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. 2014 Sep 15;5:177. doi: 10.3389/fneur.2014.00177

Table 4.

Non-pharmacological interventions for fatigue in MS.

Study, year country Study design Potential intervention Outcome measures for fatigue Main findings Level of evidencea
MULTI-DISCIPLINARY (MD) REHABILITATION
Khan et al. 2011 (17, 31), Australia Systematic review, n = 10 trials (nine RCTs and one CCT) Extended MD outpatient rehabilitation Fatigue, frequency, FIS; MS-related symptom checklist composite score

  • Fatigue symptoms significantly

  • Improved social functioning and depression

 I
Inpatient MD rehabilitation MSIS29, VAS

  • No significant benefits on perceived fatigue or disability level
PHYSICAL MODALITIES
Exercise
Asano and Finlayson 2014 (11), Canada Meta-analysis, n = 10 RCTs Various types of exercises (progressive resistance, aerobic, inspiratory exercises, aquatic exercises, vestibular rehabilitation, and leisure exercises) FSS, MFIS, FIS

  • Significant beneficial effect in managing fatigue [pooled effect size (ES) was 0.57; 95% CI: 0.10–1.04, p = 0.02]

  • ES for the exercise interventions range: −0.24 (95% CI: −1.15 to 0.64) to 2.05 (95% CI: 1.00–3.11)

 I
Latimer-Cheung et al. 2013 (42), Canada Systematic review, n = 54 trials (30 evaluating fatigue outcomes: 15 RCTs and 15 other design) Aerobic fitness; muscle strength (resistance training) and combined FSS, FIS, MFIS, SF-36 (vitality subscale), PMS (energy and fatigue subscales), MSQL-54 (energy subscale)

  • Aerobic exercise: significant improvements in some general fatigue symptoms but not specific symptoms after 2–6 months of light to moderate cycling for 40–60 min three times/week; decreases in general, physical, and psychological fatigue symptoms after 8 weeks of moderate-intensity aerobic activities two times/week

  • Traditional resistance training: improvements in general symptomatic fatigue after a 12-week, two times/week resistance training program (8–15 RM); decreased fatigue overall or specifically physical and psychological fatigue after 8 weeks of moderate-intensity resistance training two times/week (6–15 RM)

  • Combined training programs: significant increase in vitality or decrease in fatigue severity after 5–8 weeks of supervised aerobic and resistance training performed at moderate to high intensity; significant improvements in fatigue symptoms or severity after 8–10 weeks of two to three times/week combined training

  • Other types of exercise (sport, yoga, body weight support treadmill training, aquatic exercise, cycling, and Pilates): a significant decrease on at least one indicator of fatigue (general or specific) symptoms

 III-1
Andreasen et al. 2011 (39), Denmark Systematic review, n = 21 trials (11 RCTs, 1 CCT, 9 other design) Endurance training, resistance, training, combined training, or “other” training modalities FSS, MFI, MFIS, FCMC

  • Exercise therapy on MS fatigue show heterogeneous results and only few studies have evaluated MS fatigue as the primary outcome

  • All type of exercise modalities have potential to reduce MS fatigue

  • Not clear whether any exercise modalities are superior to others

 III-1
Neill et al. 2006 (43), Australia Systematic review, n = 11 trials [combined for MS, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); various study design] Aerobic exercise, resistance training FIS, FSS, SF-36, POMS, VAS,

  • Aerobic exercise (home-based or supervised classes) is effective in managing fatigue for some people with MS, RA and SLE

  • Six studies reported statistically significant reductions in fatigue from aerobic exercise interventions

  • Low-impact aerobics, walking, cycling, and jogging were effective interventions

 III-1
Aquatic therapy
Kargarfard et al. 2012 (50), Iran RCT, n = 32 women with MS Aquatic exercise: joint mobility, flexor and extensor muscle strength, balance movements (60 min session three times/week), control group: usual care MFIS, MSQL-54

  • Patients in the aquatic exercise group showed significant improvements in fatigue and QoL after 4 and 8 weeks (p = 0.002 and <0.001, respectively)

 II
Castro-Sánchez et al. 2012 (48), Spain RCT, n = 73 pwMS Treatment group: aquatic Tai-Chi (40 sessions) (n = 36); control group: relaxation (n = 37) FSS, MFIS

  • Treatment group showed a significant score reduction in fatigue at week 20 (p < 0.032) that was maintained at week 24 (p < 0.038)

  • An improvement was shown by 48% of the treatment group

  • Significant improvement in pain, spasms, disability, fatigue, and depression was also reported in treatment group

 II
Bayraktar et al. 2013 (53), Turkey CCT, n = 23 pwMS Treatment group: aquatic Tai-Chi (n = 15); control group: exercise at home (n = 8) FSS

  • Significant in reduction in fatigue in the treatment group (p < 0.05)

  • Improvement in balance, functional mobility, upper and lower extremity muscle strength was also noted in treatment group (p < 0.05)

 III-1
Tai chi
Castro-Sánchez et al. 2012 (48), Spain RCT, n = 73 pwMS Treatment group: aquatic Tai-Chi (40 sessions) (n = 36); control group: relaxation (n = 37) FSS, MFIS See “Aquatic Therapy” section above II
Bayraktar et al. 2013 (53), Turkey CCT, n = 23 pwMS Treatment group: aquatic Tai-Chi (n = 15); control group: exercise at home (n = 8) FSS See “Aquatic Therapy” section above III-1
Mills et al. 2000 (56), UK Comparative study, n = 8 pwMS Tai Chi/QiGong along with the teaching QiGong self-massage. TuiNa and daily home practice for 30 min POMS, 21-Item symptom checklist

  • Significant improvements in fatigue post intervention

 III-2
Cooling devices
Beenakker et al. 2001 (57), Netherlands RCT, n = 10 Wearing cooling garment for 60 min at 7°C (active cooling); control group: 26°C (sham cooling). MFIS

  • Beneficial effect of cooling therapy in reducing fatigue, improving postural stability and muscle strength in pwMS

 II
White et al. 2000 (58), USA RCT, n = 6 pwMS Immersing participants’ lower body regions in water baths at 16–17°C for 30 min before training FIS

  • Reduced fatigability during training sessions (p < 0.05)

  • Fewer heat-induced symptoms such as ataxia, blurred vision, and foot drop during exercise preceded by cooling

 II
Pulsed electro-magnetic devices
Lappin et al. 2003 (60), USA RCT, n = 117 pwMS “Enermed” – active low-level, pulsed electro-magnetic field device worn up to 24 h daily on one or more acupressure points for up to 4–8 weeks MSQLI

  • Statistically significant decreases in fatigue for the intervention groups (0.05)

  • Overall QoL significantly greater on the active device group

  • No treatment effects for bladder control and a disability composite, and mixed results for spasticity

 II
Richards et al. 1997 (61), USA RCT, n = 33 pwMS “Enermed” – see above Patient-reported performance scales

  • Significant improvement in the performance scale (PS) combined rating for bladder control, cognitive function, fatigue level, mobility, spasticity, and vision (active group –3.83 ± 1.08, p < 0.005; placebo group –0.17 ± 1.07, change in PS scale)

 II
BEHAVIORAL AND EDUCATIONAL INTERVENTIONS
Asano and Finlayson 2014 (11), Canada Meta-analysis, n = 8 RCTs Various types of psychologi-cal/educational interventions (fatigue management program, energy conservation course, CBT, mindfulness intervention) FSS, MFIS, FIS

  • Significant beneficial effect in managing fatigue [pooled effect size (ES) was 0.54; 95% CI: 0.30–0.77, p < 0.001]

  • ES for the educational interventions range: from -0.16 (95% CI: -0.72 to 0.38) to 1.11 (95% CI: 0.43 to 1.78)

 I
Neill J et al. 2006 (43), Australia Systematic review, n = 15 trials (combined for MS, RA and SLE; various study design design) Education programs, energy conservation, self-management, fatigue management program, CBT FIS, FSS, SF-36, POMS, VAS,

  • Behavioral interventions appeared effective in reducing fatigue

  • Education alone or with exercise reduced fatigue and increased vitality in pwMS

  • Rehabilitation program and counseling were effective in reducing fatigue

 III-2
Fatigue management programs
Thomas et al. 2013 (70), UK RCT, n = 164 pwMS Group-based interactive program for managing MS-fatigue [fatigue: applying cognitive behavioral and energy effectiveness techniques to lifestyle (FACETS] (90-min sessions weekly for 6 weeks facili-tated by two health pro-fessionals (n = 84); control group (n = 80) usual care) FAI, MSFS

  • At 1-month post intervention: significant differences favoring the intervention group on fatigue self-efficacy (mean difference = 9; 95% CI 4–14; ES = 0.54, p = 0.001).

  • At 4 months follow-up: positive effects of the program still remained significant with moderated effect size (ES = 0.36; p = 0.05; mean difference = 6; 95% CI 0–12); significant improvement in fatigue severity was also found in intervention group (p = 0.01)

 II
Thomas et al. 2014 (64), UK RCT, n = 164 pwMS Same as above Same as above

  • At 1-year follow-up: benefits of the FACETS program for fatigue severity and self-efficacy mostly sustained (ES = -0.29, p = 0.06 and 0.34, p = 0.09, respectively); additional significant improvements in QoL (p = 0.046)

 II
Kos et al. 2007 (34), Belgium RCT, n = 51 pwMS Multi-disciplinary fatigue management program: interactive educational sessions about possible strategies to manage fatigue and reduced energy levels (four 2 h sessions/week) (n = 28); control group: placebo MFIS

  • No efficacy in reducing the impact of fatigue compared to a placebo intervention program (ES = −0.16)

 II
Energy conservation interventions
Blikman et al. 2013 (65), Netherlands Systematic review, n = 6 trials (four RCTs and two CCTs) Energy conservation interventions: education about balancing, modifying and prioritizing activities, rest, self-care, effective communication, biomechanics, ergonomics, and environmental modification FIS

  • Energy conservation interventions were more effective than no treatment in improving subscale scores of FIS: cognitive mean difference (MD = −2.91; 95% CI, −4.32 to −1.50), physical (MD = −2.99; 95% CI, −4.47 to −1.52), and psychosocial (MD = −6.05; 95% CI, −8.72 to −3.37)

  • QoL scores on physical, social function and mental health (also improved significantly in treatment group

  • None of the studies reported long-term results

 I
Mindfulness-based interventions
Simpson et al. 2014 (66), UK Systematic review, n = 3 trials (two RCTs and one CCT) Mindfulness-based interventions: mindful breath awareness, mindful movement, and body awareness or “scanning” MFIS, POM

  • Significantly beneficial effect on fatigue scores

  • One RCT found significant post-intervention reduction in fatigue in both overall population and in subgroup analyses of those with pre-intervention impairment (p < 0.001 for both).

  • Beneficial effect maintained at 6 months

 I
Cognitive and psychological interventions
Moss-Morris et al. 2012 (68), UK RCTn = 40 pwMS Intervention group (n = 23): internet-based cognitive behavior therapy (CBT) – “MS Invigor8” (eight tailored, interactive sessions with a clinical psychologist over 8–10 weeks)Control group (n = 17): standard care MFIS

  • Significant greater improvements in fatigue severity and impact; and also in anxiety, depression and quality-adjusted life years in treatment group

 II
van Kessel et al. 2008 (69), New Zealand RCTn = 72 Treatment group (n = 35): CBT (eight weekly sessions)Control group (n = 37): relaxation therapy CFS, MFIS

  • Both groups showed clinically significant decreases in fatigue

  • Significantly greater improvements in fatigue in treatment group (p < 0.02) compared to relaxation therapy group: ES = 3.03 (95% CI 2.22–3.68) for the CBT group across 8 months compared with the relaxation therapy group (ES 1.83; 95% CI 1.26–2.34)

 II

aLevels of evidence’ categorized according to National Health and Medical Research Council (NHMRC) pilot program 2005–2006 for intervention studies (23).

CBT, cognitive behavioral therapy; CCT, clinical controlled trial; CFS, Chalder fatigue scale; ES, effect size; 95% CI, 95% confidence interval; FAI, fatigue assessment instrument; FSMC, fatigue scale for motor and cognitive functions; FSS, fatigue severity scale; FIS, fatigue impact scale; MFIS, modified fatigue impact scale; MSFS, multiple sclerosis-fatigue self-efficacy; MSIS, multiple sclerosis impairment scale; MSIS29, multiple sclerosis impact scale; MSQL-54, multiple sclerosis quality of life-54 MFI, multidimensional fatigue inventory; POMS, profile of mood states; QoL, quality of life; RCT, randomized controlled trial; SF-36, short-form health survey-36, VAS, visual analog scales.