1. John M. Bertoni, M.D., Ph.D. Creighton University Multiple Sclerosis

2. Diagnosis of MS  MS is a clinical diagnosis  Supported by –Imaging –Spinal fluid analysis

3. Multiple Sclerosis – A to Z 1.MS Pathology Inflammation Neurodegeneration 2.Immunomodulatory Therapies (IMTs) Glatiramer Acetate (Copaxone ® ) Beta Interferons (Avonex ®, Betaseron ®, Rebif ® ) Natalizumab (Tysabri ® ) – NOT CURRENTLY AVAILABLE 3.Magnetic Resonance Imaging (MRI) Conventional MRI (T1, T2) Non-conventional MRI (MRS, MTI, Brain Atrophy) 4.Clinical Data Pivotal Trials Open-Label Comparative Trial 5.Safety & Tolerability of the IMTs

5. Adapted with permission from Elsevier (The Lancet. 2002;359:1221-1231). Repairing-RemittingSecondary Progression Clinical Disability Clinical Threshold Brain Volume Inflammation Axonal Loss Frequent inflammation, demyelination, axonal transection, plasticity, and remyelination Continuing inflammation, persistent demyelination Infrequent inflammation, chronic axonal degeneration, gliosis Inflammation and Axonal Loss in MS

6. Progression of Disability MS Courses as Redefined by MRI Enhancements Early RRMS Late RRMS SPMS Time Occurrence, Extent of Severity MRI-Defined Plaque Burden Clinical Impairment Adapted with kind permission from Dr. J.S. Wolinsky.

7. MS Is More Than a Demyelinating Disease Adapted with permission from Waxman SG. N Engl J Med. 1998;338:323-325. Copyright © 2003 Massachusetts Medical Society. All rights reserved. Normal Myelinated Axon Acutely Demyelinated Axon Chronically Demyelinated Axon Degenerated Axon Conduction restored by Increase in density of sodium channels Postsynaptic neuron Sodium channels Action potential End of transected axon Myelin sheath Postsynaptic neuron Action potential Demyelination Axon A B C D

8. Axonal Transection in MS Lesions Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright © 2003 Massachusetts Medical Society. All rights reserved. 64  m 45  m

9. MS Pathogenesis CNS Autoreactive T Cells T Periphery Demyelination and Axon Loss BBB Transmigration T Danger Signal or Trigger Activation, Differentiation, Clonal Expansion T T T T Local Reactivation T T APC Adhesion/Attraction T Release of Cytokines; Recruitment of M  Antibodies B MM NO IFN-  TNF-  Adapted with kind permission from Prof. R. Hohlfeld.

10. Adapted with kind permission from Dr. W. Brück. MS: A Disease of Severe Myelin, Axonal, and Neuronal Losses Normal White MatterPlaque Myelin Axons Astrocytes Neurons Lymphocytes Macrophages

11. TISSUE DAMAGETISSUE PROTECTION Pro-inflammatory and Neurotoxic Factors  Th1 cytokines  TNF-   IL-2  Nitric oxide  Reactive oxygen species  Glutamate  Antibodies and complement  Cell-mediated neurotoxicity Anti-inflammatory and Neuroprotective Factors  Th2 cytokines  TGF-   IL-10  Neurotrophic factors –BDNF –NGF –NT-3 –CNTF –GDNF The Dual Nature of Inflammation in MS

12. Detrimental Inflammation in MS  Evidence from animal models implicates activated T cells in initiating MS pathology  Subsequent injury to CNS is mediated by T cells, B cells, and macrophages/microglia  Inflammatory components destroy myelin and oligodendrocytes  Inflammation is associated with axonal damage Neuhaus O et al. Trends Pharmcol Sci. 2003;24:131-138.

13. Inflammatory Cells May Downregulate Detrimental Inflammation  Inflammatory cells produce growth factors  Inflammatory cells remove myelin-associated inhibitory molecules  Inflammatory cells may adapt a protective suppressor phenotype Martino G et al. Lancet Neurology. 2002;1:499-509.

14. Multiple Sclerosis – A to Z 1.MS Pathology Inflammation Neurodegeneration 2.Immunomodulatory Therapies (IMTs) Glatiramer Acetate (Copaxone ® ) Beta Interferons (Avonex ®, Betaseron ®, Rebif ® ) Natalizumab (Tysabri ® ) – NOT CURRENTLY AVAILABLE 3.Magnetic Resonance Imaging (MRI) Conventional MRI (T1, T2) Non-conventional MRI (MRS, MTI, Brain Atrophy) 4.Clinical Data Pivotal Trials Open-Label Comparative Trial 5.Safety & Tolerability of the IMTs

15. TypePolypeptide mixture Recombinant protein Recombinant monoclonal antibody FDA Indication Reduction of the frequency of relapse Reduce the frequency of clinical exacerbation Decrease the frequency of clinical exacerbation Slow accumulation of disability Decrease the frequency of clinical exacerbation Slow accumulation of disability Reduce the frequency of clinical exacerbation Dosage and Administration SC Daily 20 mg SC Q O D 250 µg (8 MIU) SC 3 X Wk 22 µg 44 µg IM Weekly 30 µg IV infusion Q 4 Weeks 300 mg IFN  -1a (Avonex ® ) IFN  -1a (Rebif ® ) IFN  -1b (Betaseron ® ) Glatiramer Acetate (Copaxone ® ) Natalizumab (Tysabri ® ) Immunomodulatory Therapies

16. Mode of Action of Glatiramer Acetate: Bystander Suppression and Neuroprotection Adapted with permission from Neuhaus O et al. Neurology. 2001;56:702-708. Ziemssen T et al. Brain. 2002;125:2381-2391. Th1Th2 MacrophageMicroglia Antigen- Presenting Cell Glatiramer Acetate- Specific T Cell GA Therapy Blood-Brain Barrier Anti-inflammatory Cytokines Neuroprotection Glatiramer Acetate Bystander Suppression PeripheryCNS TCR MHC CNS Ag MHC BDNF Neurotrophins TCR

17. Progression to Disability—EDSS Steps 8.0 - 8.5 = Confined to bed or chair 7.0 - 7.5 = Confined to wheelchair 6.0 - 6.5 = Walking assistance is needed 5.0 - 5.5 = Increasing limitation in ability to walk 4.0 - 4.5 = Disability is moderate 3.0 - 3.5 = Disability is mild to moderate 2.0 - 2.5 = Disability is minimal 1.0 - 1.5 = No disability 0 = Normal neurologic exam 10.0 = Death due to MS 9.0 - 9.5 = Completely dependent Walking ability Confined to a wheelchair or bed Walks with aid (< 5 yards) Walks with assistance (22 - 110 yards or more) Walks unaided (110 - 220 yards or more) Walks unaided (330 - 550 yards or more) Fully ambulatory

18. Long-term Disability: Time from Onset of MS to EDSS 4 Confavreux C et al. Brain 2003;126:770–82 1 = 0–19 years old 2 = 20–29 years old 3 = 30–39 years old 4 = 40–49 years old 5 =  40 years old

20. Imaging in Multiple Sclerosis

21. Examples of Atrophy in MS 36 y/o woman RR MS (2 y) 43 y/o woman SP MS (19 y) 31 y/o male Healthy control Rudick et al. Neurology. 1999;53:1698-1704.

22. Diagnosis and Monitoring MS  Subjective: –detects minor sensory, visual, vestibuloauditory lesions  Clinical exam: –Motor and sensory tracts, brainstem tegmentum –Sensitive to multifocal, microscopic disease  Electrophysiology: –Characterizes, localizes, detects silent disease in sensory tracts, sensitive to microscopic disease  CSF Exam: –Detects chronic immune system activity in meninges  Neuropsychometric testing: –Cognition and mood

23. MRI detects ‘silent activity’  There are approximately 7-10+ brain lesions for every clinical event  The symptomatic lesion is seen only 20% of time  Spinal cord MRI is insensitive for lesions –Unless special techniques used and carefully inspected by reader

24. Typical callosal lesions

25. Brainstem lesion – Facial Myokymia Proton density T2 FLAIR (adjusted) T1 post GAD 21 year old, mother with MS, presents with facial myokymia Positive oligoclonal bands and elevated IgG index Negative otherwise MRI Lesion is subtle and requires anatomical knowledge to appreciate Typical subpial position, equivocal enhancement

26. Optic nerve lesion – asymptomatic prior optic neuritis Proton density T2 FLAIR Optic neuritis 8 years before, complete recovery Proton density usually sees better than T2

27. MRI spinal cord – Acute lesions, low contrast  T2 PD STIR T1 post GAD  These are very edematous (mass, STIR)  PD is more extensive than T2 (also old gliosis)  Minimal contrast extravasation

28. Heterogeneous Pathology of T2 hyperintense lesions Evolution of MS Lesions Adopted fromPatyandEbers BBB Disruption Inflammation Increased Inflammation Demyelination Reactivated Lesions Gliosis Axonal Loss Axonal Loss

29. Dawson’s fingers,Black holes

30. Seeing the brain as never before INSULAR FIBRES TEMPORAL FIBRES BROCA‘S AREA WERNICKE’S AREA LONG FIBRES SHORT FIBRES LONG FIBRES Superior Longitudinal Fasciculus Diffusion Tractography Images Courtesy of: Dr. Derek Jones, Institute of Psychiatry, London UK

31. THE END