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, anti-inflammatory 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 anti-inflammatory 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% drop-out 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/past-time.

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