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

Abstract

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.

Visuo‐vestibular and cognitive connections of the vestibular neuromatrix are conserved across age and injury populations

“…Changes to resting‐state functional networks following SRC are typically of high interest as these may reflect brain activation contributing to patient behaviors during active states, 25 but does not require a patient, who may be experiencing neurological dysfunction, to attend to or perform a task 26 . Thus, isolating altered resting‐state functional connectivity may provide key mechanistic insight into complex clinical presentations arising from the differential injury severity and time courses of patient recovery 27 . Due to the heterogenous nature of SRC injury events (e.g., impact location, magnitude of impact), combined with the variability in patient outcomes post‐SRC (e.g., differing behavioral changes, unique neurometabolic responses), there is likely no singular neural connectivity network that independently represents the SRC patient's clinical presentation.…”

“…26 Thus, isolating altered resting-state functional connectivity may provide key mechanistic insight into complex clinical presentations arising from the differential injury severity and time courses of patient recovery. 27 Due to the heterogenous nature of SRC injury events (e.g., impact location, magnitude of impact), combined with the variability in patient outcomes post-SRC (e.g., differing behavioral changes, unique neurometabolic responses), there is likely no singular neural connectivity network that independently represents the SRC patient's clinical presentation. Indeed, in an effort to guide clinical decisions for this heterogenous injury, injury subtypes or clinical profiles have been recently defined that align with commonly encountered symptom clusters (cognitive/fatigue, vestibular, ocular, migraine, anxiety/mood) and management recommendations based on the primary clinical profile.…”