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Is Aerobic or Resistance Training the Most Effective Exercise Modality for Improving Lower Extremity Physical Function and Perceived Fatigue in People With Multiple Sclerosis? A Systematic Review and Meta-analysis

Open AccessPublished:April 23, 2021DOI:https://doi.org/10.1016/j.apmr.2021.03.026

      Abstract

      Objective

      The purpose of this systematic review was to investigate whether aerobic training (AT) or resistance training (RT) is most effective in terms of improving lower limb physical function and perceived fatigue in persons with multiple sclerosis (PwMS).

      Data Sources

      Nine databases (MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health, Allied and Complementary Medicine Database, Physiotherapy Evidence Database, SPORTDiscus, PsycINFO, Web of Science, and Scopus) were electronically searched in April 2020.

      Study Selection

      Included studies were randomized controlled trials (RCTs) involving PwMS attending 1 of 2 exercise interventions: AT or RT. Studies had to include at least 1 objective or self-reported outcome of lower extremity physical function and/or perceived fatigue.

      Data Extraction

      Data were extracted using a customized spreadsheet, which included detailed information on patient characteristics, interventions, and outcomes. The methodological quality of the included studies was independently assessed by 2 reviewers using the Tool for Assessment of Study Quality for Reporting on Exercise rating scale.

      Data Synthesis

      Twenty-seven articles reporting data from 22 RCTS (AT=14, RT=8) including 966 PwMS. The 2 modalities were found to be equally effective in terms of improving short walk test (AT: effect size [ES]=0.33 [95% confidence interval (CI), −1.49 to 2.06]; RT: ES=0.27 [95% CI, 0.07-0.47]) and long walk test performance (AT: ES=0.37 [95% CI, −0.04 to 0.78]; RT: ES=0.36 [95% CI, −0.35 to 1.08]), as well as in reducing perceived fatigue (AT: ES=−0.61 [95% CI, −1.10 to −0.11]; RT: ES=−0.41 [95% CI, −0.80 to −0.02]). Findings on other functional mobility tests along with self-reported walking performance were sparse and inconclusive.

      Conclusions

      AT and RT appear equally highly effective in terms of improving lower extremity physical function and perceived fatigue in PwMS. Clinicians can thus use either modality to target impairments in these outcomes. In a future perspective, head-to-head exercise modality studies are warranted. Future MS exercise studies are further encouraged to adapt a consensus “core battery” of physical function tests to facilitate a detailed comparison of results across modalities.

      Keywords

      List of abbreviations:

      AT (aerobic training), CI (confidence interval), EDSS (Expanded Disability Status Scale), ES (effect size), MS (multiple sclerosis), MSWS-12 (12-item Multiple Sclerosis Walking Scale), PwMS (persons with multiple sclerosis), RCT (randomized controlled trial), RM (repetition maximum), RT (resistance training), 6MWT (6-minute walk test)
      Multiple sclerosis (MS) is a chronic, autoimmune, and inflammatory disease of the central nervous system, exemplified through demyelination and axonal loss.
      • Compston A
      • Coles A.
      Multiple sclerosis.
      As a consequence, multiple symptoms can appear,
      • Compston A
      • Coles A.
      Multiple sclerosis.
      • Thompson AJ
      • Baranzini SE
      • Geurts J
      • Hemmer B
      • Ciccarelli O.
      Multiple sclerosis.
      • Calabresi PA.
      Diagnosis and management of multiple sclerosis.
      with fatigue and walking limitations reported to be among the most debilitating.
      • Green R
      • Cutter G
      • Friendly M
      • Kister I.
      Which symptoms contribute the most to patients' perception of health in multiple sclerosis?.
      • Heesen C
      • Haase R
      • Melzig S
      • et al.
      Perceptions on the value of bodily functions in multiple sclerosis.
      • Zhang Y
      • Taylor BV
      • Simpson Jr, S
      • et al.
      Feelings of depression, pain and walking difficulties have the largest impact on the quality of life of people with multiple sclerosis, irrespective of clinical phenotype.
      • Hvid LG
      • Feys P
      • Baert I
      • Kalron A
      • Dalgas U.
      Accelerated trajectories of walking capacity across the adult life span in persons with multiple sclerosis: an underrecognized challenge.
      Moreover, an estimated 50% of persons with multiple sclerosis (PwMS) will require a walking aid within 15-25 years after disease onset.
      • Tremlett H
      • Paty D
      • Devonshire V.
      Disability progression in multiple sclerosis is slower than previously reported.
      ,
      • Kister I
      • Bacon TE
      • Chamot E
      • et al.
      Natural history of multiple sclerosis symptoms.
      Because physical function is associated with lowered quality of life at the individual level along with a greater economic burden at a health service and societal level,
      • Kobelt G
      • Thompson A
      • Berg J
      • Gannedahl M
      • Eriksson J.
      New insights into the burden and costs of multiple sclerosis in Europe.
      ,
      • Ness NH
      • Schriefer D
      • Haase R
      • Ettle B
      • Cornelissen C
      • Ziemssen T.
      Differentiating societal costs of disability worsening in multiple sclerosis.
      it is crucial to diminish progression of disability.
      • Gyllensten H
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      • Alexanderson K
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      • Tinghög P
      • Friberg E.
      Costs and quality of life by disability among people with multiple sclerosis: a register-based study in Sweden.
      Although pharmacologic treatments appear to have limited beneficial effect on fatigue and walking limitations,
      • Braley TJ
      • Chervin RD.
      Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment.
      exercise has proven to be a potent nonpharmacologic treatment option, being both safe and eliciting numerous beneficial effects in PwMS.
      • Pilutti LA
      • Platta ME
      • Motl RW
      • Latimer-Cheung AE.
      The safety of exercise training in multiple sclerosis: a systematic review.
      ,
      • Dalgas U
      • Stenager E
      • Ingemann-Hansen T.
      Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training.
      Specifically, exercise is an effective way of reducing fatigue
      • Latimer-Cheung AE
      • Pilutti LA
      • Hicks AL
      • et al.
      Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development.
      ,
      • Heine M
      • van de Port I
      • Rietberg MB
      • van Wegen EE
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      and improving walking performance,
      • Snook EM
      • Motl RW.
      Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis.
      ,
      • Pearson M
      • Dieberg G
      • Smart N.
      Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis.
      with the latter often considered to be clinically meaningful.
      • Hobart J
      • Blight AR
      • Goodman A
      • Lynn F
      • Putzki N.
      Timed 25-foot walk: direct evidence that improving 20% or greater is clinically meaningful in MS.
      ,
      • Baert I
      • Freeman J
      • Smedal T
      • et al.
      Responsiveness and clinically meaningful improvement, according to disability level, of five walking measures after rehabilitation in multiple sclerosis: a European multicenter study.
      Exercise constitutes a number of different modalities known to elicit different physiological adaptations (such as neuromuscular function or cardiovascular function) that in most cases are paralleled by (and perhaps even translated into) improved physical function.
      • Dalgas U
      • Langeskov-Christensen M
      • Stenager E
      • Riemenschneider M
      • Hvid LG.
      Exercise as medicine in multiple sclerosis-time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      A recent review investigating randomized controlled trials (RCTs) of exercise interventions in PwMS reported that the 2 most applied exercise modalities were aerobic training (AT) and resistance training (RT).
      • Dennett R
      • Madsen LT
      • Connolly L
      • Hosking J
      • Dalgas U
      • Freeman J.
      Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: a systematic review and meta-analyses.
      Several studies have reported positive effects of both AT
      • Collett J
      • Dawes H
      • Meaney A
      • et al.
      Exercise for multiple sclerosis: a single-blind randomized trial comparing three exercise intensities.
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      and RT
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      on parameters directly related to lower extremity physical function (eg, walking performance, chair rise, stair negotiation) as well as on parameters indirectly related to lower extremity physical function, such as perceived fatigue. However, based on the existing literature it currently remains unknown which of these 2 common exercise modalities is the most effective in terms of improving physical function and perceived fatigue in PwMS. Despite the somewhat impossible task of matching AT and RT on traditional exercise parameters such as duration, frequency, and intensity, understanding the specific effectiveness of the 2 different exercise modalities is an important factor for consideration in optimizing exercise prescription in PwMS.
      Therefore, the objectives of this systematic review were to investigate which of the 2 exercise modalities (AT or RT) is the most effective in terms of improving lower extremity physical function and reducing perceived fatigue in PwMS.

      Methods

      The present systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on systematic reviews of RCTs.
      • Liberati A
      • Altman DG
      • Tetzlaff J
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      Search strategy, study selection, eligibility criteria, methodology assessment, data extraction, and analysis were performed in accordance with a protocol preregistered in PROSPERO (CRD42020189855).

      Definitions

      In this review the following definitions were applied:
      Exercise: A form of physical activity that is planned, structured, and repetitive and is undertaken with the objective of improving or maintaining at least 1 aspect of physical fitness, comprising strength, flexibility, or aerobic endurance.
      • Caspersen CJ
      • Powell KE
      • Christenson GM.
      Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research.

      Physical activity: Any bodily movement produced by skeletal muscles that requires energy expenditure above resting levels.
      • Caspersen CJ
      • Powell KE
      • Christenson GM.
      Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research.

      Physical function: The ability of an individual to perform physical activities of daily living. For the purposes of this systematic review, this particularly relates to lower extremity tasks (eg, simple/complex/endurance walking, chair rise, stair negotiation).
      • Garber CE
      • Greaney ML
      • Riebe D
      • Nigg CR
      • Burbank PA
      • Clark PG.
      Physical and mental health-related correlates of physical function in community dwelling older adults: a cross sectional study.

      Perceived fatigue: Subjective sensations of weariness, increasing sense of effort, mismatch between effort expended, and actual performance or exhaustion.
      • Kluger BM
      • Krupp LB
      • Enoka RM.
      Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy.

      Resistance training: Performed with external resistance of varying degrees relative to maximal strength provided by either free weights, machines, body weight, or some other implements (eg, resistance bands), either with single or multiple sets of repetitions, which may or may not be performed to momentary failure (but are often performed to a relatively high effort).
      • Steele J
      • Androulakis-Korakakis P
      • Perrin C
      • et al.
      Comparisons of resistance training and "cardio" exercise modalities as countermeasures to microgravity-induced physical deconditioning: new perspectives and lessons learned from terrestrial studies.
      Aerobic training: Performed using locomotor or ergometer tasks (eg, walking, jogging, running, cycling, rowing, etc) in a continuous or intermittent fashion with respect to duration at submaximal intensities of effort, commonly determined relative to maximal heart rate, heart rate reserve, or maximum oxygen consumption or sometimes using ratings of perceived effort scales.
      • Steele J
      • Androulakis-Korakakis P
      • Perrin C
      • et al.
      Comparisons of resistance training and "cardio" exercise modalities as countermeasures to microgravity-induced physical deconditioning: new perspectives and lessons learned from terrestrial studies.
      Exercise intensity: For AT, exercise ≤63% of heart rate maximum was defined as low intensity, 64%-76% of heart rate maximum as moderate intensity, and ≥77 % of heart rate maximum as high intensity.
      • Garber CE
      • Blissmer B
      • Deschenes MR
      • et al.
      American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise.
      For RT, exercise ≥16 repetition maximum (RM) was defined as low intensity (≤64% of 1 RM), 9-15 RM as moderate intensity (65%-79% of 1 RM), and ≤8 RM as high intensity (≥80% of 1 RM).
      • Csapo R
      • Alegre LM.
      Effects of resistance training with moderate vs heavy loads on muscle mass and strength in the elderly: a meta-analysis.
      ,
      • Schoenfeld BJ
      • Grgic J
      • Ogborn D
      • Krieger JW.
      Strength and hypertrophy adaptations between low- vs. high-load resistance training: a systematic review and meta-analysis.

      Searches

      An original search was carried out as part of another review by the same authors in 2018, having the aim to summarize reported adherence and dropout data from RCT studies of exercise interventions in PwMS.
      • Dennett R
      • Madsen LT
      • Connolly L
      • Hosking J
      • Dalgas U
      • Freeman J.
      Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: a systematic review and meta-analyses.
      This search was updated in April 2020. Furthermore, in March 2020, the World Health Organization's International Clinical Trials Registry Platform, http://apps.who.int/trialsearch/, which comprises the 16 primary registries of the World Health Organization registry network and ClinicalTrials.gov, was searched for relevant ongoing trials investigating a head-to-head comparison of AT and RT in PwMS.

      Data sources and search strategy

      In brief, the search strategy was based on the key terms “multiple sclerosis” OR MS AND exercise OR “physical activity.” For full search strategy please see Dennett et al.
      • Dennett R
      • Madsen LT
      • Connolly L
      • Hosking J
      • Dalgas U
      • Freeman J.
      Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: a systematic review and meta-analyses.
      The original search was carried out in October 2018 and updated in April 2020.
      Two reviewers (L.M., R.D.) conducted the original search in the electronic databases MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health, Allied and Complementary Medicine Database, Physiotherapy Evidence Database, SPORTDiscus, PsycINFO, Web of Science, and Scopus and was limited to scientific research articles published between January 1993 and October 2018. The same databases were searched from September 2018 to March 2020 by 2 reviewers (L.M., L.C.) in April 2020. All searches were supplemented by hand searches of reference lists.

      Study selection

      The following population, intervention, comparison, and outcomes question guided the search and inclusion strategy, “Which exercise modality, AT or RT, is most effective in improving physical function (specifically lower extremity tasks such as simple/complex/endurance walking, chair rise, stair negotiation) and perceived fatigue in PwMS?”

      Eligibility criteria

      RCT studies involving adults aged >18 years with a definite diagnosis of MS, regardless of sex, disease duration, MS phenotype, or level of disability were considered eligible for inclusion. Although all identified studies could be included regardless of location, group/individual structure, level of supervision, intervention duration, session duration, intensity, progression, and frequency, the content had to be either AT or RT, with or without a follow-up period.
      Control interventions had to include nontraining controls only or active control conditions having no expected effects on the cardiovascular system or the musculoskeletal system, for example, stretching was accepted.
      Studies had to include at least 1 objective or self-reported measure of lower extremity physical function (such as simple/complex/endurance walking, chair rise, stair negotiation) and/or perceived fatigue. If reported, measures of cardiovascular function (ie, maximal oxygen uptake) and neuromuscular function (ie, maximal muscle strength or muscle power) were also extracted because these outcomes could (1) help verify the effectiveness of interventions and (2) are likely mediators of adaptations in lower extremity physical function.

      Data management and selection process

      The original search resulted in 93 articles included in the previous review, all of which were considered for inclusion in the present review (fig 1).
      Fig 1
      Fig 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram on the search result and study selection process.
      Results from the updated search were exported to EndNote,a where duplicates were removed. The remaining articles were imported into Rayyanb data management system (rayyan.qcri.org) where titles and abstracts were independently screened for eligibility by 2 reviewers (L.C., L.T.M.). If articles were included at this stage, a full-text reading by the same 2 reviewers was performed, and any discrepancies were discussed with a third party (L.G.H.). Reasons for excluding full-text RCTs were recorded.

      Data extraction

      Data were extracted using the same spreadsheet as the previous review,
      • Dennett R
      • Madsen LT
      • Connolly L
      • Hosking J
      • Dalgas U
      • Freeman J.
      Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: a systematic review and meta-analyses.
      which included detailed information on participant characteristics (age, sex, disease duration, MS phenotype, disability level, fatigue as a symptom); modality of the intervention (setting, group/individual structure, level of supervision, intervention duration, session duration, intensity, frequency); content of the intervention (aerobic or resistance); report of adverse events, percentage dropout, and adherence during the intervention period and at any follow-up.
      Furthermore, an additional customized spreadsheet was made to extract information on all outcomes of lower extremity physical function, perceived fatigue, and measures of cardiovascular and neuromuscular function. Data extraction was completed by 2 reviewers (L.C., L.T.M.).

      Quality assessment

      The methodological quality of the included studies was independently assessed by 2 reviewers (L.T.M., L.C.) using the Tool for Assessment of Study Quality for Reporting on Exercise rating scale.
      • Smart NA
      • Waldron M
      • Ismail H
      • et al.
      Validation of a new tool for the assessment of study quality and reporting in exercise training studies: TESTEX.
      Any discrepancies were discussed and resolved between the 2 reviewers.

      Synthesis of results

      In addition to the qualitative analysis (summary of identified studies and their data), we also performed quantitative analysis by calculating sample-size weighted averages across selected studies. A minimum of 2 studies was required to conduct a meta-analysis. Random-effects meta-analyses comprising data on physiological adaptations, short walking tests, long walking tests, and perceptions of fatigue were conducted by using Meta-Essentials version 1.5 designed for Excel.
      • Suurmond R
      • van Rhee H
      • Hak T.
      Introduction, comparison, and validation of Meta-Essentials: a free and simple tool for meta-analysis.
      ,c Intervention effect sizes (ESs) (between-group differences) for different outcomes at posttreatment, were calculated using Hedges’ g statistic, along with 95% confidence intervals (CIs) around the estimated ES. Also, if data were available and adequate, we performed a weighted regression of all study ESs as a function of intervention duration and frequency (weeks and number of sessions) as well as intervention intensity because these factors were hypothesized to affect the outcomes.
      • Nebiker L
      • Lichtenstein E
      • Minghetti A
      • et al.
      Moderating effects of exercise duration and intensity in neuromuscular vs. endurance exercise interventions for the treatment of depression: a meta-analytical review.
      Of note, this approach was done to establish specific within-modality information only. ESs were interpreted as follows: small=0.14, moderate=0.31, and large=0.61 based on empirical data from 99 meta-analyses examining the effects of rehabilitation/exercise.
      • Kinney AR
      • Eakman AM
      • Graham JE.
      Novel effect size interpretation guidelines and an evaluation of statistical power in rehabilitation research.
      Statistical heterogeneity was quantified using Higgins’ I2 statistic and was interpreted as follows: heterogeneity: >50%, no or limited heterogeneity: <50%.
      • Higgins JP
      • Thompson SG
      • Deeks JJ
      • Altman DG.
      Measuring inconsistency in meta-analyses.
      If studies reported on more than 1 outcome in each domain (eg, physiological adaptations such as knee extensor and knee flexor muscle strength as well as perceptions of fatigue using different questionnaires), an average was calculated and used for the meta-analyses.

      Results

      Study characteristics

      As depicted in figure 1, the search yielded 2117 hits. After removal of duplicates, 1538 articles remained for the screening process, with 12 of these assessed for full-text reading. Five articles were included, which with the addition of 22 articles from the previous review resulted in a total of 27 articles being included in the qualitative and quantitative synthesis.
      The 27 articles reported 22 RCTs (AT [n=14], RT [n=8]) that involved a total of 966 PwMS. As seen in table 1, Expanded Disability Status Scale (EDSS) ranged from 1.5-7, and disease duration ranged from 2.7-18.6 years. The duration of AT interventions ranged from 3-26 weeks (involving 9-48 sessions), with the intensity being deemed moderate (n=5),
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      high (n=4),
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      or unknown (no information, n=5).
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      ,
      • Sadeghi Bahmani D
      • Razazian N
      • Farnia V
      • Alikhani M
      • Tatari F
      • Brand S.
      Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty.
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      • Mostert S
      • Kesselring J.
      Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      The duration of RT interventions ranged from 8-24 weeks (involving 15-48 sessions), with the intensity being deemed moderate (n=1),
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      high (n=4),
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      or unknown (no information, n=3).
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      • Harvey L
      • Smith A
      • Jones R.
      The effect of weighted leg raises on quadriceps strength, EMG parameters and functional activities in people with multiple sclerosis.
      • DeBolt LS
      • McCubbin JA.
      The effects of home-based resistance exercise on balance, power, and mobility in adults with multiple sclerosis.
      Because of the missing information and the use of divergent scales of exercise intensity for both AT (eg, percentage of heart rate maximum, rating of perceived exertion, percentage of maximum oxygen consumption, percentage of peak power) and RT (percentage of 1 RM, percentage of body weight, absolute weights), we were unable to perform weighted (moderator) analysis using this parameter. Two
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      ,
      • DeBolt LS
      • McCubbin JA.
      The effects of home-based resistance exercise on balance, power, and mobility in adults with multiple sclerosis.
      of the 22 identified RCTs reported a primary outcome that was not based on a sample size calculation. Ten articles
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      ,
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      ,
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      ,
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      of the 22 identified RCTs reported a primary outcome based on a sample size calculation, with 5 of these having a primary outcome aligned with the purpose of the present systematic review.
      Table 1Characteristics of included studies
      StudyActive/Passive ControlRecruited (n)Analyzed (n)Sex (% Female)Age (y) (Mean)MS Type (% RRMS)EDSS (0-10)Disease Duration (y) (Mean)Individual/GroupSupervised/UnsupervisedFrequency (d/wk) and Duration (wk)IntensityLength of Training Session (min)
      Aerobic training
      Ahmadi et al
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M
      • Zahednejad S
      • Rajabpour M.
      Comparison of the effect of 8 weeks aerobic and yoga training on ambulatory function, fatigue and mood status in MS patients.
      and Arastoo et al
      • Arastoo A
      • Zahednejad S
      • Ahmadi A
      • Nikbakht M.
      The effects of combined treadmill training and pharmacological treatment on management of multiple sclerosis female patients.
      Wait list controlInt: 11

      Con:10
      NR

      NR
      100 10032.2 36.7NR

      NR
      2.0

      2.3
      4.7

      5.0
      NR

      NA
      Supervised

      NA
      3d/wk × 8wk

      NR
      40%-75% of HRmax

      NA

      30

      NA
      Sadeghi Bahmani et al
      • Sadeghi Bahmani D
      • Razazian N
      • Farnia V
      • Alikhani M
      • Tatari F
      • Brand S.
      Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty.
      Active control (attention control)Int: 31 Con:3126

      21
      100

      100
      38.0

      37.9
      NR2.5

      2.0
      6.9

      7.2
      Group GroupSupervised

      Supervised
      3d/wk × 8wk

      3d/wk × 8wk
      NR

      NA
      30-45

      30-45
      Baquet et al
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      Wait list control (usual activity)Int: 34

      Con:34
      34

      34
      62

      74
      38.2

      39.6
      100

      100
      1.7

      1.8
      6.8

      5.7
      Group

      NA
      Supervised

      NA
      2.5d/wk × 12wk

      NA


      RPE of 8

      NR

      27-69

      NA
      Dettmers et al
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      Active control

      (stretching and relaxation)
      Int: 15

      Con:15
      15

      15
      67 7345.8

      39.7
      772.6

      2.8
      10.7

      10.5
      Group

      Group
      Supervised

      Supervised
      3d/wk × 3wk

      3d/wk × 3wk
      NR

      NR
      45

      45
      Feys et al
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      Wait list control

      (usual activity)
      Int: 21

      Con: 21
      18

      17
      95

      86
      36.6

      44.4
      NRNR8.1

      9.2
      Indiv

      N/A
      Unsupervised

      NA
      3d/wk × 12wk

      NA
      NR

      NA
      NR

      NA
      Heine et al
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      Active control (consultation with MS nurse)Int: 43

      Con: 46
      33

      30
      74 7248.8

      48.4
      79

      74
      2.5

      3.0
      7.0

      12.0
      Group NRUnsupervised

      NR
      3d/wk × 16wk

      NR
      3min 40%, 1 min 60% and 1 min at 80% of PPO

      NA
      30

      NR
      Hebert et al
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      Wait list control

      (usual activity)
      Int: 13

      Con: 13
      13

      12
      85

      85
      42.6

      50.2
      85

      92
      NR

      NR
      5.1

      9.1
      NR NASupervised

      NA
      2d/wk × 6wk

      NA
      65%-75% of HRmax

      NA
      60

      NA
      Mokhtarzade et al
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      Passive controlInt: 25

      Con: 20
      22

      18
      100

      100
      32.0

      31.3
      100

      100
      1.84

      1.57
      2.69

      3.47
      NR

      NA
      NR

      NA
      3d/wk × 8wk

      NA
      60%-75% of Wmax

      NA
      42-66

      NA
      Langeskov-Christensen et al
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      Wait list control (habitual activity)Int: 43

      Con:43
      43

      43
      60

      60
      44.0

      45.6
      95

      79
      2.7

      2.8
      10.9

      8.6
      Group

      NA
      Supervised

      NA
      2d/wk × 24wk

      NA
      65%-95% of HRmax

      NA
      30-60

      NA
      Mostert and Kesselring
      • Mostert S
      • Kesselring J.
      Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.
      Active control

      (usual activity)
      Int: 18

      Con:18
      13

      13
      77

      85
      45.2

      43.9
      30.8

      38.5
      4.6

      4.5
      11.2

      11.6
      NR NASupervised

      NA
      5d/wk × 4wk

      NA
      NR

      NA
      30

      NA
      Oken et al
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      Wait list control

      (usual activity)
      Int: 21

      Con: 22
      15

      20
      87

      100
      48.8

      48.4
      NR2.9

      3.1
      NRIndiv

      NA
      Supervised

      NA
      1d/wk × 26wk

      NA
      NR

      NA
      NR

      NA
      Petajan et al
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      Wait list control (usual activity)Int: 21

      Con: 25
      21

      25
      71

      64
      41.1

      39.0
      NR3.8

      2.9
      9.3

      6.2
      NR N/ASupervised

      NA
      3d/wk × 15wk

      NA
      60% of V̇o2max

      NA
      50

      NA
      Schulz et al
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      Wait list control (usual activity)Int::15

      Con:13
      15

      13
      73

      62
      39.0

      42.0
      NR

      NR
      2.0

      2.5
      NR

      NR
      NR

      NR
      NR

      NR
      2d/wk × 8wk

      NA


      75% of Wmax

      NR

      30

      NA
      Tollár et al
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      Wait list control (usual activity)Int: 14

      Con:12
      14

      12
      93

      92
      48.1

      44.4
      50

      66
      5-6

      5-6
      13.2

      14.0
      Group NASupervised

      Supervised
      5d/wk × 5wk

      NA
      80% of age-predicted HRmax

      NA
      60

      NA
      Progressive resistance

      training
      Callesen et al
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      Passive control (usual activity)Int: 23

      Con: 20
      17

      18
      70 8052.0

      56.0
      70

      65
      4.0

      3.5
      15.0

      11.0
      Group NASupervised

      NA
      2d/wk × 10wk

      NA
      10 sets at 15 RM – 8 sets at 8 RM

      NA


      NR

      NA

      Dalgas et al
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • Petersen T
      • Overgaard K
      • Ingemann-Hansen T.
      Muscle fiber size increases following resistance training in multiple sclerosis.
      Passive control (wait list usual activity)Int: 19

      Con: 19
      15

      16
      66

      62
      47.7

      50.4
      1003.7

      3.9

      6.6

      8.1
      Group

      NA
      Supervised

      NA
      2d/wk × 12wk

      NA
      3-4 sets of 8-12 repetitions at 8-15 RM

      NA
      NR

      NA
      DeBolt and McCubbin
      • DeBolt LS
      • McCubbin JA.
      The effects of home-based resistance exercise on balance, power, and mobility in adults with multiple sclerosis.
      Passive control (usual activity)Int: 19

      Con: 18
      19

      17
      79

      78
      51.6

      47.8
      47

      44
      4.0

      3.5
      15.1

      13.0
      Indiv

      NA
      Unsupervised

      NA
      3d/wk × 8wk

      NA
      2-3 sets of 8-12 repetitions wearing a weighted vest (0.5% of BW) increasing by 0.5%-1.5% of BW every 2 wk35-50

      NA
      Dodd et al
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      Passive control (usual activity+social program)Int: 39

      Con: 37
      36

      35
      72

      74
      47.7

      50.4
      100NRNRGroup

      Group
      Supervised

      Supervised
      2d/wk × 10wk

      1d/wk × 10wk
      2 sets of 10-12 repetitions at 10-12 RM

      NA
      45

      60
      Harvey et al
      • Harvey L
      • Smith A
      • Jones R.
      The effect of weighted leg raises on quadriceps strength, EMG parameters and functional activities in people with multiple sclerosis.
      Passive control (usual activity)Int: 7

      Con: 5
      6

      5
      83

      80
      38.0

      43.0
      100NR5

      10
      Indiv

      NA
      Unsupervised

      NA
      2d/ wk × 8wk

      N/A
      5 sets of 10 leg extensions using 0.5- or 1-kg ankle weights

      NA
      NR

      NA
      Hosseini et al
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.


      Passive control

      (usual activity)
      Int: 9

      Con: 8
      8

      8
      55

      50
      32.9

      33.0
      NRNRNRIndiv

      N/A
      Unsupervised

      NA
      3d/wk × 8wk

      N/A
      1% of BW fastened to body increasing by 0.5%-1% every 2 wk

      NA
      35-50

      NA
      Kjølhede et al
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      and Jørgensen et al
      • Jørgensen MLK
      • Kjølhede T
      • Dalgas U
      • Hvid LG.
      Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-a randomized controlled trial.
      Passive control (wait list usual activity)Int: 18

      Con: 17
      17

      15
      NR43.210035NR NASupervised

      NA
      2d/wk × 24wk

      NA
      3-5 sets of 6-10 repetitions at 6-15 RM

      NA
      NR

      NA
      Moradi et al
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      Passive control (usual activity)Int: 10

      Con: 10
      8

      10
      0

      0
      34.4

      33.1
      62

      60
      3.0

      3.0
      8.1

      6.5
      NR

      NA
      Supervised

      NA
      3d/wk × 8wk

      NA
      1 set of 6-15 repetitions at 50-80% of 1 RM

      NA
      30

      NA
      Abbreviations: BW, body weight; Con, control; HRmax, heart rate maximum; Indiv, individual; Int, intervention; NA, not applicable; NR, not reported; PPO, peak power output achieved during incremental exercise test to exhaustion; RPE, rating of perceived exertion; RM, repetition maximum; RRMS, relapsing-remitting multiple sclerosis; V̇o2max, maximum oxygen consumption; Wmax, Watts maximum.
      The median Tool for Assessment of Study Quality for Reporting on Exercise score of the included studies was 9 of 15. Detailed information on the scores can be found in table 2.
      Table 2TESTEX scores
      StudyEligibility CriteriaRandomizationAllocation ConcealedBaseline DataBlinded Assessor Primary OMOM in >85% PatientsAE ReportedExercise AttendanceIntention-to-TreatBetween Group Stats Primary OMBetween Group Stats Secondary OMOutcomes Point EstimatesControl Physical ActivityExercise Load TitratedExercise Volume Can be CalculatedTotal
      Ahmadi et al
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      1011010000110118
      Ahmadi et al
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M
      • Zahednejad S
      • Rajabpour M.
      Comparison of the effect of 8 weeks aerobic and yoga training on ambulatory function, fatigue and mood status in MS patients.
      1011010000110006
      Arastoo et al
      • Arastoo A
      • Zahednejad S
      • Ahmadi A
      • Nikbakht M.
      The effects of combined treadmill training and pharmacological treatment on management of multiple sclerosis female patients.
      1011010000110118
      Sadeghi Bahmani et al
      • Sadeghi Bahmani D
      • Razazian N
      • Farnia V
      • Alikhani M
      • Tatari F
      • Brand S.
      Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty.
      1111000000110006
      Baquet et al
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      11111101111101113
      Callesen et al
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      10111011111101112
      Dalgas et al
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      11111001011101111
      Dalgas et al
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • Petersen T
      • Overgaard K
      • Ingemann-Hansen T.
      Muscle fiber size increases following resistance training in multiple sclerosis.
      1011000101110119
      Dalgas et al
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      10111001011101110
      DeBolt and McCubbin
      • DeBolt LS
      • McCubbin JA.
      The effects of home-based resistance exercise on balance, power, and mobility in adults with multiple sclerosis.
      1001010101110119
      Dettmers et al
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      1101010001100006
      Dodd et al
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      11111111111101013
      Feys et al
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      1001001111110019
      Harvey et al
      • Harvey L
      • Smith A
      • Jones R.
      The effect of weighted leg raises on quadriceps strength, EMG parameters and functional activities in people with multiple sclerosis.
      1101010101100007
      Hebert et al
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      10111011111100111
      Heine et al
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      11001001111111111
      Hosseini et al
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      1101010000010005
      Jørgensen et al
      • Jørgensen MLK
      • Kjølhede T
      • Dalgas U
      • Hvid LG.
      Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-a randomized controlled trial.
      1011010000100117
      Kjølhede et al
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      11100101111101111
      Langeskov-Christensen et al
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      11111011111101113
      Mokhtarzade et al
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      1011010000010117
      Moradi et al
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      11011110011101111
      Mostert and Kesselring
      • Mostert S
      • Kesselring J.
      Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.
      1011000100000004
      Oken et al
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      1011101101010008
      Petajan et al
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      1001110100010118
      Schulz et al
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      1011000001110017
      Tollár et al
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      11111111011100011
      Abbreviations: AE, adverse event; OM, outcome measure; TESTEX, Tool for Assessment of Study Quality for Reporting on Exercise.

      Physiological adaptations

      Seven of the 14 AT studies
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      ,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      reported a between-group change in aerobic capacity, with 4 of these
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      ,
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      ,
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      reporting a statistically significant improvement (table 3). The meta-analysis showed an overall large effect on aerobic capacity (ES=0.88 [95% CI, 0.25-1.50], P=.001, I2=78%) (fig 2). Aerobic capacity ES was not positively associated with AT intervention duration (weeks: slope=−0.03, r2=0.06, P=.563; number of sessions: slope=0.00, r2=0.00, P=.97.
      Table 3Effect sizes of all outcomes
      StudyStrength/V̇o2peakShort WalkLong WalkOther WalkingFunctional Mobility (Other)Perceived Fatigue
      (Positive ES = Improvement)(Positive ES = Improvement)(Positive ES = Improvement)(Negative ES = Improvement)(Negative ES = Improvement)(Negative ES = Improvement)
      Strengtho2peakT25FWT10MWT50MW2minW6minWDistanceMSWS-12TUGSSST5-STSStair climbFSSMFISCIS20rFSMC
      Aerobic training
      Ahmadi et al
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      1.29
      Article has reported a statistically significant between-group change.
      1.40
      Article has reported a statistically significant between-group change.
      −2.73
      Article has reported a statistically significant between-group change.
      Dettmers et al
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      0.47
      Article has reported a statistically significant between-group change.
      Sadeghi Bahmani et al
      • Sadeghi Bahmani D
      • Razazian N
      • Farnia V
      • Alikhani M
      • Tatari F
      • Brand S.
      Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty.
      −0.37
      Baquet et al
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      0.320.00−0.140.09
      Feys et al
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      1.06
      Article has reported a statistically significant between-group change.
      0.000.33−0.29
      Article has reported a statistically significant between-group change.
      −0.38
      Article has reported a statistically significant between-group change.
      0.0
      Heine et al
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      0.30−0.29−0.29-0.52
      Article has reported a statistically significant between-group change.
      Hebert et al
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      0.10−0.45
      Article has reported a statistically significant between-group change.
      Langeskov-Christensen et al
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      0.49
      Article has reported a statistically significant between-group change.
      0.36
      Mokhtarzade et al
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      1.40
      Article has reported a statistically significant between-group change.
      −0.71
      Article has reported a statistically significant between-group change.
      Mostert and Kesselring
      • Mostert S
      • Kesselring J.
      Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.
      −0.31
      Oken et al
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      −0.94
      Petajan et al
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      2.18
      Article has reported a statistically significant between-group change.
      Schulz et al
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      0.69−0.63
      Tollár et al
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      0.73
      Article has reported a statistically significant between-group change.
      Resistance training
      Callesen et al
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      0.73
      Article has reported a statistically significant between-group change.
      0.201.070.47−0.18−0.60
      Article has reported a statistically significant between-group change.
      Dalgas et al
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • Petersen T
      • Overgaard K
      • Ingemann-Hansen T.
      Muscle fiber size increases following resistance training in multiple sclerosis.
      0.42
      Article has reported a statistically significant between-group change.
      0.34−0.06−0.83−0.52−0.26
      Article has reported a statistically significant between-group change.
      DeBolt and McCubbin
      • DeBolt LS
      • McCubbin JA.
      The effects of home-based resistance exercise on balance, power, and mobility in adults with multiple sclerosis.
      −0.35
      Dodd et al
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      0.35
      Article has reported a statistically significant between-group change.
      0.27−0.37
      Article has reported a statistically significant between-group change.
      Hosseini et al
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      0.290.49
      Harvey et al
      • Harvey L
      • Smith A
      • Jones R.
      The effect of weighted leg raises on quadriceps strength, EMG parameters and functional activities in people with multiple sclerosis.
      ,
      ES was noncomputable because no SD was reported.
      0.07n.c.n.c.
      Kjølhede et al
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      and Jørgensen et al
      • Jørgensen MLK
      • Kjølhede T
      • Dalgas U
      • Hvid LG.
      Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-a randomized controlled trial.
      2.03
      Article has reported a statistically significant between-group change.
      0.08
      Article has reported a statistically significant between-group change.
      0.27
      Article has reported a statistically significant between-group change.
      −0.35
      Article has reported a statistically significant between-group change.
      −2.27
      Article has reported a statistically significant between-group change.
      −1.84
      Article has reported a statistically significant between-group change.
      Moradi et al
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      2.59
      Article has reported a statistically significant between-group change.
      0.42−0.87
      Article has reported a statistically significant between-group change.
      Abbreviations: CIS20r, Checklist Individual Strength; 5-STS, 5 times sit-to-stand; FSMC, Fatigue Scale for Motor and Cognitive Functions; FSS, Fatigue Severity Scale; MFIS, Modified Fatigue Impact Scale; n.c., non computable; 6minW, 6-minute walk; SSST, 6-spot step test; T50MW, timed 50-m walk; T10MW, timed 10-m walk; T25FW, timed 25-ft walk; 2minW, 2-minute walk; TUG, timed Up and Go; V̇o2peak, peak oxygen consumption.
      low asterisk Article has reported a statistically significant between-group change.
      ES was noncomputable because no SD was reported.
      Fig 2
      Fig 2Meta-analysis of the effect of aerobic training and resistance training on physiological adaptations. SMD, standardized mean difference; V̇o2max, maximum oxygen consumption. aStrength measured in knee extensor. bStrength measured in knee extensor and flexor (average). cStrength measured in leg press.
      Regarding RT studies, 7 of 9 studies
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      • Harvey L
      • Smith A
      • Jones R.
      The effect of weighted leg raises on quadriceps strength, EMG parameters and functional activities in people with multiple sclerosis.
      reported a between-group change in 1 or more strength measurements, with 5 of these changes being reported as statistically significant. The meta-analysis showed an overall large effect of RT on muscle strength (ES=0.86 [95% CI, 0.02-1.70], P=.013, I2=75%) (see fig 2). Strength ES appeared to be positively associated with RT intervention duration (weeks: slope=0.08, r2=0.25, P=.104; number of sessions: slope=0.06, r2=0.44, P=.019).

      Performance on short walking tests

      Three of the 14 AT studies
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      reported a between-group change in short walking tests, with 1 of these changes
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      reported as statistically significant (see table 3). An overall moderate effect was observed in the meta-analysis (ES=0.33 [95% CI, −1.49 to 2.06], P=.20, I2=69%) (fig 3). Short walk ES was not positively associated with AT intervention duration (weeks: slope=−0.32, r2=1.00, P=.011; number of sessions: slope=−0.10, r2=0.68, P=.15).
      Fig 3
      Fig 3Meta-analysis of the effect of aerobic training and resistance training on the performance of a short walking test. SMD, standardized mean difference.
      Six RT studies
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      • Harvey L
      • Smith A
      • Jones R.
      The effect of weighted leg raises on quadriceps strength, EMG parameters and functional activities in people with multiple sclerosis.
      reported a between-group change in any short walking test, with 1 of these reporting a significant change (see table 3). The meta-analysis showed a moderate effect of RT on short walking performance (ES=0.27 [95% CI, 0.07-0.47], P=.006, I2=0%) (see fig 3). Short walk ES was not positively associated with RT intervention duration (weeks: slope=−0.02, r2=0.64, P=.51; number of sessions: slope=−0.01, r2=0.42, P=.59).

      Performance on long walking tests

      Of the long walking tests, the 6-minute walk test (6MWT) was the most used in AT studies. Five
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      ,
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      of the 7 studies
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      ,
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      investigating performance on a long walking test used this test. The meta-analysis showed an overall moderate effect of AT on the performance during long walking tests (ES=0.37 [95% CI, −0.04 to 0.78], P=.026, I2=43%) (fig 4). Long walk ES was not positively associated with AT intervention duration (weeks: slope=0.01, r2=0.03, P=.70; number of sessions: slope=0.01, r2=0.14, P=.36).
      Fig 4
      Fig 4Meta-analysis of the effect of aerobic training and resistance training on the performance of a long walking test. SMD, standardized mean difference. a6MWT. b2-minute walk test. cMaximum walking distance.
      Four RT studies
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      reported a between-group change in any long-term walking test, with 1 of these reporting a statistically significant finding and the meta-analysis showing a moderate effect of RT on long walking test performance (ES=0.36 [95% CI, −0.35 to 1.08], P=.11, I2=48%) (see fig 4). Long walk ES was positively associated with RT intervention duration (weeks: slope=0.07, r2=0.87, P=.025; number of sessions: slope=0.07, r2=0.87, P=.025).

      Performance on functional mobility tests

      Only 1 of the AT studies
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      investigated effects on the performance of a functional mobility test and reported a statistically significant change between groups.
      Five
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      ,
      • DeBolt LS
      • McCubbin JA.
      The effects of home-based resistance exercise on balance, power, and mobility in adults with multiple sclerosis.
      of the RT studies investigated the performance on a functional mobility test between groups, with 2 of these changes
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      being reported as statistically significant.
      Because the aim of this present review was to evaluate differences between modalities, we were not able to conduct a meta-analysis on this outcome.

      Self-reported walking performance

      Two of the AT studies
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      reported a between group change in self-reported walking performance (both 12-item Multiple Sclerosis Walking Scale [MSWS-12]), with 1 of these
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      reported as statistically significant. The meta-analysis of AT on self-reported walking performance showed a negligible effect (ES=−0.04 [95% CI, −2.34 to 2.2], P=.82, I2=0%) (fig 5).
      Fig 5
      Fig 5Meta-analysis of the effect of aerobic training and resistance training on self-reported walking ability. SMD, standardized mean difference.
      Of the RT studies, 2 studies
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      reported a between-group change in self-reported walking performance (both MSWS-12), with 1 of these
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      reported as statistically significant. The meta-analysis of RT on self-reported walking performance showed a negligible effect (ES=0.07 [95% CI, −5.20 to 5.33], P=.88, I2=66%) (see fig 5).

      Perceptions of fatigue

      Nine of the 14 AT studies
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      ,
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      ,
      • Sadeghi Bahmani D
      • Razazian N
      • Farnia V
      • Alikhani M
      • Tatari F
      • Brand S.
      Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty.
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      • Mostert S
      • Kesselring J.
      Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      reported a between-group change in any measure of perceived fatigue, with 4 being reported
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      as statistically significant. The meta-analysis showed a large effect of AT on perceptions of fatigue (ES=−0.61 [95% CI, −1.10 to −0.11], P=.005, I2=58%) (fig 6). Improvements in perceived fatigue ES was not positively associated with AT intervention duration (weeks: slope=−0.05, r2=0.00, P=0.85; number of sessions: slope=0.03, r2=0.31, P=.052).
      Fig 6
      Fig 6Meta-analysis of the effect of aerobic training and resistance training on the perceptions of fatigue. SMD, standardized mean difference. aES as an average of the Fatigue Severity Scale, Modified Fatigue Impact Scale, and CIS20r: Checklist Individual Strength.
      Of the RT studies, 3 studies
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      reported a between-group change in any measurement of perceived fatigue, with all of these changes being reported as statistically significant. The meta-analysis of RT on perceived fatigue showed a moderate effect (ES=−0.41 [95% CI, −0.80 to −0.02], P<.001, I2=0%) (see fig 6). Improvement in perceived fatigue ES was not positively associated with RT intervention duration (weeks: slope=0.10, r2=0.38, P=.63; number of sessions: slope=0.05, r2=0.38, P=.63).

      Comparison between modalities

      Although both interventions were shown to elicit adaptations in favor of exercise, we were not able to detect differences in any outcomes between the 2 different exercise modalities as evidenced by the comparable ESs and overlapping CIs.

      Discussion

      Based on our findings, AT and RT present themselves as broadly equivalent modalities in terms of improving lower extremity physical function (walking performance) and reducing perceived fatigue, with meta-analyses revealing moderate-large ESs. Of note, only 14 of 23 studies reported physiological adaptations, thereby limiting the in-depth understanding of the potential mechanistic effect(s) leading to an improvement in physical function (ie, the translational potential).

      Physiological adaptations

      Although only 7 of 14 AT studies
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      ,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      reported a between-group change in aerobic capacity, the observed large ES (ES=0.88 [95% CI, 0.25-1.50]) of AT on aerobic capacity corroborates findings of a previous review
      • Langeskov-Christensen M
      • Heine M
      • Kwakkel G
      • Dalgas U.
      Aerobic capacity in persons with multiple sclerosis: a systematic review and meta-analysis.
      (ES=0.63 [95% CI, 0.00-1.26]) using broader inclusion criteria (eg, by including small pilot studies). Altogether, these provide clear evidence underlining AT as a highly effective intervention targeting the cardiovascular system in PwMS.
      The observed large ES of RT studies on lower extremity muscle strength (ES=0.86 [95% CI, 0.02-1.70]) corroborate findings by Jørgensen et al,
      • Jørgensen M
      • Dalgas U
      • Wens I
      • Hvid LG.
      Muscle strength and power in persons with multiple sclerosis - a systematic review and meta-analysis.
      who in a systematic review and meta-analysis including isokinetic dynamometry–determined muscle strength, reported an ES of 0.45 (95% CI, 0.18-0.72) after RT.
      Overall, the physiological adaptations observed by the present systematic review verify that AT and RT interventions overall work as intended, thereby establishing the potential for a translation into improvements in mobility aspects of lower extremity physical function along with reduction in perceived fatigue.

      Physical function: walking tests

      The identified AT studies predominantly focused on the longer walk tests, with only 3 studies
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      investigating the effect on the short walk tests. Despite the moderate ES on the short walk test (ES=0.33 [95% CI, −1.49 to 2.06]; data presented as walking speed) observed in the present systematic review, CIs indicate a high degree of uncertainty. This corroborates the findings of Pearson et al,
      • Pearson M
      • Dieberg G
      • Smart N.
      Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis.
      who reported ES=−1.96 (95% CI, −2.67 to −1.25) (data presented as walking time). Of note, both findings are based on very few studies (3 in the present systematic review and 2 in the study by Pearson et al) and should therefore be interpreted cautiously. Participants in 2 of the 3 identified studies in the present review were relatively high functioning at baseline, based on their short walk test performance and low EDSS,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      potentially leaving little room for improvement (because of a ceiling effect). More studies are needed to establish a robust insight into the effects of AT on short walk tests, ideally by involving PwMS who are ambulatory across a wider range of disability levels, especially in severely disabled PwMS having substantial walking limitations.
      Of the 7 studies
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      ,
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      • Langeskov-Christensen M
      • Grøndahl Hvid L
      • Nygaard MKE
      • et al.
      Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      investigating the effect of AT on the long walk tests, 3 of these
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Tollár J
      • Nagy F
      • Tóth BE
      • et al.
      Exercise effects on multiple sclerosis quality of life and clinical-motor symptoms.
      had a large ES. Yet, the meta-analysis showed an overall moderate ES of AT on this outcome (ES=0.37 [95% CI, −0.04 to 0.78]), which appeared quite certain based on CIs. As for the 2 aforementioned studies involving relatively high functioning participants at baseline,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      their long walk test performance was also quite high (6MWT>575m), again potentially leaving little room for improvement. After 12 weeks of AT, an ES of −0.14 (95% CI, −0.62 to 0.34) was observed on the 6MWT in the study by Baquet et al,
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      whereas an ES of 0.33 (−0.34; 1.01) was observed in the study of Feys et al.
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      Interestingly, participants in the study by Feys
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      performed specific walking/running exercises that may have been more beneficial for performance on the long walk test (moderate ES=0.33) than the short walk test (negligible ES=0.00). Another study whose intervention involved specific walking exercises was Dettmers et al,
      • Dettmers C
      • Sulzmann M
      • Ruchay-Plössl A
      • Gütler R
      • Vieten M.
      Endurance exercise improves walking distance in MS patients with fatigue.
      who on maximal walking distance observed a moderate ES of 0.47 (95% CI, −0.25 to 1.22).
      Of the 5 studies
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      investigating the effect of RT on short walk test performance, 3 studies
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Moradi M
      • Sahraian MA
      • Aghsaie A
      • et al.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      ,
      • Hosseini SS
      • Rajabi H
      • Sahraian MA
      • Moradi M
      • Mehri K
      • Abolhasani M.
      Effects of 8-week home-based yoga and resistance training on muscle strength, functional capacity and balance in patients with multiple sclerosis: a randomized controlled study.
      detected a moderate ES corresponding to the ES of the meta-analysis (ES=0.27 [95% CI, 0.07-0.47]).
      Previously, the effect of RT on the performance on a short walk test has been summarized in a review
      • Kjølhede T
      • Vissing K
      • Dalgas U.
      Multiple sclerosis and progressive resistance training: a systematic review.
      and in a meta-analysis based on only 1 study.
      • Pearson M
      • Dieberg G
      • Smart N.
      Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis.
      However, to our knowledge, this is the first systematic review to perform a meta-analysis on RT studies alone, examining the effects on short walk tests (and walking performance in general).
      On the long walk test, 4 RT studies
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ,
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      were included in the meta-analysis that showed a moderate ES (ES=0.36 [95% CI, −0.35-1.08]), with CIs displaying some degree of uncertainty. These variable results are in line with previous reports.
      • Kjølhede T
      • Vissing K
      • Dalgas U.
      Multiple sclerosis and progressive resistance training: a systematic review.
      Of note, Kjølhede et al
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      was the only study showing a large beneficial effect of RT on long walk test performance, ES=1.07 (95% CI, 0.34-1.86). Potentially, this is because of the length of the intervention (24 weeks) compared with the shorter interventions in the other studies (10 weeks
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      and 12 weeks
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      ). This was supported by our weighted (moderator) regression analysis, showing a positive association between intervention duration (weeks and number of sessions) and ES.
      Only a few studies investigated the effect of AT
      • Baquet L
      • Hasselmann H
      • Patra S
      • et al.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.
      ,
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      or RT
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      on self-reported walking performance. Based on the 2 identified studies in each modality, meta-analyses showed a negligible effect on MSWS-12 (AT, ES=−0.04 and RT, ES=0.07), despite both modalities being effective on all objective walking outcomes. Because these results are sparse and somewhat inconclusive, they should be interpreted cautiously. Speculatively, they may indicate that adaptations in objectively measured outcomes precede self-reported outcomes, which is somehow contradictory to what has been shown previously,
      • Langeskov-Christensen D
      • Feys P
      • Baert I
      • Riemenschneider M
      • Stenager E
      • Dalgas U.
      Performed and perceived walking ability in relation to the Expanded Disability Status Scale in persons with multiple sclerosis.
      and/or that adaptations in self-reported outcomes are limited because of a potential ceiling effect.

      Physical function: functional measurements

      Although walking performance is an essential aspect of lower extremity physical function, our sparse and inconclusive findings reveal an existing knowledge gap in terms of how the 2 exercise modalities (AT in particular) might affect other measures such as chair rise, 6-spot step test, and stair negotiation. This is problematic because complex walking tests, such as the 6-spot step test,
      • Nieuwenhuis MM
      • Van Tongeren H
      • Sørensen PS
      • Ravnborg M.
      The six spot step test: a new measurement for walking ability in multiple sclerosis.
      along with highly physically demanding walking tests, such as stair negotiation,
      • Sieljacks PS
      • Søberg CA
      • Michelsen AS
      • Dalgas U
      • Hvid LG.
      Lower extremity muscle strength across the adult lifespan in multiple sclerosis: implications for walking and stair climbing capacity.
      have the potential to give a more in-depth picture of patients walking ability. Such tests incorporate not only acceleration and endurance but also other components such as coordination and balance, which are recognized as being important for general physical function. Hence, future AT as well as RT studies should incorporate such complex functional tests in their test battery.

      Fatigue measurements

      Nine studies
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      • Hebert JR
      • Corboy JR
      • Manago MM
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      ,
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      ,
      • Sadeghi Bahmani D
      • Razazian N
      • Farnia V
      • Alikhani M
      • Tatari F
      • Brand S.
      Compared to an active control condition, in persons with multiple sclerosis two different types of exercise training improved sleep and depression, but not fatigue, paresthesia, and intolerance of uncertainty.
      • Feys P
      • Moumdjian L
      • Van Halewyck F
      • et al.
      Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.
      • Mostert S
      • Kesselring J.
      Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      investigated the effect of AT on perceived fatigue. In the majority of these a moderate-large ES
      • Heine M
      • Verschuren O
      • Hoogervorst EL
      • et al.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ,
      • Ahmadi A
      • Arastoo AA
      • Nikbakht M.
      The effects of a treadmill training programme on balance, speed and endurance walking, fatigue and quality of life in people with multiple scler1osis: original research.
      ,
      • Mokhtarzade M
      • Ranjbar R
      • Majdinasab N
      • Patel D
      • Molanouri Shamsi M
      Effect of aerobic interval training on serum IL-10, TNFα, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life.
      ,
      • Schulz KH
      • Gold SM
      • Witte J
      • et al.
      Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
      ,
      • Oken BS
      • Kishiyama S
      • Zajdel D
      • et al.
      Randomized controlled trial of yoga and exercise in multiple sclerosis.
      was observed, with an overall large ES as determined by our meta-analysis (ES=−0.61 [95% CI, −1.10 to −0.11]). This adds further weight to findings of previous systematic reviews (including a Cochrane review) in this area,
      • Heine M
      • van de Port I
      • Rietberg MB
      • van Wegen EE
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      ,
      • Moss-Morris R
      • Harrison AM
      • Safari R
      • et al.
      Which behavioural and exercise interventions targeting fatigue show the most promise in multiple sclerosis? A systematic review with narrative synthesis and meta-analysis.
      with the combined evidence indicating that AT is effective in reducing perceived fatigue.
      In this present systematic review and meta-analysis, only 3 studies
      • Dodd KJ
      • Taylor NF
      • Shields N
      • Prasad D
      • McDonald E
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ,
      • Callesen J
      • Cattaneo D
      • Brincks J
      • Kjeldgaard Jørgensen ML
      • Dalgas U
      How do resistance training and balance and motor control training affect gait performance and fatigue impact in people with multiple sclerosis? A randomized controlled multi-center study.
      ,
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      investigated the effect of RT on perceived fatigue. Hence, although remaining cautious in our interpretation, data indicate a moderate and beneficial effect of RT on perceptions of fatigue (ES=−0.41 [95% CI, −0.80 to −0.02]). This provides further evidence for already existing guidelines.
      • Latimer-Cheung AE
      • Pilutti LA
      • Hicks AL
      • et al.
      Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development.

      Comparison between modalities

      We did not detect any apparent differences in the magnitude of effect on physiological adaptations in the 2 exercise modalities. Many components such as duration, frequency, and intensity should be taken into account when comparing the 2 modalities. The average frequency and duration was somewhat comparable between the 2 exercise modalities (AT: 3 d/wk × 11wk [range, 3-26wk], 28 sessions [range, 9-48 sessions]; RT: 2 d/wk × 11wk [range, 8-24wk], 25 sessions [range, 15-48 sessions]), along with the intensity being moderate to high in both AT and RT. A plausible explanation for the lack of association between intervention duration (weeks and number of sessions) and meta-analysis ES is that the majority of interventions had durations of 8-12 weeks involving 16-24 sessions. The only exceptions showing positive associations were for RT on muscle strength and long walk test, respectively, although likely driven by 1 study only
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      having a much longer intervention duration (24wk, 48 sessions) than the remaining RT studies. Unfortunately the quantity and quality of the reported exercise intensity data (missing information, use of divergent scales of exercise intensity) did not allow us to examine the associations between exercise intensity and meta-analysis ES within each modality. Because factors such as duration, frequency, and intensity are crucial for the extent of adaptations,
      • Nebiker L
      • Lichtenstein E
      • Minghetti A
      • et al.
      Moderating effects of exercise duration and intensity in neuromuscular vs. endurance exercise interventions for the treatment of depression: a meta-analytical review.
      further studies seem warranted to help advance our understanding of any potential dose-response association between general exercise parameters (eg, duration, frequency, intensity) and physiological as well as functional adaptations in PwMS.
      To our knowledge, only 1 pilot study
      • Sabapathy NM
      • Minahan CL
      • Turner GT
      • Broadley SA.
      Comparing endurance- and resistance-exercise training in people with multiple sclerosis: a randomized pilot study.
      has previously performed a head-to-head comparison of the 2 modalities, finding no difference in either lower extremity physical function as measured by the 6MWT and the timed Up and Go or in perceived fatigue measured by the Modified Fatigue Index Scale. However, only 19 participants finished this crossover study having an 8-week washout period. Adaptations from exercise interventions may last as long as 12 weeks
      • Collett J
      • Dawes H
      • Meaney A
      • et al.
      Exercise for multiple sclerosis: a single-blind randomized trial comparing three exercise intensities.
      or 24 weeks
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ; hence, one must be cautious when interpreting results from this pilot study.
      • Sabapathy NM
      • Minahan CL
      • Turner GT
      • Broadley SA.
      Comparing endurance- and resistance-exercise training in people with multiple sclerosis: a randomized pilot study.
      With resemblance to the observations in physiological adaptions, no difference was observed in the magnitude of change on short or long walking tests with AT or RT. All meta-analyses on the walking tests had comparable moderate ES, although data, based on CIs, appeared most robust for short walk with RT and for long walk with AT, respectively. Although this is likely influenced by the number of studies for each meta-analysis, it may also be because of physiological adaptations that are intuitively associated with certain aspects of walking (AT: increment in aerobic capacity associated with walking endurance; RT: increment in muscle strength associated with walking acceleration).
      • Gijbels D
      • Dalgas U
      • Romberg A
      • et al.
      Which walking capacity tests to use in multiple sclerosis? A multicentre study providing the basis for a core set.
      Although the present findings are aligned with previously reported findings in systematic reviews and meta-analyses,
      • Snook EM
      • Motl RW.
      Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis.
      ,
      • Pearson M
      • Dieberg G
      • Smart N.
      Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis.
      these were based on a limited number of RCT studies (because the search was performed March 2014)
      • Pearson M
      • Dieberg G
      • Smart N.
      Exercise as a therapy for improvement of walking ability in adults with multiple sclerosis: a meta-analysis.
      or a combination of RCT and non-RCT studies, different exercise modalities, and different measures of walking performance (self-reported as well as clinician-rated short and long walking performance).
      • Snook EM
      • Motl RW.
      Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis.
      The novel approach of the present systematic review, apart from updating existing evidence, was to include RCTs only, clearly separate study findings across the 2 most common exercise modalities, and uphold a clear distinction between the selected walking performance outcome measures.
      Both modalities were found to be effective in terms of reducing perceived fatigue, with a large ES observed for AT and a moderate ES for RT. Although Andreasen et al
      • Andreasen AK
      • Stenager E
      • Dalgas U.
      The effect of exercise therapy on fatigue in multiple sclerosis.
      in their systematic review previously reported RT to be slightly more effective than AT in terms of reducing perceived fatigue, Heine et al
      • Heine M
      • van de Port I
      • Rietberg MB
      • van Wegen EE
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      in their Cochrane systematic review and meta-analysis reported the opposite (applying a broader definition of exercise modalities). In context of the 2 exercise modalities and their effect on perceived fatigue, Rooney et al
      • Rooney S
      • Wood L
      • Moffat F
      • Paul L.
      Is fatigue associated with aerobic capacity and muscle strength in people with multiple sclerosis: a systematic review and meta-analysis.
      performed a systematic review and meta-analysis and found a strong association between aerobic capacity and perceived fatigue (r=−0.47 [95% CI, −0.64 to −0.25]) but only a moderate association between muscle strength and perceived fatigue (r=−0.22 [95% CI, −0.40 to −0.03]).

      Translational or parallel improvements?

      Assessment of physiological adaptations are important because of 2 aspects. First, it is a simple way of validating exercise efficacy because effects on these basic primary (sensitive) physiological targets are expected (ie, AT expectedly improves aerobic capacity, whereas RT expectedly improves muscle strength). Second, physiological adaptations may be a prerequisite for improvements in physical function, thereby having a translational effect. Interestingly, the findings from the present systematic review and meta-analysis suggest that improvements in lower extremity physical function can be achieved via different physiological pathways (ie, cardiovascular system, neuromuscular system). At least we observed parallel improvements in physiological adaptions and in physical function. However, because only a limited number of studies reported parallel data of both physiological parameters and physical function of the same outcome (see table 3) and because even fewer studies report associations between changes in these outcomes, we were unable to perform any analysis of association. A small number of studies have reported data supporting an exercise-induced translational link, ie, between improvements in muscle strength and Fatigue Severity Scale
      • Dalgas U
      • Stenager E
      • Jakobsen J
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      ; aerobic capacity and Fatigue Severity Scale
      • Petajan JH
      • Gappmaier E
      • White AT
      • Spencer MK
      • Mino L
      • Hicks RW.
      Impact of aerobic training on fitness and quality of life in multiple sclerosis.
      ; and muscle strength and timed 25-foot walk, 2-minute walk test, 5 repetition sit-to-stand, and stair climb.
      • Kjølhede T
      • Vissing K
      • de Place L
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      This is nevertheless challenged by the fact that lower extremity physical function relies on different physiological systems, and adaptations in just 1 system may elicit little translational response. Also, in high functioning PwMS the ceiling effect of many commonly used walking measures may mean that changes in performance are not detectable. Nevertheless, physiological adaptations can still be achieved, building physiological reserve capacity as well as improving general health, thereby potentially postponing the onset of future physical functional limitations. To advance our understanding of any translational link, more studies examining the association between exercise-induced physiological adaptations and measures of physical function are required in PwMS across the entire disability span. This could also help elucidate why some PwMS have a positive effect of an exercise intervention whereas others do not (ie, responders vs nonresponders).

      Clinical and research implications

      The present study findings emphasize the importance of providing structured intensive AT and/or RT when aiming to improve lower extremity physical function (along with physiological adaptations). Although many different exercise modalities exist, AT and RT have consistently been shown to be among the most effective in terms of positively affecting numerous different domains.
      • Dalgas U
      • Langeskov-Christensen M
      • Stenager E
      • Riemenschneider M
      • Hvid LG.
      Exercise as medicine in multiple sclerosis-time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Because the 2 modalities proved somewhat comparable (based on magnitude of ESs), it implies that clinicians could use either modality to target impairments in lower extremity physical function; we suggest patient preference be central to this decision to optimize the likelihood of them sustaining exercise long-term. The inconsistency in reporting across studies emphasize the need for using a “core battery” of physical function tests, as previously proposed.
      • Paul L
      • Coote S
      • Crosbie J
      • et al.
      Core outcome measures for exercise studies in people with multiple sclerosis: recommendations from a multidisciplinary consensus meeting.
      This would enable comparability of findings across studies and facilitate generation of more robust evidence, which is essential for clinicians’ decision making. Moreover, exercise studies should report data for the physiological outcomes they are targeting. This would advance our understanding of potential translational links between physiology and function. Finally, future studies should compare the modalities directly by performing a head-to-head study to establish whether differences in outcomes exist.

      Study limitations

      The present systematic review and meta-analyses provides a detailed and comprehensive overview of the RCTs investigating the effect of AT and RT on lower extremity physical function and perceived fatigue. However, some methodological considerations deserve mentioning. First, the majority of identified studies included patients with mild-moderate disease severity, making the results applicable for this subgroup of patients only. Second, more studies are needed to elucidate effects of AT and RT in PwMS with higher levels of disability, including those who are nonambulatory (EDSS≥7.0), which is a problem that has been exposed previously.
      • Edwards T
      • Pilutti LA.
      The effect of exercise training in adults with multiple sclerosis with severe mobility disability: a systematic review and future research directions.
      Third, this systematic review provides an overview of existing studies evaluating the 2 modalities and hence is not able to provide a direct comparison. To provide such information, a well-considered head-to-head study of the 2 modalities, designed to diminish the difference in intensity and volume, is needed. Finally, our review focused on either solely AT or RT. As such, we cannot comment on the effectiveness of interventions that combine these 2 exercise modalities or use other exercise modalities (eg, Pilates, yoga, balance).

      Conclusions

      Based on knowledge from existing RCTs, AT and RT appear comparable in improving lower extremity physical function (walking performance in particular) and perceived fatigue. Although substantial physiological adaptations were observed, conclusions about the underlying mechanisms for the improvement are yet to be determined. Future studies should adapt a “core battery” of physical function tests to facilitate a detailed comparison of results across exercise modalities. This will enable evidence-based treatment selection according to the defined purpose of training.

      Suppliers

      • a.
        EndNote; Clarivate Analytics.
      • b.
        Rayyan; Rayyan Systems Inc.
      • c.
        Meta-Essentials for Excel, version 1.5; Erasmus Research Institute of Management

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