This document discusses demyelinating diseases that damage the white matter of the brain. It describes three major categories of leukoencephalopathies: genetic, acquired non-inflammatory, and acquired inflammatory. Genetic disorders include defects in lipid metabolism, cytoskeletal proteins, and myelin proteins. Acquired non-inflammatory disorders are toxic, metabolic, vascular or traumatic. Acquired inflammatory disorders include infectious diseases like HIV encephalitis and progressive multifocal leukoencephalopathy, as well as autoimmune diseases like multiple sclerosis. Multiple sclerosis involves inappropriate immune cell migration across the blood-brain barrier, leading to inflammation and damage to myelin, glia, axons and neurons.

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

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.