Blood Biomarkers for the Management of Mild Traumatic Brain Injury in Clinical Practice.

BACKGROUND: Despite the use of validated guidelines in the management of mild traumatic brain injury (mTBI), processes to limit unnecessary brain scans are still not sufficient and need to be improved. The use of blood biomarkers represents a relevant adjunct to identify patients at risk for intracranial injury requiring computed tomography (CT) scan. CONTENT: Biomarkers currently recommended in the management of mTBI in adults and children are discussed in this review. Protein S100 beta (S100B) is the best-documented blood biomarker due to its validation in large observational and interventional studies. Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyterminal hydrolase L-1 (UCH-L1) have also recently demonstrated their usefulness in patients with mTBI. Preanalytical, analytical, and postanalytical performance are presented to aid in their interpretation in clinical practice. Finally, new perspectives on biomarkers and mTBI are discussed. SUMMARY: In adults, the inclusion of S100B in Scandinavian and French guidelines has reduced the need for CT scans by at least 30%. S100B has significant potential as a diagnostic biomarker, but limitations include its rapid half-life, which requires blood collection within 3 h of trauma, and its lack of neurospecificity. In 2018, the FDA approved the use of combined determination of GFAP and UCH-L1 to aid in the assessment of mTBI. Since 2022, new French guidelines also recommend the determination of GFAP and UCH-L1 in order to target a larger number of patients (sampling within 12 h post-injury) and optimize the reduction of CT scans. In the future, new cut-offs related to age and promising new biomarkers are expected for both diagnostic and prognostic applications.

Multidomain Predictors of Protracted Recovery following Concussion Among 5- to 9-Year-Old Patients: A Preliminary Study.

OBJECTIVE: To determine which components from a multidomain assessment best predict protracted recovery in pediatric patients with a concussion. STUDY DESIGN: A prospective cohort of patients aged 5-9 years who presented within 21 days of concussion to a specialty clinic were categorized into normal (≤30 days) and protracted (>30 days) recovery. Participants provided demographic and medical history information, and completed the Child Sport Concussion Assessment Tool-5 symptom report and balance assessment, the Vestibular/Ocular Motor Screen-Child (VOMS-C), and the Pediatric Immediate Post-concussion Assessment and Cognitive Testing. Univariate logistic regressions (LR) were used to inform a follow-up forward stepwise LR to identify the best predictors of protracted recovery. Receiver operating characteristic analysis of the area under the curve (AUC) was used to identify which predictors retained from the LR model best discriminated recovery. RESULTS: The final sample included 68 patients (7.52 ± 2.3 years; 56% male), 36 (52.9%) with normal and 32 (47.1%) with protracted recovery. Results of the LR to identify protracted recovery were significant (P < .001) and accounted for 39% of the variance. The model accurately classified 78% of patients, with days to first clinic visit (OR, 1.2; 95% CI, 1.1-1.4; P = .003) and positive VOMS-C findings (OR, 8.32; 95% CI, 2.4-28.8; P < .001) as significant predictors. A receiver operating characteristic analysis of the AUC of this 2-factor model discriminated protracted from normal recovery (AUC, 0.82; 95% CI, 0.71-0.92; P < .001). CONCLUSIONS: Days to first clinic visit and positive findings on the VOMS-C were the most robust predictors of protracted recovery after concussion in young pediatric patients.

Sports Concussion and Chronic Traumatic Encephalopathy: Finding a Path Forward.

Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222-225.

Non-invasive fluid biomarkers in the diagnosis of mild traumatic brain injury (mTBI): a systematic review.

BACKGROUND: Despite approximately 55.9 million annual mild traumatic brain injuries (mTBIs) worldwide, the accurate diagnosis of mTBI continues to challenge clinicians due to symptom ambiguity, reliance on subjective report and presentation variability. Non-invasive fluid biomarkers of mTBI offer a biological measure to diagnose and monitor mTBI without the need for blood draws or neuroimaging. The objective of this study is to systematically review the utility of such biomarkers to diagnose mTBI and predict disease progression. METHODS: A systematic review performed in PubMed, Scopus, Cochrane and Web of Science followed by a manual search of references without a specified timeframe. Search strings were generated and run (27 June 2022) by a research librarian. Studies were included if they: (1) included human mTBI subjects, (2) assessed utility of a non-invasive biomarker and (3) published in English. Exclusion criteria were (1) non-mTBI subjects, (2) mTBI not assessed separately from moderate/severe TBI, (3) required intracranial haemorrhage or (4) solely assesses genetic susceptibility to mTBI. RESULTS: A total of 29 studies from 27 subject populations (1268 mTBI subjects) passed the inclusion and exclusion criteria. Twelve biomarkers were studied. Salivary RNAs, including microRNA, were assessed in 11 studies. Cortisol and melatonin were assessed in four and three studies, respectively. Eight salivary and two urinary biomarkers contained diagnostic or disease monitoring capability. DISCUSSION: This systematic review identified several salivary and urinary biomarkers that demonstrate the potential to be used as a diagnostic, prognostic and monitoring tool for mTBI. Further research should examine miRNA-based models for diagnostic and predictive utility in patients with mTBI. PROSPERO REGISTRATION NUMBER: CRD42022329293.

Using normative modeling and machine learning for detecting mild traumatic brain injury from magnetoencephalography data.

New biomarkers are urgently needed for many brain disorders; for example, the diagnosis of mild traumatic brain injury (mTBI) is challenging as the clinical symptoms are diverse and nonspecific. EEG and MEG studies have demonstrated several population-level indicators of mTBI that could serve as objective markers of brain injury. However, deriving clinically useful biomarkers for mTBI and other brain disorders from EEG/MEG signals is hampered by the large inter-individual variability even across healthy people. Here, we used a multivariate machine-learning approach to detect mTBI from resting-state MEG measurements. To address the heterogeneity of the condition, we employed a normative modeling approach and modeled MEG signal features of individual mTBI patients as deviations with respect to the normal variation. To this end, a normative dataset comprising 621 healthy participants was used to determine the variation in power spectra across the cortex. In addition, we constructed normative datasets based on age-matched subsets of the full normative data. To discriminate patients from healthy control subjects, we trained support-vector-machine classifiers on the quantitative deviation maps for 25 mTBI patients and 20 controls not included in the normative dataset. The best performing classifier made use of the full normative data across the entire age and frequency ranges. This classifier was able to distinguish patients from controls with an accuracy of 79%. Inspection of the trained model revealed that low-frequency activity in the theta frequency band (4-8 Hz) is a significant indicator of mTBI, consistent with earlier studies. The results demonstrate the feasibility of using normative modeling of MEG data combined with machine learning to advance diagnosis of mTBI and identify patients that would benefit from treatment and rehabilitation. The current approach could be applied to a wide range of brain disorders, thus providing a basis for deriving MEG/EEG-based biomarkers.

Defining Mild Traumatic Brain Injury: From Research Definition to Clinical Practice.

INTRODUCTION: Approximately 75% of traumatic brain injuries (TBIs) qualify as mild. However, there exists no universally agreed upon definition for mild TBI (mTBI). Consequently, treatment guidelines for this group are lacking. The Center for Disease Control (CDC), American College of Rehabilitation Medicine (ACRM), Veterans Affairs and Department of Defense (VA/DoD), Eastern Association for the Surgery of Trauma (EAST), and the University of Arizona's Brain Injury Guidelines (BIG) have each published differing definitions for mTBI. The aim of this study was to compare the ability of these definitions to correctly classify mTBI patients in the acute care setting. METHODS: A single-center, retrospective cohort study comparing the performance of the varying definitions of mTBI was performed at a Level I trauma center from August 2015 to December 2018. Definitions were compared by sensitivity, specificity, positive predictive value, negative predictive value, as well as overtriage and undertriage rates. Finally, a cost-savings analysis was performed. RESULTS: We identified 596 patients suffering blunt TBI with Glasgow Coma Scale 13-15. The CDC/ACRM definitions demonstrated 100% sensitivity but 0% specificity along with the highest rate of undertriage and TBI-related mortality. BIG 1 included nearly twice as many patients than EAST and VA/DoD while achieving a superior positive predictive value and undertriage rate. CONCLUSIONS: The BIG definition identified a larger number of patients compared to the VA/DoD and EAST definitions while having an acceptable and more accurate overtriage and undertriage rate compared to the CDC and ACRM. By eliminating undertriage and minimizing overtriage rates, the BIG maintains patient safety while enhancing the efficiency of healthcare systems. Using the BIG definition, a cost savings of $395,288.95-$401,263.95 per year could be obtained at our level 1 trauma facility without additional mortality.

Role of Occupational Therapy Cognitive Assessment in Mild Traumatic Brain Injury: Is Universal Consultation Required?

INTRODUCTION: Mild traumatic brain injury (mTBI) or concussion is prevalent among trauma patients, but symptoms vary. Assessing discharge safety is not standardized. At our institution, occupational therapy (OT) performs cognitive assessments for mTBI to determine discharge readiness, potentially increasing resource utilization. We aimed to describe characteristics and outcomes in mTBI trauma patients and hypothesized that OT consultation was associated with increased length of stay (LOS). METHODS: This is a retrospective study at a level 1 trauma center over 17 mo. All patients with mTBI, without significant concomitant injuries, were included. We collected data regarding OT assessment, LOS, mechanism of injury, Glasgow coma score, injury severity score (ISS), concussion symptoms, and patient disposition. Statistical analysis was performed, and significance was determined when P < 0.05. RESULTS: Two hundred thirty three patients were included. Median LOS was 1 d and ISS 5. Ninety percent were discharged home. The most common presenting symptom was loss of consciousness (85%). No symptoms were associated with differences in LOS or discharge disposition (P > 0.05). OT consult (n = 114, 49%) was associated with longer LOS and higher ISS (P < 0.01). Representation with concussive symptoms, discharge disposition, mechanism of injury, and patient demographics were no different regardless of OT consultation (P > 0.05). CONCLUSIONS: mTBI is common and assessment for discharge safety is not standardized. OT cognitive assessment was associated with longer LOS and higher injury severity. Despite institutional culture, OT consultation was variable and not associated with improved concussion-related outcomes. Our data suggest that OT is not required for mTBI discharge readiness assessment. To improve resource utilization, more selective OT consultation should be considered. Further prospective data are needed to identify which patients would most benefit.

Effectiveness of personalized rehabilitation in adults suffering from persistent concussion symptoms as compared to usual care: a randomized control trial protocol.

BACKGROUND: Symptoms reported by patients who sustain a concussion are non-specific. As such, clinicians are better able to manage patients when a standardized clinical exam is performed to sub-type the driver(s) of symptoms. Aerobic exercise and multimodal rehabilitation have consistently shown to be a possibly effective means to manage this population; however, the optimal training prescription is unclear. Thus, there is a need to further examine the effectiveness of personalized rehabilitative treatments. Our primary aim is to evaluate the response to personalized therapy on recovery, as measured by The Rivermead Post-concussion Symptoms Questionnaire (RPQ) when compared to an active control. METHODS: We will conduct a multi-center 12-week case-crossover randomized controlled trial. 50 participants will be recruited from out-patient University Health Network clinics and community-based clinical practices around the greater Toronto area. Participants will be randomized at baseline to Group A: a personalized care program followed by an active control or Group B: an active control followed by a personalized care program. Participants will be included should they be 21 years of age and older and have symptoms that have persisted beyond 4 weeks but less than 1 year. Participants will undergo 6-weeks of care in their respective streams. After 6-weeks, participants will undergo a re-examination. They will then crossover and undertake the alternative treatment for 6 weeks. At the end of 12 weeks, participants will undertake the endpoint examinations. The primary outcome will be the Rivermead Postconcussion Questionnaire (RPQ). The secondary outcomes will be changes in standardized clinical examination, Neck Disability Index (NDI), Patient Health Questionnaire (PHQ-9) and an electroencephalography (EEG) via NeuroCatch™. The statistical analysis to be performed is composed of an adjusted model using an analysis of variance, specifically using an unpaired t-test to test for associations between variables and outcomes. DISCUSSION: Given the recommendations from reviews on the topic of rehabilitation for adults with persistent concussion symptoms, we are undertaking a controlled trial. The documented high costs for patients seeking care for persistent symptoms necessitate the need to evaluate the effectiveness of a personalized rehabilitative program compared to the current standard of care. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT06069700.

Applicability and clinical utility of the German rivermead post-concussion symptoms questionnaire in proxies of children after traumatic brain injury: an instrument validation study.

BACKGROUND: The German Rivermead Post-Concussion Symptoms Questionnaire (RPQ) can be used to assess post-concussion symptoms (PCS) after traumatic brain injury (TBI) in adults, adolescents, and children. METHODS: In this study, we examined the psychometric properties of the German RPQ proxy version (N = 146) for children (8-12 years) after TBI at the item, total and scale score level. Construct validity was analyzed using rank correlations with the proxy-assessed Post-Concussion Symptoms Inventory (PCSI-P), the Patient Health Questionnaire 9 (PHQ-9), and the Generalized Anxiety Disorder Scale 7 (GAD-7). Furthermore, sensitivity testing was performed concerning subjects' sociodemographic and injury-related characteristics. Differential item functioning (DIF) was analyzed to assess the comparability of RPQ proxy ratings for children with those for adolescents. RESULTS: Good internal consistency was demonstrated regarding Cronbach's α (0.81-0.90) and McDonald's ω (0.84-0.92). The factorial validity of a three-factor model was superior to the original one-factor model. Proxy ratings of the RPQ total and scale scores were strongly correlated with the PCSI-P (ϱ = 0.50-0.69), as well as moderately to strongly correlated with the PHQ-9 (ϱ = 0.49-0.65) and the GAD-7 (ϱ = 0.44-0.64). The DIF analysis revealed no relevant differences between the child and adolescent proxy versions. CONCLUSIONS: The German RPQ proxy is a psychometrically reliable and valid instrument for assessing PCS in children after TBI. Therefore, RPQ self- and proxy-ratings can be used to assess PCS in childhood as well as along the lifespan of an individual after TBI.

Female RNA concussion (FeRNAC) study: assessing hormone profiles and salivary RNA in females with concussion by emergency departments in New Zealand: a study protocol.

BACKGROUND: Females of reproductive age with concussion report a greater number of symptoms that can be more severe and continue for longer than age matched males. Underlying mechanisms for sex differences are not well understood. Short non-coding Ribonucleic Acids (sncRNAs) are candidate salivary biomarkers for concussion and have been studied primarily in male athletes. Female sex hormones influence expression of these biomarkers, and it remains unclear whether a similar pattern of sncRNA expression would be observed in females following concussion. This study aims to evaluate recovery time, the ratio of salivary sncRNAs and symptom severity across different hormone profiles in females presenting to emergency departments (ED) with concussion and, to investigate the presence of low energy availability (LEA) as a potential modifier of concussion symptoms. METHODS: This prospective cohort study recruits participants from New Zealand EDs who are biologically female, of reproductive age (16-50 years) and with a confirmed diagnosis of concussion from an ED healthcare professional. Participants are excluded by ED healthcare professionals from study recruitment as part of initial routine assessment if they have a pre-diagnosed psychiatric condition, neurological condition (i.e., epilepsy, cerebral palsy) or more than three previously diagnosed concussions. Participants provide a saliva sample for measurement of sncRNA's, and online survey responses relating to hormone profile and symptom recovery at 7-day intervals after injury until they report a full return to work/study. The study is being performed in accordance with ethical standards of the Declaration of Helsinki with ethics approval obtained from the Health and Disability Ethics Committee (HDEC #2021 EXP 11655), Auckland University of Technology Ethics Committee (AUTEC #22/110) and locality consent through Wellington hospital research office. DISCUSSION: If saliva samples confirm presence of sncRNAs in females with concussion, it will provide evidence of the potential of saliva sampling as an objective tool to aid in diagnosis of, and confirmation of recovery from, concussion. Findings will determine whether expression of sncRNAs is influenced by steroid hormones in females and may outline the need for sex specific application and interpretation of sncRNAs as a clinical and/or research tool. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12623001129673.

Criterion validity of a single-item measure of fear avoidance behavior following mild traumatic brain injury.

Maladaptive coping such as fear avoidance behavior can prolong recovery from mild traumatic brain injury (mTBI). Routine assessment of fear avoidance may improve management of mTBI. This study aimed to validate a single-item measure of fear avoidance to make its assessment more pragmatic. The present study is a secondary analysis of a clinical trial that involved adults with persistent post-concussion symptoms (N = 90, 63% female). Participants completed the single-item fear avoidance rating, a validated legacy measure of fear avoidance (Fear Avoidance Behavior after Traumatic Brain Injury; FAB-TBI), and measures of anxiety (General Anxiety Disorder-7), depression (Patient Health Questionnaire-9), post-concussion symptoms (Rivermead Postconcussion Symptoms Questionnaire), and disability (World Health Organization Disability Assessment Schedule 12.0). Questionnaires were completed twice, at baseline (mean 18.1 weeks post injury) and again 12-16 weeks later following study-delivered rehabilitation in addition to usual care. We analyzed the associations (Spearman's correlations) and agreement (weighted Kappa) between the single-item and FAB-TBI at baseline, posttreatment, individual FAB-TBI item scores, and the change in scores between baseline and posttreatment. In addition, we examined correlations between the single-item fear avoidance measure and related constructs, including anxiety, depression, post-concussion symptoms, and disability. The single-item fear avoidance measure correlated strongly with the FAB-TBI both at baseline and following treatment (ρ = 0.63 - 0.67, p < .001), and moderately with FAB-TBI item scores (ρ = 0.4 - 0.6). The correlation between the change in these scores from baseline to posttreatment was moderate (ρ = 0.45, p < .001). Agreement between the single-item fear avoidance measure and discretized FAB-TBI scores was moderate (κ = 0.45 - 0.51). Before and after treatment, the single-item fear avoidance measure correlated moderately with anxiety (ρ = 0.34), depression (ρ = 0.43), post-concussion symptoms (ρ = 0.50), and disability (ρ = 0.43). The FAB-TBI was more strongly correlated with these measures (ρ = 0.53 - 0.73). In summary, the present study supports the criterion validity of the single-item fear avoidance measure. This measure may be a useful screening and monitoring tool for patients with mTBI but is not a substitute for the FAB-TBI questionnaire.

Migraine epidemiology in collegiate student-athletes: Findings from the Concussion Assessment, Research, and Education (CARE) Consortium.

OBJECTIVE: This cross-sectional study evaluated de-identified data from the National Collegiate Athletic Association-Department of Defense Grand Alliance from 2014 to 2020 to determine the prevalence of migraine and migraine medication and to describe differences in migraine prevalence by sex, race, and sport. BACKGROUND: Epidemiological studies can help identify underdiagnosed and undertreated populations. Understanding migraine prevalence in collegiate student-athletes is essential for positive healthcare outcomes including development of prevention and treatment plans. METHODS: From a concussion baseline assessment, participant's self-reported demographics (e.g., age, sex, sport), migraine diagnosis (i.e., yes/no), and migraine medication usage (e.g., yes/no, type) determined prevalence of migraine and medication use in collegiate student-athletes. RESULTS: Migraine was reported in 5.6% (2617/47,060; 95% confidence interval [CI] 5.4%-5.8%) of the student-athletes, with higher prevalence in females, 7.5% (1319/17,628; 95% CI 7.1%-7.9%), than males, 4.6% (1298/28,116; 95% CI 4.4%-4.9%). Medication usage was reported by 36.2% (947/2617; 95% CI 34.3%-38.0%) of individuals with migraine. Migraine reporting differed by race, with Caucasian reporting highest (5.9%; 1990/33,913; 95% CI 5.6%-6.1%) and Asian the lowest (2.7%; 55/2027; 95% CI 2.1%-3.5%). Women's sports, including golf, gymnastics, and lacrosse, and men's diving and squash had higher migraine reporting than other sports. CONCLUSION: Caucasian females reported higher rates than other groups and sport influenced rates of migraine diagnosis.

Clinical Practice Guideline Recommendations in Pediatric Mild Traumatic Brain Injury: A Systematic Review.

STUDY OBJECTIVE: Our primary objectives were to identify clinical practice guideline recommendations for children with acute mild traumatic brain injury (mTBI) presenting to an emergency department (ED), appraise their overall quality, and synthesize the quality of evidence and the strength of included recommendations. METHODS: We searched MEDLINE, EMBASE, Cochrane Central, Web of Science, and medical association websites from January 2012 to May 2023 for clinical practice guidelines with at least 1 recommendation targeting pediatric mTBI populations presenting to the ED within 48 hours of injury for any diagnostic or therapeutic intervention in the acute phase of care (ED and inhospital). Pairs of reviewers independently assessed overall clinical practice guideline quality using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The quality of evidence on recommendations was synthesized using a matrix based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Evidence-to-Decision framework. RESULTS: We included 11 clinical practice guidelines, of which 6 (55%) were rated high quality. These included 101 recommendations, of which 34 (34%) were based on moderate- to high-quality evidence, covering initial assessment, initial diagnostic imaging, monitoring/observation, therapeutic interventions, discharge advice, follow-up, and patient and family support. We did not identify any evidence-based recommendations in high-quality clinical practice guidelines for repeat imaging, neurosurgical consultation, or hospital admission. Lack of strategies and tools to aid implementation and editorial independence were the most common methodological weaknesses. CONCLUSIONS: We identified 34 recommendations based on moderate- to high-quality evidence that may be considered for implementation in clinical settings. Our review highlights important areas for future research. This review also underlines the importance of providing strategies to facilitate the implementation of clinical practice guideline recommendations for pediatric mTBI.

Confounding factors of the expression of mTBI biomarkers, S100B, GFAP and UCH-L1 in an aging population.

OBJECTIVES: To evaluate some confounding factors that influence the concentrations of S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L-1 (UCH-L1) in older individuals. Indeed, recent guidelines have proposed the combined use of S100B and the "GFAP-UCH-L1" mTBI test to rule out mild traumatic brain injuries (mTBI). As older adults are the most at risk of mTBI, it is particularly important to understand the confounding factors of those mTBI rule-out biomarkers in aging population. METHODS: The protein S100B and the "GFAP and UCH-L1" mTBI test were measured using Liaison XL (Diasorin) and Alinity I (Abbott), respectively, in 330 and 341 individuals with non-suspected mTBI from the SarcoPhAge cohort. RESULTS: S100B, GFAP and UCH-L1 were all significantly correlated with renal function whereas alcohol consumption, Geriatric Depression Score (GDS), smoking habits and anticoagulant intake were not associated with any of these three biomarkers. Body mass index (BMI) and age were associated with GFAP and UCH-L1 expression while sex and mini-mental state examination (MMSE) were only associated with GFAP. According to the manufacturer's cut-offs for mTBI rule-out, only 5.5 % of participants were positive for S100B whereas 66.9 % were positive for the "GFAP-UCH-L1" mTBI test. All positive "GFAP-UCH-L1" mTBI tests were GFAP+/UCH-L1-. Among individuals with cystatin C>1.55 mg/L, 25 % were positive for S100B while 90 % were positive for the mTBI test. CONCLUSIONS: Our data show that confounding factors have different impacts on the positivity rate of the "GFAP-UCH-L1" mTBI test compared to S100B.

The effects of cytomegalovirus on brain structure following sport-related concussion.

The neurotrophic herpes virus cytomegalovirus is a known cause of neuropathology in utero and in immunocompromised populations. Cytomegalovirus is reactivated by stress and inflammation, possibly explaining the emerging evidence linking it to subtle brain changes in the context of more minor disturbances of immune function. Even mild forms of traumatic brain injury, including sport-related concussion, are major physiological stressors that produce neuroinflammation. In theory, concussion could predispose to the reactivation of cytomegalovirus and amplify the effects of physical injury on brain structure. However, to our knowledge this hypothesis remains untested. This study evaluated the effect of cytomegalovirus serostatus on white and grey matter structure in a prospective study of athletes with concussion and matched contact-sport controls. Athletes who sustained concussion (n = 88) completed MRI at 1, 8, 15 and 45 days post-injury; matched uninjured athletes (n = 73) completed similar visits. Cytomegalovirus serostatus was determined by measuring serum IgG antibodies (n = 30 concussed athletes and n = 21 controls were seropositive). Inverse probability of treatment weighting was used to adjust for confounding factors between athletes with and without cytomegalovirus. White matter microstructure was assessed using diffusion kurtosis imaging metrics in regions previously shown to be sensitive to concussion. T1-weighted images were used to quantify mean cortical thickness and total surface area. Concussion-related symptoms, psychological distress, and serum concentration of C-reactive protein at 1 day post-injury were included as exploratory outcomes. Planned contrasts compared the effects of cytomegalovirus seropositivity in athletes with concussion and controls, separately. There was a significant effect of cytomegalovirus on axial and radial kurtosis in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion showed greater axial (P = 0.007, d = 0.44) and radial (P = 0.010, d = 0.41) kurtosis than cytomegalovirus negative athletes with concussion. Similarly, there was a significant association of cytomegalovirus with cortical thickness in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion had reduced mean cortical thickness of the right hemisphere (P = 0.009, d = 0.42) compared with cytomegalovirus negative athletes with concussion and showed a similar trend for the left hemisphere (P = 0.036, d = 0.33). There was no significant effect of cytomegalovirus on kurtosis fractional anisotropy, surface area, symptoms and C-reactive protein. The results raise the possibility that cytomegalovirus infection contributes to structural brain abnormalities in the aftermath of concussion perhaps via an amplification of concussion-associated neuroinflammation. More work is needed to identify the biological pathways underlying this process and to clarify the clinical relevance of this putative viral effect.

The Efficacy of Vestibular Rehabilitation Therapy for Mild Traumatic Brain Injury: A Systematic Review and Meta-analysis.

OBJECTIVE: Mild traumatic brain injury (mTBI) or concussion is a common yet undermanaged and underreported condition. This systematic review and meta-analysis aim to determine the efficacy of vestibular rehabilitation therapy (VRT) as a treatment option for mTBI. METHOD: This review and meta-analysis was performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. It included randomized controlled trials and pre-VRT/post-VRT retrospective chart reviews. Records meeting the inclusion criteria were extracted from the following databases: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). RESULTS: Eight articles met the inclusion criteria, from which 6 randomized controlled trials were included in the meta-analysis. VRT demonstrated significant improvement in decreasing perceived dizziness at the end of the intervention program as shown by Dizziness Handicap Inventory (DHI) scores (standardized mean difference [SMD] = -0.33, 95% confidence interval [CI]: -0.62 to -0.03, P = .03, I2 = 0%). However, no significant reduction in DHI was evident after 2 months of follow-up (SMD = 0.15, 95% CI: -0.23 to 0.52, P = .44, I2 = 0%). Quantitative analysis also depicted significant reduction in both Vestibular/Ocular Motor Screening (SMD = -0.40, 95% CI: -0.60 to -0.20, P < .0001, I2 = 0%) and Post-Concussion Symptom Scale (SMD= -0.39, 95% CI: -0.71 to -0.07, P = .02, I2 = 0%) following the intervention. Finally, there was no significant difference between intervention groups on Balance Error Scoring System scores (SMD = -31, 95% CI: -0.71 to 0.10, P = .14, I2 = 0%) and return to sport/function (95% CI: 0.32-30.80, P = .32, I2 = 82%). CONCLUSIONS: Current evidence on the efficacy of VRT for mTBI is limited. This review and analysis provides evidence that supports the role of VRT in improving perceived symptoms following concussion. Although findings from this analysis suggest positive effects of VRT on included outcomes, the low certainty of evidence limits the conclusions drawn from this study. There is still a need for high-quality trials evaluating the benefit of VRT using a standardized approach.PROSPERO registration number: CRD42022342473.

Sports-Related Concussion in Collegiate Athletes: The Potential Benefits of Using Graded Neuropsychological Tests With High Ceilings.

OBJECTIVE: Sports-related concussion management in collegiate athletes has been focused on return-to-play. However, resuming schoolwork without a gradual stepwise reintroduction contributes to symptom exacerbation, delayed recovery, and adverse academic performance. Return-to-learn guidelines are limited by a lack of sensitivity in methods monitoring cognitive function. This study evaluated 2 neuropsychological tests, the Sternberg test and the Paced Auditory Serial Addition Test (PASAT), with high ceilings for sensitivity to deficits in speed of information processing, cognitive efficiency, and complex attention. SETTING: Academic center research laboratory. PARTICIPANTS: We recruited 56 male and female collegiate contact and noncontact sports athletes. They were categorized into as follows: (1) nonconcussed ( n = 23; 7F, 16M); (2) chronic ( n = 21; 4F, 17M), at least 1 year from their last concussion; and (3) acute ( n = 12; 1F, 11M), within 2 weeks from concussion. DESIGN: Observational cohort study. MAIN MEASURES: The PASAT assesses complex attention. The Sternberg test examines processing speed and cognitive efficiency. Cognitive difficulty increases with progression through the tasks for both the PASAT and the Sternberg test. The mean outcome differences of the 3 groups (nonconcussed, acute, and chronic) across the 3 or 4 conditions (difficulty level) were measured with repeated-measures analysis of variance and subsequent pairwise comparison. RESULTS: For processing speed (Sternberg reaction time), the acute group responded slower than the chronic group on the medium ( P = .021, Bonferroni corrected) and hard difficulty tasks ( P = .030, Bonferroni corrected). For cognitive efficiency (Sternberg reaction time variability), the acute group had increased reaction time variability compared with the chronic group on the medium difficulty task ( P = .04, Bonferroni corrected). For complex attention (PASAT omissions), there was a difference between the acute and nonconcussed groups on the moderate-hard difficulty trial ( P = .023, least significant difference [LSD] corrected) and between the acute and chronic groups for hard difficulty trial ( P = .020, LSD corrected). The acute group performed worse, with progressively shorter interstimulus intervals. CONCLUSION: Neuropsychological testing without ceiling effects can capture higher-level cognitive dysfunction and and use of such tests can contribute to the understanding of how collegiate athletes are affected by SRC. Future studies can investigate optimal testing batteries that include neuropsychological testing with high ceilings and whether the pattern of performance has implications for the return-to-learn process after SRC in the college setting.

Trajectories of Daily Postconcussion Symptoms in Children.

OBJECTIVES: To identify trajectories of daily postconcussion symptoms (PCS) from the acute postinjury period to symptom resolution among concussed children and examine demographic factors and acute PCS associated with the identified symptom trajectories. SETTING AND PARTICIPANTS: Seventy-nine participants with a concussion were enrolled within 72 hours of injury and completed a daily survey that assessed PCS from enrollment until symptom resolution. DESIGN: This was a prospective cohort study among concussed children aged 11-17 years. MAIN MEASURES: Children rated their concussion symptoms daily using the Post-Concussion Symptom Scale. Symptom duration was assessed using participants' date of symptom resolution and coded as a dichotomous variable: (1) PCS duration 14 days or less or (2) PCS duration longer than 14 days. RESULTS: Of the 79 participants, most were male ( n = 53, 67%), injured during a sporting activity ( n = 67, 85%), or had PCS that persisted for more than 14 days post-injury ( n = 41, 52%). Group-based trajectory modeling yielded 4 trajectory groups: (1) low acute/resolved PCS ( n = 39, 49%), (2) moderate/persistent PCS ( n = 19, 24%), (3) high acute/persistent PCS ( n = 13, 16%), and (4) high acute/resolved PCS ( n = 8, 10%). No significant associations were found between demographic factors and the trajectory group. A higher symptom burden at injury was associated with an increased odds of being in the high acute/resolved or high acute/persistent recovery groups than being in the low acute/resolved group (odds ratio [OR] 1.39, 95% CI = 1.11-1.74; OR = 1.33, 95% CI = 1.11-1.60, respectively), as was a higher symptom severity at injury (OR = 1.09, 95% CI = 1.03-1.15; OR = 1.06, 95% CI = 1.02-1.11, respectively). CONCLUSION: Our findings may help clinicians identify concussed children on slower recovery trajectories, and implement early, individualized treatment plans that foster optimal recovery for concussed children.

Rationale for the Development of a Traumatic Brain Injury Case Definition for the Pilot National Concussion Surveillance System.

BACKGROUND: Current methods of traumatic brain injury (TBI) morbidity surveillance in the United States have primarily relied on hospital-based data sets. However, these methods undercount TBIs as they do not include TBIs seen in outpatient settings and those that are untreated and undiagnosed. A 2014 National Academy of Science Engineering and Medicine report recommended that the Centers for Disease Control and Prevention (CDC) establish and manage a national surveillance system to better describe the burden of sports- and recreation-related TBI, including concussion, among youth. Given the limitations of TBI surveillance in general, CDC took this recommendation as a call to action to formulate and implement a robust pilot National Concussion Surveillance System that could estimate the public health burden of concussion and TBI among Americans from all causes of brain injury. Because of the constraints of identifying TBI in clinical settings, an alternative surveillance approach is to collect TBI data via a self-report survey. Before such a survey was piloted, it was necessary for CDC to develop a case definition for self-reported TBI. OBJECTIVE: This article outlines the rationale and process the CDC used to develop a tiered case definition for self-reported TBI to be used for surveillance purposes. CONCLUSION: A tiered TBI case definition is proposed with tiers based on the type of sign/symptom(s) reported the number of symptoms reported, and the timing of symptom onset.

Analysis of a novel virtual pediatric concussion clinic in a rural setting.

PURPOSE: Children and adolescents who sustain concussion in rural communities are lost to follow-up after initial evaluation more often than their urban counterparts. Thus, this study aims to determine the feasibility and accessibility of a novel virtual pediatric concussion clinic at a rural academic hospital. METHODS: Data regarding patients referred to a virtual concussion clinic at a rural Pediatric Level 2 Trauma Center over a 16-month period was prospectively collected. Patients experiencing concussive symptoms were referred to the pediatric neurosurgery clinical registered nurse and received a phone call following an injury. Referrals to therapy were made based on symptoms reported. RESULTS: Data from 44 patients was collected: 9 did not follow-up in concussion clinic despite leaving a voicemail. Forty-three were referred from the emergency department. The median time from referral placed to completing a virtual follow-up was 4.5 days. Among the referrals, 3 (8.6%) were to pediatric neurology, 10 (28.6%) to occupational therapy (OT), 6 (17.1%) to physical therapy (PT), 4 (11.4%) to speech-language pathology (SLP), and 25 (71.4%) did not receive referrals as their symptoms had abated. Patients followed with pediatric neurology post-injury for an average of 75.9 days, OT for an average of 52.7 days, and PT for an average of 2.3 days. CONCLUSION: This is a feasible model to follow patients and place referrals for additional therapeutic services in a rural community. With 79.5% of patients completing a follow-up, the clinic demonstrates easy accessibility and reliable adherence.