Updates

1. Prevention of demyelination:
1.1 Blocking interferon gamma production
Agent & comment	Type of disease	Outcome measure*	Result	Reference
Interferon beta 1a	relapsing/ remitting n=560	time to first relapse	increased by 5 months by higher dose; increased by 3 months by lower dose compared with placebo	Ebers and PRISMS Study group Lancet 1998 352:1498-504
		reduction in MRI new lesions	3.8% reduction cf. 10.9% increase with placebo
BUT: -	no clear relationship with disability adverse reactions ('flu like symptoms) cost
Agent & comment	Type of disease	Outcome measure*	Result	Reference
Interferon beta 1b	secondary progressive n=718	Prevention of progression over 2 years	39% cf. 50% with placebo	Kappos & European Study group Lancet 1998 352:1491-7
		avoidance of wheel-chair	17% cf. 26% with placebo
		reduction in MRI new lesions	5% reduction cf. 8% increase with placebo
BUT: -	moderate adverse reactions 60% in first 3 months neutralising ntibodies in20-30% in 2 years cost

1.2 Block T cell activation
Agent & comment	Type of disease	Outcome measure*	Result	Reference
*Antigen specific:*
Glatiramer acetate (copolymer 1)	early relaps/remitting n=251	reduction of relapse rate	29% reduction over 2 years cf. placebo	Johnson et al. Neurology 1998 50:701-8
Agent & comment	Type of disease	Outcome measure*	Result	Reference
*Non specific:*
Azathioprine	relapsing/ remitting n=34	reduction of relapse rate in open trial with IVIg	1.7 relapses pa cf. 0 in 3 year trial	Kalanie et al. Europ. Neurology 1998 39: 178-81
Cyclosporin A Methotrexate Cyclophos- phamide Interferon gamma Monoclonal ab to CD4	} minimal effect / excess toxicity / increased relapse rate
Cladribine	in pilot trials			Romine et al. Proc Ass Am Physicians 1999 111: 35-44

2. Encourage remyelination
Agent & comment	Type of disease	Outcome measure*	Result	Reference
Intravenous immunoglobulin	relapsing/ remitting n=148	reduction in disability score [EDSS]	reduced 3.33 to 3.05 on IVIg cf. increase 3.37 to 3.49 on placebo	Fazekas et al. Mult. Scler. 1997 3: 137-41

3. Anti-viral therapies
Agent & comment	Type of disease	Outcome measure*	Result	Reference
Interferon alpha 2a	relapsing/ remitting n=97	reduction in MRI new lesions over 6 months	0.28 new lesions whilst on IFN cf. 4.7 8 on placebo	Myhr et al. Neurology 1999 23: 1049-56
*Symptomatic treatment*
Reduction of acute oedema (short course of oral/IV steroids), reduction of spasticity, control of bladder & sexual functions, relief of fatigue, neuralgia and convulsions, spasms, tremor & mood disorders recognition of cognitive impairment and provision of support.
* Outcome measures
Type	Measure	Problem	Solutions/ comment	Reference
Clinical
Symptomatic	disease remission	spontaneous remission is common	long follow-up
			large numbers of patients
			equal numbers matching placebo treated/control patients
	frequency of new	variable rate	long follow-up
	episodes	silent episodes	needs imaging or missed
		result in variable disability
	change in disability scores	disability scores do not reflect new plaques
Type	Measure	Problem	Solutions/ comment	Reference
Signs	appearance of new signs	observer variability	two independent but constant observers
			double blind trial design
Type	Measure	Problem	Solutions/ comment	Reference
Imaging (surrogate)	MRI	does not reflect new plaques difficult to quantitate cost		Miller DH Sem. Neurol. 1998 18: 317-25
Type	Measure	Problem	Solutions/ comment	Reference
Laboratory markers		none available yet		Laman et al Mult. Sclerosis 1998 4: 266-9