Methods

Design: random assignment to aerobic treadmill training (AT), yoga (Y) or a wait‐list control (NEX)

Setting: physiotherapy clinic, Iran

Categorization: AT = endurance, Y = other

Participants

n = 31; AT = 10, Y = 11, NEX = 10

Inclusion criteria: physician diagnosis MS, self reported EDSS 1 >< 4.0, able to walk a treadmill > 5 minutes at stable speed, no physical activity in the last 3 months

Exclusion criteria: cardiovascular disease, liver or kidney failure, lung disease, diabetes, thyroid disorder, gout or orthopaedic limitations, pregnant, addicted (i.e. smoking)

Type MS: ?

Disease duration (yr) ± SD: AT = 5.6 ± 3.3, Y = 4.7 ± 5.6, NEX = 5.0 ± 3.1

Mean age (yr) ± SD: AT = 36.8 ± 9.2, Y = 32.3 ± 8.7, NEX = 36.7 ± 9.3

% Female: 100%

Mean EDSS ± SD: AT = 2.4 ± 1.2, Y = 2.0 ± 1.1, NEX = 2.3 ± 1.3

Interventions

AT: 8 weeks, 3x per week, 30 minutes physiotherapist‐led treadmill training at 40‐75% of predicted maximal heart rate + 20 minutes of stretching. Comfortable walking speed as starting point, progression directed by participant

Y: 8 weeks, 3x per week, 60‐70 minutes Hatha yoga led by a physiotherapist and neurologist. Hatha yoga included stretching, postures, breathing, and meditation

NEX: wait list control

Outcomes

FSS, BDI, BAI, BBS, 10MWT, 2MWT (walking speed, walking endurance)

Notes

Drop‐outs

No drop‐outs reported

Measurements

Baseline, 8 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs reported

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to supervised hospital‐based callisthenic exercise (EX) OR home‐based callisthenic exercise (Home‐EX)

Setting: outpatient clinic, Iran

Categorization: EX = muscle power, Home‐EX = muscle power

Participants

n = 40; EX = 20, Home‐EX = 20

Inclusion criteria: RRMS, EDSS < 4.5, aged 18‐50 years

Exclusion criteria: acute exacerbation; Ashworth spasticity score > 2.0; thyroid disorder; history of serious psychiatric disorders, alcohol abuse, or other chronic diseases

Type MS: RRMS

Disease duration (yr) ± SD: EX = 6.43 ± 2.78, Home‐EX = 7.40 ± 3.43

Mean age (yr) ± SD: EX = 32.62 ± 3.15, Home‐EX = 33.00 ± 4.06

% Female (n/n group): EX = 9/16, Home‐EX = 11/20

Mean EDSS ± SD: EX = 3.6 ± 1.3, Home‐EX = 3.4 ± 2.1

Interventions

EX: 12 weeks, 5x per week, 60 minutes hospital‐based exercise supervised by a physiatrist. 3 out 5 session/week were callisthenic exercise (60 minutes), 2 out of 5 sessions were relaxation exercises (20 minutes). Callisthenic exercises were focused on the large muscles and were applied rhythmically and in combination with breathing exercises. The callisthenic training sessions consisted of 15 minutes' warming up, 20 minutes' intensive training, 10 minutes' cooling down, and 15 minutes' relaxation

Home‐EX: same as EX yet participants were asked to perform the exercise at home and their exercise schedule was followed by telephone every day

Outcomes

FSS, 10MWT, BBS, MusiQoL, HADS

Notes

Drop‐outs

EX: 2 failure to adapt to exercise, 2 transportation problems

Home‐EX: no drop‐outs

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated numbers

Allocation concealment (selection bias)

Low risk

Concealed allocation procedure

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Drop‐out rate of 10% in the exercise condition, 0 drop‐outs reported in the control condition

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to Ergometer Land Group (ELG) or Ergometer Water Group (EWG)

Setting: Department of Sports Therapy, Rehabilitationsklinik Valens, Valens, Switzerland

Categorization: ELG = endurance, EWG = endurance

Participants

n = 60; ELG = 30, EWG = 30

Inclusion criteria: EDSS 1.0‐6.5

Exclusion criteria: incontinent, persistent infections, cardiovascular and pulmonary diseases, or immunosuppressive therapy

Type MS: ?

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: ELG = 52 ± 14.2, EWG = 50 ± 14.2

% Female (n/n group): ELG = 18/28, EWG = 17/25

Mean EDSS ± SD: ELG = 4.7 ± 1.5, EWG = 4.6 ± 1.4

Interventions

ELG: 3 weeks, 5x per week; 30‐minute physiotherapist‐led overland ergometry training at 60% of peak oxygen uptake/70% maximal heart rate

EWG: 3 weeks, 5x per week; 30‐minute physiotherapist‐led aquatic training at 70% maximal heart rate corrected for water temperature (‐7 beats per minute). Water temperature at 28°C

Outcomes

FSMC, neurotrophin, cytokines

Notes

Drop‐outs

ELG: 2 immunosuppressive medication during training

EWG: 3 immunosuppressive medication during training, 3 unable to comply with daily time schedule

Measurements

Baseline, 3 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate < 15%, without indications of differences in reasons

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to Nintendo^® Wii^® balance training (EX) or control (NEX)

Setting: Italian Multiple Sclerosis Foundation, Genoa, Italy

Categorization: EX = other

Participants

n = 36; EX = 18, NEX = 18

Inclusion criteria: no relapse < 6 months, EDSS ≤ 6.0, Ambulation Index ≤ 4

Exclusion criteria: psychiatric disorder, blurred vision, severe cognitive impairment

Type MS: ?

Disease duration (yr) ± SD: EX = 11.2 ± 6.4, NEX = 12.3 ± 7.2

Mean age (yr) ± SD: EX = 40.7 ± 11.5, NEX = 43.2 ± 10.6

% Female (n/n group): EX = 10/18, NEX = 12/18

Mean EDSS ± SD: EX = 3.9 ± 1.6, NEX = 4.3 ± 1.6

Interventions

EX: 4 weeks, 3x per week; 1 hour Nintendo^® Wii^® balance board training. Special focus on soccer heading, skiing, table tilt, snowboarding, tight rope walking, and zazen (relaxation)

NEX: 4 weeks, 3x per week; 1 hour static and dynamic lower body exercise using single and double leg stances with or without an equilibrium board

Outcomes

MFIS, BBS, open and closed eye stabilometry

Notes

Drop‐outs

No drop‐outs reported

Measurements

Baseline, 4 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Biased‐coin randomization procedure

Allocation concealment (selection bias)

Unclear risk

Allocation concealment procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs reported

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to arm‐cycling (ARM), rowing (ROW), bicycling (BIC), and a control (NEX)

Setting: MS outpatient clinic, Germany

Categorization: ARM = endurance, ROW = endurance, BIC = endurance

Participants

n = 47; ARM = 12, ROW = 12, BIC = 12, NEX = 11

Inclusion criteria: definite secondary‐progressive or primary‐progressive MS, EDSS 4.0‐6.0

Exclusion criteria: contraindications for exercise, start immunomodulatory treatment < 6 months, steroid treatment < 4 weeks, MS relapse < 12 months, abnormal liver or kidney function, immunodeficiency, other serious medical illness or psychiatric, developmental or neurological disorder

Type MS: SPMS and PPMS

Disease duration (yr) ± SD: ARM = 17.1 ± 7.2, ROW = 14.1 ± 6.1, BIC = 13.3 ± 5.4, NEX = 18.9 ± 9.8

Mean age (yr) ± SD: ARM = 49.1 ± 8.5, ROW = 50.9 ± 9.2, BIC = 48.8 ± 6.8, NEX = 50.4 ± 7.6

% Female (n/n group): ARM = 5/10, ROW = 7/11 , BIC = 6/11 , NEX = 6/10

Mean EDSS ± SD: ARM = 5.2 ± 0.9, ROW = 4.7 ± 0.8, BIC = 5.0 ± 0.8, NEX = 4.9 ± 0.9

Interventions

ARM, ROW, and BIC: 8‐10 weeks, 2 or 3 times per week, 15‐45 minutes aerobic training led by licensed physiotherapists at the individual determined aerobic threshold (AT), 120%AT and 130%AT. Aim was to perform 20 training sessions in which the time spent at the higher levels was increased. Only the mode of exercise (i.e. ARM, ROW, or BIC) different between groups

NEX: wait list control

Outcomes

MFIS, VO_2peak, 6MWT, SDMT, VLMT, TAP, LPS, RWT, IDS ‐ SR30

Notes

Drop‐outs

ARM: 1, logistics + 1 did not receive allocated intervention

ROW: 1, unrelated injury

BIC: 1, fatigued

NEX: 1, lost to follow‐up

Measurements

Baseline, 8‐10 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Automated biased coin procedure

Allocation concealment (selection bias)

Low risk

Randomization after determining eligibility

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 10%, equally balanced across groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: Random assignment to Tai Chi (EX) or treatment as usual (NEX)

Setting: Department of neurology, Bayreuth, Germany

Categorization: EX = other

Participants

n = 38; EX = 21, NEX = 17

Inclusion criteria: diagnosis of any type of MS, able to walk without a walking aid, EDSS < 5, relapse‐free < 4 weeks

Exclusion criteria: severe cognitive impairment

Type MS: RRMS, SPMS, and clinically isolated syndrome (n = 1)

Disease duration (yr) ± SD: EX = 6.0 ± 4.7, NEX = 7.8 ± 6.8

Mean age (yr) ± SD: EX = 42.6 ± 9.4, NEX = 43.6 ± 8.0

%Female (n/n group): EX = 10/15, NEX = 12/17

Median EDSS (range): EX = 2 (1‐4), NEX = 4 (1‐4.5)

Interventions

EX: 6 months, 1x per week, 90 minutes of centre‐based, structured, compact Tai Chi. The Tai Chi programme was based on the Yang‐style 10‐form. Exercises were structured so that during each session of the course, the same essential elements were repeated

NEX: treatment as usual

Outcomes

FSMC, balance, co‐ordination, CES‐D, QLS

Notes

Drop‐outs

EX: 5 time constraints, 1 health problems

Measurements

Baseline, 6 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Assignment to EX or NEX was based on participants' weekday preference

Allocation concealment (selection bias)

High risk

Unconcealed allocation

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Drop‐out rate in EX group was 29%, no drop‐outs reported in the control condition. In the EX group, adherence varied between 15 and 44 out of 50 classes offered

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Unclear risk

There was an apparent (yet non‐significant) difference in the disease severity and baseline fatigue scores between the EX and NEX group

Methods

Design: random assignment to progressive resistance training group (PRT), home‐based resistance training (EX), or control (NEX)

Setting: rehabilitation clinic, Ankara, Turkey

Categorization: PRT = muscle power, EX = muscle power

Participants

n = 45; PRT = 15, EX = 15, NEX = 15

Inclusion criteria: definite RRMS or SPMS, EDSS ≤ 6.0 stand upright > 4 seconds, no steroid or immunosuppressive therapy (or both) < 1 month

Exclusion criteria: severe MS, acute exacerbation, active physical therapy or regular exercise training programme < 1 month, unable to cycle a static bike, visual involvement or diplopia, high level of spasticity, persistent severe fatigue or depression

Type MS: RRMS or SPMS

Disease duration (yr) ± SD: PRT = 9.2 ± 5.0, EX = 6.2 ± 2.2, NEX = 6.6 ± 2.4

Mean age (yr) ± SD: PRT = 36.4 ± 10.5, EX = 43.0 ± 10.2, NEX = 35.5 ± 10.9

%Female (n/n group): PRT = 9/14, EX = 8/10, NEX = 6/9

Mean EDSS ± SD: ?

Interventions

PRT: 2x per week for 8 weeks; 30 minutes' cycling progressive resistance training, 5 minutes' walking/stretching and 20‐25 minutes' balance exercises supervised by a physiatrist

EX: 2x per week for 8 weeks; home‐based exercise programme consisting of 5 minutes' walking/stretching and 20‐25 minutes' balance exercises

NEX: wait list

Outcomes

FSS, number of relapses, duration of exercise, W_max, TUG, DGI, FR, FES, 10MWT, BDI, SF‐36

Notes

Drop‐outs

PRT: 1 acute exacerbation

EX : 2 work‐related, 2 acute exacerbation, 1 unknown

NEX: 3 acute exacerbation, 3 unknown

Measurements

Baseline, 8 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers were used

Allocation concealment (selection bias)

Unclear risk

Unclear who performed the randomization procedure

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate was 27%, with a relative higher drop‐out rate in the control (40%) versus the exercise group (combined 20%). However, no indications for differences in reasons between groups

Selective reporting (reporting bias)

Low risk

All introduced outcomes were reported

Other bias

High risk

The PRT intervention included group‐based components

Methods

Design: random assignment to pragmatic exercise intervention + usual care (EX) or usual care (NEX)

Setting: MS clinic, UK

Categorization: EX = mixed

Participants

n = 120; EX = 60, NEX = 60

Inclusion criteria: clinical diagnosis MS, EDSS 1‐6.5, able to walk 10 metres, aged 18‐65 years, clinically stable, and stable medical treatment < 3 months

Exclusion criteria: structured exercise ≥ 3x per week, ≥ 30 minutes; living ≥ 20 minutes travelling from study centre, co‐morbid conditions precluding exercise participation

Type MS: RRMS, SPMS, and PPMS

Disease duration (yr) ± SD: EX = 8.4 ± 7.4, NEX = 9.2 ± 7.9

Mean age (yr) ± SD: EX = 45.7 ± 9.1, NEX = 46.8 ± 8.4

% Female (n/n group): EX = 43/60, NEX = 43/60

Mean EDSS ± SD: EX = 3.8 ± 1.5, NEX = 3.8 ± 1.5

Interventions

EX: 12 weeks, 3x per week; partly home based with more supervised sessions in the first 6 weeks of the intervention and vice‐versa in the second 6 weeks. Short bouts (5 x 3 minutes) of low to moderate intensity aerobic exercise at 50‐69% of predicted maximal heart rate or 12‐14 on the BORG scale. Participants were encouraged during the intervention period to increase the duration of the bouts or reduce the resting time in between bouts. When appropriate, participants could also perform 6 different resistance exercises using body resistance, light weights, or Therabands. Generally, 1‐3 sets of 20 repetitions based on the participant's level of disability, strength, and stage of the programme. In case of balance or control problems, also balance board and exercise ball work was included. The supervised exercise sessions included also cognitive behavioural techniques to promote long‐term physical activity behaviour

NEX: usual care

Outcomes

MFIS, GLTEQ, Accelerometer, MSQoL‐54, MSFC, 6MWT, EDSS

Notes

Drop‐outs

EX: 2 relapse, 2 ill health, 1 poor adherence, 6 unable to contact

NEX: 1 relapse, 2 ill health, 1 work commitments, 1 no reason give, 5 unable to contact

Measurements

Baseline, 12 weeks, 6 months' follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Distant randomization service; minimization according to gender and EDSS. Allocation not disclosed until after baseline measurement

Allocation concealment (selection bias)

Low risk

Independent and off‐site randomization service

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop‐out rate in the combined exercise group was 17%, in the control group 18%. No indication for differences in reasons

Selective reporting (reporting bias)

Low risk

Study protocol published

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to Ai‐Chi aquatic exercise programme (EX) or control group (NEX)

Setting: Multiple Sclerosis Association of Almeria, Almeria, Spain

Categorization: EX = other

Participants

n = 73; EX = 36, NEX = 37

Inclusion criteria: diagnosis MS, aged 18‐75 years, VAS pain score > 4 for at least two months, EDSS ≤ 7.5

Exclusion criteria: treatment with other complementary and alternative medicine ≤ 3 months, relapse requiring hospitalization or steroid treatment ≤ 2 months

Type MS: ?

Disease duration (yr) ± SD: EX = 10.7 ± 9.1, NEX = 11.9 ± 8.7

Age (yr): EX = 46 ± 9.97, NEX = 50 ± 12.31

% Female (n/n group): EX = 26/36, NEX = 24/37

Mean EDSS ± SD: EX = 6.3 ± 0.8, NEX = 5.9 ± 0.9

Interventions

EX: Ai‐Chi exercise programme (20 weeks, 2x per week, 60 minutes per session) in shoulder‐depth 36°C water; consisting of 16 different slow and broad movements of the arms, legs, and torso to work on balance, strength, relaxation, flexibility, and breathing. Each physiotherapist‐led session began and ended with 10 minutes of relaxation. During the course of each session relaxing tai‐chi music was played

NEX: 20 weeks, 2x per week, 60 minutes per session led by a physiotherapist identical to the 10‐minute relaxation (breathing, contraction ‐ relaxation) periods of the intervention group yet in a therapy room (26°C), on an exercise mat without ambient music

Outcomes

FSS, MFIS, number of relapses, pain (VAS), MPQ‐PRI, MPQ‐PPI, RMDQ, spasm (VAS), MSIS‐29, BDI, BI

Notes

Drop‐outs

NEX: 2 relapsed

Measurements

Baseline, 20 weeks, 24 weeks, 30 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random list

Allocation concealment (selection bias)

Low risk

Participants were randomly assigned by a blinded researcher

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop‐out rate was 3%

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Unclear risk

Large proportion of participants with unknown disease course despite 'a definite diagnosis of MS' as inclusion criterion

Methods

Design: random assignment to continuous (CON), intermittent (INT), or mixed endurance training (CB)

Setting: Oxford Brookes University and at 4 community leisure centres, London, UK

Categorization: CON = endurance, INT = endurance, CB = endurance

Participants

n = 61; CON = 20, INT = 18, CB = 20

Inclusion criteria: none

Exclusion criteria: medical condition precluding safe exercise, unable to walk 2 minutes, unable to sit 60 seconds on cycling ergometer and pedal 60 seconds with no resistance

Type MS: RRMS, SPMS, PPMS and unknown

Disease duration (yr) ± SD: CON = 15 ± 8, INT = 11 ± 7, CB = 12 ± 11

Mean age (yr) ± SD: CON = 52 ± 8, INT = 50 ± 10, CB = 55 ± 10

% Female (n/n group): CON = 16/20, INT = 14/18, CB = 9/17

Mean EDSS ± SD: ?

Interventions

CON: 12 weeks, 2x per week; 20 minutes supervised continuous endurance training at 45% of maximal power

INT: 12 weeks, 2x per week; 20 minutes of supervised intermittent endurance training consisting of 30 seconds at 90% maximal power, 30 seconds rest

CB: 12 weeks, 2x per week; 20 minutes of supervised intermittent (10 minutes) endurance training followed by continuous endurance training (10 minutes)

Outcomes

FSS, 2MWT, TUG, leg extensor power, BI, SF‐36

Notes

Drop‐outs

CON: no drop‐outs

INT: 1 loss of consciousness during intervention, 1 exacerbation of symptoms, 1 knee pain during cycling, 1 leg pain during cycling

CB: 1 exacerbation of knee injury, 1 leg pain during cycling

Measurements

Baseline, 6 weeks, 12 weeks (post‐intervention), 24 weeks (follow‐up)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomization list

Allocation concealment (selection bias)

Low risk

Central randomization by statistician

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate 10%, unequally balanced in favour of the continuous exercise protocol versus the intermittent and combined protocol

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to progressive resistance training (PRT) or progressive resistance training augmented by neuromuscular electrical stimulation (NMES)

Setting: MS Society, Ireland

Categorization: PRT = muscle power, NMES = muscle power

Participants

n = 37; PRT = 18, NMES = 19

Inclusion criteria: definite MS, use of walking aid most of the time, and could walk at least 10 metres unaided

Exclusion criteria: contraindications to electrical stimulation, had participated in an exercise programme < 1 month, relapse or steroid treatment < 3 months

Type MS: RRMS, PPMS, SPMS, benign, unknown

Disease duration (yr) ± SD: PRT = 12.2 ± 4, NMES = 11.8 ± 5.5

Mean age (yr) ± SD: PRT = 51.8 ± 12.1, NMES = 51.8 ± 12.6

% Female (n/n group): PRT = 6/10, NMES = 11/15

Mean EDSS ± SD: ?

Interventions

PRT: 12 weeks, 2x per week for weeks 1‐6, 3x per week for week 7‐12. The programme consisted of 6 lower limb exercises performed in the home environment. Participants progressed from 1 set of 12 repetitions to 3 sets of 12 repetitions. Once 3 sets of 12 repetitions could be completed, free‐weights in the hands, around the ankle, or in a backpack were added in increments of 0.5 or 1 kg as advised during weekly telephone calls. Rest period of 2‐3 minutes between sets were advised

NMES: participants in the NMES group followed the same PRT programme while wearing The Kneehab®. The Kneehab® is a synthetic garment that consists of 4 electrodes strategically placed to activate the quadriceps muscle through a novel Multipath® system. It is placed on the thigh and attached using Velcro fastenings. The pre‐set programme parameters used were a frequency of 50 Hz, on/off time 5/10 seconds, ramp up/down of 1/0.5 seconds. Participants were encouraged to use the highest tolerable intensity

Outcomes

MFIS, muscle strength and endurance, VAS lower limb spasticity, TUG, MSWS‐12, BBS, MSIS29v2

Notes

Drop‐outs

PRT: 3 relapse, 2 musculoskeletal injury, 2 MS‐related fatigue, 1 non‐compliance

NMES: 2 muscle spasm with device use, 1 non‐compliance, 1 medical problem

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

60 randomizations were generated by repeatedly drawing cards from a pool of 3 PRT and 3 NMES cards

Allocation concealment (selection bias)

Low risk

'The sequence of allocation was concealed from all study personnel'

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate was 32%, with indications for differences in reasons

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other bias identified

Methods

Design: random assignment to progressive resistance training (EX) or control (NEX) stratified by gender

Setting: outpatients MS Clinic, Aarhus University Hospital, Aarhus, Denmark

Categorization: EX = muscle power

Participants

n = 38; EX = 19, NEX = 19

Inclusion criteria: definite RRMS according to McDonald criteria, EDSS 3.0 ≥ ≤ 5.5; pyramid function score ≥ 2.0, ability to walk ≥ 100 metres, no help with transportation to training facility, aged > 18 years, acceptation of diagnosis and treatment

Exclusion criteria: serious medical co‐morbidities, MS attack < 2 months, pregnant, systematic resistance training < 3 months

Type MS: RRMS

Disease duration (yr) ± SD: EX = 6.6 ± 5.9, NEX = 8.1 ± 6.0

Mean age (yr) ± SD: EX = 47.7 ± 10.4 NEX = 49.1 ± 8.4

% Female (n/n group): EX = 10/15, NEX = 10/16

Mean EDSS ± SD: EX = 3.7 ± 0.9, NEX = 3.9 ± 0.9

Interventions

EX: progressive resistance training (PRT) programme (12 weeks, 2x per week). 5 minutes warm‐up on stationary bike followed by leg press, knee extension, hip flexion, hamstring curl, and hip extension exercises. Progression was achieved by decreasing the repetition maximum (15RM ‐ 8RM) and varying the number of sets (3 or 4) and repetitions (8‐12). Between sets and exercises 2‐3 minutes of rest was allowed. All sessions were supervised and in groups of 2‐4 participants

NEX: no training; training programme offered at completion of trial

Outcomes

FSS, MFI‐20 (sub‐scales), MDI, SF‐36 (PCS, MCS), muscle strength, functional capacity

Notes

Drop‐outs

EX: 1 lower back problems, 1 sick relative, 1 personal problems, 1 lack of time

NEX: 1 personal problems, 1 broken arm, 1 problems with psoriasis

Measurements

Baseline, 12 weeks, 24 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information on sequence generation provided

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 18%, equally balanced across the exercise group (21%) and control group (16%). No indication for differences in reasons or reasons related to the exercise condition. Adherence to exercise regimen > 80%

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Unclear risk

Imbalance in attention between NEX and EX

Methods

Design: random assignment to endurance training (EX) and control treatment (NEX)

Setting: inpatient rehabilitation unit, Schmieder Konstanz clinic, Konstanz, Germany

Categorization: EX = endurance

Participants

n = 30; EX = 16 (see drop‐outs), NEX = 15

Inclusion criteria: mild to moderate MS (EDSS < 4.5), complained of fatigue, walking distance < 2500 metres

Exclusion criteria: serious leg weakness (degree of paresis < 4), ataxia at rest, spasticity at rest, relapse < 3 months, corticosteroid treatment < 3 months, prominent cognitive deficits, major depression, insufficient motivation for additional training

Type MS: RRMS, SPMS, PPMS

Disease duration (yr) ± SD: EX = 8.0 ± 5.9, NEX = 6.1 ± 4.3

Mean age (yr) ± SD: EX = 45.8 ± 7.9, NEX = 39.7 ± 9.1

% Female (n/n group): EX = 10/15, NEX = 11/15

Mean EDSS ± SD: EX = 2.6 ± 1.2, NEX = 2.8 ± 0.7

Interventions

EX: 3 weeks, 3x per week, 45 minutes per session. Warming up, mild strength training, repetitive endurance exercise followed by relaxation and feedback. All sessions were supervised and playful elements were introduced to camouflage training difficulties

NEX: 3 weeks, 3x per week, 45 minutes per session. Warming up, sensory training, stretching, balance, co‐ordination training, and periods of relaxation

Outcomes

MFIS, FSMC, maximal walking distance, relative walking ability, BDI, HAQUAMS

Notes

Drop‐outs

EX: 1 training too demanding; replaced by a newly recruited 16th participant

Measurements

Baseline, 3 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random order list

Allocation concealment (selection bias)

Unclear risk

Allocation concealment procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

6% drop‐out rate in the exercise condition. However, only 19 of 30 forms completed at discharge (63%)

Selective reporting (reporting bias)

High risk

No point and variance measures reported

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to group progressive resistance training programme (EX) or usual care in combination with a social programme (NEX); stratified by ambulation index score

Setting: MS outpatient clinic, Victoria, Australia

Categorization: EX = muscle power

Participants

n = 76; EX = 39, NEX = 37

Inclusion criteria: aged ≥ 18 years, confirmed RRMS, Ambulation index score of 2, 3, or 4, medical clearance to participate

Exclusion criteria: acute exacerbation < 2 months, benign or progressive/relapsing types of MS, serious unstable medical condition, any concurrent condition, progressive resistance training < 6 months

Type MS: RRMS

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: EX = 47.7 ± 10.8, NEX = 50.4 ± 9.6

% Female (n/n group): EX = 26/36, NEX = 26/35

Mean EDSS ± SD: ?

Interventions

EX: group PRT programme (10 weeks, 2x per week). Exercise targeted the key lower limb muscles for supporting body weight and for generating and absorbing power during walking (leg press, knee extension, calf raise, leg curl, and reverse leg press). Training intensity was 10‐12 repetitions at 10‐12 repetition maximum. Load was increased if 2 sets of 12 repetitions were completed. 2 minutes rest between each set

NEX: usual care + social programme 1 hour per week

Outcomes

MFIS, MSSS‐88, adverse events, number of relapses, 2MWT, 1RM seated leg press, 1RM reversed leg press, WHOQoL‐BREF

Notes

Drop‐outs

EX: 3 withdrew after allocation (2 experienced relapse but did attend assessment)

NEX: 2 withdrew after allocation, 3 experienced relapse, 1 did not attend at follow‐up

Measurements

Baseline, 10 weeks, 22 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Separate randomization procedure for each stratum using permuted blocks

Allocation concealment (selection bias)

Low risk

Sealed, opaque envelopes made by research co‐ordinator

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate 12%. Not equally balanced across the exercise (8%) and control group (16%); however, no indication for differences in reasons taken into account the 2 participants who did have a relapse but attended the assessment

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: internet‐based home training (IBT) versus hippotherapy (HT)

Setting: regional MS groups, Germany

Categorization: IBT = other, HT = other

Participants

n = 18; IBT = 9, HT = 9

Inclusion criteria: definite MS, EDSS 2‐6, aged 18‐60 years, clinically stable < 4 weeks

Exclusion criteria: internal or orthopaedic diseases unrelated to MS, allergy or aversion to horses, previous hippotherapy post‐diagnosis

Type MS: RRMS and SPMS

Disease duration (yr) ± SD: IBT = 16.1 ± 11.3, HT = 22.3 ± 8.3

Mean age (yr) ± SD: IBT = 44.3 ± 8.1, HT = 46.9 ± 7.6

% Female (n/n group): IBT = 7/9, HT = 8/9

Mean EDSS ± SD: IBT = 3.8 ± 1.5, HT = 3.8 ± 1.1

Interventions

IBT: 12 weeks, 2x per week, 45 minutes' balance and strength e‐training; exercise performed on unstable surface in eyes open or closed condition. 5‐8 different exercise, 2‐3 sets, 8‐15 repetitions. BORG 11‐14. Perceived exertion monitored by physical therapist

HT: 12 weeks, 12x per week, 30 minutes' balance exercises by means of horse riding exercises and riding patterns/movements

Outcomes

MFIS, FSS, BBS, DGI, isometric muscle strength, TUG, 2MWT, HAQUAMS

Notes

Drop‐outs

IBT: 1 unable to work with computer

HT: 1 MS relapse

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Drawing lots

Allocation concealment (selection bias)

Low risk

Opaque envelopes were used

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate 11% equally balanced across groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to home‐based inspiratory muscle training (EX) or control (NEX)

Setting: Physical Therapy Department, University of Michigan‐Flint, Flint, Michigan, USA

Categorization: EX = other

Participants

n = 46; EX = 23, NEX = 23

Inclusion criteria: ambulatory, aged ≥ 18 years

Exclusion criteria: acute respiratory infection, oral temperature > 100°F (37.8°C), smoking, cardiac of musculoskeletal condition unrelated to MS

Type MS: RRMS, SPMS, PPMS or primary relapsing MS

Disease duration (yr): ?

Mean age (yr) ± SD: EX = 50 ± 9.1, NEX = 46.2 ± 9.4

% Female (n/n group): EX = 21/23, NEX = 17/23

Mean EDSS ± SD: EX = 3.96 ± 1.80, NEX = 3.36 ± 1.47

Interventions

EX: 10 weeks, daily; 3x 15 repetitions of home‐based Inspiratory muscle training using a Threshold Inspiratory Muscle Trainer. Resistance was adjusted to match a perceived exertion of 15, 16 on the BORG scale

NEX: no intervention; informative telephone call 4, 8, and 10 weeks

Outcomes

FSS, 6MWT, PCI, RPE

Notes

Drop‐outs

2 due to illness unrelated to a neurological exacerbation, 3 no longer wished to participate

Measurements

Baseline, 10 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Randomized by date of enrolment

Allocation concealment (selection bias)

High risk

Researcher could foresee date of enrolment

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Overall drop‐out rate 11%. No information provided on the distribution between groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to robot‐assisted gait training (RAGT) or sensory integration balance training (SIBT)

Setting: outpatient clinic, Neurological Rehabilitation Unit, Italy

Categorization: RAGT = other, SIBT = other

Participants

n = 26; RAGT = 14, SIBT = 12

Inclusion criteria: aged 30‐60 years, EDSS 1.5‐6.5, MMSE > 23, ability to maintain standing position without aids for at least 1 minute and ability to walk independently for at least 15 metres, absence of concomitant neurological or orthopaedic conditions that may interfere with ambulation

Exclusion criteria: any rehabilitation treatment < 1 month, MS relapse < 3 months, pharmacological treatment not well defined or changed during study, presence of paroxysmal vertigo, lower limb botulinum toxin injections < 12 weeks

Type MS: RRMS or SPMS

Disease duration (yr): RAGT = 13.5 ± 7.6, SIBT = 14.9 ± 8.68

Mean age (yr) ± SD: RAGT = 50.83 ± 8.42, SIBT = 50.1 ± 6.29

% Female (n/n group): RAGT = 7/12, SIBT = 9/10

Mean EDSS ± SD: RAGT = 3.96 ± 0.75, SIBT = 4.35 ± 0.67

Interventions

RAGT: 6 weeks, 2x per week, 50‐minute individual sessions of RAGT. The RAGT group was treated by means of the electromechanical Gati Trainer GT1 (Reha‐stim, Berlin, Germany). Participants received 40 minutes of RAGT followed by 10 passive lower limb joint mobilizations and stretching exercises. Each training consisted of 2 x 15‐minute sessions separated by 5 minutes of rest if required. The first session was performed at 20% supported body‐weight and 1.3 km/hour speed; the second sessions at 10% supported body weight and 1.6 km/hour speed

SIBT: 6 weeks, 2x per week, 50‐minute individual sensory integration balance training. Each session consisted of exercises fitting to 3 different levels of difficulty and repeated under 3 different sensory conditions (free vision, wearing a mask, and wearing a helmet). Level I included tasks that induced external destabilization of the centre‐of‐body mass (CoP). Level II included exercises of self destabilization of the CoP. Level III consisted of exercises of external destabilization and exercise of self destabilization of CoP while standing on different types of compliant surfaces. During each treatment session, a total of 10 exercises (3 from level I, 3 from level II and 4 from level III) were repeated 2‐5 times with a 5‐minute period

Outcomes

FSS, spatiotemporal gait parameters, BBS, SOT, stabilometric assessment, MSQoL‐54, ABC

Notes

Drop‐outs

RAGT: 2 difficulties in transportation

SIBT: 2 medical complications

Measurements

Baseline, 6 weeks, 1‐month follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

'Simple software‐generated randomisation scheme'

Allocation concealment (selection bias)

Low risk

Randomization by an independent blinded collaborator not involved in the treatment or care of participants

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate 15.4% equally balanced across groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to physiotherapists‐led exercise (PT), yoga (YG), fitness‐instructor led exercise (FI), or control (NEX)

Setting: Clinical Therapies Department, University of Limerick, Limerick, Ireland

Categorization: PT = mixed, YG = other, FI = mixed

Participants

n = 314; PT = 80, YG = 77, FI = 86, NEX = 71

Inclusion criteria: 0‐2 on the GNDR mobility sub‐scale, aged > 18 years, diagnosis of MS

Exclusion criteria: relapse/steroid treatment < 3 months, pregnant, serious co‐morbidity

Type MS: RRMS, SPMS, PPMS, benign, or unknown

Disease duration (yr): PT = 9.8 ± 7.0, YG = 11.6 ± 8.0, PI = 10.5 ± 6.9, NEX = 10.6 ± 8.2

Mean age (yr) ± SD: PT = 51.7 ± 10.0, YG = 49.6 ± 10.0, PI = 50.3 ± 10.0, NEX = 48.8 ± 11.0

% Female (n/n group): PT = 50/63, YG = 44/63, PI = 45/77, NEX = 43/49

Mean EDSS ± SD: ?

Interventions

PT: 10 weeks, 1x per week; 1‐hour circuit style ‐ body weight/free weight resisted group (6‐8 participants) training. Exercises consisted of, for example: sit to stand, bridging, shoulder flexion, walking, cycling. Classes were supervised by a trained physiotherapist. Difficulty of the exercises was aimed to fail at the 12th repetition. In addition, participants were advised to do aerobic training of choice, 2x per week at 65% HR_max

YG: 10 weeks, 1x per week; 1‐hour sessions led by YG instructors. The YG sessions were not pre‐defined; but consisted of breathing exercise, relaxation, range of motion exercise, and dynamic weight‐bearing poses

FI: 10 weeks, 1x per week; 1‐hour community fitness led by local fitness instructors. The content of the intervention was not pre‐defined

NEX: no change in exercise habits for 10 weeks

Outcomes

MFIS, MSIS‐29v2, 6MWT

Notes

Drop‐outs

PT: 7 health condition, of which 2 relapse, 1 personal factors, 2 environmental factor, 7 unknown

YG: 5 health condition, of which 2 relapse, 3 personal factors, 1 environmental factor, 5 unknown

FI: 7 health condition, of which 3 relapse, 5 personal factors, 7 unknown

NEX: 11 health condition, of which 6 relapse, 6 personal factors, 1 environmental factor, 4 unknown

Measurements

Baseline, 12 weeks (post intervention), 24 weeks follow‐up for intervention groups only

A secondary analysis to predict the response of each therapy on gait function was also published (Kehoe 2014). The results of a second study strand, in more severely disabled people with MS, has been included as a separate study (Hogan 2014)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Block randomization per geographical region

Allocation concealment (selection bias)

Low risk

Randomization performed by central co‐ordinator

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate 23% equally balanced across the different exercise conditions.

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to home walking programme (EX) and no training (NEX)

Setting: Department of Physical Therapy, The George Washington University, Washington, USA

Categorization: EX = task‐oriented

Participants

n = 15; EX = 9, NEX = 6

Inclusion criteria: aged 18‐65 years, diagnosis MS > 1 year, no exacerbation < 6 months, no participation in regular aerobic exercise < 6 months, EDSS ≤ 6.0

Exclusion criteria: cardiovascular, pulmonary, or orthopaedic conditions

Type MS: ?

Disease duration (yr): EX: 3‐30 (information provided for 5 participants), NEX = ?

Age range (yr): EX = 40‐64, NEX = 22‐50

% Female (n/n group): EX = 6/8, NEX = 3/4

Mean EDSS ± SD: ?

Interventions

EX: individualized home walking programme (12 weeks, 3x per week). Training heart rate (THR) range was determined based on 6MWT using the Karvonen formula. Each session consisted of 5 minutes below THR, 15 minutes in THR, and cooling down below THR. Time within THR increased gradually during training programme

NEX: no training, walking programme offered following completion of trial

Outcomes

FSS, 6MWT, PCI, RPE

Notes

Drop‐outs

EX: 1 poor compliance and failure to show at post‐test assessment

NEX: 2 poor compliance and failure to show at post‐test assessment

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization by coin toss

Allocation concealment (selection bias)

Unclear risk

Unclear who performed coin toss

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 20%, equally balanced across groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

High risk

Small and unevenly distributed sample

Methods

Design: random assignment to standard exercise programme plus supplementary resistance training (EX) or standard exercise programme (STD)

Setting: Department of Physical Therapy, University of Utah, Salt Lake City, USA

Categorization: EX = mixed, STD = endurance

Participants

n = 22; EX = 11, STD = 11

Inclusion criteria: definite MS, no exacerbation < 3 months, aged 18‐65 years, ambulatory, impaired gait pattern, no lower extremity joint problems

Exclusion criteria: participation in regular strength training

Type MS: ?

Disease duration (yr) ± SD: EX = 12.5 ± 11.2, STD = 11.8 ± 7.3

Mean age (yr) ± SD: EX = 48.0 ± 11.9, STD = 49.7 ± 10.98

% Female (n/n group): EX = 5/9, STD = 6/10

Mean EDSS ± SD: EX = 5.3 ± 1.0, STD = 5.2 ± 1.0

Interventions

EX: supplementary lower extremity eccentric ergometric resistance training (12 weeks, 3x per week). During the course of the training programme resistance was increased based on perceived exertion (BORG 7/20 ‐ BORG 13/20)

STD: aerobic training, lower extremity stretching, upper extremity strength training, and balance exercises (12 weeks, 3x per week)

Outcomes

FSS, voluntary maximal isometric strength (flexion/extension of knee, hip, dorsi, and sum), TUG, 6MWT, stair test, 10MWT, BBS

Notes

Drop‐outs

EX: 1 difficulty committing to 3x per week schedule

STD: 1 during pre‐testing, 1 discontinued intervention

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information on randomization procedure

Allocation concealment (selection bias)

Unclear risk

Allocation concealment procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 14% equally balanced across the exercise groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other risk of bias identified

Methods

Design: random assignment to vestibular rehabilitation (VES), exercise control (EX), or wait‐list control group (NEX); stratified by yes/no involvement of brain stem/cerebellar

Setting: Department of Physical Medicine and Rehabilitation, and Department of Neurology, University of Colorado, Aurora, USA. Medical Campus

Categorization: VES = other, EX = endurance

Participants

n = 38; VES = 12, EX = 13, NEX = 13

Inclusion criteria: definite MS, aged 18‐65 years, able to walk 100 metres with at most a single‐sided device, score ≥ 45/85 on the MFIS, score < 72 on SOT; limited standing balance

Exclusion criteria: unable to walk, use of pharmacological agent that control or cause fatigue, change in MS medication < 3 months, MS‐related relapse < 6 months, other conditions that cause fatigue, impaired or limited upright postural control, participation in a vestibular or endurance exercise programme < 2 months

Type MS: RRMS or SPMS

Disease duration (yr) ± SD: VES = 6.5 ± 5.6, EX = 5.1 ± 3.2, NEX = 9.1 ± 7.3

Mean age (yr) ± SD: VES = 46.8 ± 10.5, EX = 42.6 ± 10.4, NEX = 50.2 ± 9.2

% Female (n/n group): VES = 9/12, EX = 11/13, NEX = 11/13

Mean EDSS ± SD: ?

Interventions

VES: standardized vestibular rehabilitation programme (6 weeks, 2x per week, 55 minutes). In addition, individual exercises were selected and constituted an individualized home training programme (postural control, eye movement). Also 5 minutes of fatigue management education was provided

EX: endurance and stretching exercises (6 weeks, 2x per week); 5 minutes warming up, 2 x 15 minutes at 65‐75% HR_peak, 2‐5 minutes cooling down. In addition, an individualized home training programme (endurance and stretching) at a similar intensity as the supervised programme and 5 minutes of fatigue management education were provided

NEX: wait list control

Outcomes

MFIS, SOT, 6MWT, DHI, BDI

Notes

Drop‐outs

NEX: 1 refused continuation after wait‐list control allocation

Measurements

Baseline (weeks 1, 2, 4), intervention phase (weeks 6, 8, 10), follow‐up phase (weeks 12, 14); not all measures assessed at each occasion

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Low risk

Randomization performed by a clinician not involved in the trial

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop‐out rate was 3%

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to group physiotherapy (GP), individual physiotherapy (IP), yoga (Y), or control (C)

Setting: Clinical Therapies Department, University of Limerick, Limerick, Ireland

Categorization: GP = muscle power, IP = muscle power, Y = other

Participants

n (drop‐outs) = 146; GP = 66, IP = 45, Y = 16, C = 19

Inclusion criteria: confirmed diagnosis of MS, GNDS score of 3 or 4

Exclusion criteria: relapse or steroid treatment < 12 weeks, pregnant, aged < 18 years

Type MS: RRMS, SPMS, PPMS, unknown

Disease duration (yr) ± SD: GP = 18 ± 9, IP = 13 ± 8, Y = 15 ± 8, C = 10 ± 3

Mean age (yr) ± SD: GP = 57 ± 10, IP = 52 ± 11, Y = 58 ± 8, C = 49 ± 6

% Female (n/n group): GP = 30/48, IP = 20/35, Y = 8/13, C = 13/15

Mean EDSS ± SD: ?

Interventions

GP: 10 weeks, 1x per week, 1‐hour group physiotherapy. GP was a self paced circuit style class of exercises (sit to stand, squat, heel raises, step‐ups, side stepping, and tandem) that targeted strength and balance with the aim of increasing balance and mobility. The aim was to perform 1 set of 12 repetitions and according to the progression was increased to 3 sets of 12 repetitions

IP: 10 weeks, 1x per week, 1‐hour individual physiotherapy with the same content as the GP

Y: 10 weeks, 1x per week, 1‐hour yoga classes by yoga instructors of the Yoga Federation of Ireland. The content of each yoga class was kept in a diary

C: usual care

Outcomes

MFIS, BBS, 6MWT, MSIS29v2

Notes

Drop‐outs

GP: 1 relapse, 5 unwell at day of measurement, 3 unwell and discontinued intervention, 1 steroids for lower back pain, 2 moved to different study strand, 1 on holiday, 1 requested 1 : 1 treatment, 1 fall, 3 unknown

IP: 2 relapse, 1 unwell at day of measurement, 1 inclement weather, 2 on holidays, 3 moved to different study strand, 1 unknown

Y: 1 discontinued intervention by choice, 2 unknown

C: 2 relapse, 1 rapidly progressing MS, 1 conflicting appointments

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Block randomization per geographical region

Allocation concealment (selection bias)

Low risk

Randomization performed by central co‐ordinator

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

The overall drop‐out rate was 24%, equally balanced across exercise (24%) and control (21%)

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Unclear risk

Unequal group sizes

Methods

Design: random assignment to 8‐week aquatic exercise programme (EX) or no training/wait list (NEX)

Setting: Faculty of Physical Education and Sport Sciences, University of Isfahan, Isfahan, Iran

Categorization: EX = endurance

Participants

n = 32; EX = 16, NEX = 16

Inclusion criteria: definite MS, > 2 years after diagnosis, no relapse < 1 month, ability to participate regular exercise sessions

Exclusion criteria: relapse during intervention, disease preventing participation

Type MS: RRMS

Disease duration (yr) ± SD: EX = 4.9 ± 2.3, NEX = 4.6 ± 1.9

Mean age (yr) ± SD: EX = 33.7 ± 8.6, NEX = 31.6 ± 7.7

% Female (n/n group): EX = 10/10, NEX = 11/11

Mean EDSS ± SD: EX = 2.9 ± 0.9, NEX = 3.0 ± 0.7

Interventions

EX: 8‐week aquatic exercise (3x per week, 60 minutes); 10‐minute warm‐up, 40‐minute exercise, 10‐minute cool‐down at 50‐75% heart rate reserve. Exercises included activities focused on joint mobility, flexor and extensor muscle strengths, balance movements, posture, functional activities, and intermittent walking

NEX: no training/maintain current habits

Outcomes

MFIS, MSQoL‐54

Notes

Drop‐outs

EX: 6, no reasons specified

NEX: 5, no reasons specified

Measurements

Baseline, 4 weeks, 8 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Shuffled envelopes

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Overall drop‐out rate 34%, equally balanced across groups. Reasons for drop‐out not specified

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

High risk

A large increase in fatigue in the control condition

Methods

Design: random assignment to 10 weeks' inspiratory muscle training (EX) or control group (NEX)

Setting: 3 rehabilitation outpatient clinics in Stockholm, Sweden

Categorization: EX = other

Participants

n = 15; EX = 7, NEX = 8

Inclusion criteria: progressive MS according to Poser criteria, EDSS 6.5‐9.5

Exclusion criteria: EDSS < 6.0, chronic obstructive airways, asthma, emphysema, cystic fibrosis, heart insufficiency, another diagnosis/disorder

Type MS: progressive MS

Disease duration (yr); range: EX = 12 (3‐19), NEX = 20 (12‐35)

Mean age (yr); range: EX = 46 (37‐49), NEX = 52.5 (38‐61)

% Female (n/n group): EX = 1/7, NEX = 5/8

Mean EDSS; range: EX = 7.5 (6.5‐8.0), NEX = 8.0 (6.5‐9.0)

Interventions

EX: inspiratory muscle training (10 weeks, 70 sessions). Each session consisted of 3x 10 loaded inspirations with 1‐minute rest in between at 40‐60% of maximal inspiratory pressure

NEX: no additional training besides regular physiotherapy

Outcomes

FSS, maximal inspiratory ‐ expiratory pressure, FVC, FEV, VC, RPE after morning bathing/dressing

Notes

Drop‐outs

No drop‐outs reported

Measurements

Baseline, 10 weeks, 14 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation concealment procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs reported

Selective reporting (reporting bias)

High risk

Not all outcomes reported

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to leisure centre‐based exercise group (EX) or control group (NEX); separate randomization for 2 different treatment sites

Setting: Multiple Sclerosis Service, Scotland, UK

Categorization: EX = mixed

Participants

n = 32; EX = 20, NEX = 12

Inclusion criteria: confirmed diagnosis MS, EDSS 5‐6.5, stable rehabilitation and drug therapy < 1 month, cognitive score > 24 on the MMSE

Exclusion criteria: exacerbation < 3 months, medical condition that may preclude participants from exercise intervention

Type MS: ?

Disease duration (yr) ± SD: EX = 13.4 ± 6.4, NEX = 12.6 ± 8.1

Mean age (yr) ± SD: EX = 51.4 ± 8.06, NEX = 51.8 ± 8.0

% Female (n/n group): EX = 15/20, NEX = 8/12

Mean EDSS ± SD: EX = 6.14 ± 0.36, NEX = 5.82 ± 0.51

Interventions

EX: leisure centre‐based exercise group (12 weeks, 2x per week). 10‐minute warm‐up of aerobic and stretching components; 30‐40 minutes of circuit exercises (8‐12) designed for aerobic endurance, resistance, and balance

NEX: usual routine, avoid new exercise regimen for the 12‐week study period

Outcomes

FSS, T25FW, 6MWT, BBS, TUG, QPW, BMI, PF, ABC, HADS, LMSQoL

Notes

Drop‐outs

EX: 1 family commitments, 1 participate in other study, 1 increased work commitments, 1 influenza‐like symptoms, 1 suspected trigeminal neuralgia

NEX: 1 unable to commit time for assessments, 1 unable to attend due to weather conditions

Measurements

Baseline, 8 weeks, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerized randomization procedure

Allocation concealment (selection bias)

High risk

Randomization list was generated beforehand to include a potential 20 participants

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate 22%, without indication of differences in reasons

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to 12‐week group circuit training (EX) or control group (NEX)

Setting: Physiotherapy Gym, Dublin, Ireland

Categorization: EX = mixed

Participants

n = 30; EX = 17, NEX = 13

Inclusion criteria: definite MS, independently mobile without use of aids, able to attend twice weekly + exercise independently at home

Exclusion criteria: relapse < 3 months; history of cardiac conditions that would limit exercise capacity; cognitive or psychosocial condition that would limit class participation

Type MS: RRMS and SPMS

Disease duration (yr) ± SD: EX = 5.4 ± 4.35, NEX = 5 ± 3.52

Mean age (yr) ± SD: EX = 40.5 ± 12.68, NEX = 33.58 ± 6.1

% Female (n/n group): EX = 14/17, NEX = 10/13

Mean EDSS ± SD: ?

Interventions

EX: leisure centre‐based group classes (12 weeks, 2x per week) 5‐minute warm‐up, 40‐minute exercises. 4 different stations (10 minutes each): treadmill walking/running, cycling, stair‐master training, arm‐strengthening exercises, volleyball, and outdoor walking. In addition, participants were required to do a single type home exercise programme of choice for 40‐60 minutes at RPE 11‐13

NEX: normal activity + physiotherapy once monthly

Outcomes

MFIS, FAMS, MSIS‐29, exercise capacity (HR_max, RPE)

Notes

Drop‐outs

EX: 2 relapses, 1 inconvenient timing of classes, 1 pregnancy, 1 personal reasons

NEX: 1 moved home

Measurements

Baseline, 3 months, 6 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization by blinded withdrawal of labelled slips from box

Allocation concealment (selection bias)

Unclear risk

Only 2 slips were present in the box during the allocation of each participant

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate 20%, unequally balanced across exercise (29%), and control (8%)

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

High risk

After 17 people had been allocated to the experimental group the remaining people were allocated to the control group to maintain equal group sizes

Methods

Design: random assignment to transcranial magnetic stimulation (TMS), exercise group (EX), or control (NEX); group allocation was counter‐balanced by EDSS score

Setting: outpatient clinical service of the University of Tor Vergata, Rome, Italy

Categorization: TMS = mixed, EX = mixed

Participants

n = 30; TMS = 10, EX = 10, NEX = 10

Inclusion criteria: RRMS according to McDonald criteria, remitting phase of disease, EDSS 2.0‐6.0, lower limb spasticity

Exclusion criteria: gadolinium‐induced cerebral or spinal lesion enhancement 2‐30 days before beginning of trial

Type MS: RRMS

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: TMS = 39.1 ± 10.7, EX = 37.7 ± 12.3, NEX = 38.3 ± 11.9

% Female (n/n group): TMS = 3/10, EX = 4/10, NEX = 5/10

Mean EDSS ± SD: TMS = 3.6 ± 1.2, EX = 3.8 ± 1.6, NEX = 3.5 ± 1.0

Interventions

TMS: intermittent theta burst stimulation of the soleus muscle at 80% of the active motor threshold for a total of 600 stimuli + exercise therapy (2 weeks, 5x per week); 2‐hour daily sessions. 1 hour on land, 1 hour aquatic, 2 or 3 sets per exercise type, 15 repetitions per set. Exercises were scheduled in order to improve range of motion, muscular flexibility, equilibrium reactions, motor co‐ordination, postural passages and transfers, and ambulation. Intensity was reduced with increasing disability

EX: exercise therapy as for TMS group however with sham TMS

NEX: TMS only

Outcomes

FSS, MAS, MSSS‐88, BI, EDSS, MSQoL‐54 (physical and mental composite)

Notes

Drop‐outs

No drop‐outs, training adherence unknown

Measurements

Baseline, 2 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs reported

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment of patients (EXMS) and healthy controls (EXH) to short‐term exercise programme or control (patients: NEXMS, healthy controls: NEXH); healthy people were matched with respect to gender, age, and level of physical activity

Setting: Rehabilitation Centre, Valens, Switzerland

Categorization: EX = endurance

Participants

n = 52; EXMS = 20, NEXMS = 18, EXH = 13, NEXH = 13

Inclusion criteria: definite MS; able to pedal on free‐standing ergometer; no history of cardiovascular, respiratory, orthopaedic, metabolic diseases, or other medical conditions; no acute exacerbation < 2 months

Exclusion criteria: ?

Type MS: RRMS, PPMS, and SPMS

Disease duration (yr) ± SD: EXMS = 11.2 ± 8.5, NEXMS = 12.6 ± 8.1

Mean age (yr) ± SD: EXMS = 45.23 ± 8.66, NEXMS = 43.92 ± 13.90, EXH = 44.7 ± 10.0, NEXH = 41.69 ± 11.15

% Female (n/n group): EXMS = 10/13, NEXMS = 11/13, EXH = 10/13, NEXH = 11/13

Mean EDSS ± SD: EXMS = 4.6 ± 1.2, NEXMS = 4.5 ± 1.9

Interventions

EXMS: short‐term inpatient exercise programme (3‐4 weeks, 5x per week). Consisted of 30 minutes' bicycle exercise training at individually determined anaerobic threshold

NEXMS: normal inpatient physiotherapy yet not increase physical activity level

EXH: identical training programme as people with MS

NEXH: no intervention, no change increase in physical activity level

Outcomes

FSS, VO_2max, anaerobic threshold, FVC, MVV, BAECKE, SF‐36

Notes

Drop‐outs

EXMS: 3 quit after allocation to exercise group, 2 excluded based on ST segment change during exercise electrocardiogram (ECG), 2 had elevated spasticity of the lower extremities following exercise testing

NEXMS: 3 motivational problems to sustain intervention programme, 2 symptom exacerbations

Measurements

Baseline, 4 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate was 32% equally balanced across groups, but with some indication of differences in reasons

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to massage therapy (M), exercise therapy (EX), massage + exercise therapy (MEX), or a control (C); the massage therapy group was excluded from this review

Setting: Musculoskeletal Rehabilitation Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Categorization: EX = mixed, MEX = mixed

Participants

n = 48; M = 12, EX = 12, MEX = 12, C = 12

Inclusion criteria: RRMS or SPMS, EDSS 2‐6, walk 10 metres, stand unassisted for > 60 seconds

Exclusion criteria: severe relapse < 1 month, participation in an physiotherapy programme before start of trial, cardiovascular disease, diabetes, or lower limb arthritis

Type MS: RRMS or SPMS

Disease duration (months) ± SD: M = 148.7 ± 97.11, EX = 102 ± 81.06, MEX = 115.3 ± 78.28, C = 86.58 ± 34.33

Mean age (yr) ± SD: M = 36.33 ± 7.62, EX = 36.67 ± 6.69, MEX = 36.67 ± 7.63, C = 36.83 ± 8.74

% Female (n/n group): M = 10/12, EX = 10/12, MEX = 10/12, C = 10/12

Mean EDSS ± SD: M = 3.75 ± 1.37, EX = 3.50 ± 1.13, MEX = 3.75 ± 1.43, C = 3.83 ± 1.39

Interventions

M: 5 weeks, 5x per week, 30‐minute standard Swedish massage by a trained massage therapist. The following techniques were applied to the bilateral quadriceps femoris, hip adductors, peroneal, and calf muscles: petrissage, effleurage, and friction. Participants were asked to lie in a supine position on a treatment table and a 7‐minute massage was applied on the quadriceps femoris and hip adductors. In addition, a 4‐minute massage was applied both on the peroneal muscles and the calf muscles

EX: 5 weeks, 3x per week, 30‐minute combined set of strength, stretch, endurance, and balance exercises. Exercise included leg raising, forward lunge, hip adductor, and calf muscle stretching, and walking on a treadmill

MEX: 5 weeks, 3x per week, 15‐minute exercise therapy (EX) + 15 minutes of passive massage therapy (M)

C: participants in the control group were asked to continue their standard medical care

Outcomes

FSS, VAS scale for pain, MAS, BBS, TUG, 10MWT, 2MWT, MSQoL‐54

Notes

Drop‐outs

No drop‐outs reported

Measurements

Baseline, 5 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Table of random numbers

Allocation concealment (selection bias)

Unclear risk

Unclear who had access to table of random numbers

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs or adverse events reported

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: Random assignment to Iyengar yoga classes plus home programme (YOGA), weekly bicycle exercise classes along with home exercise (EX) or wait‐list control group (NEX) using a minimization procedure.

Setting: Oregon Health & Science University, Portland, USA

Categorization: YOGA = other, EX = endurance

Participants

n = 69; YOGA = 26, EX = 21, NEX = 22

Inclusion criteria: EDSS ≤ 6.0

Exclusion criteria: insulin‐independent diabetes, uncontrolled hypertension, liver or kidney failure, symptomatic lung disease, alcoholism/drug abuse, ischaemic heart disease or signs of congestive heart failure, visual acuity worse than 20/50 binocularly, yoga/tai‐chi < 6 months, regular aerobic exercise > 30 minutes/day

Type MS: ?

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: YOGA = 49.8 ± 7.4, EX = 48.8 ± 10.4, NEX = 48.4 ± 9.8

% Female (n/n group): YOGA = 20/22, EX = 13/15, NEX = 20/20

Mean EDSS ± SD: YOGA = 3.2 ± 1.7, EX = 2.9 ± 1.7, NEX = 3.1 ± 2.1

Interventions

YOGA: 90‐minute Iyengar yoga classes, 1x per week for 6 months; all poses were supported by chair, wall, or floor. Each pose was held 10‐30 seconds with rest periods of 30‐60 seconds. Emphasis on breathing and relaxation. Each session ended with 10 minutes' deep relaxation, supine on the floor. Participants were encouraged to practice yoga at home by means of a demonstration booklet

EX: bicycle exercise classes 1x per week ‐ up to 60 minutes for 6 months. Each class began and ended with 5 minutes' stretching. Primary mode of exercise was cycling at modified BORG 2‐3. Each participant was provided with a home bicycle and encouraged to continue cycling at home or do any other mode of exercise

NEX: wait‐list control

Outcomes

POMS fatigue sub‐scale, MFI, SSS, POMS, SF‐36, STAI, CES‐D‐10, MSFC including 25‐foot walk, 9HPT, Stroop colour‐word interference, Electroencephalography median power frequency

Notes

Drop‐outs

YOGA: 1 exacerbation

EX: 1 exacerbation

Other drop‐outs not specified to a single trial arm: 3 unrelated surgeries, 1 low back pain related to car accident, 6 not able to attend classes for various reasons

Measurements

Baseline, 3 months, 6 months. Data from 3 months concerned only limited outcomes and was not presented in the report

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Minimization procedure

Allocation concealment (selection bias)

Low risk

By independent statistician

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate 17%, equally balanced across groups. Drop‐outs not specified to study arm unlikely to be related to treatment allocation

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to 15 weeks' aerobic training programme (EX) or control group (NEX)

Setting: University of Utah, Salt Lake City, USA

Categorization: EX = endurance

Participants

n = 54; EX = 27, NEX = 27

Inclusion criteria: clinically definite MS; EDSS ≤ 6.0; no history of cardiovascular respiratory, orthopaedic, metabolic, or other medical condition that would preclude participation in the training programme; no regular physical activity < 6 months

Exclusion criteria: ?

Type MS: ?

Disease duration (yr) ± SD: EX = 9.3 ± 1.6, NEX = 6.2 ± 1.1

Mean age (yr) ± SD: EX = 41.1 ± 2.0, NEX = 39.0 ± 1.7

% Female (n/n group): EX = 15/21, NEX = 16/25

Mean EDSS ± SD: EX = 3.8 ± 0.3, NEX = 2.9 ± 0.3

Interventions

EX: aerobic training (15 weeks, 3x per week) under supervision. 5‐minute warm‐up 30% VO_2max, 30 minutes at 60% VO_2max, 5‐minute cool‐down. 5‐10 minutes of stretching. Workload was updated at week 5 and 10

NEX: control group instructed to not change activity pattern; programme was offered after completion of trial

Outcomes

POMS fatigue sub‐scale, FSS, number of relapses, EDSS, ISS, VO_2max, maximum voluntary contractions of five upper and lower extremity muscle groups, skin‐fold thickness, % body fat, blood lipids, POMS, SIP

Notes

Drop‐outs

EX: 4 relapses

NEX: 3 relapses

Measurements

Baseline, 5 weeks, 10 weeks, 15 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate, equally balanced across exercise (15%) versus control (11%)

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to individualized physical rehabilitation (IPR) or a group wellness intervention (GWI)

Setting: Department of Physical Medicine & Rehabilitation, University of Minnesota, Minneapolis, USA

Categorization: IPR = mixed

Participants

n = 50; IPR = 22, GWI = 20

Inclusion criteria: physician‐confirmed diagnosis MS, ability to walk with or without an assistive device

Exclusion criteria: pregnancy, cardiovascular disease, more than 2 falls in past month, inability to understand trial

Type MS: ?

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: IPR = 48.5 ± 12.3, GWI = 48.5 ± 9.1

% Female (n/n group): IPR = 17/20, GWI = 16/20

Mean EDSS ± SD: ?

Interventions

IPR: individualized home‐exercise programme (8 weeks, 5x per week). 3x per week indoor cycling and stretching. 2x per week strength and balance exercises. Additional physical therapy session every other week

GWI: home‐exercise programme without individual adjustment but with additional energy conservation modules based on Packer 1995. (8 weeks, 2 hours/week)

Outcomes

MFIS, MHI, SF‐36, HPLP‐II physical activity sub‐scale, BMI, % body fat, waist circumference, blood pressure, resting heart rate, VO_2max (YMCA protocol), bench‐press (repetitions/1 minute), military‐press (repetitions/1 minute), sit‐to‐stand (repetitions/45 seconds), hamstring flexibility, balance

Notes

Drop‐outs

8 participants excluded from analyses, as they did not receive intervention (reason not provided). An additional 4 participants excluded from analyses due to missing values of primary outcome (GWI = ‐3, IPR = ‐1)

Measurements

6 weeks pre‐intervention, immediately pre‐intervention, post‐intervention, 8 weeks post‐intervention

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate 29% with a larger proportion in the GWI (35%) versus the IPR (23%). Reasons for not receiving intervention were not provided

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design (cross‐over): random assignment to aerobic training (EX) first or neurorehabilitation programme (NRP) first

Setting: MS outpatient clinics at Parma University Hospital and Piacenza Hospital, Italy

Categorization: EX = endurance

Participants

n = 19; EX = 8, NRP = 11

Inclusion criteria: diagnosis MS according to Poser criteria, EDSS ≤ 6.0, aged 20‐55 years

Exclusion criteria: relapse < 1 month; history of cardiac, pulmonary, orthopaedic, metabolic, or other medical condition precluding participation; receiving steroid treatment < 2 months

Type MS: ?

Disease duration (yr) ± SD: EX + NRP = 6 ± 4

Mean age (yr) ± SD: EX + NRP = 41 ± 8

% Female (n/n group): EX + NRP = 14/11; 4 more drop‐outs after cross‐over

Mean EDSS (range): EX + NRP = 3.5 (1‐6)

Interventions

EX: aerobic training (8 weeks, 3x per week) under supervision. 5‐minute warm‐up 30% VO_2max, 30 minutes at 60% VO_2max, 5‐minute cool‐down. 5‐10 minutes of stretching. Similar to the trial by Petajan 1996

NRP: neurorehabilitation programme (8 weeks, 3x per week). 60 minutes of exercise aimed at improving respiratory‐motor synergies and stretching

Outcomes

MFIS, EDSS, MSQoL‐54, pulmonary function, 6MWT, walking speed, cost of walking, W_max, VO_2max, VO₂/HR

Notes

Drop‐outs

EX: 1 relapse, 1 did not adhere to protocol; after cross‐over, 3 more drop‐outs in EX due to relapse (1) and not adhering to protocol (2)

NRP: 1 relapse, 1 did not adhere to protocol; after cross‐over, 1 more drop‐out due to relapse

Measurements

Baseline, 8 weeks, 16 weeks, 24 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerized randomization procedure

Allocation concealment (selection bias)

Unclear risk

Unclear who performed randomization procedure

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Overall drop‐out rate 42% for which high risk. However, a large proportion dropped out during the wash‐out phase. No imbalances in drop‐outs during intervention phase

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Unclear risk

No data on 'success' of wash‐out phase presented

Methods

Design (cross‐over): random assignment to endurance training (ET) first or resistance training (RT) with 8‐week wash‐out period between interventions

Setting: Queensland Health, Queensland, Australia

Categorization: ET = endurance, RT = muscle power

Participants

n = 21; ET = 6, RT = 15

Inclusion criteria: ambulant (with or without aid)

Exclusion criteria: ?

Type MS: RRMS, PPMS, SPMS

Disease duration (yr) ± SD: ET + RT = 10 ± 10

Mean age (yr) ± SD: ET + RT = 55 ± 7

% Female (n/n group): ET + RT = 12/16

Mean EDSS ± SD: ?

Interventions

ET: endurance training (8 weeks, 2x per week); circuit of 8 exercise stations (step‐ups, arm cranking, upright cycling, arm cranking, recumbent cycling, cross‐trainer, treadmill walking, arm cranking (5 minutes each). Intensity was increased based on RPE (3‐5 on BORG 10 scale)

RT: resistance training (8 weeks, 2x per week); 3 upper, 3 lower body exercises, 1 core strength, 1 stability. 2‐3 sets of 6‐10 repetitions

Outcomes

MFIS, grip strength, functional reach test, four step square test, TUG, 6MWT, MSIS‐29, SF‐36

Notes

Drop‐outs

ET: no drop‐outs during or directly following endurance training

RT: 1 for time reasons; following the wash‐out period, 2 participants drop‐out due to time constrains, 1 moved house and 1 became ill dependent

Measurements

Baseline, directly following 8 weeks' intervention 1, after an 8‐week wash‐out period and following 8 weeks' intervention 2

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Coin toss

Allocation concealment (selection bias)

High risk

A large proportion of the participants randomized to resistance training first

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 24%. No imbalances in the number of drop‐outs during endurance or resistance training

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to a combination exercise therapy (EX) and a control (NEX)

Setting: physiotherapy clinic, Tehran, Iran

Categorization: EX = mixed

Participants

n = 72; EX = 42, NEX = 30

Inclusion criteria: RRMS, aged 18‐50 years, no MS attack < 3 months, EDSS 0‐4.0

Exclusion criteria: ?

Type MS: RRMS

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: EX = 33.05 ± 7.68, NEX = 32.05 ± 6.35

% Female (n/n group): EX = 24/39, NEX = 15/22

Mean EDSS: EX = 1.7, NEX = 1.96

Interventions

EX: 10 weeks, 3x per week, 90 minutes of combination exercises. 7‐10 minutes of stretching exercises including movements for spine, neck, upper, and lower limbs. 20‐40 minutes of aerobic exercise on cycle or treadmill of which the duration progressively increased based on the fatigue perception. Intensity started at 40% of HR_max and was increased to 70% of HR_max. Subsequently, 10‐20 minutes of strength and balance exercises

NEX: usual care

Outcomes

FSS, EDSS, BBS, 6MWT, MQoL, PQoL

Notes

Drop‐outs

EX = 1 lack of time, 1 muscular pain and stiffness, 1 MS attack

NEX = 5 performed exercise or rehabilitation, 1 MS attack, 2 unable to contact

Measurements

Baseline, 10 weeks ('after all exercise sessions')

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number tables

Allocation concealment (selection bias)

Unclear risk

Allocation was done before invitation to participate

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 15%. Unequal distribution between exercise (7%) and control (27%)

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Unclear risk

There was no clarity regarding the reported means, mean differences, and time points; unequal group‐sizes

Methods

Design: random assignment to aerobic training (EX) or control (NEX)

Setting: University Hospital Eppendorf, Hamburg, Germany

Categorization: EX = endurance

Participants

n = 28; EX = 15, NEX = 13

Inclusion criteria: diagnosis MS according to Poser criteria, EDSS < 5.0, without steroid or immunosuppressive therapy < 4 weeks

Exclusion criteria: no clear diagnosis, acute relapse, severe cognitive deficits, signs of any psychiatric disease

Type MS: RRMS (19 participants), SPMS (5 participants), PPMS (2 participants), not reported (2 participants)

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: EX = 39 ± 9, NEX = 40 ± 11

% Female (n/n group): EX = 11/15, NEX = 8/13

Mean EDSS (range): EX = 2.0 ± 1.4, NEX = 2.5 ± 0.8

Interventions

EX: aerobic interval training (8 weeks, 2x per week) under supervision. Maximal intensity at 75% W_max from ergometry test

NEX: wait list

Outcomes

MFIS, fitness parameters, immune‐ and neurotrophic factor, HAQUAMS

Notes

Drop‐outs

No drop‐outs, adherence unknown; 18 participants withdrawn from initial 46 included due to inability to cycle 30 minutes at 100 Watt

Measurements

Baseline, 8 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs reported

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

High risk

18 participants withdrawn from 46 included due to inability to complete exercise test

Methods

Design: random assignment to endurance training (EX) or control (NEX)

Setting: Danish MS Hospital, Ry, Denmark

Categorization: EX = endurance

Participants

n = 11; EX = 6, NEX = 5

Inclusion criteria: EDSS 6.5‐8.0, aged > 18 years, SPMS or PPMS, no serious comorbidity

Exclusion criteria: n.a.

Type MS: SPMS or PPMS

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: EX = 62.0 ± 5.9, NEX = 55.2 ± 8.2

% Female (n/n group): ?

Mean EDSS (range): ?

Interventions

EX: 4 weeks' inpatient rehabilitation + 10 supervised upper‐body exercise sessions. Exercise consisted of 5 minutes' warming‐up followed by 6x 3‐minute intervals at a target heart rate corresponding to 65‐75% of VO_2peak. To ensure physical exhaustion, short 30‐ to 60‐second sprints at the highest possible intensity were performed at the end of each interval. The inpatient rehabilitation programme was provided by a highly specialized multidisciplinary team consisting of difference active treatments ranging from self management education to various exercise therapies depending on the person's goals and needs

NEX: 4 weeks' inpatient rehabilitation similar to the programme in the exercise group

Outcomes

FSMC, VO_2peak, peak HR, 9HPT, hand grip power, Box and Blocks, 6‐minute wheelchair, MDI, MSIS‐29

Notes

Drop‐outs

EX: 1 due to hospitalization unrelated to the intervention

Measurements

Baseline, 4 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure unknown

Allocation concealment (selection bias)

Low risk

It was stated that the randomization occurred while 'applying concealed allocation (with respect to gender)'

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 drop‐out reported in the exercise condition, unrelated to the intervention. 96% of planned exercise sessions completed

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to Norway‐based physiotherapy programme (NOR) first or Spain‐based physiotherapy programme (ESP) first; wash‐out phase of 1 year

Setting: Departments of Neurology at Haukeland University Hospital and Akershus University Hospital, Norway (recruitment); treatment was provided in Tenerife, Spain and Hakadal, Norway

Categorization: NOR = other, ESP = other

Participants

n = 60; NOR = 30, ESP = 30

Inclusion criteria: gait problems, EDSS 4.0‐6.5, aged 18‐60, no relapse < 1 month

Exclusion criteria: heat intolerance or excessive fatigue, pregnancy, breastfeeding, severe cognitive dysfunction, other co‐morbidities that could influence participation

Type MS: RRMS, PPMS, SPMS

Disease duration (yr) ± SD: ? (age at onset NOR = 33.0 ± 9.2, ESP = 29.6 ± 9.8)

Mean age (yr) ± SD: NOR = 49.9 ± 8.0, ESP = 47.0 ± 9.8

% Female (n/n): NOR = 16/30, ESP = 20/30

Mean EDSS ± IQR: NOR = 4.5 ± 1.5, ESP = 4.75 ± 1.5

Interventions

NOR and ESP both comprehended the same physiotherapy programme (4 weeks, 5x per week, 60 minutes) based on the Bobath concept aimed to improve physical functioning through motor learning

Outcomes

FSS, 6MWT (+ RPE), TUG, 10MWT, BBS, TIS, MSIS‐29, MHAQ, pain, balance, gait

Notes

Drop‐outs

Not specified to intervention; 2 relapses, 1 pregnancy, 1 college studies, 1 accident with bone fracture, 4 personal reasons

Measurements

Baseline, 4 weeks, 3 months' follow‐up, 6 months' follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 15%. Distribution across exercise conditions unknown; however, reasons for drop‐out unlikely related to exercise intervention. Training adherence was 99%

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random allocation to task‐oriented circuit training + home exercise (EX) or control (NEX)

Setting: outpatient clinic of the Physical Medicine and Rehabilitation Department, Ferrara, Italy

Categorization: EX = task‐oriented

Participants

n: 24; EX = 12, NEX = 12

Inclusion criteria: aged 18‐75 years, definite diagnosis MS, EDSS 4‐5.5, no relapse < 3 months

Exclusion criteria: other conditions that affect motor function, MMSE < 24

Type MS: RRMS, PPMS, and SPMS

Disease duration (yr) ± SD: ?

Mean age (yr) ± SD: EX = 49.92 ± 7.51, NEX = 55.25 ± 13.82

% Female (n/n): EX = 7/12, NEX = 10/12

Mean EDSS ± SD: EX = 4.95 ± 0.61, NEX = 4.83 ± 0.49

Interventions

EX: 2 weeks, 5x per week, 1 hour' task‐oriented circuit training + 30 minutes' treadmill training (2 hours including rest) followed by 3 months, 3x per week, 60 minutes' home‐based exercise. The task‐oriented circuit training consisted of 6 workstations in which participants exercised for 5 minutes in each (3 minutes of exercise + 2 minutes of rest). 2 laps of each workstation were done with 10 minutes of rest after each lap. Subsequently, walking endurance was trained for 30 minutes on the treadmill. Each session included up to 3 participants. A home‐based exercise brochure was provided so that they could independently train for the following 3 months. The brochure included similar exercises as for the task‐oriented circuit training

NEX: usual care; exercise in non‐rehabilitative contexts was allowed

Outcomes

FSS, 10MWT, 6MWT, TUG, DGI, MSWS‐12, MSIS‐29

Notes

Drop‐outs

NEX = 3 (denial)

Measurements

Baseline, 2 weeks (post task‐oriented training), 3 months (post home‐based exercise)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

www.randomization.com

Allocation concealment (selection bias)

Low risk

www.randomization.com

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop‐out rate was 13% in the control condition

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other bias identified

Methods

Design: random assignment to 3‐week inpatient rehabilitation programme followed by 23 weeks of home‐based exercise (EX) or no exercise (NEX)

Setting: Masku Neurological Rehabilitation Centre, Masku, Finland

Categorization: EX = mixed

Participants

n = 95; EX = 47, NEX = 48

Inclusion criteria: aged 30‐54 years, EDSS 1.0‐5.5

Exclusion criteria: cardiovascular disease, musculoskeletal disorder, relapse < 1 month, intensive exercise (5x per week, 30 minutes) < 3 months, medical or psychological or other reasons indicating potential drop‐out

Type MS: RRMS, PPMS, SPMS

Disease duration (yr) ± SD: EX men = 6 ± 7, EX women = 6 ± 6, NEX men = 5 ± 6, NEX women = 6 ± 7

Mean age (yr) ± SD: EX men = 45 ± 6, EX women = 43 ± 6, NEX men = 44 ± 7, NEX women = 44 ± 7

% Female (n/n): EX = 30/47, NEX = 31/48

Mean EDSS ± SD: EX men = 2.9 ± 1.2, EX women = 2.0 ± 0.8, NEX men = 3.1 ± 1.2, NEX women = 2.5 ± 1.0

Interventions

EX: 3 weeks' inpatient rehabilitation course of 5 resistance and 5 aquatic aerobic exercise (65‐70% HR_max) sessions followed by 23 weeks of individualized home‐based exercise; 4‐5x weekly. Home exercise consisted of 8 progressive resistance exercises using elastic bands

NEX: no participation in any exercise programme; asked to continue normal living

Outcomes

FSS, leg flexor/extensor torque, motor fatigue, ambulatory fatigue index

Notes

Drop‐outs

EX: 2 refused measurement, 1 traffic accident

NEX: 2 refused, 1 data conversion failed, 1 knee pain

Measurements

Baseline, 3 weeks, 26 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerized randomization procedure

Allocation concealment (selection bias)

Low risk

Randomization by project statistician

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop‐out rate was 8% equally balanced across groups

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to aquatic aerobic training (EX) or control (NEX). Matched by age and gender

Setting: Victoria University, Melbourne, Australia

Categorization: EX = endurance

Participants

n = 22; EX = 11, NEX = 11

Inclusion criteria: EDSS ≤ 5.0, no exercise programme < 6 months

Exclusion criteria: cardiovascular disease, musculoskeletal disorder, relapse < 1 month, intensive exercise (5x per week, 30 minutes) < 3 months, medical or psychological or other reasons indicating potential drop‐out

Type MS: ?

Disease duration (yr) ± SD: EX = 7.00 ± 5.59, NEX = 6.18 ± 3.63

Mean age (yr) ± SD: EX = 47.18 ± 4.75, NEX = 45.45 ± 5.05

% Female (n/n): EX = 6/11, NEX = 6/11

Mean EDSS ± SD: EX men = 2.9 ± 1.2, EX women = 2.0 ± 0.8, NEX men = 3.1 ± 1.2, NEX women = 2.5 ± 1.0

Interventions

EX: supervised aerobic aquatic training programme for 10 weeks, 3x per week, 45 minutes. Weeks 5 and 6 were land‐based weight resistance training. Aquatic exercise consisted of water jogging and deep water running

NEX: control group was requested to not change their exercise habits

Outcomes

POMS‐SF (including fatigue sub‐scale), MSPSS, MSQoL‐54

Notes

Drop‐outs

No drop‐outs; mean adherence 27/30 training sessions

Measurements

Baseline, 8 weeks (2 weeks prior to end of intervention)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No drop‐outs reported

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to group exercise training (EX) or control (NEX)

Setting: Division of Physiotherapy and Rehabilitation, Istanbul University, Istanbul, Turkey

Categorization: EX = mixed

Participants

n = 110; EX = 55, NEX = 55

Inclusion criteria: definite MS, EDSS 2.0‐6.5, no relapse < 30 days, stable medication, no transport difficulties

Exclusion criteria: other central nervous system disease, pregnant, medical condition precluding exercise participation, regular exercise < 3 months

Type MS: RRMS, PPMS, and SPMS

Disease duration (yr) ± SD: EX = 9.00 ± 4.71, NEX = 8.42 ± 5.38

Mean age (yr) ± SD: EX = 49.49 ± 9.37, NEX = 39.6 ± 11.18

% Female (n/n group): EX = 34/51, NEX = 30/48

Mean EDSS ± SD: EX = 4.38 ± 1.37, NEX = 4.21 ± 1.44

Interventions

EX: 12 weeks, 3x per week; 60‐minute group exercise programme (up to 7 participants per group) including flexibility, range of motion, strengthening with/without Theraband for lower extremity, core stabilization, balance, and co‐ordination exercises. Perceived exertion < 14 (6‐20 scale)

NEX: waiting list

Outcomes

FSS, BBS, 10MWT, 10‐stair climbing test, MAS, MusiQoL

Notes

Drop‐outs

EX: 1 exacerbation, 1 personal problems, 2 < 80% participation

NEX: 1 participation in exercise programme, 3 exacerbation, 3 not coming to assessment

Measurements

Baseline, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated list

Allocation concealment (selection bias)

High risk

Complete randomization outcome known prior to trial

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate was 10%. Somewhat imbalanced across exercise (7%) and control (13%)

Selective reporting (reporting bias)

Low risk

No selective reporting identified

Other bias

Low risk

No other sources of bias identified

Methods

Design (cross‐over): random assignment to immediate or delayed (EX) supervised treadmill training; the follow‐up phase of the immediate group and the phase prior to training in the delayed group served as control (NEX)

Setting: School of Health Sciences, University of Birmingham, Birmingham, UK

Categorization: EX = endurance

Participants

n = 19; EX = 10, NEX = 9

Inclusion criteria: confirmed clinical diagnosis of MS, ability to follow training instructions, walk 10 metres < 60 seconds without hands on support, using an aid if necessary, able to walk on treadmill with or without hands on support

Exclusion criteria: significant relapse < 2 months, serious medical condition that might impair ability to walk on a treadmill and participate in aerobic exercise

Type MS: ?

Disease duration (yr) ± SD: ?

Age (yr): 30‐65

% Female (n/n group): 14/17

Mean EDSS ± SD: ?

Interventions

EX: supervised treadmill training 3x per week/4 weeks. Walking duration increased up to 30 minutes, subsequently walking speed increased; target HR 55‐85% age predicted HR_max

NEX: wait list or follow‐up phase

Outcomes

FSS, 10MWT, 2MWT, GDNS, RMI, heart rate walking

Notes

Drop‐outs

EX: 2 unknown reason

NEX: 1 unknown reason

Measurements

Baseline, 7 weeks, 12 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Block‐randomization using computer‐generated numbers

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Overall drop‐out rate 17%; reasons for drop‐out not provided.

Selective reporting (reporting bias)

Unclear risk

Outcome on Rivermead Mobility Index was not reported

Other bias

Low risk

No other sources of bias identified

Methods

Design: random assignment to sports climbing (SC) or Hatha Yoga (HY)

Setting: Multiple Sclerosis Center at the Division of Neurology, University Medical Center, Ljubljana, Slovenia

Categorization: SC = other, HY = other

Participants

n = 20; SC = 10, HY = 10

Inclusion criteria: RRMS, PPMS, or SPMS; EDSS ≤ 6.0; EDSS pyramidal functions score > 2.0; aged 26‐50

Exclusion criteria: none reported

Type MS: RRMS, PPMS, and SPMS

Disease duration (yr) ± SD: ?

Median age (yr): SC = 42, HY = 41

% Female (n): ?

Median EDSS: SC = 4, HY = 4.2

Interventions

SC: 10 weeks, 1x per week sports climbing on a 5‐metre wall, 90° inclination adjusted for participants by increasing the size and number of holds

HY: 10 weeks, 1x per week Hatha yoga; stretching and strengthening exercises, breathing exercises

Outcomes

MFIS, EDSS, MAS, executive function, selective attention, CES‐D

Notes

Drop‐outs

?

Measurements

Baseline, 10 weeks

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization procedure was not described

Allocation concealment (selection bias)

Unclear risk

Allocation procedure unknown

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, neither participants nor personnel could be blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Fatigue was self reported and therefore outcome assessment was not blinded