Biomarkers to aid the return to play decision following sports-related concussion: a systematic review

Premature return to play (RTP) following sports-related concussion (SRC) is associated with significant morbidity including risk of neurological and non-neurological injury, persistent post-concussion symptoms and chronic neurological deficits. Assessing athletes for RTP is critical but these decisions are currently based on clinical assessments that are subject to bias and symptomatic reporting that rely on compliance. An objective and easily obtained biomarker that can indicate recovery following SRC would aid clinicians to make safer RTP decisions. We performed a systematic review to identify potential biomarkers from saliva, urine and blood sources that could inform the clinical RTP decision. The MEDLINE database was searched. Inclusion criteria were studies focusing on adults diagnosed with SRC, fluid biomarkers from blood, saliva or urine and clinical recovery from SRC or at RTP. We assessed each biomarker for their time course post SRC and relationship to clinical recovery. Secondary outcomes included correlation with symptom scores and predictive value for prolonged RTP. We identified 8 studies all investigating blood-based markers of diffuse axonal injury (tau, NFL, SNTF), neuroglial injury (NSE, VLP-1, UCH-L1, S100B, GFAP), inflammation and hormonal disturbances. Tau, SNTF, UCH-1, GFAP, S100B and the inflammatory cytokine MCP-4 are raised post SRC and return to baseline by RTP. Changes in tau, NFL, SNTF, GFAP and MCP-4 post SRC correlate with severity of concussion as measured by symptom severity or RTP duration. There is only preliminary case-reporting for hormonal biomarkers. The evidence is limited by a lack of highly powered studies, variation in use of athletic and Contact sport controls (CSC) and a lack of consistent sampling and assessment protocols. There is promise for biomarkers to aid RTP decisions following SRC, most notably in use alongside clinical assessment in RTP criteria to allow greater precision in identifying mild and severe concussion.

Longitudinal assessment of hemodynamic alterations after mild traumatic brain injury in adolescents: Selected case study review

Alterations in the neurovasculature after traumatic brain injury (TBI) represents a significant sequelae. However, despite theoretical and empirical evidence supporting the near-ubiquity of vascular injury, its pathophysiology remains elusive. Although this has been shown for all grades of TBI, the vascular changes after injuries with the broad mild traumatic brain injuries (mTBI) classification, remain particularly difficult to describe. Our group has previously demonstrated hemodynamic alterations in mTBI by utilizing transcranial Doppler ultrasound and cerebrovascular reactivity in a cross-sectional study. That work identified a phasic progression of deviations over varying days post-injury. These phases were then characterized by a set of inverse models that provided a hypothetical process of hemodynamic dysfunction after mTBI. This model set provides a framework with the potential for guiding clinical treatment over the course of recovery. However, it is still unclear if individual patients will progress through the phases of dysfunction similar to that found at the population level. The work presented here explores six individual patients with high-density data collected during their post-injury recovery. Breath-hold index (BHI) was found to be the most robust feature related to mTBI longitudinally. All six subjects exhibited BHI recovery curves that followed the population model's progression. The changes in pulsatile features lacked the universality of BHI, but were present in subjects with higher self-reported symptom scores and longer periods of recovery. This work suggests neurovascular dysfunction after an mTBI may be a robust phenomenon. Additionally, the capabilities of TCD in capturing these changes highlights its potential for aiding clinicians in monitoring patient's recovery post mTBI.

Brain smart – Let's play safely: Evaluation of a concussion education program in schools

Objectives There are two objectives for this paper. First, to determine effects of a concussion education program in a local school board in terms of concussion-specific knowledge in children and confidence in identifying and managing concussion in adults. Second, to identify differences and similarities in concussion knowledge between children who participate in sports and those who do not and between children with a history of one or more concussions and those without. Design A cross sectional survey regarding concussion knowledge was distributed randomly to students and adults at both pre- and posteducation timepoints. A concussion education program was disseminated across the school board for students between the distribution survey timepoints. Following the education program, adults and students completed their respective post-test surveys. Chi-squared tests in SPSS determined the significance of between-group differences. Results All 17 adults (100.0%) who had received concussion education recently reported confidence in their knowledge of concussion management, compared to 35.7% adults who had not received education for over a year (p = 0.020). For students, all of whom completed the concussion education training between the pre- and post-tests, there were no significant differences in concussion knowledge scores between athletes and non-athletes (either in or outside of school) or between those with a history of concussion and those without. There were no significant changes in concussion knowledge between the pre- and post-tests, except for one question. Conclusion Concussion education programs increase confidence of concussion management protocols in adults involved in sport, but they require improvements to better support knowledge amelioration, particularly for target groups that are at high risk of sustaining another injury.

Sleep quality in the chronic stage of concussion is associated with poorer recovery: A systematic review

Background Recovery from a concussion varies based on a multitude of factors. One such factor is sleep disturbances. In our prior review, it was observed that in the acute phase, sleep disturbances are predictive of poor outcomes following a concussion. The literature gap remains on how sleep in the chronic phase of recovery affects outcomes. Objective To examine the association between sleep quality during the chronic stage of concussion and post-concussion outcomes. Literature Survey: Literature searches were performed during 1 July to 1 August 2019 in selected databases along with searching grey literature. Out of the 733 results, 702 references were reviewed after duplicate removal. Methods Three reviewers independently reviewed and consented on abstracts meeting eligibility criteria ( n = 35). The full-text articles were assessed independently by two reviewers. Consensus was achieved, leaving four articles. Relevant data from each study was extracted using a standard data-extraction table. Quality appraisal was conducted to assess potential bias and the quality of articles. Results One study included children (18–60 months) and three studies included adolescents and/or adults (ranging 12–35 years). The association between sleep and cognition (two studies), physical activity (one study), and emotion symptoms (one study) was examined. Sleep quality was associated with decreased cognition and emotional symptoms, but not with meeting physical activity guidelines six months post-concussion injury. Conclusions The heterogeneity in age of participants and outcomes across studies and limited number of included studies made interpretations difficult. Future studies may consider if addressing sleep quality following concussion will improve outcomes.

Autonomic cardiovascular response during and after a graded exercise test in concussed athletes and healthy controls

Objective Dysfunction of the autonomic cardiovascular system after a concussion is known to cause exercise intolerance due to symptoms exacerbation. The aim of this study was to compare athletes with symptoms of a sport-related concussion and healthy controls with regard to their heart rate during a graded exercise test and their heart rate recovery during the 5 min cool-down after the graded exercise test. Methods Sport-related concussion patients ( N = 61; 31% female) and controls ( N = 16; 50% female) participated in a graded exercise test on a cycle ergometer followed by 5 min active cool-down. Based on the results of graded exercise tests they were divided into four groups: (1) patients who reached the symptom threshold and had to stop the graded exercise test (symptom threshold; N = 39; 33.3% female), (2) patients with symptoms who finished the graded exercise test (S; N = 16; 25% female), (3) patients without symptoms (NS; N = 6; 33.3% female), (4) controls ( N = 16; 50% female). Main outcome measures Heart rate, severity of headache and dizziness during graded exercise test, heart rate recovery (median (heart rate recoveries/maximal heart rate) ± median absolute deviation (MAD)) 30, 60 and 300 s after the start of cool-down. Results Heart rate recovery at 30 s was significantly slower in symptom (0.95 ± 0.01) compared to all other groups ( p < 0.002; symptom threshold: 0.92 ± 0.02, NS: 0.91 ± 0.02, controls: 0.93 ± 0.02). Heart rate recovery at 60 s was significantly slower in symptom (0.90 ± 0.02) compared to the symptom threshold and controls ( p < 0.041; 0.86 ± 0.03, 0.85 ± 0.04). Heart rate recovery at 300 s was significantly slower in symptom threshold (0.72 ± 0.05) compared to controls ( p = 0.003; 0.66 ± 0.02). Conclusions Heart rate measurements in athletes with symptoms of sport-related concussion should be continued during cool-down after the graded exercise test, as dysfunction of the autonomic cardiovascular system might manifest also during cool-down.

Biofeedback as an intervention for persistent post-concussive symptoms: A randomized feasibility trial

Background Case reports indicate that low-resolution electromagnetic tomography neurofeedback and heart rate variability biofeedback may improve physiological functioning in individuals with persistent post-concussive symptoms. However, it is unclear whether larger-scale studies are feasible. Purpose To evaluate the feasibility of a combined low-resolution electromagnetic tomography neurofeedback and heart rate variability biofeedback intervention for individuals with persistent post-concussive symptoms. Methods Individuals with persistent post-concussive symptoms were randomized into intervention and control groups, and their baseline and post-test assessments were compared to a healthy control group. Outcomes included self-report questionnaires, resting electroencephalograph and electrocardiograph recordings, and a driving simulation task. Participants in the intervention group completed three 20 min low-resolution electromagnetic tomography neurofeedback sessions per week and at-home heart rate variability biofeedback training every morning and night for 8 weeks. Feasibility was evaluated according to recruitment capability and sample characteristics, data collection procedures, suitability of the intervention and study procedures, management and implementation of the study intervention, and preliminary participant responses to the intervention. Results Thirty-three individuals were recruited and 24 completed this study (seven intervention participants, nine persistent post-concussive symptoms control participants, and eight healthy control participants). One-quarter of participants (four intervention participants and three persistent post-concussive symptoms control participants) experienced simulator sickness during the driving simulator task and had to withdraw from the study. Intervention participants had an 88% and 86% compliance rate for the low-resolution electromagnetic tomography neurofeedback and heart rate variability biofeedback sessions, respectively. Low-resolution electromagnetic tomography neurofeedback sessions took approximately 1 h to complete per participant. Preliminary analysis indicated that the intervention reduced electroencephalograph z-score deviation with a very large effect size ( d = 1.36) compared to the other study groups. Conclusions Pilot studies evaluating the efficacy of low-resolution electromagnetic tomography neurofeedback and heart rate variability biofeedback should be performed to confirm these preliminary findings. However, the protocol should be modified to reduce participant fatigue and withdrawal. This trial was registered with Clinicialtrials.gov (NCT03338036; https://clinicaltrials.gov/ct2/show/NCT03338036?term=03338036&draw=2&rank=1 ).

Reversible temporal hypodensity on CT in a patient with minor head injury: Transient global amnesia or contusion?

Transient global amnesia (TGA) is a condition characterized by a sudden, temporary lapse in memory without focal neurological deficits, usually in middle aged adults, sometimes precipitated by an inciting event. We describe a case of a young patient, who presented with a constellation of symptoms consistent with TGA post-concussion with a right temporal lobe hypodensity on CT head. This patient’s memory returned to baseline within 24 hours, with only a mild residual headache which resolved within the next day and no MRI findings 48 hours after, illustrating that his clinical trajectory favours TGA rather than post-concussive amnesia. While the pathophysiology of TGA is still a mystery, clinicians and researchers continue to hypothesize the anatomical basis of this condition.

Does time since injury and duration matter in the benefits of physical therapy treatment for concussion?

Objective To determine if there are differences in post-concussion symptom levels depending on 1) when physical therapy treatment is begun after the concussion and 2) the length of treatment. Method Retrospective chart review yielded 202 patients who sustained concussions and were referred for physical therapy. Participants/patients were assigned to independent groups based on time elapsed between concussion and physical therapy (0–14, 15–30, 31–60, 61–120, 121–365 days), and on months spent in treatment (1–4). Pre- and post- treatment scores were documented for the following measures: Sport Concussion Assessment Tool (SCAT), Convergence Insufficiency Symptom Survey (CISS), Dizziness Handicap Inventory (DHI), and Modified Clinical Test of Sensory Interaction on Balance (mCTSIB) using ANOVAs, with a Bonferroni-corrected p-value of p < .005. Results All patients demonstrated improvements with treatment, with no significant differences in outcomes for time elapsed since injury (SCAT Symptom Score ( p = .80), SCAT Symptom Severity Score ( p = .97), CISS ( p = .61), DHI ( p = .65), mCTSIB ( p = .13)); or for months in treatment (SCAT Symptom Score ( p = .23), SCAT Symptom Severity Score ( p = .04), CISS ( p = .41), DHI ( p = .37), mCTSIB ( p = .50)). Conclusions Improvements were similar for all patients receiving post-concussive physical therapy, regardless of time between injury and treatment onset, and regardless of time spent in treatment. These results may have implications for clinical decision-making and for third party payors’ coverage of post-concussion treatment. Longer periods of treatment may not necessarily be of greater benefit and application of treatment if delayed may also be beneficial. Limitations to the study, such as its retrospective nature, lack of randomization, and convenience sample size are discussed.

Concussion assessment potentially aided by use of an objective multimodal concussion index

Objective Prompt, accurate, objective assessment of concussion is crucial as delays can lead to increased short and long-term consequences. The purpose of this study was to derive an objective multimodal concussion index (CI) using EEG at its core, to identify concussion, and to assess change over time throughout recovery. Methods Male and female concussed ( N = 232) and control ( N = 206) subjects 13–25 years were enrolled at 12 US colleges and high schools. Evaluations occurred within 72 h of injury, 5 days post-injury, at return-to-play (RTP), 45 days after RTP (RTP + 45); and included EEG, neurocognitive performance, and standard concussion assessments. Concussed subjects had a witnessed head impact, were removed from play for ≥ 5 days using site guidelines, and were divided into those with RTP < 14 or ≥14 days. Part 1 describes the derivation and efficacy of the machine learning derived classifier as a marker of concussion. Part 2 describes significance of differences in CI between groups at each time point and within each group across time points. Results Sensitivity = 84.9%, specificity = 76.0%, and AUC = 0.89 were obtained on a test Hold-Out group representing 20% of the total dataset. EEG features reflecting connectivity between brain regions contributed most to the CI. CI was stable over time in controls. Significant differences in CI between controls and concussed subjects were found at time of injury, with no significant differences at RTP and RTP + 45. Within the concussed, differences in rate of recovery were seen. Conclusions The CI was shown to have high accuracy as a marker of likelihood of concussion. Stability of CI in controls supports reliable interpretation of CI change in concussed subjects. Objective identification of the presence of concussion and assessment of readiness to return to normal activity can be aided by use of the CI, a rapidly obtained, point of care assessment tool.

Predictors of six-month inability to return to work in previously employed subjects after mild traumatic brain injury: A TRACK-TBI pilot study

Introduction Return to work (RTW) is an important milestone of mild traumatic brain injury (mTBI) recovery. The objective of this study was to evaluate whether baseline clinical variables, three-month RTW, and three-month postconcussional symptoms (PCS) were associated with six-month RTW after mTBI. Methods Adult subjects from the prospective multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with mTBI (Glasgow Coma Scale 13–15) who were employed at baseline, with completed three- and six-month RTW status, and three-month Acute Concussion Evaluation (ACE), were extracted. Univariate and multivariable analyses were performed for six-month RTW, with focus on baseline employment, three-month RTW, and three-month ACE domains (physical, cognitive, sleep, and/or emotional postconcussional symptoms (PCS)). Odds ratios (OR) and 95% confidence intervals [CI] were reported. Significance was assessed at p < 0.05. Results In 152 patients aged 40.7 ± 15.0 years, 72% were employed full-time at baseline. Three- and six-month RTW were 77.6% and 78.9%, respectively. At three months, 59.2%, 47.4%, 46.1% and 31.6% scored positive for ACE physical, cognitive, sleep, and emotional PCS domains, respectively. Three-month RTW predicted six-month RTW (OR = 19.80, 95% CI [7.61–51.52]). On univariate analysis, scoring positive in any three-month ACE domain predicted inability for six-month RTW (OR = 0.10–0.11). On multivariable analysis, emotional symptoms predicted inability to six-month RTW (OR = 0.19 [0.04–0.85]). Subjects who scored positive in all four ACE domains were more likely to be unable to RTW at six months (4 domains: 58.3%, vs. 0-to-3 domains: 9.5%; multivariable OR = 0.09 [0.02–0.33]). Conclusions Three-month post-injury is an important time point at which RTW status and PCS should be assessed, as both are prognostic markers for six-month RTW. Clinicians should be particularly vigilant of patients who present with emotional symptoms, and patients with symptoms across multiple PCS categories, as these patients are at further risk of inability to RTW and may benefit from targeted evaluation and support.