BACKGROUND: Multiple sclerosis (MS) is the most common cause of non-traumatic disability in people aged 10 to 65 years. Evidence exists for the effectiveness of multidisciplinary rehabilitation and exercise. However, the effectiveness of other rehabilitation approaches in MS needs further evaluation. OBJECTIVE: We aimed to systematically synthesize and evaluate knowledge on effectiveness of rehabilitation interventions and determinants for participation among people with MS (pwMS) to inform clinical guidelines on rehabilitation. METHODS: Joanna Briggs Institute methodology was used. PubMed, Embase, CINAHL, PsycINFO and Web of Science were searched for reviews, systematic reviews, meta-analyses, and meta-syntheses published during 2009 to 2019. All types of rehabilitation interventions provided to pwMS at any time and in all settings were eligible. Two reviewers independently screened and extracted data. The most recently published reviews on mixed and specific modalities were included. The findings were reported in a narrative summary and a mixed-methods analysis. RESULTS: Among 108 eligible reviews, 6 qualitative or mixed-methods reviews and 66 quantitative reviews were included (total pwMS > 90,000). This overview provides solid evidence for the effectiveness of a spectrum of modalities. Among the modalities, there was strong evidence for the effectiveness of multidisciplinary, cognitive and exercise approaches, physiotherapy, and occupational therapy, including full body training on functioning, and participation outcomes. Employment significantly affected quality of life; thus, vocational rehabilitation should be initiated early. Healthcare professionals should identify personal factors including relations and coping, and the rehabilitation process should involve partners or close family. CONCLUSIONS: The mixed-methods analysis revealed insufficient consensus between the perspectives of pwMS on their rehabilitation and reported effects, indicating that further research should target the experiences of pwMS. Furthermore, rehabilitation should be patient-centred, focus on the complexity of needs, and be organised and performed by an experienced multidisciplinary team. Evidence-based rehabilitation should be initiated early after pwMS are diagnosed and follow international guidelines. DATABASE REGISTRATION: PROSPERO ID CRD42020152422.

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