ms patient cases iran may 2007 l.
Skip this Video
Loading SlideShow in 5 Seconds..
MS Patient Cases Iran May 2007 PowerPoint Presentation
Download Presentation
MS Patient Cases Iran May 2007

Loading in 2 Seconds...

play fullscreen
1 / 124

MS Patient Cases Iran May 2007 - PowerPoint PPT Presentation

  • Uploaded on

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.

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about 'MS Patient Cases Iran May 2007' - Lucy

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
ms patient cases iran may 2007

MS Patient CasesIranMay 2007

Jack Burks, MD

Clinical Professor, NeurologistUniversity of Nevada School of MedicineReno, Nevada

Vice President/Chief Medical Officer

Multiple Sclerosis Association of America


Multiple Sclerosis Alliance

important issues in treating ms illustrative patient cases
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?
patient 1 deciding when to initiate treatment4
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
patient 1 deciding when to initiate treatment5
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
neurologist s assessment
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?
treat early diagnosis of ms in clinical isolated syndrome cis lesions in time and space
Treat Early! Diagnosis of MSin 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

mcdonald mri criteria for dissemination in time
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

The exact relationship between MRI findings and clinical status of patients is not completely understood.

McDonald WI et al. Ann Neurol. 2001;50:121-127.



3 months


Example Application of

New Diagnostic Criteria


polman revision of mcdonald criteria 2005
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.

patient 1 follow up
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
neurologist s assessment at follow up
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?
patient was treated with ifn 1b
Patient was treated with IFNβ-1b
  • BENEFIT Trial
  • 17 year follow-up data
  • AAN Treatment Guidelines
ii benefit betaferon in cis
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

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
Design of the BENEFIT study

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.

betaferon reduced the risk of cdms by clinical criteria
Betaferon Reduced the Risk of CDMSby clinical criteria




Risk reduction* of 50% over 2 years(Hazard ratio= 0.5)


Clinically Definite MS (%)


*by adjusted proportional hazards regression


betaferon delayed the onset of cdms

+ 363 days: + 142%


Day 618

Day 255

Betaferon Delayed the Onset of CDMS




Clinically Definite MS (%)



most patients develop ms by mri criteria within 2 years









Most Patients Develop MS by MRI Criteria Within 2 Years



McDonald MS (%)


The BENEFIT Study Group

betaferon doubles the probability of not developing ms
Betaferon Doubles the Probability of Not Developing MS
  • Cumulative probability for patients not to develop MS according to McDonald Criteria over 2 years


2 x

Cumulative probability


(n= 176)


(n= 292)

The BENEFIT Study Group

benefit trial early vs delayed treatment 3 year follow up 2007
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
benefit study discontinuation rates
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.

The BENEFIT Study. Betaferon® in newly emerging multiple sclerosis for initial treatment: Clinical results [poster].

lessons from benefit trial
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
17 year follow up rationale
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

credibility factors in betaferon 17 year follow up data
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?
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

*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.

betaferon 17 year ltf mortality data by treatment group
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%
using evidenced based medicine to guide ms therapy
Using Evidenced Based Medicine to Guide MS Therapy
  • AAN Guidelines
  • Cochrane Committee Reports
  • Head to Head Class I Trials
evidence based medicine aan guidelines
Evidence-based Medicine: AAN Guidelines

Goodin DS, et al. Neurology. 2002;58:169-178.

aan guidelines on dmt s
AAN Guidelines on DMT’s
  • Relapses and MRI
    • All better than placebo (A)
  • Disability Progression
    • Interferons: Probably Effective (B)
    • Copaxone: Possibly Effective (C)
  • IFNs: Higher Dose / frequency more effective (B)
  • NAb: Conflicting data (U)
    • Utility of measuring is uncertain
    • Did not recommend testing requirements
patient 2 evaluating response to dmt
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
patient 2 evaluating response to dmt cont
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
patient 2 evaluating response to dmt cont33
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)
neurologists assessment
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.
neurologist s action plan
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
  • 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?
  • 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.
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

nab results 6698 patients
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

  • 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

evaluating response to dmt patient 2 follow up
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
patient 4 managing side effects of dmt s43
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
neurologist s assessment44
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.
neurologist s actions
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
patient 4 outcome
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
patient discussion
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
patient 5 deciding when treatment is not working
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
patient 5 summary of disease course
Patient 5: Summary of Disease Course
  • A 43 yr old salesman is referred to you for a second opinion
  • Case history
neurologist s assessment51
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
questions raised by patient 5
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?
patient 5 summary of disease course53
Patient 5: Summary of Disease Course
  • A 43 yr old salesman is referred to you for a second opinion
  • Case history
deciding when treatment is not working discussion
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
differential diagnosis for worsening symptoms on dmt s
Differential Diagnosis for Worsening Symptoms on DMT's
  • Poor compliance (common)
  • Side effects of DMT’s
  • Co-morbid conditions (hypothyroid, anemia, depression, infection)
  • Suboptimal Response (SORs) to DMT
    • Diagnosis challenging (vs. natural treatment history)
    • Under-diagnosed: (30%)
    • Treatment unclear: Lack of EBM data
identifying sors ongoing documentation is critical
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
sor when to think about changing treatment
SOR: When to think about changing treatment?
  • Major relapse
  • 2 minor relapses in one year (Documented)
  • EDSS progression - not related to relapse
  • Decrease in cognitive function on testing
  • 1 new GAD lesion on MRI (Interferons)
  • 2 new T-2 lesions in MRI in one year
  • NAbs?
sor when to think why should i not change treatment
SOR: When to think “Why should I NOT Change treatment?”
  • 2 major relapses in one year
  • Documented further EDSS progression on 2 exams 6 months apart
  • Documented further decline of cognition on 2 exams 6 months apart.
  • 2 or more GAD lesions in 2 years (interferons)
  • 3 or more new T-2 lesion in 2 years
  • Considerable increase in brain atrophy, permanent black holes
management of sor
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
managing sor on avonex
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
independent comparison of interferon incomin trial study group

A Multicenter Trial Comparing Clinical and MRI Efficacy of Betaferon® and Avonex® in RRMS

INdependent COMparison of INterferon (INCOMIN) Trial Study Group

Durelli et al. Lancet 2002, 359:1453-60


Avonex Betaferon (n=92) (n=96) %  p

Relapse-free (0-24 mo) 30 (33%) 46 (48%) +35 0.036

% 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

T2 Lesion Free (0-24 mo) 19 (26%) 42 (55%) +53% 0.0003

Gd Lesion Free (0-24 mo) 18 (25%) 39 (51%) +51 0.0008

Betaferon vs. AvonexThe INCOMIN TrialResults: First 24 Months

NAbs did not effect outcomes

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

Neurology. 2002;59:1496-1506

EVidence of Interferon Dose-response:European North American Comparative

Efficacy Trial

Panitch H. Neurology 59: 1496-1503 (2004)

summary efficacy at week 24 and week 48
Summary Efficacy at Week 24 and Week 48

Week 24

Week 48











Rebif vs Avonex

Rebif vs Avonex




Odds ratio




Hazard ratio, time to








Relapse rate





CU active




T2 lesions





T2 active scans





T2 inactive patients



Panitch H. Neurology 59: 1496-1503 (2004)



P< 0.001







Annualized relapse rate (mean)






Rebif to Rebif (n=272)

Avonex to Rebif (n=223)

Rebif 44 mcg tiw final

comparative phase

Avonex 30 mcg qw final

comparative phase

Rebif 44 mcg tiw posttransition

from Rebif/Avonex

Avonex to Rebif Switch TrialAnnualized Relapse RateFinal Comparative Phase vs Posttransition Phase

Panitch H. Neurology 59: 1496-1503 (2004)

managing sor on avonex66
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
managing sor on betaferon
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
independent comparison of interferon incomin trial study group68

A Multicenter Trial Comparing Clinical and MRI Efficacy of Betaferon® and Avonex® in RRMS

INdependent COMparison of INterferon (INCOMIN) Trial Study Group

Durelli et al. Lancet 2002, 359:1453-60

dose reduction study betaferon to avonex switch trial

INCOMIN Trial Continuation

Dose-Reduction StudyBetaferon® to Avonex®Switch Trial

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

Avonex® Betaferon®

Barbero P. J. Neurol Sci. 15;222(1-2):13-9 (2004)

managing sor on betaferon70
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
managing sor on rebif
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
managing sor on copaxone
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
other sors treatment options immunosuppression
Other SORs Treatment OptionsImmunosuppression:
  • Mitoxantrone (Novantrone)
    • For worsening MS (RRMS and SPMS)
    • Approved by FDA
    • Popular for SOR treatment of ABCR drugs
    • Relatively well tolerated
    • Issues:
      • Occasional permanent amenorrhea
      • Cardiotoxicity: Dose dependent (2-3) years
      • Uncommon Risk of Leukemia (1 in 500?)
other sor options
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
summary conclusions sor diagnosis
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
summary conclusions sor treatment
Summary & Conclusions: SOR Treatment
  • Little EBM data but therapeutic window closing: Options include:
    • Increase dose/frequency within class
    • Change class of treatment
    • Add different class of therapy (not natalizumab)
What is New?

Current and Emerging Therapies

a betaferon
A. Betaferon
  • BENEFIT Trial in CIS
  • 17 Year Follow up data
  • Betaferon vs. Double Dose Betaferon vs. Copaxone
b rebif
B. Rebif
  • Reformulated Rebif
  • Rebif vs. Copaxone
  • Rebif in CIS
  • Cladribine Induction before Rebif
  • Rebif vs. Betaferon tolerability study
c copaxone
C. Copaxone
  • Copaxone in Primary Progressive MS: Discouraging
  • Double Dose Copaxone in RRMS: Encouraging
  • Copaxone in CIS (in progress)
  • Copaxone vs. Betaferon (in progress)
  • Copaxone vs. Rebif (data being analyzed)
d natalizumab tysabri
D. Natalizumab (Tysabri)
  • Natalizumab vs. Placebo in RRMS
  • Natalizumab vs. Avonex
  • The PML issue
oral therapies
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
monoclonal antibodies mabs background
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
mabs conclusions
MAbs: Conclusions
  • Some striking efficacy results with MAbs in MS
  • Safety concerns must be allayed before MAbs are widely used in MS
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


Stem Cell Transplant

Marijuana (symptomatic)

Testosterone (Cognitive)

Small Molecules

CellCept (mycophenolate)

Other Emerging Treatments
other treatment approaches
Other Treatment Approaches
  • Stem cells (bone marrow and embryonic)
  • Remyelinating agents
  • Neuroprotective agents
patient 5a
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.

patient 5a89
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).

patient 5a90
Patient 5A
  • What is your best treatment option
    • Keep on Rebif but double the dose
    • Get an NAb test and stop Rebif if positive
    • Switch to IFNβ-1b at double dose (500 ug)
    • Add or Switch to Mitoxantrone
    • Add or switch to Azathioprine
    • Add or switch to cyclophosphide
    • IVIG
    • Add Natalizumab (No!)
    • Switch to Natalizumab
    • Other options?
patient 5b a 36 year old lady from sari with severe ms wants a child
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
sari ms patient
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.
36 year old sari patient
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
36 year old sari patient94
36 year old Sari patient
  • Meds include

Numerous vitamins


St John wort


  • MRI : 2003 Many T2 lesions

: 2005 More lesions with brain atrophy

issues for sari patient
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
36 year old sari patient my thoughts on treatment
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
patient 6
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.

patient 699
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”.

patient 6100
Patient 6

She comes to you for a second opinion:

  • Does she have MS? (or something else?)
  • Should she have an L.P., another MRI (GAD?), Evoked Potential testing, other workups?
  • Should she be treated with steroids or specific MS therapies
patient 6101
Patient 6
  • What is your Differential Diagnosis?
  • How would you work up and treat this patient?
patient 6 differential diagnosis
Collagen vascular disease (SLE)


Thyroid disease


Vitamin deficiencies

Sjögren syndrome

Behçet’s disease

Myasthenia gravis




Lyme disease


TB & other CNS infections


CNS malignancy

CNS embolic disease



Patient 6Differential Diagnosis
patient 6 evaluation for ms diagnosis and progression
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
patient 6104
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

patient 6105
Patient 6
  • Would you diagnose MS?
  • Would you treat with Steroids?
  • Would you treat with Interferons?
  • Would you treat with both Steroids & Interferons?
patient 6106
Patient 6
  • She was not given the diagnosis of MS and was not treated
patient 6107
Patient 6
  • If she had an identical twin with MS, would that change your opinion?
    • Identical twins have a 30% concordance rate for MS
patient 6108
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?
patient 6109
Patient 6
  • She was not diagnosed as MS and was not treated
patient 6110
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?
patient 6111
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?
patient 7 differentiating ms neuromyelitis optica devic s and asian optica spinal ms
Patient 7: Differentiating MS, Neuromyelitis Optica (DEVIC’s), and Asian Optica-spinal MS
patient 7
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.

patient 7114
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.

patient 7115
Patient 7
  • What is the most likely diagnosis?
    • Classical MS
    • Asian MS (optic-spinal MS)
    • Neuro myelitis optica (NMO or Devics Disease)
    • CNS lymphoma or metastatic cancer
    • Other
spectrum of ms neuromyelitis optica devic s
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%
spectrum of ms optic spinal multiple sclerosis
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)
spectrum of ms recurrent optic neuritis
Spectrum of MSRecurrent 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
spectrum of ms recurrent myelitis
Spectrum of MSRecurrent Myelitis
  • If brain MRI normal, unlikely CDMS
  • If NMO Antibodies +, may be NMO
  • Treat with IV Steroids and Immunosuppressants
patient 7121
Patient 7
  • Patient was diagnosed as DEVIC’S (NMO)
  • He was treated with IV steroids only. He recovered considerable function but not completely.
patient 7122
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
patient 7123
Patient 7
  • How would you treat him?
    • No treatment
    • IV Steroids
    • Interferon
    • Azathioprine
    • Mitoxantrone
    • Rituximab
    • Cyclophosphamide
    • IVIG
    • Natalizumab
    • Other drugs
patient 7124
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