009
  • 2. Learning Objectives
    • Describe an algorithmic approach to the differential diagnosis of a patient with white matter disease.
    • Provide examples of diseases representing the three major categories of leukoencephalopathies (genetic, acquired non-inflammatory & inflammatory) and discuss diagnostic features of each.
    • Discuss the pathophysiology of Charcot’s triad, Uhthoff’s phenomenon, and L’hermitte’s symptom.
  • 3. Normal myelinated axon
    • Lipid-rich myelin sheath produced by oligodendrocytes
    • Axon insulation
    • Sodium channels clustered at nodes of Ranvier
    • Increased conduction speed and metabolic efficiency
  • 4. Demyelination
    • Decreased conduction velocity or block
    • Destablization of axonal cytoskeleton
    • Remodelling of internodal membrane
    • Progressive axonal loss
  • 5. Oligodendroglial pathology
    • Inborn errors
      • Leukodystrophies
    • Acute injury
      • Inflammatory (multiple sclerosis and related disorders) ‏
      • Toxic and metabolic disturbances
    • Chronic injury
      • Multiple system atrophy, progressive supranuclear palsy
    • Viral infection
      • Progressive multifocal leukoencephalopathy
    • Neoplastic transformation
      • Oligodendrogliomas
  • 6. Leukoencephalopathies: White matter damage with relative axonal preservation
    • Inherited
      • Lipid, Protein, Mitochondrial, Vascular
    • Acquired, non-inflammatory
      • Toxic, Metabolic, Vascular, Traumatic
    • Acquired, inflammatory
      • Infectious, Immunologic
  • 7. MRI in Leukoencephalopathies
    • Diffuse (Leukodystrophies)
    • Discrete
    • (Multiple sclerosis)
    • Diverse
    • (everything else)
  • 8. Genetic disorders of white matter
    • Lipid disorders (e.g. Adrenoleukodystrophy)
    • Cytoskeletal disorders (e.g. Alexander disease)
    • Myelin protein disorders
    • (e.g Pelizaeus-Merzbacher disease)
    • Organic acid disorders (e.g Canavan disease)
    • Disorders of energy metabolism (e.g. MELAS)
    • Other (e.g. CADASIL)
  • 9. Normal vs. Leukodystrophy (ALD)
  • 10. Rosenthal fibers Cytoskeletal Alexander disease Perivascular inflammation Peroxisomal Adreno- leukodystrophy Globoid (multinucleated) microglia Lysosomal Krabbe Disease Metachromatic sulfatides within macrophages Lysosomal Metachromatic Leukodystrophy Pathologic features Cellular defect Disease
  • 11. Subcortical U-fibers Krabbe Disease Alexander Disease Now you see ‘em Now you don’t
  • 12. Globoid cell leukodystrophy (Krabbe) ‏
  • 13. Adrenoleukodystrophy Alexander disease Pelizaeus-Merzbacher Disease
  • 14. Non-inflammatory Leukoencephalopathies
    • Toxic (e.g. antineoplastic agents)
    • Metabolic (e.g. B12 deficiency)
    • Vascular (e.g hypertension)
    • Traumatic (e.g diffuse axonal injury)
  • 15. Toxic leukoencephalopathies
    • Structural alteration of white matter in which myelin suffers most
    • Particularly involves tracts devoted to higher cerebral functioning
    • Language usually preserved
    • Focal neurologic signs usually less prominent than mental status changes
  • 16. Radiation leukoencephalopathy
    • Months to years after therapy (usually doses of 20 Gy or more)
    • Vascular damage with hyalinization
    • Coagulative necrosis of white matter
  • 17. Central pontine myelinolysis Marchifava-Bignami disease
  • 18. Inflammatory Leukoencephalopathies
    • Infectious
      • HIV encephalitis
      • Progressive multifocal leukoencephalopathy
    • Immunologic
      • Multiple sclerosis & related disorders
  • 19. HIV encephalitis P24 immunostaining
  • 20. Progressive multifocal leukoencephalopathy
  • 21. Progressive multifocal leukoencephalopathy JC virus immunostaining
  • 22. Carswell, 1838 Babinski, 1885
  • 23. 1868 Nystagmus, intention tremor, scanning speech Barber Chair phenomenon Worsening of vision with exercise in optic neuritis 1890 1920
  • 24. Site Symptoms Signs Cerebrum Cognitive impairment Attention deficit, dementia (late) Optic Nerve Unilateral painful visual loss Scotoma, afferent pupillary defect Cerebellum Tremor Clumsiness Intention tremor Ataxia, dysarthria Brainstem Diplopia, vertigo, emotional lability Nystagmus, INO, ophthalmoplegias Spinal cord Spasms; bowel, bladder, erectile dysfunction Spasticity
  • 25.
    • Reduced capacitance of thinly or unmyelinated axon segments underlies Uhthoff symptom
    • Increased mechanical sensitivity of partially demyelinated axons underlies L’hermitte’s symptom
  • 26. Clinical DDx of MS
    • Systemic diseases with relapsing CNS involvement (vasculitis, collagen vascular disease, B12 deficiency)
    • Progressive CNS system degenerations (hereditary ataxias, neuroaxonal dystrophies)
    • Focal lesions with relapsing or progressive course (especially CNS tumors)
    • Disseminated monophasic disorders (e.g. acute disseminated encephalomyelitis)
    • Non-organic symptoms that mimic MS
  • 27. MS Pathogenesis
    • Molecular mimicry causes inappropriate migration of autoreactive myelin T cells across the blood-brain barrier, initiating an inflammatory reaction against proteins of the oligodendrocyte-myelin unit
    • T cells activated by IL-23 secrete IL-17, disrupting the blood-brain barrier
    • Th17 cells and activated microglia damage glia, axons, and neurons
  • 28. Glia limitans perivascularis
  • 29. 2 steps to neuroinflammation 1 2 Glia limitans perivascularis Post-capillary venule
  • 30.  
  • 31. Active demyelinating plaque CD68 IHC
  • 32. Gross pathology
  • 33. Gross pathology
  • 34. Inactive plaque
  • 35. MS: Active & inactive plaques
  • 36. Evolution of an MS plaque
  • 37. Axonal pathology in MS
    • Plaque associated axonal swellings (Charcot, 1880)
    • More axons lost than generally believed (Marburg, 1906)
    • Axonal sprouts arising from terminal spheroids (Jakob, 1915)
    • Axonal transections in MS (Trapp et.al., NEJM , 1998)
    • Nitric oxide donors produce reversible conduction block
    • Prolonged NO causes NMDA receptor mediated toxicity
    • Loss of oligodendroglial IGF1 support contributes to neuronal & axonal loss
  • 38. Primary demyelination vs. primary neuroaxonal degeneration
    • Primary demyelination demonstrates:
    • Lack of anatomic restriction
    • Extension to pial surface
    • Complete absence of myelin (occasionally with partial loss at interface secondary to remyelination)
  • 39. MS: Recent advances
    • Remyelination occurs in ~20% of people with MS, and is probably an important factor in re-establishing conduction
    • Premyelinating oligodendrocytes are present in MS plaques
    • In chronic MS plaques, persisting axons appear unreceptive to remyelination
  • 40. Learning Objectives
    • Describe an algorithmic approach to the differential diagnosis of a patient with white matter disease.
    • Provide examples of diseases representing the three major categories of leukoencephalopathies (genetic, acquired non-inflammatory & inflammatory) and discuss diagnostic features of each.
    • Discuss the pathophysiology of Charcot’s triad, Uhthoff’s phenomenon, and L’hermitte’s symptom.
  • 41. References
    • Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17.
    • Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol. 2008 Dec;67(12):1113-21.