Measuring the effects of exercise in neuromuscular disorders: a systematic review and meta-analyses

Abstract

Background: The benefit and safety of exercise training for patients with neuromuscular disorders (NMDs) has long been a contentious topic. This is, in part, due to recognised challenges associated with rare diseases including small and heterogenous patient populations. We performed a systematic review and meta-analyses to evaluate the effectiveness and safety of interventional exercise and establish minimal clinically important differences (MCID) in outcomes to facilitate clinical interpretation. Methods: We searched six databases from inception to Mar 2018. Aerobic, strength, and combined (aerobic and strength) intervention were eligible. Meta-analyses compared outcomes at baseline with those after at least six weeks (before-after exercise within individuals). A further meta-analysis compared outcomes before-after exercise between groups (exercise training versus usual care). Disease heterogeneity was explored using a random effect model. This study was registered (PROSPERO, CRD42018102183). An interactive database was developed to facilitate full interrogations of data. Results: We identified 130 articles describing 1,805 participants with 35 different forms of NMD. Of these studies, 76 were suitable for meta-analyses. Within group and between group meta-analyses detected an increase in peak aerobic capacity (p=0·04), and peak power (p=0·01). Six-minute walk test (p=0·04), sit-to-stand (STS) (repetitions) (p=0·03), STS (seconds) (p=0·04), rise from supine (p=0·008), SF-36 (p=0·0003), fatigue severity (p=<0·0001), citrate synthase (p=0·0002), central nuclei (p=0·04), type 1 (p=0·002) and type II muscle fibre area (p=0·003), were only able to detect change within group meta-analyses. Substantial I ² statistic heterogeneity was revealed for STS (seconds) ( I²=58·5%; p=0·04) and citrate synthase ( I²=70·90%; p=0·002), otherwise heterogeneity for all outcomes was low. No study-related serious adverse events were reported nor significant increases in creatine kinase. Conclusions: Exercise training in patients with NMDs appears to cause no harm across a range of outcomes. With the emergence of new therapeutic strategies, defining MCID is vital in informing future clinical trial design.

Keywords: Neuromuscular; aerobic; exercise training; functional exercise; minimal important clinical difference; muscle biopsies; outcome measures; strength.

Figure 1.. Flow chart of study selection.

Figure 2.. VO _2peak (ml/kg/min) (exercise training versus usual care).

Random-effects meta-analysis of exercise-trained (Ex) compared to usual care (UC) on VO _2peak (ml/kg/min); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; green, combined training.

Figure 3.. Peak power (watts) (exercise training versus usual care).

Random-effects meta-analysis of exercise-trained (Ex) compared to usual care (UC) on peak power (watts); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; green, combined training.

Figure 4.. VO _2peak (ml/kg/min) (before versus after exercise training).

Random-effects meta-analysis of exercise training on VO _2peak (ml/kg/min); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.*mitochondrial myopathies; **McArdle’s disease; ‡non-mitochondrial myopathies; §hospital-based training; §§home-based training.

Figure 5.. Peak power (watts) (before versus after exercise training).

Random-effects meta-analysis of exercise training on Peak Power (watts); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.* mitochondrial myopathies; ** McArdle’s disease.

Figure 6.. 6MWT (metres) (before versus after exercise training).

Random-effects meta-analysis of exercise training on 6MWT (metres); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.

Figure 7.. Sit-to-stand (STS) (repetitions) (before versus after exercise training).

Random-effects meta-analysis of exercise training on STS (repetitions); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.

Figure 8.. Sit-to-stand (STS) (seconds) (before versus after exercise training).

Random-effects meta-analysis of exercise training on STS (seconds); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training.

Figure 9.. Rise from supine (seconds) (before versus after exercise training).

Random-effects meta-analysis of exercise training on Rise from supine (seconds); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.

Figure 10.. SF-36 (before versus after exercise training).

Random-effects meta-analysis of exercise training on Short Form 36 health survey (SF-36); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training. ‡non-mitochondrial myopathies; *mitochondrial myopathies.

Figure 11.. Fatigue severity scale (before versus after exercise training).

Random-effects meta-analysis of exercise training on fatigue severity scale (FSS); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training. §hospital-based training; §§home-based training.

Figure 12.. Central nuclei (%) (before versus after exercise training).

Random-effects meta-analysis of exercise training on central nuclei (%); pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training.

Figure 13.. Type I fibre size area (µm or µm ²) (before versus after exercise training).

Random-effects meta-analysis of exercise training on type I fibre size area; pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.

Figure 14.. Type II fibre size area (µm ²) (before versus after exercise training).

Random-effects meta-analysis of exercise training on type II fibre size area; pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; blue, strength training; green, combined training.

Figure 15.. Citrate synthase (before versus after exercise training).

Random-effects meta-analysis of exercise training on citrate synthase; pooled analysis of all trials using the final training intervention time point. Red denotes aerobic training; green, combined training.