1. Boston Medical Center is the primary teaching affiliate of the Boston University School of Medicine. PRESENTATION TITLE Subtitle & Date

2. Boston Medical Center is the primary teaching affiliate of the Boston University School of Medicine.

3. SLIDE TITLE First bullet –Second bullet Third bullet 9/21/2015 3 Footer copy to go here.

4. Boston Medical Center is the primary teaching affiliate of the Boston University School of Medicine. MULTIPLE SCLEROSIS CLINICAL UPDATE James A.D. Otis, M.D. Associate Professor of Neurology Boston University School of Medicine

5. 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

6. 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

7. 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.

8. 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.

9. 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

10. CLINICAL COURSE Primary progressive Relapsing-remitting Secondarily progressive

11. 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

12. DIFFERENTIAL DIAGNOSIS Encephalomyelitis Infection Vasculitis/angiitis Behcet’s disease Sarcoidosis Adrenoleukodystrophy Other dysmyelinating diseases

13. DIAGNOSTIC EVALUATION Examination MRI with contrast CSF with IgG synthesis index and oligoclonal bands and myelin basic protein Evoked potentials to find occult lesions

14. OLIGOCLONAL BANDS Oligoclonal bands in CSF phoresis

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

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

17. MRI MRI showing typical periventricular demyelination

18. CLINICAL SYMPTOMS Fatigue (most common) Visual loss secondary to optic nerve demyelination Weakness Ataxia Bladder/bowel dysfunction Paresthesias Cranial nerve abnormalities

19. 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

20. 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

21. 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

22. 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

23. 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