Abstract
Introduction
Multiple sclerosis is the most common cause of neurological disability in young adults. Irreversible disability can occur, but life expectancy is generally not affected.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions aimed at reducing relapse rates and disability in people with multiple sclerosis? What are the effects of interventions to improve symptoms during acute relapse? What are the effects of treatments for fatigue, spasticity, and multidisciplinary care on disability in people with multiple sclerosis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2011 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 71 systematic reviews, RCTs, and observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following key interventions: amantadine, azathioprine, behaviour modification, botulinum toxin, corticosteroids, exercise, gabapentin, inpatient or outpatient rehabilitation, interferon beta, intrathecal baclofen, intravenous immunoglobulin, methotrexate, mitoxantrone, modafinil, natalizumab, oral drug treatments, parenteral glatiramer acetate, physiotherapy, and plasma exchange.
Key Points
Multiple sclerosis is characterised by central nervous system lesions causing neurological dysfunction and other problems, such as fatigue, pain, depression, and anxiety.
Early disease is usually relapsing and remitting, but most people develop secondary-progressive disease over time. No treatment has been shown to affect long-term outcome.
Irreversible disability can occur, but life expectancy is generally not affected.
In people with relapsing and remitting disease, glatiramer acetate and azathioprine may reduce relapse rates, but have not been shown to affect disease progression. Toxicity associated with azathioprine means that 10% of people cannot tolerate it at therapeutic doses.
Interferon beta may reduce exacerbations and disease progression in relapsing and remitting multiple sclerosis, and may reduce the risk of conversion to clinically definite multiple sclerosis in people experiencing a first demyelinating event.
Intravenous immunoglobulin may prevent relapse after a first demyelinating event, but we don't know whether it is effective in people with relapsing and remitting disease.
Mitoxantrone may reduce exacerbations and disease progression.
Natalizumab may increase the proportion of people who are relapse-free at 2 years in relapsing and remitting multiple sclerosis.
CAUTION: Interferon beta and mitoxantrone have been associated with serious adverse effects. Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), and the long-term benefits and risks are still unknown.
We don't know whether interferon beta, intravenous immunoglobulin, or methotrexate delay disease progression in people with secondary-progressive multiple sclerosis, as studies have given conflicting results.
Corticosteroids (methylprednisolone or corticotropin) may improve symptoms in people with an acute exacerbation of multiple sclerosis compared with placebo.
We don't know whether plasma exchange, intravenous immunoglobulin, or natalizumab are beneficial.
We don't know whether amantadine, behavioural modification, modafinil, or exercise reduce fatigue. Exercise may help to maintain strength, fitness, mobility, and improve quality of life, but studies have been difficult to compare.
We don't know whether botulinum toxin, gabapentin, intrathecal baclofen, oral antispasmodic drugs, or physiotherapy improve spasticity.
Inpatient rehabilitation may improve function in the short term, but we don't know whether outpatient rehabilitation is also of benefit.
About this condition
Definition
Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Diagnosis requires evidence of lesions that are separated in both time and space, and the exclusion of other inflammatory, structural, or hereditary conditions that might give a similar clinical picture. The disease takes three main forms: relapsing and remitting multiple sclerosis, characterised by episodes of neurological dysfunction interspersed with periods of stability; primary-progressive multiple sclerosis, in which progressive neurological disability occurs from the outset; and secondary-progressive multiple sclerosis, in which progressive neurological disability occurs later in the course of the disease. Axonal loss is the major determinant of the accumulation of irreversible (progressive) disability as a result of inflammation during both the relapsing and remitting and progressive phases of multiple sclerosis, but also because of possible neurodegeneration through loss of trophic support. The emergence of treatment for multiple sclerosis has led to the recognition of a first demyelinating event or "clinically isolated syndrome" (CIS), a single episode of neurological dysfunction lasting for >24 hours, which can be a prelude to multiple sclerosis. Characteristic episodes include optic neuritis, solitary brainstem lesions, and transverse myelitis that, when associated with magnetic resonance imaging (MRI) changes, result in a 30% to 70% risk of developing multiple sclerosis. Increasingly recognised are other demyelinating syndromes thought to be distinct from multiple sclerosis; these include Devic's disease (neuromyelitis optica), relapsing optic neuritis, and relapsing myelitis. Other than episodes of neurological dysfunction, chronic symptoms produce much of the disability in multiple sclerosis. Symptoms include fatigue (main symptom in two-thirds of people), spasticity, bladder/bowel problems, ataxia/tremor, visual problems, pain, depression/anxiety, dysphagia, and sexual dysfunction.
Incidence/ Prevalence
Prevalence varies with geography and racial group. It is highest in white populations in temperate regions. In Europe and North America, prevalence is 1/800 people, with an annual incidence of 2–10/100,000, making multiple sclerosis the most common cause of neurological disability in young adults. Age of onset is broad, peaking between 20 and 40 years.
Aetiology/ Risk factors
The cause remains unclear, although current evidence suggests that multiple sclerosis is an autoimmune disorder of the central nervous system resulting from an environmental stimulus in genetically susceptible individuals. Multiple sclerosis is currently regarded as a single disorder with clinical variants, but there is some evidence that it may consist of several related disorders with distinct immunological, pathological, and genetic features.
Prognosis
In 90% of people early disease is relapsing and remitting. Although some people follow a relatively benign course over many years, most develop secondary-progressive disease, usually 6–10 years after onset. In 10% of people, initial disease is primary progressive. Apart from a minority of people with "aggressive" multiple sclerosis, life expectancy is not greatly affected, and the disease course is often of >30 years' duration.
Aims of intervention
To prevent or delay disability; to improve function; to alleviate symptoms of spasticity; to prevent complications (contractures, pressure sores); to optimise quality of life; with minimal adverse effects.
Outcomes
For question on interventions aimed at reducing relapse rates and disability: Neurological disability; sustained disease progression; relapse rates, quality of life; and adverse effects of treatment. For question on interventions to improve symptoms during acute relapse: Symptom improvement, including remission rates; neurological disability; quality of life; and adverse effects. For question on effects of treatments for spasticity: Spasticity; quality of life; and adverse effects. For question on effects of treatments for fatigue: Fatigue; quality of life; and adverse effects. For question on effects of multidisciplinary care on disability: Neurological disability; quality of life; and adverse effects. Neurological disability: In clinical trials, disability in multiple sclerosis is usually measured using the disease-specific Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death from multiple sclerosis) in half-point increments. Lower scores (0–4) reflect specific neurological impairments and disability; higher scores reflect reducing levels of mobility (4–7) and upper-limb and bulbar function (7.0–9.5). The scale is non-linear and has been criticised for indicating change poorly, for emphasising neurological examination and mobility, and for failing to reflect other disabilities (e.g., fatigue, sexual disability). Some timed outcomes include ambulation (time taken to walk a specified short distance), the 9-hole peg test (time taken to place pegs into holes in a block), and the box and block test (time taken to transfer blocks between boxes). Sustained disease progression: This is reported when an increase in disability from either disease progression or incomplete recovery from relapse is sustained for 3 or 6 months. A relapse that resolves within this time period constitutes non-sustained progression. Spasticity: A variety of clinical measures are used, the most common being the Ashworth Scale, which scores muscle tone on a scale of 0 (normal tone) to 4 (severe spasticity). For the purposes of this review, the Ashworth Scale was considered to represent an appropriate clinical outcome, and was selected over other outcome measures for spasticity (e.g., neurophysiological measures, examination ratings) that represent proxy clinical outcomes. Quality of life: Attempts have been made to customise generic health-related quality of life scales, but these scales have not been widely used. Magnetic resonance imaging (MRI): MRI is a commonly used surrogate outcome in RCTs. Several parameters are measured but, as these have a weak correlation with clinical outcomes, this review focuses only on clinical outcomes.
Methods
Clinical Evidence search and appraisal July 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2011, Embase 1980 to July 2011, and The Cochrane Database of Systematic Reviews, Issue 2, 2011 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we did an observational harms search for specific harms as highlighted by the contributor, peer reviewer, and editor. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Multiple sclerosis.
| Important outcomes | Fatigue, Neurological disability, Quality of life, Relapse rates, Spasticity, Sustained disease progression, Symptom improvement | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of interventions aimed at reducing relapse rates and disability in people with multiple sclerosis? | |||||||||
| 1 (251) | Relapse rates | Glatiramer acetate versus placebo in relapsing and remitting multiple sclerosis | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (251) | Neurological disability | Glatiramer acetate versus placebo in relapsing and remitting multiple sclerosis | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and no direct comparison between groups |
| 2 (1049) | Sustained disease progression | Glatiramer acetate versus placebo in progressive multiple sclerosis | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for premature termination of larger RCT |
| 4 (1372) | Sustained disease progression | Interferon beta versus placebo in people having first demyelinating event | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for poor follow-up in 1 RCT |
| 3 (919) | Sustained disease progression | Interferon beta-1a versus placebo in people with relapsing and remitting multiple sclerosis | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results on performing sensitivity analysis |
| 3 (919) | Relapse rates | Interferon beta-1a versus placebo in people with relapsing and remitting multiple sclerosis | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results on performing sensitivity analysis |
| 1 (188) | Relapse rates | Interferon beta-1a versus interferon beta-1b in people with relapsing and remitting multiple sclerosis | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and lack of blinding |
| 4 (2711) | Sustained disease progression | Interferon beta-1a versus placebo in people with secondary-progressive multiple sclerosis | 4 | –2 | –1 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results and poor follow-up. Consistency point deducted for conflicting results. Directness point deducted for uncertainty about measurement of outcome in 1 RCT |
| 1 (618) | Relapse rates | Interferon beta-1a versus placebo in people with secondary-progressive multiple sclerosis | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (91) | Sustained disease progression | Intravenous immunoglobulin versus placebo in people having a first demyelinating event | 4 | –2 | 0 | 0 | +1 | Moderate | Quality points deducted for sparse data and incomplete reporting of results. Effect-size point added for odds ratio 0.2 to 0.5 |
| 6 (685) | Relapse rates | Intravenous immunoglobulin versus placebo in relapsing and remitting multiple sclerosis | 4 | 0 | 0 | 0 | 0 | High | |
| 5 (308) | Neurological disability | Intravenous immunoglobulin versus placebo in relapsing and remitting multiple sclerosis | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for inclusion of people with secondary-progressive multiple sclerosis |
| 1 (80) | Relapse rates | Intravenous immunoglobulin versus interferon beta-1a in relapsing and remitting multiple sclerosis | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (515) | Sustained disease progression | Intravenous immunoglobulin versus placebo in secondary-progressive multiple sclerosis | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (515) | Relapse rates | Intravenous immunoglobulin versus placebo in secondary-progressive multiple sclerosis | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for no assessment of statistical significance between groups |
| 1 (128) | Sustained disease progression | Mitoxantrone versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of co-intervention |
| 4 (270) | Relapse rates | Mitoxantrone versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of co-intervention |
| 2 (175) | Neurological disability | Mitoxantrone versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of intervention |
| 7 (793) | Relapse rates | Azathioprine versus placebo | 4 | –1 | –1 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs. Directness points deducted for inclusion of different disease states and differences in relapse definitions |
| 7 (793) | Neurological disability | Azathioprine versus placebo | 4 | –1 | –2 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency points deducted for heterogeneity between RCTs and conflicting results. Directness points deducted for inclusion of different disease states and differences in relapse definitions |
| 1 (942) | Sustained disease progression | Natalizumab versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (942) | Relapse rates | Natalizumab versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (1171) | Sustained disease progression | Natalizumab plus interferon beta-1a versus interferon beta-1a alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (1171) | Relapse rates | Natalizumab plus interferon beta-1a versus interferon beta-1a alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (60) | Sustained disease progression | Methotrexate versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (60) | Relapse rates | Methotrexate versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of interventions to improve symptoms during acute relapse in people with multiple sclerosis? | |||||||||
| 1 (51) | Symptom improvement | Corticosteroids versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (31) | Symptom improvement | Corticosteroids versus each other | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of different disease states |
| 1 (31) | Neurological disability | Corticosteroids versus each other | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of different disease states |
| 2 (138) | Neurological disability | Plasma exchange versus sham treatment | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness points deducted for different disease states and differences in co-interventions used |
| 1 (76) | Neurological disability | Intravenous immunoglobulin plus corticosteroids versus corticosteroid alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and short follow-up |
| 1 (180) | Neurological disability | Natalizumab versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of treatments for fatigue in people with multiple sclerosis? | |||||||||
| 4 (236) | Fatigue | Amantadine versus placebo | 4 | –3 | –1 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results, methodological flaws (uncertainty about blinding, randomisation, poor follow-up, and no intention-to-treat analysis). Consistency point deducted for conflicting results. Directness point deducted for different methods of assessing fatigue |
| 2 (71) | Fatigue | Exercise versus no exercise | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for wide range of outcomes measured |
| 1 (31) | Quality of life | Exercise versus no exercise | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and no intention-to-treat analysis |
| 1 (115) | Fatigue | Modafinil versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of treatments for spasticity in people with multiple sclerosis? | |||||||||
| 1 (33) | Spasticity | Botulinum toxin versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (20) | Spasticity | Intrathecal baclofen versus intrathecal saline | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data. Directness points deducted for no direct comparison between groups and inclusion of people with spinal cord injuries |
| 1 (30) | Spasticity | Baclofen versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (407) | Spasticity | Tizanidine versus placebo | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for conflicting results. Directness point deducted for uncertainty about clinical relevance of outcome |
| 3 (876) | Spasticity | Oral cannabis versus placebo | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and not assessing results before crossover. Consistency point deducted for lack of consistency in results for different measures of the same outcome |
| 3 (105) | Spasticity | Oral baclofen versus tizanidine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and lack of significance assessments |
| 1 (30) | Spasticity | Oral diazepam versus tizanidine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting |
| 2 (85) | Spasticity | Physiotherapy versus no physiotherapy or delayed physiotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (38) | Spasticity | Physiotherapy plus botulinum toxin versus botulinum toxin alone | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted as unclear if absolute differences in scores between groups were of clinical importance |
| What are the effects of multidisciplinary care on disability in people with multiple sclerosis? | |||||||||
| 3 (222) | Neurological disability | Inpatient rehabilitation versus control | 4 | –1 | –2 | 0 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency points deducted for heterogeneity among RCTs and conflicting results |
| 1 (25) | Neurological disability | Outpatient rehabilitation versus no treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for wide range of outcomes measured |
| 4 (308) | Quality of life | Outpatient rehabilitation versus no treatment | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and inclusion of poor-quality trials. Consistency point deducted for heterogeneity among RCTs |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Corticosteroids
Synthetic glucocorticoids (similar to hormones) are used to treat atopic eczema, among other diseases, to suppress inflammation, allergy, and immune responses.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Intravenous immunoglobulins
Immunoglobulin preparations derived from donated human plasma containing antibodies prevalent in the general population.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Contributor Information
Richard Nicholas, Imperial Healthcare Trust, London, UK.
Waqar Rashid Waqar Rashid, Brighton and Sussex University Hospitals NHS Trust, Sussex, UK.
References
- 1.Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705–2712. [DOI] [PubMed] [Google Scholar]
- 2.Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 2003;206:165–171. [DOI] [PubMed] [Google Scholar]
- 3.Miller D, Barkhof F, Montalban X, et al. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281–288. [DOI] [PubMed] [Google Scholar]
- 4.Compston A. Genetic epidemiology of multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;62:553–561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ford HL, Gerry E, Johnson M, et al. A prospective study of the incidence, prevalence and mortality of multiple sclerosis in Leeds. J Neurol 2002;249:260–265. [DOI] [PubMed] [Google Scholar]
- 6.Sloka JS, Pryse-Phillips WE, Stefanelli M. Incidence and prevalence of multiple sclerosis in Newfoundland and Labrador. Can J Neurol Sci 2005;32:37–42. [DOI] [PubMed] [Google Scholar]
- 7.Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. 1. Clinical course and disability. Brain 1989;112:133–146. [DOI] [PubMed] [Google Scholar]
- 8.Lucchinetti CF, Bruck W, Rodriguez M, et al. Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesis. Brain Pathol 1996;6:259–274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kurtzke JF. Rating neurological impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444–1452. [DOI] [PubMed] [Google Scholar]
- 10.Vickrey BG, Hays RD, Genovese BJ, et al. Comparison of a generic to disease-targeted health-related quality-of-life measures for multiple sclerosis. J Clin Epidemiol 1997;50:557–569. [DOI] [PubMed] [Google Scholar]
- 11.Munari L, Lovati R, Boiko A. Glatiramer acetate for multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2009. 20464733 [Google Scholar]
- 12.Johnson KP, Brooks BR, Cohen JA, et al. Copolymer-1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a Phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268–1276. [DOI] [PubMed] [Google Scholar]
- 13.Wolinsky JS, Narayana PA, O'Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007;61:14–24. [DOI] [PubMed] [Google Scholar]
- 14.Clerico M, Faggiano F, Palace J, et al. Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2007. [DOI] [PubMed] [Google Scholar]
- 15.Pakdaman H, Sahraian MA, Fallah A, et al. Effect of early interferon beta-1a therapy on conversion to multiple sclerosis in Iranian patients with a first demyelinating event. Acta Neurol Scand 2007;115:429–431. [DOI] [PubMed] [Google Scholar]
- 16.Rice GP, Incorvaia B, Munari L, et al. Interferon in relapsing-remitting multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2007. 11687131 [Google Scholar]
- 17.Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once weekly interferon beta-1a for multiple sclerosis: results of a 2 year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453–1460. [DOI] [PubMed] [Google Scholar]
- 18.Stangel M, Hartung HP, Marx P, et al. Side-effects of high-dose intravenous immunoglobulins. Clin Neuropharmacol 1997;20:385–393. [DOI] [PubMed] [Google Scholar]
- 19.Oliver BJ, Kohli E, Kasper LH. Interferon therapy in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis of the comparative trials. J Neurol Sci 2011;302:96–105. [DOI] [PubMed] [Google Scholar]
- 20.Panitch H, Miller A, Paty D, et al. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004;63:1788–1795. [DOI] [PubMed] [Google Scholar]
- 21.Kappos L, Polman C, Pozzilli C, et al. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491–1497. [PubMed] [Google Scholar]
- 22.King J, McLeod J, Gonsette RE, et al. Randomised controlled trial of interferon beta-1a in secondary progressive MS: clinical results. Neurology 2001;56:1496–1504. [DOI] [PubMed] [Google Scholar]
- 23.Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002;59:679–687. [DOI] [PubMed] [Google Scholar]
- 24.Achiron A, Kishner I, Sarova-Pinhas I, et al. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Arch Neurol 2004;61:1515–1520. [DOI] [PubMed] [Google Scholar]
- 25.Gray OM, McDonnell GV, Forbes RB, et al. Intravenous immunoglobulins for multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2009. 14583956 [Google Scholar]
- 26.Fergusson D, Hutton B, Sharma M, et al. Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review. Transfusion 2005;45:1640–1657. [DOI] [PubMed] [Google Scholar]
- 27.Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing–remitting multiple sclerosis. Lancet 1997;349:589–593. [DOI] [PubMed] [Google Scholar]
- 28.Kalanie H, Gharagozli K, Hemmatie A, et al. Interferon beta-1a and intravenous immunoglobulin treatment for multiple sclerosis in Iran. Eur Neurol 2004;52:202–206. [DOI] [PubMed] [Google Scholar]
- 29.Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004;364:1149–1156. [DOI] [PubMed] [Google Scholar]
- 30.Martinelli Boneschi F, Rovaris M, Capra R, et al. Mitoxantrone for multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005. 16235298 [Google Scholar]
- 31.Ghalie RG, Edan G, Laurent M, et al. Cardiac adverse events associated with mitoxantrone (novantrone) therapy in patients with MS. Neurology 2002;59:909–913. [DOI] [PubMed] [Google Scholar]
- 32.Ghalie RG, Mauch E, Edan G, et al. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002;8:441–445. [DOI] [PubMed] [Google Scholar]
- 33.US Food and Drug Administration. Safety information: mitoxantrone hydrochloride (marketed as Novantrone and generics). July 2008. Available at http://www.fda.gov (accessed on 11 January 2012). [Google Scholar]
- 34.Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 1991;338:1051–1055. Search date 1989. [DOI] [PubMed] [Google Scholar]
- 35.Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. 17943809 [Google Scholar]
- 36.Confavreux C, Saddier P, Grimaud J, et al. Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology 1996;46:1607–1612. [DOI] [PubMed] [Google Scholar]
- 37.Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Eng J Med 2006;354:899–910. [DOI] [PubMed] [Google Scholar]
- 38.Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Eng J Med 2006;354:911–923. [DOI] [PubMed] [Google Scholar]
- 39.Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Eng J Med 2006;354:924–933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Phillips JT, O'Connor PW, Havrdova E, et al. Infusion-related hypersensitivity reactions during natalizumab treatment. Neurology 2006;67:1717–1718. [DOI] [PubMed] [Google Scholar]
- 41.Gray O, McDonnell GV, Forbes RB. Methotrexate for multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2007. 15106195 [Google Scholar]
- 42.Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7.5�mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995;37:30–40. [DOI] [PubMed] [Google Scholar]
- 43.Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Taus C, Solari A, D'Amico R, et al. Amantadine for fatigue in multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. 12804439 [Google Scholar]
- 45.Weinshenker BG, O'Brien PC, Petterson TM, et al. A randomised trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999;46:878–886. [DOI] [PubMed] [Google Scholar]
- 46.Weiner HL, Dau PC, Khatri BO, et al. Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology 1989;39:1143–1149. [DOI] [PubMed] [Google Scholar]
- 47.Soelberg PS, Haas J, Sellebjerg F, et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology 2004;63:2028–2033. [DOI] [PubMed] [Google Scholar]
- 48.O'Connor PW, Goodman A, Willmer-Hulme AJ, et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology 2004;62:2038–2043. [DOI] [PubMed] [Google Scholar]
- 49.Branas P, Jordan R, Fry-Smith A, et al. Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Health Technol Assess 2000;4:1–73. Search date 1999. [PubMed] [Google Scholar]
- 50.Rietberg MB, Brooks D, Uitdehaag BM, et al. Exercise therapy for multiple sclerosis. In: The Cochrane Library 2011, Issue 2. Chichester, UK: John Wiley & Sons, Ltd. Search date 2004. 15674920 [Google Scholar]
- 51.Motl RW, Gosney JL. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Mult Scler 2008;14:129–135. [DOI] [PubMed] [Google Scholar]
- 52.Mutluay FK, Demir R, Ozyilmaz S, et al. Breathing-enhanced upper extremity exercises for patients with multiple sclerosis. Clin Rehabil 2007;21:595–602. [DOI] [PubMed] [Google Scholar]
- 53.Dalgas U, Stenager E, Jakobsen T, et al. Fatigue, mood and quality of life improve in MS patients after progressive resistance training. Mult Scler 2010;16:480–490. [DOI] [PubMed] [Google Scholar]
- 54.Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005;64:1139–1143. [DOI] [PubMed] [Google Scholar]
- 55.Hyman N, Barnes M, Bhakta B, et al. Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study. J Neurol Neurosurg Psychiatry 2000;68:707–712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517–1521. [DOI] [PubMed] [Google Scholar]
- 57.Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003. 14583932 [Google Scholar]
- 58.Brar S, Smith MB, Nelson LM, et al. Evaluation of treatment protocols on minimal to moderate spasticity in multiple sclerosis. Arch Phys Med Rehabil 1991;72:186–189. [PubMed] [Google Scholar]
- 59.Smith C, Birnbaum G, Carter JL, et al. Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. Neurology 1994;44:34–42. [PubMed] [Google Scholar]
- 60.Barnes MP, Bates D, Corston RN, et al. A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis. Neurology 1994;44:S70–S78. [PubMed] [Google Scholar]
- 61.Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362:1517–1526. [DOI] [PubMed] [Google Scholar]
- 62.Vaney C, Heinzel-Gutenbrunner M, Jobin P, et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler 2004;10:417–424. [DOI] [PubMed] [Google Scholar]
- 63.Collin C, Davies P, Mutiboko IK, et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007;14:290–296. [DOI] [PubMed] [Google Scholar]
- 64.Stien R, Nordal HJ, Oftedal SI, et al. The treatment of spasticity in multiple sclerosis: a double-blind clinical trial of a new anti-spastic drug tizanidine compared with baclofen. Acta Neurol Scand 1987;75:190–194. [DOI] [PubMed] [Google Scholar]
- 65.Smolenski C, Muff S, Smolenski-Kautz S. A double-blind comparative trial of new muscle relaxant, tizanidine (DS 103-282), and baclofen in the treatment of chronic spasticity in multiple sclerosis. Curr Med Res Opin 1981;7:374–383. [PubMed] [Google Scholar]
- 66.Pellkofer M, Paulig M. Comparative double-blind study of the effectiveness and tolerance of baclofen, tetrazepam and tizanidine in spastic movement disorders of the lower extremities. Med Klin (Munich) 1989;84:5–8. [In German] [PubMed] [Google Scholar]
- 67.Groves L, Shellenberger MK, Davis CS. Tizanidine treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Adv Ther 1998;15:241–251. Search date not reported. [PubMed] [Google Scholar]
- 68.Wiles CM, Newcombe RG, Fuller KJ, et al. Controlled randomised crossover trial of the effects of physiotherapy on mobility in chronic multiple sclerosis. J Neurol Neurosurg Psychiatry 2001;70:174–179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Fuller KJ, Dawson K, Wiles CM. Physiotherapy in chronic multiple sclerosis: a controlled trial. Clin Rehabil 1996;10:195–204. [Google Scholar]
- 70.Giovannelli M, Borriello G, Castri P, et al. Early physiotherapy after injection of botulinum toxin increases the beneficial effects on spasticity in patients with multiple sclerosis. Clini Rehabil 2007;21:331–337. [DOI] [PubMed] [Google Scholar]
- 71.Khan F, Turner-Stokes L, Ng L, et al. Multidisciplinary rehabilitation for adults with multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005. 17443610 [Google Scholar]
- 72.Storr LK, Sorensen PS, Ravnborg M. The efficacy of multidisciplinary rehabilitation in stable multiple sclerosis patients. Mult Scler 2006;12:235–242. [DOI] [PubMed] [Google Scholar]
- 73.Freeman JA, Langdon DW, Hobart JC, et al. The impact of inpatient rehabilitation on progressive multiple sclerosis. Ann Neurol 1997;42:236–244. [DOI] [PubMed] [Google Scholar]
- 74.Solari A, Fillipini G, Gasco P, et al. Physical rehabilitation has a positive effect on disability in multiple sclerosis patients. Neurology 1999;52:57–62. [DOI] [PubMed] [Google Scholar]
- 75.Khan F, Ng L, Turner-Stokes, L. Effectiveness of vocational rehabilitation intervention on the return to work and employment of persons with multiple sclerosis. In: The Cochrane Library, Issue 2, 2011. Chichester, UK: John Wiley & Sons, Ltd. Search date 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Broekmans T, Roelants M, Alders G, et al. Exploring the effects of a 20-week whole-body vibration training programme on leg muscle performance and function in persons with multiple sclerosis. J Rehabil Med 2010;42:866–872. [DOI] [PubMed] [Google Scholar]
- 77.Broekmans T, Roelants M, Feys P, et al. Effects of long-term resistance training and simultaneous electro-stimulation on muscle strength and functional mobility in multiple sclerosis. Mult Scler 2011;17:468–477. [DOI] [PubMed] [Google Scholar]