Physical activity is well supported as an effective intervention with numerous benefits for people with multiple sclerosis (MS). Recent research has suggested stronger physical activity guidelines for people with MS (PAG-MS). This systematic review and meta-analysis aims to assess the impact of PAG-MS on quality of life (QOL). A secondary aim is the assessment of the number of adverse effects across studies to gauge physical activity safety in people with MS.

A systematic search was conducted from inception to October 2024 in PubMed, Embase, Web of Science, SPORTDiscus, Scopus, and PsycINFO. Two independent reviewers assessed included studies for eligibility, extracted data, and evaluated risk of bias using the Cochrane Revised Tool for Risk of Bias in Randomized Trials. Randomized controlled trials assessing QOL with an intervention meeting PAG-MS were included. Extracted data were analyzed via meta-analysis and compared with clinical significance thresholds where possible.

Nineteen studies including 891 people with MS were identified. Meta-analysis revealed significant increases in overall QOL (standardized mean difference [MD], 1.13; 95% CI, 0.40-1.86; 

.01) as well as physical (MD, 12.84; 95% CI, 5.29-20.39; 

 .01) and mental (MD, 16.75; 95% CI, 11.9-21.59; 

 .04) subscale scores. Physical and mental subscale scores surpassed clinical significance thresholds. The majority of studies were rated to have a high risk of bias.

The current PAG-MS appear to be effective in improving QOL in people with MS. Multiple forms of physical activity that met the PAG-MS demonstrated comparable efficacy, supporting the feasibility of individualized physical activity prescriptions based on patient-specific needs
and preferences.

From the Kansas City University College of Osteopathic Medicine, Kansas City University, Kansas City, MO (TM, JP, CR); (dis)Ability Design Studio, The Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL (JP); College of Liberal Arts and Sciences, University of Illinois at Urbana-Champaign, Urbana, IL (ET); Department of Physical Medicine and Rehabilitation, Michigan Medicine, and Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI (LA). 

: Joseph Peters, PhD, Kansas City University College of Osteopathic Medicine, Kansas City University, 1750 Independence Ave, Kansas City, MO, 64106; 

The authors declare no conflicts of interest.

Libak Abou, PhD, is supported by the Michigan Institute for Clinical and Health Research-MICHR K12 program (K12TR004374) from the National Center for Advancing Translational Sciences. All other authors have no support to declare.

Data were presented as a poster at the Kansas City Medical Conference in December 2024.

Tanner Murphy, BS

Joseph Peters, PhD

Courtney Robinson, BS

Ethan Truong, BA

Libak Abou, PhD, MPT

Research strongly supports physical activity to help alleviate multiple sclerosis (MS) symptoms, specifically with notable improvements in both physical and mental quality of life (QOL).

Research has yet to assess clinical significance metrics of meeting the current physical activity guidelines on QOL in people with MS since the guidelines’ inception.

This systematic review and meta-analysis supports the safety and utility of these guidelines to improve both mental and physical QOL in people with MS to clinically significant levels.

Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting neuronal myelination, leading to neurological dysfunction.

 The inflammatory demyelination effects on the central nervous system as well as the axonal loss characteristic of this disease lead to both cognitive and physical dysfunctions.

 This commonly manifests with symptoms such as muscle weakness, decreased mobility, autonomic dysfunction, anxiety, depression, cognitive decline, and fatigue.

 Overall, the sequelae of both physical and mental symptoms often lead to a decreased quality of life (QOL) in people with MS.

QOL is an umbrella term that describes outcomes considered important in an individual’s daily life, which can include physical, social, and mental aspects of well-being.

 It is recognized as an important treatment outcome.

 QOL has been reported to be lower in people with MS, even in comparison with other autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel disease).

 Thus, there has been an increased interest in the study of QOL and clinicians should strive to improve QOL in people with MS.

Physical activity has consistently been recognized as a safe and effective intervention for people with MS, offering numerous benefits.

 Research strongly supports its role in managing various MS symptoms, specifically with notable improvements in both physical and mental QOL.

 This, combined with the health benefits, such as reduced cardiovascular risk, explains why it has been suggested that clinicians recommend physical activity to people with MS.

 However, qualitative research found that many clinicians believed they lacked the expertise to design an appropriate regimen,

 driving the development of MS physical activity guidelines based on feasibility, safety, and effectiveness to help clinicians make supported recommendations.

 Kalb et al, in association with the National Multiple Sclerosis Society, reached a consensus that health care providers should encourage 150 minutes per week or more of exercise and/or 150 minutes per week or more of lifestyle physical activity for people with Expanded Disability Status Scale (EDSS) scores from 0 to 9.

 Research by Kim et al recommended 2 to 3 days per week of aerobic training and 2 to 3 days per week of resistance training.

 In this study, we define meeting either of these guidelines as meeting physical activity guidelines for MS (PAG-MS).

 Even though prior systematic reviews have shown improvements in QOL following exercise interventions,

 stronger evidence supporting PAG-MS may enable clinicians to best prescribe this therapy.

An important distinction to make is the definitions of physical activity and exercise. This study will follow the definition of Kalb and colleagues: Physical activity is performed repeatedly over an extended period with an external objective and encompasses both structured exercise routines and lifestyle physical activity (leisure, occupational, or household activities that are at least moderate to vigorous in their intensity).

Following a 2008 review by Motl and Gosney that found significant but small QOL changes in people with MS who completed exercise regimens, more recent reviews in 2023 and 2024 showed that exercise consistently improves QOL.

 The results of the study by Flores et al support that aerobic, resistance, and combined exercise all improve physical and mental subcategories of QOL.

 Overall, these prior systematic reviews have reported a modest positive impact of a variety of exercise interventions on QOL in MS.

What remains unclear is whether meeting PAG-MS is sufficient to improve QOL. Further, a meta-analysis has not determined whether meeting PAG-MS can lead to a minimal clinically important difference (MCID) in QOL improvements. MCID is a research metric that is increasingly being assessed in clinical trials.

 Evidence directly supporting PAG-MS with clinically significant implications would further increase confidence in using these guidelines to make physical activity recommendations for people with MS. Therefore, this systematic review aims to determine whether meeting PAG-MS is associated with improvements in QOL compared with interventions that do not meet PAG-MS and inactivity and to define whether improvements meet clinical significance thresholds. Although physical activity appears to be safe for people with MS, we hope to support the safety of PAG-MS specifically by assessing adverse effects (AEs) that occur in studies where people with MS meet PAG-MS.

 We expect that directly assessing PAG-MS and their clinical significance will help clinicians provide more confident recommendations.

This systematic review was conducted in accordance with the 

Cochrane Handbook for Systematic Reviews of Interventions

 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

 As this was a systematic review of previously published data, ethical approval was not sought. It is part of a larger project, which has been preregistered on PROSPERO (CRD 42023387305), to investigate the effects on nonmotor symptoms such as fatigue,

 cognition, and various mental health outcomes when people with MS meet physical activity guidelines.

A search was conducted in PubMed, Web of Science, Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature, SPORTDiscus, and PsycINFO using a combination of Medical Subject Headings terms, Emtree terms, keywords, and synonyms (where appropriate) from the inception of the database to October 2024. The database-adjusted Boolean search criteria were built upon keywords: 

(‘multiple sclerosis OR MS’) AND (exercise OR ‘physical activity’) AND ‘quality of life.’

 The complete search strategy for each database is available in 

 (supplementary materials are available as a PDF at the end of the online article).

All identified articles were screened by 2 independent reviewers (J.P., E.T.) to assess eligibility, with differences mediated by a third reviewer (L.A.). First, titles and abstracts were screened in Zotero (version 6.0.30) using broad keywords based on search strategy keywords. Next, full texts of potential studies were independently screened by J.P. and E.T. for the determination of final eligibility using the inclusion-exclusion criteria. Disagreements were mediated by L.A. until consensus was reached. A manual forward search of articles that cited articles included in this review and a manual backward search of reference lists of included articles were performed to identify any missing manuscripts.

Study eligibility was determined based on the Population, Intervention or Exposure, Comparators, Outcomes, and Study designs framework. Its inclusion criteria were the following: (1) Population: adults with an MS diagnosis; (2) Intervention: physical activity that met PAG-MS criteria (≥ 150 min/wk of physical activity or biweekly sessions of 10-30 minutes of moderate-intensity aerobic exercise with 2 sessions of resistance training

); (3) Comparators: no intervention or an active control group that did not meet PAG-MS; (4) Outcomes: measures of QOL (eg, Multiple Sclerosis Quality of Life-54 [MSQOL-54], Multiple Sclerosis International Quality of Life [MusiQOL], and Health-Related Quality of Life [HRQOL]); (5) Study design: Only randomized controlled trials (RCTs) were included. Both intention-to-treat and per-protocol studies were considered for this review. Studies were excluded if they did not meet PAG-MS, were not RCTs, were feasibility or pilot studies, or were not published in English.

Data were independently extracted by J.P. and E.T. and then compared for accuracy by L.A. before final table compilation. Data extracted from the included studies were authors, year of publication, characteristics of population (eg, sample size, age, female %, MS type, MS duration, EDSS score), physical activity intervention characteristics (eg, mode, intensity, intervention duration, frequency, session duration, AEs), and QOL assessment tool utilized. A summary of changes in QOL from baseline to posttest between intervention and control groups was identified for each study, with significant changes in mean difference from baseline to posttest extracted and presented as a percentage change in mean QOL. Across studies, the number of AEs potentially associated with participating in physical activity was also reported in order to preliminarily assess the safety of PAG-MS modalities. A risk ratio was calculated for safety in accordance with Fleiss et al.

Studies were screened for biases by 2 independent reviewers (T.M., J.P.) using the Cochrane risk-of-bias tool for randomized trials (RoB 2)

; discrepancies between reviewers were addressed by a third reviewer (L.A.). RoB 2 is a 5-part assessment tool used to make an explicit judgment on risk of bias in the following domains: (1) randomization process, (2) deviations from the intended interventions, (3) missing outcome data, (4) measurement of the outcome, and (5) selection of reported result with a series of questions in each domain.

 Each category is ranked using an algorithm as low concern, some concern, or high concern.

 The overall risk of bias is determined based on the least favorably scored category, with low concern being the most favorable and high concern being the least favorable.

Meta-analyses were performed following Cochrane guidelines.

 Studies were excluded from the meta-analysis if they did not include a control who did not meet PAG-MS. If a study contained multiple intervention groups, only one was included, in accordance with Cochrane recommendations.

 Researchers analyzed overall QOL as well as physical and mental health–related QOL subscales. These separate analyses were performed because the MSQOL-54 only provides these subscales without an overall score.

 Only studies using MSQOL-54 were used to assess clinical significance, as MCID requires a singular outcome measure for analysis. All analyses and funnel plots were completed on the Review Manager online (Cochrane). Differences in mean change between groups were computed using the inverse variance model, and heterogeneity was estimated using 

 Researchers performed visual inspection for asymmetry on funnel plots. A formal asymmetry test (eg, Egger) was not performed due to the low number of studies, in accordance with the recommendations of the Cochrane guidelines.

After considering the variability in interventions, patient samples, and the large calculated heterogeneity (> 50%), the random-effects model was chosen for all analyses

; a sensitivity analysis for overall QOL used the fixed-effects model due to low heterogeneity (

). No sensitivity analyses were performed for physical and mental QOL, as no studies rated with a low to moderate risk of bias provided physical or mental subscale data. Mean difference (MD) was used when only 1 outcome measure was pooled (eg, MSQOL-54), whereas standard MD (SMD) was used when multiple outcome measures were pooled.

 The measurements from the EuroQol 5-Dimension assessment tool, MusiQOL, and MSQOL-54 were combined in the overall QOL meta-analysis. A 95% CI was used. To account for multiple testing done in this review across the 3 separate QOL meta-analyses, the authors implemented the Benjamini-Hochberg correction to control for the false detection rate and provided an adjusted 

 value following the protocol provided by Benjamini et al.

 values were rounded to 2 decimal places.

Clinical significance was determined by comparing observed change to the MCID of a respective assessment tool.

 Because MCID has not yet been established for the MSQOL-54, researchers used 0.5 times the experimental groups’ pooled baseline SD to calculate an estimated MCID.

 This method has been used in similar MS studies.

A total of 6911 articles were identified. Following the removal of 4877 duplicates, 2034 abstracts were screened and 1858 articles were excluded. Researchers then retrieved the full texts of the remaining 176 articles. Following secondary screening, 157 were excluded, leaving 19 articles to be included in the review.

 shows a flow diagram of the selection process.

Identification of Studies via Databases and Registers

In total, 891 people with MS were included in these studies. The mean age of participants ranged from 32.65 to 50.0 years. The percentage of female participants included in the studies varied from 56% to 100%. Fourteen of the studies provided participant MS type: relapsing-remitting MS (RRMS), primary progressive MS, and secondary progressive MS.

 RRMS was the most common form. The average disease duration ranged from 2.69 to 13.6 years. Of the 16 studies reporting EDSS, the average score ranged from 1.5 to 5.0. 

All studies contained an intervention group that met PAG-MS. Of the studies, 6 assessed 2 or more intervention groups that met PAG-MS.

 The duration of studies ranged from 3 to 109 weeks of physical activity.

Five RCTs had multiple study groups that met PAG-MS and no control group (in accordance with our study’s control group criteria).

 Of the remaining 14 studies, 12 contained control groups that received no intervention. There were 2 outliers. Kerling et al contained a control group that participated in aerobic exercise that did not meet PAG-MS.

 Ozkul et al contained a control group that practiced a relaxation protocol.

 Further details of control and physical activity interventions are provided in 

Ten studies assessed QOL using MS-specific QOL questionnaires (MSQOL-54 and MusiQOL),

 and 9 studies used questionnaires not tailored to MS, such as the HR-QOL and the 36-Item Short Form Survey Instrument.

 Additional information on QOL assessment tools is provided in Table 2.

Eleven studies reported an overall QOL score.

 Of the intervention groups assessed for overall QOL measures, 90% showed improvement from baseline to posttest in at least 1 QOL outcome measure. Six studies were included in a meta-analysis and showed a statistical significance favoring PAG-MS (SMD, 1.13; 95% CI, 0.40-1.86; 

 An exploratory funnel plot for overall QOL did not show excessive asymmetry on visual inspection, with larger studies clustering closer to the pooled estimate. Due to the low number of studies, this funnel plot should be interpreted cautiously. Of these 6 studies included in the meta-analysis, 4 were rated with a high concern of bias,

 1 was rated moderately concerning for risk of bias,

Several studies and interventions included within this review were not included in the meta-analysis for various reasons. The results from Ozgen et al’s balance intervention showed a statistically significant increase in overall QOL compared with control, but they were not included due to reporting a range instead of an SD.

 had multiple intervention groups that met PAG-MS with a single control group, so only 1 group (ie, the exergaming intervention) was included in the meta-analysis, in accordance with Cochrane recommendations.

 Notably, all intervention groups that met PAG-MS within these studies showed significant changes in QOL from baseline to posttest compared with the control group.

Four studies included 2 groups that met PAG-MS but had no control,

 so they were not in the meta-analyses. Of these studies, 3 showed statistically significant improvements in overall QOL from baseline to posttest in both groups.

 In contrast, 1 study found no significant change in either group meeting PAG-MS.

To support robustness, a sensitivity analysis on overall QOL (Table S2) was done using the 2 studies rated with low to moderate risk of bias in the meta-analysis

 = 0%). Additionally, the study by Ozgen et al—not included in the meta-analyses—was rated with a low risk of bias and showed significantly greater improvements from baseline to posttest compared with the control condition.

Effects of Meeting PAG-MS on Physical Health–Related QOL

Eleven studies assessed physical health–related QOL.

 Six of these used the MSQOL-54, and all were included in a meta-analysis (

 Their results showed a statistically significant improvement in physical QOL favoring the physical activity group (MD, 12.84; 95% CI, 5.29-20.39; 

 = 86%) and surpassed the MCID of 10.96 we estimated for the MSQOL-54 physical health–related QOL. An exploratory funnel plot for physical QOL showed notable asymmetry on visual inspection, with smaller studies tending to report larger effects. This brings about a concern for nonreporting biases or bias from studies inflating effects in smaller studies.

 Due to the low number of studies, this funnel plot should be interpreted cautiously. All 6 studies included in the meta-analysis were rated with high concern of bias.

 Physical Health–Related QOL Meta-Analysis

Of the 5 studies not included in the meta-analysis that examined physical health–related QOL,

 results from 4 showed improvements in physical health–related QOL metrics following PAG-MS.

 The results from Cakt et al showed statistically significant improvements in physical activity from baseline to posttest compared with the control group, and results from Ozgen et al showed significant improvements for the same.

 In the study by Bansi et al, 2 experimental groups met PAG-MS and had significant improvements in physical health–related QOL from baseline to posttest, but these results were not significantly greater than the results from the control group.

 The data from the experimental group in the study by Canning et al had significantly greater improvements in physical health–related QOL than the control group.

 Notably, the data from Kerling et al failed to show significant improvements in physical health-related QOL following a PAG-MS intervention.

The only study rated with a low risk of bias assessing this outcome was from Ozgen et al, where data showed significantly greater improvements in physical QOL from baseline to posttest compared with the control condition.

Effects of Meeting PAG-MS on Mental Health–Related QOL

Eleven studies assessed mental health–related QOL.

 Six of these used the MSQOL-54 assessment tool and were included in a meta-analysis (

 The results of this comparison showed a statistically significant improvement in mental health–related QOL favoring the physical activity group (MD, 16.75; 95% CI, 11.9-21.59; 

 = 56%). These results surpassed the clinical significance thresholds with an MCID of 11.35, which we estimated for MSQOL-54 mental health–related QOL. Of these 6 studies included in the meta-analysis, 100% were rated with a high concern of bias.

 An exploratory funnel plot for mental QOL did not show excessive asymmetry on visual inspection, with larger studies clustering closer to the pooled estimate. Due to the low number of studies, this funnel plot should be interpreted cautiously. A heat map summary of risk of bias scoring is available in 

Mental Health–Related QOL Meta-Analysis

Of the 5 studies not included in the meta-analysis,

 results from 4 showed improvements in mental health–related QOL following PAG-MS.

 Cakt et al and Ozgen et al showed statistically significant improvements in mental health-related QOL from baseline to posttest compared with the control group.

 Kerling et al showed significant improvements in mental health–related QOL from baseline to posttest in both experimental and control groups; however, the control group had an aerobic exercise intervention that did not meet PAG-MS.

 Canning et al showed significantly greater improvements in mental health–related QOL in their experimental group vs the control group from baseline to posttest.

 Bansi et al’s study contained 2 experimental groups that met PAG-MS; however, neither group showed significant improvements in mental health–related QOL from baseline to posttest.

The only study rated with a low risk of bias assessing this outcome was from Ozgen et al, where data showed significantly greater improvements in mental QOL from baseline to posttest compared with the control condition.

Of the studies reporting AE findings, results from 10 studies found no exacerbations of symptoms of MS.

 a total of 18 patients experienced exacerbations of MS symptoms, with 10 in the control condition and 8 in the experimental condition (risk ratio, 0.60; 95% CI, 0.24-1.51; 

 .42). Results from only 1 study reported more AEs in the experimental condition than in the comparison condition (3 and 2, respectively).

 The study consisted of a biweekly
40-minute combined aerobic and resistance training protocol in the experimental condition, with 30 participants each in the intervention and comparison group and an average EDSS score of 2.6 and 3.1, respectively.

 Results from 4 studies did not report any information on exacerbation of MS symptoms or the occurrence of AEs in their study.

This review assesses the impact of following PAG-MS on QOL. Although not a primary aim, we also assessed the safety of physical activity for people with MS by reporting the AEs in the studies analyzed. The results support PAG-MS improving overall QOL as well as scores on the physical and mental health–related QOL subscales. Further, people with MS who met PAG-MS did not have more AEs than those who did not meet PAG-MS, supporting the safety of these interventions. Our results should be interpreted with caution due to the high risk of bias identified in the majority of the studies, with substantial heterogeneity observed across all meta-analyses.

The improvements in overall QOL observed in PAG-MS studies following meta-analysis are consistent with findings from other studies assessing exercise in people with MS.

 Although these previous findings were statistically significant, we were unable to compare the effects of PAG-MS on overall QOL with clinical significance thresholds due to heterogeneity across overall QOL outcome measures.

 Although it may seem reasonable to expect standardized overall QOL reporting, Motl and Gosney write that QOL metrics should be less generalized and more focused on MS-specific aspects of physical and mental health–related QOL.

 Currently, the most common questionnaire used to assess QOL in people with MS, MSQOL-54,

 stratifies disease-specific measures of MS-related QOL into physical and mental domains rather than giving an overall score.

 Excluding studies with a high risk of bias and the results from Ozgen et al, the sensitivity analysis showed similar improvements to the meta-analyses. These results are supportive of the benefits of physical activity on QOL not being solely driven by high-risk biased studies.

Across the included studies, physical health–related QOL significantly improved in the majority of intervention groups meeting PAG-MS, with meta-analysis surpassing estimated MCID for physical health-related QOL improvements. This finding is in line with a review that showed that physical health–related QOL improved following exercise interventions in MS: Du et al showed exercise could reduce risk of falls, emphasizing that improvements in strength, balance, and mobility would mitigate fall risk, which has a large negative influence on QOL in MS.

 Evidence also supports that exercise enhances fatigue resistance.

 We believe this played a role in improving the physical health–related QOL scores, as fatigue is a defining symptom of MS

 and heavily weighted in MS-specific QOL assessments.

Results from our review also support that adhering to PAG-MS can improve mental health–related QOL in people with MS, surpassing estimated clinical significance thresholds. Currently, 20% to 30% of people with MS experience anxiety and depression, which likely contribute to their reduced mental health–related QOL.

 As research supports the use of physical activity to improve depression and anxiety in adult populations,

 we believe that physical activity’s positive effect on psychological well-being may be able to explain the improved mental health–related QOL observed across studies. Interestingly, results from 2 studies in this review that examined depression and anxiety did not show changes in either, in light of significant mental health–related QOL improvements.

 It may be the case that other factors mediate this relationship.

However, not all studies had results that showed significant differences between groups in QOL. The results of the study by Kerling et al showed equal improvements from baseline to posttest in both intervention and control conditions but no significant differences between groups.

 This study’s comparison group had an active aerobic intervention that, although close, did not meet PAG-MS. We believe that this active comparison condition contributed to the improvements observed in QOL within the control group and decreased between-group differences.

 This highlights a challenge within our study that may have limited the overall effects of PAG-MS observed across this review.

Intrinsic motivation plays a key role in people’s ability to adhere to exercise.

 Exercise autonomy and enjoyment lead to higher self-determined motivation to engage in exercise, whereas a mismatch in intensity or type of exercise can decrease motivation and adherence.

 Our study includes a large array of physical activities and characteristics, allowing us to surmise that there are many variations of physical activity routines that meet PAG-MS that may improve QOL. Therefore, clinicians and therapists should feel confident in their ability to customize interventions that meet PAG-MS based on the patient’s physical and accessibility needs to improve adherence.

Results from the majority of studies within this review showed no AEs,

 and across results from studies that did, there did not appear to be a difference in AEs when compared with the control conditions.

 Therefore, we believe that PAG-MS are safe for people with MS, which has been reported in other exercise-related reviews.

 The high risk of bias due to poor blinding in the majority of studies reduces confidence in our findings. However, considering the consistency of results across other reviews on this topic and physical activity in general,

 the results of this study indicate that the use of PAG-MS may be safe and effective in improving QOL for people with MS.

Our review has several limitations. First, only studies published in English were included, which may have caused researchers to miss studies published in other languages, potentially introducing study selection bias. Next, studies examining clinical significance typically rely on anchor-based methods to determine MCIDs, which provide thresholds directly tied to patient-reported outcomes and perceptions of improvement.

 Unfortunately, due to the lack of anchor-based MCIDs for the MSQOL-54 at the time of this study, researchers utilized a distribution-based method to estimate relevant thresholds.

 Although this method is commonly used in exploratory analyses, anchor-based methods are considered stronger, and these specific results should be considered exploratory.

 We also wish to acknowledge the potential for publication bias as a limitation of this meta-analysis, as no formal assessment for this was performed due to the limited number of studies. In addition, authors provided analyses for overall as well as physical and mental health-related QOL. This resulted in multiple testing of data, which increases the risk for a type I error. Further, many studies included in the meta-analyses had small sample sizes, which can introduce small-study effect bias.

 This concern is bolstered when consideration is given to the exploratory funnel plot for physical activity meta-analysis (

, Figure 2), as asymmetry in smaller studies adds concern for missing studies with negative or null reporting. As a result, pooled estimates derived from these studies should be interpreted with caution, as they may not accurately reflect the true underlying effect. Future work should explore an anchor-based approach to create a definitive MCID for commonly used QOL metrics such as the MSQOL-54. It must also be noted that the observed improvements in mental and physical health–related QOL come from studies that were considerably heterogeneous and had a high risk of bias. Designing effective placebos for physical activity interventions is inherently difficult and introduced a methodological vulnerability across many studies. Further, the results of the analyses are based on highly heterogeneous control conditions, as both active and sedentary controls were included. This highlights the need for more methodologically rigorous research to strengthen confidence in these findings, though blinding is inherently challenging in exercise interventions.

 Nevertheless, we argue that the consistency of results across studies substantially reduces the likelihood that a type I error attributable to potential bias occurred in this review. We also want to highlight the narrow range of average disease duration assessed across studies (ie, 2.7-13.6 years), which may challenge the applicability of results to patients with disease durations outside this range. Last, the variability of questionnaires used in the studies included in the overall QOL meta-analysis further increased study heterogeneity.

The results of this study support the effectiveness and safety of PAG-MS to improve QOL in people with MS. This review found improvements in mental and physical health-related QOL that surpassed clinical significance thresholds, supporting PAG-MS utility. In addition, multiple forms of PAG-MS regimens demonstrated comparable efficacies, which may allow clinicians to feel confident in individualizing physical activity prescription based on patient-specific needs and preferences. 

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Volume 28, Issue 2

Impact of Physical Activity Guidelines on Quality of Life in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Self-Management in Youth With Multiple Sclerosis During Transition to Adult Care and Adulthood: A Qualitative Study Using Interpretive Description

Ofatumumab Interruption Results in Disease Reactivation: A Case Report

Two Sides of the Same Coin: A Randomized Clinical Trial of the Unified Protocol for Addressing Depression and Anxiety in People With Multiple Sclerosis

Using Wearable Sensors and Video Analysis to Improve Functional Electrical Stimulation Prescription in Individuals With Multiple Sclerosis: A Case Series

Finding Your Stride: Navigating Running With Multiple Sclerosis. A Qualitative Study

Influence of Food Security and Social Support on Quality of Life Among Rural and Urban Iowans With Multiple Sclerosis: A Mixed-Methods Pilot Study