Systematic Review of Sex and Gender Effects in Traumatic Brain Injury: Equity in Clinical and Functional Outcomes.

Background: Although traumatic brain injury (TBI) is a leading cause of death and disability in male and female patients worldwide, little is known about the effect of sex and gender on TBI outcomes. Objectives: This systematic review summarizes the evidence on the effect of sex and gender on core TBI outcomes. Methods: All English-language studies from six literature databases that addressed core outcomes in adults with TBI and included sex or gender, TBI severity, and age in their analyses were considered eligible. Two reviewers extracted data, and two reviewers assessed study quality using tools recommended by the National Institutes of Health. The results were sorted according to time post-injury, injury severity, gender equity ranking of the study's country of origin, and outcomes studied. The results from the included studies were grouped based on the approach taken in reporting their respective findings. Results and Limitations: Of 172 articles assessed, 58 studies were selected, comprising 1, 265, 955 participants with TBI (67% male across all studies) of all injury severities. All studies were conducted in countries with a very high or high human development index, while the Gender Inequality Index (GII) varied. While the heterogeneity across studies limited any meaningful conclusions with respect to the role of sex and gender, we did observe that as gender equality ranking improved, differences between male and female participants in outcomes would diminish. Inclusion of social equity parameters in the studies was limited. Conclusions and Implications: The non-uniform findings observed bring forth the need to develop and use a comprehensive and consistent methodology in the study of sex and gender post-TBI, incorporating social equity parameters to uncover the potential social underpinnings of gender effects on health and functional outcomes. Systematic Review Registration: CRD42018098697.

Interventions and cognitive functioning in adults with traumatic spinal cord injuries: a systematic review and meta-analysis.

AIM: This research synthesized scientific evidence on the impact of interventions for adults with traumatic spinal cord injury on cognition, to understand if current intervention approaches are appropriate in light of the risk of post-injury cognitive impairments. METHOD: Medline, Central, Embase, Scopus, PsycINFO and PubMed were searched for intervention in persons with SCI assessing cognition pre- and post-intervention. Study quality was completed using the National Institutes of Health quality assessment tools. Results were grouped by type of intervention. The meta-analysis involved calculation of pooled effect sizes for interventions utilizing the same cognitive measure. RESULTS: Eleven studies of moderate quality discussed drug therapy, transcutaneous tibial nerve stimulation, diet modification and dietary supplements, and inpatient rehabilitation. Some aspects of cognition were negatively affected by drugs while diet modification and supplement use, and transcutaneous tibial nerve stimulation showed no evidence of a difference in cognitive scores when compared with no intervention. Inpatient rehabilitation revealed a small but beneficial effect, when results of seven studies were pooled. CONCLUSION: Evidence on the effects of interventions on cognitive functioning in patients with traumatic spinal cord injury is sparse and inconclusive, so work in this area is timely. It is valuable to know not only which interventions are effective for improving cognition, but also how other commonly used interventions, intended to treat other injury sequela, can affect cognition. PROSPERO: CRD42018087238.Implications for rehabilitationHistorically, rehabilitation of patients with traumatic spinal cord injury has targeted physical impairments, with little attention to cognition; this research aimed to understand if current interventions are appropriate in light of the risk of patients' cognitive impairments. Evidence on the effects of drug therapy, diet and dietary supplements interventions on cognitive functioning in traumatic spinal cord injury is sparse and inconclusive.Combining multiple inpatient rehabilitation interventions shows a positive but heterogeneous effect on the cognitive functioning; interventions applied earlier show greater gains.A major challenge for clinicians is to select an outcome measure sensitive to change over time, and to relate the results to patients' change in cognitive abilities with intervention applicationResearch to understand the functional effect of spinal cord injury on the widely distributed networks of the central and autonomic nervous systems subserving cognition, is timely.

A gender-transformative approach to improve outcomes and equity among persons with traumatic brain injury.

INTRODUCTION: The initiation and translation of sex-sensitive and gender-sensitive research programmes into clinically useful considerations for patients with traumatic brain injury (TBI) have been difficult. Clinical frameworks are currently not specific according to sex and gender, despite evidence that these constructs influence the incidence, course and outcome of patients with TBI. The present protocol outlines a strategy for a research programme, supported by the Canadian Institutes of Health Research (CIHR) Institute of Gender and Health, which explores sex and gender topics in the context of TBI, with the goal of building an infrastructure to facilitate the implementation of sex/gender-sensitive research findings into clinical considerations. METHODS AND ANALYSIS: A comprehensive multistep research programme is proposed to support three research objectives: (1) documentation of important concepts and ideas for education on topics of sex and gender in the TBI context using a knowledge-user feedback framework, current scientific evidence and the research team's expertise; (2) development of educational materials for patients with TBI, significant others and clinicians providing care that account for sex/gender and (3) testing the application of these educational materials for feasibility and effectiveness. This programme supports the CIHR Institute's mission by facilitating partnership with knowledge users across clinical, research, academic and community sectors, through a range of platforms and activities. ETHICS AND DISSEMINATION: The Research Ethics Board of the University Health Network has approved the programme. It is anticipated that this work will add significant value to the advancement of the field of sex, gender and health by serving as a model to foster the integration of these constructs across the spectrum of disorders. This will transform clinical practices and ensure that generated knowledge is translated into improved training programmes, policies and health services that are responsive to the diverse needs of men and women with TBI. PROSPERO REGISTRATION NUMBER: CRD42018098697.

Measuring Change Over Time: A Systematic Review of Evaluative Measures of Cognitive Functioning in Traumatic Brain Injury.

Objectives: The purpose of evaluative instruments is to measure the magnitude of change in a construct of interest over time. The measurement properties of these instruments, as they relate to the instrument's ability to fulfill its purpose, determine the degree of certainty with which the results yielded can be viewed. This work systematically reviews all instruments that have been used to evaluate cognitive functioning in persons with traumatic brain injury (TBI), and critically assesses their evaluative measurement properties: construct validity, test-retest reliability, and responsiveness. Data Sources: MEDLINE, Central, EMBASE, Scopus, PsycINFO were searched from inception to December 2016 to identify longitudinal studies focused on cognitive evaluation of persons with TBI, from which instruments used for measuring cognitive functioning were abstracted. MEDLINE, instrument manuals, and citations of articles identified in the primary search were then screened for studies on measurement properties of instruments utilized at least twice within the longitudinal studies. Study Selection: All English-language, peer-reviewed studies of longitudinal design that measured cognition in adults with a TBI diagnosis over any period of time, identified in the primary search, were used to identify instruments. A secondary search was carried out to identify all studies that assessed the evaluative measurement properties of the instruments abstracted in the primary search. Data Extraction: Data on psychometric properties, cognitive domains covered and clinical utility were extracted for all instruments. Results: In total, 38 longitudinal studies from the primary search, utilizing 15 instruments, met inclusion and quality criteria. Following review of studies identified in the secondary search, it was determined that none of the instruments utilized had been assessed for all the relevant measurement properties in the TBI population. The most frequently assessed property was construct validity. Conclusions: There is insufficient evidence for the validity and reliability of instruments measuring cognitive functioning, longitudinally, in persons with TBI. Several instruments with well-defined construct validity in TBI samples warrant further assessment for test-retest reliability and responsiveness. Registration Number: www.crd.york.ac.uk/PROSPERO/, identifier CRD42017055309.

The course and prognostic factors of cognitive outcomes after traumatic brain injury: A systematic review and meta-analysis.

Despite indications that TBI may be a precursor of cognitive decline and subsequent development of Alzheimer's disease, little is known about the time course of this relationship and the factors involved. This systematic review summarizes the evidence pertinent to this subject matter. All English language studies of longitudinal design, and works cited within them, found in six literature databases, were considered, and their quality assessed. Of 65 articles appraised, 44 studies were selected. Results were organized by timing of assessments, injury severity, and cognitive domains assessed. Differences in the course of cognitive performance were observed across injury severity groups and cognitive domains, with differential proportions of reports of improvement, decline, or no change over time. The evidence for genetic, sex-, age-, and injury-related factors as determinants of cognitive outcome was inconsistent. The non-uniform trajectory of cognitive performance post-TBI supports the notion that this construct is non-homogeneous, and that different factors influence its course. Agreement on a core set of predictors and consideration of psychometric properties of outcome measures is needed.

Traumatic brain injury: sex, gender and intersecting vulnerabilities.

Over the past decade, traumatic brain injury (TBI) has emerged as a major public health concern, attracting considerable interest from the scientific community, clinical and behavioural services and policymakers, owing to its rising prevalence, wide-ranging risk factors and substantial lifelong familial and societal impact. This increased attention to TBI has resulted in increased funding and advances in legislation. However, many questions surrounding TBI remain unanswered, including questions on sex and gender trends with respect to vulnerability to injury, presentation of injury, response to treatment, and outcomes. Here, we review recent research efforts aimed at advancing knowledge on the constructs of sex and gender and their respective influences in the context of TBI, and discuss methodological challenges in disentangling the differential impacts of these two constructs, particularly in marginalized populations.

The involvement of Rhopr-CRF/DH in feeding and reproduction in the blood-gorging insect Rhodnius prolixus.

Rhodnius prolixus is a blood-gorging insect and a vector for human Chagas disease. The insect transmits the disease following feeding, when it excretes urine and feces contaminated with the Trypanosoma cruzi parasite. A corticotropin-releasing factor-like peptide acts as a diuretic hormone in R. prolixus (Rhopr-CRF/DH); however, its distribution throughout the insect's central nervous system (CNS) and the expression of its receptor in feeding-related tissue as well as the female reproductive system suggests a multifaceted role for the hormone beyond that of diuresis. Here we investigate the involvement of Rhopr-CRF/DH in feeding and reproduction in R. prolixus. Immunohistochemistry of the CNS showed diminished CRF-like staining in neurosecretory cells (NSCs) of the mesothoracic ganglionic mass (MTGM) immediately following feeding, and partial restocking of those same cells two hours later, indicating Rhopr-CRF/DH stores in this regions are involved in feeding. The results of the temporal qPCR analysis were consistent with the immunohistochemical findings, showing an increase in Rhopr-CRF/DH transcript expression in the MTGM immediately after feeding, presumably capturing the restocking of Rhopr-CRF/DH in the lateral NSCs following release of the peptide during feeding. Elevating haemolymph Rhopr-CRF/DH titres by injection of Rhopr-CRF/DH prior to feeding resulted in the intake of a significantly smaller blood meal in 5th instars and adults without an apparent effect on the rate of short-term diuresis. When adult females were injected with Rhopr-CRF/DH, they also produced and laid significantly fewer eggs. Finally, in vitro oviduct contraction assays illustrate that Rhopr-CRF/DH inhibits the amplitude of contractions of the lateral oviducts, highlighting a potential mechanism via which the hormone diminishes reproductive capacity. To conclude, the study of the Rhopr-CRF/DH pathway, its components and mechanisms of action, has implications for vector control by highlighting targets to alter feeding, diuresis, and reproduction of this disease vector.

Sleep and Psychiatric Disorders in Persons With Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) frequently challenges the integrity of sleep function by affecting multiple brain areas implicated in controlling the switch between wakefulness and sleep and those involved in circadian and homeostatic processes; the malfunction of each causes a variety of disorders. In this review, we discuss recent data on the dynamics between disorders of sleep and mental/psychiatric disorders in persons with mTBI. This analysis sets the stage for understanding how a variety of physiological, emotional and environmental influences affect sleep and mental activities after injury to the brain. Consideration of the intricate links between sleep and mental functions in future research can increase understanding on the underlying mechanisms of sleep-related and psychiatric comorbidity in mTBI.

Post-Traumatic Sleep-Wake Disorders.

All living organisms that face a traumatic life event are susceptible to sleep-wake disturbances. Stress, which can result in trauma, evokes a high level of physiological arousal associated with sympathetic nervous system activation, during both sleep and wakefulness. Heredity, sex hormones, early losses, developmental factors and intra- and interpersonal conflicts, contribute to the level of baseline physiological arousal, producing either subclinical, clinical or complex clinical traits, acutely and at any time after exposure to a traumatic event. The risk of acute sleep-wake disturbances becoming disorders and syndromes depends on the type of traumatic event and all of the aforementioned factors. Taken together, with consideration for behavioural and environmental heterogeneity, in research, will aid identification and understanding of susceptibility factors in long-term sleep and wakefulness pathology after exposure to traumatic events.

Concussion/mild traumatic brain injury-related chronic pain in males and females: A diagnostic modelling study.

Pain is an unpleasant, complex, and perceived experience that places a significant burden on patients and clinicians. Its severity may be mediated by emotion, attitude, and environmental influences, and pain may be expressed differently in males and females. Traumatic brain injury (TBI) is frequently associated with chronic pain. This diagnostic modeling study examined sex differences in the construct of chronic pain in patients with delayed recovery from concussion/mild traumatic brain injury (mTBI).Data were collected from standardized questionnaires, neuroimaging records, and comprehensive clinical assessments. Bivariate associations were calculated using the Spearman correlation coefficient or analysis of variance. We established sex-specific stepwise multivariate linear regression models of factors associated with pain.Of the 94 participants diagnosed with mTBI (the mean age was 45.20 ±â€Š9.94 years; 61.2% were males; the median time since injury was 197 days [interquartile range 139-416]), head/neck, and bodily pain were reported by 93% and 64%, respectively. No sex differences were identified in pain frequencies or severity. Pain was significantly associated with certain socio-demographic, injury-related, behavioral, and clinical variables. In the multivariable regression analysis, several determinants explained 60% of the pain variance in males and 46% in females.Pain is common in patients with delayed recovery from mTBI and is significantly associated with potentially modifiable clinical and nonclinical variables. Examining the multidimensional construct of pain in concussion/mTBI through a sex lens garners new directions for future longitudinal research on the pain mechanisms involved in postconcussion syndrome.

Sex differences in work-related traumatic brain injury due to assault.

OBJECTIVES: To examine the etiology, prevalence and severity of assault-precipitated work-related traumatic brain injury (wrTBI) in Ontario, Canada through a sex lens. METHODS: Cross-sectional study using data abstracted from the Ontario Workplace Safety and Insurance Board (WSIB) claims files in 2004. Descriptive analyses were conducted to determine the distribution of worker/employment/incident characteristics. RESULTS: Workplace physical violence that resulted in a TBI accounted for 6.6% percent of all TBI injury claims. Female workers, primarily in the health care/social services sector, accounted for over half of all TBIs. Most workers were assaulted by consumers/clients. Forty five percent of injuries occurred among workers with less than 3 years of employment. CONCLUSIONS: This paper identifies profiles of workers and workplaces for targeted preventive efforts. Future studies are needed to further address risk factors by sex and outcomes, such as length of disability and health care cost.

The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury.

Sleep disorders and mild traumatic brain injury (mTBI) are among the most commonly occurring neurological problems clinicians encounter simultaneously. Each can cause the other, and both share common predisposing factors. An important question that remains to be addressed is whether high-risk groups can be defined. We observed an accumulation of considerable knowledge on sleep dysfunction in mTBI in recently published works. The results highlight sleep disturbances in mTBI as the product of diverse internal and external influences, acting on a genetically determined substrate. This may partially explain the clinical heterogeneity of mTBI, pointing to the importance of establishing an accurate history on the onset and course of a specific sleep disorder in the early stages post-mTBI in the individual patient. Such an approach will aid not only diagnosis and treatment but may also lead to identification of disorders whose symptoms mimic those of TBI and thereby direct the most suitable treatment and management.

The relationship between insomnia and disability in workers with mild traumatic brain injury/concussion: Insomnia and disability in chronic mild traumatic brain injury.

AIM/BACKGROUND: The principal aim of this study was to, for the first time, examine the relationship between insomnia and perceived disability among workers with mild traumatic brain injury (mTBI)/concussion. PATIENTS/METHODS: A cross-sectional study was conducted at the Workplace Safety and Insurance Board Clinic of the largest rehabilitation teaching hospital in Canada. Data from questionnaires, insurer records and clinical investigations were analysed. The Insomnia Severity Index measured the primary independent variable, and the Sheehan Disability Scale measured disability outcomes, classified as 'mild/moderate' or 'marked/extreme'. Two-sided t-tests and Chi-squared tests were used for bivariate associations. A binomial logistic regression model was fit using previously identified variables. RESULTS: The sample comprised 92 workers (45.1 ± 9.9 years old, 61% male) with mTBI/concussion at median time 196 days after injury. When compared with workers reporting lower disability, workers with higher disability were found with more severe insomnia, depression, anxiety and pain. In the multivariable analysis, the odds of reporting higher global disability increased with increasing insomnia and pain [adjusted odds ratio (OR) 1.16 (95% CI 1.03-1.31) and 1.117 (95% CI 1.01-1.24), respectively]. Insomnia was the only significant covariate in a fully adjusted work disability model. None of the variables studied were statistically significant in the social and family life disability models. CONCLUSIONS: Greater attention should be given to the diagnosis and management of insomnia in persons with mTBI/concussion.

Insomnia in workers with delayed recovery from mild traumatic brain injury.

OBJECTIVE/BACKGROUND/AIM: Insomnia has not been explored as it relates to recovery after mild traumatic brain injury (mTBI). We aimed to evaluate the prevalence of insomnia among Ontario workers with delayed recovery from mTBI, and its relationship with sociodemographic, TBI- and claim-related, behavioral, and clinical factors. PATIENTS/METHODS: This was a cross-sectional study carried out over a period of 24 months in a large rehabilitation hospital in Ontario. To assess the prevalence of insomnia, we used the Insomnia Severity Index (ISI). Data were collected from standardized questionnaires, insurer records, and clinical assessment at the time of recruitment. Bivariate associations were calculated using the Spearman's correlation coefficient or analysis of variance. We established stepwise multivariate linear regression models of factors associated with insomnia. Additional analyses, including the assessment of the internal consistency of the ISI, were performed. RESULTS: Of the 94 participants diagnosed with mTBI, clinical insomnia was reported by 69.2%. The mean age was 45.20 ± 9.94 years; 61.2% were men. No sex-related differences were observed in insomnia prevalence or severity. Insomnia was significantly associated with certain sociodemographic, claim-related, behavioral, and clinical variables. In the multivariable regression analysis, several determinants explained 53% of the insomnia variance. The internal consistency of the ISI, as measured by Cronbach's α, was 0.86. CONCLUSIONS: Insomnia is common in persons with delayed recovery from mTBI, and is significantly associated with potentially modifiable clinical and nonclinical variables. Care of persons with brain injury requires greater attention with regard to the diagnosis and management of insomnia and associated disorders.

The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: A systematic review and meta-analysis.

This review appraises the process of development and the measurement properties of the Pittsburgh sleep quality index (PSQI), gauging its potential as a screening tool for sleep dysfunction in non-clinical and clinical samples; it also compares non-clinical and clinical populations in terms of PSQI scores. MEDLINE, Embase, PsycINFO, and HAPI databases were searched. Critical appraisal of studies of measurement properties was performed using COSMIN. Of 37 reviewed studies, 22 examined construct validity, 19 - known-group validity, 15 - internal consistency, and three - test-retest reliability. Study quality ranged from poor to excellent, with the majority designated fair. Internal consistency, based on Cronbach's alpha, was good. Discrepancies were observed in factor analytic studies. In non-clinical and clinical samples with known differences in sleep quality, the PSQI global scores and all subscale scores, with the exception of sleep disturbance, differed significantly. The best evidence synthesis for the PSQI showed strong reliability and validity, and moderate structural validity in a variety of samples, suggesting the tool fulfills its intended utility. A taxonometric analysis can contribute to better understanding of sleep dysfunction as either a dichotomous or continuous construct.

Modeling community integration in workers with delayed recovery from mild traumatic brain injury.

BACKGROUND: Delayed recovery in persons after mild traumatic brain injury (mTBI) is poorly understood. Community integration (CI) is endorsed by persons with neurological disorders as an important outcome. We aimed to describe CI and its associated factors in insured Ontario workers with delayed recovery following mTBI. METHODS: A cross-sectional study of insured workers in the chronic phase following mTBI was performed at a rehabilitation hospital in Ontario, Canada. Sociodemographic, occupational, injury-related, clinical, and claim-related data were collected from self-reports, medical assessments, and insurers' referral files. Community Integration Questionnaire (CIQ) scores were compared using analysis of variance or Spearman's correlation tests. Stepwise multivariable linear regression models were used to evaluate the associations with CI. RESULTS: Ninety-four workers with mTBI (45.2 ± 9.9 years old, 61.2% male) at 197 days post-injury (interquartile range, 139-416 days) were included. The CIQ total and subscale scores were similar to those reported in more severe TBI samples. The CIQ scores were moderately to strongly correlated with various sociodemographic, claim-related, and clinical variables. In the multivariable regression analysis, several covariates accounted for 36.4% of the CIQ variance in the final fully adjusted model. DISCUSSION: This study evaluated CI in workers with mTBI, and analyzed its associated variables. Analysis revealed insomnia, head or neck pain, being married or in a relationship, time since injury, and a diagnosis of possible/probable malingering were independently associated with limited CI. CONCLUSIONS: Workers with delayed recovery from mTBI experience difficulty with CI. Insomnia is a particularly relevant covariate, explaining the greater part of its variance. To enhance participation, care should focus on clinical and non-clinical covariates.

A systematic review of fatigue in patients with traumatic brain injury: the course, predictors and consequences.

BACKGROUND: Fatigue is common after traumatic brain injury (TBI). Its risk factors, natural history and consequences are uncertain. Best-evidence synthesis was used to address the gaps. METHODS: Five databases were searched for relevant peer-reviewed studies. Of the 33 articles appraised, 22 longitudinal studies were selected. Results were reported separately based on their timing of baseline assessment. RESULTS: All studies document changes in fatigue frequency and severity with time, irrespective of setting or TBI severity. There is limited evidence for certain clinical and psychosocial variables as predictors of fatigue severity at follow-up. Early fatigue severity predicted persistent post-concussive symptoms and Glasgow outcome score at follow-up. CONCLUSIONS: Fatigue is present before and immediately following injury, and can persist long term. The variation in findings supports the idea of fatigue in TBI as a nonhomogeneous entity, with different factors influencing the course of new onset or chronic fatigue. To decrease the heterogeneity, we emphasize the need for agreement on a core set of relevant fatigue predictors, definitions and outcome criteria. PROSPERO registry number: CRD42013004262.

Screening for sleep dysfunction after traumatic brain injury.

Numerous studies on the high prevalence of sleep disorders in individuals with traumatic brain injury (TBI) have been conducted in the past few decades. These disorders can accentuate other consequences of TBI, negatively impacting mood, exacerbating pain, heightening irritability, and diminishing cognitive abilities and the potential for recovery. Nevertheless, sleep is not routinely assessed in this population. In our review, we examined the selective screening criteria and the scientific evidence regarding screening for post-TBI sleep disorders to identify gaps in our knowledge that are in need of resolution. We retrieved papers written in the English-language literature before June 2012 pertinent to the discussion on sleep after TBI found through a PubMed search. Within our research, we found that sleep dysfunction is highly burdensome after TBI, treatment interventions for some sleep disorders result in favorable outcomes, sensitive and specific tests to detect sleep disorders are available, and the cost-effectiveness and sustainability of screening have been determined from other populations. The evidence we reviewed supports screening for post-TBI sleep dysfunction. This approach could improve the outcomes and reduce the risks for post-TBI adverse health and nonhealth effects (e.g., secondary injuries). A joint sleep and brain injury collaboration focusing on outcomes is needed to improve our knowledge.

Fatigue in adults with traumatic brain injury: predictors and consequences. A systematic review of longitudinal study protocols.

BACKGROUND: Despite strong indications that fatigue is the most common and debilitating symptom after traumatic brain injury, little is known about its frequency, natural history, or relation to other factors. The current protocol outlines a strategy for a systematic review that will identify, assess, and critically appraise studies that assessed predictors for fatigue and the consequences of fatigue on at least two separate time points following traumatic brain injury. METHODS/DESIGN: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, CINAHL, and PsycINFO will be systematically searched for relevant peer-reviewed studies. Reference lists of eligible papers will also be searched. All English language studies with a longitudinal design that focus on fatigue in adults with primary-impact traumatic brain injury will be included. Studies on fatigue following brain injury due to secondary pathological processes (intracranial complications, edema, ischemia/infarction, and systemic intracranial conditions) will be excluded. Excluded studies, along with the reasons for exclusion will be reported. Two independent reviewers will conduct all levels of screening, data abstraction, and quality appraisal. Randomized control trial data will be treated as a cohort. The quality will be assessed using the criteria defined by Hayden and colleagues. The review will be conducted and reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. CONCLUSIONS: The review will summarize the current knowledge in the field with the aim of increasing understanding and guiding future research on the associations between fatigue and clinically important factors, as well as the consequences of fatigue in traumatic brain injury. PROSPERO registry number: CRD42013004262.