1
MS Patient Cases
Iran
May 2007
Jack Burks, MD
Clinical Professor, Neurologist
University of Nevada School of Medicine
Re...
2
Important Issues in Treating MS:
Illustrative Patient Cases
 When to start therapy?
 How to decide on which therapy is...
9
Patient 1:
Deciding When to
Initiate Treatment
10
Patient 1: Deciding When to
Initiate Treatment
 History

26-year-old secretary, mother of twins; no history of MS
or ...
11
Patient 1: Deciding When to
Initiate Treatment
 MRI

6 periventricular lesions, 1 pontine lesion, 1 high
cervical les...
12
Neurologist’s Assessment
 Patient had a CIS but does not meet the
criteria for CDMS, could be ADEM
 Steroids should b...
13
Treat Early! Diagnosis of MS
in Clinical Isolated Syndrome (CIS)
Lesions in Time and Space
Clinical Presentation Space ...
14
McDonald MRI Criteria for
Dissemination in Time
 First scan ≥3 months after clinical event

New Gadolinium lesion
• M...
15.
Example Application of
New Diagnostic Criteria
≥3 months
T2
Gd
16
Polman Revision of
McDonald Criteria (2005)
 New T-2 MRI lesions at 1 month after
CIS MRI (lesions in time)
 Spinal c...
17
Patient 1: Follow-up
 After being treated with a course of IV
Solu-Medrol, the patient’s symptoms
improved
 At a 3-mo...
18
Neurologist’s Assessment at
Follow-up
 Patient meets the McDonald criteria for
CDMS/RRMS
 The patient was started on ...
19
Patient was treated with IFNβ-1b
 BENEFIT Trial
 17 year follow-up data
 AAN Treatment Guidelines
20Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversio...
21
Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversi...
22
28%
45%
Placebo
Betaferon
Risk reduction* of
50% over 2 years
(Hazard ratio= 0.5)
*by adjusted proportional hazards reg...
23
28%
45%
Placebo
Betaferon
25%
+ 363 days: + 142%
Day 255 Day 618
Betaferon Delayed the Onset
of CDMSClinicallyDefiniteM...
24
Most Patients Develop MS by
MRI Criteria Within 2 YearsMcDonaldMS(%)
days
MRI MRI MRI MRI MRI MRIMRI
Placebo
51%
85%
Th...
25
Betaferon Doubles the Probability
of Not Developing MS
 Cumulative probability for patients not to develop
MS accordin...
26
BENEFIT Trial: Early vs. Delayed
Treatment: 3 year follow-up (2007)
 Confirmed Progression (EDSS)

Placebo then Betaf...
27
The BENEFIT Study. Betaferon®
in newly emerging multiple sclerosis for initial treatment: Clinical results [poster].
BE...
28
Lessons from BENEFIT Trial
 Placebo patients studied in BENEFIT had a high risk
of progressing to MS according to the ...
29
17 year follow-up Rationale
 IFNB-1b was approved for the treatment of relapsing forms of
multiple sclerosis (MS) base...
30
Credibility factors in Betaferon 17
year follow-up data
 Positive:

Independent analysis

Intent to treat analysis: ...
31
*Versus patients on other DMTs or no treatment.
Goodin DS, Ebers G, Traboulsee A, et al, for the Betaferon®
LTF Study g...
32
Betaferon 17-Year LTF:
Mortality Data by treatment group
 Betaferon standard dose (n=124) 6%
 Betaferon lower dose (n...
33
Using Evidenced Based
Medicine to Guide MS Therapy
AAN Guidelines
Cochrane Committee Reports
Head to Head Class I Tr...
34Goodin DS, et al. Neurology. 2002;58:169-178.
Evidence-based Medicine:
AAN Guidelines
35
AAN Guidelines on DMT’s
1) Relapses and MRI
• All better than placebo (A)
1) Disability Progression
• Interferons: Prob...
36
Patient 2:
Evaluating the
Response to Disease
Modifying Therapy
(DMT) in MS
37
Patient 2: Evaluating
Response to DMT
 Current complaint

28-year-old surgical resident with RRMS

Recently develope...
38
Patient 2: Evaluating Response
to DMT (Cont.)
 Past Neurological History

3.5 yrs ago: first symptom (unsteadiness of...
39
Patient 2: Evaluating
Response to DMT (Cont.)
 Current evaluation:

Neuro Exam Normal: Possible depression?

MRI: No...
40
Neurologists Assessment
 Since IFN B-1b, this patient has had only
one episode of (likely) mild optic neuritis –
short...
41
Neurologist’s Action Plan
 Patient should remain on IFN B-1b
 Treat symptomatically for fatigue &
depression
 Patien...
42
Questions
What is the utility of NAb testing in this
clinically stable patient?
What will be the patient’s response t...
43
Comments
 There remain differences of opinion regarding the
use NAb testing. 2007 AAN guidelines using EBM
principles ...
44
Neutralizing Antibodies to
Interferon B-1b are not
Associated with Disease
Worsening in Multiple Sclerosis
Goodin DS., ...
45
NAb Results:
6698 Patients
 Australia: All Patients on IFNβ-1b

37% NAb positive
 North America: Suboptimal Responde...
46
Conclusions:
 Poor responders were less likely to
have NAbs than responders
 NAbs are not responsible for poor
clinic...
47
Evaluating Response to DMT:
Patient 2 Follow-up
 6 months later she was NAb Θ on retest
 The patient has remained on ...
48
Patient 4:
Managing Side
Effects of DMT's
49
Patient 4:
Managing Side Effects of DMT’s
34 yr old RRMS patient has been on IFN B-1b for 4
months
Neurologically sta...
50
Neurologist’s Assessment
 Since beginning therapy she has had no
relapses or new MRI lesions
 Side effects are caused...
51
Neurologist’s Actions
 Drug holiday for one month
 Re-start IFN B-1b at ¼ dose and titrate to ½,
then ¾ and then full...
52
Patient 4: Outcome
 At 1 year patient tolerated treatment well
with very few side effects and no
recurrence of depress...
53
Patient : Discussion
 Drug side effects may mimic worsening
of MS
 Proper initiation of therapy prevents
most early s...
54
Patient 5:
Evaluating Possible
Treatment Failures
55
Patient 5: Deciding When
Treatment Is Not Working
 A 43-year-old patient seeks a second opinion
 5-year history MS
 ...
56
Patient 5: Summary of Disease
Course
 A 43 yr old salesman is referred to you for a second opinion
 Case history
2002...
57
Neurologist’s Assessment
 The initial diagnosis of RRMS was correct
 The patient had 4 exacerbations during the
3 yea...
58
Questions Raised by Patient 5
 Was DMT started at the right time?
 What did his NAb test results mean?
 When did thi...
59
Patient 5: Summary of Disease
Course
 A 43 yr old salesman is referred to you for a second opinion
 Case history
2002...
60
Deciding When Treatment Is
Not Working: Discussion
 To provide optimal, care one must be
prepared to change treatment ...
61
Differential Diagnosis for
Worsening Symptoms on DMT's
1. Poor compliance (common)
2. Side effects of DMT’s
3. Co-morbi...
62
Identifying SORs:
Ongoing documentation is critical
 Relapses
 Progression of Disability
 New MRI lesions (GAD lesio...
63
SOR: When to think about
changing treatment?
1. Major relapse
2. 2 minor relapses in one year (Documented)
3. EDSS prog...
64
SOR: When to think “Why should
I NOT Change treatment?”
1. 2 major relapses in one year
2. Documented further EDSS prog...
65
Management of SOR
Data is incomplete: Little EBM data:
“Therapeutic Window” is closing
 Increase dose/frequency within...
66
Managing SOR on Avonex
Increase Dose

Double Dose weekly: Negative results
Increase frequency

Give every 2-4 days,...
67
INdependent COMparison of INterferon
(INCOMIN)
Trial Study Group
Durelli et al. Lancet 2002, 359:1453-60
A Multicenter ...
68
Betaferon vs. Avonex
The INCOMIN Trial
Results: First 24 Months
Avonex Betaferon
(n=92) (n=96) % ∆ p
T2 Lesion Free (0-...
69
The EVIDENCE Trial
Head-to-head, randomized, open label,
evaluator-blinded comparison of Rebif (44
mcg tiw SC) with Avo...
70
Summary Efficacy at Week 24
and Week 48
Week 24 Week 48
p-value Relative
improvement
p-value Relative
improvement
Odds ...
71
Avonex to Rebif Switch Trial
Annualized Relapse Rate
Final Comparative Phase vs Posttransition Phase
Panitch H. Neurolo...
72
Managing SOR on Avonex
 Increase Dose

Double Dose weekly: Negative results
 Increase frequency

Give every 2-4 day...
73
Managing SOR on Betaferon
 Increase Dose: Reasonable Pilot data: Well tolerated

OPTIMS Trial

BEYOND Trial
 Switch...
74
INdependent COMparison of INterferon
(INCOMIN)
Trial Study Group
Durelli et al. Lancet 2002, 359:1453-60
A Multicenter ...
75
Dose-Reduction Study
Betaferon®
to Avonex®
Switch Trial
Avonex®
Betaferon®
Exacerbation rate .09* .02*
% of patients wi...
76
Managing SOR on Betaferon
 Increase Dose: Reasonable Pilot data: Well tolerated

OPTIMS Trial

BEYOND Trial
 Switch...
77
Managing SOR on Rebif
 Increase Dose: No data: Not very practical
 Switch to Betaferon: No data: Maybe easier
to give...
78
Managing SOR on Copaxone
 Increase dose? Double dose: positive PILOT data
 Switch to Interferon: No EBM data: Most po...
79
Other SORs Treatment Options
Immunosuppression:
 Mitoxantrone (Novantrone)

For worsening MS (RRMS and SPMS)

Approv...
80
Other SOR Options
 Pulses Methylprednisolone (I.V., monthly)
 Methotrexate (oral, weekly)
 Azathioprine (Imuran) (or...
81
Summary & Conclusions:
SOR Diagnosis
 SORs are common (30% or greater) but are
under diagnosed
 Is patient Compliant ...
82
Summary & Conclusions:
SOR Treatment
 Little EBM data but therapeutic window
closing: Options include:
1. Increase dos...
83
What is New?
Current and Emerging Therapies
84
A. Betaferon
1. BENEFIT Trial in CIS
2. 17 Year Follow up data
3. Betaferon vs. Double Dose
Betaferon vs. Copaxone
85
B. Rebif
1. Reformulated Rebif
2. Rebif vs. Copaxone
3. Rebif in CIS
4. Cladribine Induction before Rebif
5. Rebif vs. ...
86
C. Copaxone
1. Copaxone in Primary Progressive MS:
Discouraging
2. Double Dose Copaxone in RRMS:
Encouraging
3. Copaxon...
87
D. Natalizumab (Tysabri)
1. Natalizumab vs. Placebo in RRMS
2. Natalizumab vs. Avonex
3. The PML issue
88
Oral Therapies
 May improve convenience and
compliance in MS therapy
 Oral therapies now in phase 3 trials may
be ava...
89
Monoclonal Antibodies
(MAbs): Background
 MAbs offer more favorable dosing regimens
compared with current MS therapies...
90
MAbs: Conclusions
 Some striking efficacy results with
MAbs in MS
 Safety concerns must be allayed before
MAbs are wi...
91
Other Emerging Treatments
 Fingolimod (oral)
 Campath (yearly)
 MBP82-98 (6 months)
 Rituximab (B-cell AB) (? PML)
...
92
Other Treatment Approaches
 Stem cells (bone marrow and embryonic)
 Remyelinating agents
 Neuroprotective agents
93
Patient 5A:
Management of
Suboptimal Responders
to both low and high
Dose Interferons
94
Patient 5A
39 year old male with very active RRMS for
3 years. He averages 2 attacks per year for
all three years with ...
95
Patient 5A
He is stable between attacks, but ongoing
MRI activity is present. His exam reveals a
bilateral intramuscula...
96
Patient 5A
 What is your best treatment option
1. Keep on Rebif but double the dose
2. Get an NAb test and stop Rebif ...
97
Patient 5B
A 36 year old lady from Sari with
severe MS wants a child
 36 year old, married11 years, MS started
9 years...
98
Sari MS patient
 Relapse after 4 months, Treated with IV steroids and
improved back to “normal”
 Treated with Betafer...
99
36 year old Sari patient
 Brief Exam reveals tearful lady with only
slight movement in legs in a wheelchair
 Spastici...
100
36 year old Sari patient
 Meds include
Numerous vitamins
Baclofen
St John wort
Amantadine
 MRI : 2003 Many T2 lesion...
101
Issues for Sari patient
 Early Treatment value
 Problems with Adherence to Betaferon
 Chemotherapy in lady who want...
102
36 Year old Sari patient:
My thoughts on Treatment
 Must treat relapse immediately with IV steroids!
 If failure, tr...
103
Patient 6:
The Dilemma of
“Asymptomatic” MS
104
Patient 6
24 year old female with bitemporal throbbing
“migraine” headaches associated with nausea,
vomiting for 4 yea...
105
Patient 6
Her neurological exam was normal. MRI
was done to rule out Meningioma,
Aneurysm, or Arterial-venous malforma...
106
Patient 6
She comes to you for a second opinion:
1. Does she have MS? (or something else?)
2. Should she have an L.P.,...
107
Patient 6
 What is your Differential Diagnosis?
 How would you work up and treat this
patient?
108
Patient 6
Differential Diagnosis
 Collagen vascular
disease (SLE)
 CADASIL
 Thyroid disease
 Hypoglycemia
 Vitami...
109
Patient 6
Evaluation for MS:
Diagnosis and Progression
 Clinical history and exam best
 Ancillary tests

MRI

CSF
...
110
Patient 6
Her evoked potential tests, ANA, Sed Rate,
thyroid screen, VDRL, and other screening
tests are normal. She h...
111
Patient 6
 Would you diagnose MS?
 Would you treat with Steroids?
 Would you treat with Interferons?
 Would you tr...
112
Patient 6
 She was not given the diagnosis of MS
and was not treated
113
Patient 6
 If she had an identical twin with MS, would
that change your opinion?

Identical twins have a 30% concord...
114
Patient 6
 One year later, she remained
asymptomatic with a normal exam, but a
repeat MRI showed 2 new T-2 lesions, b...
115
Patient 6
 She was not diagnosed as MS and was
not treated
116
Patient 6
 One year later she had an episode of numbness on
left arm and leg along with fatigue and ataxia. Her
MRI r...
117
Patient 6
 She was diagnosed as MS and treated with
steroids and Interferon β-1b with no further
attacks in 5 years o...
118
Patient 7:
Differentiating MS,
Neuromyelitis Optica
(DEVIC’s), and Asian
Optica-spinal MS
119
Patient 7
18 year old Asian male presented with
decreased vision in right eye over 3 days with
pain on eye movement: o...
120
Patient 7
Babinski test was positive bilaterally, DTR’s
were very active with transient clonus at At
ankles. CSF tests...
121
Patient 7
 What is the most likely diagnosis?
1. Classical MS
2. Asian MS (optic-spinal MS)
3. Neuro myelitis optica ...
122
Neuromyelitis Optica
Optic-Spinal MS
Recurrent Optic
Neuritis
Recurrent Myelitis
123
Spectrum of MS:
Neuromyelitis Optica (DEVIC's)
 NMO

Gender predilection: Female to Male ~10:1

Onset in all ages
...
124
Spectrum of MS:
Optic-Spinal Multiple Sclerosis
 OSMS (Asia)

Gender predilection: Female to Male ~3:1 or more

Eth...
125
Spectrum of MS
Recurrent Optic Neuritis
 If Brain and Spinal cord MRI normal

CDMS less likely

BUT may convert to ...
126
Spectrum of MS
Recurrent Myelitis
 If brain MRI normal, unlikely CDMS
 If NMO Antibodies +, may be NMO
 Treat with ...
127
Patient 7
 Patient was diagnosed as DEVIC’S (NMO)
 He was treated with IV steroids only. He
recovered considerable f...
128
Patient 7
 Eight months later has another episode
with decreased vision in left eye and
numbness from his mid chest t...
129
Patient 7
 How would you treat him?
1. No treatment
2. IV Steroids
3. Interferon
4. Azathioprine
5. Mitoxantrone
6. R...
130
Patient 7
 He was treated with IVMP and
Aziathiaprine. He had 2 more attacks
within the next 18 months, which left hi...
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Patient 1: Deciding When to Initiate Treatment

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Patient 1: Deciding When to Initiate Treatment

  1. 1. 1 MS Patient Cases Iran May 2007 Jack Burks, MD Clinical Professor, Neurologist University of Nevada School of Medicine Reno, Nevada Vice President/Chief Medical Officer Multiple Sclerosis Association of America President Multiple Sclerosis Alliance
  2. 2. 2 Important Issues in Treating MS: Illustrative Patient Cases  When to start therapy?  How to decide on which therapy is the most effective for a specific patient?  How should patients be monitored to determine good/poor Rx. responses?  What is a poor response to treatment and how should it be managed?  How are side effects best managed?  What is the future for current and emerging therapies?
  3. 3. 9 Patient 1: Deciding When to Initiate Treatment
  4. 4. 10 Patient 1: Deciding When to Initiate Treatment  History  26-year-old secretary, mother of twins; no history of MS or SLE  Over 5-day period notices double vision, weakness in the right arm and leg, unsteady gait, fatigue, and difficulty with memory when multitasking  Exam  Diplopia on right gaze, mild right hemiparesis, and wide-based, slightly ataxic gait  Normal bedside mental status  Husband stresses patient’s recent disorganization
  5. 5. 11 Patient 1: Deciding When to Initiate Treatment  MRI  6 periventricular lesions, 1 pontine lesion, 1 high cervical lesion on T2 MRI  4 GAD+ lesions  Lab work  All negative  Spinal tap not done
  6. 6. 12 Neurologist’s Assessment  Patient had a CIS but does not meet the criteria for CDMS, could be ADEM  Steroids should be used in this patient, but a DMT is not appropriate at this stage  Is this the appropriate diagnosis?  What goes into the decision process to determine the appropriateness of utilizing a DMT?
  7. 7. 13 Treat Early! Diagnosis of MS in Clinical Isolated Syndrome (CIS) Lesions in Time and Space Clinical Presentation Space Time (Add’l Requirements) (Add’l Requirements) 2 attacks; 2 locations No No 2 attacks; 1 location MRI abnormal or No 2 MRI lesions + CSF 1 attack; 2 locations No MRI ≥3 months or second attack 1 attack; 1 location (CIS) MRI abnormal or MRI ≥3 months 2 MRI lesions + CSF or second attack Ref: McDonald, I. Annals of Neurology 2002
  8. 8. 14 McDonald MRI Criteria for Dissemination in Time  First scan ≥3 months after clinical event  New Gadolinium lesion • Must not be the same site  No new Gadolinium lesion: • Repeat MRI at ≥3 months  New T2 or gadolinium lesion McDonald WI et al. Ann Neurol. 2001;50:121-127. The exact relationship between MRI findings and clinical status of patients is not completely understood.
  9. 9. 15. Example Application of New Diagnostic Criteria ≥3 months T2 Gd
  10. 10. 16 Polman Revision of McDonald Criteria (2005)  New T-2 MRI lesions at 1 month after CIS MRI (lesions in time)  Spinal cord lesions can be considered as a brain infratentorial and, if Gd- enhancing, can substitute for a brain Gd-enhancing lesion Polman CH et al. Ann Neurol. 2005;58:840-846.
  11. 11. 17 Patient 1: Follow-up  After being treated with a course of IV Solu-Medrol, the patient’s symptoms improved  At a 3-month follow-up visit:  Clinical signs resolved  Fatigue and memory problems less  Neurology exam normal  Previous GAD+ lesions had resolved  1 new GAD+ lesion and 2 new T2 lesions
  12. 12. 18 Neurologist’s Assessment at Follow-up  Patient meets the McDonald criteria for CDMS/RRMS  The patient was started on treatment  Do you agree with decision to treat?  How do you decide which DMT to utilize in this situation?  Is there a difference or are they all the same?  What do Evidence Based Medicine Analysis and Class I Head to Head Trial indicate?
  13. 13. 19 Patient was treated with IFNβ-1b  BENEFIT Trial  17 year follow-up data  AAN Treatment Guidelines
  14. 14. 20Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242-1249. II. BENEFIT: Betaferon in CIS  Objective:  To assess efficacy, safety, and tolerability of every-other-day (EOD) interferon beta-1b treatment in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis  Study design:  Randomized, double-blind, placebo-controlled, parallel-group, multicenter study with 468 patients  Participants had experienced a first clinical demyelinating event, and at least 2 clinically significant MRI-detected brain lesions  Patients received Betaferon 250 µg or placebo SC EOD for 24 months or until CDMS  Primary endpoints:  Time to CDMS according to the modified Poser criteria  Time to diagnosis of MS according to McDonald diagnostic criteria
  15. 15. 21 Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242-1249. Design of the BENEFIT study
  16. 16. 22 28% 45% Placebo Betaferon Risk reduction* of 50% over 2 years (Hazard ratio= 0.5) *by adjusted proportional hazards regression days p<0.0001 Betaferon Reduced the Risk of CDMS by clinical criteria ClinicallyDefiniteMS(%)
  17. 17. 23 28% 45% Placebo Betaferon 25% + 363 days: + 142% Day 255 Day 618 Betaferon Delayed the Onset of CDMSClinicallyDefiniteMS(%) days
  18. 18. 24 Most Patients Develop MS by MRI Criteria Within 2 YearsMcDonaldMS(%) days MRI MRI MRI MRI MRI MRIMRI Placebo 51% 85% The BENEFIT Study Group
  19. 19. 25 Betaferon Doubles the Probability of Not Developing MS  Cumulative probability for patients not to develop MS according to McDonald Criteria over 2 years 15% 31% 0% 10% 20% 30% 40% 50% Placebo Betaferon Cumulativeprobability Placebo (n= 176) Betaferon (n= 292) 2 x The BENEFIT Study Group P<0.00001
  20. 20. 26 BENEFIT Trial: Early vs. Delayed Treatment: 3 year follow-up (2007)  Confirmed Progression (EDSS)  Placebo then Betaferon 24%  Betaferon from CIS 16%  40% decrease of confirmed progression with early Betaferon treatment! (P=0.02)  No effect of NAbs on clinical outcomes
  21. 21. 27 The BENEFIT Study. Betaferon® in newly emerging multiple sclerosis for initial treatment: Clinical results [poster]. BENEFIT study: Discontinuation rates  Only 2.7% of Betaferon patients discontinued due to adverse events*  The majority of patients experienced no flu-like symptoms over 2 years Factors for low rate of discontinuation include:  Dosage Titration  Analgesics: before injection *From an analysis of patients who adhere to study protocol.
  22. 22. 28 Lessons from BENEFIT Trial  Placebo patients studied in BENEFIT had a high risk of progressing to MS according to the McDonald criteria  85% within 2 years, 51% after 6 months  In the BENEFIT study, every-other-day Betaferon significantly  Reduced the risk of progression to CDMS (by 50%)  Prolonged the time to CDMS by 1 year (+142%) (based on the 25th percentiles)  Delayed EDSS disability scores at 3 years  Every-other-day Betaferon is well tolerated and well accepted in patients
  23. 23. 29 17 year follow-up Rationale  IFNB-1b was approved for the treatment of relapsing forms of multiple sclerosis (MS) based on the results of a double-blind placebo-controlled study in which patients received placebo or IFNB-1b for 104 weeks and were followed up for up to 5 years  Results of this pivotal study showed IFNB-1b to be effective and well tolerated over this period  There are few data regarding the long-term benefit of IFNB treatment for more than 10 years. However, given that MS evolves over several decades, there is a need for longer-term data on treatment outcomes  This study assessed the long-term impact of IFNB-1b therapy in patients involved in the pivotal study Ebers, George 2007
  24. 24. 30 Credibility factors in Betaferon 17 year follow-up data  Positive:  Independent analysis  Intent to treat analysis: treated vs. placebo • About 90% case ascertainment • Betaferon effective and safe for 17 years  Concerns:  Unknown treatment modalities for some patients after trial ended  High rate of mortality in placebo group after trial ended. Is untreated MS a potentially fatal disease?
  25. 25. 31 *Versus patients on other DMTs or no treatment. Goodin DS, Ebers G, Traboulsee A, et al, for the Betaferon® LTF Study group [poster]. American Neurological Association. October 8-11, 2006. Ebers G, Traboulsee A, Langdon D, Goodin D, Konieczny A, for the Betaferon® /Betaferon® LTF Study Group [poster]. American Academy of Neurology. April 1-8, 2006. Long-term follow-up study: Betaferon significantly delayed disease progression over 17 years of treatment  Patients who continuously used Betaferon had nearly 60% more cane-free years from time of diagnosis*  Treatment with Betaferon delayed progression to SPMS by 6.6 years compared to other treatments or no treatment  After 17 years, the tolerability and safety profile of Betaferon remains excellent
  26. 26. 32 Betaferon 17-Year LTF: Mortality Data by treatment group  Betaferon standard dose (n=124) 6%  Betaferon lower dose (n=125) 9%  Placebo (n=123) 19%
  27. 27. 33 Using Evidenced Based Medicine to Guide MS Therapy AAN Guidelines Cochrane Committee Reports Head to Head Class I Trials
  28. 28. 34Goodin DS, et al. Neurology. 2002;58:169-178. Evidence-based Medicine: AAN Guidelines
  29. 29. 35 AAN Guidelines on DMT’s 1) Relapses and MRI • All better than placebo (A) 1) Disability Progression • Interferons: Probably Effective (B) • Copaxone: Possibly Effective (C) 3) IFNs: Higher Dose / frequency more effective (B) 4) NAb: Conflicting data (U) • Utility of measuring is uncertain • Did not recommend testing requirements
  30. 30. 36 Patient 2: Evaluating the Response to Disease Modifying Therapy (DMT) in MS
  31. 31. 37 Patient 2: Evaluating Response to DMT  Current complaint  28-year-old surgical resident with RRMS  Recently developed fatigue and frustration but without impairment of surgical skills, even during extended operations  She is considering changing her MS therapy
  32. 32. 38 Patient 2: Evaluating Response to DMT (Cont.)  Past Neurological History  3.5 yrs ago: first symptom (unsteadiness of gait) resolved without treatment or evaluation  3 years ago: bladder urgency, difficulty handwriting, mild weakness in right leg • Brain MRI revealed 2 GAD+ lesions and 10 T2 lesions: locations included periventricular areas, brain stem, cerebellum and corpus Callosum. • CSF: + bands and IgG Synthesis: Other labs normal • Diagnosis of RRMS was made and treatment was I.V. Steroids for 5 days. IFN B-1b was also begun. She recovered completely in one month  6 months later: mild blurred vision in left eye for two weeks with spontaneous recovery without steroids. No Evaluation
  33. 33. 39 Patient 2: Evaluating Response to DMT (Cont.)  Current evaluation:  Neuro Exam Normal: Possible depression?  MRI: No GAD lesions: T2 lesions are smaller. No black holes or atrophy  NAb test: + (1:100 titer)
  34. 34. 40 Neurologists Assessment  Since IFN B-1b, this patient has had only one episode of (likely) mild optic neuritis – shortly after beginning therapy 3 yrs ago  Neuro exam was normal  MRI demonstrated improvement since beginning therapy  Patient does not have enough evidence to diagnose “suboptimal response” to current therapy.
  35. 35. 41 Neurologist’s Action Plan  Patient should remain on IFN B-1b  Treat symptomatically for fatigue & depression  Patient and NAb status should be reevaluated in 6 months
  36. 36. 42 Questions What is the utility of NAb testing in this clinically stable patient? What will be the patient’s response to changing a treatment that is apparently working, especially if the change results in a treatment that may not work as well?
  37. 37. 43 Comments  There remain differences of opinion regarding the use NAb testing. 2007 AAN guidelines using EBM principles do not support routine NAb testing because  No class I EBM results on utility of NAb testing  No standardized NAb test  No established level of NAb relevance (?100-200) titer  No EBM data on timing of NAb test  No EBM data on clinical outcomes after changing therapy based on + NAb test  Recent data fails to correlate NAbs with poor response to treatment.
  38. 38. 44 Neutralizing Antibodies to Interferon B-1b are not Associated with Disease Worsening in Multiple Sclerosis Goodin DS., Hurwitz B., Noronha A. The Journal of International Medical Research, 2007; 35: 173-187
  39. 39. 45 NAb Results: 6698 Patients  Australia: All Patients on IFNβ-1b  37% NAb positive  North America: Suboptimal Responders  21.3 % NAb positive  Europe: Suboptimal Responders  27.6% NAb positive Goodin, 2007
  40. 40. 46 Conclusions:  Poor responders were less likely to have NAbs than responders  NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value. Goodin DS., Hurwitz B., Noronha A. The Journal of International Medical Research, 2007; 35: 173-187
  41. 41. 47 Evaluating Response to DMT: Patient 2 Follow-up  6 months later she was NAb Θ on retest  The patient has remained on IFN B-1b with no new symptoms for the last 2 years  Modafinil was added for fatigue: improvement  SSRI taken for depression for one year.  She is now a fully functioning surgeon with no depression and minimal fatigue
  42. 42. 48 Patient 4: Managing Side Effects of DMT's
  43. 43. 49 Patient 4: Managing Side Effects of DMT’s 34 yr old RRMS patient has been on IFN B-1b for 4 months Neurologically stable but experiences flu like side effects and redness/pain at injection sites. She is unable to work because she feels “sick”, agitated, and depressed. Although feeling better in the past 2 months, she still wants to stop or switch treatment. Initially she was started on the full dose of IFN B-1b without titration or analgesia pre-injection medication. Her husband has been injecting the drugs at an angle “to avoid going too deep”. Liver function and CBC tests are normal MRI is unchanged
  44. 44. 50 Neurologist’s Assessment  Since beginning therapy she has had no relapses or new MRI lesions  Side effects are caused by lack of dose titration when starting treatment and improper injection technique (Intradermal injections).  Depression could be from learning of her diagnosis of MS or worry about drug side effects vs. a direct effect from drug.
  45. 45. 51 Neurologist’s Actions  Drug holiday for one month  Re-start IFN B-1b at ¼ dose and titrate to ½, then ¾ and then full dose each 2-3 weeks  Close supervision and counseling  Take analgesics before each shot  Inject at 90 degrees  Evaluate for depression on each visit, but no anti depression medication at this time
  46. 46. 52 Patient 4: Outcome  At 1 year patient tolerated treatment well with very few side effects and no recurrence of depression symptoms.  No missed days from work
  47. 47. 53 Patient : Discussion  Drug side effects may mimic worsening of MS  Proper initiation of therapy prevents most early side effects  Aggressive side effect management can often avoid terminating therapy
  48. 48. 54 Patient 5: Evaluating Possible Treatment Failures
  49. 49. 55 Patient 5: Deciding When Treatment Is Not Working  A 43-year-old patient seeks a second opinion  5-year history MS  Treated for 3 years with IFNβ-1a IM weekly  Clinical exam  Weakness in extremities (worst in left lower)  Uses cane for balance (4 months)  Bilateral extensor plantar responses  decreased vibration and position sensation in both legs and left hand  Dysmetria bilaterally on finger to nose, and rapid alternating movements bilaterally; dysmetria on heel to shin  Mild memory dysfunction
  50. 50. 56 Patient 5: Summary of Disease Course  A 43 yr old salesman is referred to you for a second opinion  Case history 2002 2003 2004 2005 2006 Exacerbations 1 1 1 2 1 T2 lesions 12 ↑ ↑ ↑  GAD+ lesions 4 2 1 2 1 Brain atrophy No No No Yes Yes Cognitive dysfunction No No No No Yes Progression No No No No Yes IFNβ-1a IM No No Yes Yes Yes NAb status ND ND Negative Negative Negative
  51. 51. 57 Neurologist’s Assessment  The initial diagnosis of RRMS was correct  The patient had 4 exacerbations during the 3 years on INF B-1a IM weekly  The disease has transitioned from RRMS to SPMS in the past 6 months  Response to IFNB-1a has been suboptimal in spite of negative NAb testing  Therefore, treatment was switched to IFN B-1b, 250 mcg god
  52. 52. 58 Questions Raised by Patient 5  Was DMT started at the right time?  What did his NAb test results mean?  When did this patient’s disease become sub-responsive to IFN B-1a IM?  What criteria are most important for determining when a patient has a suboptimal response to treatment?  When should natalizumab, and/or immunosuppressant drugs be considered?
  53. 53. 59 Patient 5: Summary of Disease Course  A 43 yr old salesman is referred to you for a second opinion  Case history 2002 2003 2004 2005 2006 Exacerbations 1 1 1 2 1 T2 lesions 12 ↑ ↑ ↑  GAD+ lesions 4 2 1 2 1 Brain atrophy No No No Yes Yes Cognitive dysfunction No No No No Yes Progression No No No No Yes IFNβ-1a IM No No Yes Yes Yes NAb status ND ND Negative Negative Negative
  54. 54. 60 Deciding When Treatment Is Not Working: Discussion  To provide optimal, care one must be prepared to change treatment if the course of the disease changes  Worsening neurological status (including cognition) with or without relapses are the most important criteria for deciding if a patient is progressing
  55. 55. 61 Differential Diagnosis for Worsening Symptoms on DMT's 1. Poor compliance (common) 2. Side effects of DMT’s 3. Co-morbid conditions (hypothyroid, anemia, depression, infection) 4. Suboptimal Response (SORs) to DMT 1. Diagnosis challenging (vs. natural treatment history) 2. Under-diagnosed: (30%) 3. Treatment unclear: Lack of EBM data
  56. 56. 62 Identifying SORs: Ongoing documentation is critical  Relapses  Progression of Disability  New MRI lesions (GAD lesions on T1)  Increased MRI Burden of Disease (T2)  Cognition? Often overlooked /undocumented  New Imaging technologies? Not Yet
  57. 57. 63 SOR: When to think about changing treatment? 1. Major relapse 2. 2 minor relapses in one year (Documented) 3. EDSS progression - not related to relapse 4. Decrease in cognitive function on testing 5. 1 new GAD lesion on MRI (Interferons) 6. 2 new T-2 lesions in MRI in one year 7. NAbs?
  58. 58. 64 SOR: When to think “Why should I NOT Change treatment?” 1. 2 major relapses in one year 2. Documented further EDSS progression on 2 exams 6 months apart 3. Documented further decline of cognition on 2 exams 6 months apart. 4. 2 or more GAD lesions in 2 years (interferons) 5. 3 or more new T-2 lesion in 2 years 6. Considerable increase in brain atrophy, permanent black holes
  59. 59. 65 Management of SOR Data is incomplete: Little EBM data: “Therapeutic Window” is closing  Increase dose/frequency within class of drug  Change class of treatment  Add drug/combination therapy
  60. 60. 66 Managing SOR on Avonex Increase Dose  Double Dose weekly: Negative results Increase frequency  Give every 2-4 days, IM: No data: ?Practical Switch to higher dosed, more frequent Interferon  Betaferon: INCOMIN Trial Data (MRI-Class I)  Rebif: EVIDENCE Trial Data (Class I) : EVIDENCE Trial Extension Data: Not Class I Switch to or add Copaxone: No Data: Combination Trial underway: Appears safe Add/switch to Mitoxantrone or other immuno- suppressants Switch to Natalizumab
  61. 61. 67 INdependent COMparison of INterferon (INCOMIN) Trial Study Group Durelli et al. Lancet 2002, 359:1453-60 A Multicenter Trial Comparing Clinical and MRI Efficacy of Betaferon® and Avonex® in RRMS
  62. 62. 68 Betaferon vs. Avonex The INCOMIN Trial Results: First 24 Months Avonex Betaferon (n=92) (n=96) % ∆ p T2 Lesion Free (0-24 mo) 19 (26%) 42 (55%) +53% 0.0003 % Change Lesion Load +11.7% -2.8% >100 0.0001 EDSS progression (0-24 mo) 28 (30%) 13 (14%) -46 0.005 New T2 lesions (6-12 mo) 33 (45%) 16 (21%) -52 0.002 Gd+ lesions (6-12 mo) 16 (22%) 7 (9%) -56 0.03 Gd Lesion Free (0-24 mo) 18 (25%) 39 (51%) +51 0.0008 Relapse-free (0-24 mo) 30 (33%) 46 (48%) +35 0.036 NAbs did not effect outcomes
  63. 63. 69 The EVIDENCE Trial Head-to-head, randomized, open label, evaluator-blinded comparison of Rebif (44 mcg tiw SC) with Avonex (30 mcg qw IM) in patients with RRMS EVidence of Interferon Dose-response: European North American Comparative Efficacy Trial Panitch H. Neurology 59: 1496-1503 (2004)
  64. 64. 70 Summary Efficacy at Week 24 and Week 48 Week 24 Week 48 p-value Relative improvement p-value Relative improvement Odds ratio - relapsing 0.0005 47% 0.009 33% Hazard ratio, time to relapse 0.001 37% 0.003 30% Relapse rate 0.025 26% 0.093 16% CU active <0.001 48% T2 lesions <0.001 50% <0.001 36% T2 active scans <0.001 45% <0.001 38% T2 inactive patients <0.001 39% <0.001 40% Rebif vs Avonex Rebif vs Avonex Panitch H. Neurology 59: 1496-1503 (2004)
  65. 65. 71 Avonex to Rebif Switch Trial Annualized Relapse Rate Final Comparative Phase vs Posttransition Phase Panitch H. Neurology 59: 1496-1503 (2004) Rebif 44 mcg tiw f44 mcg tiw final comparative phase Avonex 30 mcg qw final comparative phase Rebif 44 mcg tiw posttransition44 mcg tiw posttransition from Rebif/Avonexfrom Rebif/Avonex 26% 0 0.2 0.4 0.6 0.8 Annualizedrelapserate(mean) Avonex to Rebif (n=223) P< 0.001 P=0.028 50% Rebif to Rebif (n=272) 0.46 0.34 0.64 0.32
  66. 66. 72 Managing SOR on Avonex  Increase Dose  Double Dose weekly: Negative results  Increase frequency  Give every 2-4 days, IM: No data: ?Practical  Switch to higher dosed, more frequent Interferon  Betaferon: INCOMIN Trial Data  Rebif: EVIDENCE Trial Data : EVINDENCE Trial Extension Data  Switch to Copaxone: No EBM data: Safe  Add Copaxone: No Data: Combination Trial underway: Appears safe  Add/switch to Mitoxantrone or others  Switch to Natalizumab
  67. 67. 73 Managing SOR on Betaferon  Increase Dose: Reasonable Pilot data: Well tolerated  OPTIMS Trial  BEYOND Trial  Switch to Rebif: No data:  Switch to Avonex: No: INCOMIN Dose Reduction study  Switch to Copaxone: Safe, No EBM data  Add Copaxone: No data  Add/Switch to Mitoxantrone or other immunosuppression  Switch to Natalizumab
  68. 68. 74 INdependent COMparison of INterferon (INCOMIN) Trial Study Group Durelli et al. Lancet 2002, 359:1453-60 A Multicenter Trial Comparing Clinical and MRI Efficacy of Betaferon® and Avonex® in RRMS
  69. 69. 75 Dose-Reduction Study Betaferon® to Avonex® Switch Trial Avonex® Betaferon® Exacerbation rate .09* .02* % of patients with exacerbations 77%* 21%* % of patients with sustained 23% (ns) 0% (ns) EDSS worsening % of patients with MRI activity 85%* 36%* * Statistically significant p<0.05 INCOMIN Trial Continuation Barbero P. J. Neurol Sci. 15;222(1-2):13-9 (2004)
  70. 70. 76 Managing SOR on Betaferon  Increase Dose: Reasonable Pilot data: Well tolerated  OPTIMS Trial  BEYOND Trial  Switch to Rebif: No data  Switch to Avonex: No: INCOMIN Dose Reduction study  Switch to Copaxone: Safe, No EBM data  Add Copaxone: No data  Add/Switch to Mitoxantrone or other immunosuppression  Switch to Natalizumab
  71. 71. 77 Managing SOR on Rebif  Increase Dose: No data: Not very practical  Switch to Betaferon: No data: Maybe easier to give even higher dose  Switch to or add Copaxone : No data. Safe  Add/Switch to Mitoxantrone or other immunosuppression  Switch to Natalizumab
  72. 72. 78 Managing SOR on Copaxone  Increase dose? Double dose: positive PILOT data  Switch to Interferon: No EBM data: Most popular option: safe  Add Interferon: Combination Trial underway: safe  Add/switch to Mitoxantrone or others
  73. 73. 79 Other SORs Treatment Options Immunosuppression:  Mitoxantrone (Novantrone)  For worsening MS (RRMS and SPMS)  Approved by FDA  Popular for SOR treatment of ABCR drugs  Relatively well tolerated  Issues: 1. Occasional permanent amenorrhea 2. Cardiotoxicity: Dose dependent (2-3) years 3. Uncommon Risk of Leukemia (1 in 500?)
  74. 74. 80 Other SOR Options  Pulses Methylprednisolone (I.V., monthly)  Methotrexate (oral, weekly)  Azathioprine (Imuran) (oral, daily)  Cyclophosphamide (Cytoxan)  Micophenolate (Cell Cept)  IVIG  Tysabri (Natalizumab): DO NOT ADD!  Natalizumab (Tysabri) switch
  75. 75. 81 Summary & Conclusions: SOR Diagnosis  SORs are common (30% or greater) but are under diagnosed  Is patient Compliant with drug?  Regular documentation of MS course is crucial: Relapses, MRI lesions, disability progression, ? Cognition  Rule out other causes of worsening MS : co- morbid conditions, pseudo exacerbations, depression, UTI, thyroid dysfunction
  76. 76. 82 Summary & Conclusions: SOR Treatment  Little EBM data but therapeutic window closing: Options include: 1. Increase dose/frequency within class 2. Change class of treatment 3. Add different class of therapy (not natalizumab)
  77. 77. 83 What is New? Current and Emerging Therapies
  78. 78. 84 A. Betaferon 1. BENEFIT Trial in CIS 2. 17 Year Follow up data 3. Betaferon vs. Double Dose Betaferon vs. Copaxone
  79. 79. 85 B. Rebif 1. Reformulated Rebif 2. Rebif vs. Copaxone 3. Rebif in CIS 4. Cladribine Induction before Rebif 5. Rebif vs. Betaferon tolerability study
  80. 80. 86 C. Copaxone 1. Copaxone in Primary Progressive MS: Discouraging 2. Double Dose Copaxone in RRMS: Encouraging 3. Copaxone in CIS (in progress) 4. Copaxone vs. Betaferon (in progress) 5. Copaxone vs. Rebif (data being analyzed)
  81. 81. 87 D. Natalizumab (Tysabri) 1. Natalizumab vs. Placebo in RRMS 2. Natalizumab vs. Avonex 3. The PML issue
  82. 82. 88 Oral Therapies  May improve convenience and compliance in MS therapy  Oral therapies now in phase 3 trials may be available in late 2010  Fingolimod (FTY720)  Teriflunomide  Cladribine  Laquinimod
  83. 83. 89 Monoclonal Antibodies (MAbs): Background  MAbs offer more favorable dosing regimens compared with current MS therapies (less frequent)  MAbs currently in use appear to be associated with specific side effects, eg, PML, Graves disease, ITP  Clinical trials of MAbs in MS are less advanced than those of oral therapies  Possible that no MAb currently in development will enter MS market before 2010
  84. 84. 90 MAbs: Conclusions  Some striking efficacy results with MAbs in MS  Safety concerns must be allayed before MAbs are widely used in MS
  85. 85. 91 Other Emerging Treatments  Fingolimod (oral)  Campath (yearly)  MBP82-98 (6 months)  Rituximab (B-cell AB) (? PML)  Cladribine (oral)  Fumarate (BG-12) (oral)  Teriflunomide (oral)  Statins (oral): blocks IFNs  Minocycline (oral  Estriol (oral)  Laguinimod (oral)  Fampridine-SR (Ambulation)  NeuroVax (T-cell vaccine)  Tovarin (anti T-cell)  Bone Marrow Transplant  IVIG  Stem Cell Transplant  Marijuana (symptomatic)  Testosterone (Cognitive)  Small Molecules  CellCept (mycophenolate)
  86. 86. 92 Other Treatment Approaches  Stem cells (bone marrow and embryonic)  Remyelinating agents  Neuroprotective agents
  87. 87. 93 Patient 5A: Management of Suboptimal Responders to both low and high Dose Interferons
  88. 88. 94 Patient 5A 39 year old male with very active RRMS for 3 years. He averages 2 attacks per year for all three years with only partial response to IV steroids. He was started on INFβ1-a I.M. (Avonex) weekly for the next two years. He was then switched to Rebif 44 TIW for the past year. He had 2 attacks during that last year with incomplete recovery with steroids.
  89. 89. 95 Patient 5A He is stable between attacks, but ongoing MRI activity is present. His exam reveals a bilateral intramuscular opthalmoplegia; right hemiparesis and ataxic gait requiring a cane to walk (EDSS=6).
  90. 90. 96 Patient 5A  What is your best treatment option 1. Keep on Rebif but double the dose 2. Get an NAb test and stop Rebif if positive 3. Switch to IFNβ-1b at double dose (500 ug) 4. Add or Switch to Mitoxantrone 5. Add or switch to Azathioprine 6. Add or switch to cyclophosphide 7. IVIG 8. Add Natalizumab (No!) 9. Switch to Natalizumab 10. Other options?
  91. 91. 97 Patient 5B A 36 year old lady from Sari with severe MS wants a child  36 year old, married11 years, MS started 9 years after Mother died in her arms  Initial Symptoms 9 years ago: Fatigue, legs weak, falling.  After 3 months Neurologist diagnosed MS by symptoms, exam and MRI with multiple lesions. She does remember an CSF.  Treated with IV steroids and improved
  92. 92. 98 Sari MS patient  Relapse after 4 months, Treated with IV steroids and improved back to “normal”  Treated with Betaferon in 2000 and did well until 2004 when she stopped treatment to try “magic” therapy with alternative medicines, herbs and acupuncture.  Much worse symptoms until 2004 when saw a Neurologist and got Methetrexate followed by Betaferon. Her MS became more stable.  In 2006 stopped Betaferon to become pregnant. She had a miscarriage at 3 months and now wants to become Pregnant again. She fears her may leave her if she doesnot have a child.  3 weeks ago she became paraplegic with decreased feelings in both legs. She is considering Novantrone.
  93. 93. 99 36 year old Sari patient  Brief Exam reveals tearful lady with only slight movement in legs in a wheelchair  Spasticity in legs with sustained clonus at the ankles  Mild to moderate weakness in arms - L. more than R side  Ataxia and tremor - L more than R  Marked decrease in position sense in legs  Cranial nerves OK
  94. 94. 100 36 year old Sari patient  Meds include Numerous vitamins Baclofen St John wort Amantadine  MRI : 2003 Many T2 lesions : 2005 More lesions with brain atrophy
  95. 95. 101 Issues for Sari patient  Early Treatment value  Problems with Adherence to Betaferon  Chemotherapy in lady who wants kids  “Alternative” medicine versus Betaferon  Pregnancy desires versus treatment desires  Acute treatment and long term treatment options  Rehab, Depression and family issues
  96. 96. 102 36 Year old Sari patient: My thoughts on Treatment  Must treat relapse immediately with IV steroids!  If failure, try plasma phoresis or IVIG.  Since she has done well on Betaferon in past, restart with dose escalation ASAP – with IV steroids  Treat with Betaferon for one year and re-evaluate. If sub optimal response, try double dose of Betaferon if available data and positive by then. Or consider Novantrone or Tysabri. If she continues to do badly, consider Rituxamab in future – or other new med  Rehab, depression Rx and family counseling ASAP  Consider adoption and not delay treatment for MS
  97. 97. 103 Patient 6: The Dilemma of “Asymptomatic” MS
  98. 98. 104 Patient 6 24 year old female with bitemporal throbbing “migraine” headaches associated with nausea, vomiting for 4 years associated with menstrual periods. Headaches last 2-6 hours and are helped with sumatriptan (Imitrex) if taken early in the course of the headache. She denies any fevers or chills. She is otherwise healthy with no family history of Neurological disease. No history of previous head injury.
  99. 99. 105 Patient 6 Her neurological exam was normal. MRI was done to rule out Meningioma, Aneurysm, or Arterial-venous malformation (AVM). Her T-2 weighted MRI revealed 6 white matter lesions ranging from 3-8mm, mainly periventricular. Radiologist conclusion “Multiple lesions, consistent with multiple sclerosis”.
  100. 100. 106 Patient 6 She comes to you for a second opinion: 1. Does she have MS? (or something else?) 2. Should she have an L.P., another MRI (GAD?), Evoked Potential testing, other workups? 3. Should she be treated with steroids or specific MS therapies
  101. 101. 107 Patient 6  What is your Differential Diagnosis?  How would you work up and treat this patient?
  102. 102. 108 Patient 6 Differential Diagnosis  Collagen vascular disease (SLE)  CADASIL  Thyroid disease  Hypoglycemia  Vitamin deficiencies  Sjögren syndrome  Behçet’s disease  Myasthenia gravis  Spino-cerebellar  Degeneration  Adrenoleukodystrophies  Lyme disease  Syphilis  TB & other CNS infections  Sarcoidosis  CNS malignancy  CNS embolic disease  AIDS  PML
  103. 103. 109 Patient 6 Evaluation for MS: Diagnosis and Progression  Clinical history and exam best  Ancillary tests  MRI  CSF  Evoked potentials  Urological testing  Cognitive tests  EDSS, MSFC scale, Scripps scale
  104. 104. 110 Patient 6 Her evoked potential tests, ANA, Sed Rate, thyroid screen, VDRL, and other screening tests are normal. She has no GAD lesions or new T-2 lesions on repeat MRI done 2 weeks later. CSF is normal
  105. 105. 111 Patient 6  Would you diagnose MS?  Would you treat with Steroids?  Would you treat with Interferons?  Would you treat with both Steroids & Interferons?
  106. 106. 112 Patient 6  She was not given the diagnosis of MS and was not treated
  107. 107. 113 Patient 6  If she had an identical twin with MS, would that change your opinion?  Identical twins have a 30% concordance rate for MS
  108. 108. 114 Patient 6  One year later, she remained asymptomatic with a normal exam, but a repeat MRI showed 2 new T-2 lesions, but no GAD + lesions.  Does she now have MS?  Would you treat?
  109. 109. 115 Patient 6  She was not diagnosed as MS and was not treated
  110. 110. 116 Patient 6  One year later she had an episode of numbness on left arm and leg along with fatigue and ataxia. Her MRI revealed 4 new T-2 lesions and 2 GAD + lesions  Would you diagnose MS?  Would you treat with Steroids?  Would you treat with Interferons?  Would you treat with both Steroids & Interferons?
  111. 111. 117 Patient 6  She was diagnosed as MS and treated with steroids and Interferon β-1b with no further attacks in 5 years of follow-up.  Her MRI revealed no new T-2 or GAD lesions.  Would you stop her Interferon Treatment?
  112. 112. 118 Patient 7: Differentiating MS, Neuromyelitis Optica (DEVIC’s), and Asian Optica-spinal MS
  113. 113. 119 Patient 7 18 year old Asian male presented with decreased vision in right eye over 3 days with pain on eye movement: ophthalmologist diagnosed “optic neuritis” and treated with IV steroids with good results. Four months later he developed numbness and weakness in his legs with difficulty walking over a one week time period. His examination showed optic palor on right, decreased sensation below umbilicus and decreased strength in both legs.
  114. 114. 120 Patient 7 Babinski test was positive bilaterally, DTR’s were very active with transient clonus at At ankles. CSF tests were negative, except for 15 WBCs, MRI of spine showed a patchy longitudinal lesion from L1-4. Brain MRI showed 2 periventricular T-2 lesions. Extensive work up for other diseases was negative but acquaporin-4 antibody test was positive.
  115. 115. 121 Patient 7  What is the most likely diagnosis? 1. Classical MS 2. Asian MS (optic-spinal MS) 3. Neuro myelitis optica (NMO or Devics Disease) 4. CNS lymphoma or metastatic cancer 5. Other
  116. 116. 122 Neuromyelitis Optica Optic-Spinal MS Recurrent Optic Neuritis Recurrent Myelitis
  117. 117. 123 Spectrum of MS: Neuromyelitis Optica (DEVIC's)  NMO  Gender predilection: Female to Male ~10:1  Onset in all ages  Ethnic predilection: No clear ethnic predilection • May be present in all areas of the world at very low prevalence • In areas with high prevalence of MS, may be misdiagnosed as atypical MS • In areas with low MS prevalence, differentiation from classic MS becomes easier  Investigation  Spinal cord–longitudinally extensive, central necrotic lesions  Brain–some lesions now permitted  CSF–pleocytosis (>50 white cells/μL), polymorphonuclear cells, oligoclonal band negative  NMO Antibody (Aquaporin 4) found in 70%
  118. 118. 124 Spectrum of MS: Optic-Spinal Multiple Sclerosis  OSMS (Asia)  Gender predilection: Female to Male ~3:1 or more  Ethnic predilection: Far-east Asian, Japanese, Latin American  Investigation  Brain–generally normal, but typical MS-like lesions can be observed  Spinal cord–multiple cord lesions of variable lengths  CSF–Oligoclonal bands in about 30% of cases  NMO Antibody found in >50% if long cord lesions (?NMO)
  119. 119. 125 Spectrum of MS Recurrent Optic Neuritis  If Brain and Spinal cord MRI normal  CDMS less likely  BUT may convert to CDMS years later  Treat with IV steroids, not DMT's
  120. 120. 126 Spectrum of MS Recurrent Myelitis  If brain MRI normal, unlikely CDMS  If NMO Antibodies +, may be NMO  Treat with IV Steroids and Immunosuppressants
  121. 121. 127 Patient 7  Patient was diagnosed as DEVIC’S (NMO)  He was treated with IV steroids only. He recovered considerable function but not completely.
  122. 122. 128 Patient 7  Eight months later has another episode with decreased vision in left eye and numbness from his mid chest to his legs. Thoracic MRI revealed a new thoracic lesion covering 3 segments
  123. 123. 129 Patient 7  How would you treat him? 1. No treatment 2. IV Steroids 3. Interferon 4. Azathioprine 5. Mitoxantrone 6. Rituximab 7. Cyclophosphamide 8. IVIG 9. Natalizumab 10. Other drugs
  124. 124. 130 Patient 7  He was treated with IVMP and Aziathiaprine. He had 2 more attacks within the next 18 months, which left him blind in his left eye and he required a cane to walk. He was switched to IVIG and had another attack in 3 months. He was switched to Rituximab and has had no further attacks in 1 year of follow up

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