1. MS Mentorship Forum Foundation of the Consortium of Multiple Sclerosis Centers Promoting the Best and Latest in Multiple Sclerosis Care

3. Introductions  Faculty  Corey Ford, MD, PhD, Chair  Guy Buckle, MD, MPH  Scott Newsome, DO  Nancy Sicotte, MD  June Halper  Peer Mentors: Dr. Gabriele DeLuca, Dr. Jennifer Graves, Dr. Irene Cortese  Why the field of MS?

4. Purpose of Mentorship Forum  To discuss the vital role clinicians and researchers play in caring for patients with MS  To understand more about the appropriate diagnosis and management of MS as well as future challenges  To provide a platform of networking and mentorship opportunities for future leaders in the field  To develop content and resources for other professionals-in-training considering neurology and MS as a career path

5. Needs Assessment A CMSC survey of neurologists and residents told us you would appreciate:  Networking with peers who have recently completed residencies or fellowships  More information about career challenges in current healthcare environments  Updated information on principles of MS, clinical classifications, scope and evolution of current MS care

6. Outcomes for this Meeting  Information for other students and residents on career milestones and mentorship opportunities  In depth information on advances in MS  Content development for web-based programs for professionals-in-training  A foundation for future networking

7. Focus for the Mentorship Forum  What is exciting and inspiring to someone contemplating MS as a specialization? ​  What pieces of pathology, imaging, clinical care are you amazed by or consider important enough to spend time telling someone about? ​ ​  What are the newest revelations that provide insight and might guide the future of better diagnosis or treatment?

8. Pathology of MS, Neuroimmunology, Unmet Needs in MS Treatment Corey C. Ford, MD, PhD, Chair

9. Multiple Sclerosis  Immune-mediated, chronic, inflammatory disease  Precipitated by unknown environmental factors in genetically susceptible individuals  Inflammation, demyelination, axonal loss in the CNS  Most common chronic neurological disease in young adults  Characterized by relapses and remissions of neurological symptoms and progression of disability over time Compston A, Coles A. Lancet. 2002;359:1221-1231. Fleming JO, Carrithers MS. Neurology. 2010;74:876-877.

10. Epidemiology of MS  Approximately 400,000 cases in the United States 1  (estimates range from 250,000–500,000)  Estimated 2.3 million cases worldwide 2  Higher prevalence with northern European ancestry 3  Highest incidence in Caucasians  Higher incidence in women (≥3:1) 2,3  3/4 of cases present between ages of 15-45 1.National MS Society Information Sourcebook. www.nationalmssociety.org/sourcebook. Accessed March 6, 2007. 2.National MS Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know- about-ms/who-gets-ms/index.aspx. Accessed: February 1, 2014. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know- about-ms/who-gets-ms/index.aspxhttp://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know- about-ms/who-gets-ms/index.aspx 3.Hogancamp WE, et al. Mayo Clin Proc. 1997;72:871-878.

11. Pathophysiology of MS  Pathologic hallmarks of MS:  breakdown of the blood brain barrier (BBB)  multifocal inflammation  demyelination and oligodendrocyte loss  gliosis  axonal degeneration  Major cause of neurologic disability is axonal loss

12. Pathophysiology of MS: Demyelination Spencer S. Eccles Health Sciences Library. http://www-medlib.med.utah.edu. Accessed March 6, 2007.

13. Arrowheads = areas of active demyelination. Arrow = terminal axon ovoid. Pathophysiology: Axonal Loss Trapp BD, et al. N Engl J Med. 1998;338:278-285 Trapp BD, et al. N Engl J Med. 1998;338:278-285.

14. Brain Atrophy in MS  Brain atrophy can occur early in the disease and represents the cumulative effect of:  Demyelination and axonal loss  Diffuse, nonfocal tissue damage  Global brain atrophy: brain tissue decreases at an approximate mean rate of:  0.7%–2.0% per year in patients with MS  0.1%–0.32% per year in normal controls Kalkers NF, et al. Arch Neurol. 2002;59:1572-1576. Rovaris M, et al. J Neurol. 2000;247:960-965. Scahill RI, et al. Arch Neurol. 2003;60:989-994.

15. Immunology of MS  Autoimmune, neurodegenerative disease of CNS  T-cell activated mediated inflammatory disorder  Overproduction of pro-inflammatory cytokines  B-cells also involved in inflammatory process

16. Immunology of MS  Lesions result from a highly selective, destructive process orchestrated by the immune system  Old lesions: inactive, few immune cells, scaring  New lesions: activated immune cells  Immune system responses at the blood-brain-barrier  Effects of the CNS responses on the biology of invading inflammatory cells

17. Immune Cells: Key Players  Antigen-presenting cells (APCs)  Macrophages, microglia, etc.  T cells (T lymphocytes)  Responsible for cell-mediated immune response  T Helper cells  B cells (B lymphocytes)  Responsible for the production of antibodies

18. A Model of Immune Mechanisms in MS: Overview

19. Diagnosis of MS: Basic Principles  Clinical profile and diagnosis  No definitive laboratory test  Laboratory evaluation  Evidence of dissemination of lesions in space and time  Exclusion of other diagnoses Poser CM, et al. Ann Neurol. 1983;13:227-231. Miller DH, Weinshenker BG, Filippi M, et al. Mult Scler. 2008;14:1157-1174.

20. Evolution of Diagnostic Criteria for MS  Poser criteria published in 1983  Required clinical evidence of 2 attacks occurring disseminated in time and space  McDonald criteria published in 2001  Reaffirms importance of diagnosis based on clinical findings  Expands role of MRI findings as an alternate method of meeting time or space criteria  McDonald criteria revised in 2005  Diagnosis can still be made per clinical findings  Earlier diagnosis facilitated with expanded role of MRI findings (particularly spinal MRI findings) to meet dissemination in time or space criteria, when available Poser CM, et al. Ann Neurol. 1983;13:227-231. McDonald WI, et al. Ann Neurol. 2001;50:121-127. Polman CH, et al. Ann Neurol. 2005;58:840-846.

21. Diagnosis of MS: McDonald Criteria (2005)  Objective evidence of dissemination in time and space of lesions is essential  All other explanations for clinical features must be excluded prior to diagnosis of MS  Clinical evidence must be based on objective clinical signs  MRI, CSF, and visual evoked potentials (VEPs) are helpful for diagnosis when clinical presentation is not characteristic of a particular disease  Following evaluation, diagnosis will be MS, not MS, or possible MS McDonald WI, et al. Ann Neurol. 2001;50:121-127.

22. Diagnostic Criteria for MS: 2010 Revisions to McDonald Criteria  Simplified dissemination in space (DIS) and dissemination in time (DIT)  DIS and DIT can be shown in a single scan with asymptomatic gadolinium enhancing lesion  Allows for more rapid diagnosis of MS  Requires fewer diagnostic MRI examinations  Focus on application of criteria  Pediatric, Asian and Latin American populations Polman CH, et al. Ann Neurol. 2011; 69:292-302

23. Summary of 2010 Revised McDonald Diagnostic MS Criteria CLINICAL ATTACKSMRI CHANGES ADDITIONAL INFORMATION NEEDED TO MAKE THE DIAGNOSIS 2 or more 2 or more lesions on MRI or clinical evidence of one lesion with reasonable evidence of a prior attack  Clinical evidence may be adequate but additional changes must be consistent with MS. 2 or more Objective clinical evidence of one lesion Dissemination in space:  One or more T2 lesion in typical MS locations in the CNS (central nervous system) (periventricular, juxtacortical, infratentorial, spinal cord Await further clinical attack(s) in a different area of the CNS 1 Objective clinical evidence or two or more lesions Dissemination in time  Simultaneous, asymptomatic gadolinium enhancing or non- enhancing lesions  A new T2 and/or gadolinium enhancing lesion Await a second clinical attack Polman, C. et al. Annals of Neurology (2011; 69:292-302)

24. Summary of 2010 Revised McDonald Diagnostic MS Criteria Polman, C. et al. Annals of Neurology (2011; 69:292-302) CLINICAL ATTACKSMRI CHANGES ADDITIONAL INFORMATION NEEDED TO MAKE THE DIAGNOSIS 1 Objective clinical evidence of one lesion Dissemination in space  One or more T2 lesions in at least two typical CNS locations Await further clinical attacks Dissemination in time  Simultaneous asymptomatic gadolinium enhancing or non-enhancing lesion at any time  A new T2 or gadolinium enhancing lesion(s) on follow-up MRI (no timing required) A second clinical attack 0 Progression from onset One year of disease progression (retrospective or prospective and at least two out of three criteria  Dissemination in space in the brain based on one or more T2 lesions in areas typical of MS  Dissemination in space in spinal cord based on two or more T2 lesions  Positive CSF

25. Assessment Tools to Diagnose MS  Medical history:  Age/gender/ethnicity  Identify any events that might be indicative of MS-related symptoms  Complete differential diagnosis  Neurologic examination  Mental status and affect, cranial nerves, motor, sensory, balance and coordination, gait

26. Assessment Tools to Diagnose MS MRI  Clinical attacks  MRI changes support diagnosis  brain and spinal cord imaging  detect subclinical lesions in some people  identify active inflammation with gadolinium (Gd) contrast enhancement

27. Assessment Tools to Diagnose MS  Lumbar Puncture with CSF analysis  IgG elevation, Oligoclonal bands, Mild leukocytosis  Laboratory studies: exclude disease mimics  Metabolic illness, infections, other inflammatory illnesses  Evoked potential testing:  Visual Evoked Potentials (VEP)

28. Consortium of MS Centers: Clinical MRI Guidelines  For patients with Clinically Isolated Syndrome (CIS) and suspected MS: baseline Gd-enhanced brain MRI  For patients with established diagnosis of MS: baseline Gd- enhanced brain MRI  Indications for spinal MRI  If symptoms are at level of spinal cord or not resolved  If results of brain MRI are equivocal  Perform follow-up MRI  To demonstrate new activity  Before initiating or modifying therapy  Standardized protocols should define:  Field strength, slice thickness, core sequences, resolution Traboulsee A, et al. Consortium of MS Centers. 2003. Simon J, et al. AJNR Am J Neuroradiol. 2006;27:455-461.

29. Diseases That Resemble MS Hurwitz B, et al. Advances in Diagnosis of RRMS: Highlights of the Revised Guidelines. MS Update. 2006. Bourdette D. Conversations on MS: Diagnosing and Treatment Strategies in RRMS. 2006.

30. Clinical Features That May Suggest Misdiagnosis  Normal neurological examination  No dissemination over time and space  Onset of symptoms before age 10 or after age 55  Progressive course before age 35  Localized disease Coyle P. 7th Annual Review of Multiple Sclerosis. May 2004.

31. Clinical Features That May Suggest Misdiagnosis  Atypical presentation  Fever  Headache  Abrupt hemiparesis  Abrupt hearing loss  Prominent pain  Normal optic exam  Normal sensory exam Coyle P. 7th Annual Review of Multiple Sclerosis. May 2004.

32. Clinical Features That May Suggest Misdiagnosis  Normal bladder/bowel function  Progressive myelopathy  Impaired level of consciousness  Prominent uveitis  Peripheral neuropathy  Gray matter features  Early dementia, seizures, aphasia, extrapyramidal features

33. MS: Clinical Subtypes  Four established clinical courses differ by the time course of relapse and progression  Relapsing-Remitting MS (RRMS)  Secondary Progressive MS (SPMS)  Primary Progressive MS (PPMS)  Progressive Relapsing MS (PRMS) Lublin FD, Reingold SC. Neurology. 1996;46:907-911. Goodin DS, et al. Neurology. 2002;58:169-178. Craig J, et al. J Neurol Neurosurg Psychiatry. 2003;74:1225-1230.

34. Clinical Courses of MS: The 2013 revisions  Clinically Isolated syndrome (CIS)  Not active  Active  Relapsing-remitting (RRMS)  Not active  Active Lublin FD et al. Neurology 2014;83(3):278-286.

35. Clinical Courses of MS: The 2013 revisions (continued)  Secondary progressive (SPMS)  Active and with progression  Active but without progression  Not active but with progression  Not active and without progression (stable disease)  Primary progressive (PPMS)  Active and with progression  Active but without progression  Not active but with progression  Not active and without progression (stable disease) Lublin FD et al. Neurology 2014;83(3):278-286.

36. Radiological Isolated Syndrome (RIS): May Raise Suspicion of MS FLAIR T2 Axial T2 FLAIR T2 FLAIR Axial T1 Post Gad Images courtesy of Aliza Ben-Zacharia, DrNP, ANP-BC, MSCN

37. Why Treat Early ?  Relapses and impairment have been shown to parallel MRI burden of disease 1,2  Axonal damage occurs early  May cause permanent neurological dysfunction 3  Number of MRI lesions may be predictive of future disability 4  Number of MRI lesions may be predictive of future disability 4  Preventing development of lesions may delay progression of disability 5  Preventing early relapses may delay long-term disability 6 1. Comi G. Curr Opin Neurol. 2000;13:235-240; 2. Munschauer FE 3rd et al. Clin Ther. 1997;19:868-882; 3. Trapp BD et al. N Engl J Med. 1998;338:278-285; 4. Brex PA. N Engl J Med. 2002;346:158-164; 5. O’Riordan JI. Brain. 1998;121:495-503; 6. Weinshenker BG et al. Brain. 1989;112:1419-1428

38. Unmet Treatment Needs DMTs  No MS cure  No DMTs for progressive MS  No proven CNS repair strategies  No biomarkers to identify optimal DMT, early response to therapy

39. Unmet Treatment Needs Symptomatic  Better therapies for all MS symptoms Relapse  Better treatment for steroid unresponsive attacks  Treatments to improve recovery from attacks

40. CNS Reserve  Brain is shrinking 0.1-0.3% per year  This is accelerated in MS  Hypertension, diabetes, smoking, obesity all increase brain shrinkage  There is loss of neural circuits, and brain plasticity  Exercise can improve brain function  Aerobic exercise and strength training  Over 30 minutes per session

41. Summary: Unmet Treatment Needs  We need to take advantage of strategies to improve CNS reserve  This should be initial treatment substrate for all MS  Relapsing MS patients need to start DMT quickly, and to be followed closely in the early years  Poor response should trigger DMT switch  We need to puzzle out MS neurodegeneration  CNS repair may involve devices, and not just cell/soluble factor therapies

42. Wellness/Health Maintenance/Vascular Risk Factor Program  Optimum body weight, no smoking, moderate alcohol  Good sleep hygiene  Healthy diet (no vitamin issues), limited salt  Regular exercise several times a week (aerobic and muscle strengthening)

43. Wellness/Health Maintenance/Vascular Risk Factor Program  Take care of blood pressure, glucose issues (hemoglobin A1c), lipids  Dental health  Regular mental exercise, socialization

44. Summary  MS is a complex immune mediated disease that affects the central nervous system  Inflammation, demyelination and axonal damage.  MS remains a clinical diagnosis supported by paraclinical evidence  MRI, CSF analysis, lab studies, and evoked potential testing  More accurate clinical course descriptions help to clarify communication among clinicians  CIS, RRMS, SPMS, PPMS

45. Questions & Discussion  What is exciting and inspiring to someone contemplating MS as a specialization? ​  What pieces of pathology, imaging, clinical care are you amazed by or consider important enough to spend time telling someone about? ​ ​  What are the newest revelations that provide insight and might guide the future of better diagnosis or treatment?