Rehabilitation for people with multiple sclerosis: an overview of Cochrane Reviews
Abstract
Background
Multiple sclerosis (MS) is a major cause of chronic, neurological disability, with a significant long‐term disability burden, often requiring comprehensive rehabilitation.
Objectives
To systematically evaluate evidence from published Cochrane Reviews of clinical trials to summarise the evidence regarding the effectiveness and safety of rehabilitation interventions for people with MS (pwMS), to improve patient outcomes, and to highlight current gaps in knowledge.
Methods
We searched the Cochrane Database of Systematic Reviews up to December 2017, to identify Cochrane Reviews that assessed the effectiveness of organised rehabilitation interventions for pwMS. Two reviewers independently assessed the quality of included reviews, using the Revised Assessment of Multiple Systematic Reviews (R‐AMSTAR) tool, and the quality of the evidence for reported outcomes, using the GRADE framework.
Main results
Overall, we included 15 reviews published in the Cochrane Library, comprising 164 randomised controlled trials (RCTs) and four controlled clinical trials, with a total of 10,396 participants. The included reviews evaluated a wide range of rehabilitation interventions, including: physical activity and exercise therapy, hyperbaric oxygen therapy (HBOT), whole‐body vibration, occupational therapy, cognitive and psychological interventions, nutritional and dietary supplements, vocational rehabilitation, information provision, telerehabilitation, and interventions for the management of spasticity. We assessed all reviews to be of high to moderate methodological quality, based on R‐AMSTAR criteria.
Moderate‐quality evidence suggested that physical therapeutic modalities (exercise and physical activities) improved functional outcomes (mobility, muscular strength), reduced impairment (fatigue), and improved participation (quality of life). Moderate‐quality evidence suggested that inpatient or outpatient multidisciplinary rehabilitation programmes led to longer‐term gains at the levels of activity and participation, and interventions that provided information improved patient knowledge. Low‐qualitty evidence suggested that neuropsychological interventions, symptom‐management programmes (spasticity), whole body vibration, and telerehabilitation improved some patient outcomes. Evidence for other rehabilitation modalities was inconclusive, due to lack of robust studies.
Authors' conclusions
The evidence suggests that regular specialist evaluation and follow‐up to assess the needs of patients with all types of MS for appropriate rehabilitation interventions may be of benefit, although the certainty of evidence varies across the different types of interventions evaluated by the reviews. Structured, multidisciplinary rehabilitation programmes and physical therapy (exercise or physical activities) can improve functional outcomes (mobility, muscle strength, aerobic capacity), and quality of life. Overall, the evidence for many rehabilitation interventions should be interpreted cautiously, as the majority of included reviews did not include data from current studies. More studies, with appropriate design, which report the type and intensity of modalities and their cost‐effectiveness are needed to address the current gaps in knowledge.
Plain language summary
Rehabilitation for persons with multiple sclerosis
Review questions
Do people with multiple sclerosis (MS), who participate in rehabilitation programmes, improve in their functional activities, disability, and quality of life compared with those who receive no rehabilitation treatment, placebo, or different types of interventions?
Background
MS is a complex condition, which requires comprehensive, long‐term management. Rehabilitation programmes aim to improve function, well‐being, and quality of life for people with MS. Currently, a wide variety of rehabilitation therapies are used to treat MS. Published literature, including Cochrane Reviews, that evaluates these interventions, has grown. To guide clinicians, this review assessed current Cochrane Reviews, and provides an overview of the effectiveness of rehabilitation therapies used to treat people with MS.
Study characteristics
We searched for all published Cochrane Reviews of MS clinical trials that evaluated the effectiveness of rehabilitation interventions compared with various control groups (no intervention or different type of intervention). We evaluated all relevant reviews, and summarised the findings.
Key results and quality of evidence
We included a total of 15 Cochrane Reviews, which included 168 clinical trials, and a total of 10,396 people with MS. These good‐quality reviews evaluated a range of rehabilitation interventions, including: physical activity and exercise therapy, hyperbaric oxygen therapy, whole‐body vibration, occupational therapy, cognitive and psychological interventions, nutritional and dietary supplements, vocational rehabilitation, information provision, telerehabilitation, and interventions for the management of spasticity.
The findings showed some benefits for people with MS who participated in exercise and physical activity programmes or multidisciplinary rehabilitation programmes (where the intervention is provided by a team of health professionals from different professions). They found improvements in everyday activities, function, and health‐related quality of life, compared with those who were not offered rehabilitation. Evidence for other rehabilitation modalities was limited, due to lack of good‐quality studies. More research is needed to determine whether various types of rehabilitation modalities are effective in reducing disability in people with MS.
Authors' conclusions
Background
Description of the condition
Multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system, is a major cause of chronic neurological disability in young and middle‐aged adults (aged 18 to 50 years (Barten 2010)). MS affects approximately 1.3 million people worldwide, with a median estimated incidence of 2.5 per 100,000 (range 1.1 to 4) globally (WHO 2008). The global prevalence rate of MS is estimated to be 30 per 100,000 (range 5 to 80), with a female preponderance (female to male ratio of 3:1 (Trisolini 2010; WHO 2008)). MS is characterised by significant variability in presentation and prognosis, and is associated with complex disabilities, including disorders of strength, sensation, co‐ordination and balance, visual, and cognitive deficits (Beer 2012; Khan 2007a; Khan 2007b). These impairments usually lead to progressive limitation of functioning in daily life and require long‐term multidisciplinary management. Factors associated with worse prognosis are: older age at onset, progressive disease course, multiple onset symptoms, pyramidal or cerebellar symptoms, and a short interval between onset and first relapse (Hammond 2000).
MS has an unpredictable disease course and varied patterns of presentation, which include: 'relapsing‐remitting' MS (80% of all MS cases), characterised by exacerbations and remissions, which may convert to a 'secondary‐progressive' form of MS with progressive disability between attacks; 'primary‐progressive' MS (15% of all MS cases), where progressive disability develops from onset; and 'progressive‐relapsing' MS (5% of all MS cases), where the disease worsens gradually and subsequently results in discrete attacks (Amatya 2013; Khan 2007b).
People with MS (pwMS) can present with various combinations of functional deficits, such as physical disability (motor weakness, spasticity, sensory dysfunction, visual loss, ataxia, etc.), fatigue, pain, incontinence, cognitive deficits (memory, attention, executive dysfunctions), psychosocial, behavioural, and environmental problems. These have a multidimensional impact on a person's activity (function) and participation (Khan 2006; Khan 2007b). The International Classification of Functioning, Disability and Health (ICF) provides a global conceptual framework to categorise abilities and problems of persons with different health conditions, within a standard system (WHO 2001). It offers a common language for clinicians to describe functioning, disability, and health of an individual (WHO 2001). A simulated case example of the ICF model related to MS is given in Figure 1.
International Classification of Functioning, Disability and Health (ICF) model with case example for multiple sclerosis
Description of the interventions
People with MS have complex care needs, due to the cumulative effects of impairments and disabilities, and the impact of ageing with disabilities, requiring comprehensive disease management, which includes rehabilitation. Medical rehabilitation is "a set of measures that assist individuals who experience (or are likely to experience) disability to achieve and maintain optimal physical, sensory, intellectual, psychological, and social functioning in interaction with their environment" (WHO 2011). It is a process of delivering a co‐ordinated interdisciplinary care programme, comprising a series of therapies, which are often individualised and goal‐oriented to meet the specific needs of a patient (Khan 2017). The goal of rehabilitation is to improve functional independence and enhance participation, with emphasis on patient education and self‐management (Khan 2015; Beer 2012; WHO 2011).
A comprehensive rehabilitation approach uses a range of individual or combined therapies and treatments (Khan 2007b; Khan 2010; WHO 2008). These include:
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Unidisciplinary therapy, i.e. therapy provided by a single discipline, which may include (but is not limited to): physiotherapy, occupational therapy, strengthening exercises, endurance training, resistance training, stretching, orthotics (splints, garments), casting, hyperbaric oxygen therapy (breathing pure oxygen in a specially designed pressurised room or chamber), transcutaneous electric nerve stimulation (use of electric current produced by a device to stimulate the nerves for therapeutic purposes), hippotherapy (therapy that uses the natural gait and movement of a horse to provide motor, and sensory input), vibration therapy (exercise training using vibratory platforms), vocational rehabilitation, acupuncture, psychological interventions, nutritional interventions (such as polyunsaturated fatty acids, vitamin D), mental practice, educational interventions, and specific rehabilitation programmes (such as, telerehabilitation, fatigue management, upper limb rehabilitation, and spasticity management).
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Multidisciplinary rehabilitation programmes provide a co‐ordinated programme delivered by a specialised team of health professionals from two or more disciplines (medical, nursing, physiotherapy, occupational therapy, speech and language therapy, social work, orthotists, and others).
How the intervention might work
With advances in MS management, there has been improvement in survival rates of pwMS. Therefore, issues related to progressive disability (physical and cognitive), psychosocial adjustment, and social reintegration need to be addressed over time (Khan 2007b). In recent years, a range of rehabilitation interventions trialled in pwMS have provided increasing evidence of improved patient outcomes (Bennett 2010; Khan 2011; Khan 2017). Specifically, physical therapeutic modalities, such as physical therapy and exercise, improve muscle power and strength, exercise tolerance, and mobility‐related activities (Campbell 2016; Haselkorn 2015; Heine 2015), and exercise‐based programmes reduce patient‐reported fatigue (Andreasen 2011; Asano 2014; Heine 2015). Other potential benefits associated with physical activities include improvements in strength and muscle activity, improvement in functional capacity (including cardiorespiratory capacity), enhanced cognitive function, and haemodynamic activity (Cruickshank 2015), and neurobiological processes that could promote neuroprotection and neuroplasticity, and reduce long‐term disability (White 2008a; White 2008b). These affect multiple sensorimotor processes (visual, vestibular, proprioception) to generate co‐ordinated movements that maintain the centre of gravity within the limits of stability, improving balance and gait patterns (Paltamaa 2012).
There is also evidence for multidisciplinary rehabilitation for longer‐term gains at the levels of activity (disability) and participation (Khan 2007b). However, other rehabilitation interventions, such as occupational therapy (Steultjens 2003), transcutaneous electrical nerve stimulation (Glinsky 2007), vibration therapy (Kantele 2015), hippotherapy (Bronson 2010), and hyperbaric oxygen therapy (Bennett 2004) have been found to have no, or limited additional benefit in pwMS (Khan 2017).
Why it is important to do this overview
MS is complex and requires a comprehensive, multidimensional approach to disease management that incorporates integrated rehabilitation interventions. The body of research for rehabilitation interventions is growing, and there are currently a number of Cochrane Reviews published on the efficacy and safety of various rehabilitation approaches. However, the published reviews vary in scope and methodology, with different, and at times diverse, conclusions about the effectiveness of the intervention evaluated. However, some review findings overlap with each other, in terms of interventions and comparisons.
Therapeutic values, including benefits and harms, associated with MS rehabilitation interventions need to be established. The most efficacious approaches, timing, and intensity of these interventions, resource requirements, and associated costs require investigation. To our knowledge, to date, no studies have comprehensively evaluated the existing Cochrane Reviews of various rehabilitation interventions in MS. Therefore, a systematic evaluation of the existing evidence from published Cochrane Reviews is required to provide the best evidence on the effectiveness of these interventions, to guide treating clinicians to achieve optimal patient outcomes. This overview can serve as a 'guiding tool' for evidence‐based decisions on appropriate management approaches in pwMS, future programme improvement and design, to inform policy and healthcare decision makers, and for future research in MS.
Objectives
To systematically evaluate evidence from published Cochrane Reviews of clinical trials to summarise the evidence regarding the effectiveness and safety of rehabilitation interventions for people with multiple sclerosis (pwMS), to improve patient outcomes, and highlight current gaps in knowledge. Specific questions addressed included:
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Are rehabilitation interventions (unidisciplinary, multidisciplinary, or both) effective in minimising impairment, activity limitation, and participation restriction in pwMS?
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Are rehabilitation interventions (unidisciplinary, multidisciplinary, or both) effective in minimising the burden of care and improving quality of life in pwMS?
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What types of rehabilitation interventions (unidisciplinary, multidisciplinary, or both) are effective in pwMS, and in which setting?
Methods
Criteria for considering reviews for inclusion
Types of studies
In accordance with the Cochrane Handbook for Systematic Reviews of Interventions, we searched the Cochrane Database of Systematic Reviews (up to December 2017) to identify Cochrane Reviews that assessed the effectiveness of organised rehabilitation interventions (unidisciplinary, multidisciplinary, or both) for pwMS (Becker 2011). We did not update the individual Cochrane Reviews. We listed all published protocols of ongoing Cochrane Reviews of rehabilitation for people with MS in the 'Classification pending references' section, for inclusion in future updates of this overview.
Types of participants
We included all adults (18 years or over), with all subgroups of MS (relapsing‐remitting, secondary‐progressive, primary‐progressive, and progressive‐relapsing MS).
Types of interventions
We included all modalities of rehabilitation interventions in pwMS:
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unidisciplinary therapy, e.g. physiotherapy or occupational therapy only, and other interventions (as described in Description of the interventions).
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multidisciplinary rehabilitation programmes, defined as any co‐ordinated therapy programme delivered by two or more disciplines (occupational therapy, physiotherapy, exercise physiology, prosthetics and orthotics, speech and language therapy, diet, and nursing care), in conjunction with medical input (neurologist or rehabilitation medicine physician) that aimed to achieve patient‐centred goals (Khan 2007b).
The settings of rehabilitation programmes included:
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Ambulatory settings: outpatient or day treatment settings, which may be located within private or public hospitals, community rehabilitation centres, or specialist rehabilitation centres.
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Home‐based settings (patients' own homes) and community rehabilitation settings.
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Inpatient rehabilitation settings: specialised medical rehabilitation units or hospital wards, where care is delivered 24 hours per day.
Types of outcome measures
Given the varied presentations of MS‐related disability, and goals of treatment related to MS severity, we identified diverse outcomes. The list below is not conclusive, as there is a range of outcome measures that can be used to assess a particular domain. Specific outcome measures (subjective or objective) did not form part of the inclusion criteria for this review.
Primary outcomes
We categorised primary outcomes according to the International Classification of Functioning, Disability and Health (ICF (WHO 2001)). These included:
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Function (mobility, activities of daily living (ADL)): e.g. Functional Independence Measure (FIM (Granger 1990)), Timed Up And Go (TUAG (Podsiadlo 1991)), Barthel Index (BI (Mahoney 1965)), 10‐metre walk test (Green 2002), or other subjective measures alone, or in combination.
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Symptoms or impairments, e.g. pain (measured by verbal scores, visual analogue scales), spasticity (using the Modified Ashworth Scale (MAS (Ansari 2009; Bohannon 1987)), and the Tardieu scale (Ansari 2008; Mehrholz 2005));
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Restriction in participation, e.g. quality of life (QoL; MS Quality of Life, MSQOL 54 (Vickrey 1997))
Secondary outcomes
These included specific outcomes that reflected:
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Measure of achievement of intended goals for treatment, e.g. goal attainment scaling or other measure of goal achievement;
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Impact on caregivers (measured with Caregiver Strain Index (CSI (Robinson 1983)));
We reported any adverse events from these interventions. For this review, we defined serious adverse events as those events that result in death, life‐threatening adverse experience, inpatient hospitalisation or prolongation of existing hospitalisation (for > 24 hours), disability or permanent damage, and other important medical events (FDA 2016).
Search methods for identification of reviews
We searched the Cochrane Database of Systematic Reviews (CDSR; 2017, Issue 12 of 12) in the Cochrane Library (searched December 2017, Issue 12 of 12) for all potential reviews. We included all Cochrane Reviews registered in the CDSR that fulfilled the inclusion criteria, and reported a systematic electronic search of literature for a defined period of time. The search strategy is listed in Appendix 1. We did not apply any restriction on publication date.
Data collection and analysis
We adhered to all data collection and synthesis methodology outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Becker 2011). We had no intention to repeat the assessment of eligibility, the assessment of risk of bias, or meta‐analyses from the included reviews, nor to identify systematically any additional studies, or to extract additional outcomes from individual studies included in the original Cochrane Reviews (Higgins 2011).
Selection of reviews
Two review authors (BA, FK) independently screened and short‐listed all abstracts and titles of Cochrane Reviews identified by the search strategy for inclusion and appropriateness, based on the selection criteria. They independently evaluated the full text of the review to determine whether it met the inclusion and exclusion criteria. Any disagreement regarding the possible inclusion or exclusion of any review was resolved through discussion with a third review author (MG), and by a final consensus amongst all authors. We did not exclude any published Cochrane Reviews based on methodological quality.
Data extraction and management
Two review authors (BA, FK) independently extracted data from included Cochrane Reviews, using a predefined, customised electronic data extraction form. A third review author (MG) checked all extracted data for accuracy and consistency. The information obtained from the included reviews is presented in Table 1, which comprised review objectives, publication and search date, characteristics of included studies, population characteristics, characteristics of intervention(s) covered within the scope of the review, comparison intervention(s), outcomes (primary and secondary), intervention effects, including the pooled effects, e.g. risk ratios (RRs), odds ratios (ORs), or mean differences (MDs); 95% confidence intervals (CIs), and review limitation (Higgins 2011). We extracted a narrative text of the results if no meta‐analyses were performed, or statistical results were not available. We resolved any discrepancies by a final group consensus.
| Author and Year | Date assessed as up to date | Population | Intervention | Comparision interventions | Outcomes for which data were reported | Meta‐analysis | Review limitations | R‐AMSTR score* |
| 1996 to June 2012 | N = 9 RCTs, 341 participants with all types of MS | Non‐pharmacological spasticity management interventions | Sham or placebo interventions; lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment; interventions given in different settings | Primary Reduction in spasticity; improvement in upper limb functioning and (upper limb‐related) ADL; improvement in mobility Secondary improvement in symptoms or impairments; restriction in participation and impact on caregivers; costs | No |
| 41 | |
| up to 25 February 2011 | N = 9 RCTs, 504 participants with all types of MS | HBOT | Placebo or no treatment | Primary Disability status, objective assessment; suffering ≥ 1 exacerbation at 6 to 12 months; side effects Secondary Functional scores assessed by neurologists | Yes |
| 41 | |
| up to June 2015 | N = 15 RCTs, 989 participants with all types of MS | Memory rehabilitation | No treatment or placebo | Primary Subjective and objective reports of memory Secondary Mood, functional abilities, QoL | Yes |
| 42 | |
| up to November 2011 | N = 6 RCTs, 794 participants with all types of MS | Dietary intervention (polyunsaturated fatty acids, vitamins) | No dietary modification or placebo | Primary Disability progression; exacerbation during study period Secondary HRQoL; cognitive functio; physical and psychological functions; safety (adverse events) | No |
| 42 | |
| 1966 to October 2014 | N = 45 RCTs, 2250 participants with all type of MS | Exercise therapy (fatigue) | Non‐exercise control or another intervention | Primary Fatigue Secondary Safety, relapses | Yes |
| 40 | |
| up to 17 May 2010 | N = 1 RCTs, 49 participants with all types of MS | Dietary intervention (vitamin D) | Placebo or no supplementation | Primary Number of relapses; time‐to‐first treated relapse; QoL; disability status; safety and adverse effects Secondary Hospitalisation; cognitive functions; physical symptoms; psychological symptoms; change in MRI parameters; serum levels of 25‐hydroxyvitamin D (25(OH)D); vitamin D & calcium; bone mineral density (BMD); cytokine profile; T lymphocyte proliferation response & plasma metalloprotease‐9 activity | No |
| 40 | |
| up to 25 February 2011 (updated) | N = 9 RCTs & 1 CCT, 954 participants with moderate to severe disabilities | Multidisciplinary rehabilitation | Lower level or different types of interventions; intervention given in different settings; lower intensity of intervention | Primary Minimisation of disability (limitation in activity) Secondary Participatory issues, such as QoL, psychological adjustment; cost; service utilisation; and care burden | No |
| 40 | |
| 1981 to February 2011 | N = 1 RCT & 1 CCT, 80 MS participants of working age (mean age 18 to 65 years) | Vocational rehabilitation | Alternative programmes or care as usual | Primary Competitive employment; supported employment Secondary Return to work; disability pension; work ability; costs | No |
| 40 | |
| up to 9 July 2014 | N = 9 RCTs, 531 participants, (469 included in analyses); majority RRMS | Telerehabilitation | Lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment (or usual care); interventions given in different settings | Primary Improvement in functional activity (ADLs, mobility, continence, etc.); symptoms or impairments (pain, spasm frequency, joint range of movement, involuntary movements, spasticity, etc.); participation and environmental, personal context, or both (QoL, psychosocial function, employment, education, social and vocational activities, patient and caregiver mood, relationships, social integration, etc.) Secondary Compliance; service utilisation and cost; adverse events | No |
| 42 | |
| up to 12 June 2013 | N = 10 RCTs, 1314 participants with all types of MS | Information provision that aims to promote informed choice and improve patient outcomes | Usual care or other types of information‐provision interventions | Primary Disease‐related (risk) knowledge; measures of (shared) decision making Secondary QoL; informed choice; psychological status; treatment choices; treatment compliance; satisfaction with information received, decisional process; hospital admissions and use of healthcare services; ADLs; coping; disability; role preferences; averse events | No |
| 38 | |
| 1966 to March 2004 | N = 9 RCTs, 260 participants with low to moderate disabilities | Physical (exercise) therapy | Control interventions (details not provided) | Primary Activities limitation; HRQoL Secondary None | No |
| 35 | |
| up to 28 May 2013 | N = 20 RCTs, 986 participants with all types of MS | Neuropsychological rehabilitation | Other interventions or no intervention | Primary Measures of cognitive function Secondary Depression; fatigue; personality disturbance; anxiety; QoL; return to work; activity level | Yes |
| 42 | |
| 1964 to 6 May 2011 | N = 4 RCTs, 64 participants with all types of MS | WBV | Passive intervention (waiting list, non‐treatment, usual lifestyle); any other active physical therapy intervention (balance programme, walking, resistance training, etc.); another WBV under different vibration parameters. | Primary Functional performance according to basic ADL Secondary Signs and symptoms of the disease; body balance, including all the assessments (test, scale, etc.) that analyse equilibrium, postural control, or proprioception in a standing position; gait, including all the measurements (test, scale, etc.) that analyse the action of walking; muscle performance; QoL; adverse events | Yes |
| 39 | |
| up to January 2003 | N = 1 RCT & 2 CCTs, 274 participants with all types of MS | OT | Control interventions (details not provided) | Primary Fatigue; pain; functional ability; social participation; QoL Secondary Knowledge about disease management; self‐efficacy; motor co‐ordination and balance | No |
| 34 | |
| up to December 2004 | N = 16 RCTs, 1006 participants with all types of MS | Cognitive rehabilitation | Usual care or standard care; placebo; waiting‐list controls; other psychological interventions; other interventions | Primary Disease‐specific and general QoL; psychiatric symptoms; psychological functioning; disability; cognitive outcomes Secondary Number of relapses; pain; fatigue; healthcare utilisation; changes in medication; adherence to other therapies | Yes |
| 41 |
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 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
*R‐AMSTAR = Revised Assessment of Multiple Systematic Reviews (Total score out of 44; details in: Appendix 2; Appendix 3)
We did not review the original or primary trials included in the Cochrane Reviews for additional data; we only analysed data presented in the included reviews.
We discussed all outcomes reported in the included studies of the Cochrane Reviews. We accessed the published reports of the individual trials, and had planned to contact individual researchers if any information from the reviews was unclear or missing, however, this was not required.
Assessment of methodological quality of included reviews
Quality of included reviews
Two review authors (BA, FK) independently assessed the methodological quality of each review, using the Revised‐Assessment of Multiple Systematic Reviews (R‐AMSTAR) appraisal tool (Kung 2010). Similar to the original AMSTAR tool (Shea 2007a; Shea 2007b), the R‐AMSTAR tool contains 11 questions for assessing the methodological quality of systematic reviews (Appendix 2; Appendix 3).
We assigned a score of 1 to 4, based on predefined criteria for each item (yes = considered adequate, or no = considered inadequate), to each domain of the R‐AMSTAR tool. We used the sum of total scores, which ranged from 11 to 44, to grade overall methodological quality. For this overview, we considered reviews that obtained scores of 40 or higher to be high quality; scores of 30 or higher to be medium quality; and scores below 29 to be low quality (Shepherd 2016). We resolved any disagreements by consensus among all review authors.
Quality of included studies within reviews
We did not assess the risk of bias of individual included studies within reviews. All of our reported study quality was according to the original Cochrane Review authors' assessments.
Quality of evidence in included reviews
We categorised all outcomes according to the ICF into: function (activity), impairment (symptoms), and participation (QoL, psychological outcomes, vocational outcomes). We used the GRADEpro GDT tool to assess quality of evidence for each type of intervention (Balshem 2011; GRADEpro GDT 2015). Two review authors (BA, FK) independently evaluated the quality of the body of evidence, based on the judgements made by the authors of the original Cochrane Reviews, such as by using the information from 'Summary of findings' tables in the included reviews, if provided. We used the GRADE system to assess the following features of the evidence of outcomes.
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Study limitations (risk of bias): internal validity of the evidence.
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Inconsistency: heterogeneity or variability in the estimates of effect across studies.
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Indirectness: degree of differences between population, intervention, comparator, for the intervention and outcome of interest.
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Imprecision (random error): extent to which confidence in the effect estimate is adequate to support a particular decision.
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Publication bias: degree of selective publication of studies.
Both review authors (BA, FK) resolved discrepancies through discussion with the third review author (MG). The quality of evidence was classified, according to Balshem 2011 as:
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High‐quality: very confident that the true effect lies close to that of the estimate of the effect.
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Moderate‐quality: moderately confident in the effect estimate, such that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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Low‐quality: confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect.
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Very low‐quality: very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of the effect.
The evidence for all relevant outcomes is summarised in a 'Summary of findings' table, along with the number of participants and studies addressing each outcomes, and the GRADE rating for each outcome. The GRADE assessments presented in the 'Summary of findings from included reviews’ table are judgements made by the review authors of this overview.
Data synthesis
We compiled a narrative description of the characteristics of the included Cochrane Reviews. We considered the differences in participants, interventions, duration of follow‐up, and type of data analysis in each review, along with the main findings of the effects of the interventions investigated in the included reviews, based on the GRADE system.
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Effective interventions: we found high‐quality evidence of effectiveness for an intervention.
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Promising interventions (more evidence needed): we found moderate‐quality evidence of effectiveness for an intervention, but more evidence is needed.
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Ineffective interventions: we found high‐quality evidence of lack of effectiveness for an intervention.
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Probably ineffective interventions (more evidence needed): we found moderate‐quality evidence suggesting lack of effectiveness for an intervention, but more evidence is needed.
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No conclusions possible: we found low‐ or very low‐quality evidence, or insufficient evidence to comment on the effectiveness of an intervention.
We provided a summary of the results and statistical analysis reported in each included review in summary tables and figures, where possible. As anticipated, we found more than one eligible review of some interventions, such as physical therapy. We reported the common conclusion if these reviews had similar conclusions, and where the conclusions differed, we explored the reasons for any difference in relation to the AMSTAR scores, differences in participants, interventions, duration of follow‐up, and type of data analyses in the included reviews. Further, we anticipated some overlap in the trials included among the reviews evaluating similar interventions. In such cases, we compared the results from all reviews and collated the findings, where possible.
Results
The search retrieved 85 published reviews evaluating different interventions currently used in the management of multiple sclerosis (MS). Of these, the majority (N = 64) evaluated pharmacological interventions, and we excluded them. Twenty‐one reviews met the abstract inclusion criteria, and we selected them for closer scrutiny. We retrieved the full texts of these reviews, and all review authors performed the final selection. Of these, we excluded two reviews: one review did not provide specific targeted rehabilitation intervention (Mills 2007), and another did not provide any data for the MS population (Regan 2014). Four reviews were still in the protocol stage (Amatya 2017; Cui 2010; Hayes 2017; Rietberg 2011). Overall, we included 15 reviews in this overview that were published in the Cochrane Database of Systematic Reviews (Amatya 2013; Bennett 2004; das Nair 2016; Farinotti 2012; Heine 2015; Jagannath 2010; Khan 2007b; Khan 2009; Khan 2015; Kopke 2014; Rietberg 2005; Rosti‐Otajärvi 2014; Sitjà Rabert 2012; Steultjens 2003; Thomas 2006). We provided a flow diagram of the review selection process in Figure 2.
Study flow diagram
Description of included reviews
The characteristics of the 15 included Cochrane Reviews are summarised in Table 1. The included reviews were published (or updated) between 2003 and 2016. In all reviews, searches were limited to randomised controlled trial (RCT) or clinical controlled trial (CCT) designs, and in three cases, the inclusion was limited to RCTs with follow‐up of six months or longer. Overall, these 15 reviews included 164 RCTs and four CCTs, with a total of 10,396 participants.
Methodological quality of included reviews
The results of the R‐AMSTAR quality assessment are provided in Appendix 2 and Appendix 3 and total scores for each included reviews are provided in Table 1. The kappa level of agreement between the two review authors for the R‐AMSTAR assessment was 0.91. Overall, 11 included reviews were of high methodological quality (R‐AMSTAR score ≥ 40), and four were of moderate quality (R‐AMSTAR score = 30 to 39 (Kopke 2014; Rietberg 2005; Sitjà Rabert 2012; Steultjens 2003)). The mean R‐AMSTAR methodological quality score for included reviews was 39.8 (standard deviation 2.5), and ranged from 34 to 42, out of a possible maximum of 44. All reviews, except one, performed a comprehensive literature search of medical science databases (Steultjens 2003), however, only half of the reviews included a grey literature search. All reviews, except two, assessed the scientific quality of the included primary studies using validated tools (Rietberg 2005; Thomas 2006). All reviews provided their funding sources, however, surprisingly, even though the reviewers declared their own conflicts of interest, none addressed the potential competing interests and source of support of authors of the primary studies. None of the reviews provided an explicit statement on the impact of findings on clinical practice guidelines.
There was heterogeneity amongst the included reviews in the tools used to assess the methodological quality of the primary studies: eight reviews used core items of the Cochrane 'Risk of bias' tool (Amatya 2013; das Nair 2016; Farinotti 2012; Jagannath 2010; Khan 2015; Kopke 2014; Rosti‐Otajärvi 2014; Sitjà Rabert 2012), three used van Tulder's methodological quality checklist (Khan 2007b; Khan 2009; Steultjens 2003), one used both the PEDro checklist and the Cochrane 'Risk of bias' tool (Heine 2015), one used the Jadad score (Bennett 2004), one used a self‐designed 11‐point checklists (Rietberg 2005), and Thomas 2006 just used a single item; 'random allocation had been adequately concealed'. The review authors of seven included reviews used the GRADE method to rate the quality of the evidence supported by the primary trials (Amatya 2013; das Nair 2016; Heine 2015; Khan 2015; Kopke 2014; Rosti‐Otajärvi 2014; Sitjà Rabert 2012).
Effect of interventions
A rehabilitation approach to people with MS (pwMS) included a range of treatments and interventions. We summarised the characteristics of included reviews in Table 1, and summarised the best‐evidence syntheses for rehabilitation interventions in MS below. We summarised the findings from the included reviews for each type of intervention based on outcomes according to the International Classification of Functioning, Disability and Health (ICF; Table 2). The summary of the impact of these interventions based on specific settings are shown in Figure 3.
Impact of outcomes of rehabilitation interventions based on the settings of care
| Rehabilitation interventions for people with multiple sclerosis (pwMS) | ||||||
| Outcome* | Intervention and Comparison intervention | Illustrative comparative risks (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE)** | Comments | |
| Assumed risk | Corresponding risk | |||||
| With comparator | With intervention | |||||
| Function (mobility, ADLs) | Intervention: Multidisciplinary rehabilitation (MD) ‐ inpatient Comparison: Lower level or different types of interventions; intervention given in different settings; lower intensity of intervention. | There was evidence that inpatient MD rehabilitation can improve functional independence, mobility and locomotion (wheelchair users only) | 217 participants (3 RCTs) | ⊕⊕⊕⊝ Moderate1 | Data were not pooled in this review due to design differences and use of different outcome measures | |
| Intervention: Multidisciplinary rehabilitation (MD) ‐ inpatient or outpatient Comparison: Lower level or different types of interventions; intervention given in different settings; lower intensity of intervention. | There was evidence that an inpatient or outpatient MD rehabilitation program can improve function and bladder impairment | 101 participants (1 RCT) | ⊕⊕⊕⊝ Moderate2 | Findings are based on one single centred trial. | ||
| Intervention: Exercise Comparison: Control interventions (details not provided) | There was evidence that exercise therapy can improve muscle power, function, exercise tolerance, and mobility‐related activities more than no exercise. | 260 participants (9 RCTs) | ⊕⊕⊕⊝ Moderate1 | Data were not pooled in this review due to variation in outcome measures | ||
| Intervention: Whole‐body vibration Comparison: Passive intervention; any other active physical therapy intervention; another vibration therapy under different vibration parameters | The mean body balance ranged across control groups from 242 to 245 mm | The mean body balance in the intervention groups was 19.83 higher (20.99 lower to 60.65 higher) | 64 participants (4 RCTs) | ⊕⊕⊝⊝ Low3 | Body balance measured using the Functional Reach Test. | |
| Intervention: Telerehabilitation programme Comparison: Lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment (or usual care); interventions given in different settings | There was evidence that a telerehabilitation programme may improve functional activities, such as physical activity, walking, balance capacity, and postural control for the short‐term (up to 3 months) | 45 participants (1 RCT) | ⊕⊕⊝⊝ Low4 | Data were not pooled in this review due to various interventions and use of different outcome measures | ||
| Impariments (symptoms) | Intervention: Various non‐pharmacological spasticity management interventions Comparison: Sham or placebo interventions; lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment; interventions given in different settings | There was evidence that addition of active physiotherapy after BoNT injection may reduce spasticity up to 12 weeks: MAS score at week 2 (2.73 versus 3.22 in control), at week 4 (2.64 versus 3.33 in control), and at week 12 (2.68 versus 3.33 in control); P < 0.01 for all time points. There was evidence that iTBS alone or in combination with exercise therapy may reduce spasticity after 2 weeks: MAS scores in the stimulated leg (2.1 ± 0.4 before treatment; 1.3 ± 0.4 after treatment; P < 0.05), MSSS‐88 (74.3 ± 11.4 before treatment; 53.2 ± 10.9 after treatment; P < 0.001), FSS (39.5 ± 4.2 before treatment; 31.6 ± 4.6 after treatment; P < 0.05). There was evidence that rTMS may reduce spasticity (MAS score; mean change ‐3.3 ± 4.7 AU versus 0.7 ± 2.5 AU in control group; P = 0.003). There was evidence that pulsed electromagnetic therapy may reduce spasticity (P < 0.005) and fatigue (P = 0.04). There was evidence that magnetic pulsing device may improve a performance scale (PS) combined rating for bladder control, cognitive function, fatigue level, mobility, | 341 participants (9 RCTs) | ⊕⊕⊝⊝ Low3 | Data were not pooled in this review due to various interventions and use of different outcome measures | |
| Intervention: HBOT Comparison: Placebo or no treatment | There was evidence that HBOT may reduce mean EDSS at 12 months (group mean reduction in EDSS compared to sham ‐0.85, P = 0.0001). | 504 participants (9 RCTs) | ⊕⊕⊝⊝ Low3 | Data from only 2 RCTs showed some benefits and majority of trials (7 RCTs) reported no evidence | ||
| Intervention: Different exercise therapy: endurance training (23 interventions), muscle power training (9 interventions), task‐oriented training (5 interventions), mixed training (15 interventions), or other (e.g. yoga (17 interventions)) Comparison: Non‐exercise control or another intervention | There was evidence that overall, exercise therapy can reduce fatigue (SMD ‐0.53; P < 0.01). There was evidence that different types of exercise therapy can reduce fatigue: endurance training (SMD ‐0.43; P < 0.01), mixed training (SMD ‐0.73; P < 0.01), and other training, e.g. yoga (SMD ‐0.54; P < 0.01) | 2250 participants (45 RCTs) | ⊕⊕⊕⊝ Moderate5 | There was significant heterogeneity between | ||
| Intervention: Telerehabilitation program Comparison: Lower level or different types of intervention; minimal intervention; waiting‐list controls, no treatment, or usual care; interventions given in different settings | There was evidence that a telerehabilitation programme can reduce or improve impairments, such as fatigue in the short term (up to 3 months) and long term; and improved symptoms, such as pain and insomnia in the long term. | 489 participants (4 RCTs) | ⊕⊕⊝⊝ Low1 | Data were not pooled in this review due to various interventions and use of different outcome measures. | ||
| Participation (quality of life, psychological outcomes, vocational and social activities) | Intervention: Exercise Comparison: Control interventions (details not provided) | There was evidence that exercise therapy can improve mood more than no exercise. | 260 participants (9 RCTs) | ⊕⊕⊕⊝ Moderate1 | Data were not pooled in this review due to variation in outcome measures | |
| Intervention: Memory rehabilitation Comparison: No treatment or placebo | There was evidence that memory rehabilitation may show improvement in objective assessments of memory in both immediate follow‐up (SMD 0.23, 95% CI 0.05 to 0.41) and long‐term (3 to 8 months) follow‐up (SMD 0.26, 95% CI 0.03 to 0.49) There was evidence that memory rehabilitation may improve QoL in the immediate follow‐up (SMD 0.23, 95% CI 0.05 to 0.41) | 989 participants (15 RCTs) | ⊕⊕⊝⊝ Low3 | The evidence is limited and does not extend to subjective reports of memory functioning or mood. Objective measures used were not valid, potentially limiting generalisability of findings. | ||
| Intervention: Neuropsychological rehabilitation Comparison: Other interventions or no intervention | There was evidence that cognitive training may improve memory span (SMD 0.54, 95% CI 0.20 to 0.88; P = 0.002) and working memory (SMD 0.33, 95% CI 0.09 to 0.57; P = 0.006). There was evidence that cognitive training, combined with other neuropsychological rehabilitation methods, might improve attention (SMD 0.15, 95% CI 0.01 to 0.28; P = 0.03), immediate verbal memory (SMD 0.31, 95% CI 0.08 to 0.54; P = 0.008), and delayed memory (SMD 0.22, 95% CI 0.02 to 0.42; P = 0.03). | 986 participants (20 RCTs) | ⊕⊕⊝⊝ Low3 | Interventions and outcome measures included in the review were heterogeneous, which limited the comparability of the studies | ||
| Intervention: Telerehabilitation program Comparison: Lower level or different types of intervention; minimal intervention; waiting‐list controls, no treatment, or usual care; interventions given in different settings | There was evidence that telerehabilitation programs might improve psychological outcomes and QoL for the long term (> 3 months) | 392 (6 RCTs) | ⊕⊕⊝⊝ Low3 | Data were not pooled in this review due to various interventions and use of different outcome measures | ||
| Intervention: Information‐provision interventions included: decision aids, educational programmes, self‐care interventions, and personal interviews with physicians Comparison: Usual care or other types of information‐provision interventions | There was evidence that information provision for patients can improve patients' disease‐related knowledge. | 524 participants (4 RCTs) | ⊕⊕⊕⊝ Moderate6 | Data were not pooled in this review due to the marked heterogeneity of the interventions and outcome measures. | ||
ADL = activities of daily living; BI = Barthel Index; CBT = cognitive behavioural therapy; CCT = clinical controlled trial; CI = confidence interval; EDSS = Expanded Disability Status Scale; HBOT = hyperbaric oxygen therapy; FSS = Fatigue Severity Scale; HRQoL = health‐related quality of life; iTBS = intermittent theta burst stimulation; MS = multiple sclerosis; MSQOL‐54 = Multiple Sclerosis Quality of Life; MSSS‐88 = Multiple Sclerosis Spasticity Scale; OT = occupational therapy; pwMS = persons with multiple sclerosis; PT = physical therapy; PUFAs = polyunsaturated fatty acids; QoL = quality of life; RCT = randomised controlled trial; rTMS = repetitive transcranial magnetic stimulation; SMD = standardised mean difference; TENS = transcutaneous electrical nerve stimulation; VAS = visual analogue scale
*Outcomes categorised according to the International Classification Functioning, Disability and Health (ICF, WHO 2001).
**GRADE 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.
1Downgraded by one level for imprecision and inconsistency of findings and use of different outcome measures.
2 Downgraded by one level due to high risk for imprecision (one single site study).
3Downgraded by two levels for imprecision and inconsistency of findings, due to a number of methodological flaws (high risk of bias in randomisation sequence generation, allocation concealment and blinding) and use of different outcome measures.
4Downgraded two levels because the singular study was considered at high risk of bias (unclear risk of bias in randomisation, sequence generation, allocation concealment and blinding of outcome assessors).
5Downgraded by one level for imprecision and inconsistency of findings and majority of trials had small sample size and assessed fatigue as a secondary measure.
6Downgraded by one level for imprecision and inconsistency of findings,use of different outcome measures and high risk of bias.
We found marked heterogeneity of the evaluated interventions and measured outcomes amongst the included reviews. Various specific rehabilitation interventions evaluated in included reviews and key findings are summarized below:
Multidisciplinary rehabilitation (1 review)
Khan 2007b included 10 trials (9 RCTs and 1 CCT), with 954 participants, which evaluated various types of multidisciplinary rehabilitation in pwMS. The authors reported strong evidence for inpatient multidisciplinary rehabilitation (3 RCTs, N = 217) in producing short‐term gains at the levels of activity (disability) and participation. Strong evidence was reported for improvement in disability (total Functional Independence Measure (FIM) and Barthel Index (BI)), and level of participation (London Handicap Scale (LHS), and Human Activities Profile (HAP)). There was moderate‐level evidence indicating that inpatient rehabilitation could improve symptoms (Guy’s Neurological Disability Scale (GNDS)), self‐care and sphincter control (FIM), and mobility and locomotion (wheelchair users only (Amended Motor Club Assessment (AMCA)).
In this review, one RCT evaluated an individualised, multidisciplinary rehabilitation programme provided in inpatient settings compared to outpatient settings (N = 84 participants), and reported limited evidence for short‐term gains at the level of activity (ambulatory status and Incapacity Status Scale (ISS)). There was no evidence at the level of participation and reduction in the need for aids or assistance at home. The trial authors did not report details of participants and interventions, such as length of rehabilitation and contents of the rehabilitation programme. One trial, with two reports (N = 101 participants), compared individualised (three to six weeks), multidisciplinary inpatient (three hours of intensive therapy, with blocks of sessions with physiotherapists, occupational therapists, and other allied health professionals, such as speech therapist, neuropsychologist, and social work as required), or outpatient rehabilitation (similar low intensity programme based on patient needs), with a waiting‐list control group, and reported moderate evidence for reduced disability, and bladder impairment outcomes, and improved continence‐related quality of life (QoL) and participation. Four RCTs evaluated the effectiveness of outpatient multidisciplinary rehabilitation versus control (N = 351 participants), and found limited evidence for improved impairment, measured by the Expanded Disability Status Scale (EDSS), short‐term benefits at the level of activity (FIM), and improved fatigue, mood, and social function. There was no convincing evidence for the cost‐effectiveness of any multidisciplinary programmes, or the best ‘dose’ of therapy (Khan 2007b).
Physical therapeutic modalities
We identified three Cochrane Reviews that assessed physical therapeutic modalities in pwMS; findings are summarised below.
Exercise (2 reviews)
Two reviews evaluated the effectiveness of different types of exercise programmes (Heine 2015; Rietberg 2005).
Heine 2015 evaluated the effectiveness and safety of exercise therapy on fatigue in pwMS. The authors included 45 RCTs (N = 2250 participants), which evaluated 69 different exercise interventions: endurance training (23 interventions), muscle power training (9 interventions), task‐oriented training (5 interventions), mixed training (15 interventions), or other (e.g. yoga (17 interventions)). Of these, 36 trials, with 1603 participants, provided sufficient data for the meta‐analysis on fatigue. The review authors reported a significant effect on fatigue in favour of exercise therapy compared to non‐exercise control (standardised mean difference (SMD) ‐0.53, 95% confidence interval (CI) ‐0.73 to ‐0.33; P < 0.01). Despite the significant heterogeneity between trials (I² > 58%) and the overall methodological quality, the combined body of evidence was of moderate quality. In a subgroup analysis, the authors also reported a significant effect on fatigue in favour of exercise therapy compared to no exercise for endurance training (SMD ‐0.43, 95% CI ‐0.69 to ‐0.17; P < 0.01), mixed training (SMD ‐0.73, 95% CI ‐1.23 to ‐0.23; P < 0.01), and other training (SMD ‐0.54, 95% CI ‐0.79 to ‐0.29; P < 0.01). Across all studies, exercise did not seem to be associated with a significant risk of a relapse of MS or adverse events. The authors concluded that exercise therapy (endurance, mixed, or other training) could reduce self‐reported fatigue, and could be prescribed for pwMS without harm.
Rietberg 2005 examined the effectiveness of exercise therapy for pwMS on activities of daily living (ADL) and health‐related QoL (9 RCTs, 260 participants). Six trials compared exercise therapy with no exercise therapy, while three trials compared two different types of exercise therapy interventions. There was strong evidence that exercise‐based rehabilitation improved muscle power, exercise tolerance, and mobility‐related activities; moderate evidence that it improved mood; but no evidence for fatigue. Exercise therapy was found to be safe, with no adverse events. The review authors reported that there was no evidence on optimal type, duration, intensity, or frequency of training sessions, due to diversity amongst included trials. The authors concluded that exercise therapy could be beneficial for pwMS who were not experiencing an exacerbation.
Hyperbaric oxygen therapy (HBOT; 1 review)
Bennett 2004 evaluated the efficacy and safety of HBOT in pwMS (9 RCTs, 504 participants). The initial treatment course of HBOT consisted of 20 treatment sessions over four weeks; the dose of oxygen per treatment session varied between studies. Two trials produced modest, positive results; however, these were isolated, and difficult to ascribe biological plausibility. There was some improvement in the mean EDSS score at 12 months in the HBOT group (group mean reduction in EDSS compared to sham ‐0.85 of a point, 95% CI ‐1.28 to ‐0.42; P = 0.0001). Seven trials reported no evidence of a general treatment effect. There was inconsistent evidence of benefit for the secondary outcomes, such as fatigue, pyramidal system function, and sphincter function. Overall findings suggested that there was no consistent evidence to confirm a beneficial effect of HBOT in pwMS.
Whole‐body vibration (WBV; 1 review)
Sitjà Rabert 2012 examined the efficacy of WBV on functional performance in persons with neurodegenerative diseases, including MS. Of 10 RCTs identified, 4 RCTs, with 64 participants, were conducted in the MS population. The included trials used different vibration parameters (range from 2 to 26 Hz) and different vibration platform types (rotational platform, platform that generates vertical sinusoidal displacements, or random platform). The authors found no evidence of a short‐term or long‐term effect of WBV on any functional outcomes (body balance, gait, muscle performance) or QoL, compared with other active physical therapy or passive interventions.
Occupational therapy (1 review)
Steultjens 2003 evaluated the efficacy of occupational therapy (OT) on functional outcomes, and social participation, health‐related QoL, or both, in pwMS. The authors found three trials (1 RCT and 2 CCTs, 274 participants). The OT approach evaluated a group energy conservation course (2 trials) and counselling intervention. The review authors found inconclusive evidence for any OT interventions in pwMS. Two included trials (both CCTs) reported a beneficial effect of energy conservation group therapy, however, the evidence was insufficient, due to methodological flaws.
Cognitive and psychological interventions (3 reviews)
Rosti‐Otajärvi 2014 assessed the effects of neuropsychological, cognitive rehabilitation on cognitive performance and emotional well‐being in pwMS (20 RCTs, 986 participants). The review authors reported that cognitive training improved memory span (SMD 0.54, 95% CI 0.20 to 0.88; P = 0.002), and working memory (SMD 0.33, 95% CI 0.09 to 0.57; P = 0.006). Cognitive training combined with other neuropsychological rehabilitation methods also improved attention (SMD 0.15, 95% CI 0.01 to 0.28; P = 0.03), immediate verbal memory (SMD 0.31, 95% CI 0.08 to 0.54; P = 0.008), and delayed memory (SMD 0.22, 95% CI 0.02 to 0.42; P = 0.03). No improvement was found for emotional function. The overall quality of the included studies was low, due to methodological limitations and heterogeneity of interventions and outcome measures. The review authors concluded there was low‐quality evidence suggesting that neuropsychological rehabilitation improved cognitive functions (improved memory span, working memory, attention), but none for emotional function.
Thomas 2006 evaluated the effectiveness of psychological interventions, including cognitive behavioural therapy (CBT), in pwMS (16 RCTs, 1006 participants). CBT was found to be beneficial in the treatment of depression, and in helping people adjust to, and cope with, having MS. The authors were unable to interpret results conclusively, due to the range of outcome measures used, and heterogeneity amongst the trials. Psychological interventions were diverse in nature; CBT was the most frequently used approach. None of the studies focused on psychological approaches to managing common symptoms of MS, such as fatigue and pain. The majority of the included studies had various methodological flaws, including small sample size, lack of proper randomisation and allocation concealment methods, and lacked a clear description of withdrawals.
das Nair 2016 evaluated the effectiveness of memory rehabilitation on memory functions and functional abilities in a subgroup of pwMS with memory problems, compared to those who were given no treatment, or received a placebo. The review authors included 15 RCTs, with a total of 989 participants, which evaluated a wide range of memory retraining techniques, such as computerised programmes, and internal and external memory aids. The findings suggested a significant effect of the interventions on objective assessments of memory at both the immediate‐ (SMD 0.23, 95% CI 0.05 to 0.41), and long‐term follow‐up (SMD 0.26, 95% CI 0.03 to 0.49), and on QoL in the immediate‐term follow‐up (SMD 0.23, 95% CI 0.05 to 0.41). The intervention group performed significantly better than the control group in ADLs at long‐term follow‐up (SMD ‐0.33, 95% CI ‐0.63 to ‐0.03). There was no significant effect on subjective reports of memory problems at short‐term (SMD 0.04, 95% CI ‐0.19 to 0.27), or long‐term follow‐up (SMD 0.04, 95% CI ‐0.19 to 0.27); on mood at short‐term (SMD 0.02, 95% CI ‐0.16 to 0.20), or long‐term follow‐up (SMD ‐0.01, 95% CI ‐0.21 to 0.20); at short‐term follow‐up for ADL (SMD ‐0.13, 95% CI ‐0.60 to 0.33); or at long‐term follow‐up for QoL (SMD 0.16, 95% CI ‐0.03 to 0.36). The authors concluded that there was low‐quality evidence suggesting that memory rehabilitation techniques may improve memory function and QoL.
Nutritional and dietary supplement intervention (2 reviews)
Farinotti 2012 evaluated the efficacy and safety of dietary regimens for pwMS (6 RCTs, 794 participants). These studies evaluated different form of polyunsaturated fatty acids, given for 12 to 30 months, including omega‐6 fatty acids (N‐6 PUFA) – linoleic acid, or omega‐3 fatty acids (N‐3 PUFA) – fish oil. The review authors reported that polyunsaturated fatty acids did not have significant effects on clinical outcomes in MS (disease progression). Similarly, they found that omega‐6 fatty acids and linoleic acid had no beneficial effects. There were inconclusive data on safety.
Jagannath 2010 assessed the safety and effectiveness of vitamin D in the management of MS. The authors found only one RCT conducted over 52 weeks, which treated 25 patients with escalating doses of vitamin D compared with controls (N = 24). Participants in the intervention group received 40,000 IU/day over 28 weeks to raise serum 25‐hydroxyvitamin D (25(OH)D) rapidly, followed by 10,000 IU/day for 12 weeks; they were then down‐titrated to 0 IU/day. The control group received a regular dose (4000 IU/day) of vitamin D. There was limited evidence that escalating doses of vitamin D might improve relapse rates, disability scores, and suppression of T‐cell proliferation. Vitamin D was safe, with no adverse effects. However, the study was of low quality, with a potential high risk of bias, which limited the generalisability of the findings.
Vocational rehabilitation (1 review)
Khan 2009 examined the effectiveness of vocational rehabilitation programmes compared to alternative programmes or usual care on return to work, work ability, and employment in pwMS. The authors only found two poor quality trials (1 RCT and 1 CCT, 80 participants). The evidence was inconclusive for the effects of specific vocational interventions on outcomes, such as: competitive employment, altering rates of job retention, changes in employment, rates of re‐entry into labour force, altering work ability, employability maturity, or job‐seeking activity. The authors highlighted the need for clinicians to be aware of vocational issues, to incorporate practical solutions to deal with work disability, and workplace accommodation, and to educate employers and the wider community to understand and manage barriers for maintaining employment.
Information‐provision interventions (1 review)
Kopke 2014 evaluated the effectiveness of information‐provision interventions for pwMS, to promote informed choices and improve patient‐relevant outcomes. The authors found 10 RCTs (1314 participants), which included interventions providing disease‐specific information, such as information leaflets, booklets, manuals or pamphlets, educational programmes or lectures, audio‐visual aids, like videos, tape recordings, computer programmes or websites, web systems, including podcasts, social networks or other information technologies (smartphones, decision‐support tools), or personal information (e.g. house visits or telephone calls). The authors reported moderate‐quality evidence for MS‐related knowledge delivery programmes (N = 4 RCTs, 524 participants) in successfully increasing participants’ knowledge. There were mixed results and low‐quality evidence from studies reporting effects on decision‐making (N = 4 RCTs, 836 participants), and from studies assessing QoL (N = 5 RCTs, 605 participants). The authors concluded that providing information to pwMS seemed to increase disease‐related knowledge, with less clear results on decision making and QoL.
Other reviews on specific rehabilitation interventions
Telerehabilitation (1 review)
Khan 2015 examined the effectiveness and safety of telerehabilitation intervention in pwMS (9 RCTs, 531 participants). These studies evaluated various telerehabilitation interventions with more than one rehabilitation component, and predominantly included physical activity, educational, behavioural, and symptom‐management programmes. There was low‐quality evidence for any form of telerehabilitation interventions in reducing short‐term disability, impairments (such as fatigue, pain, insomnia); or in improving functional activities, psychological outcomes, or QoL in the longer term. There were no data on cost‐effectiveness or process evaluation (participants' and therapists' satisfaction). Despite the lack of high‐quality evidence, the authors concluded that a range of telerehabilitation interventions could be an alternative efficient and cost‐effective method to deliver rehabilitation treatment in a setting convenient to the patient, and in remote areas where there were limited rehabilitation services.
Interventions for the management of spasticity (1 review)
Amatya 2013 evaluated non‐pharmacological interventions for treating spasticity in pwMS. The authors included 9 RCTs, with 341 participants, which evaluated a wide range of non‐pharmacological interventions: physical activity programmes (such as physiotherapy, structured exercise programmes, sports climbing), transcranial magnetic stimulation (intermittent theta burst stimulation (iTBS), repetitive transcranial magnetic stimulation (rTMS)), electromagnetic therapy, transcutaneous electrical nerve stimulation (TENS); and whole body vibration. The authors reported low‐quality evidence that physical activity programmes used in isolation, or in combination with other interventions (pharmacological or non‐pharmacological), and for magnetic stimulation (iTBS, rTMS), with or without adjuvant exercise therapy may improve spasticity in pwMS. There was no evidence to support the use of TENS, sports climbing, or vibration therapy for treating spasticity in this population.
Discussion
Summary of main results
This review systematically summarised the best, up‐to‐date evidence from published Cochrane Reviews for the effectiveness of rehabilitation interventions in people with multiple sclerosis (pwMS). Rehabilitation is considered to be a key supportive treatment in MS. A range of rehabilitative approaches have been evaluated in this population. However, findings indicate that evidence to support the use of various interventions is relatively poor. There is a lack of high‐quality evidence for the effectiveness of various modalities, due to the limited number of methodologically robust studies. The key findings of this review, based on outcomes according the International Classification Functioning, Disability and Health (ICF) framework that focus on the following categories, are outlined in Table 2, and summarised below:
Function
-
Moderate‐quality evidence that inpatient or outpatient multidisciplinary rehabilitation programmes improved functional activities and bladder related activity.
-
Moderate‐quality evidence that physical therapeutic modalities (exercise, physical activities) improved functional outcomes (mobility, muscular strength).
-
Low‐quality evidence that exercise therapy may improve balance.
-
Low‐quality evidence that whole body vibration may improve any functional outcomes (balance, gait, muscle performance), or QoL.
-
Low‐quality evidence that telerehabilitation may reduce short‐term disability and improve functional activities.
Impairments
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Moderate‐quality evidence that physical therapeutic modalities (exercise, physical activities) reduced patient‐reported fatigue.
-
Low‐quality evidence that multidisciplinary rehabilitation (outpatient and home‐based) programmes might provide short‐term improvements in symptoms.
-
Low‐quality evidence that specific therapy programmes targeting MS‐related spasticity may improve spasticity.
-
Low‐quality evidence that telerehabilitation may reduce symptoms (such as fatigue, pain, insomnia).
Participation
-
Moderate‐quality evidence that inpatient or outpatient multidisciplinary rehabilitation programmes improved participation outcomes (such as QoL) up to 12 months.
-
Moderate‐quality evidence that information provision increased patient’s knowledge.
-
Moderate‐quality evidence that exercise therapy improved psychological symptoms (such as mood) and QoL
-
Low‐quality evidence that neuropsychological interventions may improve memory span, working memory, and attention.
-
Low‐quality evidence that cognitive behavioural therapy may improve depression, adjustment, and the ability to cope with MS.
-
Low‐quality evidence that memory rehabilitation programmes may improve memory immediately, and in the long‐term.
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Low‐quality evidence that whole body vibration may improve QoL.
-
Low‐quality evidence that vocational rehabilitation may improve competitive employment, job retention, changes in employment, rates of re‐entry into the labour force; work ability by improving participants’ confidence in the accommodation request process, employability maturity, or job seeking activity.
-
Low‐quality evidence for telerehabilitation may improve QoL and psychological outcomes.
Synthesis of best evidence from this review, based on type of rehabilitation interventions, suggest there was:
Moderate‐quality evidence for:
-
Inpatient or outpatient multidisciplinary rehabilitation programmes to improve disability, bladder related activity, and participation outcomes up to 12 months.
-
Physical therapeutic modalities (exercise, physical activities) to improve functional outcomes (mobility, muscular strength) and QoL, reduce patient‐reported fatigue.
-
Information provision to increase patient’s knowledge.
-
Exercise therapy to improve psychological symptoms (such as mood).
Low‐quality evidence for:
-
Multidisciplinary rehabilitation (outpatient and home‐bases) programmes that may improve symptoms and disability in the short term.
-
Exercise therapy that may improve balance and symptoms.
-
Neuropsychological interventions that may improve memory span, working memory, and attention.
-
Cognitive behavioural therapy that may improve depression, adjustment, and the ability to cope with MS.
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Memory rehabilitation programmes that may improve memory or functional abilities, immediately or in the long term.
-
Whole body vibration that may improve any functional outcomes (balance, gait, muscle performance), or QoL.
-
Specific therapy programmes targeting MS‐related spasticity that may improve spasticity.
-
Vocational rehabilitation that may improve competitive employment, job retention, changes in employment, rates of re‐entry into the labour force; work ability by improving participants’ confidence in the accommodation request process, employability maturity, or job seeking activity.
-
Telerehabilitation that may reduce short‐term disability, improve functional activities, impairments (such as fatigue, pain, insomnia), QoL, and psychological outcomes.
Inconclusive evidence for:
-
Occupational therapy strategies on functional ability, social participation, QoL, or a combination.
-
Hyperbaric oxygen therapy on any patient outcomes.
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Neuropsychological interventions on emotional function.
-
Dietary interventions (polyunsaturated fatty acids, vitamin D) on clinical outcomes.
Overall completeness and applicability of evidence
This overview of Cochrane Reviews investigating the effectiveness of rehabilitation interventions in pwMS found a large degree of variation in interventions, outcome measurement tools, control protocols, and length of follow‐up. Due to this heterogeneity, we were unable to pool data in meta‐analyses, and were only able to conduct best‐evidence syntheses using qualitative analyses. The identified heterogeneity may also reflect the wide variety of rehabilitation interventions, conducted in different settings, under different healthcare systems, with patients with varied severity and stages of MS. This review only included published Cochrane Reviews. The authors acknowledge that the overall summary reported in this review cannot be regarded as the best and most inclusive findings, as we excluded many published, relevant non‐Cochrane reviews in this area (Andreasen 2011; Asano 2014; Bilkman 2013; Bronson 2010; Campbell 2016; Cruickshank 2015; Dalgas 2015; Glinsky 2007; Haselkorn 2015; Kalron 2015; Kantele 2015; Kjolhede 2012; Latimer‐Cheung 2013; Mitolo 2015; Paltamaa 2012; Snook 2009; Yu 2014; Yu 2014a). However, the non‐Cochrane reviews varied in scope and methodology, and lacked a standardised reporting protocol, which resulted in diverse conclusions. Therefore, we believe that including only Cochrane Reviews in this overview, potentially provided the least biased estimate of the impact of rehabilitation interventions in pwMS. It also provided reassurance about whether or not the conclusions of individual reviews were consistent (Smith 2011).
Despite strong recommendations to update Cochrane Reviews every two years, it was more than two years since the majority of the included reviews were last published or updated. Of the 15 included reviews, only one review included evidence up to June 2015 (das Nair 2016). Four included reviews could be considered out of date, as these reviews only included evidence published prior to 2010, implying that recent trials may have been missed (Jagannath 2010; Rietberg 2005; Steultjens 2003; Thomas 2006). For the rest of the reviews, the literature search date had already exceeded two years, so technically, they would also be considered out of date.
Rehabilitation for pwMS should include a wide spectrum of treatment, and use different interventions, which need to be individualised, because of the diverse clinical presentations, varying levels of disability, and changing needs of these individuals (Khan 2010). This reflects the wide variety of rehabilitation interventions included in this review. However, we found that many of the evaluated interventions were broadly described; specifically exercise interventions (aerobic, strength, flexibility, mobility, range of motion, postural control and balance training, bicycle, ergometry, etc. (Rietberg 2005)), and psychological interventions (cognitive behavioural therapy, psychoanalytic therapy, counselling, psycho‐education, compute‐based psychological training programmes, memory aids, etc. (das Nair 2016; Thomas 2006)). Sufficient details to enable replication of many of these interventions were lacking, and few studies demonstrated the implementation of their included interventions. Many of these interventions have yet to be included in comprehensive multidisciplinary rehabilitation programmes (Khan 2007b). Included reviews also failed to provided information on optimal settings, type, intensity, and duration of therapy, and cost‐effectiveness of the rehabilitation inventions.
Rehabilitation interventions are complex and difficult to quantify, and the active ingredient in the intervention is not directly identifiable (Khan 2015). The majority of the reviews included a study population with all types of MS. The included reviews consistently remarked on the relatively small numbers of patients, with marked heterogeneity of disease type, clinical presentation, and goals for treatment in the primary trials. The majority of review authors also argued that control arms, specifically those that used 'usual care’, were poorly described across the primary trials. There was also a marked heterogeneity amongst the outcome measures used, even to evaluate similar functional or psychological outcomes, and assessment time points in the primary trials. This was reflected in the challenges encountered in assimilating, or pooling the data in meta‐analyses, or both. Therefore, the quality of the overall evidence for many of the rehabilitation interventions, and external validity of the findings, should be interpreted cautiously.
Quality of the evidence
We assessed that all included reviews were of high to moderate quality, however, many were not recently published or updated. The quality of the evidence supporting the findings was limited by the small number of primary studies, and methodological limitations of these trials within the included reviews. The main sources of bias in the primary studies were methodological limitations, such as inadequate or lack of blinding of participants and outcome assessors, and inadequate reporting of allocation concealment and randomisation methods. There were also inconsistencies and heterogeneity in the outcome measures, and assessment and follow‐up periods. Many studies included relatively small numbers of participants (statistically underpowered), and there was a marked heterogeneity in disease types and clinical presentation of the participants, and goals for treatment. We could not rule out some degree of selection, publication, and reference bias from the literature searches in the included reviews.
Potential biases in the overview process
Overall, data from the included Cochrane Reviews did not provide clinically relevant evidence for the majority of rehabilitation interventions of interest. This might be due to several limitations in the review process. We only included currently published Cochrane Reviews. Although these reviews strictly followed the Cochrane guidelines, and adopted a thorough search strategy, many were not updated; therefore, there is a strong likelihood there were missing relevant articles published beyond the search date of the included reviews. Four included reviews were conducted by the present authors' team (Amatya 2013; Khan 2007b; Khan 2009; Khan 2015), and one author (FK) was involved in another review (Kopke 2014). Independence of assessors' judgment evaluating these reviews cannot be confirmed. However, as Cochrane sets the standards for research synthesis, and as we independently followed a strict, standard appraisal protocol for all included reviews, and resolved disagreement by consensus among all review authors, we think this might have minimal impact on the overall quality assessment process. The majority of the reviews only searched for papers published in English, hence, there was a likelihood of missing data available in other languages.
Agreements and disagreements with other studies or reviews
Haselkorn 2015 conducted a systematic review that provided an overview of the evidence for physical rehabilitation for pwMS. In contrast to this overview review, the authors included 142 individual trials (all designs; published between 1970 and 2013), rated the evidence using American Academy of Neurology criteria, and focused specifically on individual trials of physical therapies. However, this present overview used a global approach to scrutinise the MS literature, by evaluating all published Cochrane Reviews that explored a broad range of rehabilitation modalities, and using globally‐endorsed appraisal methodology (AMSTAR and GRADE).
Bennett 2010 conducted a narrative review to present evidence for a specific type of exercise to control MS symptoms and improve functional recovery, but did not provide a systematic approach to the evaluation of the evidence.
Both of these reviews varied in quality, scope, and methodology, with diverse findings.
Most recently, two authors (BA, FK) systematically evaluated the evidence from published systematic reviews of clinical trials on the effectiveness of rehabilitation to improve function and participation in pwMS (Khan 2017). This overview included both Cochrane and non‐Cochrane reviews, published up to 31 January 2016. Given that Khan 2017 included all the Cochrane Reviews that we included in this overview, there is considerable overlap in the findings and conclusions. Similar to Khan 2017 and Haselkorn 2015, we found that inpatient and outpatient physical therapy, and comprehensive multidisciplinary rehabilitation, improved function and disability in pwMS. However, in contrast to the previous reviews, we found only moderate‐quality evidence supporting physical therapy for pwMs. This discrepancy is likely due to the stringent methodological approach we followed for this review, and the different inclusion criteria among the reviews.
International Classification of Functioning, Disability and Health (ICF) model with case example for multiple sclerosis
Impact of outcomes of rehabilitation interventions based on the settings of care
| Author and Year | Date assessed as up to date | Population | Intervention | Comparision interventions | Outcomes for which data were reported | Meta‐analysis | Review limitations | R‐AMSTR score* |
| 1996 to June 2012 | N = 9 RCTs, 341 participants with all types of MS | Non‐pharmacological spasticity management interventions | Sham or placebo interventions; lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment; interventions given in different settings | Primary Reduction in spasticity; improvement in upper limb functioning and (upper limb‐related) ADL; improvement in mobility Secondary improvement in symptoms or impairments; restriction in participation and impact on caregivers; costs | No |
| 41 | |
| up to 25 February 2011 | N = 9 RCTs, 504 participants with all types of MS | HBOT | Placebo or no treatment | Primary Disability status, objective assessment; suffering ≥ 1 exacerbation at 6 to 12 months; side effects Secondary Functional scores assessed by neurologists | Yes |
| 41 | |
| up to June 2015 | N = 15 RCTs, 989 participants with all types of MS | Memory rehabilitation | No treatment or placebo | Primary Subjective and objective reports of memory Secondary Mood, functional abilities, QoL | Yes |
| 42 | |
| up to November 2011 | N = 6 RCTs, 794 participants with all types of MS | Dietary intervention (polyunsaturated fatty acids, vitamins) | No dietary modification or placebo | Primary Disability progression; exacerbation during study period Secondary HRQoL; cognitive functio; physical and psychological functions; safety (adverse events) | No |
| 42 | |
| 1966 to October 2014 | N = 45 RCTs, 2250 participants with all type of MS | Exercise therapy (fatigue) | Non‐exercise control or another intervention | Primary Fatigue Secondary Safety, relapses | Yes |
| 40 | |
| up to 17 May 2010 | N = 1 RCTs, 49 participants with all types of MS | Dietary intervention (vitamin D) | Placebo or no supplementation | Primary Number of relapses; time‐to‐first treated relapse; QoL; disability status; safety and adverse effects Secondary Hospitalisation; cognitive functions; physical symptoms; psychological symptoms; change in MRI parameters; serum levels of 25‐hydroxyvitamin D (25(OH)D); vitamin D & calcium; bone mineral density (BMD); cytokine profile; T lymphocyte proliferation response & plasma metalloprotease‐9 activity | No |
| 40 | |
| up to 25 February 2011 (updated) | N = 9 RCTs & 1 CCT, 954 participants with moderate to severe disabilities | Multidisciplinary rehabilitation | Lower level or different types of interventions; intervention given in different settings; lower intensity of intervention | Primary Minimisation of disability (limitation in activity) Secondary Participatory issues, such as QoL, psychological adjustment; cost; service utilisation; and care burden | No |
| 40 | |
| 1981 to February 2011 | N = 1 RCT & 1 CCT, 80 MS participants of working age (mean age 18 to 65 years) | Vocational rehabilitation | Alternative programmes or care as usual | Primary Competitive employment; supported employment Secondary Return to work; disability pension; work ability; costs | No |
| 40 | |
| up to 9 July 2014 | N = 9 RCTs, 531 participants, (469 included in analyses); majority RRMS | Telerehabilitation | Lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment (or usual care); interventions given in different settings | Primary Improvement in functional activity (ADLs, mobility, continence, etc.); symptoms or impairments (pain, spasm frequency, joint range of movement, involuntary movements, spasticity, etc.); participation and environmental, personal context, or both (QoL, psychosocial function, employment, education, social and vocational activities, patient and caregiver mood, relationships, social integration, etc.) Secondary Compliance; service utilisation and cost; adverse events | No |
| 42 | |
| up to 12 June 2013 | N = 10 RCTs, 1314 participants with all types of MS | Information provision that aims to promote informed choice and improve patient outcomes | Usual care or other types of information‐provision interventions | Primary Disease‐related (risk) knowledge; measures of (shared) decision making Secondary QoL; informed choice; psychological status; treatment choices; treatment compliance; satisfaction with information received, decisional process; hospital admissions and use of healthcare services; ADLs; coping; disability; role preferences; averse events | No |
| 38 | |
| 1966 to March 2004 | N = 9 RCTs, 260 participants with low to moderate disabilities | Physical (exercise) therapy | Control interventions (details not provided) | Primary Activities limitation; HRQoL Secondary None | No |
| 35 | |
| up to 28 May 2013 | N = 20 RCTs, 986 participants with all types of MS | Neuropsychological rehabilitation | Other interventions or no intervention | Primary Measures of cognitive function Secondary Depression; fatigue; personality disturbance; anxiety; QoL; return to work; activity level | Yes |
| 42 | |
| 1964 to 6 May 2011 | N = 4 RCTs, 64 participants with all types of MS | WBV | Passive intervention (waiting list, non‐treatment, usual lifestyle); any other active physical therapy intervention (balance programme, walking, resistance training, etc.); another WBV under different vibration parameters. | Primary Functional performance according to basic ADL Secondary Signs and symptoms of the disease; body balance, including all the assessments (test, scale, etc.) that analyse equilibrium, postural control, or proprioception in a standing position; gait, including all the measurements (test, scale, etc.) that analyse the action of walking; muscle performance; QoL; adverse events | Yes |
| 39 | |
| up to January 2003 | N = 1 RCT & 2 CCTs, 274 participants with all types of MS | OT | Control interventions (details not provided) | Primary Fatigue; pain; functional ability; social participation; QoL Secondary Knowledge about disease management; self‐efficacy; motor co‐ordination and balance | No |
| 34 | |
| up to December 2004 | N = 16 RCTs, 1006 participants with all types of MS | Cognitive rehabilitation | Usual care or standard care; placebo; waiting‐list controls; other psychological interventions; other interventions | Primary Disease‐specific and general QoL; psychiatric symptoms; psychological functioning; disability; cognitive outcomes Secondary Number of relapses; pain; fatigue; healthcare utilisation; changes in medication; adherence to other therapies | Yes |
| 41 | |
| 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 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 *R‐AMSTAR = Revised Assessment of Multiple Systematic Reviews (Total score out of 44; details in: Appendix 2; Appendix 3) | ||||||||
| Rehabilitation interventions for people with multiple sclerosis (pwMS) | ||||||
| Outcome* | Intervention and Comparison intervention | Illustrative comparative risks (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE)** | Comments | |
| Assumed risk | Corresponding risk | |||||
| With comparator | With intervention | |||||
| Function (mobility, ADLs) | Intervention: Multidisciplinary rehabilitation (MD) ‐ inpatient Comparison: Lower level or different types of interventions; intervention given in different settings; lower intensity of intervention. | There was evidence that inpatient MD rehabilitation can improve functional independence, mobility and locomotion (wheelchair users only) | 217 participants (3 RCTs) | ⊕⊕⊕⊝ Moderate1 | Data were not pooled in this review due to design differences and use of different outcome measures | |
| Intervention: Multidisciplinary rehabilitation (MD) ‐ inpatient or outpatient Comparison: Lower level or different types of interventions; intervention given in different settings; lower intensity of intervention. | There was evidence that an inpatient or outpatient MD rehabilitation program can improve function and bladder impairment | 101 participants (1 RCT) | ⊕⊕⊕⊝ Moderate2 | Findings are based on one single centred trial. | ||
| Intervention: Exercise Comparison: Control interventions (details not provided) | There was evidence that exercise therapy can improve muscle power, function, exercise tolerance, and mobility‐related activities more than no exercise. | 260 participants (9 RCTs) | ⊕⊕⊕⊝ Moderate1 | Data were not pooled in this review due to variation in outcome measures | ||
| Intervention: Whole‐body vibration Comparison: Passive intervention; any other active physical therapy intervention; another vibration therapy under different vibration parameters | The mean body balance ranged across control groups from 242 to 245 mm | The mean body balance in the intervention groups was 19.83 higher (20.99 lower to 60.65 higher) | 64 participants (4 RCTs) | ⊕⊕⊝⊝ Low3 | Body balance measured using the Functional Reach Test. | |
| Intervention: Telerehabilitation programme Comparison: Lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment (or usual care); interventions given in different settings | There was evidence that a telerehabilitation programme may improve functional activities, such as physical activity, walking, balance capacity, and postural control for the short‐term (up to 3 months) | 45 participants (1 RCT) | ⊕⊕⊝⊝ Low4 | Data were not pooled in this review due to various interventions and use of different outcome measures | ||
| Impariments (symptoms) | Intervention: Various non‐pharmacological spasticity management interventions Comparison: Sham or placebo interventions; lower level or different types of intervention; minimal intervention; waiting‐list controls or no treatment; interventions given in different settings | There was evidence that addition of active physiotherapy after BoNT injection may reduce spasticity up to 12 weeks: MAS score at week 2 (2.73 versus 3.22 in control), at week 4 (2.64 versus 3.33 in control), and at week 12 (2.68 versus 3.33 in control); P < 0.01 for all time points. There was evidence that iTBS alone or in combination with exercise therapy may reduce spasticity after 2 weeks: MAS scores in the stimulated leg (2.1 ± 0.4 before treatment; 1.3 ± 0.4 after treatment; P < 0.05), MSSS‐88 (74.3 ± 11.4 before treatment; 53.2 ± 10.9 after treatment; P < 0.001), FSS (39.5 ± 4.2 before treatment; 31.6 ± 4.6 after treatment; P < 0.05). There was evidence that rTMS may reduce spasticity (MAS score; mean change ‐3.3 ± 4.7 AU versus 0.7 ± 2.5 AU in control group; P = 0.003). There was evidence that pulsed electromagnetic therapy may reduce spasticity (P < 0.005) and fatigue (P = 0.04). There was evidence that magnetic pulsing device may improve a performance scale (PS) combined rating for bladder control, cognitive function, fatigue level, mobility, | 341 participants (9 RCTs) | ⊕⊕⊝⊝ Low3 | Data were not pooled in this review due to various interventions and use of different outcome measures | |
| Intervention: HBOT Comparison: Placebo or no treatment | There was evidence that HBOT may reduce mean EDSS at 12 months (group mean reduction in EDSS compared to sham ‐0.85, P = 0.0001). | 504 participants (9 RCTs) | ⊕⊕⊝⊝ Low3 | Data from only 2 RCTs showed some benefits and majority of trials (7 RCTs) reported no evidence | ||
| Intervention: Different exercise therapy: endurance training (23 interventions), muscle power training (9 interventions), task‐oriented training (5 interventions), mixed training (15 interventions), or other (e.g. yoga (17 interventions)) Comparison: Non‐exercise control or another intervention | There was evidence that overall, exercise therapy can reduce fatigue (SMD ‐0.53; P < 0.01). There was evidence that different types of exercise therapy can reduce fatigue: endurance training (SMD ‐0.43; P < 0.01), mixed training (SMD ‐0.73; P < 0.01), and other training, e.g. yoga (SMD ‐0.54; P < 0.01) | 2250 participants (45 RCTs) | ⊕⊕⊕⊝ Moderate5 | There was significant heterogeneity between | ||
| Intervention: Telerehabilitation program Comparison: Lower level or different types of intervention; minimal intervention; waiting‐list controls, no treatment, or usual care; interventions given in different settings | There was evidence that a telerehabilitation programme can reduce or improve impairments, such as fatigue in the short term (up to 3 months) and long term; and improved symptoms, such as pain and insomnia in the long term. | 489 participants (4 RCTs) | ⊕⊕⊝⊝ Low1 | Data were not pooled in this review due to various interventions and use of different outcome measures. | ||
| Participation (quality of life, psychological outcomes, vocational and social activities) | Intervention: Exercise Comparison: Control interventions (details not provided) | There was evidence that exercise therapy can improve mood more than no exercise. | 260 participants (9 RCTs) | ⊕⊕⊕⊝ Moderate1 | Data were not pooled in this review due to variation in outcome measures | |
| Intervention: Memory rehabilitation Comparison: No treatment or placebo | There was evidence that memory rehabilitation may show improvement in objective assessments of memory in both immediate follow‐up (SMD 0.23, 95% CI 0.05 to 0.41) and long‐term (3 to 8 months) follow‐up (SMD 0.26, 95% CI 0.03 to 0.49) There was evidence that memory rehabilitation may improve QoL in the immediate follow‐up (SMD 0.23, 95% CI 0.05 to 0.41) | 989 participants (15 RCTs) | ⊕⊕⊝⊝ Low3 | The evidence is limited and does not extend to subjective reports of memory functioning or mood. Objective measures used were not valid, potentially limiting generalisability of findings. | ||
| Intervention: Neuropsychological rehabilitation Comparison: Other interventions or no intervention | There was evidence that cognitive training may improve memory span (SMD 0.54, 95% CI 0.20 to 0.88; P = 0.002) and working memory (SMD 0.33, 95% CI 0.09 to 0.57; P = 0.006). There was evidence that cognitive training, combined with other neuropsychological rehabilitation methods, might improve attention (SMD 0.15, 95% CI 0.01 to 0.28; P = 0.03), immediate verbal memory (SMD 0.31, 95% CI 0.08 to 0.54; P = 0.008), and delayed memory (SMD 0.22, 95% CI 0.02 to 0.42; P = 0.03). | 986 participants (20 RCTs) | ⊕⊕⊝⊝ Low3 | Interventions and outcome measures included in the review were heterogeneous, which limited the comparability of the studies | ||
| Intervention: Telerehabilitation program Comparison: Lower level or different types of intervention; minimal intervention; waiting‐list controls, no treatment, or usual care; interventions given in different settings | There was evidence that telerehabilitation programs might improve psychological outcomes and QoL for the long term (> 3 months) | 392 (6 RCTs) | ⊕⊕⊝⊝ Low3 | Data were not pooled in this review due to various interventions and use of different outcome measures | ||
| Intervention: Information‐provision interventions included: decision aids, educational programmes, self‐care interventions, and personal interviews with physicians Comparison: Usual care or other types of information‐provision interventions | There was evidence that information provision for patients can improve patients' disease‐related knowledge. | 524 participants (4 RCTs) | ⊕⊕⊕⊝ Moderate6 | Data were not pooled in this review due to the marked heterogeneity of the interventions and outcome measures. | ||
| ADL = activities of daily living; BI = Barthel Index; CBT = cognitive behavioural therapy; CCT = clinical controlled trial; CI = confidence interval; EDSS = Expanded Disability Status Scale; HBOT = hyperbaric oxygen therapy; FSS = Fatigue Severity Scale; HRQoL = health‐related quality of life; iTBS = intermittent theta burst stimulation; MS = multiple sclerosis; MSQOL‐54 = Multiple Sclerosis Quality of Life; MSSS‐88 = Multiple Sclerosis Spasticity Scale; OT = occupational therapy; pwMS = persons with multiple sclerosis; PT = physical therapy; PUFAs = polyunsaturated fatty acids; QoL = quality of life; RCT = randomised controlled trial; rTMS = repetitive transcranial magnetic stimulation; SMD = standardised mean difference; TENS = transcutaneous electrical nerve stimulation; VAS = visual analogue scale *Outcomes categorised according to the International Classification Functioning, Disability and Health (ICF, WHO 2001). **GRADE Working Group grades of evidence 1Downgraded by one level for imprecision and inconsistency of findings and use of different outcome measures. 2 Downgraded by one level due to high risk for imprecision (one single site study). 3Downgraded by two levels for imprecision and inconsistency of findings, due to a number of methodological flaws (high risk of bias in randomisation sequence generation, allocation concealment and blinding) and use of different outcome measures. 4Downgraded two levels because the singular study was considered at high risk of bias (unclear risk of bias in randomisation, sequence generation, allocation concealment and blinding of outcome assessors). 5Downgraded by one level for imprecision and inconsistency of findings and majority of trials had small sample size and assessed fatigue as a secondary measure. 6Downgraded by one level for imprecision and inconsistency of findings,use of different outcome measures and high risk of bias. | ||||||
