practical issues in multiple sclerosis

1. NOTE: To change the image on this slide, select the picture and delete it. Then click the Pictures icon in the placeholde r to insert your own image. Practical Issues in Multiple Sclerosis Amr Hassan, M.D. Associate professor of Neurology - Cairo University 2016

2. AGENDA • Immunopathogenesis • Diagnosis • Biomarkers • Treatment options • Optimization of treatment 2

3. Immunopathogenesis 3

4. Genetics Autoimmunity Environment

6. Immunopathogenesis of M.S. Inflammed Tissue 3) IL-12 VCAM 2) B7 CD28 auto- reactive auto- reactive auto- reactiv e TH 1 TH P TH 1 VLA-4 1) Engagement of T cell receptor by crossreactive microbial antigen auto- reactive TH 1 Peripheral Immune System 6

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8. Immunopathogenesis of M.S. Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage Remyelination Axonal loss 8

9. Immunopathogenesis of M.S. Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage Remyelination Axonal loss 9

10. Immunopathogenesis of M.S. IL-2 IFN-  TNF-  3) IL-12 2) B7 CD28 CD28 B7 auto-reactive TH P auto- reactive tissue APC TH 1 1) Engagement of T cell receptor by crossreactive microbial antigen CD154 CD40 IL-12 autoantigens Peripheral Immune System Tissue Damage 10

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12. Immunopathogenesis of M.S. Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage Remyelination Axonal loss 12

13. Immunopathogenesis of M.S. Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage Remyelination Axonal loss 13

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17. More Than a Demyelinating Disease 17

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19. Helper T-Cell Differentiation TH1 IFN-  IL-12/STAT4 Pro-inflammatory IL-4 IL-5 IL-10 IL-13 Anti-inflammatory/ Allergy IL-4/STAT6 TH2 IL-17 TH17 Pro-inflammatory IL-6 + TGF-β IL-23 TGF-β TGF-β Treg Regulatory Graphic courtesy of Dr. Scott Zamvil.

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21. Immunopathogenesis of M.S. Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage Remyelination Axonal loss 21

22. More Than a Demyelinating Disease INFLAMMATORY ACTIVITY INFLAMMATORY ACTIVITY Relapses Relapses cMRI cMRI WMLs WMLs Poor Rx effect Poor Rx effect Disease Parameter FLAIR FLAIR T1 Gd+ T1 Gd+ Rx effect Rx effect No New No New WMLs WMLs PROGRESSION PROGRESSION FLAIR FLAIR Time (Years) NEURODEGENERATION NEURODEGENERATION 22

23. Inflammation and Neurodegeneration in MS Diseas e Stage Dominant Component Main Clinical Outcome MRI INFLAMMATION Edema Demyelination (axonal loss, brain atrophy) Early Relapses Gd enhancement Late NEURODEGENERATION Severe axonal injury Permanent tissue loss Disability Black Holes Gd enhancement Brain Atrophy Filippi et al., EJN 2001, 8:291-297 23

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26. Fingolimod Fingolimod 26

27. Mechanism of action of DMD (Fingolimod) 27

28. Mechanism of action of DMD (Fingolimod) 28

29. Diagnosis 29

30. Multiple Sclerosis Diagnosis Diagnosis relies on clinical judgment. • MS is extremely variable. • There is no specific test. • The diagnosis has dramatic implications. • 30

31. Multiple Sclerosis Diagnosis Diagnosis of MS includes To exclude other diagnoses To prove it is M.S 31

32. How to diagnose MS? Clinical: Paraclinical: History and examination. • Neuroimaging. • Evidence of CNS involvement. • Evoked potentials. • Dissemination in space and time. • CSF analysis. • 32

33. Diagnostic Criteria • Dawson criteria: 1916 • Schumacher criteria: 1965 • Poser criteria: 1983 • McDonald criteria: 2001 • McDonald criteria: 2005 • McDonald criteria: 2010 All criteria require dissemination in time and space

34. Summarized Diagnostic Criteria 1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS 2. Dissemination in Time: Onset of neurological deficits separated by at least one month 3. Rule out other explanations! 2010 2014

35. Diagnostic Criteria 2005 • Incorporate use of MRI • Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis DIS August November DIT

36. New Diagnostic Criteria 2010 • Incorporate use of MRI • Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis DIS August August DIT

38. Magnetic resonance imaging T1 weighted Pre & Post Contrast 38

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41. Magnetic resonance imaging T2 weighted images showing plaques 41

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45. INVESTIGATIONS

46. CSF examination IgG index: [ [IgG IgGCSF CSF/ /albumin albuminCSF CSF]/[ ]/[IgG IgGserum serum/ /albumin albuminserum serum] ] • MS patients elevated IgG index (>1.7). (normal is <0.77) 46

47. Oligoclonal Bands in CSF 47

48. Mental map for diagnosis of MS Clinical/Paraclinical/Imaging Typical for MS Fulfills Criteria Atypical for MS Red Flags Present Typical for MS not Fulfilling Criteria Work Up for Alternative Diagnoses Clinical/Imaging Follow Up Clinical/Imaging Follow Up Further clinical/imaging typical for MS Alternative Diagnosis Established MS Diagnosis 48

49. PRESENTING SYMPTOMS IN MS Total % SENSORY LOSS IN LIMBS 30.7 VISUAL LOSS 15.9 MOTOR WEAKNESS 14.2 DIPLOPIA 6.8 GAIT DISTURBANCE 4.8 INCOORDINATION 2.9 SENSORY LOSS-FACE 2.8 LHERMITTE’S 1.8 VERTIGO 1.7 BLADDER SYMPTOMS 1 AUTE TRANSVERSE MYELOPATHY 0.7 PAIN 0.5 OTHERS 2.5 POLYSYMPTOMATIC 13.7

50. The Red Flags 50