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 1

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
Immuno-fluorescent confocal micrographs showing segmental demylination and axonal swelling in acute MS lesion.
Trapp, 1998 4

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 6

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

8. Natural History of RRMS and PPMS
22 years from onset
5 years
50% need a cane
50% bed bound
15% PPMS
85% RRMS
26 years from onset
50% SPMS and 50% need a cane
90% SPMS
11-15 years
Not completely ascertained cohort.
from longitudinal natural history studies that have been done
50% (majority) will require assistance to walk in 10 years
20-25yrs is important because you are talking about a person who is maybe years old.
30 years from onset
83% need cane
~ 34% bed bound
Weinshenker, 1989

9. CLINICALLY Pathologically Radiographically Rx Response
Isolated Syndrome
Relapsing-
Remitting
Pre- Clinical
Secondary
Progressive
INFLAMMATORY ACTIVITY
Relapses
Atrophy
Active WML
Poor Rx effect
Rx effect
No New WMLs
Inflam dam occurs in early RRMS
Brain dam by recur bouts of inflam even during ‘remission’
Accum disability at least in part 2/2 early active inflam dz
We can treat inflam, At later dz stage, Rx not as effective
PROGRESSION
NEURODEGENERATION
Time (Years)

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 11

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 12

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

14. MS Diagnosis “Dissemination in space and time”14

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 16

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

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

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

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 20

21. CSF Analysis • Most helpful for suggesting an alternative Dx
-high protein, marked pleocytosis, PMNs
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 21

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 22

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 23

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

25. Disease Modifying Therapies: 1993-2002
Glatiramer Acetate
(Copaxone®)
1997
IFN -1b
(Betaseron®)
1993
IFN -1a
(Rebif®)
2002
IFN -1a
(Avonex®)
1996
Type Polypeptide Recombinant Recombinant Recombinant
mixture protein protein protein
Indication Reduce freq. Reduce freq. Reduce freq. Slow prog.
of relapses of relapses of relapses in relapsing
in RRMS Slow Delay forms
disability in disability in Prevent 2nd
relapsing forms relapsing forms attack in CIS
Injection SC SC SC IM
Administration Daily Every other day 3x/week Weekly
Dosage 20 mg 250 g (8 MIU) 44 g 30 g
Immunomodulatory Treatments
The long-term data that was published on glatiramer acetate1 involves a 6-year interim analysis of the ongoing 10-year open-label study. Some 8-year data are available.
An extension of the pivotal North American study of IFN -1b (Betaseron®) provided placebo-controlled data for up to 5 years (median treatment period, 48.0 months).2 More recently, data from the 4-year extension of the PRISMS trial suggest that IFN -1a SC (Rebif®) may be efficacious for up to 4 years.3 No long-term studies (>2 years) have been published describing neurologic outcomes following the long-term use of IFN -1a IM (Avonex®).
1. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Mult Scler. 2000;6:
2. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:
3. The PRISMS (Prevention of Relapses and Disability by Interferon--1a Subcutaneously in Multiple Sclerosis) Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology. 2001;56:

26. Reduction in Relapse Rate:
2 year data from Phase III Studies 70 60 50 40 32
% Reduction vs Placebo 29 30 28
Reduction in Relapse Rate: Phase III Studies
Glatiramer Acetate
The effect of SC administration of glatiramer acetate (20 mg daily) on decreasing the primary endpoint of relapse rate in glatiramer acetate patients (n = 125) and placebo patients (n = 126) was evaluated in a randomized, placebo-controlled trial of RRMS patients. Data were analyzed at 3-month intervals using an ITT analyses using ANCOVA with tests for study-drug-by-center interaction and including the a priori–defined covariates: gender, disease duration (years), prior 2-year relapse rate, and baseline EDSS.
The beneficial treatment effect of glatiramer acetate compared to placebo on decreasing relapse rate at month 3 was 17%, P = NS; at month 6 was 27%, P = 0.074; at month 9 was 25%, P = 0.047; at month 12 was 27%, P = 0.018; at month 15 was 24%, P = 0.034; at month 18 was 27%, P = 0.014; at month 24 was 29%, P = 0.007; and at approximately 30 months was 32%, P =
IFN -1a IM
Number of patients and P values given below are for ITT analyses using the likelihood ratio test done by CBER statistical review.
3-month 6.7% reduction stated in the summary basis for approval for Avonex 1995, on file at FDA, p.18. Annualized relapse rates for placebo patients (n = 142) = 1.04, for IFN-1a IM patients (n = 157) = 0.97, NS.
12-month 9.6% reduction stated in the OWIMS trial paper (Figure 3) by the OWIMS Study group.2 Original source: summary basis for approval for Avonex 1995, on file at FDA, p.18. Annualized exacerbation rates for placebo patients = 0.94, for IFN -1a IM patients = 0.85, so ( )/.94 = 9.57% reduction, NS.
24-month 18.3% reduction is derived from annualized relapse rates of all placebo (0.82) and all IFN -1a patients (0.67) as stated in Table 5 of the Jacobs et al.3: ( )/0.82 = 18.29% reduction, P = Summary basis for approval shows a similar 17.4% reduction (IFN -1a patients 0.673; n = 158; placebo patients 0.815; n = 143, P = 0.039). Jacobs et al. results were analyzed using ITT data assessment with likelihood ratio test.3
Note: Avonex advertises 32% reduction. That comes from a subgroup analysis of the data. Subgroup analysis data (placebo = 0.90 and IFN  -1a = 0.61 annualized relapse rate, 32% reduction P = 0.002) includes only patients who completed the 104 weeks of the trial before it was stopped. 
IFN -1b
Analyses of 12- and 24-month data comes from IFNB MS study group article in Neurology Analyses included a modified intent-to-treat analysis in which all data available for any given patient to the point of study completion or dropout was used.
12-month reduction of 33% comes from Table 1 of the IFNB MS study group article in Neurology Annual exacerbation rates for year 1 listed as 1.44 for Placebo (n = 123) and .96 for IFN-1b patients on 8 MIU (n = 124), P <
24-month reduction of 28% comes from Table 1 of the IFNB MS study group article in Neurology Annual exacerbation rates for year 2 listed as 1.18 for placebo (n = 110) and .85 for IFNB patients on 8 MIU (n=107), P < 0.03.
Note: IFNB MS study group paper in Neurology 1993 (43 p. 657) lists a 33.8% reduction in relapse rate for 24 months (exacerbation rate for placebo patients = 1.27 and for IFN-1b patients 8 MIU = .84, P = ).  
IFN-1a SC
3-month reduction: in promotional materials the following is stated, “32% reduction in relapse frequency seen as early as Month 3 and continuing through Year 2 (1.73 vs 2.56; P < )” Information listed in promotional material as data on file.
12-month reduction of 37% for patients taking 44 ug of Rebif comes from page 1502 of the PRISMS report in Lancet 1998; 352: , P <
24-month reduction reduction of 32% for patients taking 44 ug of Rebif comes from Table 2 on page 1501 of the PRISMS report in Lancet 1998; 352: , P < Note: keep in mind, the percent value for mean relapses per patient listed in promotion material as stated as starting in month 3 is the same as that for 24 months as stated in PRISMs report.
1. Johnson KP, Brooks BR, Ford CC, et al. Onset of benefit of glatiramer acetate (Copaxone®) in patients with relapsing remitting multiple sclerosis (RRMS). ACRTIMS/ECTRIMS, September 2002, abstract 22.
2. The OWIMS (Once-Weekly Interferon for MS) Study Group. Evidence of Interferon B-1a dose response in relapsing-remitting MS: The OWIMS study. Neurology. 1999; 53:
3. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39:
4. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45: 18 20 10
Copxone
Avonex
Betaseron
Rebif

27. DMT Side Effects Glatiramer Acetate Interferons Flu-like symptoms
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
3 patients with confirmed PML :
2 of 1171 MS patients (SENTINEL study: Natalizumab and INFβ-1a IM)
1 of 248 Crohn’s disease patients
Incidence ~1:1000 for PML with Natalizumab
Kleinschmidt-DeMasters, 2005

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

32. High School Football Star
CASE 2
High School Football Star

33. CASE 2 - 16yo AAM, High school Football star
Optic Neuritis, a Clinical Isolated Syndrome
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.

34. CASE 2 “Yes” “We need an MRI and LP” “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
1a=reference category; N1=#pts developing CDMS; N2=#pts fulfilling baseline criteria; HR=hazard ratio adjusted by age, time on Rx, presence of OCB).

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

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

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 ACUTE MS RELAPSE 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

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

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

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 OUTPATIENT 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 Rapidly Worsening MS 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

55. Rapidly Worsening MS Treatment: Intense Immunosuppression
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
GOOD IIS CANIDATE
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
Boster, Lancet Neurology, 2008

58. Boster, Lancet Neurology, 2008
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

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/m2 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
CTX
MITO
Nausea / Alopecia +
Myelosuppression
Amenorrhea
Hemorrhagic Cystitis -
Remote Cancer
+ *
Treatment Related Acute Leukemia
~ 0.23%
Cardiotoxicity
Amenorrhea: reversible in 1/3 women. Perm: 7% women < 35yo; 14% women >35yo
Remote CA: not reported in MS but in Rx of CA and other AI d/o
Cardio: max lifetime dose 140mg/m2. MUGA/ECHO before each infusion.

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

64. 45yo Automotive Executive
CASE 5
45yo Automotive Executive

65. CASE 5 SPMS 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

66. Natural History of RRMS and SPMS
50% SPMS and 50% need a cane
85% RRMS
11-15 years
26 years from onset
90% SPMS
30 years from onset
Not completely ascertained cohort.
from longitudinal natural history studies that have been done
50% (majority) will require assistance to walk in 10 years
20-25yrs is important because you are talking about a person who is maybe years old.
83% need cane
~ 34% bed bound
Weinshenker, 1989 66

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 Wants to become pregnant 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. Pre-pregnancy Counseling
MS not worsened
by pregnancy
Pregnancy not
worsened by MS
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 population
F 0.5 ; M 0.3
Child of MS patient
3-5
Sibling of MS patient 3
Monozygotic twin of MS patient
25-30
Only 10-15% of MS is familial

74. Pregnancy and Relapse Rate
Pre-Pregnancy
Post Partum
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
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. Therapeutic Agents Under Investigation
MECHANISM
ROUTE
PHASE
Rituxan
Anti CD20
IV (2 x year)
Phase II
Campath
Anti CD52
IV (1 x year)
Daclizumab
Anti CD25
IV or SC (q mo)
Anti IL-12
SC (qw or qow)
Statins
immunomodulator
oral
Teriflunomide
Phase III
Anti VLA-4
SAM inhibitor
FTY 720
Oral Cladribine
immunosuppressant
Minocycline
Estriol
MBP 8292
IV (q month)

80. Questions?