This document provides information on multiple sclerosis (MS), including its epidemiology, pathogenesis, clinical presentations, diagnosis, and treatment options. It summarizes that MS is the most common autoimmune demyelinating disease of the central nervous system characterized by inflammation and demyelination in the brain and spinal cord. Current first-line treatments for relapsing-remitting MS include interferon beta, glatiramer acetate, fingolimod, fumarate, teriflunomide, natalizumab, mitoxantrone, and alemtuzumab, which aim to reduce relapse rates and progression of disability.

1. Multiple Sclerosis
DMW Dharmakeerthi (MD)
Senior Registrar in clinical
Neurophysiology

2. Epidemiology
Compston A, et al. McAlpine‟s Multiple Sclerosis, 4th ed. Churchill Livingston, London
Prevalence 5–200/100,000 population
Sex distribution 70%–75% female
Age at onset 20–40 years
Ethnic origin Predominantly Caucasian

3. The Basics - Revision
The most common autoimmune
inflammatory demyelinating disease of the
CNS.
Episodes affecting different parts of the
central nervous system at different times.
Inflammation, leading to demyelination
and temporary conduction
block, symptomatic only if it occurs in an
eloquent area.

4. Pathogenesis
Pathogenesis of MS involves complex interactions
between genetic and environmental factors
Multiple genes are involved
Timing of environmental factors is important
– The 1st event: in utero or early postnatal period
– The 2nd event: after birth to age 15
– The 3rd event: in adulthood (may be several)
Vitamin D deficiency is a plausible candidate for the 1st factor; EBV
infection is a plausible candidate for the 2nd factor
MS incidence has increased over the past 30 years due to a change
in environmental exposure

5. Characterized pathologically by multifocal
areas of demyelination with loss of
oligodendrocytes and astroglial scarring.
Axonal injury is increasingly recognized as
a prominent pathologic feature of MS.

6. Extravasation
astrocytes BRAIN
TISSUE
M Y E L I
oligodendrocyte
B cell
Rolling Adhesion
4 Integrin
VCAM
B L O O D F L O W
LUMEN OF
VENULE
B A S A L L A M I N A
Circulation
Activated T cell Proteases
Antigen presenting cell
(Astrocyte or Microglial cell)
Activated
microglia/macro
phages
T CELL
REACTIVA
TION
Activated
Macrophage
Autoantibodies
Complement
IL-1, IL-12,
chemokines
Cytokines and
chemokines
Proteases
TNF-
O2
•-
NO•
AXONAL
DAMAGE
Courtesy of Sergio Baranzini, PhD.
MS Disease Pathology

7. Oligodendrocyte Damage
Apoptotic Myelin Membranes
Macrophages phagocytose
Myelin sheaths
Denuded Axons
Chronic Demyelinated Axons
Accumulating
axon loss
Progressive Disability
Acute
Inflammation
?
Conduction Block
Remyelination
Slow, Insecure
Conduction
Transient Symptoms
Acute
Relapse
Axon
Protected
Chronic
Inflammation
within BBB

8. Pathogenesis of Multiple Sclerosis
Microscopic Pathology
Courtesy of D.P. Agamanolis, MD. http://neuropathology.neoucom.edu.

10. Some Definitions
A Relapse:-
Onset of new neurological symptoms, or a substantial
deterioration of previous symptoms, lasting more than 24
hours, not explicable on the basis of infection or other
process
Clinically Isolated Syndrome:-
Single neurological episode without clinical evidence of
previous episodes, with a normal MRI scan has a ~20%
chance of progressing to MS, with and abnormal scan
fulfilling certain criteria has an 85% chance of developing
MS

11. Some more definitions
Relapsing Remitting :- disease
characterised by relapses with substantial
regression of symptoms afterwards – 70% start
like this
Primary Progressive :- gradual
progressive disease from onset without
relapses. ~15% of MS cases
Secondary Progressive :- progressive
disease following period or relapsing remitting
disease

12. 2005 McDonald criteria revisions diagnostic criteria for
multiple sclerosis
Clinical presentation Additional data needed for MS diagnosis
Two or more attacks*; objective clinical evidence
of two or more lesions
None•
Two or more attacks*; objective clinical evidence
of one lesion
Dissemination in space, demonstrated by: - MRIΔ
or
- Two or more MRI-detected lesions consistent
with MS plus positive CSF or- Await further
clinical attack* implicating a different site
One attack*; objective clinical evidence of two or
more lesions
Dissemination in time, demonstrated by: - MRI
or- Second clinical attack*
One attack*; objective clinical evidence of one
lesion (monosymptomatic presentation; clinically
isolated syndrome)
Dissemination in space, demonstrated by:- MRIΔ
or- Two or more MRI-detected lesions consistent
with MS plus positive CSF and Dissemination in
time, demonstrated by:- MRI or Second clinical
attack*
Insidious neurological progression suggestive of
MS
One year of disease progression (retrospectively
or prospectively determined) and Two of the
following:
- Positive brain MRI (nine T2 lesions or four or
more T2 lesions with positive VEP)¥- Positive
spinal cord MRI (two focal T2 lesions)
- Positive CSF

13. Diagnosis
MRI

15. CSF
CSF total leukocyte count is normal in two-thirds of
patients
CSF protein (or albumin) level is usually normal
Oligoclonal bands
Antimyelin antibodies - myelin oligodendrocyte
glycoprotein (MOG) and myelin basic protein (MBP)

16. Time
Preclinical
MRI Activity
Relapses/Disability
MRI T2 Burden of Disease
Axonal Loss
Disability
CIS
*
Reprinted from Trapp BD, et al. Neuroscientist. 1999;5:48-57, with permission from Sage Publications.
Relapsing-Remitting MS
Secondary Progressive MS
Natural History of MS
Clinical and MRI Measures

17. Acute relapses
Indications for treatment of a relapse
include functionally disabling symptoms
with objective evidence of neurologic
impairment.

18. Steroids in Acute Relapses
Speed recovery from an acute relapse
Do not alter the outcome at 6 months
If relapse severe + not improving in a few days
– Exclude infection
– Need adequate doses (>60mg)
IV methyl pred 1g 3/7 or 500mg po for 5/7
Gastric protection if a risk factors
Avoid oral tail-off unless prev. bad withdrawal
– Avoid long term steroids
– Counsel about long term side effects (inc
weakness, avascular necrosis)
– PE for those not responding to steroids

19. Treatment of RRMS
Immunomodulatory agents
A decreased relapse rate
A reduced progression of disability
A slower accumulation of lesions on MRI
Interferon beta-1a
Interferon beta-1b
Glatiramer acetate

20. Current First-Line MS Therapies
Interferon beta-1b
30 mcg Interferon beta-1a once weekly
Glatiramer acetate
Generally very safe and well tolerated
All require self-injection

21. When to treat?
Potent immune modulation (alemtuzumab) given early
in the disease appears not just to stop relapses but to
halt progression in the medium term (~5 years)
Coles et al NEJM „08 359(17)
The same treatment in patients with established
secondary progression stops relapses but fails to halt
progression
Coles et al Annals Neurol. „99 46

22. Interferon beta-1b & 1a
First medication approved by the US FDA
Administered EOD subcutaneously by self
injection
Injection site necrosis and Flu-like
symptoms
Neutralizing antibodies reduce the
bioavailability of interferon

23. Glatiramer acetate
Polymers of four amino acids compete
with APC to T cell
Inducer of specific T helper 2 type
suppressor cells
Injection site reactions, chest pain,
flushing, dyspnea, palpitations
No laboratory monitoring is necessary
BEYOND, BECOME and REGARD trials

24. Fingolimod
Sphingosine-1-phosphate receptor modulator
Induces rapid and reversible sequestration of
lymphocytes in lymph nodes
– Prevents activated and autoreactive cells from
migrating to target organs
Lymphocytes remain functional and may still be
activated as part of an immune response
Crosses blood brain barrier and may have
neuroprotective properties
Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457; Pinschewer DD, et al. J Immunol. 2000;164:5761-5770;
Chiba K, et al. J Immunol. 1998;160:5037-5044.

25. Fingolimod
OH
NH2
HO

26. Fingolimod
Daily oral tablet, first dose given in hospital
due to potential for bradycardia and AV
block
Relapse reduction 55% (0.18 cf 0.4
relapse/yr)
Macular oedema (?high dose only)
Hypertension
2 deaths from HSV/ZVZ encephalitis
stopped two months prior to conception
FREEDOMS TRANSFORM
S
Placebo 0.40 /yr
0.5 mg Fingolimod 0.18 /yr 0.16 /yr
1.25 mg
Fingolimod
0.16 /yr 0.20 /yr
IFN-β1a (Avonex) 0.33 /yr

27. 16
12
8
4
0
CumulativeGad+Lesion
(No.perpatient)
14.8 8.4 5.7
Placebo
(n = 81)
Fingolimod 1.25 mg
(n = 83)
Fingolimod 5 mg
(n = 77)
43%
P <0.001
61%
P <0.006
Adapted from Kappos L, et al. N Engl J Med. 2006;355:1124-1140. Copyright
©2006. Massachusetts Medical Society. All rights reserved.
Fingolimod
Primary Endpoint

28. Fumarate
O
O
O
O
O
O
O
O

29. Fumaric Acid Esters
Derived from common fumitory (Fumaria officinalis), a
plant rich in fumaric acid
Used to treat skin disorders since the 17th century
Fumaric acid esters used in severe psoriasis
– First reported by Schweckendiek in 1959
Inhibits T-cell activity
– Induction of activated lymphocyte apoptosis
– Shift in cytokine profile from Th1 to Th2
Effective in chronic experimental autoimmune
encephalomyelitis
May have neuroprotective properties by activating
antioxidant response genes
Schilling S, et al. Clin Exp Immunol. 2006;145:101-107.

30. Fumarate
Conclusions
Fumarate reduced the cumulative number of
Gad+ lesions, with a trend toward reduced
relapses
Adverse effects profile favorable with
discontinuations due to nausea, flushing,
headache, nasopharingitis (known effects in
psoriasis)
Phase III trials are actively recruiting, completion
expected in 2011, launch in 2012

31. Teriflunomide
O
N
H
N
F
F
F
OH
H3C

32. Teriflunomide
Leflunomide parent compound used in treatment
of rheumatoid arthritis
Inhibits pyrimidine synthesis
– Binds dihydroorotate dehydrogenase, the fourth
enzyme in de novo pyrimidine synthesis
Inhibits T-cell division
Inhibits murine experimental autoimmune
encephalomyelitis
Zeyda M, et al. Arthritis Rheum. 2005;52:2730-2739.

33. Teriflunomide Phase II
Primary Outcome
13.4
5.2 5.3
0
2
4
6
8
10
12
14
16
Placebo 7 mg/day 14 mg/day
CumulativeNo.ofUniqueActiveLesions
61%, P <0.03
O‟Connor PW, et al. Neurology.

34. Teriflunomide Conclusions
Reduced cumulative number of Gad + lesions with
favorable trends for relapse rate reduction and disability
Overall well tolerated with acceptable adverse effect
profile
Teriflunomide is teratogenic in animals
Reproductive toxicity in humans is not fully understood
– Women are advised not to become pregnant and men
cautioned not to parent children while on therapy
Women who wish to become pregnant
– Washout with cholestyramine or activated charcoal and
confirmation of acceptable plasma levels of
teriflunomide
– Without washout up to 2 years before plasma levels
decrease sufficiently
O‟Connor PW, et al. Neurology.
2006;66:894-900.

35. Cladribine
Purine analogue, preferentially depleting
lymphocytes,
Leads to prolonged immune modulation
Short oral course at yearly intervals
Relapse reduction 58% (CLARITY trial )
Infections – zoster
Tumours – uterine fibroids, ?cancers
Rejected by European Medicines Agency
– “Risks outweigh benefits”
CLARITY
Placebo 0.33 /yr
Cladribine 3.5 mg/kg 0.14 /yr
Cladribine 5.25 mg/kg 0.15 /yr

36. Summary
Cumulative Number of
Gad+ lesions
Annualized
Relapse Rate
Fingolimod (1.25 mg)
(3-arm study, N = 277)
-43%, P <0.001 -55%, P =0.009
Teriflunomide (7 mg)
(3-arm study, N = 178)
-61%, P <0.03 -32%, NS
Laquinimod (0.6 mg)
(3-arm study, N = 306)
-38%, P =0.005 -32%, NS
Fumarate (720 mg)
(4-arm study, N = 256)
-69%, P <0.001 -32%, NS
Cladribine (2.1 mg)
(2-arm study, N = 52)
-94%, P <0.001 -32%, P =0.01
1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. O‟Connor PW, et al.
Neurology. 2006;66:894-900. 3. Comi G, et al. 59th AAN Meeting; April 28-May 5,
2007. Abstract S02.002. 4. Kappos L, et al. 22nd ECTRIMS 2006; September 27-

37. Natalizumab Tysabri
Integrin α4 blockade
Stops circulating lymphocytes entering the CNS
Well tolerated monthly infusions
Effective relapse suppression (68% cf placebo)
Risk of PML appears to increase with time on
treatment:-
Very low in first year
By 2 years around 1 in 1000 per year of treatment
Risk of rebound disease activity when stopped

38. Mitoxantrone
Originally suggested for highly active
RRMS and possibly early progression
50% reduction in relapse rate
Cardiotoxicity, less common with newer
regimes
Risk of Leukaemia – particularly
Promyelocytic leukaemia ?0.3%++

39. Alemtuzumab Campath
Anti CD52 monoclonal depletes all
lymphocytes,
Prolonged immunomodulation
Highly effective relapse reduction (78% cf
IFNβ1a)
Stops progressive disability when given early
30% risk of Autoimmunity
ITP
Thyroid

40. Campath (Alemtuzumab)
– Unlicensed, and cheap! (at present)
No effect on established progression
Marked reduction in relapse rate for those
with highly active disease – 74% cf IFN
Most convincing effect on progression of
any drug, when started early enough
25% occurrence of other autoimmune
disease (Graves, ITP etc)

41. Azathioprine
One small, open-label study found that
azathioprine up to 3 mg/kg per day was
well tolerated and reduced the rate of new
gadolinium-enhancing brain lesions in
patients with RRMS

42. Cyclophosphamide
Limited observational evidence supports
the use of pulse (eg, monthly) IV
cyclophosphamide for RRMS

43. Conclusions
To date, treatment has been successful in
suppressing relapses and enhancing MRI
lesions
Early treatment with effective immune
therapy may alter the course of disease,
preventing/ delaying later disability