Is Exercise Training Beneficial in Progressive Multiple Sclerosis?

Abstract

Background:

There is substantial evidence for the benefits of exercise training in people with multiple sclerosis (MS). These benefits, however, have primarily been established in the early, relapsing disease phase or are derived from heterogeneous MS samples (ie, relapsing and progressive MS). This makes it challenging to determine whether the consequences of exercise training are similar in the relapsing and progressive disease courses. The role of exercise training in progressive MS is far less clear. This study examined the potential role of exercise training in people with progressive MS.

Methods:

We review the current evidence from studies examining conventional exercise training modalities (eg, cycle ergometry) as well as specialized exercise training approaches (eg, functional electrical stimulation cycling) in samples involving exclusively individuals with progressive MS.

Results:

The evidence reviewed from nine trials provides preliminary support for the benefits of exercise training with regard to fitness, symptom, and quality of life outcomes in progressive MS, although these data are currently limited and at times conflicting.

Conclusions:

Considering the prevalence of progressive MS (ie, 1 million people worldwide), the lack of effective treatment options, and the considerable frustration of researchers, clinicians, and patients, we believe that exercise training represents a viable therapeutic option worthy of further consideration. Future research should involve well-designed, randomized clinical trials with appropriate sample sizes and control conditions to establish the safety, feasibility, and therapeutic efficacy of exercise training in progressive MS.

Progressive multiple sclerosis (MS) is clinically characterized by gradual disease progression and accumulation of neurologic disability, independent of relapses.1 At onset, approximately 80% to 90% of individuals with MS present with a relapsing-remitting (RRMS) disease course, characterized by acute bouts of neurologic dysfunction (ie, relapses) with partial or full recovery.1 Over time, recovery from relapses is incomplete, and progressive accumulation of neurologic disability ensues. Most individuals with RRMS will transition into a secondary progressive MS phase, characterized by gradual worsening with or without relapses after an initial RRMS course.1 Approximately 10% to 20% of individuals with MS present with primary progressive MS, characterized by gradual neurologic deterioration from disease onset.1,2 The clinical, imaging, and genetic differences between primary and secondary progressive MS are now considered more relative than absolute; collectively, the progressive disease phase is characterized by significant neurodegeneration and accumulation of neurologic disability.1,3

Current disease-modifying therapies have been effective for reducing the frequency and severity of relapses during the RRMS course; however, therapeutic options for managing progressive MS have largely been ineffective.4,5 This is likely attributable, in part, to an incomplete understanding of the pathologic mechanisms in progressive MS as well as methodological limitations of clinical trials (eg, inappropriate biomarkers and clinical endpoints).3,5 Although more recent efforts have focused on the development of neuroprotective and repair-promoting agents,3,4 the current lack of effective treatment options remains a significant source of frustration for patients, providers, and caregivers.6 Progressive MS was recently described as the greatest therapeutic challenge facing the MS community,7 and more than half of the people diagnosed as having MS (ie, 1 million people worldwide) are currently living with progressive MS.8,9 It is critical that we now evaluate alternative approaches for managing and treating progressive MS, and one such approach is exercise training. There is mounting evidence for the benefits of exercise training early in the disease; however, the role of exercise training in progressive MS remains unclear. The purpose of this report was to postulate the potential role of exercise training in progressive MS. We begin with a review of the evidence for exercise training in primarily relapsing or mixed MS samples, as well as theoretical rationale from the gerontology literature. We then evaluate the current evidence for exercise training in progressive MS, highlighting important limitations and directions for future research.

Exercise Training in MS

There is substantial evidence for the benefits of exercise training in people with MS. Indeed, several systematic reviews and meta-analyses support the benefits of exercise training for cardiorespiratory and muscular fitness,10,11 fatigue,12 depression,13,14 ambulation,15,16 and quality of life (QOL).17 These meta-analyses computed an overall effect of exercise training on the outcome of interest, and this was expressed as Hedges' g (ie, standardized mean difference).18,19 A meta-analysis of 20 randomized controlled trials (RCTs) examined the effect of exercise training on cardiorespiratory and muscular fitness in people with MS.10 Overall, exercise training was associated with a moderate improvement (g = 0.47) in cardiorespiratory fitness and a small improvement (g = 0.27) in muscular strength.10 Fatigue is recognized as one of the most common and debilitating symptoms of MS, and it has a major effect on daily functioning and independence.20 A meta-analysis of 17 RCTs reported that exercise training had a small-to-moderate effect (g = 0.45) in reducing symptoms of fatigue in people with MS.12 One meta-analysis of 13 RCTs determined that exercise training was associated with a small reduction (g = 0.36) in depressive symptoms in people with MS.13 Indeed, impaired ambulation is one of the most prevalent and life-altering consequences associated with MS.21,22 One meta-analysis of 22 studies examined the effect of exercise training for improving ambulation in individuals with MS and reported a small positive effect (g = 0.19).15 A separate meta-analysis of 13 RCTs demonstrated a small overall positive effect (g = 0.23) of exercise training on QOL in people with MS.17 Finally, a systematic review involving data from 26 RCTs supports the safety of exercise training in people with MS.23 The relative risk of relapse, an important clinical indicator of disease activity and progression, was 0.67 for exercise training compared with nonexercising controls with MS, suggesting that exercise does not increase relapse risk.23 The relative risk of adverse events for exercise training was 1.67 compared with controls and was not greater than risk levels reported in healthy populations.23 We further note that the overall rate of dropout from exercise training reported in this review was 15.5%.23 Establishing the safety and feasibility of exercise training is particularly important considering early views that exercise may, in fact, be harmful or exacerbate disease progression in MS.23

Unfortunately, there is less consistent evidence for the effect of exercise training in MS on other important outcomes, such as cognitive function and disease pathology. A recent systematic review identified nine studies examining the effect of long-term exercise training on cognition.24 This review determined that the current evidence involving exercise training was too limited and conflicting to provide any definitive conclusions. The effect of exercise training on MS disease pathology is also unclear.25,26 There is conflicting and limited evidence for the effect of exercise training on peripheral inflammatory and neurotrophic markers.25 There is cross-sectional evidence supporting a positive association between structural and functional brain imaging parameters and physiological fitness27,28 or physical activity29,30 in MS; however, there are no reports of prospective studies of the effect of exercise training on brain imaging outcomes.25,26 Considering the limited evidence, we draw on the well-established body of literature involving exercise training in older adults as rationale for the potential benefits of exercise training for brain health in MS.31,32 Indeed, studies of exercise training in older adults have reported changes in brain structure and function, particularly increases in hippocampal volume, and these changes have been associated with improved cognitive performance.32–34 This supports a potential neuroprotective role for exercise training in people with MS.

Collectively, the current evidence suggests that exercise training is safe and has numerous physical and psychosocial benefits in people with MS (Table 1). However, these benefits have primarily been established in the early, relapsing disease phase or are derived from heterogeneous samples with varying clinical courses, making it difficult to determine whether the benefits of exercise training are similar in the relapsing and progressive disease phases.35 Although the underlying pathogenesis in progressive MS is incompletely understood, the current evidence points to diffuse immune and neurodegenerative mechanisms, including microglia activation, oxidative injury, mitochondrial damage, and age-related iron accumulation.4,36 These processes contribute to a state of chronic cell stress and imbalance, resulting in ongoing axonal and neuronal loss.36 Consequently, there may be concerns that intervention strategies in the progressive phase, including exercise training, could introduce additional stress to an already stressed environment, promoting further damage and disability. To address these concerns, we explore and evaluate the current evidence involving exercise training in individuals with progressive MS. The evidence reviewed examined RCTs or pre-post interventions involving exercise training in samples that included exclusively individuals with progressive MS (ie, secondary progressive, primary progressive, or both). Relevant studies were identified through searches of reviews and meta-analyses involving exercise training in people with MS10–13,15,16,22–24,35 as well as electronic databases and the authors' personal databases.

Table 1.

Summary of the evidence for exercise training in the studies reviewed involving people with progressive MS compared with previous evidence from primarily relapsing MS or mixed MS samples

Outcome	Progressive MS	Relapsing andmixed MS
MS pathogenesis	↔	↔
Fitness (cardiorespiratory and muscular)	↑	↑
Cognition	↔	↔
Fatigue	↓	↓
Depression	↔	↓
Spasticity	↔	↔
Ambulation	↔	↑
Quality of life	↑	↑

Abbreviation: MS, multiple sclerosis.

Note: ↓ = decrease in outcome; ↑ = increase in outcome; and ↔ = inconclusive or mixed evidence for outcome.

Exercise Training in Progressive MS: Current Evidence

Few studies have examined the role of exercise training in samples of people with progressive MS exclusively; however, there is preliminary evidence to support the potential benefits of this therapy. We review the evidence from nine studies examining conventional exercise training modalities (eg, cycle ergometry, rowing, and aquatic exercise) as well as specialized or adapted exercise training approaches (eg, functional electrical stimulation [FES] cycling and body weight–supported treadmill training [BWSTT]) in people with progressive MS.

We report on three studies37–39 that involved conventional exercise training modalities in people with progressive MS. The largest (n = 42) exercise training intervention conducted in people with progressive MS (Expanded Disability Status Scale [EDSS] score = 4.0–6.0) examined 8 to 10 weeks of arm cycle ergometry, rowing, or leg cycle ergometry compared with a waitlist control condition.37 Significant improvements were noted in response to aerobic exercise training in peak oxygen consumption (P = .029), fatigue (P = .02), depressive symptoms (P < .001), walking endurance (P = .012), and some domains of cognitive function (P < .001–.011). There were no changes, however, in resting serum levels of irisin (P = .53), brain-derived neurotrophic factor (P = .27), or interleukin 6 (P = .76) after aerobic exercise training.40 The dropout rate from exercise training overall was 10.6%, somewhat lower than that reported in studies of exercise training involving people with primarily RRMS and mixed MS samples (15.5%).23 The reported reasons for dropping out included logistic and ambulatory difficulties (n = 3), fatigue (n = 1), and injury unrelated to exercise participation (n = 1). Adverse events during the intervention were not reported on in this study. One smaller RCT evaluated ten sessions of upper-body aerobic exercise (eg, arm ergometry) in addition to 4 weeks of standard inpatient rehabilitation compared with inpatient rehabilitation alone in 11 participants with progressive MS (EDSS score = 6.5–8.0).38 That study reported a nonsignificant improvement in peak oxygen consumption (P = .06) in the aerobic training condition compared with the control condition. However, there were no changes in fatigue (P = .94), depression (P = .32), physical function (P = .34–.86), or QOL (P = .35). One dropout was reported in the exercise condition due to a hospitalization unrelated to exercise participation. No other adverse events were reported during the intervention. Finally, one pre-post trial examined 12 weeks of group-based aquatic exercise in 31 people with progressive MS (EDSS score = 1.5–8.0).39 Significant improvements were noted only for the Social Function subscale of the 36-item Short Form Health Status Survey (P = .015). Furthermore, there were improvements on fatigue (P = .035) and social support (P = .050) scales, but no significant changes for pain, sexual satisfaction, bladder and bowel control, visual impairment, perceived deficits, or mental health scales (P values not reported). Twelve participants dropped out of the study: six before beginning the intervention and six during the intervention. Reasons for dropping out during the intervention included relapse (n = 2), difficulty completing daily tasks (n = 2), dissatisfaction with the exercise class (n = 1), and lack of caregiver support (n = 1). Barriers to exercise participation were identified by participants in this trial and most commonly included medical issues (eg, illnesses, medical appointments, and symptoms), transportation difficulties, social conflicts, and lack of caregiver assistance during the program.

One specialized exercise training approach that has been examined in progressive MS is FES cycling, an activity-based rehabilitation modality that involves systematic transcutaneous electrical stimulation of the leg muscles as an approach to producing leg cycle ergometry.41 There are three uncontrolled pre-post trials of FES cycling in people with progressive MS.42–44 One trial demonstrated that six sessions of inpatient FES cycling significantly improved acute spasticity (ie, pre-post training session) (P = .05) in 12 people with progressive MS (EDSS score = 4.0–8.0), although no changes were observed for muscle strength (P = .56), spasticity (P = .92), or walking speed (P > .67) immediately after 2 weeks of training.42 Four of the 12 participants dropped out of the training program due to early discharge from the inpatient clinic, medication changes, failure to comply, and difficulty with transferring due to disability level. Adverse events were not reported on in this trial.

A somewhat longer supervised FES cycling intervention (18 sessions) reported a significant increase in thigh volume (left: P = .005, right: P > .001), assessed as leg circumference, in eight participants with progressive MS (EDSS score = 6.5–8.5).43 Participants in this trial reported on perceived therapeutic benefits and detrimental effects of training, which included improved transfer ability overall, improved circulation (n = 3), increased muscle strength (n = 2), reduced spasticity (n = 2), and increased stiffness the morning after exercise training (n = 1) and that exercise training was especially tiring (n = 1). No other adverse events were reported. One participant dropped out of the exercise intervention.

The third FES cycling trial was conducted in the home setting (ie, unsupervised) and included five people with progressive MS (EDSS score = 5.0–7.0).44 Following 6 months of home-based FES cycling, the most notable improvements were observed for walking speed (36%), agility (22%), gait (17%–35%), QOL (13%–20%), and strength of the leg muscles that were stimulated by FES (15%–35%) (statistical tests not performed). No changes were noted in EDSS score (0%), and strength of the leg muscles that were not stimulated by FES decreased after 6 months (19%–30%). An exploratory analysis of 120 cytokines, chemokines, and growth factors in the cerebrospinal fluid revealed a significant decrease in only monocyte chemotactic protein 1 after exercise training (P = .03). Safety was well documented in this trial. No serious adverse events were reported. Three nonserious events were reported and included increased spasticity (n = 1), bowel incontinence in one participant with irritable bowel syndrome (n = 1), and one fall unrelated to exercise training (n = 1), which resulted in discontinuation in the trial (ie, n = 4 completers).

There is evidence for potential benefits of BWSTT in people with progressive MS. BWSTT is a specialized exercise training modality that consists of a motorized treadmill with an overhead counterbalancing system that allows an individual to be suspended in a harness over the treadmill.41 Therapist or robotic assistance can be provided to facilitate treadmill walking. Two small, uncontrolled trials have been reported involving BWSTT in people with progressive MS.45,46 One trial involving 40 sessions of BWSTT reported improvements in muscle strength, walking speed and endurance, balance, spasticity, and QOL (statistical tests not performed) in four people with progressive MS (EDSS score = 7.0–7.5).45 Another pre-post trial of 36 sessions of BWSTT reported significant improvements in physical (P = .02) and mental QOL (P = .01) and nonsignificant, large effects (d = −0.93, P = .22) for reducing the impact of fatigue in six participants with progressive MS.46 Nonsignificant, small positive changes in physical function were noted in this trial (d = 0.23, P = .35); however, there was no change in EDSS score (d = −0.08, P = .36). All the participants completed the BWSTT interventions (ie, no dropouts occurred), and adverse events were not specifically reported on in these trials.

Recently, BWSTT was compared with recumbent stepper training in 12 people with progressive MS (EDSS score = 6.0–8.0).47 Recumbent stepper training involves coupled arm levers and foot pedals that allow for combined upper- and lower-body aerobic exercise training. This study reported a significant effect of exercise training overall on physical and psychosocial fatigue (d = −0.46 to −1.58, P = .01–.04) and moderate-to-large, nonsignificant effects on total and cognitive fatigue (d = −0.59 to −1.23, P > .05). There were small-to-moderate positive effects of recumbent stepper training on QOL (d = 0.34–0.51) and large positive effects of BWSTT on QOL (d = 0.70–0.97). No significant changes in physical function were observed in response to either intervention (P < .05). One participant dropped out of the BWSTT condition (no longer interested in participating), and one participant dropped out of the recumbent stepper training condition (injury unrelated to the exercise protocol). Safety was well documented in this trial. Adverse events were reported by four participants in the BWSTT condition and included physical discomfort, minor bruising, joint pain, and excessive fatigue. One participant in the recumbent stepper training condition reported experiencing physical discomfort, muscle pain, and excessive fatigue.

Conclusions, Limitations, and Future Directions

Table 1 provides a summary of the evidence reviewed for exercise training in people with progressive MS compared with evidence from primarily relapsing MS or mixed MS samples in previous articles, reviews, or meta-analyses. Overall, there seems to be preliminary support for the benefits of exercise training in people with progressive MS, with the most consistent evidence for cardiorespiratory and muscular fitness, fatigue, and QOL outcomes. The effect of exercise training on disease pathology and other functional and symptomatic outcomes is less clear, although there does not seem to be a detrimental effect at this time. The exercise training approaches used in these studies were feasible and well tolerated by people with progressive MS, although further evaluation of all aspects of trial feasibility (eg, process, resources, management, and scientific assessment)48 is necessary. Few trials provided detailed reporting on the safety of exercise training in people with progressive MS. When reported, adverse events were mild in severity and expected in response to a novel exercise stimulus (eg, spasticity changes, muscle soreness, or fatigue). This is supported by meta-analytic data on the safety of exercise training in people with MS overall, which included samples with both relapsing and progressive MS.23

There are substantial limitations of the current literature involving exercise training in people with progressive MS, including small sample sizes, short trial durations, inconsistencies in exercise training protocols and prescriptions, appropriateness of the outcome measures, and a lack of reporting on specific outcomes, including safety and feasibility. Considering these critical limitations, there are a plethora of questions that remain unanswered regarding the potential role of exercise training in the progressive disease phase. A critical next step will involve establishing the safety, feasibility, and therapeutic efficacy of exercise training in progressive MS through well-designed RCTs with appropriate sample sizes and control conditions. Determining the impact of high-quality interventions on disease progression and modification through clinical, radiologic, and neuroperformance-based outcomes49 is needed, and longer training and follow-up protocols are required to establish these effects. The neuroprotective role of exercise training may be particularly important in the progressive disease phase, and future work should include basic and applied research strategies to develop a more complete understanding of the role of exercise training in progressive MS. Collectively, these efforts will contribute to our understanding of the potential benefits and harms of exercise training for long-term disease management.

An important consideration will be the selection or development of the most appropriate and sensitive outcome measures for clinical trials in people with progressive MS, as we may require modified or different tools than those used with people with relapsing MS. For instance, rate of relapse as an indicator of disease activity and progression may not be a suitable outcome in progressive MS.50 Furthermore, progressive MS is often accompanied by severe symptoms and disease burden, which has important implications for the prescription and delivery of exercise training. The EDSS scores reported in most (90%) of the exercise training studies reviewed fell within the moderate-to-severe disability range (ie, EDSS score = 4.0–8.0). Optimizing the prescription, accessibility, and acceptability of exercise training will be critical to ensuring that training benefits are realized in people with progressive MS. For instance, home-based exercise training may be the most accessible option for this population. Increasing the accessibility of exercise should be balanced with the potential need for increased supervision or assistance with exercise training.

An important consideration and limitation when examining the literature involving interventions in people with progressive MS is the challenge in truly defining and diagnosing the progressive MS phenotype. The results of this report and previous studies involving exercise training in individuals with MS are limited by the standard clinical course definitions proposed by Lublin and colleagues.1 However, there has been debate regarding the classification of disease phenotypes in MS. Some researchers have advocated for abandoning phenotype classification in favor of a single disease continuum differentiated by the absence or presence of disease activity or progression.51 Further research is clearly needed to better understand the underlying disease pathology in progressive MS and the role of clinical phenotype classification. The evolution and refinement of the definition of progressive MS will affect the design, evaluation, and dissemination of exercise training approaches. Identification of the specific characteristics of people with progressive MS who respond most favorably to exercise therapy will also be critical to developing the most effective intervention strategies.

There are additional limitations of this report that should be considered. The purpose of this report was to explore the potential role of exercise training in people with progressive MS. We did not perform a systematic review or meta-analysis, and, therefore, other relevant literature may have been missed. Furthermore, the report may be subject to selection bias, the quality of the evidence examined was not formally evaluated, and we were unable to provide an overall quantitative effect for exercise training on the various outcomes examined.

We are cautiously optimistic about the benefits of exercise training in people with progressive MS. We hope that this article serves as a platform for considering rehabilitation approaches, specifically exercise training, along the complete disease spectrum in individuals with MS. Considering the prevalence of progressive MS, the lack of effective therapeutic options, and the considerable frustration of researchers, clinicians, and patients, we believe that exercise training presents a viable therapeutic option worthy of further consideration. The time is now to shift our focus to the progressive disease phase to determine the full potential of exercise training.

PracticePoints

• Evidence for the benefits of exercise training in people with MS has primarily been established in the early, relapsing disease phase, making it difficult to conclude whether similar benefits exist for people with progressive MS.

• There is preliminary support for the benefits of exercise training in people with progressive MS, with the most consistent evidence for improvements in physical fitness, fatigue, and quality of life.

• High-quality research is needed to fully establish the safety, feasibility, and therapeutic efficacy of exercise training for people with progressive MS.