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DISEASES OF WHITE MATTER Charles L. White, III, M.D. November 19, 2009
Description of myelin (1854)
Oligodendroglia <ul><li>“ Few processes” </li></ul><ul><li>Cell membranes are enriched in lipid-rich myelin </li></ul><ul>...
Oligodendroglia in white matter
Oligodendroglia in white matter
Oligodendroglia in white matter
Oligodendroglia:  Myelin stain
Oligodendroglia:  Nodes of Ranvier <ul><li>Saltatory conduction: action potentials “jump” from node to node, resulting in ...
Phenomenon of “selective vulnerability” <ul><li>A given insult will produce damage in restricted brain regions or componen...
Demyelinating disorders: Substrates of selective vulnerability <ul><li>Enzymes associated with myelin production or mainte...
Primary demyelination  vs. secondary loss of myelin <ul><li>Primary demyelination: </li></ul><ul><ul><li>Dysmyelinating an...
Secondary loss of myelin: Amyotrophic lateral sclerosis
Primary demyelinating disorders <ul><li>Dysmyelinating  (Leukodystrophies) </li></ul><ul><ul><li>Metabolic derangements </...
Demyelinating disorders: General features <ul><li>Myelin loss with relative sparing of axons </li></ul><ul><li>CNS has onl...
Dysmyelinating disorders (leukodystrophies) <ul><li>Krabbe disease (Globoid cell leukodystrophy)  </li></ul><ul><li>Adreno...
Dysmyelinating disorders (leukodystrophies) <ul><li>Clinical features </li></ul><ul><ul><li>Inherited </li></ul></ul><ul><...
Leukodystrophy: Confluent demyelination
Leukodystrophy: Subcortical “U-fiber” sparing
Leukodystrophies: Pathogenesis Disease Enzyme deficiency Toxic agent Krabbe disease Galactocerebroside  β -galactosidase (...
Krabbe disease (globoid cell leukodystrophy) <ul><li>Autosomal recessive inheritance </li></ul><ul><li>GALC gene on chromo...
Krabbe disease
Krabbe disease: “Globoid” cells
Krabbe disease (LFB/PAS)
Metachromatic leukodystrophy <ul><li>Autosomal recessive inheritance </li></ul><ul><li>Arylsulfatase gene on chromosome 22...
Metachromatic leukodystrophy: Peripheral nerve involvement
Adrenoleukodystrophy <ul><li>X-linked recessive inheritance </li></ul><ul><li>ALD gene encodes “ATP binding cassette, subf...
Adrenoleukodystrophy: Asymmetrical frontal demyelination
Adrenoleukodystrophy
Adrenoleukodystrophy
Adrenoleukodystrophy: Adrenal cortical cytoplasmic inclusions
Adrenomyeloneuropathy <ul><li>Occurs in same families as ALD </li></ul><ul><li>Onset in adulthood </li></ul><ul><li>May be...
Myelinoclastic disorders <ul><li>Multiple sclerosis </li></ul><ul><li>Parainfectious disorders </li></ul>
Multiple sclerosis: Clinical features <ul><li>Lesions distributed “over time and space” </li></ul><ul><ul><li>Episodic (ex...
Multiple sclerosis: Epidemiology <ul><li>Age and gender </li></ul><ul><ul><li>Onset predominantly in young to middle aged ...
Multiple sclerosis: Laboratory findings <ul><li>Cerebrospinal fluid </li></ul><ul><ul><li>Myelin basic protein (MBP) </li>...
Multiple sclerosis: Widely distributed lesions
Multiple sclerosis: Widely distributed lesions
Multiple sclerosis: Periventricular plaques
Multiple sclerosis: Gross plaque morphology
Multiple sclerosis: Gross plaque morphology
Multiple sclerosis: active plaque
Multiple sclerosis Active plaque
Multiple sclerosis: Active demyelination Myelin stain (blue) with PAS counterstain CD68 (histiocytes)
Multiple sclerosis: Microscopic plaque morphology H&E Myelin stain CD68 (histiocytes) Axon stain H&E
Multiple sclerosis:  Relative axonal preservation Normal white matter Demyelinated plaque
Multiple sclerosis: Pathogenesis <ul><li>Autoimmune factors </li></ul><ul><ul><li>Initiated by CD4+ T cells reacting with ...
MS variants <ul><li>Marburg type </li></ul><ul><ul><li>Rapidly progressive, monophasic course, typically fatal </li></ul><...
Animal models of MS <ul><li>Experimental allergic encephalomyelitis (EAE) </li></ul><ul><ul><li>Immunization of animals wi...
Parainfectious disorders <ul><li>Inflammatory demyelination </li></ul><ul><li>Autoimmune mechanism </li></ul><ul><li>Typic...
Parainfectious disorders <ul><li>Acute disseminated encephalomyelitis (ADEM) </li></ul><ul><li>Acute hemorrhagic leukoence...
ADEM
ADEM Small foci of perivenular demyelination
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  1. 1. DISEASES OF WHITE MATTER Charles L. White, III, M.D. November 19, 2009
  2. 2. Description of myelin (1854)
  3. 3. Oligodendroglia <ul><li>“ Few processes” </li></ul><ul><li>Cell membranes are enriched in lipid-rich myelin </li></ul><ul><ul><li>Phospholipids </li></ul></ul><ul><ul><li>Glycolipids </li></ul></ul><ul><ul><li>Cholesterol </li></ul></ul><ul><ul><li>Proteins </li></ul></ul>
  4. 4. Oligodendroglia in white matter
  5. 5. Oligodendroglia in white matter
  6. 6. Oligodendroglia in white matter
  7. 7. Oligodendroglia: Myelin stain
  8. 8. Oligodendroglia: Nodes of Ranvier <ul><li>Saltatory conduction: action potentials “jump” from node to node, resulting in more rapid signal conduction along the axon </li></ul>
  9. 9. Phenomenon of “selective vulnerability” <ul><li>A given insult will produce damage in restricted brain regions or components </li></ul><ul><li>Basis of selective vulnerability (the brain is the most inhomogeneous organ in the body): </li></ul><ul><ul><li>location </li></ul></ul><ul><ul><li>biochemical properties (e.g., neurotransmitter) </li></ul></ul><ul><ul><li>other factors </li></ul></ul><ul><li>Determining basis of selective vulnerability in a particular disease process may lead to: </li></ul><ul><ul><li>Improved understanding of the mechanism of damage </li></ul></ul><ul><ul><li>Design of specific treatment for the disease </li></ul></ul>
  10. 10. Demyelinating disorders: Substrates of selective vulnerability <ul><li>Enzymes associated with myelin production or maintenance (leukodystrophies) </li></ul><ul><li>Antigens associated with myelin (immune-mediated disorders) </li></ul>
  11. 11. Primary demyelination vs. secondary loss of myelin <ul><li>Primary demyelination: </li></ul><ul><ul><li>Dysmyelinating and myelinoclastic disorders (the subject of this lecture) </li></ul></ul><ul><li>Secondary loss of myelin: </li></ul><ul><ul><li>Loss of myelin due to degeneration of axons (Wallerian degeneration) </li></ul></ul>
  12. 12. Secondary loss of myelin: Amyotrophic lateral sclerosis
  13. 13. Primary demyelinating disorders <ul><li>Dysmyelinating (Leukodystrophies) </li></ul><ul><ul><li>Metabolic derangements </li></ul></ul><ul><ul><ul><li>Abnormal synthesis or turnover of myelin </li></ul></ul></ul><ul><ul><ul><li>Lysosomal or peroxisomal enzyme deficiencies </li></ul></ul></ul><ul><li>Myelinoclastic </li></ul><ul><ul><li>Immune-mediated </li></ul></ul><ul><ul><ul><li>Examples </li></ul></ul></ul><ul><ul><ul><ul><li>Multiple sclerosis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Parainfectious demyelinating disorders </li></ul></ul></ul></ul><ul><ul><li>Others: infectious, toxic </li></ul></ul>
  14. 14. Demyelinating disorders: General features <ul><li>Myelin loss with relative sparing of axons </li></ul><ul><li>CNS has only limited capacity for remyelination (vs. PNS) </li></ul><ul><li>Clinical manifestations due to interruption of saltatory conduction, and some secondary injury to axons </li></ul><ul><li>Clinical manifestations are primarily motor in nature </li></ul>
  15. 15. Dysmyelinating disorders (leukodystrophies) <ul><li>Krabbe disease (Globoid cell leukodystrophy) </li></ul><ul><li>Adrenoleukodystrophy (ALD) </li></ul><ul><ul><li>Adrenomyeloneuropathy (AMN) </li></ul></ul><ul><li>Metachromatic leukodystrophy (MLD) </li></ul>
  16. 16. Dysmyelinating disorders (leukodystrophies) <ul><li>Clinical features </li></ul><ul><ul><li>Inherited </li></ul></ul><ul><ul><ul><li>Autosomal recessive (most) </li></ul></ul></ul><ul><ul><ul><li>X-linked recessive (ALD) </li></ul></ul></ul><ul><ul><li>Age of onset varies by disease </li></ul></ul><ul><ul><ul><li>Infancy </li></ul></ul></ul><ul><ul><ul><ul><li>Krabbe disease, MLD </li></ul></ul></ul></ul><ul><ul><ul><li>Childhood and adolescence </li></ul></ul></ul><ul><ul><ul><ul><li>ALD, MLD </li></ul></ul></ul></ul><ul><ul><ul><li>Adulthood </li></ul></ul></ul><ul><ul><ul><ul><li>AMN, MLD </li></ul></ul></ul></ul><ul><ul><li>Younger onset usually associated with more severe (often fatal) disease </li></ul></ul>
  17. 17. Leukodystrophy: Confluent demyelination
  18. 18. Leukodystrophy: Subcortical “U-fiber” sparing
  19. 19. Leukodystrophies: Pathogenesis Disease Enzyme deficiency Toxic agent Krabbe disease Galactocerebroside β -galactosidase (GALC) Galactosylsphingosine (psychosine) Metachromatic leukodystrophy (MLD) Arylsulfatase A Sulfatides Adrenoleukodystrophy (ALD) ABCD1 VLCFA
  20. 20. Krabbe disease (globoid cell leukodystrophy) <ul><li>Autosomal recessive inheritance </li></ul><ul><li>GALC gene on chromosome 14 </li></ul><ul><li>Rapidly progressive clinical course </li></ul><ul><ul><li>Onset by age 6 months </li></ul></ul><ul><ul><li>Death by age 2 years </li></ul></ul><ul><li>Multinucleated “globoid cells” derived from microglia (macrophages) </li></ul><ul><li>Hyporeflexia due to PNS involvement </li></ul>
  21. 21. Krabbe disease
  22. 22. Krabbe disease: “Globoid” cells
  23. 23. Krabbe disease (LFB/PAS)
  24. 24. Metachromatic leukodystrophy <ul><li>Autosomal recessive inheritance </li></ul><ul><li>Arylsulfatase gene on chromosome 22 </li></ul><ul><li>Late infantile, juvenile, and adult onset forms </li></ul><ul><li>Lower enzyme activity associated with earlier onset </li></ul><ul><li>Metachromatic material </li></ul><ul><ul><li>CNS: macrophages </li></ul></ul><ul><ul><li>PNS: Schwann cells, macrophages, axons </li></ul></ul>
  25. 25. Metachromatic leukodystrophy: Peripheral nerve involvement
  26. 26. Adrenoleukodystrophy <ul><li>X-linked recessive inheritance </li></ul><ul><li>ALD gene encodes “ATP binding cassette, subfamily D, member 1” (ABCD1) </li></ul><ul><ul><li>Normal function is to transport VLCFA’s into peroxisome for catabolism </li></ul></ul><ul><li>VLCFA’s accumulate in blood, brain, and adrenal cortex </li></ul><ul><li>Chronic CNS lesions may show marked inflammatory infiltrate at periphery </li></ul>
  27. 27. Adrenoleukodystrophy: Asymmetrical frontal demyelination
  28. 28. Adrenoleukodystrophy
  29. 29. Adrenoleukodystrophy
  30. 30. Adrenoleukodystrophy: Adrenal cortical cytoplasmic inclusions
  31. 31. Adrenomyeloneuropathy <ul><li>Occurs in same families as ALD </li></ul><ul><li>Onset in adulthood </li></ul><ul><li>May be seen in heterozygous females </li></ul><ul><li>Clumsiness and ataxia due to involvement of long tracts of spinal cord and peripheral nerve </li></ul><ul><li>Adrenal insufficiency also common </li></ul>
  32. 32. Myelinoclastic disorders <ul><li>Multiple sclerosis </li></ul><ul><li>Parainfectious disorders </li></ul>
  33. 33. Multiple sclerosis: Clinical features <ul><li>Lesions distributed “over time and space” </li></ul><ul><ul><li>Episodic (exacerbations and remissions) </li></ul></ul><ul><ul><li>Multifocal </li></ul></ul><ul><ul><ul><li>Cerebrum </li></ul></ul></ul><ul><ul><ul><li>Brainstem </li></ul></ul></ul><ul><ul><ul><li>Cerebellum </li></ul></ul></ul><ul><ul><ul><li>Spinal cord </li></ul></ul></ul><ul><ul><ul><li>Optic tracts </li></ul></ul></ul><ul><li>Debilitating </li></ul>
  34. 34. Multiple sclerosis: Epidemiology <ul><li>Age and gender </li></ul><ul><ul><li>Onset predominantly in young to middle aged adults (peak onset in 20’s) </li></ul></ul><ul><ul><li>Frequency of relapses decreases over course of disease </li></ul></ul><ul><ul><li>2:1 female:male predominance </li></ul></ul><ul><li>Geographic distribution </li></ul><ul><ul><li>Higher latitudes (northern US, Canada, northern Europe) </li></ul></ul><ul><ul><li>Partly a result of genetic differences between populations and subsequent migration patterns of susceptible groups </li></ul></ul>
  35. 35. Multiple sclerosis: Laboratory findings <ul><li>Cerebrospinal fluid </li></ul><ul><ul><li>Myelin basic protein (MBP) </li></ul></ul><ul><ul><li>Oligoclonal bands </li></ul></ul><ul><ul><li>Increased IgG </li></ul></ul><ul><li>Neuroimaging </li></ul><ul><ul><li>MRI especially useful in imaging white matter lesions </li></ul></ul>
  36. 36. Multiple sclerosis: Widely distributed lesions
  37. 37. Multiple sclerosis: Widely distributed lesions
  38. 38. Multiple sclerosis: Periventricular plaques
  39. 39. Multiple sclerosis: Gross plaque morphology
  40. 40. Multiple sclerosis: Gross plaque morphology
  41. 41. Multiple sclerosis: active plaque
  42. 42. Multiple sclerosis Active plaque
  43. 43. Multiple sclerosis: Active demyelination Myelin stain (blue) with PAS counterstain CD68 (histiocytes)
  44. 44. Multiple sclerosis: Microscopic plaque morphology H&E Myelin stain CD68 (histiocytes) Axon stain H&E
  45. 45. Multiple sclerosis: Relative axonal preservation Normal white matter Demyelinated plaque
  46. 46. Multiple sclerosis: Pathogenesis <ul><li>Autoimmune factors </li></ul><ul><ul><li>Initiated by CD4+ T cells reacting with myelin antigens (e.g., MBP) </li></ul></ul><ul><ul><li>Demyelination effected by activated macrophages </li></ul></ul><ul><li>Genetic factors </li></ul><ul><ul><li>15X increased risk among first-degree relatives </li></ul></ul><ul><ul><ul><li>Even higher among monozygotic twins </li></ul></ul></ul><ul><ul><li>Susceptibility linked to MHC DR2 haplotype </li></ul></ul><ul><li>Environmental factors </li></ul><ul><ul><li>?Microbial triggers? </li></ul></ul>
  47. 47. MS variants <ul><li>Marburg type </li></ul><ul><ul><li>Rapidly progressive, monophasic course, typically fatal </li></ul></ul><ul><li>Bal ό concentric sclerosis </li></ul><ul><ul><li>Very rare </li></ul></ul><ul><ul><li>Rapidly fatal course </li></ul></ul><ul><li>Devic neuromyelitis optica </li></ul><ul><ul><li>Lesions predominate in optic nerves, spinal cord </li></ul></ul><ul><ul><li>Plaques more inflammatory and extensive </li></ul></ul>
  48. 48. Animal models of MS <ul><li>Experimental allergic encephalomyelitis (EAE) </li></ul><ul><ul><li>Immunization of animals with myelin or myelin components results in autoimmune CNS demyelination </li></ul></ul><ul><li>Theiler virus encephalomyelitis </li></ul><ul><ul><li>Brain infection induces similar CNS demyelination </li></ul></ul><ul><li>Important for understanding pathogenesis and testing potential therapies </li></ul>
  49. 49. Parainfectious disorders <ul><li>Inflammatory demyelination </li></ul><ul><li>Autoimmune mechanism </li></ul><ul><li>Typically monophasic, usually following a “flu-like illness” or vaccination </li></ul>
  50. 50. Parainfectious disorders <ul><li>Acute disseminated encephalomyelitis (ADEM) </li></ul><ul><li>Acute hemorrhagic leukoencephalopathy </li></ul>
  51. 51. ADEM
  52. 52. ADEM Small foci of perivenular demyelination

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