“Multiple Sclerosis Overview” January 17, 2008 Khurram Bashir, MD, MPH

1. “Multiple Sclerosis Overview” January 17, 2008 Khurram Bashir, MD, MPH Associate Professor of Neurology Director, Multiple Sclerosis Center

2. Optic Neuritis

3. MS History – Saint Lidwina (1421)

4. 1794-1848 » Sir Augustus d'Esté Grand-son of George III The Regent did not approve of the marriage of his son, Prince Augustus Frederick, to Lady Augusta Murray, and had the marriage annulled Although later given a knighthood, Augustus was made illegitimate

5. 1868 » First detailed clinicopathological description of MS Charcot became the Professor of Neurology at the University of Paris and is often referred to as the "Father of Modern Neurology".

6. Immune-mediated, demyelinating disease of the central nervous system white matter characterized by neurologic dysfunction separated in time and space Multiple Sclerosis

7. Immune-mediated and neurodegenerative, demyelinating with axonal lossdisease of the central nervous system white and gray matter characterized by neurologic dysfunction separated in time and space Multiple Sclerosis

8. CHALLENGES FOR THE HEALTHCARE PROVIDER • Difficult diagnosis • No single specific test • No two cases of MS are alike • No proven cause • No known cure • MS is unpredictable • Partially effect treatments

9. Epidemiology of Multiple Sclerosis • Age: 20-40 yrs (mean 30 yrs) • F:M ratio: 1.5-2.0 : 1 • Race: W > B > Other racial groups • Incidence • Worldwide 2.5 million • US 365,000 – 400,000 • Clusters/”Epidemics”: Faroe Islands, Iceland • Effect of migration: Exposure at < 15 yrs of age is important

10. Epidemiology of Multiple Sclerosis • Geographical Increases with increasing Association: and decreasing latitude

11. Epidemiology of Multiple Sclerosis • Duration of disease > 30 years • Severely disabled 30% (w/o Rx) • Unemployed 70% • Average care cost $30,000/year (1998 $) • US economy cost $9.6 billion/year (1998 $)

12. Pathophysiology of Multiple Sclerosis • Genetic Factors • Polygenic • Monozygotic twin concordance rate of ~25-30% compared to dizygotic twin concordance rate of ~4-5% • MS is more common in Caucasians • Minor influence of HLA (on chromosome 6) in familial cases and Caucasian patients with RR MS • Several areas of interest - 17q11, 6p21, 5q11, 17q22, 16p13, 3p21, 12p13, and 6qtel.

13. Pathophysiology of Multiple Sclerosis • Environmental Factors • Infectious ? • Toxins ? • Unknown • No increased risk of MS in adoptees • No increased risk in spouses

14. Genetic predisposition Infectious agent? Environmental factors Abnormal immunologic response MS Pathophysiology of Multiple Sclerosis

15. Noseworthy J., Progress in determining the causes and treatment of multiple sclerosis. Nature. June 1999: A40-A47.

16. Activation of Immune System in MS

17. Inflammation and the CNS in MS

18. Axonal Damage and Lesion Formation in MS

19. Multiple Sclerosis – Gross Pathology

20. Inflammation Demyelination Axonal Loss Multiple Sclerosis Pathology

21. Remyelinating Oligodendrocyte

22. Normal White Matter Plaque Lymphocytes Neurons Myelin Axons Astrocytes Macrophages Multiple Sclerosis : Severe Myelin, Axonal, and Neuronal Loss Adapted with kind permission from Dr. W. Brück.

23. Gray Matter Lesion Patterns Patients often experience neurologic symptoms that do not correlate with white matter pathology Restricted to the cortex, small in size, circular intracortical lesions, often centered on vessels Affects subcortical and white matter and cortex Extend from the pial surface into the cortex, often involve multiple gyri Peterson JW et al. Neurol Clin. 2005;23:107-129.

24. Symptoms at Onset of MS Paty. In: Multiple sclerosis, diagnosis, medical management, and rehabilitation. 2000.

25. MS: Common Symptoms Goodin et al. Mult Scler. 1999;5:78-88.

26. Disability ProgressionNo Distinct Relapses Relapses with Disability Increasing Disability Relapses Increasing disability Increasing disability Increasing disability Time Time Time Relapsing- remitting 55% Secondary progressive 30% Primary progressive 5%-10% Some of the available therapies can slow disability progression in relapsing forms of MS. Forms of MS

27. SPECTRUM OF MS DISEASE ACTIVITY Genetic Susceptibility Environmental Factors Immune System Activation in the CNS Demyelination ± Axonal Loss Multiple Sclerosis Benign RR SP Transitional PP PR Malignant Minimal Disability Severe Disability

28. Laboratory and Imaging Studies • MRI • Brain • Spinal cord • CSF • Evoked Potential Studies • Visual • Brainstem auditory • Somatosensory

29. T1 “black hole” Gdenhancement Brain atrophy Spinal cord lesion T2 lesion Multiple Sclerosis: Cranial MRI

30. Multiple Sclerosis : Serial MRI Findings

31. Visual Evoked Potentials

32. Common CSF Abnormalities MS Profile MBP Elevated IgG Index Elevated IgG Synthesis Rate Elevated OCB Present

33. Revised MacDonald Diagnostic Criteria • Relapse Definition • Neurological disturbance consistent with MS • Subjective report or objective observation • 24 hour duration, minimum • Excludes psudorelapses, single paroxysmal episodes • At least 30 days between onset of event 1 and event 2

34. Revised MacDonald Diagnostic Criteria

35. Revised MacDonald Diagnostic Criteria

36. Revised MacDonald Diagnostic Criteria • Caveat • No Better Explanation • Need to rule out other potential etiologies that might explain clinical or imaging abnormalities

37. Clinical Stages in Relapsing MS SP MS Late RR MS Early RR MS Pre- Symptomatic BPF Gd + lesions Clinical Relapse Accumulated disability WM NAA T2W lesion burden

38. Multiple Sclerosis Treatment • Treatment of Relapse (“Exacerbation”) • Treatment of Underlying Disease • Treatment of Symptoms • Psychosocial Support • Patient Education

39. Acute Relapse SP MS Late RR MS Early RR MS Pre- Symptomatic

40. Treatment of an Acute Relapse • Standard Treatment(s): • IV Methylprednisolone • Oral Prednisone • ACTH injections • Therapeutic Plasma Exchange (for steroid unresponsive severe demylinating relapses)

41. Relapsing MS SP MS Late RR MS Early RR MS Pre- Symptomatic

42. Treatment for Relapsing MS • Interferon Agents • IFN -1b (Betaseron) • IFN -1a intramuscular (Avonex) • IFN -1a subcutaneous (Rebif) • Non-Interferon Agents • Synthetic Polymer • Glatiramer acetate (Copaxone) • Selective Adhesion Molecule (SAM) Inhibitor • Natilzumab (Tysabri)

43. SP MS SP MS Late RR MS Early RR MS Pre- Symptomatic

44. Treatment for SP MS • Interferon Agents • IFN -1b (Betaseron)* • IFN -1a (Avonex, Rebif)** • Natalizumab (Tysabri)** • Non-Interferon Agents • Anthracenedione Derivative • Mitoxantrone (Novantrone)*** * Approved therapy for SP MS in Europe and Canada * And ** Appropriate for use in relapsing SP MS *** Only FDA-approved therapy for SP MS in the US

45. Goals of Treatment of MS • Therapeutic Effects of Current Therapies: • Reduction in • Relapse rate • Progression of disability • MRI • Total burden of disease • Gad enhancing lesions on MRI • Brain atrophy

46. PP MS

47. Treatment for PP MS • Currently no treatments proven to slow or stop progression of disease • Management focused on: • Treating symptoms • Maximizing function • Improving quality of life

48. MS symptom and side effect management SYMPTOMS PHARMACOLOGIC TREATMENT OPTIONS Spasticity Baclofen, Diazepam, Gabapentin, Tizanidine, Dantrium Urinary Dysfunction Propantheline Bromide, Oxybutynin, Hyoscyamine Sulfate, Tolterodine Tartrate Fatigue Amantadine, Pemoline, Fluoxetine, Methylphenidate, Modafinil Depression SSRIs:Fluoxetine, Sertraline Tricyclics: Amitriptyline, Nortriptyline, Desipramine Venlafaxine Pain Anticonvulsants: Carbamazepine, DPH, Gabapentin Antidepressants: Amitriptyline, Nortriptyline, Desipramine, Venlafaxine Sexual Dysfunction Sildenafil, Vardenafil, Tidalafil Ataxia Ondansetron, Clonazepam, Propranolol, Levetiracetam Aug2000

49. Other Demyelinating Diseases • Acute Disseminated Encephalomyelitis • Hyper-acute, severe, monophasic, multifocal, paraifectious/paravaccination, demylinating • Devic’s Diseases (Neuromyelitis Optica, NMO) • Severe, necrotizing, relapsing/rapidly progressive, demyelinating, associated with NMO IgG, involving optic nerves and spinal cord • Balo’s Concentric Sclerosis • MS variant, acute, large, demyelinating lesions, with concentric rings of demyelination and remyelination • Marburg Variant • MS variant, severe, rapidly progressive, involves large area of CNS white matter, death usually within months

50. Questions ?