DEMYELINATING DISEASE MULTIPLE SCLEROSIS

1. DEMYELINATING DISEASEMULTIPLE SCLEROSIS ELLEN MARDER MD PHD, 8/4/2005

2. MYELIN • PROTEOLIPID INSULATION OF AXONS • ENHANCES NERVE SIGNAL TRANSMISSION • SUPPORTS AXON FUNCTION • OLIGODENDROCYTES FORM CNS MYELIN • SCHWANN CELLS FORM PNS MYELIN

3. DEMYELINATION DESTRUCTION OF MYELIN ETIOLOGIES Infection: Progressive multifocal leuko- encephalopathy (PML) Postinfectious:Guillain Barre Syndrome (AIDP) Autoimmune: Multiple sclerosis Genetic/metabolic: Adrenoleukodystrophy

4. DEMYELINATING DISEASES • CENTRAL NERVOUS SYSTEM: Multiple sclerosis, progressive multifocal leukoencephalopathy, acute disemminated encephalomyelitis, adrenoleukodystrophy • PERIPHERAL NERVOUS SYSTEM: Guillain Barre Syndrome(AIDP), chronic inflammatory demyelinating polyneuropathy(CIDP)

5. ACUTE V CHRONIC • ACUTE or SUBACUTE: ADEM, GBS, PML • CHRONIC: MS, CIDP, ALD, MLD

6. RESULTS OF DEMYELINATION • CONDUCTION BLOCK • AXONAL DEATH

7. MULTIPLE SCLEROSIS • Chronic central nervous system demyelinating disease • 85% relapsing - remitting • Most common cause of nontraumatic disability in young adults • Prevalence in the US – 400, 000 • Reduction in life expectancy <5-7 years

8. INTERNAL MEDICINE AND MULTIPLE SCLEROSIS (MS) INVOLVEMENT AT EVERY STAGE • Recognition: first clinical episode • Referral: for diagnosis and treatment • Return or continuing care: for health maintainence and treatment of the complications of chronic disease

9. WHAT IS MS? • MS is an autoimmune disease caused by myelin-reactive T cells in the peripheral circulation that become activated by a trigger (?viral or bacterial), invade the central nervous system and cause destruction of myelin and axons directly and by initiating the release of various inflammatory mediators. There is often ineffective or no repair of damage.

10. IMMUNOLOGY-MS

11. PATHOPHYSIOLOGY OF MS • Focal areas of myelin destruction associated with inflammatory infiltrates (T-cells, macrophages) around periventricular venules • Axonal loss – even in early stages • Eventual scarring and more axonal loss • Brain atrophy

12. MULTIPLE SCLEROSISGROSS PATHOLOGY

13. MRI in MS

14. EARLY AXONAL INJURY

15. BRAIN ATROPHY

16. DIAGNOSIS - TRADITIONAL • The demonstration of abnormal physical SIGNS indicating the presence of lesions at TWO SEPARATE sites in the CNS, in an individual with a history of at least two episodes of neurological disturbance of the kind seen in MS, and there is no better explanation for the clinical picture. • THESE CRITERIA CAN BE FULFILLED BY CLINICAL ASSESSMENT ALONE

17. LABORATORY ASSISTED DIAGNOSIS MS lesions in various stages can now be seen on MRI Cerebrospinal fluid analysis can identify immunoglobulin synthesis Evoked potentials can demonstrate clinically and even MRI silent lesions

18. NEW DIAGNOSTIC CRITERIA(MacDonald Criteria*) • Allows separation in space criterion to be met by MRI lesions or evoked potential abnormalities (e.g. visual evoked response or VER) • Allows new MRI lesions or contrast enhancing lesions to substitute for a second physical sign or clinical attack McDonald Ann Neurol 2001;50:121

19. DIAGNOSIS – HOW EARLY?CHAMPS STUDY* • First isolated, well defined neurologic event: optic nerve,spinal cord,brain stem or cerebellum, clinically documented • At least 2 (>3mm) MRI lesions characteristic of MS • 50% chance of another attack in 3 years • 35% chance of second attack if treated with weekly interferon beta-1a Jacobs NEJM 2000; 343:898

20. MRI - DISEASE SURROGATE? • Easily accomplished • Objective • Readily measurable – volume and number of lesions, enhancement of lesions, brain atrophy • Weak correlation with disability

21. IS IT MS? • Women 2x> men • Peak incidence 3rd and 4th decade • Highest incidence in Caucasians • Increased incidence with distance from equator • Family history: 50% concordance in identical twins and 5% increased incidence among first degree relatives

22. MS: PRESENTATION • Visual: loss, dim, blurred (49%) • Oculomotor: impaired eye movements, nystagmus(42%) • Paresis:unilateral,mono-,paraparesis(42%) • Incoordination:extremity,gait,tremor(23%) • GU/bowel: incontinence, retention(10%) • Cerebral: cognitive impairment(4%)

23. CLINICAL COURSERELAPSES • 58% Have one relapse in first 2 years • 21% Have two relapses “ • 9% Have 3 or more attacks • 80% Have full recovery • There is a correlation between relapses in the first two years and the time to significant disability* Weinshenker Brain 1989;112:1419

24. CLINICAL COURSE • 10-15% “Benign” disease – patients fully functional at 15 years after disease onset • Less than 10% have “malignant” disease – rapid progression to significant disability or death in a short time • Over 50% accumulate neurologic deficits over time, that affect gait, coordination, vision, and cognitive function. • Once accumulation starts, time to significant disability is predictable – 4-6 years* Confavreaux NEJM 2000;343:1430

25. CLINICAL COURSE CHRONIC DEFICITS* • 100% Develop problems with vision • 88% Develop problems with weakness – usually paraparesis • 82% Develop some form of incoordination • 63% Have problems with bladder and/or bowels • 39% (conservative estimate) have cognitive impairment Whitaker Multiple Sclerosis 1997: 3-19

26. TREATMENT • EXACERBATIONS • RELAPSING AND REMITTING DISEASE • REFRACTORY RELAPSING REMITTING DISEASE • CHRONIC PROGRESSIVE DISEASE

27. TREATMENT OF EXACERBATIONS • Methylprednisolone 500-1000mg qd x 5 +/- oral taper (Durelli Neurology 1986;36: 238) • Oral high dose steroids(Morrow Neurology2004;63:1079) • Plasma exchange(WeinshenkerAnn Neurol 1999;46:878) • Intravenous immunoglobulin (AchironNeurology 1998;50:398)

28. DISEASE MODULATING AGENTS • All demonstrate reduction of clinical relapses (30%) and new MRI lesions in 3 year double blind, placebo-controlled studies. They are FDA approved • INTERFERONS Beta interferon-1a: Avonex, Rebif Beta interferon-1b: Betaseron • GLATIRAMER ACETATE: Copaxone Galetta.Archives of Int Med. 2002;162:2161

29. INTERFERONS • Part of the innate immune system • Up-regulates immunosuppression • Blocks entry of activated T-cells into the CNS

30. INTERFERONS • Injected IM weekly, SC tiw or qod • Injections side reactions • Common side effects: flu-like syndrome with headache, fever, myalgias • Hepatic enzyme elevations, bone marrow suppresion • Antibody formation affects efficacy

31. GLATIRAMER ACETATE(COPAXONE) • Random copolymer of amino acids alanine, lysine, glutamic acid, tyrosine • Interferes with antigen presentation and T-cell activation • Drives T-cell population to Th2 type - suppression

32. GLATIRAMER ACETATE • Daily subcutaneous injection • Injection site reactions: erythema, lipodystrophy • Idiosyncratic reactions: chest tightness, shortness of breath, usually single episode

33. REFRACTORY R-R MSADD-ON THERAPY • High dose methylprednisolone pulse therapy • IVIG • Plasma exchange • Immunosuppressives -mitoxantrone -cyclophosphamide -azathioprine -methotrexate

34. MITOXANTRONE (NOVANTRONE*) • FDA approved • Inhibits DNA synthesis • Infusions well tolerated • Side effects: cardiomyopathy, leukemia • Infusions every 3 months 12mg/m2; total 82 mg Millefiorini J Neuro 1997;244:153l

35. CONCLUSION • MS is a chronic immunologic disease caused by peripheral T-cell activation in a susceptible host • The clinical course is variable but it results in significant disability for the majority • MS patients should be treated at the time of diagnosis because those at risk cannot be identified

36. CONCLUSION • MRI is now used as a surrogate for disease activity for treatment and drug testing • There is no long term data on the value of MRI as a surrogate marker • Suppression of clinical and MRI evidence of disease activity are now treatment goals

37. CONCLUSION There is no evidence that suppression of disease activity clinically or on MRI affects long-term outcome but despite that there is a general feeling that early treatment will be beneficial in the long run.