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Rehabilitation in Multiple Sclerosis: A Systematic Review of Systematic Reviews

Archives of Physical Medicine and Rehabilitation, In Press, Corrected Proof, Available online 20 May 2016

Abstract

Objectives

To systematically evaluate existing evidence from published systematic reviews of clinical trials for the effectiveness of rehabilitation for improving function and participation in persons with multiple sclerosis (MS).

Data Sources

A literature search was conducted using medical and health science electronic databases (MEDLINE, EMBASE, CINAHL, PubMed, Cochrane Library) up to January 31, 2016.

Study Selection

Two reviewers independently applied inclusion criteria to select potential systematic reviews assessing the effectiveness of organized rehabilitation for persons with MS. Data were summarized for type of interventions, type of study designs included, outcome domains, method of data synthesis, and findings.

Data Extraction

Data were extracted by 2 reviewers independently for methodological quality using the Assessment of Multiple Systematic Reviews. Quality of evidence was critically appraised with the Grades of Recommendation, Assessment, Development, and Evaluation.

Data Synthesis

Thirty-nine systematic reviews (one with 2 reports) evaluated best evidence to date. There is “strong” evidence for physical therapy for improved activity and participation, and for exercise-based educational programs for the reduction of patient-reported fatigue. There is “moderate” evidence for multidisciplinary rehabilitation for longer-term gains at the levels of activity (disability) and participation, for cognitive-behavior therapy for the treatment of depression, and for information-provision interventions for improved patient knowledge. There is “limited” evidence for better patient outcomes using psychological and symptom management programs (fatigue, spasticity). For other rehabilitation interventions, the evidence is inconclusive because of limited methodologically robust studies.

Conclusions

Despite the range of rehabilitative treatments available for MS, there is a lack of high-quality evidence for many modalities. Further research is needed for effective rehabilitation approaches with appropriate study design, outcome measurement, type and intensity of modalities, and cost-effectiveness of these interventions.

Keywords: Multiple sclerosis, Patient outcome assessment, Rehabilitation, Treatment outcome.

List of abbreviations: AMSTAR - Assessment of Multiple Systematic Reviews, GRADE - Grades of Recommendation, Assessment, Development, and Evaluation, MDR - multidisciplinary rehabilitation, MS - multiple sclerosis, pwMS - persons with multiple sclerosis.

Multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system, affects approximately 1.3 million people worldwide.1 It is a major cause of chronic neurologic disability in young adults (aged 18–50y), associated with complex disabilities including disorders of strength, sensation, coordination, and balance, as well as visual, cognitive, and affective deficits.2 and 3 These disabilities usually lead to progressive limitation of functioning in daily life, requiring longer-term multidisciplinary management. MS has a variable prognosis, and studies report factors associated with worse prognosis such as older age at onset, progressive disease course, multiple-onset symptoms, pyramidal or cerebellar symptoms, and a short interval between onset and first relapse.4 and 5 With advances in MS management, persons with multiple sclerosis (pwMS) are living longer (median survival time from the time of diagnosis, 40y6); therefore, issues related to progressive disability (physical and cognitive), psychosocial adjustment, and social reintegration need to be addressed over time.2 and 3

Persons with MS can present with various combinations of deficits such as physical (motor weakness, spasticity, sensory dysfunction, visual loss, ataxia), fatigue, pain (neurogenic, musculoskeletal, and mixed patterns), incontinence (urinary urgency, frequency), cognitive (memory, attention), psychosocial, behavioral, and environmental problems, which limit a person's activity (function) and participation.7 The International Classification of Functioning, Disability and Health provides a global conceptual framework to categorize abilities and problems of pwMS within a standard system and offers common language for clinicians for describing function, disability, and health of an individual.8 A simulated case example of the International Classification of Functioning, Disability and Health model related to MS is given in figure 1.

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Fig 1

International Classification of Functioning, Disability and Health model with case example for MS.

 

Medical rehabilitation is defined as “a set of measures that assist individuals who experience disability to achieve and maintain optimal physical, sensory, intellectual, psychological and social functioning in interaction with their environment.”9(p96) It is a complex process of delivering a coordinated interdisciplinary care program, comprising a series of individualized and goal-oriented therapies tailored for specific patient needs.10 The goal of rehabilitation is to improve functional independence and enhance participation, with an emphasis on patient education and self-management. Despite advances in medical management, MS continues to have a greater disability burden over long periods. The complex care needs of pwMS are due to the cumulative effects of impairments and disabilities, the “wear and tear” and the impact of aging with a disability. Maintaining functional gains and social reintegration over a longer-term with multidisciplinary rehabilitation (MDR) is recommended, both in the hospital and in the community.1, 7, and 11

In recent years, many rehabilitation interventions have been trialed in pwMS for improved clinical outcomes.7 and 12 Haselkorn et al,13 in a systematic review, provided an overview of evidence for physical rehabilitation for pwMS. The authors included 142 individual trials (all designs, published during 1970–2013) and rated evidence using American Academy of Neurology criteria.13 Bennett,14 in another narrative review, presented evidence for a specific type of exercises for MS symptoms and functional recovery. Although these reviews present current evidence on specific interventions, they vary in quality, scope, and methodology, at times with diverse findings.15 The approach of a “systematic” review of “systematic reviews” draws together the current evidence across specialities of the same or very similar intervention, to provide a synthesis of treatment effect in a much broader concept.15 This review, therefore, systematically evaluated evidence from currently published systematic reviews of clinical trials to determine the effectiveness of rehabilitation interventions for pwMS, using global criteria recommended by evidence-based literature, and evaluated a wider range of therapeutic modalities.

Methods

A comprehensive search of the Cochrane Library database (including Database of Abstracts and Reviews of Effectiveness), MEDLINE, CINAHL, EMBASE, and PubMed was undertaken till January 31, 2016 for systematic reviews evaluating rehabilitation interventions currently used in the management of pwMS. The search strategy included combinations of multiple search terms for 2 themes: MS and interventions (rehabilitation). The keywords used to search for studies for this review are listed in appendix 1. All systematic reviews, meta-analyses registered in these databases that reported a systematic electronic search of literature for a defined period, were included. Bibliographies of identified articles as well as relevant journals were manually searched for additional references. Authors and known experts in the field were contacted. A grey literature search was conducted using different internet search engines and websites, such as the System for Information on Grey Literature in Europe, the New York Academy of Medicine Grey Literature Collection, the National Quality Measures Clearinghouse, and Google Scholar. In addition, various health care institutions and governmental and nongovernmental organizations associated with management of pwMS were also explored for relevant reviews. All systematic reviews that assessed effectiveness of organized rehabilitation (both uni- and multidisciplinary) for pwMS were included. Systematic reviews involving other medical conditions, where data were specifically provided for MS, were also included. The exclusion criteria included reviews conducted in the pediatric population (<18y); reviews evaluating pharmacologic, surgical intervention, or diagnostic procedures; non-English reviews; theses; narrative reviews; reviews on economic evaluation; and reviews listed only in conference proceedings.

Study selection and data extraction

Both authors independently screened and shortlisted all abstracts and titles of reviews identified by the search strategy for inclusion and appropriateness based on selection criteria. Each study was evaluated independently, and the full-text article was obtained for assessment to determine whether the article met the inclusion/exclusion criteria. Any disagreement regarding the possible inclusion/exclusion of any individual study was resolved by a final consensus. Data extraction was conducted by both authors independently, using a standard pro forma. The information obtained from all reviews included publication and search date, objectives, characteristics of included studies and study subjects, interventions, findings/patient outcomes in the review, and limitations. Any discrepancies were resolved by both authors re-reviewing the study.

Assessment of methodological quality of included studies

Both reviewers independently assessed the methodological quality of each review, using the Assessment of Multiple Systematic Reviews (AMSTAR) appraisal tool (appendix 2).16 The AMSTAR tool has acceptable interrater agreement, construct validity, and feasibility.17 Any disagreements were resolved with consensus from both authors. There was heterogeneity in the included reviews in terms of methodological quality and risk-of-bias assessment methods. Therefore, based on the judgments made by the authors of the original systematic reviews regarding the quality of evidence, the Grade of Recommendation, Assessment, Development, and Evaluation (GRADE) tool was used to assess the quality of evidence for each type of intervention.18

Results

The search retrieved 214 published systematic reviews evaluating rehabilitation interventions currently used in management of MS. Of these, 53 reviews met the abstract inclusion criteria and were selected for closer scrutiny. Full texts of these articles were retrieved, and both reviewers performed the final selection. One review that met the inclusion criteria was identified from the bibliographies of relevant articles. Overall, 15 reviews published in the Cochrane Library database and 24 (one with 2 reports) published in other academic journals were included. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) of the study selection process is provided in figure 2.

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Fig 2

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram showing selection of reviews.

 

Quality of systematic reviews

Table 1 provides the results of the AMSTAR quality assessment. The kappa level of agreement between both authors for AMSTAR assessment was .88. The overall mean ± SD AMSTAR methodologic quality score for included systematic reviews was 7.0±2.6 and ranged from 3 to 10 out of 11. Seven reviews were of low quality (ie, AMSTAR scores of 0–4), 16 of moderate quality (5–8), and 16 of high quality (9–11) (see table 1).

Table 1

Quality assessment (AMSTAR) of included systematic reviews

 

Author, Year AMSTAR Criteria
1 2 3 4 5 6 7 8 9 10 11 Total Score/11
Amatya et al,19 2013 Y Y Y Y Y Y Y Y Y Y N 10
Andreasen et al,20 2011 UA N Y N N Y N Y Y N N 4
Asano and Finlayson,21 2014 UA Y Y N N Y Y Y Y N N 6
Baker and Tickle-Degnen,22 2001 N N N N N N Y Y Y N N 3
Bennett and Herd,23 2004 Y Y Y Y Y Y Y Y Y Y N 10
Blikman et al,24 2013 UA Y Y N N Y Y Y Y N N 6
Bronson et al,25 2010 N Y Y N Y Y Y N N N N 5
Campbell et al,26 2016 UA Y Y N N Y Y Y Y N N 7
Cruickshank et al,27 2015 UA Y Y N N Y Y Y Y N N 6
Dalgas et al,28 2015 N Y Y N N Y Y Y Y N N 6
Das Nair et al,29 2012 Y Y Y Y Y Y Y Y Y Y N 10
Farinotti et al,30 2012 Y Y Y Y Y Y Y Y Y Y N 10
Glinsky et al,31 2007 N N Y N N Y Y Y Y N N 5
Heine et al,32 2015 Y Y Y Y Y Y Y Y Y Y N 10
Hind et al,33 2014 Y Y Y N N Y Y Y Y Y Y 9
Jagannath et al,34 2010 Y Y Y Y Y Y Y Y Y Y N 10
Kalron et al,35 2015 UA Y Y N N Y Y N Y N N 5
Kantele et al,36 2015 Y Y Y N N Y Y N N N N 5
Khan et al,7 2007 Y Y Y Y Y Y Y Y Y Y N 10
Khan et al,37 2009 Y Y Y Y Y Y Y Y Y Y N 10
Khan et al,10 2015 Y Y Y Y Y Y Y Y Y Y N 10
Kjolhede et al,38 2012 UA Y Y N N Y Y Y Y N N 6
Kopke et al,39 2014 Y Y Y Y Y Y Y Y Y Y N 10
Lamers et al,40 2016 N Y N N N Y Y Y Y N N 5
Latimer-Cheung et al,41 2013 UA Y Y N N Y Y Y Y Y N 7
Malcomson et al,42 2007 N UA Y N N Y Y Y Y N N 5
Martín-Valero et al,43 2014 N N Y N N Y Y N N N N 3
Mitolo et al,44 2015 N UA N N N Y Y Y Y N N 4
O'Brien et al,45 2008 N UA N N N Y Y Y Y N N 3
Paltammaa et al,46 2012 UA Y Y N N Y Y Y Y N N 6
Pearson et al,47 2015 UA Y Y N N Y Y Y Y N N 6
Rietberg et al,48 2005 Y Y Y Y Y Y Y Y Y Y N 10
Rosti-Otajärvi et al,49 2014 Y Y Y Y Y Y Y Y Y Y N 10
Sitjà Rabert et al,50 2012 Y Y Y Y Y Y Y Y Y Y N 10
Snook et al,51 2009 N N N N N N Y Y Y N N 3
Spooren et al,52 2012 N N Y N N Y Y Y Y N N 5
Steultjens et al,53 2003 Y Y Y Y Y Y Y Y Y Y Y 10
Thomas et al,54 2006 Y Y Y Y Y Y Y Y Y Y N 10
Yu and Mathiowetz,55 and 56 2014 Y UA Y N N N Y N Y N N 4

AMSTAR criteria13 (see appendix 2).

NOTE. Yes indicates that the criteria has been met and equals 1 point; No indicates criteria not met and equals 0 points; Unable to answer indicates criteria not explained by authors and equals 0 points.

Abbreviations: N, no; UA, unable to answer; Y, yes.

Evidence synthesis of rehabilitation interventions

The rehabilitation approach to pwMS included a range of treatments and interventions. Of the included systematic reviews evaluating various interventions, most (n=14 reviews) addressed different physical activity programs in isolation or concomitant with other interventions; 7 reviews evaluated cognitive and psychological interventions; 3 reviews, occupational therapy interventions; 2 reviews, whole-body vibration; and 2 reviews, dietary interventions. Other interventions included MDR, hyperbaric oxygen therapy, electrical nerve stimulation, hippotherapy, vocational rehabilitation, information provision interventions, and specific rehabilitation programs (such as telerehabilitation, fatigue management programs, upper limb rehabilitation programs, spasticity management programs). The existing best-evidence synthesis for rehabilitation interventions in MS is summarized in table 2. A summary of the impact of the outcomes of these interventions based on specific settings is shown in figure 3. The findings indicate that, although a spectrum of interventions is used in pwMS, the evidence for many of these is limited, unclear, or both, because of a paucity of robust, methodologically strong studies.

Table 2

Rehabilitation interventions in MS (based on systematic reviews)

 

Author, Year Intervention No. of Included Studies, Design, Search Dates Total No. of Participants, Participant Group Main Results/Findings Meta-Analysis Quality of Evidence (GRADE)
Khan et al,7 2007 Multidisciplinary rehabilitation 9 RCTs,1 CCT
Search date: up to 25 February 2011 (update)
954 participants with moderate to severe disabilities Strong evidence for improvement in disability, participation, and QoL outlasting treatment period
Moderate evidence for inpatient or outpatient rehabilitation programs for improving disability, bladder-related activity, and participation outcomes up to 12 months
Limited evidence for short-term improvements in symptoms and disability for outpatient and home-based rehabilitation programs
No Moderate
Rietberg et al,48 2005 Physical therapy 9 RCTs
Search date: 1966 to March 2004
260 participants with low to moderate disabilities Strong evidence for exercise therapy compared with no exercise in terms of muscle power function, exercise tolerance functions, and mobility-related activities
Moderate evidence for improved mood
No evidence on fatigue and perception of handicap when compared with no exercise therapy
No High
Campbell et al,26 2016 Physical therapy 13 RCTs (15 reports)
Search date: up to December 2014
Sample size ranged from 6 to 111; participants with progressive MS Limited evidence regarding PT for people with progressive MS No Low
Kjolhede et al,38 2012 Progressive resistance training 6 RCTs, 6 noncontrolled trials
Search date: up to March 30, 2011
289 participants with low to moderate motor impairments Strong evidence for lower extremity muscle strength
Limited evidence for improved strength demanding functional tasks, balance, and fatigue
Limited evidence in improvement in walking ability, mood, and QoL
No Low
Cruickshank et al,27 2015 Strength training 20 trials (PD and MS) 5 RCTs and 2 CCTs in MS
Search date: up to July 2014
249 MS participants with all MS types Improved muscle strength, mobility, fatigue, functional capacity, power, and electromyography activity
Improved overall QoL
Yes Moderate
Latimur-Ceung et al,41 2013 Exercise therapy 54, including 23 RCTs
Search date: 1967 to week 4 March 2011
Patients with low to moderate disabilities Exercise performed 2 times a week at a moderate intensity increased aerobic capacity and muscular strength in pwMS with mild to moderate disability
Limited evidence on improvement in mobility, fatigue, and HRQoL
No Moderate
Pearson & Dieberg,47 2015 Exercise therapy (walking) 13 RCTs
Search date: 1966 to March 31, 2014
655 participants, ambulatory with or without a walking aid Significant improvement in walking speed, endurance, and distance Yes High
Snook et al,51 2009 Exercise therapy (walking) 22 RCTs
Search date: 1960 to November 2007
600 participants with all types of MS Significant improvement in walking mobility
Larger effects associated with supervised exercise training, programs <3 months in RRMS and progressive MS types
Yes High
Heine et al,32 2015 Exercise therapy (fatigue) 45 RCTs,
Search date:1966 to October 2014
2250 participants with all types of MS Significant improvement in fatigue
Larger effect associated with endurance training, mixed training, and yoga
Yes High
Andreasen et al,20 2011 Exercise therapy (fatigue) 15 RCTs, 9 other design
Search date: up to July 7, 2010
702 participants with all types of MS (with and without fatigue) Exercises have potential to reduce fatigue, but unclear which exercise modalities were superior to others No Low
Paltammaa et al,46 2012 Physical therapy (balance) 11 RCTs
Search date: up to March 2011
340 participants, ambulatory with all types of MS Low-level evidence for specific balance exercises, PT based on individualized problem-solving approach; resistance and aerobic exercises on improving balance Yes Low
Dalgas et al,28 2015 Exercise therapy (depressive symptoms) 15 RCTs
Search date: up to October 16, 2013
591 participants with all types of MS Limited effect on depressive symptoms Yes Low
Kalron et al,35 2015 Exercise therapy (cognition) 8 RCTs in MS
Search date: up to December 2014
644 participants with all types of MS Inconclusive evidence for improved cognition Yes Low
Martín-Valero et al,43 2014 Therapeutic respiratory muscle training 15 trials (including 6 RCTs)
Search date: between 1993 and 2013
Participants with all types of MS Limited evidence for improved respiratory muscle function No Low
Blikman et al,24 2013 Energy conservation management 4 RCTs, 2 CCTs
Search date: up to May 8, 2012
494 participants with all types of MS Short-term reduction in fatigue and QoL Yes Moderate
Bennett and Herd,23 2004 HBOT 9 RCTs
Search date: up to February 25, 2011
504 participants with all types of MS No evidence for use of HBOT Yes Low
Sitjà Rabert et al,50 2012 WBV 4 RCTs
Search date: 1964 to May 6, 2011
64 participants with all types of MS No evidence for WBV on any functional outcomes (body balance, gait, muscle performance) or QoL Yes Low
Kantele et al,36 2015 WBV 7 RCTs
Search date: 2000 to October 2013
250 participants with all types of MS Limited evidence for improved walking endurance Yes Low
Glinsky et al,31 2007 Electrical stimulation 18 RCTs all neurologic conditions, including 1 in MS
Search date: 1966 to March 2006
40 participants with all types of MS Inconclusive evidence for improved muscle strength No Very Low
Bronson et al,25 2010 Hippotherapy 3 case-series or case-control studies
Search date: up to July 2009
36 participants with all types of MS No evidence on improvement in balance and QoL No Very Low
Steultjens et al,53 2003 OT 1 RCT and 2 CCTs
Search date: up to January 2003
274 participants with all types of MS Inconclusive evidence on functional ability, social participation, and/or QoL No Very low
Yu and Mathiowetz,55 and 56 2014 OT 70 trials all designs
Search date: January 2003 to May 2011
Participants with all types of MS Limited evidence on benefit from individualized, goal-directed interventions that address functional performance (such as MDR, health promotion, and fatigue management) No Low
Baker and Tickle-Degnen,22 2001 OT 23 trials all designs
Search date: from 1980 to 1999
Participants with all types of MS Limited evidence for beneficial effects associated with MS (outcomes for capacity and ability: muscle strength, range of motion, mood) and task and activity (dressing, bathing, ambulation) levels Yes Low
Rosti-Otajärvi et al,49 2014 Neuropsychological rehabilitation 20 RCTs
Search date: up to May 28, 2013
986 participants with all types of MS Limited evidence on improved memory span, working memory, and attention
No evidence for improvement in emotional function
Yes Low
Thomas et al,54 2006 Cognitive rehabilitation 16 RCTs
Search date: up to December 2004
1006 participants with all types of MS Limited evidence of use of CBT for depression, and adjustment and coping with MS Yes Low
Das Nair et al,29 2012 Memory rehabilitation 8 RCTs
Search date: up to February 2011
521 participants with all types of MS No improvement on memory or functional abilities immediately or long-term Yes Low
O'Brien et al,45 2008 Cognitive rehabilitation 16 studies, including 4 RCTs
Search date: not specified
Participants with all types of MS Limited evidence on effects of modified story memory technique for learning and memory No Low
Mitolo et al,44 2015 Cognitive rehabilitation 33 trials
Search date: 1993 to 2014
Participants with all types of MS Inconclusive evidence for beneficial effect of different types of cognitive rehabilitation interventions on outcomes No Low
Hind et al,33 2014 Cognitive-behavioral therapy 7 RCTs
Search date: up to June/July 2013
521 participants with all types of MS Moderate-level evidence for CBT for treatment of depression in MS Yes Moderate
Malcomson et al,42 2007 Psychosocial intervention 33 trials, including 9 RCTs
Search date: up to December 2006
Participants with all types of MS Limited evidence for benefit of exercise, proactivity (on part of participant), and support (both multidisciplinary and peer) in improving psychological well-being and QoL No Low
Farinotti et al,30 2012 Dietary intervention (PUFAs) 6 RCTs
Search date: up to November 2011
794 participants with all types of MS No benefit of PUFAs on clinical outcomes No Low
Jagannath et al,34 2010 Dietary intervention (vitamin D) 1 RCT
Search date: up to 17 May 17, 2010
49 participants with all types of MS Limited evidence of potential benefit on relapse rate, disability scores, and suppression of T-cell proliferation No Very low
Khan et al,37 2009 Vocational rehabilitation 1 RCT, 1 CCT
Search date: 1981 to February 2011
80 MS participants of working age (mean age, 18–65y) Limited evidence for competitive employment, job retention, changes in employment, rates of reentry into the labor force, work ability by improving participants' confidence in the accommodation request process, or employability maturity or job-seeking activity No Low
Kopke et al,39 2014 Information provision 10 RCTs 1314 participants with all types of MS Moderate-level evidence for improved participant knowledge, mixed results on decision making and QoL No Moderate
Khan et al,10 2015 Telerehabilitation interventions 9 RCTs
Search date: up to July 9, 2014
531 participants, (469 included in analyses)
Majority RRMS
Low-level evidence for reducing short-term disability and symptoms (such as fatigue)
Low-level evidence for improved functional activities, impairments (such as fatigue, pain, insomnia), QoL, and psychological outcomes
Limited data on process evaluation (participants'/therapists' satisfaction); no data for cost-effectiveness
No Low
Asano and Finlayson,21 2014 Fatigue management programs (exercise, education, medication) 25 trials (including 18 rehabilitation)
Search date: up to August 2013
895 participants with all types of MS (in rehabilitation trials) Strong evidence for exercise-based and educational rehabilitation for reducing severity of patient-reported fatigue No High
Lamers et al,40 2016 Upper limb rehabilitation 30 trials, including 11 RCTs
Search date: up to April 2015
Participants with all types of MS Multidisciplinary and robot-based rehabilitation improved upper limb capacity No Low
Spooren et al,52 2012 Upper limb motor training 11 trials, including 5 RCTs
Search date: from 1976 to May 2011
368 participants with all types of MS Improved arm and hand performance at activity level No Low
Amatya et al,19 2013 Spasticity management interventions 9 RCTs
Search date: from 1996 to June 2012
341 participants with all types of MS Low-level evidence for physical activity programs used in isolation or in combination with other interventions (pharmacologic or nonpharmacologic); and for repetitive magnetic stimulation with or without adjuvant exercise therapy in improving spasticity No Low

GRADE = Grade of Recommendation, Assessment, Development, and Evaluation Working Group grades of evidence: High quality, further research is very unlikely to change our confidence in the estimate of effect; Moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality, we are very uncertain about the estimate.

Abbreviations: ADL, activities of daily living; CBT, cognitive- behavioral therapy; CCT, controlled clinical trial; HBOT, hyperbaric oxygen therapy; HRQol, health-related quality of life; ICF, International Classification of Functioning, Disability and Health; OT, occupational therapy; PD, Parkinson disease; PT, physiotherapy; QoL, quality of life; RCT, randomized controlled trial; RRMS, relapsing-remitting MS; WBV, whole-body vibration.

gr3

Fig 3

Summary of impact of outcomes of rehabilitation interventions based on the settings. Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) grades of evidence:

fx1High quality: Further research is very unlikely to change our confidence in the estimate of effect.

fx2Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

fx3Low 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.

fx4Very low quality: We are very uncertain about the estimate.

Abbreviations: CCT, controlled clinical trial; HBOT, hyperbaric oxygen therapy; OT, occupational therapy; PUFAs, polyunsaturated fatty acids; RCT, randomized controlled trial; WBV, whole-body vibration.

 

The overall findings of this review suggest the following:

  • High-quality evidence for:
    • Physical therapeutic modalities (exercise/physical activities) for improved functional outcomes (mobility, muscle strength, aerobic capacity), reduced fatigue, and improved quality of life
    • Comprehensive fatigue management programs for patient-reported fatigue
  • Moderate evidence for:
    • MDR for longer-term gains at the level of activity (disability) and participation
    • Cognitive-behavioral therapy for the treatment of depression
    • Information provision in increasing patient's knowledge
  • Low-quality evidence for:
    • Exercise therapy for improved balance and cognitive symptoms
    • Psychological interventions
    • Other rehabilitation interventions: occupational therapy strategies, hyperbaric oxygen therapy, whole-body vibration, upper-limb rehabilitation programs, vocational rehabilitation, and telerehabilitation
    • Specific therapy programs targeting MS-related spasticity
  • Inconclusive evidence for:
    • Dietary (polyunsaturated fatty acids, vitamin D)
    • Hippotherapy and electrical stimulation

Discussion

MS is a complex condition, and pwMS frequently present with multiple deficits (motor, sensory, cognitive, behavioral, and communication issues), which require specific and coordinated longer-term multidisciplinary rehabilitative care. This review systematically summarizes the best up-to-date evidence from published systematic reviews for the effectiveness of rehabilitation interventions in MS. The findings indicate that, although a broad range of rehabilitative approaches have been trialed in this population, there is a critical lack of high-quality evidence for the effectiveness of various modalities.

The most common interventions evaluated were different forms of physical therapeutic modalities, followed by psychological interventions. As expected, the overall findings of this review suggest strong evidence for (1) physical therapeutic modalities (exercise/physical activities) for improved functional outcomes (mobility, muscle strength, aerobic capacity), reduced fatigue, and improved quality of life; and (2) comprehensive fatigue management programs for patient-reported fatigue. There was moderate evidence for (1) MDR for longer-term gains at the level of activity (disability) and participation; (2) cognitive-behavioral therapy for the treatment of depression; and (3) information provision in increasing patients' knowledge. The evidence for other rehabilitation interventions and programs evaluated was of either low quality or inconclusive.

In recent years, clinicians have a plethora of reviews of the same topics, with inconsistent methodological quality, results, or conclusions. The findings from this review add to the existing literature to guide clinicians. Overall, the quality of methodology of included systematic reviews and evidence interpreted in this review varied significantly. As expected, the quality AMSTAR tool16 scores of the non-Cochrane reviews were significantly lower compared with the Cochrane reviews, because of variation in the standard of reporting. The non-Cochrane reviews do not publish protocols before the review; therefore, none fulfilled the first criterion of the AMSTAR tool. None met the AMSTAR criterion 11 (see appendix 2). Although the review authors declared their own conflicts of interest, none systematically reported author conflicts of interest for the included trials. The included reviews used different methodological quality and risk-of-bias assessment tools. The GRADE and Physiotherapy Evidence Database (PEDro) tools were most frequently used. Overall, the Cochrane reviews were more systematic, more recent, and had superior AMSTAR scores, which suggest a more reliable and robust source of evidence for clinicians.

The existing clinical practice guidelines recommend the interdisciplinary model of care for pwMS,57 but uptake of this integrated approach is far from universal, with lack of collaboration and poor communication between disciplines, resulting in fragmented care.10 and 58 At times it is unclear which is the best modality and when to provide it and in which dose/intensity.

Despite strong evidence for coordinated MDR for pwMS,7 the lack of such care contributes a substantial burden to patients, their families, and health service providers.59 The best evidence to date is largely for unidisciplinary rehabilitation interventions such as physical therapeutic modalities. The findings of this review add to the MS literature and are consistent with earlier reviews.13 and 14 Similar to Haselkorn,13 this review found strong evidence supporting inpatient and outpatient physical therapy, and comprehensive MDR for improving function and disability in pwMS.13 In contrast to the systematic review by Haselkorn13 that focused specifically on individual trials of physical therapies, this review took a wider, more global approach to scrutinize the MS literature, by evaluating all published systematic reviews exploring a broad range of rehabilitation modalities, and using globally endorsed appraisal methodology (using AMSTAR and GRADE).16, 18, and 60 This approach of systematic review of systematic reviews allows findings from more than 1 systematic review to be compared and contrasted, thereby providing a comprehensive summary of evidence at different levels, including the combination of different interventions, or the provision of a summary of evidence on different outcomes or problems.15

Study limitations

Several limitations in methodology and completeness of the retrieved literature in this review cannot be ruled out. Despite the extended and comprehensive search to capture the widest possible selection of relevant literature, the search principally encompassed cited literature. Only reference lists within relevant articles were scrutinized, and other possible articles (including most recent publications) may have been missed in electronic searches, which may introduce a reference bias. However, our search was comprehensive, including the Cochrane Database (including Database of Abstracts and Reviews of Effectiveness), other health science databases, and the grey literature, and we are confident that we captured most high-quality reviews (n=15 included were Cochrane reviews). Although we used the validated and commonly used tools to assessed the methodology (AMSTAR) and quality of evidence (GRADE) of these reviews, these tools have certain limitations. We included 4 reviews from our own research group (all from the Cochrane Library); therefore, the independence of assessors could not be guaranteed. However, since the Cochrane Collaboration sets the standards for research synthesis, the appraisals of these reviews are consistent with other similar included reviews and are valid. Adverse event reporting was often incomplete, inconsistent, or both. However. it was beyond the scope of this review to systematically search for evidence on the safety of included interventions. None of the trials reported an optimal dosage of therapy, associated costs, or an economic benefit of interventions.

Conclusions

MS requires specialized, flexible services for comprehensive management. There is increasing awareness of the contribution of rehabilitation in early and long-term MS care. Despite the range of rehabilitative interventions in pwMS, evidence for many is still unclear because of a lack of methodologically robust trials. More research is needed to build evidence for types of rehabilitation therapy components, modalities, and the duration and setting of therapy. Future research should focus on interventions that can be integrated into MDR programs to develop effective care-pathways and long-term functional outcomes, and to engage, educate, and empower patients and their caregivers.

Appendix 1 Keywords Used in Search Strategy

Theme 1. Multiple sclerosis:

  • Multiple Sclerosis, Demyelinating Diseases, Transverse Myelitis, Optic Neuritis, Acute Disseminated Encephalomyelitis

Theme 2. Rehabilitation interventions:

  • Rehabilitation, Ambulatory Care, Physical Therapy Modalities, Physiotherapy, Exercise Therapy, Cognitive Therapy, Psychotherapy, Behavior/Behaviour Therapy, Social Work, Counselling, Occupational Therapy, Dietetics/Nutrition, Orthotics/Brace/Orthoses, Acupuncture Patient Care Team, Multidisciplinary/Integrated Team, Cold Treatment/Cooling, Assistive Technology Device, Hydro/Pool Therapy, Electromagnetic Therapy, Nerve Stimulation, Vibration Therapy, Social Participation/Support, Vocational

Medical Subject Headings (MeSH) check words

  • Systematic Review/Meta-Analysis, Review, Adult; Humans

Appendix 2 Assessment of Multiple Systematic Reviews (AMSTAR) Criteria

1. Was an “a priori” design provided?
2. Was there duplicate study selection and data extraction?
3. Was a comprehensive literature search performed?
4. Was the status of publication (ie, grey literature) used as an inclusion criterion?
5. Was a list of studies (included and excluded) provided?
6. Were the characteristics of the included studies provided?
7. Was the scientific quality of the included studies assessed and documented?
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
9. Were the methods used to combine the findings of studies appropriate?
10. Was the likelihood of publication bias assessed?
11. Was the conflict of interest stated?

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Footnotes

a Department of Rehabilitation Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia

b Department of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia

c School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

Corresponding author Fary Khan, MBBS, MD, FAFRM (RACP), Department of Rehabilitation Medicine, Royal Melbourne Hospital, 34-54 Poplar Rd, Parkville VIC 3052, Australia.

Supported by the internal resources of the Rehabilitation Department, Royal Melbourne Hospital, Royal Park Campus, Melbourne, Australia.

Disclosures: none.


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