Disease of Myelin. Reid R. Heffner, MD Distinguished Teaching Professor Emeritus Department of Pathology and Anatomy January 9, 2019

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1 Disease of Myelin Reid R. Heffner, MD Distinguished Teaching Professor Emeritus Department of Pathology and Anatomy January 9,

2 I HAVE NO CONFLICTS OF INTEREST OR DISCLOSURES TO DECLARE. I HAVE NO FINANCIAL INTEREST IN, I RECEIVE NO FINANCIAL SUPPORT FROM AND I HAVE NO CONTRACTS WITH OR GRANTS FROM ANY PHARMACEUTICAL COMPANY OR ANY INDUSTRY

3 Contents Multiple sclerosis Devic s disease (NMO) Infection/immune-related Leukodystrophies Binswanger s disease Alcohol/nutritional 3

4 Multiple sclerosis Prototype of myelin disease Only affects CNS, not PNS Immune-mediated Clinical symptoms depend on location, extent Multiple lesions separated by time and space Typically relapsing, remitting Treatment is not definitive Kumar et al. Robbins and Cotran. Pathologic basis of Disease. 9 th edition. Chap. 23, 2017 [Big Robbins] 4

5 Multiple sclerosis epidemiology Further from the equator, the greater the risk 5

6 MS pathogenesis-the Perfect Storm Environment: infection, genetics, Vit D lack + Genetics: HLA types DR15, twins, families + Exposure to infection: EBV, measles Abs to virus cross react with myelin components and cells Stimulus for disease is unknown Autoimmunity vs myelin and oligodendroglia 6

7 Ingredients for immune dysfunction Ags MOG,MBP,PLP Th1 Astrocytic Th17cell Ifγ IL-17 Blood brain barrier Mono APC T B Complement protein 7 Ag

8 M1 Phagocyte CD4+ cells RO&NS Th1 INFγ Th17 IL-17 TNFα MHCI CD8 Abs + C MAC B APC Macs MHC I-II Ag BBB ICAM 8

9 Immunopathogenesis summary An unknown stimulus initiates immune dysfunction APCs activate T cells upregulate adhesion molecules M1 macrophages N&O 2 free radicals damage myelin CD4+ T cells Th1 cells make INFγ activate macs & induces MHC class I & II on myelin and oligos Th17 cells maketnfα demyelination & upreg ICAM on BBB Th2 cells exert an anti-inflammatory effect=remission CD8+ T cells-damage myelin, axons & oligos MHC class I ag upregulated by INFγ B cells-abs vs MOG, MBP, PLP; activation of C MAC MAC damages myelin sheath and axons Abs presumed source of oligoclonal bands in CSF 9

10 CSF electrophoresis 10

11 Oligoclonal bands OCBs suggest inflammation, 90% MS cases 11

12 Multiple sclerosis Location: periventricular, cerebral white matter, optic nerve, brainstem, spinal cord

13 Lesions in Corpus Callosum

14 MS plaque How did we get there? MS plaque NORMAL LFB STAIN

15 Oligodendroglia are a target NORMAL BRAIN Rows of oligos in white matter

16 Early MS plaque Demyelination (LFB stain) Macrophages, lymphocytes Reactive astrocytes

17 Old sclerotic plaque

18 MS plaques in pons Bodian Axons preserved-lr Axons lost-ul LFB Multiple zones of demyelination

19 Sharp Demarcation of Demyelinated Zone Loss of Axons H & E LFB Stain Bodian Stain

20 High Magnification Showing Swollen Axons

21 MS prognosis Remission Remyelination Axons remain intact Oligos regenerate Reduced inflammation Early plaque Demyelination Axons are preserved Inflammation Loss of oligos Progressive MS Lack of remyelination Inflammation remains Axons lost Relapse Further demyelination Loss of axons Inflammation 21

22 Balo s concentric sclerosis Acute MS variant Childhood onset Worse prognosis Alternate waves of demyelination and remyelination 22

23 MS treatment Interferon-β - production of Th2 cells Natalizumab- antibody vs integrins Ameltizumab- Ab vs CD52 (lymphocyte marker), lymphocyte production Copazone- production of Th2 cells Dimethyl fumarate-?, favors production of anti- inflammatory cytokines 23

24 Schilder s disease Variant of MS May follow an infection Affects children and young adults, peak age 7-12 Extensive myelin loss May present as pseudotumor (mass lesion) MS may occasionally do this as well Progressive, may be remissions Survival 10 years 24

25 Schilder s disease Diffuse white matter lesions Resembles a leukodystrophy 25

26 Schilder s disease Ring enhancing lesions look like a tumor 26

27 Schilder s Proton density weighted MRI 27

28 Devic s disease 28

29 Devic s disease Neuromyelitis optica Asians reportedly more vulnerable Middle aged women more commonly affected Patients may have another auto-immune disease Usually anti-aqp4 (astrocyte water channel) abs Aquaporin (AQP4) located on astrocyte foot processes Abs found in serum and mediate the disease Sudden onset, severe disease Optic neuritis Transverse myelitis 29

30 Devic s disease Often more on one side, multiple large lesions Weakness, paralysis, bladder/bowel incontinence 30

31 Optic Nerve Stained for Myelin LFB) Patients have unilateral optic neuritis with eye pain, visual symptoms, eventually blindness

32 Infection/immune-related demyelinating disease Acute disseminated encephalomyelitis (ADEM) Acute hemorrhagic encephalomyelitis (Hurst s encephalomyelitis) 32

33 Acute disseminated encephalomyelitis (ADEM) ADEM is monophasic, demyelinating Typically follows viral infection or immunization Usually about two weeks later Course fairly rapid 20% patients die Remainder recover, some with neurologic deficits 33

34 Acute disseminated encephalomyelitis (ADEM) Multiple, small, perivenular demyelinating areas 34

35 Acute hemorrhagic (Hurst) encephalomyelitis More severe than ADEM Follows viral infection, immunization More fulminant disease Usually fatal Patients who recover have neurologic deficits 35

36 Acute hemorrhagic (Hurst) encephalomyelitis Multiple hemorrhagic lesions with polys + lymphocytes 36

37 Leukodystrophies MLD Krabbe s ALD Alexander s disease Canavan s disease Pelizeaus-Merzbacher disease 37

38 Leukodystrophies 38

39 Alexander s disease Infantile, juvenile, adult types Usual onset before age 2 Large head, hydrocephalus Mutations in GFAP gene, Chr 7q21 Glial fibrillary acidic protein accumulates No cure or treatment 39

40 Alexander s disease Extensive white matter disease with profusion of astrocytes containing Rosenthal fibers 40

41 Peroxisome Small organelle in cytoplasm Contains oxidative enzymes Important in metabolizing very long chain fatty acids

42 Classic disease form is x-linked ALD gene on Xq28 Increased VLCFA

43 Adrenoleukodystrophy Affects brain, peripheral nerves and adrenal glands Progressive and fatal disease Scan showing lack of myelin in frontal regions

44 Learning objectives Define the terms introduced in class Compare and contrast diseases of myelin List the diagnostic features of each disease Understand the pathology of each disease Characterize the outcome of each disorder Describe the immunopathogenesis of MS Explain MS treatment based on immunolgy 44