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PRESENTATION TITLE. Subtitle & Date. SLIDE TITLE. First bullet Second bullet Third bullet. Multiple Sclerosis Clinical Update. James A.D. Otis, M.D. Associate Professor of Neurology Boston University School of Medicine. Overview.

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  1. PRESENTATION TITLE Subtitle & Date

  2. SLIDE TITLE • First bullet • Second bullet • Third bullet Footer copy to go here.

  3. Multiple SclerosisClinical Update James A.D. Otis, M.D. Associate Professor of Neurology Boston University School of Medicine

  4. Overview • An autoimmune disease of the central nervous system producing lesions separated in space and time. Although mostly demyelinating, there is axonal damage • Exact etiology unknown

  5. Epidemiology • Affect between 250,000-350,000 patients in U.S. • 100/100,000 prevalence in northern states, 20/100,000 in southern states • Most common in northern Europe, almost unknown in southeast Asia • Migration from high to low incidence area reduces risk after 15 years

  6. Biological Basis • A multiple sclerosis plaque is formed after activated peripheral T cells adhere to CNS postcapillary venules. • The T cells pass through the endothelial cells and migrate into periventricular parenchyma. • The inflammation is associated with destruction of the inner myelin lamellae and dysfunction of oligodendroglia (and likely with diffuse effects such as fatigue). • The inflammation resolves in 2 to 6 weeks, presumably suppressed by endogenous CNS and immune mechanisms, such as IL-4, IL-10, transforming growth factor-beta, prostaglandin E, a rise in cortisol, and apoptosis of invading cells. • Astrocyte hypertrophy and gliosis follow.

  7. Biological Basis • In active multiple sclerosis, lymphocytes express excessive levels of activation proteins (HLA-DR, CD71) and co-stimulatory molecules (CD80, B7-1) • Inflammatory cytokines (eg, IL-2, IL-15, interferon-gamma) and cytokine-secreting cells are seen in the serum at low, but higher than normal, levels IL-1, tumor necrosis factor-alpha, IL-6, and IL-15 are present in the CSF. Messenger ribonucleic acid for inflammatory cytokines is elevated in white blood cells • These Th1-like cytokines and monokines amplify immune responses. • . During attacks concanavalin A-induced suppressor cell function drops. Interleukin-12 production increases, likely inducing interferon-gamma. Indeed, interferon-gamma "therapy" triggers attacks of multiple sclerosis reactions • Many of these changes could lead to delayed-type hypersensitivity or Th1-type immune.

  8. Pathology • Areas of demyelination with occasional axonal loss. Periventricular white matter and other subcortical white matter most common as well as spinal cord pathways • Inflammatory cells often found near new areas of demyelination

  9. Clinical Course • Primary progressive • Relapsing-remitting • Secondarily progressive

  10. Diagnosis • High index of suspicion • MRI • Evoked potentials • Lumbar puncture • Myelin basic protein • Oligoclonal bands • IgG synthesis index • McDonald Criteria • Complex • Currently being revised • Require 2 lesions separated in space and time • LPs recommended only to rule out other diagnoses

  11. Differential Diagnosis • Encephalomyelitis • Infection • Vasculitis/angiitis • Behcet’s disease • Sarcoidosis • Adrenoleukodystrophy • Other dysmyelinating diseases

  12. Diagnostic Evaluation • Examination • MRI with contrast • CSF with IgG synthesis index and oligoclonal bands and myelin basic protein • Evoked potentials to find occult lesions

  13. Oligoclonal Bands • Oligoclonal bands in CSF phoresis

  14. MRI • Typical white matter plaque in acute MS with diffuse enhancement

  15. MRI • T1 (A) and T2 (B) images of cervical cord showing multiple plaques

  16. MRI • MRI showing typical periventricular demyelination

  17. Clinical Symptoms • Fatigue (most common) • Visual loss secondary to optic nerve demyelination • Weakness • Ataxia • Bladder/bowel dysfunction • Paresthesias • Cranial nerve abnormalities

  18. Optic Neuritis • Retro-orbital pain • Visual loss • Decreased acuity • Normal fundus in acute stage in 60% • Optic pallor and atrophy in chronic state • Visual evoked potentials show delay in cortical response on the side affected

  19. Management • Primary prophylaxis • Beta interferon (Betaseron, Avonex, Rebif) • Glatiramate acetate (Copaxone) • Natalizumab (Tysabri) • Fingolimod • Fumarate • Teriflunomide • Acute exacerbations treated with Solumedrol 1gm qd for 5-10 days • Some evidence to support plasma exchange

  20. Does Prophylaxis Work ? • There is a reduction of 30-35% in the relapse rate with all treatments • There is clear decrease in MRI plaque burden over a 5 year period • Time to loss of independent mobility is increased • Caution must be used when using natalizumab and new oral agents because of risk of PML • Tests for JC virus now commercially available and safe • Recent European study calls into question the relation between exacerbations and progression

  21. Symptomatic Treatment • Treat infections • UTI most common • Treat spasticity with lioresal or tinazidine • Treat fatigue with amantadine, modafinil or methylphenidate • Monitor liver enzymes and CBC while on prophylactic agents

  22. Advanced Treatment • Many patients progress through prophylaxis • For these, additional treatments are used to prevent further deterioration • These include methotrexate, azathioprine and monthly doses of solumedrol • There is some evidence that IV IgG is also helpful

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