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Review article| Volume 68, 104198, December 2022

Participant characteristics of existing exercise studies in persons with multiple sclerosis – A systematic review identifying literature gaps

  • Author Footnotes
    1 Jens Jakob Frandsen and Tobias Gaemelke share first authorship as they have contributed equally to this paper.
    Tobias Gaemelke
    Correspondence
    Corresponding author.
    Footnotes
    1 Jens Jakob Frandsen and Tobias Gaemelke share first authorship as they have contributed equally to this paper.
    Affiliations
    Exercise Biology, Department of Public Health, Aarhus University, Dalgas Avenue 4, Aarhus C 8000, Denmark
    Search for articles by this author
  • Author Footnotes
    1 Jens Jakob Frandsen and Tobias Gaemelke share first authorship as they have contributed equally to this paper.
    Jens Jakob Frandsen
    Footnotes
    1 Jens Jakob Frandsen and Tobias Gaemelke share first authorship as they have contributed equally to this paper.
    Affiliations
    Exercise Biology, Department of Public Health, Aarhus University, Dalgas Avenue 4, Aarhus C 8000, Denmark
    Search for articles by this author
  • Lars G. Hvid
    Affiliations
    Exercise Biology, Department of Public Health, Aarhus University, Dalgas Avenue 4, Aarhus C 8000, Denmark
    Search for articles by this author
  • Ulrik Dalgas
    Affiliations
    Exercise Biology, Department of Public Health, Aarhus University, Dalgas Avenue 4, Aarhus C 8000, Denmark
    Search for articles by this author
  • Author Footnotes
    1 Jens Jakob Frandsen and Tobias Gaemelke share first authorship as they have contributed equally to this paper.
Open AccessPublished:October 03, 2022DOI:https://doi.org/10.1016/j.msard.2022.104198
Participant characteristics of existing exercise studies in persons with multiple sclerosis – A systematic review identifying literature gaps
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      Highlights

      • •
        Few exercise studies are undertaken in young and old people with multiple sclerosis.
      • •
        Exercise is mostly studied in mild to moderate disabled people with multiple sclerosis.
      • •
        The applied exercise modalities are predominantly endurance or combined exercise.

      Abstract

      Background

      Exercise is a cornerstone in rehabilitation of persons with multiple sclerosis (pwMS), which is known to elicit beneficial effects on various symptoms and to have a potential disease-modifying effect. However, it remains to be elucidated if the existing MS exercise literature covers the full age and disability span of pwMS.

      Objective

      To systematically review MS exercise studies and provide a detailed mapping of the demographic and clinical characteristics of the included pwMS.

      Methods

      A systematic review of MS exercise studies were performed using MEDLINE and EMBASE. From the resulting MS exercise studies, mean sample characteristics were extracted.

      Results

      4576 records were identified, from which 202 studies were included. Of these, 166 studies (82.2%) enrolled pwMS aged 35–54 years, 10.9% enrolled pwMS <35 years, and 6.9% enrolled pwMS ≥55 years (only 1.5% enrolled pwMS ≥60 years). A total of 118 studies (58.4%) reported Expanded Disability Status Scale (EDSS), with 88.1% of included pwMS having an EDSS between 2.0 and 6.5, while only one study enrolled pwMS with an EDSS ≥7.0. Finally, 80% of the studies included pwMS having a disease duration of 5-14.5 years.

      Conclusion

      Exercise studies in pwMS included primarily middle-aged (35-54 years) pwMS having an EDSS of 2.0-6.5 and a disease duration of 5–14.5 years. Few exercise studies were identified in young and older pwMS, in pwMS with mild disability and severe disability, and in pwMS having shorter or longer disease durations. These findings highlight the need for further investigation of exercise in these specific subgroups of pwMS as benefits of exercise might not generalize across subpopulations.

      Keywords

      1. Introduction

      Despite major advancements in medical treatment of multiple sclerosis (MS) over the past 25 years, rehabilitation is still a cornerstone in MS treatment (
      • Feys P.
      • Giovannoni G.
      • Dijsselbloem N.
      • Centonze D.
      • Eelen P.
      • Lykke Andersen S.
      The importance of a multi-disciplinary perspective and patient activation programmes in MS management.
      Mult. Scler. J. 2016; 22: 34-46https://doi.org/10.1177/1352458516650741
      ). One of the most auspicious non-pharmacological rehabilitation interventions in MS is exercise (
      • Dalgas U.
      • Langeskov-Christensen M.
      • Stenager E.
      • Riemenschneider M.
      • Hvid L.G.
      Exercise as medicine in multiple sclerosis – time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
      ), defined as structured and planned physical activities. Several exercise modalities are known to effectively improve muscular strength and aerobic capacity as well as mobility, fatigue, mood, and quality of life, in persons with MS (pwMS) having mild to moderate disability (
      • Dalgas U.
      • Langeskov-Christensen M.
      • Stenager E.
      • Riemenschneider M.
      • Hvid L.G.
      Exercise as medicine in multiple sclerosis – time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
      ;
      • Taul-Madsen L.
      • Connolly L.
      • Dennett R.
      • Freeman J.
      • Dalgas U.
      • Hvid L.G.
      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.
      Arch. Phys. Med. Rehabil. 2021; 102: 2032-2048https://doi.org/10.1016/j.apmr.2021.03.026
      ). Furthermore, several studies have suggested that exercise might even postpone and slow down disease progression in MS thereby eliciting disease-modifying effects (
      • Dalgas U.
      • Langeskov-Christensen M.
      • Stenager E.
      • Riemenschneider M.
      • Hvid L.G.
      Exercise as medicine in multiple sclerosis – time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
      ;
      • Kjølhede T.
      • Siemonsen S.
      • Wenzel D.
      • Stellmann J.P.
      • Ringgaard S.
      • Pedersen B.G.
      • Stenager E.
      • Petersen T.
      • Vissing K.
      • Heesen C.
      • Dalgas U.
      Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?.
      Mult. Scler. J. 2018; 24: 1356-1365https://doi.org/10.1177/1352458517722645
      ;
      • Wesnes K.
      • Myhr K.M.
      • Riise T.
      • Cortese M.
      • Pugliatti M.
      • Boström I.
      • Landtblom A.M.
      • Wolfson C.
      • Bjørnevik K.
      Physical activity is associated with a decreased multiple sclerosis risk: the EnvIMS study.
      Mult. Scler. J. 2018; 24: 150-157https://doi.org/10.1177/1352458517694088
      ). Consequently, recent reviews from our group proposed to prescribe tailored exercise as "medicine" to pwMS alongside conventional medical treatment, already at an early disease stage (
      • Dalgas U.
      • Langeskov-Christensen M.
      • Stenager E.
      • Riemenschneider M.
      • Hvid L.G.
      Exercise as medicine in multiple sclerosis – time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
      ;
      • Riemenschneider M.
      • Hvid L.G.
      • Stenager E.
      • Dalgas U.
      Is there an overlooked “window of opportunity” in MS exercise therapy? Perspectives for early MS rehabilitation.
      Mult. Scler. J. 2018; 24: 886-894https://doi.org/10.1177/1352458518777377
      ). Exercise is therefore considered an essential element of MS rehabilitation.
      Even though exercise is a cornerstone of MS rehabilitation, duration and type of exercise researched across different age groups and disability levels have not been extensively mapped. Such a mapping is central when aiming to identify relevant literature gaps and clarify limitations of the existing exercise recommendations (
      • Dalgas U.
      • Stenager E.
      • Ingemann-Hansen T.
      Review: Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training.
      Mult. Scler. J. 2008; 14: 35-53https://doi.org/10.1177/1352458507079445
      ;
      • Kalb R.
      • Brown T.R.
      • Coote S.
      • Costello K.
      • Dalgas U.
      • Garmon E.
      • Giesser B.
      • Halper J.
      • Karpatkin H.
      • Keller J.
      • Ng A.V.
      • Pilutti L.A.
      • Rohrig A.
      • Van Asch P.
      • Zackowski K.
      • Motl R.W.
      Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.
      Mult. Scler. J. 2020; 26: 1459-1469https://doi.org/10.1177/1352458520915629
      ;
      • Kim Y.
      • Lai B.
      • Mehta T.
      • Thirumalai M.
      • Padalabalanarayanan S.
      • Rimmer J.H.
      • Motl R.W.
      Exercise training guidelines for multiple sclerosis, stroke, and Parkinson disease: rapid review and synthesis.
      Am. J. Phys. Med. Rehabil. 2019; 98: 613-621https://doi.org/10.1097/PHM.0000000000001174
      ;
      • Latimer-Cheung A.E.
      • Martin Ginis K.A.
      • Hicks A.L.
      • Motl R.W.
      • Pilutti L.A.
      • Duggan M.
      • Wheeler G.
      • Persad R.
      • Smith K.M.
      Development of evidence-informed physical activity guidelines for adults with multiple sclerosis.
      Arch. Phys. Med. Rehabil. 2013; 94 (e7): 1829-1836https://doi.org/10.1016/j.apmr.2013.05.015
      ). There have been attempts and preliminary studies exploring this issue (
      • Lai B.
      • Cederberg K.
      • Vanderbom K.A.
      • Bickel C.S.
      • Rimmer J.H.
      • Motl R.W.
      Characteristics of adults with neurologic disability recruited for exercise trials: a secondary analysis.
      Adapt. Phys. Act. Q. 2018; 35: 476-497https://doi.org/10.1123/apaq.2017-0109
      ;
      • Rimmer J.H.
      • Chen M.-D.
      • McCubbin J.A.
      • Drum C.
      • Peterson J.
      Exercise intervention research on persons with disabilities: what we know and where we need to go.
      Am. J. Phys. Med. Rehabil. 2010; 89: 249-263https://doi.org/10.1097/PHM.0b013e3181c9fa9d
      ), yet a comprehensive and systematic mapping of the MS populations enrolled in exercise studies is still pending in the existing literature.
      Therefore, the primary objective of the present systematic review is to perform a detailed mapping of the existing MS exercise literature in terms of participant age and disability level, as well as to categorize the applied interventions and study types.

      2. Methods

      This review is reported in accordance with the Preferred Reporting Items for Systematic Reviews guideline and preregistered at PROSPERO (CRD42022297563) (
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • Shamseer L.
      • Tetzlaff J.M.
      • Akl E.A.
      • Brennan S.E.
      • Chou R.
      • Glanville J.
      • Grimshaw J.M.
      • Hróbjartsson A.
      • Lalu M.M.
      • Li T.
      • Loder E.W.
      • Mayo-Wilson E.
      • McDonald S.
      • McGuinness L.A.
      • Stewart L.A.
      • Thomas J.
      • Tricco A.C.
      • Welch V.A.
      • Whiting P.
      • Moher D.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      BMJ. 2021; n71https://doi.org/10.1136/bmj.n71
      ). Paper screening was at all stages done independently by two reviewers (JJF and TG) using Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia). Disagreement between the two reviewers was resolved by consensus, and a third reviewer (UD) was consulted if consensus could not be reached.

      2.1 Definitions

      Many previous reviews have applied the definition of exercise proposed by
      • Caspersen C.J.
      • Powell K.E.
      • Christenson G.M.
      Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research.
      Public Health Rep. Wash. DC. 1985; 100 (1974): 126-131
      , defining exercise as ”physical activity that is planned, structured, repetitive, and purposive in the sense that improvement or maintenance of one or more components of physical fitness is an objective” (
      • Caspersen C.J.
      • Powell K.E.
      • Christenson G.M.
      Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research.
      Public Health Rep. Wash. DC. 1985; 100 (1974): 126-131
      ). Caspersen et al. further define physical activity as “any bodily movement produced by skeletal muscles that expend energy” (
      • Caspersen C.J.
      • Powell K.E.
      • Christenson G.M.
      Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research.
      Public Health Rep. Wash. DC. 1985; 100 (1974): 126-131
      ). As this definition implies that physical activity covers all activity where a person is not lying still, the following modification to Caspersen's definition of physical activity was made; “physical activity involves voluntary activation of the skeletal muscles, that results in movement of a body part in time and space”. Therefore, the following definition of exercise was applied in the present study: “Exercise involves voluntary activation of the skeletal muscles, that results in movement of a body part in time and space in addition to being planned, structured, repetitive, and purposive in the sense that improvement or maintenance of one or more components of physical fitness is an objective”.

      2.2 Search

      A systematic literature search was performed in MEDLINE/PubMed and EMBASE on November 11th, 2021. The search was based on medical subject headings and included the (MeSH-) terms “exercise” OR “exercise therapy” (“Kinesiotherapy” in EMBASE) AND “multiple sclerosis” with a date range of year 1000 to November 11th, 2021.

      2.3 Inclusion criteria

      The included studies:
      • -
        Had to evaluate one or more of the following exercise interventions (which broadly cover the exercise spectrum):
        • 1
          Resistance exercise
        • 2
          Endurance exercise
        • 3
          Balance exercise (including vestibular rehabilitation etc.)
        • 4
          Walking
        • 5
          Body & Mind Exercise (incl. Pilates, yoga/Asian movement philosophies)
        • 6
          Others (including aquatic exercise, task-oriented exercise, and exergaming)
        • 7
          Combined exercise (a combination of one or more of the mentioned exercise modalities)
      • -
        Were reported in peer-reviewed papers
      • -
        Were published in English, Danish, Swedish, Norwegian, or German.
      • -
        Had a description of the intervention that allowed characterization of the exercise modality and evaluated an exercise intervention where exercise constituted the main part of the intervention.
      • -
        Had to apply one of the following designs: Randomized controlled trial (RCT), non-randomized controlled trial, intervention trial without control, or pilot RCT (i.e., RCTs specifically described as pilot studies by the authors).

      2.4 Exclusion criteria

      Studies were excluded if:
      • -
        They evaluated acute exercise interventions or exercise interventions lasting < 2 weeks.
      • -
        They were outside study design restrictions
      • -
        They reported data from a study that was previously published (only the first published paper from a study was included).
      • -
        Evaluated interventions outside the included exercise interventions, e.g., the following interventions:
        • ○
          Breathing exercises
        • ○
          Fine motor skill
        • ○
          Pelvic floor exercise/ Pubococcygeal exercise
        • ○
          Electro muscle stimulation
        • ○
          Vibration's exercise
        • ○
          Hippotherapy
        • ○
          Cognition-Targeted Exercise
        • ○
          Physiotherapy
        • ○
          Stretching
        • ○
          Tension and trauma-releasing exercises
        • ○
          Inpatient rehabilitation
      • -
        They were lacking basic statistical information (e.g., means and SD)
      It is acknowledged that exercise is a broad term, and several of the above-listed interventions could be argued to be considered exercise. However, according to our definition of exercise, these interventions are not considered an exercise in this work. “Breathing exercise”, “pelvic floor/pubococcygeal exercise”, “Electro muscle stimulation”, and “cognition-targeted exercises” are all examples of interventions where no voluntary activation of the skeletal muscles is performed or where no significant movement of a body part in time and space is undertaken.

      2.5 Data extraction

      After screening, data extraction from the included studies was performed, extracting information on study design, intervention type, duration of intervention, study sample, and baseline characteristics. The baseline characteristics extracted included age, gender, EDSS, height weight, body mass index (BMI), MS sub-type, and disease duration (i.e., time since diagnosis). After data extraction, all data points were checked to ensure data quality. In cases where studies only reported individual values, mean values and standard deviations were calculated. This was also done if only separate groups were reported. A subgrouping based on EDSS and time since diagnosis was made to evaluate the distribution of exercise studies across disability and disease duration. EDSS was divided into ≤1.5, 2.0-2.5, 3.0-3.5, 4.0-4.5, 5.0-5.5, 6.0-6.5, and ≥7.0. Where EDSS scores represented mild disability (EDSS 0-2.5), moderate disability (EDSS 3.0-4.5), severe disability (EDSS 5-6.5), and very severe disability (EDSS 7+) (
      • Kurtzke J.F.
      Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
      Neurology. 1983; 33 (1444–1444)https://doi.org/10.1212/WNL.33.11.1444
      ). Time since diagnosis was divided into groups spanning five years: 0–4.9 years, 5–9.9 years, 10–14.9 years, 15–19.9 years, and ≥20 years. Characteristics of each study included can be found in Table 1.
      Table 1Schematic overview of included studies.
      DesignStudySample size (N)/ IG (n)Int TypesDuration (weeks)Total mean Age (yrs.)Female (%)BMI (kg/m2)EDSS (points)Disease duration (yrs.)
      RCT
      • Abasiyanik Z.
      • Ertekin O.
      • Kahraman T.
      • Yigit P.
      • Ozakbas S.
      The effects of clinical Pilates training on walking, balance, fall risk, respiratory and cognitive functions in persons with multiple sclerosis: a randomized controlled trial.
      Mult. Scler. J. 2018; 24: 862
      		33 / 148.045.5 ± 10.023 (69.7)26.4 ± 4.43.2 ± 1.711.8 ± 6.9
      • Abbaspoor E.
      • Zolfaghari M.
      • Ahmadi B.
      • Khodaei K.
      The effect of combined functional training on BDNF, IGF-1, and their association with health-related fitness in the multiple sclerosis women.
      Growth Horm. IGF Res. 2020; 52https://doi.org/10.1016/j.ghir.2020.101320
      		16 / 168.035.1 ± 6.2016 (100.0)26.1 ± 6.23.0 ± 1.110.1 ± 3.4
      • Afrasiabifar A.
      • Karami F.
      • Najafi Doulatabad S.
      Comparing the effect of Cawthorne–Cooksey and Frenkel exercises on balance in patients with multiple sclerosis: a randomized controlled trial.
      Clin. Rehabil. 2018; 32: 57-65https://doi.org/10.1177/0269215517714592
      		72 / 23+312.032.7 ± 7.4056 (77.8)23.4 ± 2.3-5.0 ± 3.1
      • Ahmadi A.
      • Arastoo A.A.
      • 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.
      Iran. Red Crescent Med. J. 2013; 15: 449-454https://doi.org/10.5812/ircmj.3597
      		31 / 22+48.035.2 ± 8.6031 (100.0)-2.2 ± 1.15.1 ± 4.0
      • Aidar F.J.
      • Gama de Matos D.
      • de Souza R.F.
      • Gomes A.B.
      • Saavedra F.
      • Garrido N.
      • Carneiro A.L.
      • Reis V.
      Influence of aquatic exercises in physical condition in patients with multiple sclerosis.
      J. Sports Med. Phys. Fit. 2018; 58: 684-689https://doi.org/10.23736/S0022-4707.17.07151-1
      		26 / 1412.042.4 ± 6.5017 (65.4)---
      • Amiri B.
      • Sahebozamani M.
      • Sedighi B.
      The effects of 10-week core stability training on balance in women with multiple sclerosis according to expanded disability status scale: a single-blinded randomized controlled trial.
      Eur. J. Phys. Rehabil. Med. 2019; 55: 199-208https://doi.org/10.23736/S1973-9087.18.04778-0
      		69 / 36+6+610.031.5 ± 4.7069 (100.0)25.4 ± 4.73.7 ± 0.3-
      • Arntzen E.C.
      • Straume B.
      • Odeh F.
      • Feys P.
      • Normann B.
      Group-based, individualized, comprehensive core stability and balance intervention provides immediate and long-term improvements in walking in individuals with multiple sclerosis: a randomized controlled trial.
      Physiother. Res. Int. 2020; 25https://doi.org/10.1002/pri.1798
      		79 / 26+66.050.1 ± 10.956 (70.9)25.7 ± 4.72.4 ± 1.510.4 ± 7.5
      • Baquet L.
      • Hasselmann H.
      • Patra S.
      • Stellmann J.P.
      • Vettorazzi E.
      • Engel A.K.
      • Rosenkranz S.C.
      • Poettgen J.
      • Gold S.M.
      • Schulz K.H.
      • Heesen C.
      Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis – a randomized controlled trial.
      PeerJ. 2018; 2018https://doi.org/10.7717/peerj.6037
      		68 / 1212.038.9 ± 9.5039 (57.4)-1.8 ± 0.96.3 ± 5.8
      • Bonzano L.
      • Pedullà L.
      • Tacchino A.
      • Brichetto G.
      • Battaglia M.A.
      • Mancardi G.L.
      • Bove M.
      Upper limb motor training based on task-oriented exercises induces functional brain reorganization in patients with multiple sclerosis.
      Neuroscience. 2019; 410: 150-159https://doi.org/10.1016/j.neuroscience.2019.05.004
      		30 / 158.049.7 ± 10.221 (70.0)-4.3 ± 1.411.7 ± 9.0
      • Broekmans T.
      • Roelants M.
      • Feys P.
      • Alders G.
      • Gijbels D.
      • Hanssen I.
      • Stinissen P.
      • Eijnde B.O.
      Effects of long-term resistance training and simultaneous electro-stimulation on muscle strength and functional mobility in multiple sclerosis.
      Mult. Scler. J. 2011; 17: 468-477https://doi.org/10.1177/1352458510391339
      		36 / 21+120.047.9 ± 10.223 (63.9)-4.3 ± 1.1-
      • Cakit B.D.
      • Nacir B.
      • Genç H.
      • Saraçoğlu M.
      • Karagöz A.
      • Erdem H.R.
      • Ergün U.
      Cycling progressive resistance training for people with multiple sclerosis: a randomized controlled study.
      Am. J. Phys. Med. Rehabil. 2010; 89: 446-457https://doi.org/10.1097/PHM.0b013e3181d3e71f
      		33 / 22+68.038.2 ± 10.523 (69.7)24.0 ± 4.1-7.6 ± 3.5
      • Callesen J.
      • Cattaneo D.
      • Brincks J.
      • Kjeldgaard Jørgensen M.L.
      • 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.
      Mult. Scler. J. 2020; 26: 1420-1432https://doi.org/10.1177/1352458519865740
      		71 / 21+510.051.6 ± 9.6055 (77.5)26.7 ± 6.23.9 ± 1.313.3 ± 9.3
      • Carter A.M.
      • Daley A.J.
      • Kesterton S.W.
      • Woodroofe N.M.
      • Saxton J.M.
      • Sharrack B.
      Pragmatic exercise intervention in people with mild to moderate multiple sclerosis: a randomised controlled feasibility study.
      Contemp. Clin. Trials. 2013; 35: 40-47https://doi.org/10.1016/j.cct.2013.04.003
      		30 / 1610.040.2 ± 7.3026 (86.7)26.5 ± 5.53.1 ± 1.4-
      • Carter A.
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      • Humphreys L.
      • Snowdon N.
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      • Petty J.
      • Roalfe A.
      • Tosh J.
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      • Saxton J.M.
      Pragmatic intervention for increasing self-directed exercise behaviour and improving important health outcomes in people with multiple sclerosis: a randomised controlled trial.
      Mult. Scler. 2014; 20: 1112-1122https://doi.org/10.1177/1352458513519354
      		120 / 1612.045.9 ± 8.7086 (71.7)27.6 ± 5.63.8 ± 1.58.8 ± 7.6
      • Castro-Sánchez A.M.
      • Matarán-Peñarrocha G.A.
      • Lara-Palomo I.
      • Saavedra-Hernández M.
      • Arroyo-Morales M.
      • Moreno-Lorenzo C.
      Hydrotherapy for the treatment of pain in people with multiple sclerosis: a randomized controlled trial.
      Evid. Based Complement. Alternat. Med. 2012; 2012: 1-8https://doi.org/10.1155/2012/473963
      		73 / 1420.048.0 ± 11.150 (68.5)-6.1 ± 0.811.3 ± 8.8
      • Cattaneo D.
      • Jonsdottir J.
      • Regola A.
      • Carabalona R.
      Stabilometric assessment of context dependent balance recovery in persons with multiple sclerosis: a randomized controlled study.
      J. NeuroEngineering Rehabil. 2014; 11: 100https://doi.org/10.1186/1743-0003-11-100
      		53 / 133.048.3 ± 11.433 (62.3)---
      • Coghe G.
      • Corona F.
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      • Fenu G.
      • Frau J.
      • Lorefice L.
      • Crisafulli A.
      • Galli M.
      • Concu A.
      • Marrosu M.G.
      • Pau M.
      • Cocco E.
      Fatigue, as measured using the Modified Fatigue Impact Scale, is a predictor of processing speed improvement induced by exercise in patients with multiple sclerosis: data from a randomized controlled trial.
      J. Neurol. 2018; 265: 1328-1333https://doi.org/10.1007/s00415-018-8836-5
      		22 / 1624.045.5 ± 10.912 (54.5)-3.3 ± 0.9-
      • Correale L.
      • Buzzachera C.F.
      • Liberali G.
      • Codrons E.
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      • Cattaneo D.
      Intensive multimodal training to improve gait resistance, mobility, balance and cognitive function in persons with multiple sclerosis: a pilot randomized controlled trial.
      Front. Neurol. 2018; 9https://doi.org/10.3389/fneur.2018.00800
      		38 / 22+14.053.1 ± 9.228 (73.7)-5.5 ± 1.017.9 ± 7.9
      • Jonsdottir Johanna
      • Bertoni R.
      • Lawo M.
      • Montesano A.
      • Bowman T.
      • Gabrielli S.
      Serious games for arm rehabilitation of persons with multiple sclerosis. A randomized controlled pilot study.
      Mult. Scler. Relat. Disord. 2018; 19: 25-29https://doi.org/10.1016/j.msard.2017.10.010
      		16 / 25+54.054.7 ± 9.413 (81.3)--19.4 ± 7.8
      • Kalron A.
      • Fonkatz I.
      • Frid L.
      • Baransi H.
      • Achiron A.
      The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial.
      J. NeuroEng. Rehabil. 2016; 13: 13https://doi.org/10.1186/s12984-016-0124-y
      		30 / 156.045.6 ± 9.819 (63.3)25.5 ± 4.34.2 ± 1.411.0 ± 6.9
      • Lamberti N.
      • Straudi S.
      • Donadi M.
      • Tanaka H.
      • Basaglia N.
      • Manfredini F.
      Effectiveness of blood flow-restricted slow walking on mobility in severe multiple sclerosis: a pilot randomized trial.
      Scand. J. Med. Sci. Sports. 2020; 30: 1999-2009https://doi.org/10.1111/sms.13764
      		22 / 176.055.0 ± 10.015 (68.2)23.5 ± 3.46.0 ± 0.213.5 ± 9.1
      • Learmonth Y.C.
      • Paul L.
      • Miller L.
      • Mattison P.
      • McFadyen A.K.
      The effects of a 12-week leisure centre-based, group exercise intervention for people moderately affected with multiple sclerosis: a randomized controlled pilot study.
      Clin. Rehabil. 2012; 26: 579-593https://doi.org/10.1177/0269215511423946
      )      		32 / 1612.051.5 ± 7.823 (71.9)-6.0 ± 0.413.1 ± 6.8
      • Lo A.C.
      • Triche E.W.
      Improving gait in multiple sclerosis using robot-assisted, body weight supported treadmill training.
      Neurorehabil. Neural Repair. 2008; 22: 661-671https://doi.org/10.1177/1545968308318473
      		13 / 27+73.049.9 ± 10.76 (46.2)-4.9 ± 1.2-
      • McAuley E.
      • Wójcicki T.R.
      • Learmonth Y.C.
      • Roberts S.A.
      • Hubbard E.A.
      • Kinnett-Hopkins D.
      • Fanning J.
      • Motl R.W.
      Effects of a DVD-delivered exercise intervention on physical function in older adults with multiple sclerosis: a pilot randomized controlled trial.
      Mult. Scler. J. - Exp. Transl. Clin. 2015; 1 (205521731558483)https://doi.org/10.1177/2055217315584838
      		48 / 1126.059.7 ± 1.436 (75.0)--19 ± 9.2
      • McCullagh R.
      • Fitzgerald A.P.
      • Murphy R.P.
      • Cooke G.
      Long-term benefits of exercising on quality of life and fatigue in multiple sclerosis patients with mild disability: a pilot study.
      Clin. Rehabil. 2008; 22: 206-214https://doi.org/10.1177/0269215507082283
      		30 / 1612.037.5 ± 10.024 (80.0)27.3 ± 5.6-5.2 ± 3.9
      • Monjezi S.
      • Negahban H.
      • Tajali S.
      • Yadollahpour N.
      • Majdinasab N.
      Effects of dual-task balance training on postural performance in patients with Multiple Sclerosis: a double-blind, randomized controlled pilot trial.
      Clin. Rehabil. 2017; 31: 234-241https://doi.org/10.1177/0269215516639735
      		38 / 164.036.0 ± 7.830 (78.9)23.6 ± 3.62.8 ± 1.17.4 ± 5.2
      • Munari D.
      • Fonte C.
      • Varalta V.
      • Battistuzzi E.
      • Cassini S.
      • Montagnoli A.P.
      • Gandolfi M.
      • Modenese A.
      • Filippetti M.
      • Smania N.
      • Picelli A.
      Effects of robot-assisted gait training combined with virtual reality on motor and cognitive functions in patients with multiple sclerosis: A pilot, single-blind, randomized controlled trial.
      Restor. Neurol. Neurosci. 2020; 38: 151-164https://doi.org/10.3233/rnn-190974
      		17 / 27+56.054.2 ± 8.010 (58.8)-3.1 ± 0.913.9 ± 6.6
      • Mähler A.
      • Balogh A.
      • Csizmadia I.
      • Klug L.
      • Kleinewietfeld M.
      • Steiniger J.
      • Šušnjar U.
      • Müller D.N.
      • Boschmann M.
      • Paul F.
      Metabolic, mental and immunological effects of normoxic and hypoxic training in multiple sclerosis patients: a pilot study.
      Front. Immunol. 2018; 9: 2819https://doi.org/10.3389/fimmu.2018.02819
      		34 / 27+74.050.0 ± 9.222 (64.7)24.7 ± 4.5--
      • Negahban H.
      • Rezaie S.
      • Goharpey S.
      Massage therapy and exercise therapy in patients with multiple sclerosis: a randomized controlled pilot study.
      Clin. Rehabil. 2013; 27: 1126-1136
      		48 / 38+6+65.036.6 ± 7.440 (83.3)23.9 ± 3.83.7 ± 1.39.4 ± 6.1
      • Pompa A.
      • Morone G.
      • Iosa M.
      • Pace L.
      • Catani S.
      • Casillo P.
      • Clemenzi A.
      • Troisi E.
      • Tonini A.
      • Paolucci S.
      • Grasso M.G.
      Does robot-assisted gait training improve ambulation in highly disabled multiple sclerosis people? A pilot randomized control trial.
      Mult. Scler. 2017; 23: 696-703https://doi.org/10.1177/1352458516663033
      		43 / 27+74.048.5 ± 9.522 (51.2)-6.6 ± 0.415.5 ± 7.4
      • Prosperini L.
      • Leonardi L.
      • De Carli P.
      • Mannocchi M.L.
      • Pozzilli C.
      Visuo-proprioceptive training reduces risk of falls in patients with multiple sclerosis.
      Mult. Scler. J. 2010; 16: 491-499https://doi.org/10.1177/1352458509359923
      		52 / 136.040.3 ± 11.724 (46.2)---
      • Prosperini L.
      • Fortuna D.
      • Giannì C.
      • Leonardi L.
      • Marchetti M.R.
      • Pozzilli C.
      Home-based balance training using the Wii balance board: a randomized, crossover pilot study in multiple sclerosis.
      Neurorehabil. Neural Repair. 2013; 27: 516-525https://doi.org/10.1177/1545968313478484
      		36 / 1512.036.2 ± 8.525 (69.4)22.6 ± 3.8-10.8 ± 5.5
      • Sadeghi Bahmani D.
      • Razazian N.
      • Motl R.W.
      • Farnia V.
      • Alikhani M.
      • Pühse U.
      • Gerber M.
      • Brand S.
      Physical activity interventions can improve emotion regulation and dimensions of empathy in persons with multiple sclerosis: an exploratory study.
      Mult. Scler. Relat. Disord. 2020; 37https://doi.org/10.1016/j.msard.2019.101380
      		60 / 25+58.037.7 ± 7.360 (100.0)--7.3 ± 3.9
      • Sebastião E.
      • McAuley E.
      • Shigematsu R.
      • Adamson B.C.
      • Bollaert R.E.
      • Motl R.W.
      Home-based, square-stepping exercise program among older adults with multiple sclerosis: results of a feasibility randomized controlled study.
      Contemp. Clin. Trials. 2018; 73: 136-144https://doi.org/10.1016/j.cct.2018.09.008
      		25 / 1312.064.3 ± 4.522 (88.0)--21.1 ± 10.7
      • Siengsukon C.F.
      • Aldughmi M.
      • Kahya M.
      • Bruce J.
      • Lynch S.
      • Ness Norouzinia A.
      • Glusman M.
      • Billinger S.
      Randomized controlled trial of exercise interventions to improve sleep quality and daytime sleepiness in individuals with multiple sclerosis: a pilot study.
      Mult. Scler. J. Exp. Transl. Clin. 2016; 2https://doi.org/10.1177/2055217316680639
      		22 / 22+712.049.8 ± 12.419 (86.4)--10.0 ± 6.9
      • Skjerbæk A.G.
      • Næsby M.
      • Lützen K.
      • Møller A.B.
      • Jensen E.
      • Lamers I.
      • Stenager E.
      • Dalgas U.
      Endurance training is feasible in severely disabled patients with progressive multiple sclerosis.
      Mult. Scler. 2014; 20: 627-630https://doi.org/10.1177/1352458513505351
      		11 / 124.058.9 ± 6.38 (72.7)26.5 ± 4.7--
      • Sosnoff J.J.
      • Finlayson M.
      • McAuley E.
      • Morrison S.
      • Motl R.W.
      Home-based exercise program and fall-risk reduction in older adults with multiple sclerosis: phase 1 randomized controlled trial.
      Clin. Rehabil. 2014; 28: 254-263https://doi.org/10.1177/0269215513501092
      		27 / 1612.060.1 ± 6.021 (77.8)--15.9 ± 9.0
      • Straudi S.
      • Benedetti M.G.
      • Venturini E.
      • Manca M.
      • Foti C.
      • Basaglia N.
      Does robot-assisted gait training ameliorate gait abnormalities in multiple sclerosis? A pilot randomized-control trial.
      NeuroRehabilitation. 2013; 33: 555-563https://doi.org/10.3233/NRE-130990
      		16 / 27+66.055.3 ± 9.811 (68.8)-5.8 ± 0.717.9 ± 10.7
      • Straudi S.
      • Martinuzzi C.
      • Pavarelli C.
      • Sabbagh Charabati A.
      • Benedetti M.G.
      • Foti C.
      • Bonato M.
      • Zancato E.
      • Basaglia N.
      A task-oriented circuit training in multiple sclerosis: a feasibility study.
      BMC Neurol. 2014; 14: 124https://doi.org/10.1186/1471-2377-14-124
      		24 / 1514.052.6 ± 11.217 (70.8)-4.9 ± 0.515.2 ± 8.7
      • Uszynski M.K.
      • Purtill H.
      • Donnelly A.
      • Coote S.
      Comparing the effects of whole-body vibration to standard exercise in ambulatory people with Multiple Sclerosis: a randomised controlled feasibility study.
      Clin. Rehabil. 2016; 30: 657-668https://doi.org/10.1177/0269215515595522
      		27 / 21+112.048.1 ± 11.223 (85.2)---
      • Zrzavy T.
      • Pfitzner A.
      • Flachenecker P.
      • Rommer P.
      • Zettl U.K.
      Effects of normobaric hypoxic endurance training on fatigue in patients with multiple sclerosis: a randomized prospective pilot study.
      J. Neurol. 2021; https://doi.org/10.1007/s00415-021-10596-5
      		39 / 22+22.043.2 ± 7.629 (74.4)--11.3 ± 7.2
      Data presented in Mean ± SD. RCT = Randomized controlled trail; IWC = Intervention without control; Int. Type = Intervention type, 1 = Resistance training; 2 = Endurance training; 3 = Balance training; 4 = Walking; 5 = Body and Mind exercise; 6 = Others; 7 = Combination of two or more modalities; 8 = Non-Exercise (a study that has tested the effects an exercise intervention but also of a non-training component e.g. temperature, smell, sound etc).; IG = Number of intervention groups; BMI = Body Mass Index; and EDSS = Expanded Disability Status Scale.
      Data from all groups included in RCTs were extracted, including control groups. The categorization of RCT groups were performed the following way: All groups in RCTs with a superiority design, comparing two or more exercise interventions, were reported as exercise groups, despite one of these groups being the methodological comparator. Further, RCTs including, in addition to the exercise group, a group receiving a non-exercise intervention (e.g. massage or scent impression), were categorized as having a “non-exercise” group although this is beside the applied exercise definition. Hence the total number of intervention groups surpasses the total number of studies included.

      2.6 Statistics

      All statistical analysis was undertaken using STATA software version 17 (STATA, IC 17, Stata Corp, College Station, TX, USA), and graphs were made using GraphPad Prism version 9.3.1 (GraphPad Software Inc., California, USA). Means and standard deviations (SD) were calculated.

      3. Results

      3.1 Study inclusion

      The systematic search yielded a total of 4576 records, which after the removal of duplicates, resulted in 3714 records. Screening identified 556 records deemed relevant for full-text inspection. Of the 556 records, 5 records could not be retrieved, hence 551 records were assessed for eligibility at a full-text level. While screening the 551 records, one additional report was found from searching the reference lists. Of the 552 records, a total of 202 records were deemed eligible and subsequently included in the review (for further review details see Fig. 1 and for all included studies see Table 1).
      Fig 1
      Fig. 1Flow diagram of the literature search according to items in the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guideline.

      3.2 Study content

      Table 2 summarizes population demographics, clinical characteristics, and study designs of the included studies. The identified studies covered a total of 8037 pwMS, having a mean EDSS of 3.7 ± 1.4 and a mean disease duration of 11 ± 4.1 years. Of these, information on MS-subtypes was reported in 5149 (64.1%) pwMS. The mean age across all studies was 44.7 ± 7.2 years, with more females (73.6%) than males being enrolled. The mean intervention group size across all studies was 17 participants (range: 5-67). The duration of the exercise interventions ranged from 2 to 52 weeks with a mean of 10.7 ± 7.7 weeks. 70 studies had more than one intervention group, which explains why the total number of interventions (n = 285) exceeded the total number of studies included in this review (n = 202). Of the 202 included records, a total of 108 were RCTs (53.5%), 17 were controlled trials (8.4%), 40 were intervention studies without controls (19.8%), and 37 were pilot RCT studies (18.3%).
      Table 2Summary of participant demographics, intervention type and study design reported by age group for the enrolled studies.
      Age groups≤ 2930-3435-3940-4445-4950-5455-59≥ 60TotalNumber of studies reporting (%)
      Number of studies, N (%)2 (1.0)20 (9.9)29 (14.4)48 (23.8)59 (29.2)30 (14.9)11 (5.9)3 (1.5)202 (100)202 (100)
      Participants sample, N (avg. participant number per study)63 (32)825 (41)1135 (39)1819 (38)2217 (38)1517 (51)375 (32)86 (29)8037 (40)202 (100)
      Age [years]--------44.7 ± 7.2202 (100)
      Gender [% Females]74.8 ± 9.681.1 ± 26.780.8 ± 15.572.8 ± 13.370.9 ± 13.868.7 ± 8.668.6 ± 6.475.7 ± 3.073.6 ± 15.8196 (96.6)
      BMI [kg⋅m−2]23.4 ± 3.624.8 ± 1.224.7 ± 1.124.9 ± 1.825.6 ± 2.225.6 ± 2.023.8 ± 2.5-25.0 ± 1.8100 (49.3)
      EDSS [points]1.98 ± 1.12.71 ± 1.02.73 ± 1.03.17 ± 0.93.95 ± 1.34.72 ± 1.36.04 ± 0.2-3.7 ± 1.4118 (58.4)
      Disease duration [years]9.9 ± 3.06.8 ± 4.07.2 ± 1.79.7 ± 2.412.3 ± 3.313.2 ± 2.816.3 ± 4.218 .0 ± 2.711.0 ± 4.1125 (61.9)
      MS subtype [avg. %], RRMS/SPMS/PPMS/PRMS48/12/28/055/1/6/2491/20/5/086/14/11/077/26/16/456/40/19/051/35/28/075/16/13/03697/924/514/14*125 (61.9)
      Training Duration, [weeks]10.0 ± 2.89.1 ± 2.112.4 ± 11.712.5 ± 6.811.4 ± 8.47.1 ± 4.28.3 ± 6.512.0 ± 0.010.7 ± 7.7202 (100)
      Intervention type
       Endurance Training14112216105068 (24.9)-
       Combined Training13111615153367 (24.5)-
       Resistance Training21072242038 (13.9)-
       Other02747101031 (11.4)-
       Body and Mind Exercise0655720025 (9.2)-
       Walking0100865020 (7.3)-
       Balance Training0243621119 (7.0)-
       Non-Exercise001030015 (1.8)-
       Total41939578449165273 (100)-
      Study design
       RCT1181623351131108 (53.5)-
       Control trail0037511017 (8.4)-
       Intervention without control024139102040 (19.8)-
       RCT pilot10651085237 (18.3)-
       Total22029485930113202 (100)-
      Note: Data presented are Mean ± SD, percentages, or number of studies/participants. EDSS = Expanded Disability Status Scale; BMI = Body Mass Index; RRMS = Relapse-remitting multiple sclerosis; SPMS = Secondary progressive multiple sclerosis; PPMS = Primary progressive multiple sclerosis; PRMS = Progressive-relapsing multiple sclerosis; RCT = Randomized controlled trail, Non-Exercise = An exercise intervention study that also tests a non-training component (e.g. temperature, smell, sound etc.). *MS subtype total is presented as the total number of participants in the 4 subtypes of MS.

      3.3 Exercise modalities

      Fig. 3 shows the distribution of the different exercise modalities. Endurance exercise (24.9%) and combined exercise (24.5%) constitutes 49.5% of the total number of interventions. The least prevalent modalities are balance exercise (7.0%), walking (7.3%), and body & mind exercise (9.2%).

      3.4 Studies by age-groups

      Table 2 and Fig. 2 summarize the distribution of studies by age. A total of 29.2% of the tested pwMS were in the age-group 45-49, and 82.2% of the studies were conducted in participants aged 35-54. Only 1.5% of all studies were conducted in pwMS ≥60 years. The proportion of studies applying a RCT design varies between age groups from 27.3% (age-group 55–59 years; 3 of 11 studies) to 90% (age-group 30-34 years; 18 of 20 studies). Controlled trials have not been applied in 3 out of 8 age groups.
      Fig 2
      Fig. 2Exercise modalities divided by study design.
      Fig 3
      Fig. 3Number of MS exercise studies by age group.
      When solely analysing the RCT studies, 78.7% of the studies were conducted in patients aged 35–54 (Table 5 and Fig. 2). Resistance and endurance exercise was evaluated in 38 (13.9%) and 68 (24.9%) studies, respectively. 76.3% of the resistance exercise studies were conducted in patients aged 40-49. A total of 125 (61.9%) studies reported MS subtype of the participants, which showed that 71.8% had RRMS, 17.9% had SPMS, 10.0% had PPMS, and 0.3% had PRMS (Table 2).

      3.5 Studies by disability level and disease duration

      Data presented in Tables 3 and 4 are based on the same studies as in Table 2, yet here stratified by EDSS-groups (Table 3) or disease duration (Table 4). In total, 88.1% of the studies were conducted in pwMS with EDSS-scores between 2.0 and 6.5 (Table 3). A total of 13 studies (11.0%) have been conducted in patients with an EDSS of ≤1.0, and one single study (0.8%) was found reporting data from patients with an EDSS of ≥7.0
      Table 3Summary of participant demographics, intervention type and study design reported by EDSS group for the enrolled studies.
      EDSS groups≤1.52.0-2.53.0-3.54.0-4.55.0-5.56.0-6.5≥7.0TotalNumber of studies reporting (%)
      Number of studies, N (%)13 (11.0)28 (23.7)35 (29.7)21 (17.8)9 (7.6)11 (9.3)1 (0.8)118 (100)118 (100)
      Participants sample, N (avg. participant number per study)570 (44)1205 (43)1286 (37)788 (38)327 (36)440 (40)24 (24)4640 (39)118 (100)
      Age [years]37.8 ± 5.540.9 ± 5.443.9 ± 5.546.7 ± 5.551.3 ± 6.057.3 ± 4.054.1 ± 2.644.4 ± 6.8118 (100)
      Gender [% Females]78.5 ± 14.878.4 ± 16.273.8 ± 14.763.6 ± 24.472.3 ± 12.763.1 ± 6.462.572.4 ± 17.3116 (98.3)
      BMI [kg⋅m−2]24.5 ± 1.025.5 ± 1.625.6 ± 1.824.4 ± 1.223.6 ± 1.322.5 ± 1.4-25.1 ± 1.766 (55.9)
      Disease duration [years]7.0 ± 2.78.3 ± 2.810.1 ± 2.311.3 ± 2.914.2 ± 4.315.4 ± 3.615.5 ± 3.310.6 ± 4.077 (65.6)
      MS subtype [avg. %], RR/SP/PP/PR92/5/2/083/6/10/080/9/19/1458/25/32/055/27/51/038/24/58/013/21/67/02297/240/637/14*118 (100)
      Training Duration, [weeks]15.9 ± 16.29.0 ± 4.812.6 ± 6.78.3 ± 5.14.4 ± 4.97.3 ± 4.94.010.4 ± 7.8118 (100)
      Note: Data presented are Mean ± SD, percentages, or number of studies/participants. EDSS = Expanded Disability Status Scale; BMI = Body Mass Index; RRMS = Relapse-remitting multiple sclerosis; SPMS = Secondary progressive multiple sclerosis; PPMS = Primary progressive multiple sclerosis; PRMS = Progressive-relapsing multiple sclerosis; RCT: Randomized controlled trail. *MS subtype total is presented as the total number of participants in the 4 subtypes of MS.
      Table 4Summary of participant demographics, intervention type and study design reported by Disease Duration groups for the enrolled studies.
      Disease Duration groups [years]≤4.95.0 - 9.910.0 - 14.915.0 - 19.9≥20.0TotalNumber of studies reporting (%)
      Number of studies, N (%)5 (4)51 (40.8)49 (39.2)15 (12)5 (4)125 (100)125 (100)
      Participants sample, N (avg. participant number per study)153 (31)2427 (48)2207 (45)497 (33)134 (27)5418 (43)125 (100)
      Age [years]34.2 ± 3.440.6 ± 5.447.4 ± 5.652.2 ± 6.955.2 ± 6.345.0 ± 7.5125 (100)
      Gender [% Females]74.8 ± 43.374.6 ± 13.071.3 ± 11.169.1 ± 8.460.6 ± 7.972.2 ± 14.0124 (99.2)
      BMI [kg⋅m−2]24.3 ± 1.725.0 ± 1.324.8 ± 2.524.8 ± 0.1-24.9 ± 1.859 (47.2)
      EDSS [points]2.6 ± 1.52.9 ± 1.04.2 ± 1.45.5 ± 1.36.4 ± 0.43.8 ± 1.577 (61.6)
      MS subtype [avg. %], RRMS/SPMS/PPMS/PRMS76/0/0/088/11/8/469/28/20/045/43/26/056/43/19/02710/711/404/4*90 (72)
      Training Duration, [weeks]12.6 ± 7.711.8 ± 9.79.2 ± 4.78.9 ± 6.68.6 ± 3.410.4 ± 7.5125 (100)
      Note: Data presented are Mean ± SD, percentages, or number of studies/participants. EDSS = Expanded Disability Status Scale; BMI = Body Mass Index; RRMS = Relapse-remitting multiple sclerosis; SPMS = Secondary progressive multiple sclerosis; PPMS = Primary progressive multiple sclerosis; PRMS = Progressive-relapsing multiple sclerosis; RCT: Randomized controlled trail. *MS subtype total is presented as the total number of participants in the 4 subtypes of MS.
      Table 5Summary of participant demographics, intervention type and study design reported by age group for the enrolled RCT studies.
      Age groups≤ 2930-3435-3940-4445-4950-5455-59≥ 60TotalNumber of studies reporting (%)
      Number of studies, N (%)1 (0.9)18 (16.7)15 (13.9)24 (22.2)35 (32.4)11 (14.2)3 (2.8)1 (0.9)108 (100)108 (100)
      Participants sample, N (avg. participant pr. study)38 (38)781 (43)639 (43)1140 (48)1613 (46)839 (76)142 (47)34 (34)5226 (48)108 (100)
      Age [yrs]--------44.7 ± 7.2202 (100)
      Gender [% Females]81.682.6 ± 26.881.4 ± 17.673.0 ± 12.771.0 ± 13.170.0 ± 10.662.6 ± 7.773.574.7 ± 16.8105 (96.6)
      BMI [kg⋅m−2]23.4 ± 3.524.8 ± 1.324.6 ± 0.925.3 ± 1.425.4 ± 2.626.1 ± 2.7--25.1 ± 1.955 (49.3)
      EDSS [points]2.0 ± 1.12.6 ± 1.02.7 ± 1.23.1 ± 0.74.0 ± 1.34.4 ± 1.45.8 ± 1.0-3.4 ± 1.364 (58.4)
      Disease duration [yrs]7.7 ± 3.36.8 ± 4.36.7 ± 1.78.7 ± 2.112.3 ± 2.811.3 ± 2.010.0 ± 10.017.0 ± 8.69.7 ± 3.169 (61.9)
      MS subtype [avg. %], RR/SP/PP/PR-94/9/55/2490/18/5/085/13/13/077/23/16/456/33/19/048/34/31/059/27/15/02557/512/373/14*? (61.9)
      Training Duration, [weeks]8.08.7 ± 1.910.1 ± 4.914.0 ± 7.212.0 ± 7.28.3 ± 3.25.0 ± 2.712.010.9 ± 6.1108 (100)
      Intervention type
       Combined Training114111451138 (26.8)-
       Endurance Training1489511029 (20.4)-
       Body and Mind Exercise0621620017 (11.9)-
       Resistance Training0004931017 (11.9)-
       Balance Training0242520015 (10.6)-
       Other0231540015 (10.6)-
       Walking010012307 (4.9)-
       Non-Exercise001020014 (4.9)-
       Total2162228471962142 (100)-
      Note: Data presented are Mean ± SD, percentages, or number of studies/participants. EDSS = Expanded Disability Status Scale; BMI = Body Mass Index; RR = Relapse-remitting multiple sclerosis; SP = Secondary progressive multiple sclerosis; PP = Primary progressive multiple sclerosis; PR = Progressive-relapsing multiple sclerosis; Non-Exercise is when a study has tested the effects of a non-training component (e.g., temperature, smell, sound etc.) *MS subtype Total are presented as the total number of participants in the 4 subtypes of MS.
      Table A1Summary of participant demographics, intervention type and study design reported by age group for the enrolled RCT studies.
      Age groups≤ 2930-3435-3940-4445-4950-5455-59≥ 60TotalNumber of studies reporting (%)
      Number of studies, N (%)1 (0.9)18 (16.7)15 (13.9)24 (22.2)35 (32.4)11 (14.2)3 (2.8)1 (0.9)108 (100)108 (100)
      Participants sample, N (avg. participant number per study)38 (38)781 (43)639 (43)1140 (48)1613 (46)839 (76)142 (47)34 (34)5226 (48)108 (100)
      Age [years]--------44.7 ± 7.2202 (100)
      Gender [% Females]81.682.6 ± 26.881.4 ± 17.673.0 ± 12.771.0 ± 13.170.0 ± 10.662.6 ± 7.773.574.7 ± 16.8105 (96.6)
      BMI [kg*m−2]23.4 ± 3.524.8 ± 1.324.6 ± 0.925.3 ± 1.425.4 ± 2.626.1 ± 2.7--25.1 ± 1.955 (49.3)
      EDSS [points]2.0 ± 1.12.6 ± 1.02.7 ± 1.23.1 ± 0.74.0 ± 1.34.4 ± 1.45.8 ± 1.0-3.4 ± 1.364 (58.4)
      Disease duration [years]7.7 ± 3.36.8 ± 4.36.7 ± 1.78.7 ± 2.112.3 ± 2.811.3 ± 2.010.0 ± 10.017.0 ± 8.69.7 ± 3.169 (61.9)
      MS subtype [avg. %], RRMS/SPMS/PPMS/PRMS-94/9/55/2490/18/5/085/13/13/077/23/16/456/33/19/048/34/31/059/27/15/02557/512/373/14*? (61.9)
      Training Duration, [weeks]8.08.7 ± 1.910.1 ± 4.914.0 ± 7.212.0 ± 7.28.3 ± 3.25.0 ± 2.712.010.9 ± 6.1108 (100)
      Intervention type

      Combined Training

      Endurance Training

      Body and Mind Exercise

      Resistance Training

      Balance Training

      Other

      Walking

      Non-Exercise

      Total

      1

      1

      0

      0

      0

      0

      0

      0

      2

      1

      4

      6

      0

      2

      2

      1

      0

      16

      4

      8

      2

      0

      4

      3

      0

      1

      22

      11

      9

      1

      4

      2

      1

      0

      0

      28

      14

      5

      6

      9

      5

      5

      1

      2

      47

      5

      1

      2

      3

      2

      4

      2

      0

      19

      1

      1

      0

      1

      0

      0

      3

      0

      6

      1

      0

      0

      0

      0

      0

      0

      1

      2

      38 (26.8)

      29 (20.4)

      17 (11.9)

      17 (11.9)

      15 (10.6)

      15 (10.6)

      7 (4.9)

      4 (4.9)

      142 (100)

      -

      -

      -

      -

      -

      -

      -

      -

      -
      Note: Data presented are Mean ± SD, percentages, or number of studies/participants. EDSS = Expanded Disability Status Scale; BMI = Body Mass Index; RRMS = Relapse-remitting multiple sclerosis; SPMS = Secondary progressive multiple sclerosis; PPMS = Primary progressive multiple sclerosis; PRMS = Progressive-relapsing multiple sclerosis; Non-Exercise = A exercise intervention study but also testing a non-training component (e.g. temperature, smell, sound etc.).
      *MS subtype total is presented as the total number of participants in the 4 subtypes of MS.

      4. Discussion

      The present review aimed to map patient characteristics, exercise modality, and study design of the existing MS exercise literature to identify potential knowledge gaps for certain subgroups of pwMS. The main finding of the present review was that the majority of the existing studies (82.2%; n = 166) have enrolled pwMS aged 35-54 years. It was further observed that pwMS with mild (<2.0) or severe (>6.5) disability scores (EDSS) only constitute 11.9% (n = 14) of participants across all MS exercise studies reporting EDSS-data. Finally, pwMS with a short (<5yr) or long (>15yr) disease duration are rarely enrolled in MS exercise studies as those with a disease duration of 5-15-years account for 80% (n = 100) of all studies. Altogether, these findings emphasize limitations when generalizing evidence of exercise effects in pwMS. It further highlights the need to expand exercise research to certain subgroups of pwMS, including both young and older, mildly and severely disabled, and those with short and long disease duration.
      According to a newly published report from the Danish MS registry (
      • Magyari M.
      • Joensen H.
      • Pontieri L.
      Sclerosis Register 2022. Danish Multiple Sclerosis Center, The Danish Sclerosis Register.
      Rigshospitalet and the National Institute of Public Health, University of Southern Denmark, 2022
      ) and a US population-based study (
      • Wallin M.T.
      • Culpepper W.J.
      • Campbell J.D.
      • Nelson L.M.
      • Langer-Gould A.
      • Marrie R.A.
      • Cutter G.R.
      • Kaye W.E.
      • Wagner L.
      • Tremlett H.
      • Buka S.L.
      • Dilokthornsakul P.
      • Topol B.
      • Chen L.H.
      • LaRocca N.G.
      The prevalence of MS in the United States: a population-based estimate using health claims data.
      Neurology. 2019; 92: e1029-e1040https://doi.org/10.1212/WNL.0000000000007035
      ), only ∼1.5% of pwMS are below 25 years of age, whereas ∼49% are ≥55 years. Nonetheless, the present review observed that only 7% of the exercise studies enrolled pwMS ≥55 years and 1.5% ≥60 years. This leaves a marked discrepancy between the study population and the general population across the existing MS exercise studies. In addition, more than 80% of the existing studies have been conducted in an age span (35-54 years) covering approximately 40% of the general MS population age span, further underlining the need to focus on specific subgroups in the years to come. For instance, merely no exercise studies exist in older pwMS. This is somewhat surprising given the widely recognized positive effects of exercise among otherwise healthy older adults (
      • Davis M.P.
      • Hui D.
      Quality of life in palliative care.
      Expert Rev. Qual. Life Cancer Care. 2017; 2: 293-302https://doi.org/10.1080/23809000.2017.1400911
      ;
      • Di Lorito C.
      • Long A.
      • Byrne A.
      • Harwood R.H.
      • Gladman J.R.F.
      • Schneider S.
      • Logan P.
      • Bosco A.
      • van der Wardt V.
      Exercise interventions for older adults: a systematic review of meta-analyses.
      J. Sport Health Sci. 2021; 10: 29-47https://doi.org/10.1016/j.jshs.2020.06.003
      ;
      • Garatachea N.
      • Pareja-Galeano H.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Fiuza-Luces C.
      • Morán M.
      • Emanuele E.
      • Joyner M.J.
      • Lucia A.
      Exercise attenuates the major hallmarks of aging.
      Rejuvenation Res. 2015; 18: 57-89https://doi.org/10.1089/rej.2014.1623
      ). The missing studies of exercise effect in older pwMS could be due to older pwMS being more likely to have substantial disability (see the following section for further discussion of the impact of disability), however this indicate that they would thus benefit more from exercise. Interestingly, a recent systematic review and meta-analysis by
      • Edwards T.
      • Michelsen A.S.
      • Fakolade A.O.
      • Dalgas U.
      • Pilutti L.A.
      Exercise training improves participation in persons with multiple sclerosis: a systematic review and meta-analysis.
      J. Sport Health Sci. 2021; (S2095254621000892)https://doi.org/10.1016/j.jshs.2021.07.007
      found that the positive effects of exercise across modalities on participation (a complex component of quality of life) in pwMS were not affected by clinical variables. This suggests that exercise can potentially also improve quality of life even late in life, however, this warrants further investigations as no exercise studies have been performed in such populations. In addition, the systematic search revealed no exercise studies performed in the early stages of the disease course (<3 years after diagnosis). This is in line with recent reviews from our group highlighting the limited evidence on early exercise interventions, hence suggesting there could be a “window of opportunity” by introducing exercise at an early stage of the disease (
      • Dalgas U.
      • Langeskov-Christensen M.
      • Stenager E.
      • Riemenschneider M.
      • Hvid L.G.
      Exercise as medicine in multiple sclerosis – time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
      ;
      • Riemenschneider M.
      • Hvid L.G.
      • Stenager E.
      • Dalgas U.
      Is there an overlooked “window of opportunity” in MS exercise therapy? Perspectives for early MS rehabilitation.
      Mult. Scler. J. 2018; 24: 886-894https://doi.org/10.1177/1352458518777377
      ). However, shortly after the review process of the present systematic review, an RCT investigating 48 weeks of aerobic exercise in pwMS with a disease duration ≤2 years was published. Showing positive effects on physical function and brain microstructure in these newly diagnosed pwMS (
      • Riemenschneider M.
      • Hvid L.G.
      • Ringgaard S.
      • Nygaard M.K.E.
      • Eskildsen S.F.
      • Gaemelke T.
      • Magyari M.
      • Jensen H.B.
      • Nielsen H.H.
      • Kant M.
      • Falah M.
      • Petersen T.
      • Stenager E.
      • Dalgas U.
      Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES).
      Mult. Scler. J. 2022; 28: 1620-1629https://doi.org/10.1177/13524585221079200
      ). Supporting the notion that if exercise is initiated before the disease causes irreversible neurological damage, this will offer a superior preventive approach as opposed to the more symptomatic treatment approach currently applied (
      • Riemenschneider M.
      • Hvid L.G.
      • Stenager E.
      • Dalgas U.
      Is there an overlooked “window of opportunity” in MS exercise therapy? Perspectives for early MS rehabilitation.
      Mult. Scler. J. 2018; 24: 886-894https://doi.org/10.1177/1352458518777377
      ). Such an early phase approach is inspired by the medical field, where disease-modifying therapy is recommended to be initiated as early as possible in order to maximize neurological reserve as well as cognitive- and physical function (
      • Giovannoni G.
      • Butzkueven H.
      • Dhib-Jalbut S.
      • Hobart J.
      • Kobelt G.
      • Pepper G.
      • Sormani M.P.
      • Thalheim C.
      • Traboulsee A.
      • Vollmer T.
      Brain health: time matters in multiple sclerosis.
      Mult. Scler. Relat. Disord. 2016; 9: S5-S48https://doi.org/10.1016/j.msard.2016.07.003
      ). This would further implicate that exercise from an early stage should be prescribed as “medicine” (
      • Dalgas U.
      • Langeskov-Christensen M.
      • Stenager E.
      • Riemenschneider M.
      • Hvid L.G.
      Exercise as medicine in multiple sclerosis – time for a paradigm shift: preventive, symptomatic, and disease-modifying aspects and perspectives.
      Curr. Neurol. Neurosci. Rep. 2019; 19: 88https://doi.org/10.1007/s11910-019-1002-3
      ).
      Severe disabilities are infrequently included in MS exercise studies, highlighted by the finding of this present review. This could be due to the increasing difficulty carrying out exercise interventions in pwMS with higher EDSS (
      • Kurtzke J.F.
      Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
      Neurology. 1983; 33 (1444–1444)https://doi.org/10.1212/WNL.33.11.1444
      ;
      • Pilutti L.A.
      • Edwards T.A.
      Is exercise training beneficial in progressive multiple sclerosis?.
      Int. J. MS Care. 2017; 19: 105-112https://doi.org/10.7224/1537-2073.2016-034
      ). However, two studies have evaluated exercise in pwMS with higher disability levels (EDSS ranging from 5.0 to 8.0), showing that both endurance exercise and resistance exercise are feasible and able to induce physiological adaptations (
      • Filipi M.L.
      • Kucera D.L.
      • Filipi E.O.
      • Ridpath A.C.
      • Leuschen M.P.
      Improvement in strength following resistance training in MS patients despite varied disability levels.
      NeuroRehabilitation. 2011; 28: 373-382https://doi.org/10.3233/NRE-2011-0666
      ;
      • Skjerbæk A.G.
      • Næsby M.
      • Lützen K.
      • Møller A.B.
      • Jensen E.
      • Lamers I.
      • Stenager E.
      • Dalgas U.
      Endurance training is feasible in severely disabled patients with progressive multiple sclerosis.
      Mult. Scler. 2014; 20: 627-630https://doi.org/10.1177/1352458513505351
      ). Furthermore, a review by Edwards and Pilutti investigated the effects of exercise in severely disabled pwMS (
      • Edwards T.
      • Pilutti L.A.
      The effect of exercise training in adults with multiple sclerosis with severe mobility disability: a systematic review and future research directions.
      Mult. Scler. Relat. Disord. 2017; 16: 31-39https://doi.org/10.1016/j.msard.2017.06.003
      ) by including studies where some participants had an EDSS>6.0. Their findings showed promising evidence for the benefits of exercise, but some of the included pwMS had EDSS as low as 3.0, and very few of the included studies had solely enrolled participants with an EDSS >6.0 (
      • Edwards T.
      • Pilutti L.A.
      The effect of exercise training in adults with multiple sclerosis with severe mobility disability: a systematic review and future research directions.
      Mult. Scler. Relat. Disord. 2017; 16: 31-39https://doi.org/10.1016/j.msard.2017.06.003
      ). As a consequence, the review does suggest that exercise is feasible in severe MS, whereas the conclusions regarding the effects are less robust (
      • Pilutti L.A.
      • Platta M.E.
      • Motl R.W.
      • Latimer-Cheung A.E.
      The safety of exercise training in multiple sclerosis: a systematic review.
      J. Neurol. Sci. 2014; 343: 3-7https://doi.org/10.1016/j.jns.2014.05.016
      ), emphasizing the need for further studies. This is important as a disability score ≥7.5 is a major risk factor for death, being almost 4 times the rate of healthy controls (
      • Sadovnick A.D.
      • Ebers G.C.
      • Wilson R.W.
      • Paty D.W.
      Life expectancy in patients attending multiple sclerosis clinics.
      Neurology. 1992; 42 (991–991)https://doi.org/10.1212/WNL.42.5.991
      ). Interestingly, data from healthy older adults having high physical activity levels show a substantially reduced mortality rate (
      • Sherman S.E.
      • D'Agostino R.B.
      • Cobb J.L.
      • Kannel W.B.
      Does exercise reduce mortality rates in the elderly? Experience from the Framingham heart study.
      Am. Heart J. 1994; 128: 965-972https://doi.org/10.1016/0002-8703(94)90596-7
      ), suggesting that structured physical activity (i.e., exercise) could be beneficial and perhaps even reduce the increased mortality rate of the severely disabled pwMS.
      Related to the finding that the majority of pwMS included in exercise studies have mild disability, the majority of included pwMS have RRMS (71.8%), while only smaller samples of the patients have either SPMS (17.9%), PPMS (10.0%) or PRMS (0.3%). Although the observed distribution of MS phenotypes across exercise studies does resemble the generally young and middle-aged MS population quite well (
      • Magyari M.
      • Joensen H.
      • Pontieri L.
      Sclerosis Register 2022. Danish Multiple Sclerosis Center, The Danish Sclerosis Register.
      Rigshospitalet and the National Institute of Public Health, University of Southern Denmark, 2022
      ), it can still be questioned whether the existing results from exercise studies can be generalized across all MS phenotypes. At least, it must be considered that the existing evidence is mainly based on data from RRMS patients. Of notice, an increasing focus has been put on exercise and progressive MS in recent years (
      • Pilutti L.A.
      • Edwards T.A.
      Is exercise training beneficial in progressive multiple sclerosis?.
      Int. J. MS Care. 2017; 19: 105-112https://doi.org/10.7224/1537-2073.2016-034
      ). Currently, two largescale exercise studies in progressive MS are being undertaken, the COGEx trial (
      • Feinstein A.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Chiaravalloti N.
      • Dalgas U.
      • DeLuca J.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Meza C.
      • Inglese M.
      • Motl R.W.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      on behalf of the COGEx Reseach Team
      Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx).
      BMC Neurol. 2020; 20: 204https://doi.org/10.1186/s12883-020-01772-7
      ) and the CYPRO trial (NCT05229861), underlining that high-quality studies will appear for this subgroup of patients in the near future.

      5. Clinical implications

      In May 2020, the National MS Society in the US posted recommendations for exercise to all pwMS, based on a review from the same year (
      • Kalb R.
      • Brown T.R.
      • Coote S.
      • Costello K.
      • Dalgas U.
      • Garmon E.
      • Giesser B.
      • Halper J.
      • Karpatkin H.
      • Keller J.
      • Ng A.V.
      • Pilutti L.A.
      • Rohrig A.
      • Van Asch P.
      • Zackowski K.
      • Motl R.W.
      Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.
      Mult. Scler. J. 2020; 26: 1459-1469https://doi.org/10.1177/1352458520915629
      ). These recommendations were published by some of the leading researchers and experts in the field and aimed to provide recommendations for clinicians treating pwMS (
      • Kalb R.
      • Brown T.R.
      • Coote S.
      • Costello K.
      • Dalgas U.
      • Garmon E.
      • Giesser B.
      • Halper J.
      • Karpatkin H.
      • Keller J.
      • Ng A.V.
      • Pilutti L.A.
      • Rohrig A.
      • Van Asch P.
      • Zackowski K.
      • Motl R.W.
      Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.
      Mult. Scler. J. 2020; 26: 1459-1469https://doi.org/10.1177/1352458520915629
      ). The recommendations are categorized according to EDSS subgroups (0-4.5, 5.0-6.5, 7.0-7.5, 8.0-8.5, and 9.0) and were based on both evidence and expert consensus when necessary (
      • Kalb R.
      • Brown T.R.
      • Coote S.
      • Costello K.
      • Dalgas U.
      • Garmon E.
      • Giesser B.
      • Halper J.
      • Karpatkin H.
      • Keller J.
      • Ng A.V.
      • Pilutti L.A.
      • Rohrig A.
      • Van Asch P.
      • Zackowski K.
      • Motl R.W.
      Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.
      Mult. Scler. J. 2020; 26: 1459-1469https://doi.org/10.1177/1352458520915629
      ). However, the present review finds only one exercise study investigating exercise in pwMS with EDSS ≥7.0. This entail that future exercise recommendation would benefit from more exercise studies in severely disabled pwMS, as for now expert opinion is the best resource in the development of recommendations for pwMS with EDSS ≥7.0. The same applies to old pwMS and pwMS with short (<4.5y) or long (>20y) disease duration. Together this underlines the need for further exercise studies in select MS subgroups, even though this introduces several challenges, in particular related to the most severely disabled pwMS.

      6. Limitations

      When interpreting the results from the present review, various limitations must be kept in mind. First, this review follows the PRISMA guidelines for systematic reviews, except that no quality assessment of the included studies was performed. This was omitted as several different study designs were included, which makes it complex to facilitate via one single quality assessment tool. Furthermore, the review does not evaluate the outcomes/effects of the included studies, however, it exclusively maps the demographic and clinical data of the pwMS included in the existing exercise studies. Second, since exercise can be somewhat difficult to define, the applied definition could potentially exclude studies that would be considered exercise studies by some. Third, it is acknowledged that the categorization of age groups, EDSS groups, and disease duration groups is based on average values reported by the identified studies. Consequently, some studies may have enrolled participants that are within the range of some of the sparsely investigated MS subgroups. Fourth, the distinction between RCT and pilot RCT was based solely on the author's own description of the study design in the papers. Hence, an objective distinction between RCT and pilot RCT was not made, potentially leading to some RCT and pilot RCT being very similar, e.g. in relation to sample size.

      7. Conclusion

      The present review identified a large body of exercise studies (n = 202) evaluating exercise in pwMS. These studies primarily included middle-aged (35-54 years) pwMS having disability scores of 2.0-6.5 and a disease duration of 5-14.5 years. Exercise studies have mainly evaluated short-lasting (≤ 12 weeks) endurance exercise and combined exercise interventions. Very few studies evaluating exercise interventions were identified in young (<35 years) or older (>54 years) MS populations, as well as in pwMS with mild (<2.0) or severe (>6.5) disability scores (EDSS) and short (<5 years) or long (>15 years) disease durations. Our findings suggest that no well-founded evidence-based guidelines for exercise can be given to these specific groups of pwMS, encouraging future exercise studies and research in these under-investigated MS subpopulations.

      Funding

      The study received no funding.

      Availability of data and material

      Data will be shared upon reasonable request to the corresponding author.

      CRediT authorship contribution statement

      Tobias Gaemelke: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Jens Jakob Frandsen: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Lars G. Hvid: Conceptualization, Methodology, Writing – review & editing. Ulrik Dalgas: Conceptualization, Methodology, Writing – review & editing.

      Declaration of Competing Interest

      No competing interest to declare.

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