Abstract: Forty-five trials, studying 69 exercise interventions, were eligible for this review, including 2250 people with MS. The prescribed exercise interventions were categorised as endurance training (23 interventions), muscle power training (nine interventions), task-oriented training (five interventions), mixed training (15 interventions), or 'other' (e.g. yoga; 17 interventions). Thirty-six included trials (1603 participants) provided sufficient data on the outcome of fatigue for meta-analysis. In general, exercise interventions were studied in mostly participants with the relapsing-remitting MS phenotype, and with an Expanded Disability Status Scale less than 6.0. Based on 26 trials that used a non-exercise control, we found a significant effect on fatigue in favour of exercise therapy (standardized mean difference (SMD) -0.53, 95% confidence interval (CI) -0.73 to -0.33; P value < 0.01). However, there was significant heterogeneity between trials (I2 > 58%). The mean methodological quality, as well as the combined body of evidence, was moderate. When considering the different types of exercise therapy, we found a significant effect on fatigue in favour of exercise therapy compared to no exercise for endurance training (SMDfixed effect -0.43, 95% CI -0.69 to -0.17; P value < 0.01), mixed training (SMDrandom effect -0.73, 95% CI -1.23 to -0.23; P value < 0.01), and 'other' training (SMDfixed effect -0.54, 95% CI -0.79 to -0.29; P value < 0.01). Across all studies, one fall was reported. Given the number of MS relapses reported for the exercise condition (N = 25) and non-exercise control condition (N = 26), exercise does not seem to be associated with a significant risk of a MS relapse. However, in general, MS relapses were defined and reported poorly. Exercise therapy can be prescribed in people with MS without harm. Exercise therapy, and particularly endurance, mixed, or 'other' training, may reduce self reported fatigue. However, there are still some important methodological issues to overcome. Unfortunately, most trials did not explicitly include people who experienced fatigue, did not target the therapy on fatigue specifically, and did not use a validated measure of fatigue as the primary measurement of outcome.

Plain-language summary: We searched scientific databases for clinical trials comparing exercise to no exercise or other treatments in adults with MS. The evidence is current to October 2014. We found 45 trials, involving 2250 people with MS, assessing the effect of exercise therapy using self reported fatigue. We used 36 studies, involving 1603 people with MS, in an analysis. Combined, these 36 trials supported the idea that exercise therapy may be a promising treatment to reduce fatigue without side events. This finding seems especially true for endurance training, mixed training (i.e. muscle power training mixed with endurance training), or 'other' training (e.g. yoga, tai-chi). To assess the safety of exercise therapy we counted the number of reported MS relapses in the people receiving exercise therapy and in people in a non-exercise group and did not find a significant difference. Even though these results are promising, it is worth noting some methods used in the trials may have affected the reliability of the results. For example, most trials included a low number of participants and did not primarily aim to reduce fatigue (but, for instance, aimed to improve walking capability) with the assessment of fatigue being a secondary measure. However, in contrast, exercise therapy may also be less feasible for people with MS who are severely fatigued. In addition, the reporting and definition of MS relapses was in general poor, and lacked consistency. Future, high-quality research is warranted to elucidate the feasibility, effects, and working mechanisms of exercise therapy. Future studies may benefit from a uniform definition of fatigue, and subsequently be designed to measure fatigue specifically.