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Multiple Sclerosis
Southern Neurology
Pathogenesis
 Initial systemic event  Activation of CD4+ T
cells  Breakdown of BBB; adhesion, trafficking
and penetration f T cells into brain  Reactivation
of antigen-specific T cells in brain  Release of
inflammatory cytokines from activated TH cells 
Activation of glial cells and recruitment of
lymphoid cells and macrophages  Cell-mediated
inflammation, secretion of cytokines, antibodies,
proteinases, chemokines, free radicals, NO etc 
Myelin and axonal damage  Termination of
inflammation (regulatory T cells, antiinflammatory cytokines) and remyelination.
Optic Neuritis Treatment Trial
 457 patients with acute optic neuritis – 65 with
definite or probable MS at entry.
 Randomised into three arms between 198 and
1991 – (1) oral prednisone for 14 days, (2) high
dose IV methylprednisone 1g daily for 3 days);
and (3) oral placebo for 14 days.
 Results – no lasting visual benefit to patients using
either steroid regimen and only slight acceleration
of visual improvement with Iv methylprednisone.
Initial 1 year data found increased rate of new
attacks of optic neuritis in oral steroid group.
Longitudinal Optic Neuritis
Study
 2 year follow-up of 389 patients from original
457.
 Definite MS at 2 years in 50 patients (13%) – 21
(16.7%) in placebo group, 19 in oral prednisone
group (14.7%) and 10 in IV methylprednisone
group (7.5%). The rate of developing definite MS
was 1/3 rd that of placebo group although benefit
lessened at year 3.
 Patients with 2 or more signal abnormalities > 3
mm size in periventricular region were 12 times
more likely to develop clinically definite MS
within 2 years.
Management of multiple sclerosis
–current trials and future options
 The current treatment options in
relapsing/remitting MS are a choice
between interferon--1b, interferon- -1a or
glatiramer acetate.
 Each agent reduces clinical and MRI
indicators of inflammatory disease activity
(clinical relapses, new and active MRI
lesions), although most published studies
have a short follow-up (< 3 years).
Interferons
 Two forms of recombinant IFN- have been
licensed for RRMS - IFN--1a, which is
produced in mammalian cells using the
natural human gene sequence and IFN-1b, which is produced in E coli bacterial
cells using a modified human gene
sequence that contains a genetically
engineered cysteine to serine substitution at
position 17.
IFN- mechanism of action
 Dose dependent effects on several processes
thought to be involved in the pathophysiology of
MS including: (1) inhibition of the production of
several pro-inflammatory compounds eg IFN-,
TNF- and lymphotoxin; (2) down regulation of
IFN- induced increase in MHC class II molecules
on peripheral blood monocytes; (3) inhibition of
the migration of activated T and B lymphocytes
from the BBB to the CNS; and (4) stimulation of
nerve growth factor(s) and of the antiinflammatory cytokine IL-10.
IFN- Multiple sclerosis study group
(Neurology 1993; 43: 655-61).
 In a double blind trial, 372 patients with RRMS , mild
disability and a short duration of symptoms (mean
3.9-4.7 years) were randomised to receive s.c
injections of placebo, or IFN--1b 1.6 MIU or IFN-1b 8 MIU second daily. 122 patients withdrew before
3 years.
 During the subsequent two years, the relapse rate was
1.27 per year in the placebo group, 1.17 per year in the
1.6 MIU group (p=0.01) and 0.84 per year in the 8
MIU group (p=0.0001). This represented a reduction
rate by 1/3 in the 8 MIU group.
 MRI lesions load also improved after 3 years –17%
increase in placebo group, 1.1% increase in 1.6 MIU
group and 6.2 % decrease in 8 MIU group.
Immuno-modulating drug trial
results
 IFN-1b –34% reduction in relapses (1.7 baseline
vs 1.27 placebo vs 0.84 active). 49% fewer
moderate or severe exacerbations vs placebo.
 IFN-1a (Avonex 30 g/week) –32% reduction
(1.2 baseline vs 0.9 placebo vs 0.61 active)
 IFN-1a (Rebif 44 g, s.c three times per week) –
32% reduction (1.5 baseline vs 1.33 placebo vs
0.92 active)
 Copaxone (20 mg) – 29% reduction (1.45 baseline
vs 0.84 placebo vs 0.59 active)
INCOMIN trial
 INdependent COMparison of Interferon:
188 relapsing/remitting MS patients were
randomly assigned to either interferon- -1b
8 MIU second daily or interferon- -1a 30
g once weekly. The treatment advantage
favoured interferon- -1b with more
patients relapse free (51% vs 36%) and
fewer new T2 MRI lesions (55% vs 26%) at
2 years. IFN- -1b also superior in fewer
new lesions, Gd+ lesions and MRI activity.
EVIDENCE trial
 EVidence of Interferon Dose-response: European
North American Comparative Efficacy study.
RRMS patients were randomly assigned to either
interferon--1a 44 g s.c. three times weekly or
interferon- -1a 30 g IM weekly. AT 6 months
patients receiving s.c. treatment were more likely
to be relapse free (74.9% vs 63.3%) and to have
fewer active MRI lesions. There was a higher
prevalence of neutralising antibodies in the s.c.
group (25% vs 2%) and the benefit at 52 weeks
was still present but less apparent.
European INF--1a dose
comparison study
 No additional benefit from doubling the
amount of drug administered by IM
injection from 30 to 60 g per week. NAB
titres higher in the 60 g group (5.8% vs
2.3%).
 No difference seen in EDSS progression
and no secondary measures differed
significantly.
CHAMPS
 Controlled High-risk subjects Avonex Multiple
Sclerosis Prevention Study demonstrated that
conversion of placebo-treated patients to clinically
definite MS at 18 months was partly predicted by
the degree of MRI abnormality at baseline. The
initial delay in clinical relapse extends to patients
with initial presentations of optic neuritis,
brainstem/cerebellar or spinal cord disorders. In
this study, at least 50% of IFN--1a treated
patients developed evidence of a ‘combined
clinically definite/MRI outcome’ (either clinically
definite MS or at least one new or enlarging T2
lesion on scans done at 6, 12 and 18 months).
Glatiramer acetate
 Double-blind placebo controlled trial
demonstrated a 29% reduction in relapse rate over
two years with GA. However, the proportion of
relapse free patients at 30 months and the median
time to first relapse did not differ significantly
from placebo.
 MRI data have shown 29% reduction in
cumulative total number of Gd-enhanced lesions
at 9 months and 38% reduction reduction in
number of new lesions.
Progressive MS - IMPACT
 International MS Secondary Progressive
Avonex Controlled Trial – 436 secondary
progressive MS (SPMS) patients received
either 60 g IFN--1a or placebo –
favourable benefit on outcome scores (But
not EDSS) in year 2.
Mitoxanthrone
 European mitoxanthrone (worsening RRMS and
SPMS) – mitoxanthrone 5 or 12 mg/m2 every 12
weeks for 2 years vs placebo showed benefit for
higher dose. However, only 149/194 patients
(76%) completed study.
 Furthermore, Belgian mitoxanthrone study
compared 10 treatments of 12 mg/m2 every 12
weeks vs 1 g methylprednisolone and showed
improvements in number of relapses, number off
Gd+ lesions and 1-y EDSS. However, 50% dropout rate.
Relapsing-remitting MS questions
 IV steroids generally reserved for acute relapses.
 One unblinded small study has shown that 3
annual courses of VI methylprednisolone over 5
years slowed clinical disability and cerebral
atrophy.
 ? Role of plasma exchange and IV Ig for acute
exacerbations or worsening RRMS
 Interferons reduce relapses. Yes. Which one do
you prescribe ? Are higher dose treatments better ?
Do neutralizing antibodies associated with higher
dose treatments mean higher doses are worse ?
Case 1
 29 y.o. female
 Presents with 1 week history of right sided
clumsiness on a background of a 4 week history of
dizziness and right facial sensory disturbance.
 Previous episode of headache, dizziness, diplopia
and gait disturbance of 6 week duration in
September 2001. Was administered zoladex
implant at that time which was removed due to her
symptoms.
Case 1 continued
 Past history otherwise unremarkable
 No regular medications
 Neurological examination showed mild
right pyramidal weakness grade 4/5 (upper
limb worse than lower limb), impaired joint
position sense right arm/leg, cranial nerves
showed reduced right facial sensation and
left beating nystagmus.
Investigations
 ? Provisional diagnosis
 MRI brain – 2 discrete foci in right
midbrain and corpus callosum
 Somatosensory evoked potentials – right
sided posterior tibial latency prolonged at
25.5 ms (vs 16.9 on left). BAERs and VEPs
both normal.
Figure 2. Conversion to clinically definite MS (CDMS)
in patients fulfilling the MRI McDonald criteria (MRI
McDonald positive; gray bars) and not fulfilling the
MRI McDonald criteria (MRI McDonald negative;
white bars) at 12 months.
Questions
 ? Further investigations
 ? Role of lumbar puncture
 ? Treatment recommendations
 Patient was commenced IV
methylprednisolone 1g IVI daily for 3 days
and then tapering oral prednisolone over 10
days.
 Immunomodulating therapy was discussed
Case 2
 41 y.o.female
 Presents June 2003 for follow-up review
 First seen September 1999 with 2 week
history of gait ataxia, left arm clumsiness
and left arm sensory disturbance.
 Clinical signs at the time consisted of
mildly impaired tandem gait, mild left upper
limb clumsiness and subjective left arm
sensory loss.
Case 2 continued
 MRI showed extensive white matter lesions
including C2/3 high signal abnormality in
cord.
 Visual and somatosensory evoked potential
studies both prolonged.
 Diagnosis of first episode of demyelination.
 Treated with IV methylprednisolone with
improvement.
Case 2 continued
 6 months later had further relapse which
responded to second course of steroids.
 In 2000 became pregnant and symptom free but
further relapse post-partum. Trialled betaferon and
copaxone but neither tolerate well.
 By Nov 2001, incoordination of upper and lower
limbs, brisk reflexes and mild pyramidal weakness
(left more so than right) and bilateral extensor
plantar responses. Able to walk only with
assistance.
 Offered mitoxanthrone but declined.
Case 2 continued
 June 2003, presents with further
deterioration. Significant gait ataxia, which
is mixed cerebellar and pyramidal. Unable
to walk > 10 metres and prefers to be
transported in a wheelchair.
 In June 1999 was surfing as a hobby/pasttime.
Supportive treatments
 Spasticity – baclofen, BZDPs, dantrolene
 Fatigue – amantadine 100 mg bd
 Depression – TCADs, SSRIs
 Paroxysmal disorders – tegretol or
gabapentin for trigeminal neuralgia or
paroxysmal painful syndromes eg leg pains
 Bladder dysfunction – TCADs, oxybutinin