Accepted Manuscript

Rehabilitation in Multiple Sclerosis: a Systematic Review of Systematic Reviews

Fary Khan, MBBS, MD, FAFRM (RACP), Bhasker Amatya, MD, MPH

PII: S0003-9993(16)30162-9
DOI: 10.1016/j.apmr.2016.04.016
Reference: YAPMR 56548

To appear in: ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 6 April 2016

Accepted Date: 22 April 2016

Please cite this article as: Khan F, Amatya B, Rehabilitation in Multiple Sclerosis: a Systematic Review
of Systematic Reviews, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2016), doi:
10.1016/j.apmr.2016.04.016.

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Title: Rehabilitation in Multiple Sclerosis: a Systematic Review of Systematic Reviews

Fary Khan MBBS, MD, FAFRM (RACP),a,b,c* Bhasker Amatya MD, MPH,a

aDepartment of Rehabilitation Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.

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bDepartment of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria,

Australia.

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cSchool of Public Health and Preventive Medicine, Monash University, Victoria, Australia.

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*Corresponding author:

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Professor Fary Khan
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Department of Rehabilitation Medicine,

Royal Melbourne Hospital,

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34-54 Poplar Road, Parkville, VIC 3052, Australia.

Ph: +61 3 83872146, fax: +61 3 83872222, e-mail: fary.khan@mh.org.au

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Short title: Rehabilitation in multiple sclerosis

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CONFLICT OF INTEREST
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The authors declare no competing or conflicts of interest.

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FINANCIAL DISCLOSURE

No external funding was available. No commercial party having a direct financial interest in the results of the

research supporting this article has or will confer a benefit on the authors or on any organization with which the

authors are associated.

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ACKNOWLEDGEMENT

This review was supported from internal resources of the Rehabilitation Department, Royal Melbourne

Hospital, Royal Park Campus, Melbourne, Australia.

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1 Title: Rehabilitation in Multiple Sclerosis: a Systematic Review of Systematic Reviews

2 ABSTRACT

3 Objectives: To systematically evaluate existing evidence from published systematic reviews of clinical trials

4 for the effectiveness of rehabilitation for improved function and participation.

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5 Data sources: A literature search was conducted using medical and health science electronic databases

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6 (MEDLINE, EMBASE, CINAHL, PubMed, and the Cochrane Library) up to 31st January 2016.

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7 Study Selection: Two reviewers independently applied inclusion criteria to select potential systematic

8 reviews assessing the effectiveness of organised rehabilitation for person with MS. Data were summarized

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9 for type of interventions, type of study designs included, outcome domains, method of data synthesis and
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10 findings.

11 Data extraction: Data were extracted by two reviewers independently, for methodological quality using
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12 Assessment of Multiple Systematic Reviews (AMSTAR). Quality of evidence was critically appraised with
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13 Grades of Recommendation, Assessment, Development and Evaluation (GRADE).

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14 Data synthesis: Thirty-nine systematic reviews (1 with 2 reports) evaluated best evidence to date. There is

15 ‘strong’ evidence for physical therapy for improved activity and participation, and exercise-based educational
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16 programs for reduction in patient-reported fatigue; ‘moderate’ evidence for multidisciplinary rehabilitation for

17 longer-term gains at the levels of activity (disability) and participation, for cognitive-behavior therapy for
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18 treatment of depression, and for information-provision interventions for improved patient knowledge. There
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19 is ‘limited’ evidence for better patient outcomes using psychological and symptom-management programs

20 (fatigue, spasticity). For other rehabilitation interventions, evidence was inconclusive due to limited

21 methodologically robust studies.

22 Conclusions: Despite the range of rehabilitative treatments available for MS, there is lack of high-quality

23 evidence for many modalities. Further research is needed for effective rehabilitation approaches with

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24 appropriate study design, outcome measurement, type and intensity of modalities and cost-effectiveness of

25 these interventions.

26 Keywords: multiple sclerosis, rehabilitation, disability, impairment, participation

27

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28 ABBREVIATIONS:

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29 AMSTAR: Assessment of Multiple Systematic Reviews, CBT: Cognitive-Behaviour Therapy, CCT: controlled

30 clinical trial, ES: effect size, ICF: International Classification of Functioning and Health, iTBS: Intermittent Theta

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31 Burst Stimulation, GRADE: Grades of Recommendation, Assessment, Development and Evaluation, HBOT:

32 Hyperbaric Oxygen Therapy, MDR: Multidisciplinary rehabilitation, MS: Multiple Sclerosis, OT: occupational

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therapy, PT: physiotherapy, pwMS: persons with MS, QoL: quality of life, RCT: randomised controlled trial, rTMS:
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34 Repetitive Transcranial Magnetic Stimulation, SMD: standardized mean difference, TENS: Transcutaneous

35 Electrical Nerve Stimulation, WBV: Whole-body vibration, WT: Walking Test

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37
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38 Multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system, affects

39 approximately 1.3 million people worldwide.1 It is a major cause of chronic neurological disability in young adults
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40 (aged 18–50 years), associated with complex disabilities including disorders of strength, sensation, co-ordination

41 and balance, as well as visual, cognitive and affective deficits.2, 3 These disabilities usually lead to progressive
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42 limitation of functioning in daily life, requiring longer-term multidisciplinary management. MS has a variable
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43 prognosis; and studies report factors associated with worse prognosis such as: older age at onset, progressive

44 disease course, multiple onset symptoms, pyramidal or cerebellar symptoms and a short interval between onset

45 and first relapse.4, 5 With advances in MS management, persons with MS (pwMS) are living longer (median

46 survival time from the time of diagnosis of 40 years6), therefore, issues related to progressive disability (physical

47 and cognitive), psychosocial adjustment and social re-integration need to be addressed over time2, 3.

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48 Persons with MS can present with various combinations of deficits such as physical (motor weakness,

49 spasticity, sensory dysfunction, visual loss, ataxia), fatigue, pain (neurogenic, musculoskeletal and mixed patterns),

50 incontinence (urinary urgency, frequency), cognitive (memory, attention), psychosocial, behavioural and

51 environmental problems, which limit a person’s activity (function) and participation.7 The International Classification

52 of Functioning and Health (ICF), provides a global conceptual framework to categorise abilities and problems of

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53 pwMS within a standard system and offers common language for clinicians for describing function, disability and

54 health of an individual.8 A simulated case example of the ICF model related to MS is given in Figure 1.

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55
56 (Insert Fig 1)

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57 Medical rehabilitation is defined as ‘a set of measures that assist individuals who experience disability to

58 achieve and maintain optimal physical, sensory, intellectual, psychological and social functioning in interaction with

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59 their environment’.9 It is a complex process of delivering a coordinated interdisciplinary care program, comprising a
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60 series of individualized and goal-oriented therapies tailored for specific patient needs.10 The goal of rehabilitation is

61 to improve functional independence and enhance participation with emphasis on patient education and self-
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62 management. Despite advances in medical management, MS continues to have greater disability-burden over

63 long periods of time. The complex care needs of pwMS are due to cumulative effects of impairments and
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64 disabilities, the ‘wear and tear’ and the impact of ‘aging’ with a disability. Maintaining functional gains and social re-
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65 integration over a longer-term with multidisciplinary rehabilitation is recommended, both in hospital and

66 community.1, 7, 11
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67 In recent years, many rehabilitation interventions have been trialled in pwMS for improved clinical

68 outcomes.12, 13 Haselkorn et al in a systematic review provided an overview of evidence for physical rehabilitation
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69 for pwMS.14 The authors included 142 individual trials (all designs- published between 1970–2013), and rated
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70 evidence using American Academy of Neurology criteria (2004).14 Bennett SE in another narrative review present

71 evidence for specific type of exercises for MS symptoms and functional recovery.15 Although these reviews present

72 current evidence on specific interventions, they vary in quality, scope and methodology, at times with diverse

73 findings.16 The approach of a ‘systematic’ review of ‘systematic reviews’, draws together the current evidence

74 across specialities of the same or very similar intervention, to provide synthesis of treatment effect in a much

75 broader concept.16 This review, therefore, systematically evaluated evidence from currently published ‘systematic

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76 reviews’ of clinical trials to determine effectiveness of rehabilitation interventions for pwMS, using global criteria

77 recommended by evidence-based literature, and evaluated a wider range of therapeutic modalities.

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79 METHODS

80 A comprehensive search of the Cochrane Library database (including DARE), MEDLINE, CINHAL, EMBASE and

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81 PubMed was undertaken till 31stth January 2016 for systematic reviews evaluating rehabilitation interventions

82 currently used in management of pwMS. The search strategy included combinations of multiple search terms for

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83 two themes: MS and interventions (rehabilitation). The keywords used to search for studies for this review are

84 listed in Appendix 1. All systematic reviews, meta-analyses registered in these databases that reported a

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85 systematic electronic search of literature for a defined period of time, were included. Bibliographies of identified

86 articles and manual search of relevant journals for additional references was conducted. Authors and known

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experts in the field were contacted. Grey literature search was conducted using different internet search engines
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88 and websites: such as System for Information on Grey Literature in Europe; New York Academy of Medicine Grey

89 Literature Collection, National Quality Measures Clearinghouse and Google Scholar. In addition, various healthcare
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90 institutions; and governmental and non-governmental organisations associated with management of pwMS were
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91 also explored for relevant reviews. All systematic reviews that assessed effectiveness of organised rehabilitation
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92 (both uni- and multi-disciplinary) for pwMS were included. Systematic reviews involving other medical conditions,

93 where data were specifically provided for MS, were also included. The exclusion criteria included; reviews
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94 conducted in paediatric population (<18 years), reviews evaluating pharmacological, surgical intervention or

95 diagnostic procedures, non-English reviews, theses, narrative reviews, reviews on economic evaluation and
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96 reviews listed only in conference proceedings.

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98 Study selection and data extraction

99 Both authors independently screened and shortlisted all abstracts and titles of reviews identified by the search

100 strategy for inclusion and appropriateness based on selection criteria. Each study was evaluated independently,

101 and the full text article obtained for assessment to determine whether the article met the inclusion/exclusion criteria.

102 Any disagreement regarding the possible inclusion/exclusion of any individual study was resolved by a final

103 consensus. Data extraction was conducted by both authors independently, using a standard pro-forma. The

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104 information obtained from all reviews included: publication and search date, objectives, characteristics of included

105 studies and study subjects, intervention, findings/patient outcomes in the review; limitations. Any discrepancies

106 were resolved by both authors re-reviewing the study.

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108 Assessment of methodological quality of included studies

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109 Both reviewers independently assessed the methodological quality of each review, using the Assessment of

110 Multiple Systematic Reviews (AMSTAR) appraisal tool (See Appendix 2 for details).17 The AMSTAR tool has

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111 acceptable inter-rater agreement, construct validity and feasibility.18 Any disagreements were resolved with

112 consensus from both authors. There was heterogeneity in the included reviews in terms of methodological quality

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113 and risk of bias assessment methods. Therefore, based on the judgements made by the authors of the original

114 systematic reviews regarding the quality of evidence, the Grade of Recommendation, Assessment, Development

115
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and Evaluation (GRADE) tool was used to assess quality of evidence for each type of intervention.19
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116

117 RESULTS
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118 The search retrieved 214 published systematic reviews evaluating rehabilitation interventions currently used in
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119 management of MS. Of these, 53 reviews met the abstract inclusion criteria and were selected for closer scrutiny.
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120 Full texts of these articles were retrieved and both reviewers performed the final selection. One review that met the

121 inclusion criteria were identified from the bibliographies of relevant articles. Overall, 15 reviews published in
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122 Cochrane Library database and 24 (one with two reports) published in other academic journals were included. A

123 PRISMA of the study selection process is provided in Figure 2.

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124 (Insert Fig 2)

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125

126 Quality of the systematic reviews

127 Table 1 provides the results of the AMSTAR quality assessment. The kappa level of agreement between both

128 authors for AMSTAR assessment was 0.88. The overall mean AMSTAR methodological quality score for included

129 systematic reviews was 7.0 (standard deviation: 2.6) and ranged from 3 -10 out of 11. Seven reviews were of low

130 quality (i.e. AMSTAR scores between 0–4), 16 moderate quality (5–8), and 16 of high quality (9–11) (Table 1).

131 (Insert Table 1)

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132

133 Evidence synthesis of rehabilitation interventions

134 The rehabilitation approach to pwMS included a range of treatments and interventions. Of the included systematic

135 reviews evaluating various interventions, majority (n = 14 reviews) addressed different physical activity programs in

136 isolation or concomitant with other interventions; seven reviews evaluated cognitive and psychological

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137 interventions; three occupational therapy (OT) interventions, two each for Whole-body vibration (WBV) and dietary

138 interventions. Other interventions included: multidisciplinary rehabilitation (MDR), Hyperbaric Oxygen Therapy

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139 (HBOT), electrical nerve stimulation, hippotherapy, vocational rehabilitation, information provision interventions,

140 and specific rehabilitation programs (such as telerehabilitation, fatigue management programs, upper limb

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141 rehabilitation programs, spasticity management programs). The existing best-evidence synthesis for rehabilitation

142 interventions in MS are summarised below in Table 2. Summary of impact of outcomes of these interventions

143
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based on specific settings are shown in Figure 3. The findings indicate that, although a spectrum of interventions is
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144 used in pwMS, the evidence for many of these are limited and/or unclear due to a paucity of robust,

145 methodologically strong studies.

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146 (Insert Table 2)

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147 The overall findings of this review suggest:

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148 High quality evidence for:

149 • Physical therapeutic modalities ( exercise/physical activities) for improved functional outcomes (mobility,
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150 muscle strength, aerobic capacity), reduced fatigue and improved quality of life (QoL)

151 • Comprehensive fatigue management programs for patient-reported fatigue

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152 Moderate evidence for:

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153 • MDR for longer-term gains at the level of activity (disability) and participation

154 • CBT for the treatment of depression

155 • Information provision in increasing patient’s knowledge

156 Low quality evidence for:

157 • Exercise therapy for improved balance and cognitive symptoms

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158 • Psychological interventions

159 • Other rehabilitation interventions: OT strategies, HBOT, WBV, upper-limb rehabilitation programs,

160 vocational rehabilitation and telerehabilitation

161 • Specific therapy programs targeting MS-related spasticity

162 Inconclusive evidence for:

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163 • Dietary (polyunsaturated fatty acids, vitamin D)

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164 • Hippotherapy and electrical stimulation

165 (Insert Fig 3)

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166

167 DISCUSSION

168

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MS is a complex condition and pwMS frequently present with multiple deficits (motor, sensory, cognitive,
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169 behavioural and communication issues), which require specific and coordinated longer-term multidisciplinary

170 rehabilitative care. This review systematically summarises the best, up-to-date evidence from published
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171 ‘systematic’ reviews for effectiveness of rehabilitation interventions in MS. The findings indicate that, though a

172 broad range of rehabilitative approaches have been trialled in this population, there is a critical lack of high-quality
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173 evidence for effectiveness of various modalities.

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174 The most common interventions evaluated were different forms of physical therapeutic modalities, followed by

175 psychological interventions. As expected the overall findings of this review suggest ‘strong’ evidence for physical
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176 therapeutic modalities (exercise/physical activities) for improved functional outcomes (mobility, muscle strength,
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177 aerobic capacity), reduced fatigue and improved QoL; comprehensive fatigue management programs for patient-
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178 reported fatigue; and ‘moderate’ evidence for MDR for longer-term gains at the level of activity (disability) and

179 participation, CBT for the treatment of depression and information provision in increasing patient’s knowledge. The

180 evidence for other rehabilitation interventions and programs evaluated was of either ‘low’ quality or inconclusive.

181 In recent years, clinicians have a plethora of reviews of same topics, with inconsistent methodological

182 quality, results or conclusions. The findings from this review add to existing literature to guide clinicians. Overall,

183 the quality of methodology of included systematic reviews and evidence interpreted in this review, varied

184 significantly. As expected, the quality AMSTAR tool17 scores of the non-Cochrane reviews were significantly lower

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185 compared with the Cochrane reviews, due to variation in standard of reporting. The non-Cochrane reviews do not

186 publish protocols prior to the review, therefore, none fulfilled the first criterion of the AMSTAR tool. None met the

187 AMSTAR criterion 11 (Appendix 2). Although, the review authors declared their own conflicts of interest, none

188 systematically reported author conflict of interest for included trials. The included reviews used different

189 methodological quality and risk of bias assessment tools. The GRADE and PeDRO tools were most frequently

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190 used. Overall, the Cochrane reviews were more systematic, more recent, and had superior AMSTAR scores which

191 suggest a more reliable and robust source of evidence for clinicians.

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192 The existing clinical practice guidelines recommend the interdisciplinary model of care for pwMS 20, but

uptake of this integrated approach is far from universal, with lack of collaboration and poor communication between

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193

194 disciplines, resulting in fragmented care.10, 21 At times it is unclear - which and when to provide the best clinical

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195 modality and in which dose/intensity. AN
196 Despite strong evidence for coordinated MDR for pwMS,7 the lack of such care contributes a substantial

197 burden to patients, their families and health service providers22. The ‘best’ evidence to date is largely for uni-
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198 disciplinary rehabilitation interventions such as physical therapeutic modalities. The findings of this review add to

199 MS literature and are consistent with earlier reviews.14, 15 Similar to Haselkorn et al,14 this review found strong
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200 evidence supporting inpatient and outpatient physical therapy, and comprehensive MDR for improving function and
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201 disability in pwMS.14 In contrast to the systematic review by Haselkorn and colleagues14 which focused specifically

202 on individual trials on physical therapies, this review took a wider, more global approach to scrutinise MS literature,
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203 by evaluating all published systematic reviews exploring a broad range of rehabilitation modalities, and using

204 globally endorsed appraisal methodology (using AMSTAR and GRADE).17, 19, 23 This approach of ‘systematic’
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205 review of systematic reviews allows findings from more than one systematic review to be compared and contrasted,
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206 thereby providing a comprehensive summary of evidence at different levels, including the combination of different

207 interventions, or the provision of summary of evidence on different outcomes or problems.16

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209 Study limitations

210 Several limitations in methodology and completeness of the retrieved literature in this review cannot be ruled out.

211 Despite the extended and comprehensive search to capture the widest possible selection of relevant literature, the

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212 search principally encompassed cited literature. Only reference lists of ‘within‘ relevant papers were scrutinised

213 and other possible articles (including most recent publications) may have been missed in electronic searches,

214 which may introduce a reference bias. However, our search was comprehensive including Cochrane Database

215 (including DARE), other healthscience databases and grey literture; we are confident of capturing most high quality

216 reviews (n =15 included were Cochrane reviews). Although we used the validated and commonly used tools to

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217 assessed the methodology (AMSTAR) and quality of evidence (GRADE) of these reviews, these tools have certain

218 limitations. We included four reviews from our own research group (all from the Cochrane Library), the

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219 independence of assessors therefore could not be guaranteed. However, since Cochrane Collaboration sets the

220 standards for research synthesis, the apprasials of these reviews are consistent with other similar included reviews

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221 and valid. Adverse event reporting was often incomplete and/or inconsistent. However. it was beyond the scope of

222 this review to systematically search for evidence on safety of included interventions. None of the trials reported

223
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optimal dosage of therapy, associated costs or economic-benefit of interventions.
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224
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225 CONCLUSIONS

226 In conclusion, MS requires specialized flexible services for comprehensive management. There is increasing
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227 awareness of the contribution of rehabilitation in early and long-term MS care. Despite the range of rehabilitative
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228 interventions in pwMS, evidence for many is still unclear due to lack of methodologically robust trials. More

229 research is needed to build evidence for types of rehabilitation therapy components, modalities, duration and
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230 setting of therapy. Future research should focus on interventions that can be integrated into a MDR programs to

231 develop effective care-pathways and long-term functional outcomes; to engage, educate, and empower patients,
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232 and their caregivers.

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233

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333 treating clients with multiple sclerosis: a meta-analysis. Am J Occup Ther 2001;55:324-31.

334 47. Rosti-Otajarvi EM, Hamalainen PI. Neuropsychological rehabilitation for multiple sclerosis. Cochrane
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335 Database Syst Rev 2014;Issue 2:CD009131.

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336 48. Thomas PW, Thomas S, Hillier C, Galvin K, Baker R. Psychological interventions for multiple sclerosis.

337 Cochrane Database Syst Rev 2006;Issue 1:CD004431.

338 49. das Nair R, Ferguson H, Stark DL, Lincoln NB. Memory Rehabilitation for people with multiple sclerosis.

339 Cochrane Database Syst Rev 2012;Issue 3:CD008754.

340 50. O'Brien AR, Chiaravalloti N, Goverover Y, Deluca J. Evidenced-based cognitive rehabilitation for persons

341 with multiple sclerosis: a review of the literature. Arch Phys Med Rehabil 2008;89(4):761-9.

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342 51. Mitolo M, Venneri A, Wilkinson ID, Sharrack B. Cognitive rehabilitation in multiple sclerosis: A systematic

343 review. J Neurol Sci 2015;354(1-2):1-9.

344 52. Hind D, Cotter J, Thake A, Bradburn M, Cooper C, Isaac C et al. Cognitive behavioural therapy for the

345 treatment of depression in people with multiple sclerosis: a systematic review and meta-analysis. BMC

346 Psychiatry 2014;14:5.

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347 53. Malcomson KS, Dunwoody L, Lowe-Strong AS. Psychosocial interventions in people with multiple

348 sclerosis: a review. J Neurol 2007;254(1):1-13.

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349 54. Farinotti M, Vacchi L, Simi S, Di Pietrantonj C, Brait L, Filippini G. Dietary interventions for multiple

350 sclerosis. Cochrane Database Syst Rev 2012;Issue 12:CD004192.

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351 55. Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the management of

352 multiple sclerosis. Cochrane Database Syst Rev 2010;Issue12:CD008422.

353 56.
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Khan F, Ng L, Turner-Stokes L. Effectiveness of vocational rehabilitation intervention on the return to work
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354 and employment of persons with multiple sclerosis. Cochrane Database Syst Rev 2009;Issue

355 1:CD007256.
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356 57. Kopke S, Solari A, Khan F, Heesen C, Giordano A. Information provision for people with multiple sclerosis.
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357 Cochrane Database Syst Rev 2014;Issue 4:CD008757.

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358 58. Asano M, Finlayson M. Meta-analysis of three different types of fatigue management interventions for

359 people with Multiple Sclerosis: exercise, education, and medication. Mult Scler Int 2014; (Article ID
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360 798285):12 pages, [Epub ahead of print].

361 59. Lamers I, Maris A, Severijns D, Dielkens W, Geurts S, Van Wijmeersch B et al. Upper Limb Rehabilitation
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362 in People With Multiple Sclerosis: A Systematic Review. Neurorehabilitation and neural repair 2016; [Epub
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363 ahead of print].

364 60. Spooren AI, Timmermans AA, Seelen HA. Motor training programs of arm and hand in patients with MS

365 according to different levels of the ICF: a systematic review. BMC Neurol 2012;12:49.

366 61. Amatya B, Khan F, La Mantia L, Demetrios M, Wade DT. Non pharmacological interventions for spasticity

367 in multiple sclerosis. Cochrane Database Syst Rev 2013;Issue 2:CD009974.

368

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369 LEGENDS

370

371 Figures

372 1. ICF model with case example for Multiple sclerosis

373 2. PRISMA flow diagram showing selection of reviews

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374 3. Summary of impact of outcomes of rehabilitation interventions based on the settings

375 * Grade of Recommendation, Assessment, Development and Evaluation GRADE grades of evidence:
376 High quality: Further research is very unlikely to change our confidence in the estimate of effect.

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377 Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect
378 and may change the estimate.
379 Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect

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380 and is likely to change the estimate.
381 Very low quality: We are very uncertain about the estimate.
382 CCT = Clinical controlled trial; HBOT = Hyperbaric oxygen therapy; OT = Occupational Therapy; PUFAs = Polyunsaturated
383 fatty acids; RCT = Randomised controlled trial; WBV = Whole body vibration

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384
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385

386 Tables
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387 1. Quality assessment (AMSTAR) of included systematic reviews

388 2. Rehabilitation interventions in MS based on systematic reviews

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389
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390 Appendix

391 1. Key words used in the search strategy

392 2. Assessment of Multiple Systematic Reviews (AMSTAR) criterions
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Table 1. Quality assessment (AMSTAR) of included systematic reviews

AMSTAR Criterions*
Author year 1 2 3 4 5 6 7 8 9 10 11 Total score/11

Amatya et al 201361 Y Y Y Y Y Y Y Y Y Y N 10

Andreasen et al 201132 UA N Y N N Y N Y Y N N 4

Asano & Finlayson 201458 UA Y Y N N Y Y Y Y N N 6

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Baker & Tickle-Degnen 200146 N N N N N N Y Y Y N N 3

Bennett and Herd 200438 Y Y Y Y Y Y Y Y Y Y N 10

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Blikman et al 201337 UA Y Y N N Y Y Y Y N N 6

Bronson et al 201042 N Y Y N Y Y Y N N N N 5

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Campbell et al 201625 UA Y Y N N Y Y Y Y N N 7

Cruickshank et al 201527 UA Y Y N N Y Y Y Y N N 6

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Dalgas et al 201534 N Y Y N N Y Y Y Y N N 6

Das Nair et al 201249 Y Y Y Y Y Y Y Y Y Y N 10

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Farinotti et al 201254 Y Y Y Y Y Y Y Y Y Y N 10

Glinsky et al 200741 N N Y N N Y Y Y Y N N 5
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Heine et al 201531 Y Y Y Y Y Y Y Y Y Y N 10

Hind et al 201452 Y Y Y N N Y Y Y Y Y Y 9
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Jagannath et al 201055 Y Y Y Y Y Y Y Y Y Y N 10
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Kalron et al 201535 UA Y Y N N Y Y N Y N N 5

Kantele et al 201540 Y Y Y N N Y Y N N N N 5

Khan et al 20077 Y Y Y Y Y Y Y Y Y Y N 10
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Khan et al 200956 Y Y Y Y Y Y Y Y Y Y N 10

Khan et al 201510 Y Y Y Y Y Y Y Y Y Y N 10
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Kjolhede et al26 UA Y Y N N Y Y Y Y N N 6
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Kopke et al 201457 Y Y Y Y Y Y Y Y Y Y N 10

Lamers et al 201659 N Y N N N Y Y Y Y N N 5

Latimur-Ceung et al28 UA Y Y N N Y Y Y Y Y N 7

Malcomson et al 200753 N UA Y N N Y Y Y Y N N 5

Martín-Valero et al 201436 N N Y N N Y Y N N N N 3

Mitolo et al 201551 N UA N N N Y Y Y Y N N 4

O’Brien et al 200850 N UA N N N Y Y Y Y N N 3
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Paltammaa et al 201233 UA Y Y N N Y Y Y Y N N 6

Pearson et al 201529 UA Y Y N N Y Y Y Y N N 6

Rietberg et al 200524 Y Y Y Y Y Y Y Y Y Y N 10

Rosti-Otajärvi et al 201447 Y Y Y Y Y Y Y Y Y Y N 10

Sitjà Rabert et al 201239 Y Y Y Y Y Y Y Y Y Y N 10

Snook et al 200930 N N N N N N Y Y Y N N 3

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Spooren et al 201260 N N Y N N Y Y Y Y N N 5
Steultjens et al 200343 Y Y Y Y Y Y Y Y Y Y Y 10

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Thomas et al 200648 Y Y Y Y Y Y Y Y Y Y N 10

Yu & Mathiowetz 201444,45 Y UA Y N N N Y N Y N N 4

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*Assessment of Multiple Systematic Reviews (AMSTAR) criterions [14] – please refer to Appendix 1.

Y = Yes, criteria met (1 point), N = No, criteria not met (0 points), UA = unable to answer (0 points)

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Table 2. Rehabilitation interventions in MS (based on systematic reviews)

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Author and Intervention No of included Total no of Main results/findings Meta- Quality of
Year studies (design, participants, analysis evidence
date range) participant group (GRADE)*

RI
Khan et al Multidisciplinary 9 RCTs,1 CCT 954 participants Strong evidence for improvement in disability, participation and QoL No Moderate
20077 rehabilitation Search date: up with moderate to outlasting treatment period

SC
to 25 February severe disabilities Moderate evidence for inpatient or outpatient rehabilitation
2011 (update) programs for improving disability; bladder related activity and
participation outcomes up to 12 months

U
Limited evidence for short-term improvements in symptoms and

AN
disability for outpatient and home-based rehabilitation programs
Rietberg et al Physical therapy 9 RCTs 260 participants Strong evidence for exercise therapy compared to no exercise in No High
200524 Search date: with low to terms of muscle power function, exercise tolerance functions and

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1966-March 2004 moderate mobility-related activities
disabilities Moderate evidence for improved mood

D
No evidence on fatigue and perception of handicap when compared
with no exercise therapy

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Campbell et al Physical therapy 13 RCTs (15 Sample size Limited evidence regarding PT for people with progressive MS No Low
201625 reports) ranged from 6 to
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Search date: up 111; participants
to December with progressive
2014 MS
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Kjolhede et al Progressive 6 RCTs, 6 non- 289 participants Strong evidence for lower extremity muscle strength No Low
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201226 resistance training controlled trials with low to Limited evidence for improved strength demanding functional tasks,
Search date: up moderate motor balance and fatigue
to 30 March impairments
Limited evidence in improvement in walking ability, mood and QoL
20111
Cruickshank Strength training 20 trials (PD and 249 MS Improved muscle strength, mobility, fatigue, functional capacity, Yes Moderate
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et al 201527 MS) 5 RCTs and participants with power and electromyography activity
2 CCTs in MS All MS types Improved overall QoL
Search date: up
to July 2014

PT
Latimur-Ceung Exercise therapy 54, including 23 Patients with low Exercise performed 2 times/week at a moderate intensity increased No Moderate
et al 201328 RCTs to moderate aerobic capacity and muscular strength in pwMS with mild to

RI
Search date: disabilities moderate disability
1967 - week 4 Limited evidence on improvement in mobility, fatigue, and HRQoL

SC
March 2011
Pearson & Exercise therapy 13 RCTs 655 participants, Significant improvement in walking speed, endurance and distance Yes High
Dieberg 201529 (walking) Search date: ambulatory with or

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1966 - March 31, without a walking
aid

AN
2014
Snook et al Exercise therapy 22 RCTs 600 participants Significant improvement in walking mobility Yes High
200930 (walking) Search date: with all type of MS Larger effects associated with supervised exercise training,

M
1960 - November programs < 3 months in RRMS and progressive MS types
2007

D
Heine et al Exercise therapy 45 RCTs, 2250 participants Significant improvement in fatigue Yes High

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201531 (fatigue) Search date:1966 with all type of MS Larger effect associated with endurance training, mixed training and
– October 2014 Yoga
Andreasen et Exercise therapy 15 RCTs, 9 other 702 participants Exercises have potential to reduce fatigue, but unclear which No Low
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al 201132 (fatigue) design with all type of MS exercise modalities were superior to others
Search date: up (with and without
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to 7 July 2010 fatigue)

Paltammaa et
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Physical therapy 11 RCTs 340 participants, Low level evidence for specific balance exercises, PT based on Yes Low
al 201233 (balance) Search date: up ambulatory with individualized problem-solving approach; resistance and aerobic
to March 2011 all types of MS exercises on improving balance
Dalgas et al Exercise therapy 15 RCTs 591 participants Limited effect on depressive symptoms Yes Low
(depressive Search date: up with all type of MS
 ACCEPTED MANUSCRIPT

201534 symptoms) to 16 October

2013
Kalron et al Exercise therapy 8 RCTs in MS, 644 participants Inconclusive evidence for improved cognition Yes Low
with all types of

PT
201535 (cognition) Search date: up
to December MS
2014

RI
Martín-Valero Therapeutic 15 trials Participants with Limited evidence for improved respiratory No Low
et al 201436 respiratory muscle (including 6 all types of MS muscle function

SC
training RCTs)
Search date:
between 1993

U
and 2013

AN
Blikman et al Energy conservation 4 RCTs, 2 CCTs 494 participants Short term reduction in fatigue and QoL Yes Moderate
201337 management Search date: up with all types of
to May 8, 2012 MS

M
Bennett and HBOT 9 RCTs 504 participants No evidence for use of HBOT Yes Low
Herd 200438 Search date: up with all types of

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to 25 February MS

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2011
Sitjà Rabert et WBV 4 RCTs 64 participants No evidence for WBV on any functional outcomes (body balance, Yes Low
al 201239 Search date: with all types of gait, muscle performance) or QoL
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1964 to 6 May MS
2011
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Kantele et al WBV 7 RCTs 250 participants Limited evidence for improved walking endurance Yes Low
with all types of
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201540 Search date:

2000 to October MS
2013
Glinsky et al Electrical stimulation 18 RCTs all 40 participants Inconclusive evidence for improved muscle strength No Very Low
200741 neurological with all types of
conditions, MS
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including 1 in MS
Search date:
1966 to March
2006

PT
Bronson et al Hippotherapy 3 case-series or 36 participants No evidence on improvement in balance and QoL No Very Low
201042 case-control with all types of

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studies MS
Search date: up

SC
to July 2009
Steultjens et al OT 1 RCT and 2 274 participants Inconclusive evidence on functional ability, social participation No Very low
200343 CCTs with all types of and/or QoL

U
Search date: up MS

AN
to January 2003
Yu & OT 70 trials all Participants with Limited evidence on benefit from individualized, goal-directed No Low
design all types of MS interventions that address functional performance (such as MDR,

M
Mathiowetz
Search date: health promotion and fatigue management)
201444, 45
January 2003 to

D
May 2011
Baker &

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OT 23 trials all Participants with Limited evidence for beneficial effects associated with MS Yes Low
Tickle-Degnen design all types of MS (outcomes for capacity and ability: muscle strength, range of
Search date: motion, mood) and task and activity (dressing, bathing, ambulation)
200146
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from 1980 to levels
1999
Rosti-Otajärvi Neuropsychological 20 RCTs 986 participants Limited evidence on improved memory span, working memory and Yes Low
C

et al 201447 rehabilitation Search date: up with all types of attention

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to 28 May 2013 MS No evidence for improvement in emotional function

Thomas et al Cognitive 16 RCTs 1006 participants Limited evidence of use of CBT for depression; adjustment and Yes Low
200648 rehabilitation Search date: up with all types of coping with MS
to December MS
2004
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Das Nair et al Memory 8 RCTs 521 participants No improvement on memory or functional abilities immediately or Yes Low
201249 rehabilitation Search date: up with all types of long-term
to February MS
2011),

PT
O’Brien et al Cognitive 16 studies, Participants with Limited evidence on effects of modified story memory technique for No Low
200850 rehabilitation including 4 RCTs all types of MS learning and memory

RI
Search date: not
specified

SC
Mitolo et al Cognitive 33 trials Participants with Inconclusive evidence for beneficial effect of different types of No Low
201551 rehabilitation Search date: all types of MS cognitive rehabilitation interventions on outcomes
1993 to 2014

U
Hind et al Cognitive 7 RCTs 521 participants Moderate level evidence for CBT for treatment of depression in MS Yes Moderate

AN
201452 behavioural therapy Search date: up with all types of
(CBT) to June/July 2013 MS

M
Malcomson et Psychosocial 33 trials, Participants with Limited evidence for benefit of exercise, proactivity (on part of No Low
al 200753 intervention including 9 RCTs all types of MS participant), and support (both multidisciplinary and peer), in

D
Search date: up improving psychological well-being and QoL
to December

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2006
Farinotti et al Dietary intervention 6 RCTs 794 participants No benefit of Polyunsaturated fatty acids on clinical outcomes No Low
201254 (Polyunsaturated Search date: up with all types of
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fatty acids) to November MS
2011
C

Jagannath et Dietary intervention 1 RCT 49 participants Limited evidence of potential benefit on relapse rate; disability No Very low
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al 201055 (Vitamin D) Search date: up with all types of scores; suppression of T-cell proliferation
to 17 May 2010 MS
Khan et al Vocational 1 RCT, 1 CCT) 80 MS Limited evidence for competitive employment, job retention, No Low
200956 rehabilitation Search date: participants of changes in employment, rates of re-entry into the labour force; work
1981-February working age ability by improving participants’ confidence in the accommodation
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2011 (mean age: 18-65 request process, or employability maturity or job seeking activity
years)
Kopke et al Information 10 RCTs 1314 participants ’Moderate level’ evidence for improved participant knowledge, No Moderate
provision with all types of mixed results on decision making and QoL

PT
201457
MS
Khan et al Telerehabilitation 9 RCTs Search 531 participants, Low-level evidence for reducing short-term disability and symptoms No Low

RI
201510 interventions date: up to 9 July, (469 included in (such as fatigue)
2014 analyses) Low-level evidence for improved functional activities, impairments

SC
Majority RRMS (such as fatigue, pain, insomnia); and QoL, psychological outcomes
Limited data on process evaluation (participants’/therapists’
satisfaction); no data for cost effectiveness

U
Asano & Fatigue management 25 trials 895 participants Strong evidence for exercise-based and educational rehabilitation No High

AN
Finlayson programs (exercise, (including 18 with all types of for reducing severity of patient-reported fatigue
education, rehabilitation) MS (in
201458 medication) rehabilitation
Search date: up

M
to August 2013 trials)
Lamers et al Upper limb 30 trials, Participants with Multidisciplinary and robot-based rehabilitation improved upper limb No Low

D
201659 rehabilitation including 11 all types of MS capacity
RCTs

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Search date: up
to April 2015
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Spooren et al Upper limb motor 11 trials, 368 participants Improved arm and hand performance at activity level No Low
201260 training including 5 RCTs with all types of
Search date: MS
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from 1976 to May

AC

2011
Amatya et al Spasticity 9 RCTs 341 participants Low level evidence for physical activity programs used in isolation No Low
210361 management Search date: with all types of or in combination with other interventions (pharmacological or non-
interventions from 1996 to MS pharmacological); for repetitive magnetic stimulation with or without
June 2012 adjuvant exercise therapy in improving spasticity
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*GRADE = Grade of Recommendation, Assessment, Development and Evaluation Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

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ADL = Activities of daily living; CBT = cognitive behavioural therapy; CCT = Clinical controlled trial; HBOT = Hyperbaric oxygen therapy; HRQol = Health-related quality of life; ICF = International Classification

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Functioning, Disability and Health; MS = Multiple sclerosis; OT = Occupational Therapy; PD = Parkinson’s disease; PT = Physical therapy; QoL = Quality of life; RCT = Randomised controlled trial; WBV = Whole
body vibration

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Health Condition
(Multiple sclerosis)

PT
Body Function & Activities
Structures (mobility, self care, Participation
(strength, balance, incontinence, pain, (work, driving, family,
spasticity, memory etc.) cognitive deficits etc.) finances etc.)

RI
SC
Environmental Personal Factors
Factors (attitude and beliefs,

U
(transportation, health self efficacy, fatigue
services, climate etc.) level etc.)
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Potential articles identified by electronic

Identification

searching
(n =214)

PT
RI
Articles screened after duplicates Articles excluded after title
Screening

removed and abstract review

(n = 169) (n = 116)

U SC
Articles excluded: (n = 15)
AN
Full-text articles assessed for eligibility  Not systematic review: 10
(n = 53)  Not rehabilitation: 3
 Not enough data on MS: 2
Eligibility

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D

Additional review identified by

cross-referencing
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(n = 1)
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Systematic reviews included = 39

Included

 Cochrane reviews: 15
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 Other reviews: 24 (1 with 2 reports)

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Intervention No studies, Inpatient Community Long-term GRADE*
participants survivorship
Multidisciplinary rehabilitation 9 RCTs, 1 CCT, Moderate
954
Physical therapy 76 trials (45 High
RCTs)
Progressive resistance training 6 RCTs, 6 non- Low
RCTs, 289

PT
Strength training 5 RCTs, 2 CCTs Moderate
249

RI
Exercise therapy (walking) 35 RCTs, 1255 High
Exercise therapy (fatigue) 60 RCTs, 2952 High

SC
Physical therapy (balance) 11 RCTs, 340 Low
Exercise therapy (depression) 15 RCTs, 591 Low
Exercise therapy (cognition) 8 RCTs, 644 Low
Respiratory muscle training
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15 trials (6 RCTs) Low
AN
Energy conservation 4 RCTs, 2 CCTs, Moderate
494
HBOT 9 RCTs, 504 Low
M

WBV 11 RCTs, 314 Low

Electrical stimulation 1 RCT, 40 Very low
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Hippotherapy 3 non-RCTs, 36 Very low

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OT 96 trials Low
Neuropsychological 20 RCTs, 986 Low
Cognitive rehabilitation 32 RCTs, 1527 Low
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Cognitive Behavioural Therapy 7 RCTs Moderate

Memory rehabilitation 8 RCTs, 521 Low
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Dietary intervention (PUFAs) 6 RCTs, 794 Low

AC

Dietary intervention (Vitamin D) 1 RCT, 49 Very low

Vocational rehabilitation 1 RCT, 1 CCT, 80 Low
Telerehabilitation 9 RCTs, 531 Low
Fatigue management programs 18 trials, 895 High
Upper limb rehab 41 trials (16 Low
RCTs)
Spasticity management 9 RCTs, 341 Low
interventions
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Appendix 1. Key words used in the search strategy

Theme 1. Multiple sclerosis:

Multiple Sclerosis, Demyelinating Diseases, Transverse myelitis, Optic Neuritis, Acute disseminated
encephalomyelitis

Theme 2. Rehabilitation interventions:

PT
Rehabilitation, Ambulatory Care, Physical Therapy Modalities, physiotherapy, Exercise therapy,
Cognitive therapy, psychotherapy, Behavior/behaviour therapy, Social work, Counselling, Occupational
Therapy , Dietetics/Nutrition, Orthotics/brace/orthoses, Acupuncture Patient Care Team,

RI
multidisciplinary/ integrated team, cold treatment/cooling, assistive technology device, hydro/pool
therapy, Electromagnetic therapy, nerve stimulation, vibration therapy, social participation/support,
vocational

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MeSH check words

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Systematic review/meta-analysis, Review, Adult; Humans
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Appendix 2. Assessment of Multiple Systematic Reviews (AMSTAR) criteria:

1. Was an ’a priori’ design provided?

2. Was there duplicate study selection and data extraction?

3. Was a comprehensive literature search performed?

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4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?

5. Was a list of studies (included and excluded) provided?

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6. Were the characteristics of the included studies provided?

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7. Was the scientific quality of the included studies assessed and documented?

8. Was the scientific quality of the included studies used appropriately in formulating conclusions?

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9. Were the methods used to combine the findings of studies appropriate?
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10. Was the likelihood of publication bias assessed?

11. Was the conflict of interest stated?

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