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Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments Aaron Boster M.D. Assistant Professor of Neurology Division of Immunology.

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Presentation on theme: "Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments Aaron Boster M.D. Assistant Professor of Neurology Division of Immunology."— Presentation transcript:

1 Practical Neuroimmunology: An update on Multiple Sclerosis Diagnosis and Treatments Aaron Boster M.D. Assistant Professor of Neurology Division of Immunology The Ohio State University

2 Objectives 1. Learn to diagnosis MS 2. Learn to assess the risk of developing MS after a Clinically Isolated Syndrome 3. Become more familiar with MS therapeutics and treatment algorithms

3 Questions: 1. When faced with a clinically isolated syndrome, which tests can help delineate the risk to develop MS? 2. True or False: Starting MS therapies early improves long term outcome. 3. True or False: MS patients have high risk pregnancies.

4 What Is MS? An chronic inflammatory demyelinating disorder of the CNS of uncertain etiology, likely autoimmune, associated with destruction of myelin sheaths and axons Trapp, 1998

5 MS Signs and Symptoms Fatigue Heat intolerance Visual symptoms Numbness, tingling, loss of sensation Weakness Imbalance Urinary and sexual dysfunction Cognitive deficits

6 Epidemiology Peak age 15 to 45 Women : Men 2.5 : 1 Geographic variation USA prevalence 0.1% Approx ½ million MS patients in USA Life expectancy essentially normal Total lifetime cost > $2,200,000

7 PreclinicalRelapsing-remitting Secondary progressive Adapted from Goodkin DE. UCSF MS Curriculum. January 1999. Natural History of Multiple Sclerosis Relapses and impairment cMRI activity (T2, T1+Gd) Axonal loss Measures of brain volume

8 Weinshenker, 1989 15% PPMS 85% RRMS 50% SPMS and 50% need a cane 90% SPMS 11-15 years 26 years from onset 50% need a cane 5 years Natural History of RRMS and PPMS 30 years from onset 83% need cane ~ 34% bed bound 22 years from onset 50% bed bound

9 INFLAMMATORY ACTIVITY NEURODEGENERATION PROGRESSION Relapses Active WML Time (Years) Pre- Clinical Clinically Isolated Syndrome Relapsing-Remitting SecondaryProgressive Rx effect Poor Rx effect No New WMLs CLINICALLYRadiographicallyPathologically Rx Response Atrophy

10 CASE 1 30yo Science Teacher

11 CASE 1 30yo WF science teacher 1year ago, 3 week history of urinary urgency & frequency, one episode of fecal incontinence and bilateral foot numbness with frequent tripping 6 months ago, 2 week history of clumsy gait and poor balance, tremors of the right hand 1 month history of blurry vision with right gaze only

12 CASE 1 EXAM Left intranuclear ophthalmoplegia Hyper-reflexia of the bilateral legs Bilateral upgoing toes (+ babinski) Absent vibration, poor proprioception in feet Mildly dysmetric finger-nose-finger and ataxic fine finger movements R>L + Romberg Ataxic gait

13 CASE 1 Does she have MS? How do we diagnose MS?

14 MS Diagnosis “Dissemination in space and time”

15 Diagnostic Criteria Dawson criteria: 1916 Schumacher criteria: 1965 Poser criteria: 1983 McDonald criteria: 2001 Revised McDonald criteria: 2005 All criteria require dissemination in time and space

16 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! August November

17 New Diagnostic Criteria Incorporate use of MRI Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis August November DIS DIT

18 3 of the following: 9 T2 or 1 Gd+ 3 Periventricular 1 Infratentorial 1 Juxtacortical lesion MRI - Dissemination in Space

19 T2 MRI - Dissemination in Time CIS > 1 month Gd > 3 months Polman, 2005 Gd T2

20 DIAGNOSTIC WORK UP History & Physical Exam Brain and Spinal Cord MRI Labs: rule out mimics of MS –Connective tissue diseases, infections, metabolic disorders Cerebrospinal Fluid (when clinical and MRI evidence inconclusive) Evoked Potentials: –Identify damage to visual, auditory, & touch perception systems – Less sensitive than MRI or cerebrospinal fluid

21 CSF Analysis Elevated IgG Index >0.7 –Increased CNS IgG synthesis, with normal serum IgG consistent with MS Oligoclonal Bands –Presence of  2 distinct bands in CSF is consistent with MS Most helpful for suggesting an alternative Dx -high protein, marked pleocytosis, PMNs

22 CSF OCB are not specific to MS! Lupus 25% Sarcoidosis 51% Behcet’s dz 8% Syphillis CJD Whipple’s disease Lyme disease Vaculitidies Devic’s disease Healthy siblings of MS patients adapted from a lecture by Peter Riskind MD PhD 11/19/05

23 Differential Diagnosis Metabolic: SCD (B12 def), Adrenomyeloneuropathy Connective Tissue Diseases: Sjogren’s, SLE Infectious: HIV, HTLV1, Lyme disease, Syphillis Structural: Chiari malformation, spinal cord compression Genetic: ataxias, paraplegias, mitochondrial Neoplastic: CNS lyphoma, paraneoplastic “MS variants”: ON, TM, ADEM, NMO Other: Neurosarcoidosis, CNS vasculitis Psychiatric

24 CASE 1 > 2 historical events with objective findings on examination MRI consistent with MS Normal “rule out labs” CXR normal NEWLY DIAGNOSED RRMS

25 Disease Modifying Therapies: 1993-2002 IFN  -1a (Avonex ® ) 1996 IFN  -1a (Rebif ® ) 2002 IFN  -1b (Betaseron ® ) 1993 Glatiramer Acetate (Copaxone ® ) 1997 Type PolypeptideRecombinant RecombinantRecombinant mixture protein protein protein Indication Reduce freq. Reduce freq. Reduce freq.Slow prog. of relapses of relapses of relapses in relapsing in RRMS SlowDelay forms disability indisability in Prevent 2 nd relapsing forms relapsing forms attack in CIS Injection SC SC SC IM Administration DailyEvery other day3x/week Weekly Dosage 20 mg 250  g (8 MIU) 44  g 30  g

26 0 10 20 30 40 50 % Reduction vs Placebo Reduction in Relapse Rate: 2 year data from Phase III Studies 28 Betaseron 32 Rebif 18 Avonex 29 Copxone 60 70

27 DMT Side Effects Glatiramer Acetate Injection Site Reactions Idiopathic Injection Reactions Interferons Flu-like symptoms Liver dysfunction Bone marrow Endocrine abnormalities Other: –Depression –Spasticity –Headaches

28 Natalizumab Humanized monoclonal Antibody against  4  1 integrin Selective adhesion-molecule inhibitor (SAM) Prevents transendothelial migration of activated leukocytes from small venules into CNS

29 “68% relative reduction in the annualized rate of relapse produced by natalizumab was maintained at two years (P<0.001)”

30 Kleinschmidt-DeMasters, 2005

31 Second Line Agents When a patient has failed or is otherwise unable to tolerate IFN and GA –Tysabri –IVIG

32 CASE 2 High School Football Star

33 CASE 2 - 16yo AAM, High school Football star History: Woke blind in left eye, complains of pain with extra occular movements Exam: Va OD 20/20, OS 20/200. Left disk pallor, Left Afferent pupillary defect. Optic Neuritis, a Clinical Isolated Syndrome

34 CASE 2 “Can I still play football?” “What is my son’s risk of developing Multiple Sclerosis?” “Yes” “We need an MRI and LP”

35 CASE 2




39 415 CIS pts with MRI & CSF and 50 month follow-up +OBC doubled conversion risk to CDMS, independent of MRI findings

40 Optic Neuritis, CIS MRI Brain & C spine CSF: IgGI, OCB, W,R,G,P IVMP 1gm daily x 5 days WHAT ABOUT EARLY DMT?

41 placebo Avonex, Rebif, Betaseron, or Copaxone Time to Second Attack Delayed with Treatment First ever attack CHAMPS, ETOMS, BENEFIT, PRECISE STUDIES Second attack



44 CASE 3 26yo IRS agent

45 CASE 3 26yo LH WF with RRMS diagnosed 2yrs ago 3 day history of difficulty writing, clumsy and numb left hand No signs/symptoms of infection No prior history of similar symptoms

46 CASE 3 IO & FE 4/5 on left hand Hyper reflexia of left arm Ataxic FFM & dysmetric FNF on left Decreased LT on left face, arm, leg ACUTE MS RELAPSE

47 Expanded Disability Status Scale CASE 3 EDSS=0 last 3 visits

48 Expanded Disability Status Scale CASE 3 Current EDSS=3 Acute MS Relapse

49 HOW TO IDENTIFY A RELAPSE? CRITICAL, compare with previous examinations (history and examination), when ever possible Relapses can be precipitated by infections and fever –Check U/A for occult UTI

50 TREATMENT OF RELAPSE INPATIENT –Severe deficits –Risk of fall or other injury –Poor social support OUTPATIENT –All other relapses

51 TREATMENT OF RELAPSE: IV Solumedrol one gram daily for 5 days Severe cases: up to 2 grams qd x 7d Oral Prednisone for special circumstances –poor veins, insurance issues, travel, etc…

52 TREATMENT OF RELAPSE: PLASMAPHERESIS Severe relapses not responding to steroids 5 to 7 courses done on alternate days for 2 weeks One course takes place over 3 to 4 hours

53 CASE 4 27yo Apartment Manager

54 CASE 4 27yo F diagnosed with RRMS 5 years ago DMT with Rebif since diagnosis Suffered 3 MS relapses in past 15 months –each treated with Solumedrol –Incomplete recovery of cerebellar and pyramidal function EDSS 1 year ago was 2.5, now 5.5 Rapidly Worsening MS

55 Documented worsening corresponding to >3 point EDSS increase in previous 12 months despite at least 6 months of IMT and at least 2 courses of IVMP Treatment: Intense Immunosuppression

56 Rationale for Intense Immunosuppression in Rapidly Worsening MS Inflammatory damage occurs during early RRMS Permanent tissue damaged from recurrent bouts of inflammation, even during the silent periods of so-called remission Accumulated disability is at least in part secondary to early active inflammatory disease We can treat inflammation During later disease stages, there is no / less inflammation and our treatments are not effective

57 Boster, Lancet Neurology, 2008 0 GOOD IIS CANIDATE 1.Active progression over past several months or frequent severe relapses 2. Age < 40 3. Ambulatory 4. Earlier disease course (RRMS or early SPMS) 5. Incomplete recovery from relapses 6. Frequent relapses leading to disability 7. Persistence of multiple Gd+ MRI lesions

58 POOR IIS CANIDATE 1. Age > 50 2. Long-standing, stable disability -Predominantly motor or cerebellar deficits -Non-ambulatory status 3. Significant spinal cord atrophy 4. Significant other medical problems Boster, Lancet Neurology, 2008 0

59 Pulsed IVMP May attempt to “stabilize” disease course 1gram IVMP q15-30 days x 3-6 months CRITICAL to have close follow-up and document objective changes on exam

60 MITOXANTRONE Chemotherapy drug used to treat a variety of cancers since 1987 FDA approved for progressive forms of MS or worsening RRMS 12 mg/m 2 q 3 months, many other regimens

61 CYCLOPHOSPHAMIDE Chemotherapy agent Also used in other autoimmune disease Monthly IV infusion as an outpatient

62 Adverse RXN and Complications CTXMITO Nausea / Alopecia++ Myelosuppression++ Amenorrhea++ Hemorrhagic Cystitis+- Remote Cancer+ *- Treatment Related Acute Leukemia -~ 0.23% Cardiotoxicity-+

63 Natalizumab Not been studied in rapidly worsening MS Extrapolate data from Phase II and AFFIRM trials Risk of PML

64 CASE 5 45yo Automotive Executive

65 CASE 5 45yo RH M with 13yr history of MS DMT with Glatiramer Acetate Last MS relapse 7 years ago Ambulation: –Cane 4 years ago –Walker 3 years ago –Wheelchair 1 year ago SPMS

66 Weinshenker, 1989 85% RRMS 50% SPMS and 50% need a cane 90% SPMS 11-15 years 26 years from onset Natural History of RRMS and SPMS 30 years from onset 83% need cane ~ 34% bed bound

67 Treating SPMS No treatment has been shown to be helpful UNLESS the patient still has superimposed relapses


69 Treating PPMS PROMiSe trial post hoc analysis Glatiramer Acetate slowed progression of disease in men with earlier disease IVIG –Delayed progression by 12 wks vs PCB (Pohlau, 2007) –Results need to be confirmed Consider challenge with steroids or IIS if relatively rapid decline in ADLs

70 CASE 6 36yo Physician

71 CASE 6 36yo WF with 4yr history of RRMS Betaseron for past 3.5 years Last MS relapse 1 year ago EDSS 2, unchanged for past year Wants to become pregnant

72 MS not worsened by pregnancy by pregnancy Pregnancy not worsened by MS Pre-pregnancy Counseling No differences in Prenatal Care MS has no known effect on fertility “High Risk” should be determined on obstetrical status and disease activity Little evidence to support increased risk of relapse with anesthesia administration Closely monitor for urinary tract infections

73 Pre-pregnancy Counseling Lifetime Risk of MS (%) General populationF 0.5 ; M 0.3 Child of MS patient3-5 Sibling of MS patient3 Monozygotic twin of MS patient 25-30 Only 10-15% of MS is familial

74 Pregnancy and Relapse Rate Pre-PregnancyPost Partum Pregnancy PRIMS, n=254

75 Pre-Pregnancy Planning Planned Pregnancy Discontinue DMT 1-2 menstrual cycles before planned conception Brain MRI Scan Unplanned Pregnancy First Trimester: Discontinue DMT Second Trimester: Review safety data

76 Relapses During Pregnancy Risk-Benefit Assessment: severe motor, sensory or cerebellar deficits that affect ambulation IV Solumedrol (Cat C) Plasmapheresis IVIG (Cat C)

77 DMT During Pregnancy Insufficient data to support use of DMT during pregnancy Interferons (Cat C, Abortifactant) Glatiramer acetate (Cat B) IVIG? (Cat C)

78 Post-Partum Management Post-Partum DMT Resume soon after delivery or after breastfeeding Breastfeeding Not contraindicated –But DMT pass into breast-milk May decrease relapse rate Post-Partum Relapses (~30%) Treat with IVMP (PE or IVIG) –IVMP may impair wound healing –? Prophylaxis with IVIG

79 AGENTMECHANISMROUTEPHASE Rituxan Anti CD20 IV (2 x year) Phase II Campath Anti CD52 IV (1 x year) Phase II Daclizumab Anti CD25 IV or SC (q mo) Phase II Anti IL-12 SC (qw or qow) Phase II Statinsimmunomodulatororal Teriflunomideimmunomodulatororal Phase III Anti VLA-4 SAM inhibitor oral Phase III FTY 720 immunomodulatororal Phase III Oral Cladribine immunosuppressan t oral Phase III Minocyclineimmunomodulatororal Phase II Estriolimmunomodulatororal MBP 8292 immunomodulator IV (q month) Phase III Therapeutic Agents Under Investigation

80 Questions?

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