Basics of Multiple Sclerosis

1. Basics of Multiple Sclerosis Elizabeth M. R. Dragan, MD Assistant Professor of Neurology Director, Neuroimmunology/Demyelinating Disease Fellowship

2. Objectives • Review basic pathogenesis of multiple sclerosis. • Understand diagnostic criteria • Recognize symptoms of multiple sclerosis • Describe some disease modifying therapies for multiple sclerosis • Review some symptomatic management

3. What is Multiple Sclerosis? • An idiopathic inflammatory/autoimmune demyelinating disease of the CNS (brain, spinal cord, and optic nerves). • Episodes of neurologic dysfunction “disseminated in time and space”. • Most common cause of non-traumatic neurologic disability in young adults.

4. How Does MS Affect the CNS?

5. Epidemiology of MS • New reports suggest there area about 1 million cases in the US. • Higher rates with increasing distance from the equator, especially north. • Rare in black Africans and Asians. • Female:male ratio of 2.5:1 • Peak age of onset is 29yo

6. Environmental Factors • Vitamin D • 1,25 dihydroxyvitamin D (calitriol) derived from D3 is effective in prevention and treatment of experimental autoimmune encephalitis (EAE) - animal model of MS • Many patients with MS are vitamin D deficient and vitamin D levels are lower during relapses. • Several small studies have demonstrated a reduction in relapse rates and +Gdlesions with higher vitamin D levels (> 40). • Smoking • Has been shown to increase rate of conversion from clinically isolated syndrome to clinically definite MS. • Smoking has also been shown increase the likelihood someone develops progressive disease.

7. 2017 Revised Diagnostic Criteria (RRMS)

8. 2017 MRI Criteria • DIS can be demonstrated by 1 T2 lesion in at least 2 of 4 areas of the CNS: • Periventricular • Juxtacortical/Cortical • Infratentorial • Spinal Cord • DIT can be demonstrated by: • A new T2 lesion and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI • Simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time

9. MRI Criteria

10. MRI Criteria

11. CSF in MS • White blood cells may be elevated (<50) with a lymphocytic predominance • Protein may be high, but usually <100 • Oligoclonal bands: • 85-95% of patients with clinically definite MS (CDMS) will have oligoclonal bands (OCB) in the CSF • Positive oligoclonal bands are bands that are found in the CSF, but not identified in the corresponding serum. • Patients with a clinically isolated syndrome and positive OCBs have a higher rate of conversion to CDMS (25% v 9% at 3 years) – hence the inclusion in 2017 criteria for DIT. • OCBs can also be seen in infections such as, subacute sclerosingpanencephalitis, viral encephalitis, Lyme disease and syphilis. • Can also be seen in 7% of normal individuals

12. Presenting symptoms of MS • Sensory in limbs • Weakness • Visual loss • Ataxia • Diplopia • Vertigo • 34% • 22% • 13% • 11% • 8% • 4.3%

13. Overview of symptoms - Optic neuritis • Acute or subacute onset of monocular visual blurring or loss, central blind spot. • Pain with eye movement (90% of patients) • Loss of color vision • May have poor visual acuity, but at least worse than baseline • Afferent pupillary defect • Initial symptom of MS in 13% of patients. • Common during the course of MS (~50% of patients). • The Optic Neuritis Treatment Trial: patients with ON (no other neurologic symptoms) • Randomized to IV steroids, oral steroids or oral placebo • All patients had MRI brain at presentation. • If MRI brain with 1 lesion had 60% chance of MS in 15 years, ≥3 lesions 78% • If MRI brain normal, 25% chance of MS in 15 years • Tx with IV steroids

14. Swinging flashlight test

15. Overview of symptoms • Sensory symptoms • 75% of patients will have some sensory disturbance • can have sensory loss or dysesthesias/pain • Lhermitte’sphenomenon - Electric sensation passing down the back and limbs upon flexion of the neck • Brainstem • Nystagmus, diplopia, intranuclearophthalmoplegia, facial weakness, vertigo, dysphagia, trigeminal neuralgia.

16. Overview of Symptoms • Motor symptoms • upper motor neuron – spasticity, hyperreflexia, atrophy uncommon • spastic paraparesis is common in primary progressive MS. • Cerebellar symptoms • often most disabling • Cognitive • occurs in up to 60% of MS patients on detailed testing. “Subcortical” dementia: information processing, visuospatial, memory, executive dysfunction. • Psychiatric • depression occurs in up to 60% of patients • Systemic • Fatigue!! Very common • Uthoff’s phenomenon

17. Differential Diagnosis • Multiple Sclerosis (MS) • NeuromyelitisOptica (NMO) • Encephalomyelitis (ADEM) • CNS Vasculitis • Lyme Disease • Lupus • Spastic Paraparesis (HTLV-1) • Transverse myelitis • Structural abnormalities/microvascular diseae • Behcet Syndrome • Sarcoid • Sjogren’s • B12 deficiency • Syphilis • Leukodystrophies • Krabbé disease, X-linked ADL, Pelizaeus-Merzbacher disease, Canavan disease, Vanishing White Matter Disease, Alexander disease, Refsum disease, and cerebrotendinousxanthomatosis • PML (JC) • HIV

18. Patterns of MS Relapsing-remitting MS (RRMS) Secondary Progressive MS (SPMS) Primary progressive MS (PPMS) Progressive relapsing MS (PRMS)

19. 2013 descriptions of MS patterns Active defined as new MRI lesions or new clinical relapse

20. 2013 descriptions of MS patterns Active defined as new MRI lesions or new clinical relapse Progression defined as clinical progression of disability

21. Clinically Isolated Syndrome • First neurologic episode lasting > 24 hours caused by inflammatory or demyelinating lesion of the CNS • Can be unifocal or multifocal symptoms • Patients with MRI showing >2 T2 WM lesions are more likely to progress to Clinically Definite MS (CDMS) compared to those with normal MRI

22. Treatment of MS • Acute exacerbations • Steroids - PO methylprednisolone for milder exacerbations. IV methlprednisolone 1 gram IV or prednisone PO 1250mg qDay x 3-5 days if more severe or for optic neuritis. • If very severe can do plasma exchange • Immunomodulatory therapy or disease modifying therapy (DMT) • Symptom and comorbidity management

23. Treatment – Disease modifying therapy

24. Disease modifying therapies

25. Symptomatic treatments • Cognitive – donepezil, memantidine, etc do not benefit MS patients. • “Brain games” • Behavior modifications – lists, reminders, etc. • Tremors – can be disabling • Propranolol, primidone, wrist weights, assistive devices • Ataxia – can be very disabling • Gait training and assistive devices • Fatigue – modafinil, armodafinil, amantadine, and stimulants. • First ensure patient is getting adequate and quality sleep • Treat any underlying depression

26. Symptomatic treatments - Gait • Dalfampridine (Ampyra) • FDA approved to improve walking in patients with MS. It is the only FDA approved symptomatic medication for MS. • In a phase III study it was shown to improve timed walking (faster walking speed over 25 feet in 3 of 4 visits) in 43% of patients v 9% in placebo. • Contraindicated in patients with a history of seizure, CrCl less than 50.

27. Question #1 • 22yo right-handed Caucasian male with no PMHx who presents with 5 days of left eye blurry vision that has progresses to near complete vision loss. • His blurry vision was preceded by a left sided headache which he still has and it has gotten worse. He has pain on eye movements. • Two days ago when driving he notes that red lights no longer looked red. • He reports a history of right leg numbness 1 year ago that resolved after about 2 weeks. He might have had urinary frequency at that time. • On exam his visual acuity is 20/200 left eye, 20/15 right eye, L RAPD, otherwise unremarkable.

28. Question #1MRI brain revealed several ovoid T2 hyperintense white matter lesions located periventricularly, several perpendicularly oriented to the ventricles. No abnormal enhancement in the brain. Enhancement of left optic nerve.What would be needed to meet requirements for a diagnosis of multiple sclerosis? • 1. Nothing, he has had 2 separate events separated in time and space. • 2. Enhancing lesion on MRI to give dissemination in time and lesion in the infratentorial (spinal cord) to give dissemination in space. • 3. Spinal cord lesion to give dissemination in space. • 4. CSF with positive oligoclonal bands to confirm the diagnosis

29. Question #1 Explanation • His right lower extremity symptoms are only self-reported. You have no documented evidence of the symptoms (need at least documented evidence on a prior clinical exam). Therefore, still need to establish dissemination in space (and ideally time, but technically not required). Lesions on MRI brain are only periventricular and all non-enhancing (enhancing optic nerve does not count). CSF studies help establish dissemination in time, not space and by history you have dissemination in time. Reference: Thompson, A.J., Banwell, B.J., Barkhof, F., et. al. Diagnostic Criteria for Multiple Sclerosis: 2017 Revisions to the McDonald Criteria. Lancet Neurol. 2017 Dec 21 [Epub ahead of print]

30. Question #1 • 1. Nothing, he has had 2 separate events separated in time and space. • 2. Enhancing lesion on MRI to give dissemination in time and lesion in the infratentorial (spinal cord) to give dissemination in space. • 3. Spinal cord lesion to give dissemination in space. • 4. CSF with positive oligoclonal bands to confirm the diagnosis

31. Question 232yo female with recently diagnosed MS (after presenting with lower extremity weakness and numbness) comes to your office with 2 days of fever (to 102), diffuse aches, cough, congestion, rhinorrhea, nausea. She was started on Betaseron 3 months ago by her neurologist. On your exam you notice that her right leg is 4/5 with decreased light touch and vibration.What should you do? • 1. Start high dose steroids immediately given her right leg weakness. • 2. Nothing, she probably has been started on an interferon and this is the cause of her fever and flu symptoms. • 3. Check for the flu and treat according. Defer steroids for now. • 4. Send him to her neurologist

32. Question #2 • 1. Start high dose steroids immediately given her right leg weakness. • 2. Nothing, she probably has been started on an interferon and this is the cause of her fever and flu symptoms. • 3. Check for the flu and treat according. Defer steroids for now. • 4. Send him to her neurologist

33. Question #2 - Explanation • It is uncommon for interferons to cause a high fever. In addition, she has been on treatment for 3 months and usually side effects decrease by this point. • Fever can cause Uthoff’s phenomenon and prior symptoms can return. It is likely the fever is causing the worsening MS symptoms. Steroids only help improve symptoms faster and do not impact overall outcome, thus in the setting of a fever, steroids are deferred. Berkovich, R. “Acute multiple sclerosis relapse”. Continuum: Lifelong Learning in Neurology. Ed. S. Krieger. 2016 June;22(3 Multiple Sclerosis):799-814. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group*. Interferon beta-lb in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. Neurology 1995;45:1277-1285.

34. Question # 340 yo female with an 8 year history of MS. She has been previously treated with interferon beta-1b, glatiramer acetate, and dimethyl fumarate. She is currently on fingolimod for the last 18 months. Her last MRI was one month ago and was stable.She overall is doing well, but complains of ongoing difficulty with walking, especially over longer distances. She is currently able to ambulate without assistance, but asks about Ampyra.What should you tell her? • She does not qualify for Ampyra as she ambulates independently. But she needs to change her disease modifying therapy because her walking has declined. • She can use Ampyra as long as renal function and EEG are within normal limits. • If she has no history of seizure, she can use Ampyra. • She can use Ampyra if her timed 25 foot walk is greater than 8 seconds, her renal function is normal, and she does not have seizures.

35. Question #3 • 1. She does not qualify for Ampyra as she ambulates independently. But she needs to change her disease modifying therapy because her walking has declined. • 2. She can use Ampyra as long as renal function and EEG are within normal limits. • 3. If she has no history of seizure, she can use Ampyra. • 4. She can use Ampyra if her timed 25 foot walk is greater than 8 seconds, her renal function is normal, and she does not have seizures.

36. Question #3 - Explanation • Ampyra was studied in patients with a timed 25 foot walk between 8 and 42 seconds with or without assistance. It is contraindicated in patients with a history of seizure or renal impairment. A renal function panel is required prior to use, but an EEG is not. • She does not appear to have disease progression – no mention of change in her exam and her last MRI one month ago was stable. She does not report it is a new problem with her walking, but an ongoing problem. Goodman, A.D., Brown, T.R., Edwards, K.R., et. al. on behalf of the MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502.

37. References • 1. Cree, B. “Diagnosis and differential diagnosis of multiple sclerosis” Continuum: Lifelong Learning in Neurology. Ed. A. Miller. 2010 Oct;16(5 Multiple Sclerosis):19-36. • 2. Di Pauli, F., Reind, M., Ehling, R., et.al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Multiple Sderosis 2008;14:1026-1030. • 3. Sundström, P. and Nyström, L. Smoking worsens the prognosis in multiple sclerosis. Multiple Sclerosis 2008;14:1031-1035. • 4. Ascherio, A., Munger, K.L., Simon, K.C. Vitamin D and multiple sclerosis. Lancet Neurology 2010;9:599-612. • 5. Thompson, A.J., Banwell, B.J., Barkhof, F., et. al. Diagnostic Criteria for Multiple Sclerosis: 2017 Revisions to the McDonald Criteria. Lancet Neurol. 2017 Dec 21 [Epub ahead of print]. • 6. Fisniku, L.K., Brex, P.A., Altmann, D.R., Miszkiel, K.A., et.al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131:808-817. • 7. The Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: Final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65(6):727-732. • 8. Lublin, F. D., Reingold, S. C., Cohen, J. A., et.al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014; 83:278-286.

38. References • 9. Johnson, K.P., Brooks, B.R., Cohen, J.A. et. al. and the Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276. • 10. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group*. Interferon beta-lb in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. Neurology 1995;45:1277-1285. • 11. PRISMS (Prevention of Relapses and Disability by Interferon b-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498-1504. • 12. Kappos, L., Freedman, M.S., Polman, C.H., et. al. for the BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 2009;8:987–97. • 13. Kappos, L., Radue, E.W>, O’Conner, P., Polman, C., et. al. for the FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401. • 14. Cohn, J.A., Barkhof, F., Comi, G., et.al. for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402-415. • 15. Polman, C.H., O’Conner, P.W., Havrdova, E., et.al. for the AFFRIM Investigators. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med 2006;354:899-910.

39. References • 16. Bloomgren, G., Richman, S., Hotermans, G., et.al. Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. N Engl J Med 2012;366:1870-80. • 17. Fox, R. J., Miller, D. H., Phillips, T., et. al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012; 367:1087-97 • 18. Gold, R., Kappos, L., Arnold, D. L., et. al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367:1098-107. • 19. O’Conner, P., Wolinsky, J. S., Confavreux, C., et. al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293-303. • 20. Cohen, J. A., Coles, A. J., Arnold, D. L., et. al. Alemtuzumab versus interferon beta-1a as first-line treatment for patients with relapsing multiple sclerosis: a randomized controlled phase 3 trial. Lancet 2012; 380:1819-28. • 21. Coles, A. J., Tywman, C. L., Cohen, J. A., et. al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial. Lancet 2012; 380:1829-39. • 22. Kappos, L. Wiendl, H., Selmaj, K., et. al. Daclizumab HYP versus interferon beta 1a in relapsing multiple sclerosis. N Engl J Med 2015;373:1418-28. • 23. Goodman, A.D., Brown, T.R., Edwards, K.R., et. al. on behalf of the MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502.