Fatigue After Traumatic Brain Injury: A Systematic Review : The Journal of Head Trauma Rehabilitation

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Original Articles

Fatigue After Traumatic Brain Injury: A Systematic Review

Ali, Arshad MHA; Morfin, Jussely BS; Mills, Judith AHIP, MLIS, NCMA; Pasipanodya, Elizabeth C. PhD; Maas, Yvonne J. MSc; Huang, Emily MD; Dirlikov, Benjamin MA; Englander, Jeffrey MD; Zedlitz, Aglaia PhD

Author Information
Journal of Head Trauma Rehabilitation: July/August 2022 - Volume 37 - Issue 4 - p E249-E257
doi: 10.1097/HTR.0000000000000710

Abstract

TRAUMATIC BRAIN INJURY (TBI) is caused by external force to the cranium and intracranial contents and can result in profound consequences.1 Approximately 2.5 million individuals sustain TBIs in the United States each year, resulting in approximately 50 000 deaths, over 80 000 permanent disabilities, and an estimated $60 billion in direct and indirect costs.2 The chronic consequences of TBI vary in type and severity but can include epilepsy, sleep disorders, cognitive and motor dysfunction, neuroendocrine dysregulation, and psychiatric problems.3–7 Post-TBI fatigue (PTBIF) is a ubiquitous sequela of TBI, with estimates suggesting a prevalence range of 21% to 70% among individuals who experienced a TBI.8 PTBIF may simultaneously interfere with, and be exacerbated by, engagement in physical and cognitive activities, subsequently restricting participation in activities of daily living, social engagement, and occupational functioning.9–12 Thus, the chronic experience of PTBIF has significant consequences on adjustment and recovery following TBI.

Although PTBIF is typically conceptualized to be a multidimensional construct, encapsulating physical (eg, tiredness and exhaustion), psychological (eg, lack of motivation), and cognitive (eg, difficulty with concentration, focus, and mental flexibility) components, a standard holistic definition of PTBIF has not been adopted in research or medicine.13 Many common scales utilized in PTBIF research tend to assess discrete aspects of fatigue. For instance, the widely used Fatigue Severity Scale largely assesses the impact, but not severity, of fatigue and has few items assessing psychological and cognitive facets of PTBIF.14 Furthermore, the vast majority of fatigue measures used in PTBIF research were validated among individuals without TBI or neurological conditions.15,16 Consequently, the various scales commonly used to measure fatigue may not characterize PTBIF adequately and may contribute to the wide range in observed PTBIF prevalence estimates (21%-70%).8

Despite variability in the definition and measurement of PTBIF, investigating treatments that may ameliorate PTBIF is important. A 2014 review identified 19 articles published in English that investigated PTBIF interventions.8 A substantial proportion of identified articles (8/19) evaluated pharmacological interventions and the majority of the remaining studies (8/11) investigated the efficacy of cognitive behavioral and physical activity interventions. However, few studies in the review investigated PTBIF as the primary outcome, most interventions had a high risk of bias, and interventions were rarely investigated in multiple cohorts. Therefore, the authors were unable to suggest specific interventions for clinical practice.8 A more recent review including studies from 2014-2016 as well as a 2017 review targeting randomized controlled trials on complementary and alternative interventions provided an update on PTBIF treatments, yet noted similar shortcomings, such as a need for larger sample sizes, replicating results, and clearer definition of PTBIF.17,18

Given equivocal findings of efficacy in past reviews, this article was motivated to provide a comprehensive review of PTBIF intervention research to date. The current systematic review provides a broad review of PTBIF treatments that expands upon previous work by including (1) PTBIF intervention research published in 6 languages, (2) peer-reviewed and non-peer-reviewed (gray) literature, and (3) studies that include TBI-specific fatigue data, regardless of the percentage of individuals with TBI included in the study.

METHODS

Search strategy, data extraction, and database preparation

The initial aim of the study was to provide a meta-analysis of published PTBIF treatments, yet due to variability in treatment types, study design, and outcome measures the study was amended to provide a review of published treatments instead (see Appendix III for Supplemental PRISMA checklist, available at: https://links.lww.com/JHTR/A462). The search strategy followed the Population Intervention Control Outcome (PICO) question: “In patients who have experienced TBI, what treatments, compared to usual care, no treatment/placebo, or alternate treatment, alleviate PTBIF symptoms?” This PICO question was supplemented by searches of interventional studies without a control condition to capture all studies investigating treatments for PTBIF. Cuijpers' (2016) guide was utilized as a reference for constructing this broad list of search terms (see Supplemental Appendixes I and II, available at: https://links.lww.com/JHTR/A457 and https://links.lww.com/JHTR/A458) that included physical, psychological, and cognitive aspects of fatigue. A medical librarian queried OneSearch and PubMed search engines in May 2019 to find relevant publications (eg, scientific manuscripts, abstracts, dissertations, and non-peer-reviewed publications). When queried, OneSearch and PubMed included 22 and 3 databases, respectively (see Supplemental Appendixes I and II, available at: https://links.lww.com/JHTR/A457 and https://links.lww.com/JHTR/A458). The search results were exported from PubMed and OneSearch as text files in MEDLINE format and generic bibliographic management format, respectively. A MATLAB script converted the long-format bibliographic information into an easy-to-read wide-format excel. All articles were assigned an identification number and columns were added to track the independent reviewers' decisions and notes.

Review process

A 2-stage review process, consisting of an abstract review followed by a full-text review, was carried out such that each abstract and full-text article were reviewed by 2 independent reviewers. Inclusion criteria were (1) an investigation of an intervention, (2) participant sample including individuals with TBI, (3) report of fatigue outcome data among individuals with TBI, and (4) articles available in English, Spanish, French, German, Afrikaans, or Dutch. Duplicate search results were removed. If information within abstracts was unclear, a full-text review was carried out to determine inclusion. Articles with conflicting reviews were discussed among the study team, and a consensus decision was reached.

Data abstraction

A subset of the included manuscripts was assigned to each author for data abstraction and risk of bias assessment. The following data were abstracted, when reported in the articles: (1) year published, (2) country where the research was conducted, (3) study design, (4) intervention information, (5) inclusion/exclusion criteria, (6) basic demographics (ie, sample size, sex, race/ethnicity, and age), (7) percentage of sample with TBI, (8) outcome measure(s) used, and (9) TBI-specific results (eg, pre- to postintervention statistics). Based on the type of intervention included, 6 intervention categories (pharmacological, psychological, exercise-based, complementary and alternative medicine [CAM], electrotherapeutic, and multimodal) were created to summarize the results.

Risk of bias assessment

For randomized studies, risk of bias was assessed using the revised Cochrane risk-of-bias tool (version 2).19 This tool provides preset questions and an algorithm to assess the level of bias in the following categories: randomization process, deviations from the intended intervention, missing outcome data, measurement of the outcome, and selection of reporting results. Ratings of overall bias are suggested at the end of the questionnaire and confirmed or modified by the user. For studies without randomization, criteria from Cuijper's guidelines were used.20 Similar to the Cochrane risk-of-bias tool, this assessment includes selection bias, performance bias, detection bias, attrition bias, reporting bias, other bias, and overall risk of bias assessments. A lack of randomization, blinding, preset analysis plan, and statistical reporting for either assessment tool yields a greater risk of bias score. Results from the risk of bias rating are summarized graphically in Figure 1.

F1
Figure 1.:
Risk of bias assessment.

RESULTS

OneSearchy and PubMed queries identified 2343 publications from March 1, 1989, to March 31, 2019 (1394 and 949, respectively; see Figure 2.21). Out of the 2343 publications, 790 were removed as duplicate entries and the remaining 1553 went through the abstract review process. Based on inclusion criteria, 1402 publications were excluded during the abstract review, leaving 151 publications eligible for full-text review. The full-text review excluded an additional 114 publications, resulting in 37 publications for inclusion in this review.

F2
Figure 2.:
PRISMA diagram.

The 37 publications included in this study were categorized into pharmacological (n = 13; see Supplemental Table 1a, available at: https://links.lww.com/JHTR/A459), psychological (n = 9; see Supplemental Table 1b, available at: https://links.lww.com/JHTR/A459), exercise-based (n = 4; see Supplemental Table 1c, available at: https://links.lww.com/JHTR/A459), complementary alternative medicine (n = 5; see Supplemental Table 1d, available at: https://links.lww.com/JHTR/A459), electrotherapeutic (n = 3; see Supplemental Table 1e, available at: https://links.lww.com/JHTR/A459), and multimodal interventions (n = 3; see Supplemental Table 1f, available at: https://links.lww.com/JHTR/A459). Only 9 out of 37 studies targeted fatigue as the primary outcome. The risk of bias assessment revealed 2 high-risk, 14 low-risk, and 7 randomized studies with some concern, while the nonrandomized studies showed 9 high-risk, 0 low-risk, and 4 studies with some concern (see Figure 1). One study was not assessed for bias since it was a nonintervention follow-up study.

Pharmacological interventions

Thirteen publications on pharmacological interventions were identified in this study (see Supplemental Table 1a, available at: https://links.lww.com/JHTR/A459). These interventions included 9 different pharmacological agents, with methylphenidate being the most investigated treatment (4/13 publications). Six studies specifically mentioned fatigue as a target of the pharmacological intervention, while other studies included broader targets, such as cognitive sequelae after TBI, or sleep. Ten of the 13 studies were randomized controlled studies, 2 used a single-arm design, and 1 study presented follow-up data. Due to the higher incidence of controlled studies, this category of studies presented generally a low risk of bias (see Figure 1).

Methylphenidate was one of the most studied treatments (4 publications, including 1 follow-up study), which include studies with multiple cohorts and significant reductions in PTBIF symptoms across studies (an 8- to 12-point reduction in the Mental Fatigue Scale [MFS] post-treatment).22–25 Two studies investigated modafinil26,27 with mixed results, while the remaining interventions used unique pharmacological agents (herbal supplement MLC901,28 monoaminergic stabilizer ((−)-OSU6162),29 melatonin,30 creatine,31 human growth hormone (HGH),32 ramelteon,33 and donepezil.34 Melatonin and creatine showed significant improvements in PTBIF compared to controls, and HGH showed improvements although no control was included. The monoaminergic stabilizer, ramelteon, and herbal supplement did not show improvements in PTBIF compared with the placebo control, and donepezil did not show PTBIF improvements in their single-arm design.

Psychological interventions

Nine studies, utilizing a range of therapeutic interventions (cognitive behavioral therapy [CBT], client-centered therapy, psychoeducation, behavioral activation, and pacing), were identified (see Supplemental Table 1b, available at: https://links.lww.com/JHTR/A459). Of these interventions, only one primarily targeted fatigue35 (see Supplemental Table 1b, available at: https://links.lww.com/JHTR/A459). Although most studies were randomized controlled (6/9), all studies were characterized by small sample sizes comprised of fewer than 50 participants (range 1-46) and short postintervention follow-up periods (0-4 months). The 3 uncontrolled studies were either a case series (n = 3),36 case study (n = 1),37 or single group study (n = 6).38 The studies included in the psychological intervention category all used different PTBIF measurements, except for 2 studies35,39 that both used the Fatigue Severity Scale. Evidence of the efficacy of psychological intervention in improving fatigue was mixed, with only 2 studies39,40 reporting unequivocal findings of improvement in fatigue after intervention.

Exercise-based interventions

Four interventions included in this study utilized exercise-based interventions41–44 (see Supplemental Table 1c, available at: https://links.lww.com/JHTR/A459). Of the 4 exercise-based interventions, 3 interventions (walking, aerobic exercise, and aquatic program) showed positive effects on fatigue assessments, with 1 intervention (walking) specifically targeting fatigue symptoms. The walking-based intervention44 included a large, randomized cohort (n = 123), crossover design, and multiple fatigue assessments (Global Fatigue Index, Barrow Neurologic Institute Fatigue Scale Overall Severity Index Score, and Multidimensional Fatigue Inventory). All measurements showed significant reductions in PTBIF post-intervention, which were sustained at follow-up 12 weeks after the intervention was completed. Both the aerobic and aquatic interventions showed within treatment group reductions in PTBIF; yet the aquatic intervention study, which included a control, did not find between-group differences. The tai chi intervention43 did not observe significant reductions in PTBIF.

Complementary and alternative medicine

Only 1 of the 5 CAM interventions included in this study targeted fatigue specifically (blue light therapy)45 (see Supplemental Table 1d, available at: https://links.lww.com/JHTR/A459). Two studies used a randomized controlled design (blue light therapy and hyperbaric oxygen), while the other 3 interventions (heart rate variability feedback,46 hand self-shiatsu,47 and singing48) did not include a control group. Only the blue light therapy intervention observed significant improvements in PTBIF compared with both control groups (yellow light and no treatment), while the singing and hand self-shiatsu studies showed within treatment group improvements.

Electrotherapeutic interventions

This review identified 2 articles and 1 abstract that included electrotherapeutic interventions (see Supplemental Table 1e, available at: https://links.lww.com/JHTR/A459). These publications used 2 interventions, electroencephalographic biofeedback49,50 and cranial electrostimulation (CES); however, only the CES study51 included control groups (sham and placebo). All 3 studies showed decreases in PTBIF symptom ratings, with the CES study also showing significant reductions in post-TBI symptoms post-intervention for the intervention group but not the control group.

Multimodal interventions

This review identified 3 multimodal studies,52–54 only 1 of which was a randomized control trial54 (see Supplemental Table 1f, available at: https://links.lww.com/JHTR/A459). All 3 studies focused on ameliorating postconcussion symptoms primarily and not fatigue specifically. However, all 3 studies reported positive findings of some fatigue diminishment after the often-extensive treatments. All studies included a combination of psychoeducational, psychotherapeutic, and exercise-based interventions, although each was distinct.

DISCUSSION

Our systematic review of the literature identified 37 studies that investigated the impact of interventions on PTBIF. Approximately 50% of the interventions included in this study were not included in earlier PTBIF treatment reviews.8,17,18 Pharmacological, psychological, and exercise-based studies were more frequently randomized controlled trials and, therefore, showed a lower overall risk of bias compared with the other types of interventions (see Figure 1).

Pharmacological interventions

Pharmacological interventions represented the group of publications with the lowest risk of bias, with 10 out of 13 publications being randomized controlled trials. Although this group of interventions showed the greatest scientific rigor, challenges remain in translating interventions into available treatments. For instance, methylphenidate was one of the most-studied treatments with the greatest effects on PTBIF, and it is already commonly prescribed for PTBIF symptoms in the United States. However, treatment with methylphenidate involves a complicated prescribing process, as it is a controlled substance with a potential for abuse and adverse side effects. Despite this, for the experienced prescriber and reliable patient, methylphenidate can be an effective option that can be quickly titrated because of its short half-life.55 Modafinil, another commonly prescribed PTBIF medication in the United States, had mixed results showing potential within treatment group improvements but significant group differences (treatment compared with control) were less clear. Recombinant human growth hormone (RHGH) is typically prescribed to individuals with diagnosed growth hormone deficiency; however, it requires daily injection, is expensive with likely a lifelong treatment, and requires frequent monitoring. Potential side effects of RHGH include fluid retention, hyperglycemia, and tumor growth. In some studies, the withdrawal of treatment resulted in worsening of cognitive symptoms.56,57 Thus, an experienced prescriber, usually an endocrinologist, is necessary when considering this treatment for indicated conditions. An investigational medication used primarily for alcohol dependence, monoaminergic stabilizer (−)-OSU6162, was also included in this review and showed within-group improvements, but no statistically significant between-group differences were observed. As it carries a hazard warning of toxicity58 and is not yet indicated for clinical use for any condition, further investigation is required. Taken together, although some of these pharmacological interventions showed preliminary promise in alleviating PTBIF symptoms, translation into clinical use has some challenges.

On the other hand, melatonin, prescribed primarily for help with sleep regulation, is inexpensive, available over-the-counter, has minimal side effects, and low abuse or overdose potential. The effect on PTBIF may be secondary to improved sleep and may only improve sleep-related fatigue. In addition, one study of creatine administration to children within 4 hours of injury to prevent some of the most common post-TBI symptoms, including fatigue, suggests that a simple amino acid supplement may have significant impact with minimal morbidity.31,59 As this was the only medication study that attempted to prevent post-TBI symptoms, replication is necessary among both children and adults to support these favorable findings. Given that creatine and melatonin are supplements and come in multiple formulations, finding the most effective formulation and dose may pose the biggest challenge. Also, complication may arise due to different drug interactions as well as variability in quality control since supplements are not FDA-approved. Despite this, of the pharmacological interventions, melatonin and creatine were considered easier and safer to use. Moreover, evaluation of medications prescribed for other medical problems may have fatigue as side effects, so modifying the dosage or type of those medications may be just as effective in pharmacological management of fatigue as adding an additional medication.60

Psychological interventions

Despite the preliminary state of research on psychological interventions for PTBIF, CBT has been proven to ameliorate fatigue in many other populations suffering from fatigue (eg, chronic fatigue syndrome, cancer, and multiple sclerosis).61–63 In Europe and the United States, psychosocial interventions are generally used to address fatigue, yet a standard treatment protocol is not established. Since CBT focuses on thoughts, behavior, and emotional aspects, it might tap into several aspects of the multidimensional nature of PTBIF. Furthermore, CBT may include pacing and physical activity and the principles of CBT can be adapted easily to patients with TBI. It is thus plausible that CBT is also effective for patients suffering from PTBIF,64–66 yet the evidence so far is thus scarce; more research focusing on fatigue and utilizing larger sample sizes is needed.

Exercise-based interventions

Physical activity has been promoted for improving general health for decades in healthy individuals67 and represents a treatment modality that is low risk and relatively easy to implement, once deemed safe for the individual with TBI. It has also been promoted in the scientific literature and popular press for slowing the progress of Alzheimer's disease and other dementias and in mitigating the fatigue associated with chronic systemic conditions such as Parkinson's disease, multiple sclerosis, congestive heart failure, obesity, systemic lupus erythematosus, and chronic fatigue syndrome.68 With the increase in availability and adoption of wearable fitness devices (eg, pedometers, GPS trackers, and heart rate monitors), individuals with TBI can get immediate and reliable feedback, set independent goals, and/or work with a treating physician, therapist, or trainer/coach to reach activity and fitness goals. Often the biggest barrier to increasing physical activity in managing fatigue is finding the activity that a given individual is eager to perform on a regular basis. In sum, exercise as simple as walking 3 times per week can be beneficial to ameliorate fatigue and should be a component of fatigue management.69,70

Complementary and alternative medicine

Growing research in CAM treatments suggests they may improve quality of life and symptoms for individuals with TBI. A 2016 review by Hernández and colleagues71 provided an overview of the use, opportunities, and challenges associated with adopting CAM interventions for individuals with TBI, which are echoed in this review. CAM treatments provide safe, effective, nonpharmacological, and often inexpensive therapies that may alleviate a variety of symptoms, including fatigue. Although further validation is required, the ability for individuals with TBI to self-administer and adopt these practices into their routine provides a promising avenue for investigating PTBIF treatments.

Electrotherapeutic interventions

Noninvasive neural stimulations, such as cranial electrotherapy stimulation (CES) and electroencephalographic biofeedback, are treatments that have been associated with promoting neuroplasticity and/or normalizing neurotransmitter homeostasis.72,73 Due to potential risk factors, such as seizures and acute amnesia, more work will be needed before translation into general clinical use is feasible.72,73 The publications included in this review provide only minimal evidence for treatment efficacy.49–51

Multimodal interventions

Evidence for efficacy of multimodal interventions in the treatment of PTBIF seems somewhat promising. This is in line with the multimodal concept of fatigue, as it includes physical, emotional, and cognitive components, and treatment of these different foci might thus aid these patients. Moreover, in individuals post-stroke, multi-modal treatment, including both graded activity and CBT, has been found effective,74 thus warranting further research in patients with TBI.

Limitations and future directions

This systematic review cast a broad net to cover 30 years of research investigating PTBIF interventions published in multiple languages. However, due to variability in study methodologies, including in primary interventional outcomes and measures, we were unable to conduct quantitative meta-analyses of the research studies.

Articles identified in this review used several validated scales to measure PTBIF; however, few of the included studies utilized TBI-specific measures. Although a significant amount of historical fatigue data has been collected using measures like the MFS, Fatigue Severity Scale, Post-Concussion Symptom Scale, and Beck's Depression Inventory, a transition to a TBI-specific scale is recommended. The Traumatic Brain Injury Quality-of-Life (TBI-QOL) is a recently validated scale using input from individuals with TBI and their caregivers, clinicians, and researchers; it is available in computerized and short-form versions.75 Although there are multiple validated scales for fatigue, future works should utilize TBI-specific measures like the TBI-QOL Fatigue Item Bank75,76 to help standardize results.

Post-TBI symptoms, including PTBIF, vary in presentation, severity, and duration, and this interindividual variability poses a challenge for research and for standardization of treatment. Given the heterogeneity in the presentation of PTBIF, statistical approaches that investigate individual variability (eg, factor analysis) and identify responder/nonresponder groups and their corresponding characteristics following intervention (eg, mixture models) may further elucidate the nature of PTBIF and identify treatment moderators.

Lastly, strong evidence to support recommendations for specific clinical treatments for PTBIF is nascent. For instance, this systematic review identified many studies with small sample sizes and only 2 treatments (methylphenidate and modafinil) that were investigated using different cohorts. Thus, future work should aim to investigate potential interventions using larger sample sizes, more robust methods, and strive for replication to bolster preliminary findings of efficacy. Additionally, due to a lengthy review process, our review explored studies up to March 2019 and the inclusion of publications after that time point is recommended for future reviews.

CONCLUSION

More research is required to further our understanding of PTBIF and effective interventions to ameliorate it. As a result of limited high-quality research investigating PTBIF, there is a paucity of unequivocal evidence to support specific treatments. Although methylphenidate can be effective, prescription should be in consideration of patient reliability characteristics. However, exercise and over-the-counter treatments to address PTBIF related to sleep disturbances, such as melatonin, represent low-risk options with several studies reporting efficacy. As PTBIF is multifaceted, multimodal clinical treatment approaches that include sustainable levels of exercise, judicious medication prescription, and/or behavioral therapy provided by a multidisciplinary rehabilitation team is recommended until more specific fatigue-related mechanisms/treatments are identified.

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Keywords:

brain injuries; fatigue; intervention; mental fatigue; TBI; traumatic; traumatic brain injury

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