|Year : 2018 | Volume
| Issue : 2 | Page : 9-36
Management of fatigue in neurological disorders: Implications for rehabilitation
Fary Khan1, Bhasker Amatya2
1 Department of Rehabilitation Medicine, Royal Melbourne Hospital; Department of Medicine, University of Melbourne; Australian Rehabilitation Research Centre, Royal Melbourne Hospital, Parkville, Victoria; School of Public Health and Preventive Medicine, Monash University, Victoria, Australia
2 Department of Rehabilitation Medicine, Royal Melbourne Hospital; Department of Medicine, University of Melbourne; Australian Rehabilitation Research Centre, Royal Melbourne Hospital, Parkville, Victoria, Australia
|Date of Web Publication||11-Jan-2019|
Department of Rehabilitation Medicine, Royal Melbourne Hospital, 34-54 Poplar Road, Parkville, Melbourne VIC 3052
Source of Support: None, Conflict of Interest: None
This review systematically evaluates existing evidence for the effectiveness and safety of different rehabilitation interventions for managing fatigue in persons with multiple sclerosis (MS), stroke, traumatic brain injury (TBI), and Parkinson's disease (PD) for improved patient outcomes. A comprehensive literature search was conducted using medical and health science electronic (MEDLINE, EMBASE, PubMed, and the Cochrane Library) databases for published articles up to March 1, 2018. Both reviewers applied inclusion criteria to select potential studies and extracted data independently. Overall, 56 studies (22 systematic reviews/meta-analyses, 32 randomized clinical trials, 2 controlled clinical trials) fulfilled the inclusion criteria for this review. Although existing best-evidence for many interventions is still sparse, the overall findings suggest “strong” evidence for physical activity, cognitive-educational programs, and energy conservation strategies in MS; “moderate” evidence for multidisciplinary rehabilitation in MS; home-based physical activities in stroke and TBI; hydrotherapy in MS and TBI, group-education in stroke and self-management programs in TBI; and mindfulness intervention in MS, stroke, and TBI. There was “low” evidence for exercise in PD and other physical modalities such as yoga and cooling therapy in MS, pulsed electromagnetic devices in MS and stroke; light therapy, and biofeedback in TBI. Effect of other interventions was inconclusive. Despite the available range of rehabilitation interventions for management of fatigue in neurological conditions, there is lack of high-quality evidence for many modalities. More robust research is needed with appropriate study design, timing and intensity of modalities, and associated costs.
Keywords: Disability, fatigue, neurological disorder, nonpharmacological intervention, rehabilitation
|How to cite this article:|
Khan F, Amatya B. Management of fatigue in neurological disorders: Implications for rehabilitation. J Int Soc Phys Rehabil Med 2018;1:9-36
|How to cite this URL:|
Khan F, Amatya B. Management of fatigue in neurological disorders: Implications for rehabilitation. J Int Soc Phys Rehabil Med [serial online] 2018 [cited 2019 Jan 16];1:9-36. Available from: http://www.jisprm.org/text.asp?2018/1/2/9/249856
| Introduction|| |
Fatigue is defined as “a subjective lack of physical or mental energy perceived by an individual (or caregiver) that interferes with usual and desired activity.”, It includes an overwhelming sense of tiredness, lack of energy, and feeling exhausted, while the International Classification of Diseases, Tenth Edition includes asthenia, debility, general physical deterioration, lethargy, and tiredness as signs and symptoms of fatigue., Fatigue is a common disabling symptom in many chronic neurological conditions in adults including multiple sclerosis (MS), stroke, Parkinson's disease (PD), traumatic brain injury (TBI), and others., Definitive cause of fatigue in many neurological conditions is unknown; however, it is understood as a multidimensional phenomenon with different aspects including complex interplay between the underlying disease process, peripheral and central control systems, and environmental factors.,
Fatigue may result from central-mediated processes characterized by the condition itself (primary fatigue) such as demyelination and axonal loss in the central nervous system or immune actions in MS or from condition-related complications (secondary fatigue) (trigeminal neuralgia, spasticity, psychological issues, etc.), musculoskeletal problems (pain, posture, gait anomalies, etc.), sleep problems, and/or medications., Fatigue can be acute (new occurring in the past 6 weeks) or chronic (lasting longer than 6 weeks). Experimental studies have shown that fatigue results from reduced voluntary activation of muscles using central mechanisms.
Fatigue can adversely impact on activities of daily livings (ADLs), ability to work, social life, mood, sleep, and quality of life (QoL)., It is associated with cognitive impairment and limitation in participation (such as relationships, social integration, employment, etc.)., Many psychosocial factors influence adjustment to fatigue, including family response, coping behaviors, psychological distress, and fatigue-related disability.,,, Fatigue is also associated with poorer general health, increased disability, and higher rates of healthcare utilization., Although the definite mechanism for fatigue is unknown, several factors may contribute to it [Table 1].,,,,,,
Fatigue in multiple sclerosis
Fatigue is the most common debilitating symptom in MS, with reported prevalence rate of 70%–90%.,, The MS International Federation recognizes two types of fatigue, namely: physical or motor fatigue (muscle weakness, slurred speech, inability to perform daily tasks, etc.) and cognitive fatigue (deterioration of cognitive function such as, reduced reaction time response, alertness during the day, difficulty in thinking, concentration, memory, recall, word finding, etc.). Further, MS-related fatigue may be classified as: “fatigability” (increased weakness with exercise or as the day progresses) and “lassitude” (abnormal constant persistent sense of tiredness). MS-related fatigue has distinctive characteristics which include: occurs daily, more easily and suddenly; worsens as day progresses; aggravate by heat/humidity; more severe; and more likely to interfere with role performance and physical functioning.,, Clinically, fatigue may manifest as exhaustion, lack of energy, increased somnolence, or worsening of MS symptoms and activity, with heat typically exacerbating symptoms.
Fatigue in stroke
Fatigue is identified as “a major, yet neglected issue” in persons with stroke, with reported prevalence rate of 36%–77%. Characteristics of stroke-related fatigue are unclear., In contrast to MS, stroke patients' level of fatigue does not change overtime; however, those who report fatigue at baseline show a relatively higher level of fatigue overtime., Stroke-related fatigue is associated with increased mortality, poor functional outcome and neurological recovery, low QoL, and participation.,,, It is also an independent determinant of inability to resume paid work following stroke. Stroke-related fatigue can be distinguished by its onset and time course: acute stage fatigue may be a normal, protective, and restorative response while chronic, persistent fatigue may be pathological in nature associated with complex etiology. Primary poststroke fatigue may be caused by minor attentional deficits due to the interruption of neural networks (such as reticular activating system). The mechanism for fatigue and several different factors believed to contribute to fatigue are shown in [Table 1].
Fatigue in traumatic brain injury
Fatigue in TBI has a prevalence of 21%–70%.,, It is primarily subjective in nature, with no accepted definition or objective measurement. TBI-related fatigue includes physical, cognitive, motivational, situational, and activity-related components.,, It is often associated with a sense of disproportionate exertion and associated mental or physical exhaustion, resulting in inability to perform ADLs., Similar to many other symptoms of TBI, TBI-related fatigue tends to decrease in the first year following injury and remains relatively unchanged in subsequent years after injury.,,, TBI-related fatigue is complex with multiple heterogeneous origins and predisposing features may include various factors [Table 1]. It has negative impact on person's QoL, specifically related to the situational stress and self-reported somatic symptoms. Many individuals with TBI tend to ignore the symptoms and/or engage in compensatory strategies such as spending extended time in bed, daytime napping, restricting participation, and activities.,,
Fatigue in Parkinson's disease
Fatigue in PD has a reported prevalence rate of 33%–58%, and not well understood., It is recognized as a nonmotor symptom and related to disease severity and progression. Commonly reported contributing factors including older age, male gender, anxiety, motor symptoms, depression, sleep disorder, and effects of medication., Although major conclusive cause of PD-related fatigue is still unclear, several mechanisms have been hypothesized: altered activation of the hypothalamic-pituitary-adrenal system due to prolonged stress, inflammatory processes, and dysfunction in the basal ganglia and striato-thalamocortical loop caused by alterations of neurotransmitters, for example, dopamine and serotonin. In persons with PD, central fatigue is partially related to dopamine deficiency and may be induced either by decreased external stimulation caused by motor impairments,,, while, peripheral fatigue (muscle fatigue, or physical or exercise fatigue) is believed to be a sense of exhaustion caused by repeated use of muscles. There is association of abnormal cortico-motoneuron excitability with motor fatigue, as levodopa normalizes the raised cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise.
The symptomatic management of fatigue in persons with neurological conditions is the achievement of individualized, functionally oriented goals set collaboratively with patients (carers) and treating multidisciplinary team.,, Although there is a lack of consensus on the best treatment approach, both pharmacological and nonpharmacological intervention are used in fatigue management. The published clinical practice guidelines on the management of MS, stroke, TBI, and PD highlight significance of diagnosis and treatment of fatigue in the management plan. However, there is lack evidence for efficacy of any pharmacological agent alone., Commonly used pharmacological agents for fatigue are summarized in [Appendix 1].
Nonpharmacological approaches used in isolation and/or in combination with pharmacological agents are the mainstay for management of fatigue.,, Specific nonpharmacological interventions for fatigue include physical activity program (such as aerobic exercise, strengthening exercises, hydrotherapy, yoga, and tai chi), behavioral management techniques (rest breaks, cognitive behavioral therapy (CBT), and mindfulness-based stress reduction programs), educational and self-management programs (e.g., relaxation, avoiding multitasking, and improved sleep hygiene); physical modalities (cooling therapy, pulsed electromagnetic devices, light therapy, etc.), alternative therapies (acupuncture), and others. The body of research investigating the effect of these interventions on fatigue is growing. The benefit and harm associated with these interventions need to be established to guide treating clinicians. Therefore, the aim of this review is to systematically evaluate the existing evidence to examine the effectiveness and safety of rehabilitation interventions for the management of fatigue in common neurological conditions, specifically in MS, stroke, TBI and PD in improving patient outcomes.
| Methods|| |
An integrated, multipronged approach was used, which includes a comprehensive review of literature (peer review and grey literature) documenting interventions currently used in the management of fatigue in MS, stroke, TBI, and PD. A comprehensive search of the literature published before March 1, 2018, was undertaken using Medline, Embase, PubMed, and Cochrane Library databases (including DARE). The search strategy included interventional studies investigating the management of fatigue, using combinations of multiple search terms for three themes: neurological conditions of interest (stroke, MS, TBI, and PD), rehabilitation interventions and fatigue [Appendix 2]. Medical subject heading (MeSH) search terms were used for all databases and a keyword search was used if the MeSH term was not available. The bibliographies of identified articles were scrutinized for additional references, and a manual search of relevant journals was undertaken. A grey literature search using different internet search engines and websites (System for Information on Grey Literature in Europe; New York Academy of Medicine Grey Literature Collection, and Google Scholar) was conducted. Additional searches of websites of prominent national and international organizations associated with management of MS, Stroke, TBI and PD identified relevant reports, health technology assessments, or other related materials. Experts in the field were contacted.
Studies that compared various rehabilitation interventions in the management of fatigue in MS, Stroke, TBI, and PD with routinely available local services or lower levels of intervention or placebo, or studies that compared such interventions in different settings or at different levels of intensity, were included in this review. This involved all systematic reviews, meta-analyses, randomized clinical trials (RCTs), and controlled clinical trials (CCTs). Studies with other medical conditions, where data were specifically provided for fatigue in aforementioned neurological conditions, were also included in this study. Where high quality systematic reviews or meta-analyses were identified, articles published before the date of that review's search strategy were excluded from the study.
Exclusion criteria included – non-English-language publications, pediatric population (aged below 18 years), observational and descriptive studies, theses, narrative reviews, editorials, case reports, economic evaluation, conference proceedings, and studies evaluating surgical intervention or diagnostic procedures.
Both authors independently screened and shortlisted all abstracts and titles of studies identified based on the selection criteria. Each study was evaluated independently by authors and full text of the article was obtained for further assessment to determine whether the article met the inclusion/exclusion criteria. A final consensus decision was made by mutual discussion, if no consensus was reached regarding the possible inclusion/exclusion of any individual study. Further information about the complete description of the interventions from the trialists was obtained, where necessary.
A standard pro forma was used to extract data from the included studies, which included: publication date and country, study design, study sample, intervention, outcome measures used and fatigue-related outcomes. Any discrepancies were resolved by the authors re-reviewing the study.
Evidence for all included studies was categorized according to study design using a hierarchy of evidence in descending order and priority was given to the most recently published high-quality systematic reviews or meta-analysis and RCT. Formal levels of evidence were assigned using a standard format defined by National Health and Medical Research Council pilot program 2005–2006 for intervention studies [Appendix 3].
| Results|| |
The electronic database search retrieved 1883 published articles on fatigue in MS (1061), stroke (474), TBI (113), and PD (235). Of these, 462 articles met title inclusion criteria of which 89 articles met the abstract inclusion criteria and went on to full-text review. Four articles that met the abstract inclusion criteria were identified from the cross referencing and bibliographies of relevant articles. Overall, 56 studies (22 systematic reviews/meta-analyses, 32 RCTs, 2 CCT) fulfilled the inclusion criteria for this review. Of these, majority 35 studies evaluated different rehabilitation interventions in MS, 6 in stroke, 10 in TBI, 2 in PD, and 3 in mixed neurological conditions. The study selection process is summarized in the PRISMA flow diagram shown in [Figure 1].
Evidence for rehabilitation interventions for fatigue
The existing evidence for various rehabilitation interventions for fatigue management in MS, stroke, TBI, and PD are summarized below and in characteristics of included studies in [Table 2].
|Table 2: Common nonpharmacological interventions for fatigue in multiple sclerosis|
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Multidisciplinary rehabilitation is the coordinated delivery of intervention by two or more disciplines (nursing, physiotherapy, occupational therapy, social work, psychology, dietetics, etc.) under medical supervision (neurologist, oncologist, rehabilitation physician). Multidisciplinary rehabilitation is often individualized cater to the needs of patients, with a goal to optimize function and promote activities and psychosocial adjustment to maximize participation.
Multiple sclerosis (Level I evidence)
Khan et al. in a systematic review (n = 9 RCTs, 1 CCT; 954 participants) evaluated multidisciplinary rehabilitation programs in MS and found only two studies which included fatigue as an outcome measure. One RCT showed a 12-week ambulatory rehabilitation program significantly reduced fatigue and improved social functioning and depression (P < 0.001). Another CCT reported that extended ambulatory rehabilitation significantly reduced fatigue symptoms in the treatment group compared with controls at 1-year follow-up (P = 0.004). There was limited evidence for fatigue outcomes from inpatient rehabilitation programs.,
Rietberg et al. in another RCT evaluated the effect of tailored, multidisciplinary outpatient rehabilitation on MS-related chronic fatigue. The multidisciplinary rehabilitation program was compared with MS-nurse consultation with no significant within-group effects regarding reducing self-reported fatigue from baseline to 12 or 24 weeks. The authors concluded that MS-related chronic fatigue varies overtime, irrespective of intervention.
Fatigue is associated with reduced physical fitness and lower levels of physical activity., Physical training therefore improves fitness and stimulates cortical excitability, which may reduce fatigue. Various physical modalities currently trialled in MS, stroke, TBI, and PD for the management of fatigue are summarized below:
Multiple sclerosis (Level I)
Safari et al. conducted a comprehensive review (n = 32 articles, 16 systematic reviews with qualitative synthesis and 16 narrative reviews) to provide an overview synthesis of meta-analytic review-generated information about a potential role for different form of exercise training interventions for MS-related fatigue. The authors included five systematic reviews with quantitative synthesis for meta-analyses and found a significant moderate random effect in favor of exercise compared with no exercise or usual care conditions on ameliorating MS-related fatigue. However, the authors suggest that results should be interpreted with caution because of high risk of bias, poor applicability of results, heterogeneity, and small sample size in the RCTs. Further, there was a paucity of information on efficacy on definite type of exercise intervention/s, intensity, frequency, or duration.
A systematic review (n = 19 articles, 12 studies reporting fatigue outcomes) evaluated various types of exercise training in individuals with MS with severe mobility disability. The authors found beneficial effect of various types of exercise modalities in reducing MS-related fatigue, including conventional exercise training, body-weight support treadmill training, total-body recumbent stepper training, and electrical stimulation cycling. The results were mixed for different interventions and details on specific fatigue outcomes were not reported.
Heine et al. in a meta-analysis (n = 45 RCTs, 2250 participants) examined effectiveness and safety of various exercise interventions (endurance, muscle-power training, task-oriented, mixed training and other - e.g., yoga) compared with no-exercise control condition or another intervention for fatigue. The authors found a significant effect in favor of exercise therapy (n = 26 trials) compared to nonexercise control (standardized mean difference [SMD]: −0.53, 95% confidence interval (CI): −0.73 to −0.33; P < 0.01). They reported a significant effect in favor of different types of exercise therapy compared to no exercise for endurance training (SMD: −0.43, 95% CI: −0.69 to −0.17; P < 0.01), mixed training (SMD: −0.73, 95% CI: −1.23 to −0.23; P < 0.01), and other training (SMD: −0.54, 95% CI: −0.79 to −0.29; P < 0.01). The evidence, however, was moderate due to heterogeneity between trials. Exercise was not associated with MS relapse.
Asano and Finlayson in another systematic review reported strong evidence for exercise-based rehabilitation for reducing the severity of patient-reported fatigue. Despite marked heterogeneity among included trials (n = 10 studies, 233 participants), exercise intervention had a significant effect for fatigue in MS (pooled effect size [ES]: 0.57; 95% CI: 0.10–1.04, P = 0.02). The extent of intervention effect varied considerably and only younger, more stable MS patients appeared to benefit. There was no evidence of benefit for other MS subgroups (older adults, progressive MS, and/or severe disability). It was not possible to identify the type or intensity of exercise needed to achieve benefit for fatigue management.
Latimer-Cheung et al. in a systematic review (n = 54 trials; 15 RCTs and 15 other design evaluating fatigue outcomes) evaluated effects of exercise training (aerobic fitness; resistance training, combined and forms of physical activity such as sport, yoga, body weight-supported treadmill training, aquatic exercise, cycling, and pilates) on physical fitness, mobility, fatigue, and health-related QoL (HRQoL) in MS. There was strong evidence that exercise performed twice weekly at moderate intensity increased aerobic capacity and muscle strength. However, overall evidence for exercise training on symptomatic fatigue was inconsistent. There was insufficient data for optimal intervention and dose.
Another meta-analysis (n = 17 RCTs, 568 participants) demonstrated a similar positive effect of exercise interventions (resistance, endurance training, aquatic exercises, stretching, relaxation, cycling, yoga, walking, and mixed modalities) for MS-related fatigue. Exercise training was associated with a significant reduction in fatigue (weighted mean ES: 0.45; 95% CI: 0.22–0.68, P ≤ 0.001) in persons with MS.
Andreasen et al. assessed the beneficial effect of different exercise categories separately; these included endurance/resistance training, combined, or “other” training modalities. The authors report heterogeneity among included trials, only a few studies evaluated MS fatigue as the primary outcome; and many studies included nonfatigued MS patients. Overall, all exercise intervention had potential to reduce MS fatigue. The authors concluded that, compared with other exercise modalities, endurance training was more frequent (n = 11 studies) and showed more consistent positive effects.
Heine et al. in an RCT (n = 90 participants) examined the effectiveness of aerobic training on MS-related fatigue and societal participation in ambulant patients with severe MS-related fatigue. The authors reported that aerobic training in MS patients with severe fatigue did not lead to a clinically meaningful reduction in fatigue or societal participation when compared with low-intensity control intervention. There was a significant improvement in fatigue postintervention with between-group mean difference on the CIS20r fatigue subscale (P = 0.014), this, however, was not sustained during follow-up. The authors concluded that these findings were not clinically meaningful.
Stroke (Level II)
Zedlitz et al. in an RCT (n = 83) reported CBT plus graded activity training (12-weeks) was more effective in reducing fatigue in stroke patients than cognitive-behavior therapy alone. Both groups showed a significant improvement in fatigue (P < 0.001), with no differences between groups. The treatment group showed clinically important change in fatigue severity (58% vs. 24%) and physical endurance compared with the controls (P < 0.001). However, authors were unable to explain whether the reduction in fatigue was due to physical training alone.
Traumatic brain injury (Level II)
Kolakowsky-Hayner et al. in a prospective, single-blind crossover RCT (n = 128) evaluated impact of a graduated physical activity program which included home-based walking program (utilizing a pedometer) and nutritional counseling on fatigue after TBI. The walking intervention group reported less fatigue at the end of both active parts of intervention (24 weeks, mean difference [MD]: 4.78, P < 0.003)) and after a wash-out period (36 weeks MD: 4.6, P < 0.003).
Another RCT (n = 62) evaluated effectiveness of a supervised fitness strength training program (3 sessions/week for 12 weeks) on cardiorespiratory fitness in severe TBI. Compared with the unsupervised home-based training program, the supervized training group improved cardiorespiratory fitness at the end of treatment and at 3-month follow-up. However, there were no differential treatment effects observed on fatigue between the two groups at 3 and 6 months follow-up (P = 0.07, 0.178, respectively).
Parkinson's disease (Level I)
Elbers et al. in a systematic review evaluated the effects of pharmacological and nonpharmacological interventions on subjective fatigue in people with PD. The authors included 2 RCTs (n = 57 participants): one study investigated the effect of home-based treadmill training, semi-supervized by a PT and another study addressed the effect of a supervised community gym-based program with information and practical advice from a physiotherapist. A meta-analysis showed no statistically significant differences between exercise and usual care on fatigue severity (SMD: −0.45, 95% CI: −1.21–0.32).
Tai Chi is reported to have favorable effects on balance, posture, muscle strength, psychological issues (stress reduction and decreased anxiety, depression and mood disturbance) and general well-being in people with various medical conditions.,
Multiple sclerosis (Level II)
One meta-analysis (n = 10 RCTs, 689 participants) examined the effect of Tai Chi for fatigue in MS. Despite, Tai Chi was found to have a significant beneficial effect on fatigue than conventional therapy overall SMD: −0.45, 95% CI: −0.70 to −0.20), no significant difference was found in MS-related fatigue (SMD: −0.77, 95% CI: −1.76–0.22). Overall, Tai Chi was also found to have positive effects on vitality (SMD: 0.63, 95% CI: 0.20–1.07), sleep (SMD:-0.32, 95% CI: −0.61 to −0.04), and depression (SMD: −0.58, 95% CI: −1.04 to −0.11).
Two trials (1 RCT, 1 CCT, n = 96 participants) investigated the effectiveness of Tai Chi aquatic exercise program in reducing symptoms, including fatigue and physical function in MS., There was a significant reduction in fatigue in the Tai Chi group compared with controls. One RCT (n = 73) suggested an aquatic exercise (Ai Chi) program for 20 weeks (40 sessions) improved fatigue, pain, spasms, disability, and depression. Bayraktar et al. in another CCT (n = 23) investigated the effects of a similar aquatic exercise program (Ai Chi) on balance, functional mobility, strength, and fatigue in ambulatory individuals with MS. The authors reported significant improvements in fatigue, static standing balance, functional mobility, and upper and lower extremity muscle strength in the treatment group (P < 0.05).
Traumatic brain injury (Level II)
Gemmell and Leathem in a waitlist RCT (n = 18) examined the effects of tai chi training (2 weekly sessions for 6 weeks) on TBI-related symptoms. Fatigue was assessed as a secondary outcome. The authors did not find any within-subject improvements or between-group differences (before and after intervention) in any vitality (fatigue) outcomes (54.42 ± 6.03 versus 52.52 ± 5.82).
Multiple sclerosis (Level I)
Cramer et al. in a systematic review (n = 7 RCTs, 670 participants) evaluated the efficacy and safety of yoga in persons with MS. The authors reported significant short-term favorable effects of yoga compared to usual care for fatigue (SMD: −0.52; 95% CI: −1.02 to −0.02; P = 0.04 and mood (SMD: −0.55; 95% CI: −0.96 to −0.13; P = 0.01), but not for HRQoL, muscle function, or cognitive function. There was no short-term or longer-term effect of yoga compared with exercise. Yoga was not associated with serious adverse events and was an option for those unable to exercise.
Hydro (aquatic) therapy
Multiple sclerosis (Level II)
One RCT (n = 32) reviewed the effectiveness of a supervized 8-week aquatic exercise training program (three 60-min sessions/week) on fatigue and HRQoL in women with MS. The participants in the aquatic exercise group showed significant improvements in fatigue and QoL after 4 and 8 weeks compared with the control group.
Traumatic brain injury (Level II)
One small RCT (n = 16) evaluated the effect of aquatic physical activity (24-session, 8-week) on symptomatic persons with chronic TBI, compared with controls (vocational rehabilitation program). The authors report reductions in Fatigue-Inertia scale scores (P < 0.05) in the intervention group compared to the control group.
Multiple sclerosis (Level II)
Beenakker et al. in a cross-over RCT (n = 10) evaluated cooling techniques for symptomatic management in heat-sensitive persons with MS. The authors found some beneficial effect of cooling therapy in reducing fatigue (P = 0.015), improving postural stability and muscle strength when wearing a cold vest with active cooling (7°C, 60 min.).
Pulsed electromagnetic devices
Multiple sclerosis (Level II)
A multicenter placebo-controlled RCT (n = 117) evaluated the effects of pulsed electromagnetic therapy on MS-related fatigue, spasticity, bladder control, and overall QoL. The authors reported significantly decreased fatigue when wearing an active low-level, pulsed electromagnetic field device on one or more acupressure points daily for up to 4–8 weeks.
Similar positive results were reported in another double-blind RCT (n = 33 participants) using a magnetic pulsing device with (“Enermed” with frequency range of 4–13 Hz). The authors found no significant change between pre- and post-treatment in the disability scales. There was, however, improvement in the performance scale 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 performance scale). The clinical effects in these trials were small and long-term follow-up data were lacking.
Traumatic brain injury (Level II)
One placebo-controlled RCT (n = 30) investigated the efficacy of short wavelength (blue) light therapy (45 min daily for 4 weeks) for fatigue in patients with TBI. The authors reported high-intensity blue-light therapy reduced fatigue and daytime sleepiness during the treatment phase, with evidence of a trend toward baseline levels 4 weeks after treatment cessation. There was no beneficial effect with lower-intensity yellow-light therapy and no significant treatment effect for self-reported depression or psychomotor vigilance performance.
Continuous positive airway pressure
Stroke (Level II)
One RCT (n = 32) assessed the effectiveness and feasibility of continuous positive airway pressure (CPAP) for sleep apnea in people with ischemic stroke. Fatigue was measured with Fatigue Severity Scale (FSS) as a secondary outcome at the end of the 3-month treatment. The authors found no evidence for the efficacy of CPAP in a reduction in fatigue severity.
Traumatic brain injury (Level II)
Schoenberger et al. in a wait-list-control RCT (n = 12) evaluated effects of 25 electroencephalographic biofeedback treatment (Flexyx Neurotherapy System 25 sessions) on a range of TBI symptoms including fatigue in persons with mild-to-moderate TBI. The authors reported a significant improvement in the treatment group on general and mental fatigue, but not physical fatigue. This study, however, was underpowered.
Multiple sclerosis (Level II)
One RCT (n = 24) evaluated the effectiveness of neurofeedback training (16 sessions) in treating depression and fatigue in persons with MS. Compared with the usual care control group participants in neurofeedback group showed significant reduction in symptoms of depression and fatigue at the end of treatment (P < 0.05) and at 2-month follow-up (P < 0.05).
Transcranial direct current stimulation
Multiple sclerosis (Level II)
One sham-controlled, double-blind cross-over intervention study (n = 14) evaluating the effectiveness of tDCS (left frontal cortex for 5 days) on fatigue, did not find any significant group differences in fatigue outcomes. However, the authors found a correlation between response to the stimulation regarding subjectively perceived fatigue and lesion load in the left frontal cortex as follows: patients responding positively to anodal tDCS had higher lesion load compared to nonresponding patients.
Educational fatigue management programs
Multiple sclerosis (Level I)
A meta-analysis (n = 8 RCTs, 662 participants) investigated the effectiveness of different types of educational programs on reducing the impact or severity of self-reported fatigue in MS, which included fatigue management, energy conservation programs, mindfulness interventions, and CBT. The authors found significant global improvement with a large pooled treatment ES for educational interventions of 0.54 (95% CI: 0.30–0.77 P < 0.001; range: −0.16–1.11).
Another meta-analysis (n = 10 RCTs, 1021 participants) evaluated the effect of patient education programs (interventions with a focus on CBT or interventions on daily fatigue management) on fatigue in MS. The findings suggest significant positive effects on fatigue severity (weighted mean difference [WMD]: −0.43; 95% CI: −0.74 to −0.11) and on fatigue impact (WMD: −0.48; 95% CI: −0.82 to −0.15), but not for depression (WMD: −0.35, 95% CI: −0.75–0.05; P = 0.08). An educational program with CBT approaches generated better results for fatigue severity compared to non-CBT approaches (WMD: −0.60 vs. −0.20). Furthermore, individual face-to-face approach seems to reduce fatigue severity more effectively than group-based approaches (WMD: −0.80 vs. −0.17).
A multi-centered parallel arm RCT (n = 164) evaluated the effectiveness of a group-based program (90-min sessions weekly for 6 weeks) for managing MS fatigue (Fatigue: Applying Cognitive behavioral and Energy effectiveness Techniques to Lifestyle [FACETS]) facilitated by two health professionals (occupational therapists, nurses or physiotherapists), based on a framework integrating elements from cognitive-behavior, social-cognitive, energy effectiveness, self-management, and self-efficacy theories. The authors found significant differences favoring the intervention group on fatigue self-efficacy at 1-month follow-up (MD: 9; 95% CI: 4–14) with a large ES (ES: 0.54, P = 0.001). The positive effects of the program still maintained at 4-month follow-up with a moderate ES (ES: 0.36; P = 0.05), with significant improvement in fatigue severity (P = 0.01). The authors reported 1-year follow-up outcomes in another study and reported the benefits of the FACETS program for fatigue severity and self-efficacy mostly sustained; however, it was not statistically significant (ES: −0.29, P > 0.06). There were significant improvements in QoL in intervention group participants (P = 0.046).
Another RCT (n = 51) evaluating the efficacy of a multidisciplinary fatigue management program showed no reduction in fatigue compared with placebo. The multidisciplinary fatigue management program comprised interactive educational sessions about possible strategies to manage fatigue and reduced energy levels (2 h sessions weekly for 4 weeks).
Stroke (Level II)
Clarke et al. in a pilot RCT (n = 16) showed that a group education program (fatigue management strategies, sleep hygiene, relaxation, exercise, education, nutrition, and mood-60 min-six sessions per week) was effective in improving fatigue symptoms compared with usual stroke management program. Both groups showed a similar improvement on FSS; however, there was a trend favoring the fatigue management education group.
Lorig et al. in an RCT (n = 125) evaluated a chronic disease self-management program on health status, health utilization; and self-efficacy outcomes. The participants in the treatment group received seven consecutive weekly sessions (peer-taught sessions, 2.5 h each session) and education. Fatigue was a secondary outcome using the energy/fatigue scale. The authors reported some reduction in fatigue severity in the treatment group (−0.44–0.12 less); however, this difference was not statistically significant.
Neurological conditions (Parkinson's disease, multiple sclerosis, and postpolio syndrome) (Level II)
Ghahari et al. in a four-arm RCT (n = 115 participants, MS = 70, PD, and postpolio syndrome = 35) evaluated the effectiveness of a face-to-face and an online fatigue self-management program using a sample of adults with neurological conditions reporting extreme fatigue and compared with two control groups (information-only and no intervention). The authors found that participants in both intervention groups (face-to-face and an online fatigue self-management program) and the information-only group showed clinically significant improvements in fatigue overtime (P < 0.05). In addition, compared to the no intervention group, face-to-face participants showed significantly greater improvement in overall and cognitive fatigue whereas participants in the online group showed a significant improvement in self-efficacy and stress.
Energy conservation interventions
Multiple sclerosis (Level I)
Blikman et al. in a systematic review (n = 4 RCTs, 2 CCTs; 494 participants) evaluated the effectiveness of energy conservation treatment (education balancing, modifying and prioritizing activities, rest, self-care, effective communication, biomechanics, ergonomics, and environmental modification) for fatigue and QoL in MS. Meta-analysis of two good quality RCTs (n = 350 participants) showed that energy conservation interventions treatment were more effective than no treatment in improving fatigue, FIS scores: cognitive (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); and QoL: role physical (MD: 17.26; 95% CI: 9.69–24.84), social function (MD: 6.91; 95% CI: 1.32–12.49), and mental health (MD: 5.55; 95% CI: 2.27–8.83). Qualitative best-evidence synthesis of other studies also showed moderate-to-strong evidence in favor of the intervention. However, the results were mixed due to heterogeneity among included studies and no studies reported long-term results.
In more recently published single-blind, two-parallel-arm RCT (n = 86 severely fatigued and ambulatory adults) evaluated the effectiveness of an individual energy conservation management intervention on fatigue and participation. Compared to the information-only control group, the authors found no significant beneficial effects of the intervention for fatigue (overall group difference in checklist individual strength (CIS20r): −0.81; 95% CI: −3.71–2.11) or restrictions in participation. Another RCT (n = 23 participants) compared energy conservation program (2-h sessions per week for 5 weeks) with a peer support group. The authors found significant improvements in FIS scores overtime in both groups with larger changes in the experimental group and were maintained at follow-up with significant differences as follows: total score (P < 0.01), physical (P < 0.007), and cognitive subscales (P < 0.015). There was a significant difference between groups in the cognitive subscale at 6-week (P = 0.01) and 3-month follow-ups (P = 0.001). This study was, however, underpowered with significant high dropout rates.
Traumatic brain injury (Level II)
Raina et al. in a RCT (n = 41) evaluated the feasibility and effectiveness of maximizing energy intervention (energy conservation education and problem-solving therapy for 8 weeks) to manage fatigue-related problems compared with control group (usual health education). There was no significant difference between the groups for fatigue measures, with ESs ranging from small (−0.17) to medium (−0.58) in favor of the intervention group.
Occupational therapy intervention
Multiple sclerosis (Level II)
Kos et al. in a RCT (n = 31) evaluated the effectiveness of an individual self-management OT intervention program, focusing on pacing, prioritizing, ergonomics, and self-management, and compared with control group with relaxation program. The authors found improvement in ADL activities in both groups (P = 0.001), with nonsignificant group differences, but trend in favor of intervention group. There were no changes in any fatigue outcomes in both groups.
Cognitive and psychological interventions
Multiple sclerosis (Level II)
van den Akker et al. in a systematic (n = 4 RCTs, 403 participants) evaluated short-term and long-term effects of CBT for the treatment of MS-related fatigue. The authors found that CBT has a moderately positive short-term effect for the treatment of fatigue in patients with MS (SMD: −0.47; 95% CI: −0.88 to −0.06); however, the effect decreased with cessation of treatment.
Many studies have evaluated the effectiveness of CBT in various settings. A multicenter RCT (n = 92) evaluated the effectiveness of CBT (12 individual sessions with a psychologist delivered over 16 weeks) to improve severe MS-related fatigue and participation. Compared to the control group (nursing consultations), the authors found the significant positive postintervention effect of CBT on fatigue at 8 weeks; however, the effect did not maintained at 52 weeks follow-up period. Another pilot RCT (n = 40) showed that an internet-based CBT program – “MS Invigor8” (eight sessions with clinical psychologist over 8–10 weeks) was effective for MS-related fatigue. Compared with standard care, the treatment group reported significantly greater improvements in fatigue severity and impact and for anxiety, depression, and quality-adjusted life years.
van Kessel et al. in another RCT (n = 72) showed significantly greater improvements in fatigue in persons with MS after CBT (8 weeks) compared with relaxation therapy (P < 0.02). Both groups showed clinically significant decrease in fatigue; however, the CBT group had greater reduction in fatigue from baseline to the end of treatment (ES = 3.03, 95%CI 2.22–3.68) compared with the relaxation group (ES = 1.83; 95%CI 1.26–2.34). In another RCT (n = 39), the same authors evaluated the efficacy of an internet-based CBT self-management program with (“MSInvigor8-Plus”) and without (“MSInvigor8”-Only) the use of E-mail support in reducing fatigue severity and impact. The authors found that participants in “MSInvigor8-Plus” resulted in significantly greater reductions in fatigue severity (P < 0.01) and impact (P < 0.02) compared with the “MSInvigor8”-only control group. There was a large between-group ESs for fatigue severity (ES = 0.99) and fatigue impact (ES = 0.81), and no significant differences were found between the groups on changes in anxiety and depression.
Stroke (Level II)
One parallel two-group pilot RCT (n = 15) evaluated the effectiveness of individual CBT (8-weekly sessions) for poststroke fatigue and sleep disturbance. Compared to usual care, the CBT group demonstrated a significantly reduction in fatigue relative (MD: 1.92, 95% CI: 0.24–3.60) at 4-month follow-up. The authors also reported significant group differences in sleep quality and depression, favoring the CBT group.
Traumatic brain injury (Level II)
Sullivan et al. (n = 4 RCTs, 789 participants) in a systematic review evaluated the evidence for psychological interventions to improve sleep and reduce fatigue after mild TBI. The interventions evaluated included CBT (one RCT) and enhanced education program (three RCTs). Overall, there was a limited evidence for favorable effect of any of these interventions for sleep and fatigue outcomes due to methodological bias among included studies. The authors reported some beneficial effect of CBT at 6-month follow-up compared to control group (usual care) (82% vs. 47%). Self-reported fatigue and sleep disturbances decreased relative to baseline for both groups after enhanced educational programs at 3 months, with no significant group differences. The authors concluded that compared with standard care, small improvements in sleep and fatigue were observed through psychological intervention postmild TBI.
Nguyen et al. in a parallel two-group RCT (n = 24) evaluated the efficacy of adapted CBT (eight sessions) for sleep disturbance and fatigue in mild-to-severe TBI. Compared to control group (usual care), the intervention group reported improved sleep quality and significantly reduction in daily fatigue levels (MD: 1.54; 95% CI: 0.66–2.42). The authors concluded that CBT could be promising for sleep disturbance and fatigue after TBI. Similarly, a significant improvement in fatigue was observed in the treatment group, and at follow-up, suggesting that improved anxiety may reduce fatigue in wait-list-controlled RCT (n = 46) investigating the effectiveness of a 12-session individualized program, formulation-based CBT program in persons with persistent postconcussion symptoms after mild-to-moderate TBI.
Brain injury (traumatic brain injury, stroke, and others) (Level II)
Björkdahl et al. conducted an RCT (n = 38: stroke = 28, TBI = five, and other = five participants) to evaluate the effects of computerized working memory training on function in everyday life in brain injury. Compared with controls (usual rehabilitation), there was a significant improvement on digit span and fatigue in the intervention group (P = 0.038). Both groups improved in motor and process skill scores. The authors concluded that additional working memory training may have a generalized effect on functional activity which may lessen fatigue.
Mindfulness-based interventions are popular in various areas of chronic disease management such as depression, stroke, and chronic pain. The interventions include meditation, relaxation and breathing techniques, yoga, Tai Chi, hypnosis, visual imagery, and spirituality.
Multiple sclerosis (Level I)
One systematic review (n = 2 RCTs, 1 CCT, 183 participants) of mindfulness-based interventions found only three trials, that emphasized mindful-breath awareness, movement, body awareness, or “scanning.” All three studies reported a beneficial effect on fatigue scores. One RCT reported a significant postintervention reduction in fatigue in both overall participants and in subgroup of those with preintervention impairment. This beneficial effect was maintained at 6 months.
Stroke and traumatic brain injury (Level II)
Lawrence et al. in a systematic review (n = 4 studies, 160 participants) evaluated the benefits of mindfulness-based interventions following transient ischemic attack and stroke. The findings suggested a positive trend in favor of the benefits of mindfulness-based interventions across a range of psychological, physiological, and psychosocial outcomes including anxiety, depression, mental fatigue, blood pressure, perceived health, and QoL. Only, one RCT (n = 18 stroke and 11 TBI participants) evaluated the effectiveness of mindfulness-based stress reduction (for 8 weeks) on long-term fatigue outcomes after TBI and stroke. Statistically significant improvements were achieved in self-assessment for mental fatigue in the treatment group postintervention compared with wait-list controls (P = 0.008).
Multiple sclerosis, stroke, and traumatic brain injury (Level I)
Ulrichsen et al. in a meta-analysis (n = 4 RCTs, 257 participants) investigated the efficacy of mindfulness-based interventions (8 weeks) for fatigue across three neurological conditions as follows: MS, stroke, and TBI. The intervention had a beneficial effect on fatigue, with moderate ES (ES: −0.37, 95% CI: −0.58 to −0.17). No subgroup analyses were provided. The authors concluded that mindfulness-based programs could be promising for fatigue after MS, stroke, or TBI.
Rhythmic-cued motor imagery
Multiple sclerosis (Level II)
Seebacher et al. in an RCT (n = 112) investigate the effect of motor imagery combined with rhythmic cueing with music or metronome cues, both with verbal cueing (17 min six times per week, for 4 weeks) on walking, fatigue, and QoL in MS. Compared with controls, the authors report significant improvements in cognitive function in the intervention groups but not in psychosocial fatigue. Physical fatigue improved only in the music-based group. Further, there was significant improvement in walking speed, distance, perception, and QoL in both groups; however, music-cued motor imagery was superior at improving health-related QoL.
Parkinson's disease (Level II)
One RCT (n = 94) evaluated the efficacy of acupuncture (biweekly for 6 weeks) on fatigue outcomes in persons with PD with moderate-to-high fatigue. The authors found that both acupuncture and sham groups showed significant improvements in fatigue at 6 and 12 weeks, but with no significant between-group differences. Overall, 63% of participants reported noticeable improvement in fatigue. No serious adverse events were observed. The authors concluded that acupuncture may help PD-related fatigue primarily through nonspecific or placebo effects.
A comprehensive Cochrane review (n = 12 trials, 703 participants) evaluated various interventions (both pharmacological and nonpharmacological) currently used for the management of poststroke fatigue. Meta-analysis of five commonly trialled pharmacological interventions as follows: fluoxetine, enerion, (-)-OSU6162, citicoline, and a combination of Chinese herbs showed some beneficial effect on fatigue severity in favor of the pharmacological treatment group compared with controls (SMD: −1.23, 95% CI: −2.40 to −0.06). There was no significant difference in fatigue severity between the nonpharmacological group (fatigue education program and mindfulness-based stress reduction program) and the control group (SMD: −0.68, 95% CI: −1.37–0.02). The evidence for both pharmacological and nonpharmacological interventions was rated very low due to significant heterogeneity between trials.
| Discussion|| |
This review presents current evidence for the effectiveness of different rehabilitation interventions used to treat fatigue in common neurological conditions as follows: MS, stroke, TBI, and PD. Although a range of interventi ons was identified, evidence for these interventions varied, primarily due to lack of methodologically robust studies and heterogeneity among the included trials. The overall findings of this review suggest high-quality evidence for fatigue management in MS as follows:
- Physical therapy (aerobic exercise/physical activities) and improved QoL
- Psychological/educational interventions (fatigue management, energy conservation, CBT, and mindfulness)
- Energy conservation interventions (education about balancing, modifying and prioritizing activities, rest, self-care, effective communication, biomechanics, ergonomics, and environmental modification).
Moderate quality evidence for minimizing fatigue:
- Multidisciplinary rehabilitation (outpatient) in MS
- Physical therapy: home-based physical activities in stroke and TBI
- Aquatic (hydro) therapy program in MS and TBI
- Group education programs in stroke and self-management programs (face-to-face and online) in TBI
- Mindfulness intervention in MS, stroke, and TBI.
Low-quality evidence for reducing fatigue in:
- Physical activities in PD
- Yoga in MS
- Cooling therapy (such as garments) in MS
- Pulsed electromagnetic devices in MS and stroke
- Light therapy for short-term relief of fatigue in TBI
- Electroencephalographic biofeedback treatment in short-term improvement in TBI
- Tai chi interventions (including aquatic) for MS and TBI.
There was inconclusive evidence for other interventions such as CPAP, acupuncture, tDCS, energy maximizing training, motor imagery combined with rhythmic cueing, and OT interventions.
The most published literature evaluating rehabilitation interventions for fatigue were in MS, and most common modalities investigated included physical therapy followed by psychological interventions. Evidence for these interventions specifically in stroke, TBI, and PD are scarce. Studies in this review varied in methodology, study design, participants, and outcome measurement to evaluate fatigue. Further, only few included studies targeted fatigue as a primary outcome. Overall, rehabilitation interventions specifically exercise and psychological/educational interventions had a significant favorable effect on reducing the impact or severity of fatigue in neurological conditions.
Fatigue is common and disabling symptom in many neurological conditions. The multidimensional elements (e.g., physical, emotional, and cognitive) are complex and subjective. This is further complicated due to fluctuating nature, unclear mechanisms of fatigue, and multidimensional factors contributing to fatigue overtime. Another challenge is lack psychometrically sound outcome measures to measure perceived fatigue. This results in difficulty not only in prescribing best clinical modality but also to decide the timing and dose/intensity of the treatment. This review presented a diversity of outcome measurement and treatment choices for treating clinicians. Notably, many interventions were difficult to characterize and standardize, due to the heterogeneous patient population, unpredictable clinical presentations, and lack of evidence for ideal patient selection criteria for fatigue management. In general, the fatigue management required comprehensive programs, delivered by Multidisciplinary teams with individualized and goal-oriented therapies tailored for patient needs.
Commonly used outcome measures
Fatigue is subjective and a poorly defined construct; hence, difficult to measure. The assessment includes systematic evaluation of history and exhaustive physical examination to identify possible predisposing and contributing factors [Table 1], quality and quantity of fatigue, and its impact on ADLs., A number of instruments assess fatigue and can be subjective (self-reported by patients) or objective (quantified by clinicians through various parameters). Despite this, many do not meet the criteria for psychometric robustness and clinical utility and limit attempts to quantify the frequency, nature, and severity of the problem. Subjective or patient-reported instruments are specifically designed to incorporate a patient's viewpoint and are more practical for use in clinical settings.,
One systematic review identified 31 self-reported fatigue measures for MS, stroke, and PD. Of these, FSS was frequently used and validated questionnaire in MS, stroke, and PD. The authors recommend fatigue scale for motor and cognitive functions and the unidimensional fatigue impact scale for assessment of fatigue in MS; functional assessment of chronic illness therapy fatigue subscale and FSS in patients with PD, and the profile of mood states fatigue subscale for patients with stroke. Tyson et al. in another systematic review (n = 17 trials) evaluated measurement tools for fatigue in neurological conditions and found none of the evaluated tools met all psychometric and utility criteria. The authors recommend the neurological fatigue indices, which was originally developed to evaluate fatigue in other conditions and then applied to people with neurological conditions with specific consideration to the construct or patients' experience of fatigue. It is recommended that clinicians should carefully consider whether a questionnaire reflects the most relevant aspects of fatigue of their interest and comprehensive evaluation of fatigue should be accompanied by the assessment of clinically related factors such as mood and sleep. A list of commonly used subjective measures of fatigue in neurological conditions is provided in [Appendix 4].
Many limitations regarding the completeness of retrieved literature and interpretation of findings in this review cannot be ruled out. First, the search principally encompassed cited literature and only most high-quality systematic reviews and clinical trials (RCTs/CCTs) were included in the study. Further, only studies published in English and reference lists of included papers were scrutinized. There is a possibility that some articles may have been missed or introduced a publication bias. However, comprehensive search of literature (both academic and grey) was conducted and experts in this area were contacted, to capture the widest possible selection of relevant literature. Second, we were not able to pull data together for a meta-analysis because of variability of interventions, methodology, participants, and outcome measurement used. Finally, we were unable to assess intervention-related adverse events, as the reports were incomplete and inconsistent. Associated costs and/or economic benefit of interventions were not mentioned, these, however, were beyond the scope of this review.
There is increased awareness of nonpharmacological interventions in early and long-term management of fatigue in neurological disorders. Although this review highlight lack of high-quality studies evaluating fatigue management strategies in MS, stroke, TBI, and PD, it adds to existing evidence by providing structured predefined “level of evidence” to support different interventions for the management of fatigue in these cohorts. Due to heterogeneity in the type/mode of intervention trialled, study population, and/or comparison groups, the evidence is insufficient to recommend any given specific treatment for routine use in clinical practice. However, the findings suggest physical activity programs and education reduce fatigue. A multilevel patient evaluation could tailor the “best” intervention, based on a stepwise approach that considers underlying comorbid conditions. Further, high-quality studies are needed for a broad range of interventions for managing fatigue in clinical settings.,
We would like to thank the Department of Rehabilitation team, Royal Melbourne Hospital for their valuable advice and suggestions, and the ISPRM for the support.
Financial support and sponsorship
This review was supported from internal resources of the Rehabilitation Department, Royal Melbourne Hospital, Royal Park Campus, Melbourne, Australia. No external financial support was received.
Conflicts of interest
There are no conflicts of interest.
Appendix 2: Key words used for the search strategy
Theme 1: Fatigue
Fatigue, lethargy, lassitude, tired or tiredness, somnolence, exhausted or exhaustion, fatigue syndrome, physical fatigue, mental fatigue, central fatigue, muscle fatigue, stress, lack of energy, apathy, weary or weariness, listlessness, malaise.
Theme 2: Rehabilitation interventions
Rehabilitation, Ambulatory Care, Physical Therapy Modalities, physiotherapy, Exercise therapy, Cognitive therapy, psychotherapy, Behavior/behavior therapy, Social work, Counseling, Occupational Therapy, Dietetics/Nutrition, Orthotics/brace/orthoses, Acupuncture, patient care team, multidisciplinary/integrated team, cold treatment/cooling, assistive technology device, hydro/pool therapy, electromagnetic therapy, nerve stimulation, vibration therapy, social participation/support, vocational rehabilitation.
Theme 3: Multiple sclerosis
Multiple sclerosis, chronic progressive or progressive relapsing multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, relapsing–remitting multiple sclerosis, acute relapsing multiple sclerosis, demyelinating disease or disorder, clinically isolated syndrome, transverse myelitis, acute disseminated encephalomyelitis. Optic neuritis.
Theme 4: Stroke
Stroke, cerebrovascular disorders, basal ganglia cerebrovascular disease, brain ischemia, carotid artery diseases, cerebrovascular accident, brain infarction, cerebrovascular trauma, hypoxia-ischemia, brain or intracranial arterial diseases, intracranial arteriovenous malformations, intracranial embolism or thrombosis, intracranial hemorrhages or vasospasm, intracranial or vertebral artery dissection, intracranial bleeding.
Theme 5: Traumatic brain injury
Traumatic brain injury or injuries, head injury or injuries, craniocerebral trauma, concussion, concussive, brain concussion, brain contusion, postconcussion, postconcussive, persistent vegetative state.
Theme 6: Parkinson's disease
Parkinsonian disorders, Parkinson disease, parkinsonian disorders, parkinsonism, Parkinson, parkinson's disease, idiopathic parkinson disease, idiopathic parkinson's disease[tiab] OR idiopathic parkinson's disease.
MeSH check words
Systematic review/meta-analysis, randomized controlled trials, controlled clinical trials, clinical trials, review, adult; humans.
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[Table 1], [Table 2]